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 .
Response to Amendment
The amendment filed July 13th, 2026 is acknowledged. Regarding the Office Action mailed January 12th, 2026:
The objections to the claims are withdrawn in view of the amendments.
The rejection set forth under 35 U.S.C. 112(b) is withdrawn in view of the amendments.
The rejection set forth under 35 U.S.C. 112(a) is withdrawn in view of the amendments.
The rejection under 35 U.S.C. 101 is withdrawn in view of the amendments and further considerations.
The rejection of claims 1-21 set forth under 35 U.S.C. 103 is withdrawn in view of the amendments.
Maintained, modified, or new rejections are set forth below, as necessitated by the amendments. Responses to arguments, if necessary, follow their respective rejection sections.
Claim Summary
Claims 1-4, 11, 13-16, and 22 have been amended. Claims 36-38 have been added. Claims 1-38 are pending. Claims 29-35 are withdrawn from consideration as being drawn to a non-elected invention/species. Claims 1-28 and 36-38 are under examination and discussed in this Office action.
Claim Rejections - 35 USC § 103 – Modified – Necessitated by Amendment
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 22-24 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Ahlquist (US20190161804A1; previously cited), hereafter referred to as Ahlquist II for clarity.
Regarding instant claim 22, Ahlquist II teaches a method comprising the steps of: (a) extracting genomic DNA from a sample obtained from a subject (Page 5, paragraph [0045]; Page 6, paragraph [0052]); (b) performing a conversion reaction on the genomic DNA in vitro to convert unmethylated cytosine (Page 5, paragraph [0045]); and (c) detecting increased nucleic acid methylation of ABCB1, BMP3, and COL23A1 in the converted genomic DNA (Page 5, paragraph [0045]; Tables 2 and 6 for DMRs; Page 5, paragraph [0046]-[0047]).
The above referenced embodiment of Ahlquist II also does not specify that the conversion reaction converts unmethylated cytosine to uracil by deamination. Instead, it more generally states treating with a reagent for selective modification of unmethylated cytosines. However, Ahlquist II later details that a reagent that modifies a nucleotide as a function of the methylation state of a nucleic acid molecule can be a reagent that deaminates unmethylated cytosine nucleotides (Page 11, paragraph [0122]). Therefore, it would be obvious to perform a conversion reaction with a reagent that deaminates unmethylated cytosines to uracils.
Regarding instant claim 23, Ahlquist II teaches the method of claim 22. Ahlquist II further teaches wherein the detecting step (c) comprises a polymerase chain reaction (PCR)-based technique (Page 6, paragraph [0052]).
Regarding instant claim 24, Ahlquist II teaches the method of claim 23. Ahlquist II further teaches wherein the PCR-based technique is quantitative methylation specific PCR (QMSP) (Page 6, paragraph [0052]).
Regarding instant claim 26, Ahlquist II teaches the method of claim 22. Ahlquist II further teaches a number of different sample types, wherein a sample can be a cell sample (Pages 18-19, paragraph [0214]).
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Ahlquist II (US20190161804A1; previously cited), as applied to claims 22-24 and 26 above, in view of Wang (US20110165565A1; previously cited).
Regarding instant claim 25, Ahlquist II teaches the method of claim 22.
Ahlquist II does not teach wherein steps (a) and (b) are performed using a methylation on beads technique.
Wang, in a reasonably pertinent field, teaches wherein extracting genomic DNA from a sample and performing a conversion reaction on the genomic DNA to convert unmethylation cytosine to uracil by deamination using a methylation on beads technique (Page 7, paragraph [0075]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Ahlquist with the methylation on beads method from Wang. Since Wang teaches on DNA extraction and conversion reaction for unmethylated cytosines, which is reasonably pertinent to Ahlquist’s method requiring DNA extraction and conversion reaction for unmethylated cytosines, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because methylation on beads provides superior yields relative to conventional methods for NA extraction and bisulfite conversion (Wang, Page 7, paragraph [0075]).
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Ahlquist II (US20190161804A1; previously cited), as applied to claims 22-24 and 26, in view of Ahlquist (US20180037958A1; previously cited).
Regarding instant claim 27, Ahlquist II teaches the method of claim 26. Ahlquist II further teaches that a sample may include cells from the esophagus (Pages 18-19, paragraph [0214]).
Ahlquist II does not teach wherein the cell sample is retrieved using a swallowable sponge device.
Ahlquist, in a reasonably pertinent field teaches wherein a sample is retrieved from the esophagus using a swallowable sponge device (Page 7, paragraph [0058]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Ahlquist II with the swallowable sponge device of Ahlquist. Since Ahlquist teaches on retrieval of cells from the esophagus, which is reasonably pertinent to Ahlquist II’s sample types, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because it was known that swallowable sponge devices are feasible, safe, and accurate for measuring biomarkers (Pages 7-8, paragraph [0066]).
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Ahlquist II (US20190161804A1; previously cited), as applied to claims 22-24 and 26, in view of Ballard (WO2015157557A1; previously cited).
Regarding instant claim 28, Ahlquist II teaches the method of claim 22.
