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 .
The preliminary amendment filed June 22, 2022 canceling claims 2-3, 5-9, 12-14, 17-29, 31-41 amending claims 1, 4, 10-11, 15-16 and adding new claims 42-46 is acknowledged. Claims 1, 4, 10-11, 15-16, 30 and 42-46 are pending and will be examined.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on September 23, 2025; June 12; 2025; December 19, 2024; June 11, 2024; July 6, 2023; March 30, 2023; January 27, 2023; December 20, 2022 was filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 15 is objected to because of the following informalities:
Claim 15 recites primer pairs for amplifying one or more DMRs as provided in Table 13.
MPEP 2173.05(s) states that, "claims are to be complete in themselves" and
that "[i]ncorporation by reference to a specific figure or table 'is permitted only in
exceptional circumstances where there is not practical way to define the invention in
words and where it is more concise to incorporate by reference than duplicating a drawing or
table into the claim". Reciting the specific DMRs within the claim would encompass the same subject matter without reference to a Table.
Appropriate correction is required.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
There are three hyperlinks within the specification. There are two hyperlinks within paragraph 183 of the published specification and one hyperlink within paragraph 235 of the specification. Correction to remove the hyperlink is required.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 4, 10-11, 15-16, 30 and 42-46 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,396,679 (‘679 patent herein). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are drawn to very similar subject matter. The instant claims and the claims of the ‘679 patent are drawn to detection of differentially methylated genes included in diagnosis of colorectal cancers. While the claims of the instant application require detection from cell free DNA and the claims of the ‘679 patent more broadly focus on determining the methylation status of the DMRs of multiple genes, including PDGFD, FGF14 and LONRF2 yet could also encompass determination of methylation within cell free DNA. Therefore, as the claims of the ‘679 patent and the instant claims include overlapping subject matter, the instant claims are not patent eligible.
Furthermore, the additional claims of claims 4-9 and 16-17 recite dependent limitations that overlap between the instant claims and the claims of the ‘659 patent. For example, both instant claim 16 and claim 6 of the ‘659 patent focus on DNA isolated from specific sample sources. Also note instant claim 30 and claim 10 of the ‘659 patent give specific guidance regarding the determination of methylation status as including methylation specific PCR and next generation sequencing. Therefore, the instant claims are not patent eligible in view of the claims of the ‘659 patent.
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.
Claim(s) 1, 4, 15-16, 30 and 42-43 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ahlquist et al. (US 20230028856 A1; January 2023), Zhang et al. (US 20160340740 A1; November 2016) and Feinberg et al. (US 20100167940 A1; July 2010)
With regard to claim 1, Ahlquist teaches a method of screening for colorectal cancer, the method comprising determining the methylation status of at least one DMR of PDGFD, and at least one DMR of FGF14 (paragraph 40, 138, 142, 145; see especially paragraph 152, where DMR in multiple genes are analyzed, including PDGFD within colorectal cancer; see also Fig 1EE, where FGF14 is detected; see also paragraph 16, 139, 145, 217 and 219, where the DMR detection is a part of a method of diagnosis);
in DNA of a human subject,
wherein the DNA is DNA of the human subject, and diagnosing colorectal cancer in the subject (paragraph 40, 138, 142, 145; see especially paragraph 152, where DMR in multiple genes are analyzed, including PDGFD within colorectal cancer; see also Fig 1EE, where FGF14 is detected; see also paragraph 16, 139, 145, 217 and 219, where the DMR detection is a part of a method of diagnosis).
With regard to claim 4, Ahlquist teaches a method of claim 1, the method comprising determining whether the one or more methylation loci are hypermethylated as compared to a reference, wherein hypermethylation is indicative of colorectal cancer (paragraph 84 and 214 where aberrant hypermethylation is analyzed).
With regard to claim 15, Ahlquist teaches a method of claim l, wherein one or more of the DMRs are amplified by oligonucleotide primer pairs provided in Table 13 (paragraph 40, 138, 142, 145; see especially paragraph 152, where DMR in multiple genes are analyzed, including PDGFD within colorectal cancer; see also Fig 1EE, where FGF14 is detected; see also paragraph 16, 139, 145, 217 and 219, where the DMR detection is a part of a method of diagnosis).
