Office Action 1: Non-Final Rejection (2024-07-19)
Rejection types: 102 - Lack of Novelty, Double Patenting

CLAIMS:
AMENDMENTS TO THE CLAIMS

This listing of claims replaces all prior versions, and listings, of claims in the application.

1\. (Cancelled)
2\. (Currently Amended) A method comprising:
extracting genomic DNA from a biological sample \[\[of\]\]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 \[\[the\]\]a methylation level of at least one differentially methylated region (DMR) in each of the ten or fewer markers \[\[by\]\]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\. (Currently Amended) 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\. (New) The method of claim 5. wherein the tissue sample comprise esophageal tissue.
7\. (New) The method of claim 2, wherein the esophageal disorder is Barrett's esophagus (BE).
8\. (New) 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 from normal tissue.
9\. (New) 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\. (New) The method of claim 2, wherein the primers specific for VAV3 comprise SEQ ID NOs: 39 and 40.

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

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

15\. (New) The method of claim 2, wherein the ten or fewer markers comprise BMP3, SFMBT2, DIO3, HUNK, ELMOI, CDl D. CDKN2A, and/or OPLAH.
2 3 4

OFFICE ACTION:
DETAILED CORRESPONDENCE
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 action is in response to the papers filed January 4, 2023.  Currently, claims 2-15 are pending.
Priority
This application claims priority to
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Drawings
The drawings are acceptable.
Requirement for Information under 37 CFR 1.105
Applicant and the assignee of this application are required under 37 CFR 1.105 to provide the following information that the examiner has determined is reasonably necessary to the examination of this application.
Significantly, an applicant's duty of disclosure of material and information is not satisfied by presenting a patent examiner with a mountain of largely irrelevant [material] from which he is presumed to have been able, with his expertise and with adequate time, to have found the critical [material]. It ignores the real world conditions under which examiners work. Rohm & Haas Co. v. Crystal Chemical Co., 722 F.2d 1556, 1573 [ 220 USPQ 289 ] (Fed. Cir. 1983), cert, denied, 469 U.S. 851 (1984). (Emphasis in original).
Patent applicant has duty not just to disclose pertinent prior art references but to make the disclosure in such way as not to bury it within other disclosures of less relevant prior art; See Golden Valley Microwave Foods Inc. v. Weaver Popcorn Co. Inc., 24 USPQ2d 1801 (N.D.I. 1992); Molins PLC v. Textron Inc., 26 USPQ2d 1889, at 1899 (D.Del. 1992); Penn Yan Boats, Inc. v. Sea Lark Boats, Inc. et al., 175 USPQ 260, at 272 (S.D. FI. 1972).
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. While art has been applied in this first 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.
The following information is required:
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.
The fee and certification requirements of 37 CFR 1.97 are waived for those documents submitted in reply to this requirement. This waiver extends only to those documents within the scope of this requirement under 37 CFR 1.105 that are included in the applicant’s first complete communication responding to this requirement. Any supplemental replies subsequent to the first communication responding to this requirement and any information disclosures beyond the scope of this requirement under 37 CFR 1.105 are subject to the fee and certification requirements of 37 CFR 1.97.
The applicant is reminded that the reply to this requirement must be made with candor and good faith under 37 CFR 1.56. Where the applicant does not have or cannot readily obtain an item of required information, a statement that the item is unknown or cannot be readily obtained may be accepted as a complete reply to the requirement for that item.
This requirement is an attachment of the enclosed Office action. A complete reply to the enclosed Office action must include a complete reply to this requirement. The time period for reply to this requirement coincides with the time period for reply to the enclosed Office action.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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 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.
Claim(s) 2-6, 11-12, 15 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Ahlquist et al. (WO2016/094839, June 16, 2016, provisional filed December 12, 2014).
