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 .
Effective Filing Date
The present application was filed on November 9, 2021 and is a 371 of PCT/KR2020/004093, filed March 26, 2020 and claims foreign priority to KOREA 10-2019-0037358, filed March 29, 2019. A certified copy of KOREA 10-2019-0037358 was submitted on 11/09/2021.
It is noted that a translation of the certified copy of the foreign priority application has not yet been provided in support of this application. In the absence of a translation of the certified copy of KOREA 10-2019-0037358, the priority date of current application is March 26, 2020, the filing date of PCT/KR2020/004093.
Election/Restrictions
Applicant’s election without traverse of the invention of Group II, claims 8-11 in the response filed March 6, 2025 is acknowledged.
Claim Status/Action Summary
Claims 1-11 are pending. Claims 1-7 are withdrawn as directed to a non-elected invention.
Claims 8-11 are under examination.
This action is in response to the papers filed on October 6, 2025.
Any objections and rejections not reiterated below are hereby withdrawn.
The objections of record to the specification have been withdrawn in view of the amended specification.
The 102(a)(1) rejection of claim 9 over dos Reis has been withdrawn in view of the amendments to claim 9 deleting reference to CpG sites disclosed by dos Reis (specifically those CpG sites that were present on the Illumina 450K array used by dos Reis).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 8, 10 and 11 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
This rejection has been updated as necessitated by the amendments to the claims.
Claim 8 recites the limitation “the thyroid cancer biomarker CpG site comprises at least one CpG site represented by Illumina ID in HumanEPIC BeadChip, the CpG site being located in a gene selected from…[list of genes]”. It is unclear what “CpG site(s)” represented by the “Illumina ID in HumanEPIC BeadChip” is/are encompassed by the limitation “the thyroid cancer biomarker”. It is unclear which CpG sites of the CpG sites present in the recited genes are encompassed by the claims because set of CpG sites is only defined as “represented by Illumina ID in HumanEPIC BeadChip”, which is a reference to a commercial product that is subject to change. Claims 10-11 depend from claim 8.
Claim 9 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
This is a new grounds of rejection necessitated by the amendments to the claims.
Claim 9 recites “the thyroid cancer biomarker CpG sites is at least one CpG site… cg15441605, cg00567113, cg06034194…” and depends on claim 8 that requires that “the CpG site being located in a gene selected from…”, however cg15441605, cg00567113, and cg06034194 are not located in any of the recited genes. cg15441605 is located in intergenic space wherein the nearest gene, POU1F1, is located approximately 60 kb away. POU1F1 is not one of the recited genes. Furthermore, cg00567113, cg06034194 are not located within the recited gene (LURAP1L-AS1) to which they are purported to correspond. It appears that the limitations to the claims are contradictory and the relationship between the recited CpG sites and the recited genes is unclear.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 9 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
This is a new grounds of rejection necessitated by the amendments to the claims.
Claim 9 recites CpG sites that are not located in any of the genes recited by claim 8, as required by claim 8. Therefore, claim 9 does not incorporate all of the limitations of the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 8-11 are/remain rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yim et al., “Identification of Tissue-Specific DNA Methylation Signatures for Thyroid Nodule Diagnostics” Clin Cancer Res; 25(2) January 15, 2019.
Regarding claim 8, Yim teaches a composition comprising substances for whole-genome reduced representation bisulfite sequencing (Yim, page 545, column 2, paragraph 2). Yim teaches analyzing methylation levels of CpG sites genome-wide in 109 thyroid specimens including 28 benign nodules, 39 PTCs, and 42 adjacent normal thyroid tissues. (Yim, page 546, column 1, paragraph 2-column 2) (i.e. the composition is capable of analyzing a methylation level of a thyroid cancer biomarker CpG site, including those “represented by Illumina ID in HumanEPIC BeadChip”). Therefore, Yim teaches all of the limitations of claim 8.
Regarding claim 9, Yim teaches a composition capable of analyzing genome-wide methylation levels at single-base resolution. (Yim, Abstract) Therefore, Yim teaches analyzing methylation levels of all of the CpG sites recited by claim 9.
