DETAILED ACTION
Election/Restrictions
Applicant’s election of Group II in the reply filed on January 20 2026 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 1-3, 23-28, 35-38, 50 and 52 are pending in the application. Claims 1-3, 35-38, 50 and 52 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on January 20 2026. Accordingly, claims 23-28 are being examined on the merits herein.
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 .
Priority
This application is a 371 of PCT/US2020/065666 (12/17/2020) which claims benefit of 62/951,836 (12/20/2019) as reflected in the filing receipt issued on June 12 2023.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on February 19 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 23-28 are rejected under 35 U.S.C. 103 as being unpatentable over Heyes et al. (WO2020093053, cited on PTO Form 1449) in view of van der Wal (Utrecht University, 2014) as evidenced by Asiaei et al. (Biomicrofluidics, 2015).
The applied reference, Heyes et al., has a common 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. 103 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); 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 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. See generally MPEP § 717.02.
Applicant Claims
The instant application claims a method of preparing a compound of formula 11B:
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. The instant application claims 11A is converted to 11B with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide in a suitable solvent.
The instant application claims a method for preparing a compound of formula 12 by converting 11B:
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.
Compound 11B is converted to compound 12 by treating 11B with compound 11 in the presence of a suitable base and solvent.
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The instant application claims a method for preparing a compound of formula 13 by reducing a compound of formula 12:
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The instant application claims the compound of formula 13 is a trifluoroacetic acid salt:
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Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Heyes et al. is directed to bivalent targeted conjugates. Bidentate GalNac targeting ligands containing two saccharide groups with targeting activities as good as or better than tri-antennary and tetra-antennary ligands (page 1) Coupling agents which are suggested include EDC as well as HATU (pages 9-10; claim 49).
Shown in Scheme 8 (page 51) is the synthesis of compounds. With compounds 48 and 49 specifically isolated (pages 53-54)
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Specific linkers taught to connect to the sugar include (claim 14):
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And
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(page 89)
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Heyes et al. teaches compound 48 which is similar to instantly claimed compound 12, Heyes et al. does not expressly teach making the compound with a compound of 11B. While Heyes et al. teaches compound 47 is the same as instantly claimed compound 11A and that coupling can be conducted with EDC, Heyes et al. does not expressly teach EDC/NHS which would give instantly claimed compound 11B. However, this deficiency is cured by van der Wal as evidenced by Asiaei et al.
Van der Wal is directed to bio-inspired and functionalized peptide materials. Provided is a discussion on coupling reagents. EDC, an asymmetric carbodiimide, contains a tertiary amine in the alkyl chain which confers water solubility on the reagent that can then be easily removed from the reaction product by extraction (page 13). It was discovered that addition of an intermediate nucleophile that is itself highly nucleophilic, but still possess a strong enough leaving group character, can form an intermediate activated ester by reacting with the too-reactive isourea. These include N-hydroxysuccinimide which has substantially racemization suppression. The increased stability of the active ester intermediate is such that the active esters can be isolated and stored for later coupling (page 13-14). Coupling reagents which incorporate an additive in their structure include HATU (page 15; Fig. 10).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Heyes et al. and van der Wal and replace the exemplified HATU with EDC/NHS. One skilled in the art would have been motivated to replace the HATU with EDC/NHS as both are taught as coupling agents for forming amide bonds. One skilled in the art would have been motivated to select EDC/NHS as this coupling pair has been shown to produce stable intermediates which can be isolated and stored for later coupling as taught by van der Wal. Since Heyes et al. suggests that coupling reagents of HATU and EDC can be utilized there is a reasonable expectation of success.
Regarding claim 23: Heyes et al. teaches compound 47:
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which is the same as instant 11A. This reagent is intended to be coupled with compound 46. As evidenced by Asiaei et al. (Fig. 1), the mechanism of coupling with EDC/NHS (shown below) first results in an acylisourea via reaction with EDC. Then reaction with NHS results in the NHS ester, which as taught by van der Wal is stable and can be isolated and stored. This NHS ester can then be reacted with an amine to form an amide bond (i.e. the coupling product of the carboxylic acid and the amine). Thus, formation of the NHS ester of compound 47 would results in instantly claimed compound 11B (i.e. the NHS ester occurs at both OH of 11A).
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Regarding claim 24, as evidenced by Asiaei et al., EDC is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (page 1). Regarding the claimed suitable solvent, Heyes et al. teaches the coupling in a suitable solvent. It is taught in van der Wal that EDC is water soluble. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Heyes et al. and van der Wal and select a suitable solvent to ensure that coupling occurs at a desired yield.
Regarding claim 25-26, Heyes et al. exemplifies a compound with one extra CH2CH2O in between the benzene ring (i.e compound 47) and the sugar (aka galactosamine). However, Heyes et al. does exemplify other compounds with the same linking group and claims linking groups that results in 3 or 4 O:
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Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Heyes et al. and van der Wal and utilize either of the linkers expressly taught in Heyes et al. Since they are substantially similar in structure there is a reasonable expectation of success. With regards to the claimed method, as set forth above the formation of compound 11B is obvious when EDC/NHS is utilized. Reaction of this compound with compound 46 (reading on the TFA salt of instantly claimed compound 11) of Heyes et al. in the presence of a suitable solvent (such as DCM as exemplified by Heyes et al.) and a suitable base (such as TEA as exemplified by Heyes et al.) would afford instantly claimed compound 12.