The applied reference has a common inventors and assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C.102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the copending application and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Ahlquist teaches a method for performing methylation detection assays.  Ahlquist teaches assaying a sample from a subject for an amount of at least one methylated marker including VAV3, BMP3, and NDRG4 (see Ahlquist ‘839 Claim 1)(limitations of Claims 2-3, 15).   Ahlquist ‘839 teaches the method may be used where the subject has esophagus neoplasm (see Ahlquist ‘839 Claim 13).  Ahlquist ‘839 teaches the assaying comprises PCR sequencing such as methylation specific PCR (see page 9, lines 5-10).  Ahlquist ‘839 teaches the sample comprises blood, serum, gastrointestinal biopsy sample from either the upper or lower gastrointestinal tract and esophagus (see page 34, lines 15-30)(limitations of Claims 4-6).
For NDRG4, SEQ ID NO: 5 of Ahlquist ‘839 is 100% identical to SEQ ID NO 15 of the instant application.
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 2-5 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-4 of U.S. Patent No. 11,104,960. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 2 of ‘960 is directed to a method of extracting genomic DNA from a biological sample of a human having or suspected of having a gastrointestinal neoplasm, treating the extracted genomic DNA with bisulfite, amplifying the bisulfite treated genomic DNA using primers for no more than 10 markers including VAV3 (Claim 2) and ZNF682 and NDRG4 and measuring the level of the CpG site for the markers by methylation-specific PCR, for example.
The instant claims require the individual is suspected of having or having an esophageal disorder. The claims of ‘960 are directed to gastrointestinal neoplasm.  The GI tract is a series of hollow organs joined in a long, twisting tube from the mouth to the anus. The hollow organs that make up the GI tract are the mouth, esophagus, stomach, small intestine, large intestine, and anus (see Your Digestive System & How it Works - NIDDK (nih.gov)
The gastrointestinal neoplasm genus encompasses the species of esophageal disorder of the instant claims.  The number of species within the genus is few enough in number that one could readily envisage each species such that the species are obvious in view of the genus (see 804(II)(B)(I) and 2131).
With respect to Claims 4-5, the biological sample comprises cells, tissues and/or secretion from the upper and lower gastrointestinal tract (see Claim 3-4 of ‘’960).
Claims 2, 4-5, 9-10, are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 10,301,680. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 1 of ‘680 is directed to a method of extracting genomic DNA from a biological sample of a human having or suspected of having a precancerous neoplasm, treating the extracted genomic DNA with bisulfite, amplifying the bisulfite treated genomic DNA using primers for no more than 3 markers including VAV3 (Claim 1 of ‘680) and measuring the level of the CpG site for the markers by methylation-specific PCR, for example.
With regard to Claim 4, 5, ‘680 teaches the biological sample is a stool sample, a tissue sample, a blood sample, a urine sample (see Claim 2 of ‘680).
With regard to Claims 9-10, Claim 3 of ‘680 is directed to primer sequences in VAV3.  SEQ ID NO: 39 and SEQ ID NO: 40 of the instant application are 100% identical to SEQ ID NO: 1 and 3 of ‘335.
Claims 2, 4-5, 9-10, are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 11,365,451. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 1 of ‘451 is directed to a method of extracting genomic DNA from a biological sample of a human having or suspected of having a precancerous neoplasm, treating the extracted genomic DNA with bisulfite, amplifying the bisulfite treated genomic DNA using primers for no more than 8 markers including VAV3 (Claim 1 of ‘680) and measuring the level of the CpG site for the markers by methylation-specific PCR, for example.
With regard to Claim 4, 5, ‘451 teaches the biological sample is a stool sample, a tissue sample, a blood sample, a urine sample (see Claim 2 of ‘451).
With regard to Claims 9-10, Claim 3 of ‘451 is directed to primer sequences in VAV3.  SEQ ID NO: 39 and SEQ ID NO: 40 of the instant application are 100% identical to SEQ ID NO: 1 and 3 of ‘335.
Claims 2-3, 5-8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 1-3 of copending Application No. 17/727,128 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 1 of ‘128 is directed to a method of characterizing an esophageal tissue sample by measuring a methylation level of the combination of markers by treating the esophageal tissue sample with a reagent that modifies DNA in a methylation specific manner.  Claim 16 of ‘128 teaches using methylation -specific PCR, for example.