Regarding claim 10, Yim teaches a multiplex bisulfite PCR assay (mb-PCR) to validate a selection of diagnostic DNA methylation signatures (DDMS) (Yim, figure 5 and page 549, column 2, paragraph 2). Therefore, Yim teaches a substance capable of analyzing a methylation level of a thyroid cancer biomarker CpG site is a primer pair capable of amplifying a fragment comprising the CpG site.
Regarding claim 11, Yim further teaches sequencing the mb-PCR products (i.e. the composition further comprises a primer for sequencing an amplification product comprising the CpG site) (Yim, figure 5 and page 549, column 2, paragraph 2).
Response to arguments
The response asserts that Yim “describes genome-wide profiling but does not specifically identify” the recited CpG sites at thyroid cancer biomarkers. This argument has been thoroughly reviewed but is not persuasive for the reasons which follow.
Claim 8 (and its dependents rejected above) are directed to “a composition comprising a substance capable of analyzing a methylation level of a thyroid cancer biomarker CpG site…”. Yim et al. use compositions to analyze the methylation level of all CpG sites (i.e. necessarily comprising all of the CpG sites in all of the recited genes recited in claim 8 presently associated with the recited “cg” identifiers in claim 9). Furthermore, Yim et al. teaches these compositions are capable of analyzing the methylation level of all CpG sites in thyroid specimens including normal tissues, benign nodules, and cancerous thyroid tissue (i.e. thyroid cancer).
Therefore, as detailed in the 102(a)(1) rejection of record and summarized here, Yim et al. teaches all of the positively recited structures and limitations of the present claim directed to compositions. As such, this rejection is maintained.
Claim 8 is/remains rejected under 35 U.S.C. 102(a)(1) as being anticipated by dos Reis et al., “Prognostic Classifier Based on Genome-Wide DNA methylation Profiling in Well-Differentiated Thyroid Tumors” J Clin Endocronl Metab, 102(11):4089-4099, November 2017.
This rejection has been updated as necessitated by the amendments to the claims.
Regarding claim 8, dos Reis teaches genome-wide DNA methylation assays comprising the Illumina 450k platform (dos Reis, page 4089, paragraph 3 “design”) (i.e. a composition capable of analyzing a methylation level of a thyroid cancer biomarker CpG site “represented by Illumina ID in HumanEPIC BeadChip”.) For example, dos Reis teaches analyzing CpG site cg24327132 (dos Reis, supplemental table 1, page 857). Furthermore, dos Reis teaches compositions capable of analyzing differential expression at CpG sites in: MICAL2 (dos Reis, page 1134), PKM “pyruvate kinase, muscle” (i.e. PKM2 “pyruvate kinase M1/2”) (dos Reis, page 1142), LTBP1 (dos Reis, page 1155), MMP7 (dos Reis, page 1163), EIF4E (dos Reis, page 1112), and DIAPH1 (dos Reis, page 113).
Therefore, dos Reis teaches all of the limitations of claim 8.
Response to arguments
The response argues that the amendment deleting the recitation of the CpG sites present on the 450K array distinguishes claim 9 from the disclosure of dos Reis. The narrower claim 9 appears not to be anticipated by dos Reis. As such, this rejection has been revised to reject claim 8 only.
Claims 8-11 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Widschwendter (US 20190330703 A1, filed December 15, 2017 and published October 31, 2019) as evidenced by NCBI GEO Platform GPL21145.
Regarding claim 8, Widschwendter teaches compositions for cancer-specific differentially methylated region discovery with Illumina 450K methylation arrays. (Widschwendter, paragraph 0027) Widschwendter further teaches the cancer can be Thyroid carcinoma (Widschwendter, paragraph 0049), and that alternative methods of detecting differential methylation include the Infinium MethylationEPIC Array (Widschwendter, paragraph 0151). Therefore, Widschwendter teaches all of the limitations of claim 8.
Regarding claim 9, Widschwendter teaches analyzing all of the recited CpG sites because all of the sites are included on the Infinium MethylationEpic BeadChip array (NCBI GEO Platform GPL21145).