Regarding claim 27, as set forth above, the linker between the galactoseamine and compound 11B is obvious. As set forth in Heyes et al., compound 48 (i.e. nitro compound) is reduced to produce the corresponding amine which would read on instantly claimed 13.
Regarding claim 28, compound 49 while containing a NH2 is not exemplified as the TFA salt. However, compound 46 which is also the free amine is converted to the TFA salt by addition of TFA. As claimed the compounds can be salts thereof (claims 1-2). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Heyes et al. and van der Wal and form the TFA salt. Heyes et al. teaches two forms, free base or TFA salt. Therefore, when desiring the salt form one skilled in the art would have been motivated to form the TFA salt based on the teachings of Heyes et al.
Claims 23-28 are rejected under 35 U.S.C. 103 as being unpatentable over Heyes et al. (WO 2020093061, referred to as Heyes 061, cited on PTO Form 1449) in view of van der Wal (Utrecht University, 2014) as evidenced by Asiaei et al. (Biomicrofluidics, 2015).
Applicant Claims
The instant claims are set forth above.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Heyes 061 is directed to therapeutic methods. Coupling reagents which can be utilized include EDC as well as HATU (page 17). Shown is a synthesis (page 223):
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wherein the synthesis of 646, 648 and 649 are specifically taught (pages 225-226).
Linking groups taught include (claim 183):
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Salts are taught (page 60; claims).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Heyes et al. teaches compound 648 which is similar to instantly claimed compound 12, Heyes et al. does not expressly teach making the compound with a compound of 11B. While Heyes et al. teaches compound 647 is the same as instantly claimed compound 11A and that coupling can be conducted with EDC, Heyes et al. does not expressly teach EDC/NHS which would give instantly claimed compound 11B. However, this deficiency is cured by van der Wal as evidenced by Asiaei et al.
The teachings of van der Wal and Asiaei et al. are set forth above.
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Heyes 061 and van der Wal and replace the exemplified HATU with EDC/NHS. One skilled in the art would have been motivated to replace the HATU with EDC/NHS as both are taught as coupling agents for forming amide bonds. One skilled in the art would have been motivated to select EDC/NHS as this coupling pair has been shown to produce stable intermediates which can be isolated and stored for later coupling as taught by van der Wal. Since Heyes 061 suggests that coupling reagents of HATU and EDC can be utilized there is a reasonable expectation of success.
Regarding claim 23: Heyes 061 teaches compound 647:
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which is the same as instant 11A. This reagent is intended to be coupled with compound 646. As evidenced by Asiaei et al., the mechanism of coupling with EDC/NHS (shown below Fig. 1) first results in an acylisourea via reaction with EDC. Then reaction with NHS results in the NHS ester, which as taught by van der Wal is stable and can be isolated and stored. This NHS ester can then be reacted with an amine to form an amide bond (i.e. the coupling product of the carboxylic acid and the amine). Thus, formation of the NHS ester of compound 647 would results in instantly claimed compound 11B (i.e. the NHS ester occurs at both OH of 11A).
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Regarding claim 24, as evidenced by Asiaei et al., EDC is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (page 1). Regarding the claimed suitable solvent, Heyes 061 teaches the coupling in a suitable solvent. It is taught in van der Wal that EDC is water soluble. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Heyes 061 and van der Wal and select a suitable solvent to ensure that coupling occurs at a desired yield.
Regarding claim 25-26, Heyes 061 exemplifies a compound with one extra CH2CH2O in between the benzene ring (i.e compound 647) and the sugar (aka galactosamine). However, Heyes 061 does exemplify other compounds with the same linking group and claims linking groups that results in 3 or 4 O:
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Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Heyes 061 and van der Wal and utilize either of the linkers expressly taught in Heyes 061. Since they are substantially similar in structure there is a reasonable expectation of success. With regards to the claimed method, as set forth above the formation of compound 11B is obvious when EDC/NHS is utilized. Reaction of this compound with compound 646 (reading on the TFA salt of instantly claimed compound 11) of Heyes 061 in the presence of a suitable solvent (such as DCM as exemplified by Heyes 061) and a suitable base (such as TEA as exemplified by Heyes 061) would afford instantly claimed compound 12.
Regarding claim 27, as set forth above, the linker between the galactoseamine and compound 11B is obvious. As set forth in Heyes 061, compound 648 (i.e. nitro compound) is reduced to produce the corresponding amine which would read on instantly claimed 13.
Regarding claim 28, compound 649 while containing a NH2 is not exemplified as the TFA salt. However, compound 646 which is also the free amine is converted to the TFA salt by addition of TFA. As claimed the compounds can be salts thereof). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Heyes 061 and van der Wal and form the TFA salt. Heyes 061 teaches two forms, free base or TFA salt. Therefore, when desiring the salt form one skilled in the art would have been motivated to form the TFA salt based on the teachings of Heyes 061.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ABIGAIL VANHORN whose telephone number is (571)270-3502. The examiner can normally be reached M-Th 6 am-4 pm EST.
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/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636