With regard to Claim 2-3 of the instant application, claim 2 of ‘128 recites NDRG4, VAV3 and ZNF682 as the methylation markers.
With regard to Claims 5-8, the tissue comprises Barrett’s esophagus, esophageal tissue (see claims 3-4 of ‘128).  Claim 20 of ‘128 teaches the human subject has or is suspected of having BE.
Claims 2, 4-5, 9-10, 15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 107-109, 113-114, 116-118, 125 of copending Application No. 18/644,335 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 107 of ‘355 is directed to a method of determining a methylation level of at least one differentially methylated region from a DNA sample by treating the sample with a reagent that modifies DNA in a methylation specific manner wherein the DMR is VAV3 (instant Claim 2), SFMBT2 (instant Claim 15).  Claim 108 of ‘335 uses a bisulfite reagent.  Claim 113 of ‘335 requires extracting DNA from the sample.  Claim 117 of ‘335 teaches using methylation -specific PCR, for example.
With regard to Claims 4-5, the tissue comprises blood, plasma, stool, secretion (see claims 109 of ‘335).
Claim 125 of ‘335 is directed to primer sequences in particular regions of chromosome 1.  The specification teaches particular examples of primer sequences in these regions.  SEQ ID NO: 39 and SEQ ID NO: 40 of the instant application are 100% identical to SEQ ID NO: 1 and 3 of ‘335.
Conclusion
No claims allowable.  Claims 11-14 are objected to as they depend on rejected claims.

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

NEXT 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

CITED REFERENCE SUMMARIES: Ref US11104960B2: Claims:
A method comprising: extracting genomic DNA from a biological sample of a human individual suspected of having or having gastro-intestinal neoplasm, treating the extracted genomic DNA with bisulfite, amplifying the bisulfite-treated genomic DNA using primers specific for no more than ten markers, wherein the no more than ten markers include either ZNF682 or ZNF682 and NDRG4, measuring the methylation level of the CpG site for the markers by methylation-specific PCR, quantitative methylation-specific PCR, methylation-sensitive DNA restriction enzyme analysis, or bisulfite genomic sequencing PCR.
extracting genomic DNA from a biological sample of a human individual suspected of having or having gastro-intestinal neoplasm,
treating the extracted genomic DNA with bisulfite,
amplifying the bisulfite-treated genomic DNA using primers specific for no more than ten markers, wherein the no more than ten markers include either ZNF682 or ZNF682 and NDRG4,
measuring the methylation level of the CpG site for the markers by methylation-specific PCR, quantitative methylation-specific PCR, methylation-sensitive DNA restriction enzyme analysis, or bisulfite genomic sequencing PCR.
The method of claim 1 , wherein one of the no more than ten markers is VAV3.
The method of claim 1 , wherein the biological sample comprises cells, tissues, and/or secretions from the upper gastrointestinal tract and/or the lower gastrointestinal tract.
The method of claim 1 , wherein the biological sample is a stool sample, a tissue sample, a blood sample, or a urine sample.
Ref US10301680B2: [content unavailable]
Ref US11365451B2: [content unavailable]
Ref WO2016094839A2: [content unavailable]
Ref WO2016094839: Claims:
WE CLAIM: 1. A method of screening for a neoplasm in a sample obtained from a subject, the
method comprising:
a) assaying a sample from a subject for an amount of at least one methylated marker gene selected from the group consisting of vimentin, septin 9, NDRG4, BMP3, VAV3, SFMBT2_897, and TFPI2a in a sample obtained from a subject;
b) assaying said sample for an amount of methylated ZDHHC1 DNA in said sample;
c) comparing the amount of said at least one methylated marker gene to the amount of methylated ZDHHC1 DNA in said sample to determine a methylation state for said at least one marker gene in said sample; and
d) generating a record reporting the methylation state for said at least one marker gene in said sample.
2. The method of claim 1, wherein said at least one marker is at least two of said markers.
3. The method of claim 1, wherein said at least one marker is all of said markers.
4. The method of claim 1 wherein the assaying comprises using polymerase chain reaction, nucleic acid sequencing, mass spectrometry, methylation specific nuclease, mass- based separation, or target capture.