With regard to claim 16, Ahlquist teaches a method of claim l, wherein the DNA is isolated from blood, plasma, urine, saliva, or stool of the human subject (paragraph 37, where the sample includes blood and other bodily fluids).
With regard to claim 30, Ahlquist teaches a method of claim 1, wherein methylation status is determined using one or more members selected from the group consisting of methylation sensitive restriction enzyme quantitative polymerase chain reaction (MSRE-qPCR), Methylation-Specific PCR, Methylation Specific Nuclease-assisted Minor-allele Enrichment PCR, and next-generation sequencing (paragraph 38, where a variety of techniques are used including next generation sequencing).
With regard to claim 42, Ahlquist teaches a method of claim 1, wherein the method comprises determining the methylation status of DMR PDGFD '921 (paragraph 40, 138, 142, 145; see especially paragraph 152, where DMR in multiple genes are analyzed, including PDGFD within colorectal cancer; see also Fig 1EE, where FGF14 is detected; see also paragraph 16, 139, 145, 217 and 219, where the DMR detection is a part of a method of diagnosis).
With regard to claim 46, Ahlquist teaches a method of claim 1. wherein methylation status is determined using massively parallel sequencing (paragraph 38, where a variety of techniques are used including next generation sequencing).
Regarding claims 1 and 43, while Ahlquist detects methylation in cancer for multiple DMRs, Ahlquist does not look to at least one DMR of LONRF2. Further, while Ahlquist mentions cell free samples, Ahlquist does not look specifically within samples wherein the DNA is cell-free DNA.
With regard to claim 1, Zhang teaches determining the methylation status of at least one DMR of LONRF2 (Table 4, p 104; see also paragraph 10-11 where Table 4 is discussed in detail) and wherein the DNA is cell-free DNA (p 4, paragraph 33, p 6, paragraph 44, where cell free DNA is analyzed).
With regard to claim 43, Zhang teaches a method of claim 1, wherein the method comprises determining the methylation status of DMR LONRF2 '387 (Table 4, p 104; see also paragraph 10-11 where Table 4 is discussed in detail).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have adjusted the teachings of Ahlquist and Zhang to include analysis of a variety of DMRs that are associated with methylated genes that are predictive and diagnostic for colorectal cancer to arrive at the claimed invention with a reasonable expectation for success. Feinberg looks to each of LONRF2, PDGFD and FGF14 and teaches the method is focused on the “discovery that some tissue-specific or cancer-related alterations in DNA methylation occur not only in promoters or CpG islands, but in sequences up to 2 kb distant from such CpG islands (such sequences are termed "CpG island shores"). In accordance with this discovery, there are provided herein differentially methylated regions (DMRs) and methods of use thereof” (paragraph 11). Therefore, one of ordinary skill in the art at the time the invention was made would have adjusted the teachings of Ahlquist and Zhang to include analysis of a variety of DMRs that are associated with methylated genes that are predictive and diagnostic for colorectal cancer to arrive at the claimed invention with a reasonable expectation for success.
Claim(s) 10-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ahlquist et al. (US 20230028856 A1; January 2023), Zhang et al. (US 20160340740 A1; November 2016) and Feinberg et al. (US 20100167940 A1; July 2010) as applied over claims 1, 4, 15-16, 30 and 42-43 above and further in view of Widschwendter et al. (WO2012104642; August 2012).
With regard to claim 10, Widschwendter teaches a method of claim l, wherein the method comprises determining the methylation status of DMRs ZNF471'558 and DMR FGF14 '577 (p 9-11, where the process of assessing methylation is described; p. 13-14, where methylation status is incorporated in “predicting risk of developing cancer in a subject” heading; see p. 31, Table 2, which is described as “top ranked 5482 cancer risk CpGs” for each gene where both ZNF471 and FGF14 are included; p. 31, where the method predicts risk to develop any cancer, which would include colorectal cancer).