Regarding claims 10-11, Widschwendter teaches analyzing differentially methylated regions (i.e. thyroid-cancer biomarker CpG sites) using PCR primers and sequencing (Widschwendter, paragraph 0136).
Response to arguments
The response argues that “Widschwendter generally applies EPIC array technology to cancer detection, but fails to disclose or suggest specific thyroid cancer CpG sites recited in the present claims.”
This argument has been thoroughly reviewed and is not persuasive. The present claims are directed to a composition comprising a substance capable of analyzing the methylation level of CpG sites in a recited list of genes (in the alternative) or specific CpG sites. As detailed in the 102(a)(1) rejection of record, Widschwendter et al. teach that Illumina 450K array or the Infinium MethylationEPIC Array are compositions comprising substances that are capable of measuring a methylation level of all of the recited CpG sites. As evidenced by the array manifest (NCBI GEO Platform GPL21145), methylation of all of the recited CpG sites are measured by said array.
Therefore, the rejection of record is maintained.
Claims 8-9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ravi et al., “Global RNA Expression and DNA Methylation Patterns in Primary Anaplastic Thyroid Cancer” Cancers, 2020, 12, 680 (published March 13, 2020) as evidenced by NCBI GEO Platform GPL21145.
Regarding claim 8, Ravi teaches analyzing methylation levels of thyroid cancer biomarkers comprising using the Infinium MethylationEpic BeadChip array (Ravi, page 7, paragraph 3) (i.e. a substance capable of analyzing…). Therefore, Ravi teaches all of the limitations of claim 8.
Regarding claim 9, Ravi teaches analyzing all of the recited CpG sites because all of the sites are included on the Infinium MethylationEpic BeadChip array (NCBI GEO Platform GPL21145).
Applicant cannot rely upon the certified copy of the foreign priority application to overcome this rejection because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Response to arguments
The response asserts that the 102(a)(1) rejection over Ravi et al. as evidenced by NCBI should be withdrawn because the application is entitled to the priority date (March 29, 2019) of the foreign “priority document KR 10-2019-0037358”, which predates the publication date of Ravi et al. (March 13, 2020). The response states “applicant is in the process of preparing a verified English translation of the priority document and will submit it as soon as it becomes available”. However, as of the date of this action, the English language translation of the certified priority document required to perfect the claim to foreign priority has not been received. Therefore, this rejection is maintained.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over dos Reis in view of NCBI GEO Platform GPL21145 and Solomon et al., “Comparison of DNA methylation measured by Illumina 450K and EPIC BeadChips in blood of newborns and 14-year-old children” Epigenetics 2018 Aug 15; 13(6):655-664.
This rejection has been updated as necessitated by the amendments to the claims.
Regarding claim 8, dos Reis teaches genome-wide DNA methylation assays comprising the Illumina 450k platform (dos Reis, page 4089, paragraph 3 “design”) (i.e. a composition capable of analyzing a methylation level of a thyroid cancer biomarker CpG site “represented by Illumina ID in HumanEPIC BeadChip”.) For example, dos Reis teaches analyzing CpG site cg24327132 (dos Reis, supplemental table 1, page 857). Furthermore, dos Reis teaches compositions capable of analyzing differential expression at CpG sites in: MICAL2 (dos Reis, page 1134), PKM “pyruvate kinase, muscle” (i.e. PKM2 “pyruvate kinase M1/2”) (dos Reis, page 1142), LTBP1 (dos Reis, page 1155), MMP7 (dos Reis, page 1163), EIF4E (dos Reis, page 1112), and DIAPH1 (dos Reis, page 113). Therefore, dos Reis teaches all of the limitations of claim 8.
Regarding claim 9, dos Reis teaches analyzing a methylation level of at least: cg24327132, cg16336556, cg17707274, and cg21341586 (dos Reis, supplemental table 1).
Dos Reis does not teach analyzing all of the CpG sites present on the HumanEPIC BeadChip.
However, NCBI GEO Platform GPL21145, publicly available on November 16, 2015, teaches the HumanEPIC BeadChip, which comprises all of the recited CpG sites.