5. The method of claim 1 wherein assaying the methylation state of the marker in the sample comprises determining the methylation state of one base.
6. The method of claim 1 wherein assaying the methylation state of the marker in the sample comprises determining the extent of methylation at a plurality of bases.
7. The method of claim 1 wherein the methylation state of the marker comprises an increased or decreased methylation of the marker relative to a normal methylation state of the marker.
8 The method of claim 1 wherein the methylation state of the marker comprises a different pattern of methylation of the marker relative to a normal methylation state of the marker.
9. The method of claim 1 comprising assaying a methylation state of a forward strand or assaying a methylation state of a reverse strand.
10. The method of claim 1 wherein the neoplasm is a gastrointestinal neoplasm.
11. The method of claim 1 wherein the neoplasm is present in the upper gastrointestinal area of the patient.
12. The method of claim 1 wherein the neoplasm is present in the lower gastrointestinal area of the patient.
13. The method of claim 1 wherein the neoplasm is a pancreas neoplasm, a colorectal neoplasm, a bile duct neoplasm, a stomach neoplasm, an esophagus neoplasm, or an adenoma.
14. The method of claim 1 wherein the neoplasm is pre-cancerous.
15. The method of claim 1 wherein the sample is a stool sample, a tissue sample, a pancreatic juice sample, a pancreatic cyst fluid sample, a blood sample, or a urine sample.
16. The method of claim 1, wherein said assay further comprises the step of identifying a KRAS mutation score in said sample, preferably wherein said measuring of said K-ras mutation score is measured by digital melt curve analysis or quantitative allele-specific PCR.
17. The method of claim 16, wherein said assay comprises detecting methylation state of ZDHHC1, BMP3, NDRG4, and identifying a KRAS mutation score in said sample.
18. The method of claim 1, wherein said method further comprises the step of determining the presence of hemoglobin in said sample.
19. The method of claim 1, wherein said subject is a patient having inflammatory bowel disease.
20. A kit, comprising:
a) at least one oligonucleotide, wherein at least a portion of said oligonucleotide specifically hybridizes to ZDHHC1; and
b) at least one additional oligonucleotide, wherein at least a portion of said oligonucleotide specifically hybridizes to marker selected from the group consisting of vimentin, NDRG4, BMP3, VAV3, SFMBT2_897, and TFPI2a.
21. The kit of claim 20, wherein said kit comprises at least two additional
oligonucleotides.
22. The kit of claim 20, wherein said kit further comprises bisulfite.
23. The kit of claim 20, wherein said kit further comprises at least one oligonucleotide, wherein at least a portion of said oligonucleotide specifically hybridizes to KRAS.
24. The kit of claim 20, wherein said kit further comprises reagents for detecting the presence of hemoglobin in a stool sample.
25. The kit of claims 20, 21, or 23, wherein said oligonucleotide is selected from one or more of a capture oligonucleotide, a pair of nucleic acid primers, a nucleic acid probe, and an INVADER oligonucleotide.
26. The kit of any one of claims 20 to 25, wherein said kit further comprises a solid support.
27. The kit of claim 26, wherein said solid support is a magnetic bead.
28. The kit of claim 25 or 26, wherein said solid support comprises one or more capture reagents.
29. The kit of claim 28, wherein said capture reagents are oligonucleotides
complementary to ZDHHC1 and said one or more markers genes.
30. A composition, comprising:
a) a complex of a ZDHHC1 nucleic acid and at least one oligonucleotide, wherein at least a portion of said oligonucleotide is hybridized to said ZDHHC1 nucleic acid; and
b) one or more additional reaction mixtures comprising a complex of a target nucleic selected from the group consisting of vimentin, NDRG4, BMP3, VAV3,
SFMBT2_897, and TFPI2a and one or more oligonucleotides that specifically hybridize to one or more target genes.
31. The composition of claim 30, wherein said oligonucleotide is selected from one or more of a capture oligonucleotide, a pair of nucleic acid primers, a nucleic acid probe, and an invasive oligonucleotide.