With regard to claim 11, Widschwendter teaches a method of claim l, wherein the method comprises determining the methylation status of DMRs ZNF471'558, FGF14'577, and DMR PDGFD '388 (p 9-11, where the process of assessing methylation is described; p. 13-14, where methylation status is incorporated in “predicting risk of developing cancer in a subject” heading; see p. 31, Table 2, which is described as “top ranked 5482 cancer risk CpGs” for each gene where both ZNF471 and FGF14 are included; p. 31, where the method predicts risk to develop any cancer, which would include colorectal cancer).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have adjusted the teachings of Ahlquist, Zhang and Feinberg to include analysis of a variety of DMRs that are associated with methylated genes that are predictive and diagnostic for colorectal cancer to arrive at the claimed invention with a reasonable expectation for success. Widschwendter teaches “inventors have found that assessment of a healthy individual's DNA methylation profile up to several years in advance of any subsequent diagnosis of cancer has the potential to predict that individual's risk of developing cancer. In particular, the inventors have identified an aberrant DNA methylation profile in genes encoding developmental transcription factors required for the differentiation of stem or progenitor cells, as well as target genes of transcription factors that are involved in stem or progenitor cell differentiation, in individuals predisposed to cancer. Thus, aberrant DNA methylation profiles are seen in genes that are required for the differentiation of stem or progenitor cells ” (p 2, lines 1-26). Therefore, one of ordinary skill in the art at the time the invention was made would have adjusted the teachings of Ahlquist, Zhang and Feinberg to include analysis of a variety of DMRs that are associated with methylated genes that are predictive and diagnostic for colorectal cancer to arrive at the claimed invention with a reasonable expectation for success.
Claim(s) 44-45 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ahlquist et al. (US 20230028856 A1; January 2023), Zhang et al. (US 20160340740 A1; November 2016) and Feinberg et al. (US 20100167940 A1; July 2010) as applied over claims 1, 4, 15-16, 30 and 42-43 above and further in view of Chong et al. (Oncology Reports, 2014, 31:2535-2544).
With regard to claim 44, Chong teaches a method of claim 1, wherein the method comprises determining the methylation status of at least one DMR of CNRIP1 (p 2541, col. 1, where CNRIP1 are frequently methylated in colorectal cancers, Fig 7 legend and p. 2543, col. 1, where CNRIP1 was an important marker).
With regard to claim 45, Chong teaches a method of claim 44, wherein the method comprises determining the methylation status of at least one of the following DMRs: CNRIP1'272 and CNRIP1'232 (p 2541, col. 1, where CNRIP1 are frequently methylated in colorectal cancers, Fig 7 legend and p. 2543, col. 1, where CNRIP1 was an important marker).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have adjusted the teachings of Ahlquist, Zhang and Feinberg to include analysis of a variety of DMRs that are associated with methylated genes that are predictive and diagnostic for colorectal cancer to arrive at the claimed invention with a reasonable expectation for success. Chong is focused on methylation within early gastric carcinogenesis and notes “C19orf35 and CNRIP1 were specific to diffuse-type compared to the intestinal-type subgroups. Both revealed a similar level of methylation in CNM regardless of the histologic subtype of tumor while the methylation of the tumor tissue varied with the histologic type (Fig. 5C and D)”. Further, Chong notes while “the function of C19orf35 is still unknown while frequent methylation of CNRIP1 has recently been reported in colorectal cancers and adenoma”. Therefore, one of ordinary skill in the art at the time the invention was made would have adjusted the teachings of Ahlquist, Zhang and Feinberg to include analysis of a variety of DMRs that are associated with methylated genes that are predictive and diagnostic for colorectal cancer to arrive at the claimed invention with a reasonable expectation for success.
Conclusion
No claims are allowed. All claims stand rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHANIE KANE MUMMERT whose telephone number is (571)272-8503. The examiner can normally be reached M-F 9:00-5:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gary Benzion can be reached at 571-272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/STEPHANIE K MUMMERT/Primary Examiner, Art Unit 1681