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 .
DETAILED ACTION
2. This Office Action is responsive to Applicant’s Amendment and Remarks, filed December 8, 2025. The amendment, filed December 8, 2025, is entered, wherein claims 1 – 2 are amended, claims 3 – 5, 11, 18 – 19, and 27 – 29 are withdrawn, and claims 26 and 30 – 38 are canceled.
Claims 1 – 2, 6 – 10, 12 – 17, and 20 – 25 are currently examined.
Priority
This application is a national stage application of PCT/US2021/020900, filed March 4, 2021, which claims benefit of domestic application 62/984,994, filed March 4, 2020.
Withdrawn Objections
4. The objection of claim 2 in the previous Office Action, mailed August 8, 2025, is withdrawn in view of the amended claim 2.
Withdrawn Rejections
5. The rejection of claims 1 and 23 – 25 in the previous Office Action, mailed August 8, 2025, under 35 U.S.C. 102(a)(1) as being anticipated by El-Subbagh et al. with evidence provided by Pouremamali et al. and Wang et al. has been considered and is withdrawn in view of the amended claim 1.
The rejection of claims 1 – 2, 6 – 10, 12 – 17, and 20 – 23 in the previous Office Action, mailed August 8, 2025, under 35 U.S.C. 102(a)(1) as being anticipated by Wang et al. has been considered and is withdrawn in view of the amended claim 1.
The following are maintained / modified grounds of rejection necessitated by Applicant’s Amendment and Remarks, filed December 8, 2025, wherein claims 1 – 2 are amended, claims 3 – 5, 11, 18 – 19, and 27 – 29 are withdrawn, and claims 26 and 30 – 38 are canceled. Previously cited references have been used to establish the maintained / modified grounds of rejection.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code in line 31 of page 117. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Responses to Applicant’s Remarks:
Applicant states that the specification has been amended to remove the embedded hyperlink and/or other form of browser-executable code. However, Applicant only amended to remove http://. Other browser-executable code, such as www, is still presence. Therefore, the objection to specification is maintained.
Maintained / Modified Claim Rejections - 35 USC § 103
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.
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:
i. Determining the scope and contents of the prior art.
ii. Ascertaining the differences between the prior art and the claims at issue.
iii. Resolving the level of ordinary skill in the pertinent art.
iv. 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 1 – 2, 6 – 10, 12 – 17, and 20 – 25 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (WO2018/236856A1, cited in the previous Office Action mailed August 8, 2025) in view of Hecht et al. (Journal of Nutrition, 1999, Vol. 129, Issue 3, cited in the previous Office Action mailed August 8, 2025) with evidence provided by Pouremamali et al. (Cell Communication and Signaling, 2022, Vol. 20, Issue 1, cited in the previous Office Action mailed August 8, 2025).
Regarding claims 1 – 2, 6 – 10, 12 – 17, and 20 – 25, Wang et al. teach selective small molecule human constitutive androstane receptor (hCAR) activators of Formula (II) (page 32, lines 6):
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wherein Z may be O or S; X is -C(O)-R8, wherein R8 is NH, R2 is C1-6-alkenyl (page 32, line 8 and 19; page 33, lines 1 and 16), and the use thereof for the treatment of hematologic malignancies and other cancers (Abstract). Wang et al. explicitly teach DL5016J (page 37, Compound 13):
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However, Wang et al. do not teach
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wherein the isothiocyanate group is present and connected to -C(O)NHCH2CH2.