32. A method of measuring the severity of inflammation in a subject having inflammatory bowel disease, comprising:
a) assaying a sample of stool from a subject to determine the presence of methylated ZDHHC1 DNA and β-actin DNA,
b) comparing the ratio of β-actin DNA to methylated ZDHHC1 DNA to a ratio of β-actin DNA to methylated ZDHHC1 DNA correlated to a known severity of inflammation in IBD,
wherein a ratio of β-actin DNA to methylated ZDHHC1 DNA in said subject higher than the ratio correlated to the known severity of inflammation is indicative of more severe inflammation in said subject than said known severity; and
wherein a ratio of β-actin DNA to methylated ZDHHC1 DNA in said subject lower than the ratio correlated to the known severity of inflammation is indicative of less severe inflammation in said subject than said known severity.
33. The method of claim 32, wherein the ratio correlated to the known severity of inflammation was previously determined by assaying a sample of stool from the same subject.
34. The method of claim 32, wherein the ratio correlated to the known severity of inflammation was previously determined by assaying a sample of stool from a normal subject.
35. The method of claim 32, wherein the assaying comprises using polymerase chain reaction, nucleic acid sequencing, mass spectrometry, methylation specific nuclease, mass- based separation, or target capture.
36. The method of claim 35, wherein the assaying comprises using a flap endonuclease assay.
37. The method of claim 32, wherein the assaying comprises bisulfite converting said ZDHHC1 DNA and said β-actin DNA.
38. A composition comprising a strand of DNA comprising the nucleotide sequence of SEQ ID NO.27, in a reaction mixture with one or more nucleic acids selected from the group consisting of: oligonucleotides of SEQ ID NOS:3-10, 33, 59, 60, 56-58, and 63-65, a strand of DNA comprising the nucleotide sequence of SEQ ID NO:54, a strand of DNA comprising the nucleotide sequence of SEQ ID NO:61, and a strand of DNA comprising the nucleotide sequence of SEQ ID NO: 68.
39. The composition of claim 38, further comprising a detection probe oligonucleotide, wherein the detection probe oligonucleotide comprises a region that is complementary to a portion of said strand of DNA comprising the nucleotide sequence of SEQ ID NO:27.
40. The composition of claim 39, wherein said detection probe oligonucleotide comprises a region that is complementary to a portion of SEQ ID NO 27.
41. The composition of claim 39, wherein said detection probe oligonucleotide comprises a reporter molecule.
42. The composition of claim 41, where said reporter molecule comprises a fluorophore.
43. The composition of claim 39, wherein said detection probe comprises a flap sequence.
44. The composition of claim 39, further comprising one or more of a FRET cassette; a FEN-1 endonuclease and a thermostable DNA polymerase.
45. The composition of claim 44, wherein said thermostable DNA polymerase is a bacterial DNA polymerase.
46. A reaction mixture comprising the composition of claim 39.
47. A set of reaction mixtures comprising a strand of DNA comprising the nucleotide sequence of SEQ ID NO.27 and one or more nucleic acids selected from the group consisting of: oligonucleotides of SEQ ID NOS:3-10, 33, 59, 60, 56-58, and 63-65, a strand of DNA comprising the nucleotide sequence of SEQ ID NO:54, a strand of DNA comprising the nucleotide sequence of SEQ ID NO:61, and a strand of DNA comprising the nucleotide sequence of SEQ ID NO: 68.
48. The set of reaction mixtures of claim 47, wherein said strand of DNA comprising the nucleotide sequence of SEQ ID NO.27 is not in a reaction mixture with any of said one or more nucleic acids.
49. The method of any one of claims 1-3, wherein the assaying comprises using polymerase chain reaction, nucleic acid sequencing, mass spectrometry, methylation specific nuclease, mass-based separation, or target capture.
50. The method of any one of claims 1-3 and claim 49, wherein assaying the methylation state of the marker in the sample comprises determining the methylation state of one base.
51. The method of any one of claims 1-3, and claims 49-50, wherein assaying the methylation state of the marker in the sample comprises determining the extent of methylation at a plurality of bases.
