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 October 16, 2025. Currently, claims 1, 5-8, 10-12, 14, 16-22 are pending.
All arguments have been thoroughly reviewed but are deemed non-persuasive for the reasons which follow. This action is made FINAL.
Any objections and rejections not reiterated below are hereby withdrawn.
The 102 rejection over Jones has been withdrawn in view of the arguments that the samples were not amplified “using primers specific for NDRG4 and ARHGEF4”.
Election/Restrictions
Applicant's election of the combination of NDRG4 and ARHGEF4 in the paper filed October 21, 2024 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)).
Claims 2-3 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
The requirement is still deemed proper and is therefore made FINAL.
Priority
This application claims priority to
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Drawings
The drawings are acceptable.
Information Disclosure Statement
It is noted that Applicant subsequentially filed with this RCE another IDS comprising another 13 pages of IDS. This is in additional to the already filed 18-page and 80-page Information Disclosure Statements (IDS). The IDS’s have been reviewed to the extent reasonably possible. Applicant is reminded that "burying" relevant references in a lengthy IDS is discouraged. See, e.g., Molins PLC v. Textron Inc., 48 F.3d 1172, 33 USPQ2d 1823, 1831 (Fed. Cir. 1995).
The court concluded that, by “burying” Wagenseil in a multitude of otherreferences, Hirsh and Smith intentionally withheld it from the PTO becausethis manner of disclosure was tantamount to a failure to disclose. Citing PennYan Boats, Inc. v. Sea Lark Boats, Inc., 359 F.Supp. 948, 175 USPQ 260(S.D. Fla. 1972), aff'd, 479 F.2d 1328, 178 USPQ 577 (5th Cir.), cert.denied, 414 U.S. 874 (1973), the court stated that Hirsh's and Smith's failureto highlight Wagenseil in light of their knowledge of Whitson's actions in theforeign prosecutions violated their duty of candor to the PTO. Citing ourprecedent, Textron asserts that Smith's and Hirsh's conduct is “inexcusable,fraudulent, and cannot operate to cure Whitson's inequitable conduct.” See
Rohm & Haas Co. v. Crystal Chem. Co., 722 F.2d 1556, 220 USPQ 289(Fed.Cir. 1983), cert. denied, 469 U.S. 851 (1984) (where intentionalmaterial misrepresentations have been made, a “cure” through voluntaryefforts during prosecution must be demonstrated by clear, unequivocal, andconvincing evidence).
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.
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 (i.e., changing from AIA to pre-AIA ) 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.
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, 5-8, 10-12, 14, 16-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jones et al. (US 2011/0318738, December 29, 2011).
Jones teaches a method of bisulfite sequencing in adenoma samples from five different patients (page 43, lines 1-3). Jones teaches changes in methylation were seen in numerous genes including NDRG4 and ARHGEF4 (page 45, col. 2; page 43, col. 1). Jones teaches the methylation from FAP adenoma tissues samples were analyzed (para 320-321). Jones teaches verification of methylation status was conducted by qPCR or MeDIP samples or bisulfite sequencing (para 317).
With respect to Claims 5-6, the sample is a colon tissue sample (para 320).
With respect to Claim 10, bisulfite sequencing relies upon bisulfite treatment.
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention to have performed bisulfite sequence on each of the listed genes that were taught be differentially methylated in FAP adenoma tissue samples to normal tissue sample. The ordinary artisan would have been motivated to have tested and verified each of the recited genes to verify their differential methylation. The ordinary artisan would have been motivated to have determined whether the methylation in each gene was increased or decreased compared to the normal control to provide information about the cancer status of the patients. The ordinary artisan would have been motivated to have analyzed CpG sites throughout the gene to provide a clear analysis of the methylation patterns.
Response to Arguments
The response traverses the rejection. The response asserts Jones discloses NDRG4 and ARHGEF4 among a lot of 7286 other genes. This argument has been considered but is not convincing because, as provided in MPEP 2123, a reference is good for all it teaches. A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Jones teaches each of the genes, including NDRG4 and ARHGEF4 are differentially methylated in colon cancer. As noted by the response, Jones teaches meDIP/WGA experiments were performed using adenoma samples and control samples and the list of genes comprising NDRG4 and ARHGEF4 were identified.