Hecht teaches that substantial quantities of isothiocyanates are released upon consumption of normal amounts of a number cruciferous vegetables. Some of these naturally occurring isothiocyanates such as phenethyl isothiocyanate (PEITC), benzyl isothiocyanate (BITC) and sulforaphane are effective inhibitors of cancer induction in rodents treated with carcinogens. A large amount of data demonstrate that isothiocyanates act as cancer chemoprotective agents by favorably modifying carcinogen metabolism via inhibition of Phase 1 enzymes and/or induction of Phase 2 enzymes (Abstract).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify DL5016J with a sulfur atom at Z as taught by Wang et al. and further modify DL5016J with an isothiocyanates (NCS) at R3 in view of Hecht because Hecht teaches that NCS are effective inhibitors of cancer. One would have been motivated to modify DL5016J with a sulfur atom at Z as taught by Wang et al. and further modify DL5016J with an isothiocyanates (NCS) in view of Hecht because Wang et al. teach that Z may be S or O and R3 may be replaced by different functional groups and Hecht teaches that NCS group has cancer inhibition property, thereby, these substitutions yield predictable and/or improved properties. According to Pouremamali et al., there are many synthetic or extracted substances that function as Nrf2 activators. One type of Nrf2 activators is isothiocyanates (page 5, Left Col., para. 1). Therefore, one of the ordinary skill in the art would have had a reasonable expectation of success to modify DL5016J with a sulfur atom at Z as taught by Wang et al. and further modify DL5016J with an isothiocyanates (NCS) at R3 in view of Hecht because Wang et al. teach a hCAR activator of the claimed core structure with an option of a sulfur atom at location Z and a changeable R3 and Hecht teaches that NCS group has the cancer inhibition property.
Responses to Applicant’s Remarks:
Applicant’s Remarks, field December 8, 2025, has been fully considered and are found to be not persuasive.
Regarding Hecht, Applicant argues that one of ordinary skill in the art would not have had a reasonable expectation that an isothiocyanate motif would result in a potent hCAR activator because Hecht discloses that the specific effects of isothiocyanate on the metabolism of a given carcinogen must be determined individually and there are some cases of isothiocyanates for which no effect or even enhancement is observed. However, the argument is not persuasive because Hecht discusses variability in the activity of specific isothiocyanates (page 769S, Table 1):
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Table 1 shows a wide range of isothiocyanates that demonstrate carcinogenesis inhibition across different models, organs, and carcinogen. Although there are a small number of studies showing no effect, the majority of the studies indicate the inhibition effect of isothiocyanates, which supports a reasonable expectation of success. The data also provide sufficient motivation for a person of ordinary skill in the art to incorporate isothiocyanates into a known bioactive compound, such as DL5016J from Wang et al.
Regarding Pouremamali et al., Applicant argues that Pouremamali et al. does not remedy the deficiencies of Hecht because Pouremamali et al. do not teach that every isothiocyanate is an Nrf2 activator. However, this argument is not persuasive. The examiner does not rely on Pouremamali et al. to establish activity of specific isothiocyanate compound, but to demonstrate that isothiocyanates are recognized in the art as a group that associated with Nrf2 activation. This reference is used to provide support that isothiocyanates are known in the art to possess Nrf2 activating property. Therefore, Pouremamali et al. confirm the motivation to modify DL5016J as taught by Wang et al. with an isothiocyanate group in view of Hecht et al. based on the known role of Nrf2 activator.
Finally, Applicant argues that Wang et al. do not teach or suggest the use of a isothiocyanate motif in compounds for cancer inhibition and therefore does not cure the deficiencies of Hecht and Pouremamali et al. However, Wang et al. teach a biologically active hCAR compound having different substituents, thereby providing a motivation for structural modification. Wang et al. is relied upon for the disclosure of the core structure, not for teaching the specific isothiocyanate substituent. Hecht is used to provide motivation for incorporating the isothiocyanate group because Hecht teaches that isothiocyanate group is effective in inhibiting carcinogenesis. Therefore, the combination of references render the claimed invention obvious.
Maintained / Modified 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 1 – 2, 6 – 10, 12 – 17, and 20 – 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 17 of U.S. Patent No. 11701345B2 in view of Hecht et al. (Journal of Nutrition, 1999, Vol. 129, Issue 3, cited in the previous Office Action) with evidence provided by Pouremamali et al. (Cell Communication and Signaling, 2022, Vol. 20, Issue 1, cited in the previous Office Action).
a. Regarding claims 1 – 2, 6 – 10, 12 – 17, and 20 – 25, ‘345B2 teaches compounds of Formula (II):
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wherein Z is O or S; X is -C(O)-R8, wherein R8 is NH, R2 is C1-6-alkyl (claim 1). ‘345B2 explicitly the compound (claim 6, col. 209):
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However, ‘345B2 does not teach
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wherein the isothiocyanate group is present and connected to -C(O)NHCH2CH2.