Ahlquist II does not teach further comprising the step (d) of performing an endoscopy on the subject.
Ballard, in the same field of endeavor, teaches performing an endoscopy after detecting biomarkers related to pancreatic cancer (Pages 1-2, paragraph [0003]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Ahlquist II with the endoscopy of Ballard. Since both Ahlquist II and Ballard are in the same field of endeavor (e.g. pancreatic cancer), one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because endoscopic examination allows for confirmation of diagnosis with biomarkers (Ballard, Page 25, paragraph [0008]).
Response to Arguments
Applicant's arguments filed July 13th, 2026 have been fully considered but they are not persuasive.
The Applicant argues that Ahlquist II “discusses detecting methylation of ABCB1, BMP3, and COL23A1 but does not teach or suggest the combination of at least three of the six specific genes in the context of the full claimed method” (Page 15 of the Remarks filed July 13th, 2026). The Applicant further states that even if Ahlquist II teaches three of the genes individually, it does not teach the specification combination of at least three from the six-gene panel discovered by the Applicant (Page 16 of the Remarks filed July 13th, 2026). The Applicant further details the unexpected results of using the six markers for EAC detection, with specific references to the specification (Page 16 of the Remarks filed July 13th, 2026).
In response to these arguments, it is noted that given the current claim language, the method as claimed for claim 22 reads “a method comprising the steps of…(c) detecting increased nucleic acid methylation of at least three of ABCB1, BMP3, COL23A1, FBN1, FADS1, and PRDM2 in the converted genomic DNA”. There is no language specifically limiting the genes to choose from to the listed 6 when applying the broadest reasonable interpretation of the claim language given that the method “comprises” the later recited steps. In other words, it may be interpreted that the method comprises detecting increased methylation of at least three of the listed genes, plus others. In the absence of language that specifically limits the genes to the six claimed, it is found that Ahlquist II teaches the method as claimed given that the teachings in Ahlquist II refer to detecting methylation changes in one or more of their identified differentially methylated regions (see Page 5, paragraph [0045] of Ahlquist II).
Furthermore, the Applicant’s reference to unexpected results in the specification is directed towards their use for detecting esophageal adenocarcinoma. In response to the Applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., detecting esophageal adenocarcinoma) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Claims 22-28 have no reference to any particular disease or condition. While the listed genes may have unexpected results when directly related to esophageal adenocarcinoma detection, that is irrelevant when the method does not claim to detect esophageal adenocarcinoma.
The Applicant further argues, with regard to the combinations of Ahlquist II with Wang, Ahlquist, and Ballard, that because Ahlquist II is relied upon as the primary citation, the rejections are overcome for the same reasons as cited for Ahlquist II (Page 16 of the Remarks filed Jul 13th, 2026).
The Applicant’s arguments rely on alleged deficiencies already addressed above and are therefore not addressed again here.
Given these considerations, the arguments are not found persuasive and the claims remain rejected based on the prior art citations presented in the rejections.
Double Patenting – Modified – Necessitated by Amendment
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 1-28 and 36-38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of copending Application No. 18654593 in view of Ahlquist (US20180037958A1; previously cited), Wang (US20110165565A1; previously cited), Arnal (Esophageal cancer: Risk factors, screening and endoscopic treatment in Western and Eastern countries, World Journal of Gastroenterology, July 2015, 21, 7933-7943; previously cited), Ahlquist II (US20190161804A1; previously cited), and Ballard (WO2015157557A1; previously cited).
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘593 reference application and the instant application claim a method and/or system for detecting an esophageal disorder comprising using a cell sample and biochemical assay; detecting methylation at one or more genes in the sample; detecting via quantitative methylation specific PCR; detecting methylation of one or more genes comprising FBN1, ABCB1, BMP3, COL23A1, FADS1, and/or PRDM2; and collecting the sample with a non-endoscopic method of a swallowable sponge device.
The ‘593 application claims do not require the esophageal disorder to be EAC; extracting genomic DNA; performing a conversion reaction on the genomic DNA; detecting increased methylation of genes; performing the extracting and conversion with a methylation on beads technique; performing an endoscopy after identifying with methylation detection; administering treatment appropriate for EAC; and performing an endoscopy after identifying with methylation detection and before treating.
However, with respect to what the ‘593 application does not require as it relates to claims 1-21 (which includes the esophageal disorder to be EAC; extracting genomic DNA; performing a conversion reaction on the genomic DNA; detecting increased methylation of genes; performing the extracting and conversion with a methylation on beads technique; performing an endoscopy after identifying with methylation detection; administering treatment appropriate for EAC; and performing an endoscopy after identifying with methylation detection and before treating), these variants are made obvious by Ahlquist, Wang, and Arnal.
