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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on May 13, 2026 has been entered.
This action is in response to the papers filed November 3, 2025. Currently, claims 1-3, 7, 9, 16-17, 22 are pending.
All arguments have been thoroughly reviewed but are deemed non-persuasive for the reasons which follow.
Any objections and rejections not reiterated below are hereby withdrawn.
Applicant filed 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 to overcome the Eisele references.
Claims 47-51 of copending Application No. 17/996,032 (reference application) have been cancelled. Thus the double patenting rejection has been overcome.
Election/Restrictions
Applicant's election of the combination of Fer1L4, ZNF568 and BMP3 in the paper filed June 18, 2025 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Claims 26-28, 30-31, 34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 the IDS filed November 3, 2025, 1/15/25 and 8/28/24 contain an extremely large number of references for consideration by the Examiner. If the Applicant and/or Applicant and/or Applicant's representative are aware of any particular reference or portion of a reference in the extensive list which the examiner should pay particular attention to, it is required that it be specifically pointed out in response to this Office action.
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 other references, Hirsh and Smith intentionally withheld it from the PTO becausethis manner of disclosure was tantamount to a failure to disclose. Citing Penn Yan 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 failure to highlight Wagenseil in light of their knowledge of Whitson's actions in the foreign prosecutions violated their duty of candor to the PTO. Citing our precedent, 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 intentional material misrepresentations have been made, a “cure” through voluntary efforts during prosecution must be demonstrated by clear, unequivocal, and convincing 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.
Claim(s) 1-3, 9, 16-17, 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Markowitz et al. (WO 2020/243240, December 3, 2020) in view of Allawi et al. (US 2018/0245157, August 30, 2018).
With respect to Claims 1-3, 6, Markowitz teaches a method of diagnosing a subject as having a neoplasia (e.g., esophageal cancer) by determining whether a target gene in a sample from the subject is more methylated than a reference target gene (page 57, lines 11-15). Markowitz teaches target genes may be one or more of VAV3, FER1L4, BMP3, ZNF568, ZNF682, NDRG4 in which differential methylation may be used for distinguishing neoplasia of the esophagus (page 32, lines 12-20). Markowitz teaches neoplasia refers to Barrett’s esophagus and esophageal cancer (page 17, lines 22-25). Markowitz teaches methods for assaying DNA methylation of BMP3, ZNF568, NDRG4, ZNF682, VAV3 and FER1L4 (see Table 1, pages 32-33 and claim 56 of Wo, for example).
With respect to Claim 9, Markowitz teaches treating the DNA with a bisulfite compound that converts cytosine bases to uracil (see Claim 80, for example).
With respect to Claim 16, Markowitz teaches numerous methods for detecting methylation such as MSP, MS-SnuPE, COBRA that rely upon primers and amplification, for example (pages 50-52).
With respect to Claim 22, Markowitz teaches the sample may be obtained by brushing of the esophagus with a brush, cytology brush, sponge, balloon or substance that contacts the esophagus and obtains and esophageal sample (page 17, lines 27-30).
Markowitz does not teach using B3GALT6 as a reference gene in the methylation analysis.
However, Allawi et al teaches the use of B3GALT6 as a gene for use in normalizing nucleic acid detection assays (para 107). Allawi teaches using reference genes such as B3GALT6 in diagnostic assay for identifying methylation associated with cancers (para 182).
Therefore, it would have been prima facie obvious at the time the invention was made to have modified the methylation detection methods of Markowitz to include the B3GALT6 reference gene. Markowitz teaches using a reference gene sequence but does not teach B3GALT6. The ordinary artisan would have been motivated to have used B3GALT6, a known methylation reference gene.
Response to Arguments
The response traverses the rejection. The response asserts there is no experimental support in Markowitz for the proposition that these genes were tested, validated, or used as diagnostic markers. This argument has been considered but is not convincing because 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. Merck & Co. v.Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989)(see MPEP 2123). Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). “A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.” Here, Markowitz teaches target genes may be one or more of VAV3, FER1L4, BMP3, ZNF568, ZNF682, NDRG4 in which differential methylation may be used for distinguishing neoplasia of the esophagus (page 32, lines 12-20 and page 57, lines 12-18)).
