Office Action 2: Notice of Allowance (2025-02-12)

CLAIMS:
PRESENTATION OF THE CLAIMSThis listing of claims will replace all prior versions, and listings, of claims in this application.

1\. (Cancelled)
2\. (Previously Presented) A method comprising:
extracting genomic DNA from a biological sample from a human individual suspected of having or having an esophageal disorder,
treating the extracted genomic DNA with bisulfite,
amplifying the bisulfite-treated genomic DNA using primers specific for each of ten or fewer markers, and
measuring a methylation level of at least one differentially methylated region (DMR) in each of the ten or fewer markers using methylation-specific PCR, quantitative methylation- specific PCR, methylation-sensitive DNA restriction enzyme analysis, or bisulfite genomic sequencing PCR,
wherein the ten or fewer markers comprise VAV3.
3\. (Previously Presented) The method of claim 2, wherein the ten or fewer markers comprise one or both of NDRG4 and ZNF682.

4\. (Previously Presented) The method of claim 2, wherein the biological sample comprises cells, tissues, and/or secretions from the upper gastrointestinal tract and/or the lower gastrointestinal tract.

5\. (Previously Presented) The method of claim 2, wherein the biological sample is a stool sample, a tissue sample, a blood sample, or a urine sample.
6\. (Previously Presented) The method of claim 5, wherein the tissue sample comprise esophageal tissue.
7\. (Previously Presented) The method of claim 2, wherein the esophageal disorder is Barrett's esophagus (BE).

8\. (Previously Presented) The method of claim 7, wherein the methylation level of the at least one DMR in each of the ten or fewer markers distinguishes BE fromnormal tissue.

9\. (Previously Presented) The method of claim 2, wherein the primers specific for VAV3 are capable of binding an amplicon bound by a sequence comprising SEQ ID NOs: 39 and 40.

10\. (Previously Presented) The method of claim 2, wherein the primers specific for VAV3 comprise SEQ ID NOs: 39 and 40.

11\. (Previously Presented) The method of claim 3, wherein the primers specific for NDRG4 are capable of binding an amplicon bound by a sequence comprising SEQ ID NOs:
15 and 16.

12\. (Previously Presented) The method of claim 3, wherein the primers specific for NDRG4 comprise SEQ ID NOs: 15 and 16.

13\. (Previously Presented) The method of claim 3, wherein the primers specific for ZNF682 are capable of binding an amplicon bound by a sequence comprising SEQ ID NOs:
31 and 32.

14\. (Previously Presented) The method of claim 3, wherein the primers specific for ZNF682 comprise SEQ ID NOs: 31 and 32.

15\. (Previously Presented) The method of claim 2, wherein the ten or fewer markers comprise BMP3, SFMBT2, DI03, HUNK, ELMO1, CD1D, CDKN2A, and/or OPLAH.

OFFICE 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 .
Reasons for Allowance
The following is an examiner’s statement of reasons for allowance:
The 102(a)(2) rejection over Ahlquist has been withdrawn in view of the 102(b)(2)(C) statement filed on December 19, 2024.
The Double Patenting rejection has been withdrawn in view of the terminal disclaimer filed over 11,104,960 on December 19, 2024.
The prior art neither teaches nor suggests analysis of VAV3 methylation levels suing primers specific for VAV3 in samples from human individuals having of or suspected of having esophageal disorders.  Thus, the claimed invention is free of the art.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee.  Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion

APPLICANT REBUTTAL: REMARK
. Status of the Claims
Claims 2-15 were pending in this application. Claim I was previously cancelled. As provided herein, no claims have been amended, cancelled, or added. Therefore, claims 2-15 are currently under consideration. No new matter has been added.
Applicant requests entry of the remarks made herein into the file history of the application and reserves the right to file a divisional or continuation application to any unclaimed subject matter.
2. Patentability Remarks
37 CF.R Q 1.105 - Request for Information
On pp. 2-3 of the Office Action, the Examiner asserts: "In total, the IDS filed prior to the writing of this first action on the merits contains
230 references on 15 pages of
IDS.
The extraordinary number of references places a serious burden on the office. The examiner finds that not each one of the greater than 230 references listed on the IDS are relevant to the instantly claimed invention which requires only measuring the methylation level of CpG sites in VAV3. For example, NPL reference 169 of the IDS, 'Screening for colorectal cancer with fecal occult blood testing and sigmoidoscopy', NPL reference 150 of the IDS, 'A sensitive, quantitative assay for measurement of allele-specific transcripts differing by a single nucleotide. (1992), reference 144 of the IDS, "the hemoquant' test: a specific and quantitative determination of heme,(hemoglobin) in feces and other materials' (2005). Therefore the burden is shifted to the applicants and they are specifically required to point out the references cited which are most relevant to instant claims. W'hile art has been applied in this first office action on the merits, the IDS filed August 24, 2021 has an enormous number of references, and so this requirement for information is set forth" (emphasis in original).
Additionally, on p. 3 of the Office Action, the Examiner asserts that the following information is required from Applicant: "A) Which references disclose methods of detecting methylation of VAV3, NDRG4, ZNF682 and which references teach that methylation of VAV3, NDRG4, ZNF682 is found in Barrett's esophageal dysplasia or esophageal disorders."
Applicant submits that all currently cited IDS references for the present application, as well as all references cited on the IDS submitted with this response, were cited or are being cited to comply with Applicant's duty of candor and good faith under 37 C.F.R. @ 1.56. Applicant does not believe that the cited references place an undue burden on the Examiner or
the UPSTO. Moreover, a request for information under 37 C.F.R. § 1.105 does not impose an obligation upon the Applicant to conduct a search on behalf of the Examiner.
Nevertheless, solely to comply with the Examiner's request, Applicant compiled a searchable database containing the references cited in the Nonpatent Literature Documents and Foreign Patent Documents sections of the IDSs submitted for the present application (including the current IDS submitted herewith). Using widely accessible document management software (i.e., iManage Work 10), Applicant conducted the following two independent searches of this database using Boolean operators to comply with the Examiner's request: (1) [VAV3]; and (2) ["esophageal disorder"]. Performance of these searches yielded the following references:
"  (1) [VAV3]: WO2023081796A1; WO2022165247A1; WO2022039904A2;
WO2021212031A1;
WO2017075061A1;
WO2016160454A1;
WO2016094839A2;
WO2015153284A1;
WO2015153283A1;
WO2012167145A2; WO2012167145A2; WO2012174256A2; Zong, L. et al., Gastric Cancer (2016) 19:361-369; Iyer, P. G. et al., Am J of Gastroenterology (2018) 113(8):1156-1166; Medina-Aguilar, R. et al., PLoS One (2016) 11(6):e0157866; Iyer, P. G. et al., Gastroenterology AGA Abstracts (2020) 158(6):Supplement S-21 1 (1084); Iyer, P. G. et al., Gastroenterology AGA Abstracts (2018) 154(6):Supplement S-175 (878); Iyer, P. G. et al., Am J of Gastroenterology (2020) 115:1201-1209; Iqbal, U. et al., European J of Gastroenterology & Hepatology (2018) 30:1261-1269; Taylor, W. R. et al., Gastroenterology AGA Abstracts (2014) 146(5):Supplement 5-30 (109); Levin, T.
R. et al., Gastroenterology AGA Abstracts (2015) 148(4):Supplement S-207
(Sa1050)
"  (2) ["esophageal disorder"]: WO202 121203 1 A 1; WO20 161 60454A 1
While Applicant has supplied the above search results in good faith solely to comply with the Examiner's request in this specific instance, Applicant respectfully submits that such Boolean operator searches for a defined set of markers within digitally searchable references are well within the advanced searching capabilities of the USPTO's Patent Search System and do not justify shifting the Examiner's obligations to Applicant.