Ahlquist teaches a method for identifying a subject having esophageal adenocarcinoma (EAC) comprising the steps of extracting DNA from a sample obtained from the subject (Page 6, paragraph [0053]). Ahlquist does not specify that genomic DNA is extracted from the sample. However, later detailed embodiments specifically state using genomic DNA isolated from esophageal tissue to look at differences in methylation related to esophageal adenocarcinoma (Page 20, paragraph [0202]). Therefore, it would be obvious to use extract genomic DNA from a sample for the purposes of the earlier embodiment of Ahlquist. Ahlquist teaches detecting increased methylation of genes (Page 6, paragraph [0054]). Ahlquist also teaches performing a conversion reaction on the genomic DNA in vitro to convert unmethylated cytosine (Page 6, paragraph [0053]). Ahlquist does not specify that that the conversion reaction converts unmethylated cytosine to uracil by deamination. Instead, it more generally states treating with a reagent for selective modification of unmethylated cytosines. However, Ahlquist later details that a reagent that modifies a nucleotide as a function of the methylation state of a nucleic acid molecule can be a reagent that deaminates unmethylated cytosine nucleotides (Page 12, paragraph [0106]). Therefore, it would be obvious to perform a conversion reaction with a reagent that deaminates unmethylated cytosines to uracils. Ahlquist teaches that subjects identified as having an esophageal disorder via methylation, including EAC, can be placed under regular screening, including endoscopic surveillance (Page 23, paragraph [0228]). Therefore, it would be obvious to perform an endoscopy after identifying the subject as having EAC. Ahlquist teaches on treating a patient with EAC comprising determining a methylation state of differentially methylated regions and administering a treatment based on these results, meaning necessarily appropriate for EAC (Page 21, paragraph [0215]). These include performing a surgery (Page 21, paragraph [0215]). Therefore, it would be obvious to administer to the subject one or more treatment modalities appropriate for a subject having EAC. Ahlquist further teaches wherein the one or more treatment modalities comprises surgery (Page 21, paragraph [0215]). These teachings make plain that the esophageal disorder being EAC; extracting genomic DNA; performing a conversion reaction on the genomic DNA; detecting increased methylation of genes; performing an endoscopy after identifying with methylation detection; and administering treatment appropriate for EAC are all obvious variants of that which is claimed in the ‘593 application.
Wang teaches wherein extracting genomic DNA from a sample and performing a conversion reaction on the genomic DNA to convert unmethylated cytosine to uracil by deamination are performed using methylation on beads technique (Page 7, paragraph [0075]). This teaching makes plain that performing the extracting and conversion with a methylation on beads technique is an obvious variant of that which is claimed in the ‘593 application.
Arnal teaches that treatment of esophageal adenocarcinoma can follow endoscopy screening (Figure 2). This teaching makes plain that performing an endoscopy after identifying with methylation detection and before treating is an obvious variant of that which is claimed in the ‘593 application.
With respect to what the ‘593 application does not require as it relates to claims 22-28 and 36-38 (which includes extracting genomic DNA; performing a conversion reaction on the genomic DNA; detecting increased methylation of genes; performing the extracting and conversion with a methylation on beads technique; and performing an endoscopy after identifying with methylation detection), Ahlquist II, in view of the provided art in the 103 rejections above, teaches these claimed limitations as discussed in the above 103 rejections, obviating these variations to the claims of the ‘593 application.
Furthermore, with regard to a computer algorithm determining a parameter and providing an output, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use this computer method of the ‘593 application in the method of the instant application. See In re Venner, 262 F.2d 91, 120 USPQ 193 (CCPA (1958), where the court held that broadly providing an automatic or mechanical means to replace a manual activity which accomplished the same result is not sufficient to distinguish over the prior art. Any additional limitations of the claims of Application No. 18654593 are encompassed by the open claim language “comprising” found in the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed July 13th, 2026 have been fully considered but they are not persuasive.
The Applicant’s argument related to the provisional non-statutory double patenting rejection is directed solely to the circumstance of the instant application having a patent term filing date earlier than the patent term filing date of the reference application (Pages 16-17 of the Remarks filed July 13th, 2026). The Applicant argues that given the amendments to the claims, the only rejection remaining would be the provisional non-statutory double patenting rejection (Page 17 of the Remarks filed July 13th, 2026). As correctly indicated by the Applicant, in the case of a provisional non-statutory double patenting rejection being the only remaining rejection, it will be withdrawn if the instant application’s patent filing term date comes before that of the reference application. However, there are still rejections remaining besides the above provisional non-statutory double patenting rejection, and it is still found that the claims have issues of non-statutory double patenting as analyzed above. Therefore, the arguments are not found persuasive.
Prior Art
In relation to claims 36-38 and the claimed list of genes, it is noted that detecting methylation in combinations of the claimed genes is taught in relation to other diseases and conditions. For instance, Ahlquist III (US 20190161806 A1) teaches on detecting methylation in COL23A1 and FBN1 as it relates to distinguishing HER2+ breast tissue from benign breast tissue. However, there are no teachings or suggestions related to detecting methylation in at least four, five, or all of ABCB1, BMP3, COL23A1, FBN1, FADS1, and PRDM2.
Conclusion
All claims stand rejected.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Allison E Schloop whose telephone number is (703)756-4597. The examiner can normally be reached Monday-Friday 8:30-5 ET.
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/ALLISON E SCHLOOP/ Examiner, Art Unit 1683
/Robert T. Crow/Primary Examiner, Art Unit 1683
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