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The response argues the five working examples are directed to VIM and CCNA1. The response provide significant discussion the passage on page 32 is generic. This argument has been reviewed but is not persuasive. The teachings of Markowitz are not limited to the working examples. A reference may be relied upon for all that it would have suggested including non-preferred embodiments.
The response (part III) argues Markowitz teaches no reference gene normalization in any diagnostic context. This argument has been reviewed but is not persuasive. The passage cited above discusses detecting differential methylation. Differential methylation is inherently a comparison between the sample and a reference. Thus, Markowitz teaches comparing to a reference or control. The second passage is directed explicitly to reference target gene from a healthy control subject.
With respect to Part IV, Markowitz specifically teaches the sample is from Barrett’s esophagus cells (page 57, lines 14).
Thus for the reasons above and those already of record, the rejection is maintained.
Claim(s) 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Markowitz et al. (WO 2020/243240, December 3, 2020) in view of Allawi et al. (US 2018/0245157, August 30, 2018) as applied to Claims 1-3, 9, 16-17, 22 above and further in view of Song et al. (WO 2021/005537, January 14, 2021).
Markowitz in view of Allawi does not teach modify DNA with a borane reducing agent.
However, Song teaches borate reducing agents are used to provide low cost methods for whole genome identification of methylation changes. Song teaches the step of converting the 5caC and/or 5fC to DHU comprises contacting the DNA sample with a reducing agent including, for example, pyridine borane, 2- picoline borane (pic-BEb), tert-butyl amine borane, borane, sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride. In a preferred embodiment, the reducing agent is pic-BEb and/or pyridine borane (para 23).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention to have used known reagents, including borane reducing agents to modify methylation to allow detection. Song teaches borane reducing agents allow complete conversions, low toxicity and high stability (para 34). Thus, the ordinary artisan would have been motivated to have used borane reducing agents to modify methylated nucleic acid sequences.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-2, 6-7, 9, 11, 16-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 14, 16-18, 20 of copending Application No. 17/233,199 (reference application) in view of Markowitz et al. (WO 2020/243240, December 3, 2020). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘199 application claims a combination comprising the instantly claimed genes.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Although the conflicting claims are not identical, they are not patentable distinct from each other because Claims 1-3, 7, 9, 11, 16-17, 22 of the instant application is directed to a method for analyzing NDRG4, VAV3, ZNF682, and BMP3 (Claim 16) in a esophageal cell sample and normalizing the amount of methylated biomarkers using B3GALT6.
17/233,199 does not claim analysis of FER1L4 and ZNF568.
However, Markowitz teaches a method of diagnosing a subject as having a neoplasia (e.g., Barretts Esophagus) by determining whether a target gene in a sample from the subject is more methylated than a reference target gene (page 57, lines 11-15). Markowitz teaches target genes may be one or more of VAV3, FER1L4, BMP3, ZNF568, ZNF682, NDRG4 in which differential methylation may be used for distinguishing neoplasia of the esophagus (page 32, lines 12-20). Markowitz teaches neoplasia refers to Barrett’s esophagus and esophageal cancer (page 17, lines 22-25). Markowitz teaches methods for assaying DNA methylation of BMP3, ZNF568, NDRG4, ZNF682, VAV3 and FER1L4 (see Table 1, pages 32-33 and claim 56 of Wo, for example).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention to have modified the method claimed in ‘199 to analyze additional known markers associated with esophageal disorders, including Barrett’s esophagus. ‘199 does not teach analysis of FER1L4 and ZNF568. However Markowitz teaches each of these genes are associated with differential methylation in Barrett’s esophagus. Thus, the ordinary artisan would be motivated to include additional methylation analysis of additional genes to obtain more robust results.
Response to Arguments
The response argues the double patenting rejection over ‘199 should be withdrawn because the pending claims are no longer anticipated by the claims of ‘199. This argument has been reviewed and the rejection has been modified to be directed to an obvious type double patenting rejection.
Conclusion
No claims allowable.
Cited pertinent art:
Jammula et al. (Gastroenterology, Vol. 158, No. 6, pages 1682, 1697, May 2020). Jammula teaches identification of subtypes of Barretts Esophagus and Esophageal adenocarcinoma based on methylation profiles. Jammula uses the Illumina 450K which comprises probes for each of the claimed gene.
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
August 24, 2026
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