The response argues that Jones fails to teach or suggest assessing methylation levels of NDRG4 and ARHGEF4 using a reagent that modifies DNA in a methylation specific manner or amplifies using primers specific for NDRG4 and ARHGEF4. This argument has been reviewed but is not persuasive. The rejection above is directed to the obviousness of taking genes identified as being differentially methylated and performing bisulfite sequencing. Jones and the instant specification each teach that bisulfite sequencing was well known at the time the invention was made. Bisulfite sequencing relies upon treatment with a reagent that modifies methylation-specific manner, bisulfite, and performs PCR amplification. Thus, using bisulfite sequencing in adenoma samples would necessarily meet the limitations of Claim 1. Since bisulfite sequencing was well known at the time the invention was made and was routine in the art, no undue experimentation would be required to practice the claimed invention.
The response argues that Jones fails to qualify as enabling prior art with respect to determining methylated levels of NDRG4 and ARHGEF4 for assessing colorectal neoplasia. This argument has been reviewed but is not persuasive. The state of the art at the time the invention was made for determining methylation levels of NDRG4 and ARHGEF4 and any other gene was extremely high. Thus, the claims are enabled.
The response argues that Jones fails to disclose determining methylated levels of NDRG4 and ARHGEF4 to assess colorectal cancer neoplasia. The instant claims doe not require a diagnostic method of assessing colorectal cancer. The claim only requires analysis of NDRG4 and ARHGEF4 in a colorectal cancer sample which is enabled by the state of the art and Jones.
Moreover, as provided by MPEP 2164.06, “[A]n extended period of experimentation may not be undue if the skilled artisan is given sufficient direction or guidance.” In re Colianni, 561 F.2d 220, 224, 195 USPQ 150, 153 (CCPA 1977). “‘The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed.’” In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) (citing In re Angstadt, 537 F.2d 498, 502-04, 190 USPQ 214, 217-19 (CCPA 1976)). Time and expense are merely factors in this consideration and are not the controlling factors. United States v. Telectronics Inc., 857 F.2d 778, 785, 8 USPQ2d 1217, 1223 (Fed. Cir. 1988), cert. denied, 490 U.S. 1046 (1989).” Thus, performing routine bisulfite sequencing for markers would not constitute undue or unpredictable experimentation. Jones identified NDRG4 and ARHGEF4 as differentially methylated by array based analysis. Jones teaches methylation specific sequencing was known in the art as early as 1997 (see para 87-88). This bisulfite sequencing was well known at the time the invention was made. Testing and verifying these genes by qPCR and bisulfite sequencing would have provided further confirmation of their association, like Jones performed for PITX2.
The response nor the specification has identified any secondary considerations or unexpected results that would overcome the obviousness rejection. Further, it is noted the claim is not limited to analysis of two and only two genes. Thus, for the reasons above and those already of record, the rejection is maintained.
Conclusion
The prior art does not teach or suggest using primers comprising SEQ ID NO: 17-18 or 35-36 for amplifying NDRG4 or ARHGEF4. Thus, claims directed to the particular primers are allowable over the art.
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.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Wang et al. PLos ONE, Vol. 11, No. 4, e0153125, April 25, 2016 teaches ARHGEF4 is differentially methylated in colon cancer specimens. This reference was published 10 days after the provisional filing date.
Xiao et al. (Oncology Letters, Vol. 9, pages 1383-1387, 2015) teaches NDRG4 gene is methylated as a biomarker for diagnosis of colorectal cancer.
US Patent 10,006,093 and US Patent 10,597,733 teaches ARHGEF4 and NDRG4 are optimal markers for detecting stomach cancer (col 8, lines 65-col. 9, lines 1- 5).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEANINE ANNE GOLDBERG whose telephone number is (571)272-0743. The examiner can normally be reached Monday-Friday 6am-3:30pm.
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, Wu-Cheng (Winston) Shen can be reached on (571) 272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JEANINE A GOLDBERG/Primary Examiner, Art Unit 1682
November 3, 2025