Taken together, Applicant respectfully submits that the Examiner's request under 37 C.F.R. § 1.105 has been satisfied.
35 U.S.C. Q 102(a)(2) - Novelty
12, and I 5 were rejected for allegedlybeing anticipated by PCT Patent Appln. Pub. No. WO20 16/094839 (hereinafter, "Ahlquist").
Applicant respectfully disagrees with these rejections. However, without addressing the merits of the rejections, Applicant submits that Ahlquist and the present application are co- owned by the same entities, namely, Exact Sciences Corporation and Mayo Foundation for Medical Education and Research. Applicant asserts that the disclosure of the subject matter on which each of the above rejections are based and the claimed invention were co-owned by Exact Sciences Corporation and Mayo Foundation for Medical Education and Research not later than the effective filing date of the claimed invention. As such, Applicant asserts that the 35 U.S.C. § 102(b)(2)(C) exception applies to Ahlquist. Because Ahlquist cannot be relied upon for these rejections, Applicant asserts that aprimafacie case of obviousness has not been established.
Therefore, Applicant respectfully requests withdrawal of the rejections of the claims under 35 U.S.C. § 102(a)(2) for allegedly being anticipated by Ahlquist.
Double Patenting
On pp. 5-7 of the Office Action, the Examiner rejects claims 2-5 on the ground of non- statutory double patenting over claims 2-4 of U.S. Patent No. 11,104,960 ("the '960 patent").
Applicant respectfully disagrees; however, solely to expedite prosecution, Applicant submits herewith terminal disclaimers over the '960 patent. Accordingly, Applicant requests that the rejection of the claims for non-statutory double patenting be withdrawn.
On p. 7 of the Office Action, the Examiner rejects claims 2, 4, 5, 9, and 10 on the ground of non-statutory double patenting over claims 1-3 of U.S. Patent No. 10,301,680 ("the '680 patent"), and on the ground of non-statutory double patenting over claims 1-3 of U.S. Patent No. 11,365,451 ("the '451 patent"). Applicant respectfully disagrees and submits that non- statutory double patenting rejections are "based on a judicially created doctrine grounded in public policy and which is primarily intended to prevent prolongation of the patent term by prohibiting claims in a second patent not patentably distinct from claims in a first patent." MPEP § 1504.06. Importantly, "[d]ouble patenting rejections are based on a comparison of the claims in a patent and an application or between two applications." MPEP § 1504.06 (emphasis added). More specifically, Applicant submits that independent claim 2 recites "extracting genomic DNA from a biological sample from a human individual suspected of having or having an esophageal disorder," and "wherein the ten or fewer markers comprise VA V3" (emphasis added). Applicant submits that neither the claims of the '680 patent nor the
claims of the '451 patent recite this subject matter; rather, the claims of the '680 patent and the claims of the '451 recite other markers besides VAV3, and also fail to recite an esophageal disorder. Therefore, Applicant respectfully submits that the currently pending claims are patentably distinct over the claims of both the '680 patent and the claims of the '451 patent, and therefore, requests that these double patenting rejections be withdrawn.
On pp. 8-10 of the Office Action, the Examiner provisionally rejects claims 2, 3, and 5-8 on the ground of non-statutory double patenting as being unpatentable over claims 1-3 of co-pending U.S. Appin Serial No. 17/727,128; and provisionally rejects claims 2, 4, 5, 9, 10, and 15 on the ground of non-statutory double patenting as being unpatentable over claims 107- 109, 1 13, 1 14, 1 16-1 18, and 125 of co-pending U.S. Appin Serial No. 18/644,335. Applicant notes the provisional nature of these rejections, as the allegedly patentably indistinct claims have not in fact been patented. Applicant accordingly requests that these rejections be held in abeyance until the claims in this application are found to be otherwise allowable.
As set forth in MPEP § 804(I)(B)(1)(b)(i), "[i]f a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earliest effective U.S. filing date (taking into account any benefit under 35 U.S.C. 120, 121, 365(c), or 386(c) with respect to the conflicting claims) compared to the reference application(s), the examiner should withdraw the rejection in the application having the earliest effective U.S. filing date and permit that application to issue as a patent." In the event that this rejection becomes the only rejection remaining rejection after the submission of this response, Applicant respectfully requests withdrawal of the provisional non-statutory double patenting rejection in this application.
CONCLUSION