Further, Solomon et al. teach that the EPIC BeadChip is a direct replacement of the 450K platform used by dos Reis (Solomon, abstract), and “we anticipate the EPIC chip to be more reliable than the 450K chip. The new EPIC chip contains 90% of the probes on 450K, and many of the 10% no longer included on the EPIC chip were previously identified as underperforming” (Solomon, page 661, column 2, paragraph 2).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to modify the composition capable of analyzing methylated CpG sites in thyroid cancer taught by dos Reis by substituting the Illumina 450K array in the composition of dos Reis for the commercially available alternative HumanEPIC BeadChip, taught by NCBI GEO Platform GPL21145. The ordinary artisan would have been motivated to substitute the HumanEPIC BeadChip array into the composition taught by dos Reis because of the teaching of Solomon that the HumanEPIC BeadChip is a direct replacement for the older 450K methylation array and the EPIC chip contains probes for more targets and removes poorly performing probes. The ordinary artisan would have had a reasonable expectation that substituting the HumanEPIC BeadChip into the composition taught by dos Reis would have allowed for discovery of new thyroid cancer methylation biomarkers.
Response to arguments
The response generally asserts that the combination of cited references do not teach the particular recited CpG sites for analyzing a methylation level of a thyroid cancer biomarker CpG site. This argument has been thoroughly reviewed and is not persuasive. The present claims are directed to “a composition comprising a substance capable of analyzing a methylation level of a thyroid cancer biomarker CpG site…”. Therefore, the claim encompasses any material or apparatus (i.e. a composition comprising a substance capable of…) that can accomplish the recited function (i.e. not a method or biomarker). As such, the cited references teach: a methylation array (HumanEPIC BeadChip) comprising substances capable of measuring the methylation levels of all of the recited CpG sites (NCBI) that is expressly capable of directly replacing the Illumina 450K array (Solomon), which was used by dos Reis to measure methylation at all of the CpG sites that were present on the Illumina 450K array. As described in the 103 rejection above, Solomon enumerates several advantages of the HumanEPIC BeadChip over the Illumina 450K array that would have motivated the ordinary artisan to have substituted the HumanEPIC BeadChip array into the composition taught by dos Reis because of the teaching of Solomon that the HumanEPIC BeadChip is a direct replacement for the older 450K methylation array and the EPIC chip contains probes for more targets and removes poorly performing probes.
Claims 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over dos Reis in view of NCBI GEO Platform GPL21145 and Solomon et al., “Comparison of DNA methylation measured by Illumina 450K and EPIC BeadChips in blood of newborns and 14-year-old children” Epigenetics 2018 Aug 15; 13(6):655-664 as applied to claims 8-9 above, and further in view of Widschwendter (US 20190330703 A1, filed December 15, 2017 and published October 31, 2019).
Regarding claim 10, dos Reis in view of NCBI and Solomon teaches a composition capable of analyzing methylation of all of the CpG sites recited by claims 8-9. dos Reis in view of NCBI and Solomon does not teach that the composition comprises a primer pair capable of amplifying a fragment comprising the CpG site, or further comprising a sequencing primer for sequencing an amplification product amplified by the primer pair.
However, Yim teaches a composition comprising a reagent for genome-wide discovery of methylation biomarkers in thyroid cancer further comprises a multiplex bisulfite PCR approach to test for specific biomarkers. Yim further teaches that MB-PCR greatly reduces the cost of the composition for individual assays relative to genome-wide methods (Yim, page 549, column 2, paragraph 2).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to modify the composition for genome-wide discovery of methylation biomarkers in thyroid cancer, taught by dos Reis in view of NCBI and Solomon with the MB-PCR components taught by Yim. The ordinary artisan would have been motivated to use the MB-PCR composition of Yim to assay specific biomarkers discovered by the genome-wide composition of dos Reis in view of NCBI and Solomon because of the teaching of Yim that MB-PCR greatly reduces the cost of the composition for individual assays relative to genome-wide methods (Yim, page 549, column 2, paragraph 2). The ordinary artisan would have been reasonably confident that the markers discovered by the composition of dos Reis in view of NCBI and Solomon would have been more economically detected by the MB-PCR composition taught by Yim.
Conclusion
No claim is allowed.
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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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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