Hecht teaches that substantial quantities of isothiocyanates are released upon consumption of normal amounts of a number cruciferous vegetables. Some of these naturally occurring isothiocyanates such as phenethyl isothiocyanate (PEITC), benzyl isothiocyanate (BITC) and sulforaphane are effective inhibitors of cancer induction in rodents treated with carcinogens. A large amount of data demonstrate that isothiocyanates act as cancer chemoprotective agents by favorably modifying carcinogen metabolism via inhibition of Phase 1 enzymes and/or induction of Phase 2 enzymes (Abstract).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the exemplary compound with a sulfur atom at Z as taught by ‘345B2 and further modify the exemplary compound with an isothiocyanates (NCS) at R3 in view of Hecht because Hecht teaches that NCS are effective inhibitors of cancer. One would have been motivated to modify the exemplary compound with a sulfur atom at Z as taught by ‘345B2 and further modify the exemplary compound with an isothiocyanates (NCS) in view of Hecht because ‘345B2 teach that Z may be S or O and R3 may be replaced by different functional groups and Hecht teaches that NCS group has cancer inhibition property, thereby, these substitutions yield predictable and/or improved properties. As ‘345B2 teaches the claimed substituents, the compound will achieve the intended result, which activates hCAR. According to Pouremamali et al., there are many synthetic or extracted substances that function as Nrf2 activators. One type of Nrf2 activators is isothiocyanates (page 5, Left Col., para. 1). Therefore, one of the ordinary skill in the art would have had a reasonable expectation of success to modify the exemplary compound with a sulfur atom at Z as taught by ‘345B2 and further modify the exemplary compound with an isothiocyanates (NCS) at R3 in view of Hecht because ‘345B2 teach a hCAR activator of the claimed core structure with an option of a sulfur atom at location Z and a changeable R3 and Hecht teaches that NCS group has the cancer inhibition property.
Responses to Applicant’s Remarks:
Applicant’s Remarks, field December 8, 2025, has been fully considered and are found to be not persuasive.
Regarding Hecht, Applicant argues that one of ordinary skill in the art would not have had a reasonable expectation that an isothiocyanate motif would result in a potent hCAR activator because Hecht discloses that the specific effects of isothiocyanate on the metabolism of a given carcinogen must be determined individually and there are some cases of isothiocyanates for which no effect or even enhancement is observed. However, the argument is not persuasive because Hecht discusses variability in the activity of specific isothiocyanates (page 769S, Table 1):
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Table 1 shows a wide range of isothiocyanates that demonstrate carcinogenesis inhibition across different models, organs, and carcinogen. Although there are a small number of studies showing no effect, the majority of the studies indicate the inhibition effect of isothiocyanates, which supports a reasonable expectation of success. The data also provide sufficient motivation for a person of ordinary skill in the art to incorporate isothiocyanates into a known bioactive compound from ‘345B2.
Regarding Pouremamali et al., Applicant argues that Pouremamali et al. does not remedy the deficiencies of Hecht because Pouremamali et al. do not teach that every isothiocyanate is an Nrf2 activator. However, this argument is not persuasive. The examiner does not rely on Pouremamali et al. to establish activity of specific isothiocyanate compound, but to demonstrate that isothiocyanates are recognized in the art as a group that associated with Nrf2 activation. This reference is used to provide support that isothiocyanates are known in the art to possess Nrf2 activating property. Therefore, Pouremamali et al. confirm the motivation to modify the compound as taught by ‘345B2 with an isothiocyanate group in view of Hecht et al. based on the known role of Nrf2 activator.
Conclusion
No claim is found to be allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 HOI YAN LEE whose telephone number is 571-270-0265. The examiner can normally be reached Monday - Thursday 7:30 - 17:30.
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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693