52. The method of any one of claims 1-3 and claims 49-51, wherein the methylation state of the marker comprises an increased or decreased methylation of the marker relative to a normal methylation state of the marker.
53. The method of claim any one of claims 1-3 and claims 49-52, wherein the methylation state of the marker comprises a different pattern of methylation of the marker relative to a normal methylation state of the marker.
54. The method of any one of claims 1-3 and claims 49-53, comprising assaying a methylation state of a forward strand or assaying a methylation state of a reverse strand.
55. The method of any one of claims 1-3 and claims 49-54, wherein the neoplasm is a gastrointestinal neoplasm.
56. The method of any one of claims 1-3 and claims 49-55, wherein the neoplasm is present in the upper gastrointestinal area of the patient.
57. The method of any one of claims 1-3 and claims 49-55, wherein the neoplasm is present in the lower gastrointestinal area of the patient.
58. The method of any one of claims 1-3 and claims 49-55, wherein the neoplasm is a pancreas neoplasm, a colorectal neoplasm, a bile duct neoplasm, a stomach neoplasm, an esophagus neoplasm, or an adenoma.
59. The method of any one of claims 1-3 and claims 49-58, wherein the neoplasm is pre- cancerous.
60. The method of claim any one of claims 1-3 and claims 49-59, wherein the sample is a stool sample, a tissue sample, a pancreatic juice sample, a pancreatic cyst fluid sample, a blood sample, or a urine sample.
61. The method of claim any one of claims 1-3 and claims 49-60, wherein said assay further comprises the step of identifying a KRAS mutation score in said sample, preferably wherein said measuring of said K-ras mutation score is measured by digital melt curve analysis or quantitative allele-specific PCR.
62. The method of claim 61, wherein said assay comprises detecting the methylation state of ZDHHC1, BMP3, NDRG4, and identifying a KRAS mutation score in said sample.
63. The method of any one of claims 1-3 and claims 49-62, wherein said method further comprises the step of determining the presence of hemoglobin in said sample.
64. The method of any one of claims 1-3 and claims 49-63, wherein said subject is a patient having inflammatory bowel disease.
65. The kit of claim 20 or claim 21, wherein said kit further comprises bisulfite.
66. The kit of any one of claims 20-21 or claim 65, wherein said kit further comprises at least one oligonucleotide, wherein at least a portion of said oligonucleotide specifically hybridizes to KRAS.
67. The kit of any one of claims 20-21 or claims 65-66, wherein said kit further comprises reagents for detecting the presence of hemoglobin in a stool sample.
68. The kit of any one of claims 20-21 or claims 65-67, wherein said oligonucleotide is selected from one or more of a capture oligonucleotide, a pair of nucleic acid primers, a nucleic acid probe, and an INVADER oligonucleotide.
69. The kit of any one of claims 20-21 or claims 65-68, wherein said kit further comprises a solid support.
70. The kit of claim 69, wherein said solid support is a magnetic bead.
71. The kit of any one of claims 20-21 or claims 65-70, wherein said solid support comprises one or more capture reagents.
72. The kit of claim 71, wherein said capture reagents are oligonucleotides
complementary to ZDHHC1 and said one or more markers genes.
73. The method of claim 32 or claim 33, wherein the ratio correlated to the known severity of inflammation was previously determined by assaying a sample of stool from a normal subject.
74. The method of any one of claims 32-33 or claim 73, wherein the assaying comprises using polymerase chain reaction, nucleic acid sequencing, mass spectrometry, methylation specific nuclease, mass-based separation, or target capture.
75. The method of claim 74, wherein the assaying comprises using a flap endonuclease assay.
76. The method of claim any one of claims 32-33 or claim 75, wherein the assaying comprises bisulfite converting said ZDHHC1 DNA and said β-actin DNA.
77. The composition of claim 39 or claim 40, wherein said detection probe
oligonucleotide comprises a reporter molecule.
78. The composition of claim 77, where said reporter molecule comprises a fluorophore.
79. The composition of any one of claims 39-40 or claims 77-78, wherein said detection probe comprises a flap sequence.
80. The composition of any one of claims 39-40 or claims 77-79, further comprising one or more of a FRET cassette; a FEN-1 endonuclease and a thermostable DNA polymerase.
81. The composition of claim 80, wherein said thermostable DNA polymerase is a bacterial DNA polymerase.
82. A reaction mixture comprising a composition of any one of claims 39-40 or claims 77-81.
Ref US11104960: Claims:
1. A method comprising:
extracting genomic DNA from a biological sample of a human individual suspected of having or having gastro-intestinal neoplasm,
treating the extracted genomic DNA with bisulfite,
amplifying the bisulfite-treated genomic DNA using primers specific for no more than ten markers, wherein the no more than ten markers include either ZNF682 or ZNF682 and NDRG4,
measuring the methylation level of the CpG site for the markers by methylation-specific PCR, quantitative methylation-specific PCR, methylation-sensitive DNA restriction enzyme analysis, or bisulfite genomic sequencing PCR.
2. The method of claim 1, wherein one of the no more than ten markers is VAV3.
3. The method of claim 1, wherein the biological sample comprises cells, tissues, and/or secretions from the upper gastrointestinal tract and/or the lower gastrointestinal tract.
4. The method of claim 1, wherein the biological sample is a stool sample, a tissue sample, a blood sample, or a urine sample.
Ref US10301680: Claims:
1. A method comprising:
extracting genomic DNA from a biological sample of a human individual suspected of having or having neoplasm, wherein the neoplasm is pre-cancerous, colorectal cancer, a large colorectal adenoma, or a sessile serrated polyp,
treating the extracted genomic DNA with bisulfite,
amplifying the bisulfite-treated genomic DNA using primers specific for three or less markers at least including CHST2 and VAV3, and
measuring methylation level of one or more CpG sites for CHST2 and VAV3 by methylation specific PCR, quantitative methylation specific PCR, methylation sensitive DNA restriction enzyme analysis, or bisulfite genomic sequencing PCR.
2. The method of claim 1, wherein the biological sample is a stool sample, a tissue sample, a colorectal cyst sample, a colorectal tumor sample, a blood sample, or a urine sample.
3. The method of claim 1,
wherein the primers specific for VAV3 consist of SEQ ID NOS: 1 and 3, and
wherein the primers specific for CHST2 consist of SEQ ID NOS: 4 and 6.
4. The method of claim 1, further comprising
amplifying the bisulfite-treated genomic DNA using primers specific for PDGFD, and
measuring methylation level of one or more CpG sites for PDGFD by methylation specific PCR, quantitative methylation specific PCR, methylation sensitive DNA restriction enzyme analysis, or bisulfite genomic sequencing PCR.
5. The method of claim 4,
wherein the primers specific for CHST2 consist of SEQ ID NOS: 16 and 18, and
wherein the primers specific for PDGFD consist of SEQ ID NOS: 55 and 57.
Ref US11365451: Claims:
1. A method comprising:
extracting genomic DNA from a biological sample of a human individual suspected of having or having neoplasm, wherein the neoplasm is pre-cancerous, colorectal cancer, a large colorectal adenoma, or a sessile serrated polyp,
treating the extracted genomic DNA with bisulfite,
amplifying the bisulfite-treated genomic DNA using primers specific for eight or less markers at least including CHST2 and VAV3, and
measuring methylation level of one or more CpG sites for CHST2 and VAV3 by methylation specific PCR, quantitative methylation specific PCR, methylation sensitive DNA restriction enzyme analysis, or bisulfite genomic sequencing PCR.
2. The method of claim 1, wherein the biological sample is a stool sample, a tissue sample, a colorectal cyst sample, a colorectal tumor sample, a blood sample, or a urine sample.
3. The method of claim 1,
wherein the primers specific for VAV3 consist of SEQ ID NOS: 1 and 3, and
wherein the primers specific for CHST2 consist of SEQ ID NOS: 4 and 6 or SEQ ID NOS: 16 and 18.
4. The method of claim 1, further comprising
amplifying the bisulfite-treated genomic DNA using primers
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