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 30, 2025. The amendment, filed December 30, 2025, is entered, wherein claims 43 – 50 are new, claims 20 – 21, 24, 36, and 40 – 42 are withdrawn and claims 1 – 16 and 31 – 34 are canceled.
Claims 17 – 30 and 35 – 50 are pending in this application and claims 17 – 19, 22 – 23, 25 – 30, 35, 37 – 39, and 43 – 50 are currently examined.
Priority
3. This application is a DIV of 16/055,661, filed August 6, 2018, and later granted Patent No. 11160874, which is a DIV of 14/878,444, filed October 8, 2015, and later granted Patent No. 10064952, which has a provisional application 62/061,989, filed October 19, 2014.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/30/2025 was filed after the mailing date of the previous Office Action on October 1, 2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
The following are maintained / modified / new grounds of rejection necessitated by Applicant’s Amendment and Remarks, filed December 30, 2025, wherein claims 43 – 50 are new. Previously and newly cited references have been used to establish the maintained / modified / new grounds of rejection.
New Claim Objections
Claims 43, 45, 47, and 49 are objected to because of the following informalities:
Claims 43 and 47, line 1, “_” immediately after “or” should be removed.
Claims 45 and 49, line 1, “glycosyltranferase” should read “glycosyltransferase”.
Appropriate correction is required.
New Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 49 – 50 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
a. Claims 49 recites the limitation "the glycosyltransferase" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 49 depends from claim 47 and recites “the glycosyltransferase”, however, claim 47 never recites “glycosyltransferase”. It is unclear which glycosyltransferase the claim is referring to. Claim 50, depending from claim 49, is also indefinite.
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 17 – 19, 22 – 23, 25 – 30, 35, 37 – 38, and 43 – 50 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (Angewandte Chemie International Edition, 2014, Vol. 53, Issue 28, page 7179 – 7182, cited in the previous Office Action mailed February 20, 2025) in view of Sampathkumar et al. (Nature Chemical Biology, 2006, Vol. 2, Issue 3, page 149 – 152, cited in the previous Office Action mailed February 20, 2025).
a. Regarding claims 17 – 19, 22 – 23, 25 – 30, 35, 37 – 38, and 43 – 50, Li et al. teach the preparation of antibody-drug conjugates (ADC) (Title), wherein the preparation comprises remodeling the oligosaccharide of an anti-CD22 monoclonal antibody and a control polyclonal antibody using CMP-sialic acid derivative 1 which has an azide at C-9 of the sialic acid moiety. The azido moieties of the glycans of the resulting antibodies can then be reacted by SPAAC using dibenzylcyclooctynol (DIBO) modified by, for example, biotin, FITC, or a cytotoxic drug, such as doxorubicin (page 2, para. 2). The azido-modified sialic acid is incorporated by treatment with CMP-sialic acid derivative 1 in the presence of recombinant ST6 β-galactoside α-2,6-sialyltransferase 1 (ST6Gal1) (page 2, para. 3). Li et al. further teach glycan remodeling of IgG antibodies to produce a homogenous glycoforms that having azido moieties suitable for strain promoted cycloadditions with compounds 2 – 4 in the following scheme (Scheme 1):
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The diagram shows glycans which are attached to the core structure (indicated by R1 in compounds 5, 6, and 7). The different shapes and colors corresponds to specific monosaccharides (e.g. GlcNAc, Man, Gal, Fuc, and Sia), indicating that these are glycan structures. During the synthesis, (i) UDP-Gal, galactosyltransferase, MOPS buffer at pH 7.2; (ii) compound 1, sialytransferase, cacodylate buffer pH 7.6; and (iii) compound 2, 3, or 4 in cacodylate buffer pH 7.6 are used. Biotin, shown as compound 2 in scheme 1, comprises PEG (Scheme 1). Li et al. also teach that glycosyltransferases often tolerate chemical modifications in their sugar nucleotide substrates, allowing installation of reactive functionalities, such as ketones, alkynes, or azides (page 2, para. 1).
However, Li et al. do not teach the sialic acid derivative comprises a terminal thiol moiety with the structure:
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wherein a thioether bond is formed between the derivative moiety and the effector moiety.
Sampathkumar et al. teach a metabolic installation of thiols into sialic acid that modulates adhesion and stem cell biology (title). Specifically, the analog Ac5ManNTGc (1) introduced by Sampathkumar et al. enable thiols to be expressed in surface sialic acid (Abstract). The display of thiols at the outer periphery of the glycocalyx renders these versatile functional groups highly accessible for chemical manipulation and endows the cell surface with unique adhesive properties. Sampathkumar et al. teach the quantitative estimation of cell surface thiols:
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and demonstrate that Ac5ManNTGc-treated cells react with maleimide PEO2-biotin to form a thioether linkage (Supplementary Scheme 3).
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 substitute the azide-sialic acid moiety as taught by Li et al. with a thiol-containing sialic acid moiety in view of Sampathkumar et al. to provide an alternative reactive functional group for bioconjugation reactions because Li et al. teach that glycosyltransferases often tolerate chemical modifications in their sugar nucleotide substrates, allowing installation of reactive functionalities, such as ketones, alkynes, or azides, and Sampathkumar et al. teach that thiol-functionalized sialic acid is a known reactive handle for bioconjugation and may be reacted with maleimide-functionalized reagents to form stable thioether linkages. Thus, it would have been obvious to substitute the azide moiety as taught by Li et al. with the known thiol moiety in view of Sampathkumar et la. because the substitution would have represented the use of one known conjugation-enabling functional group in place of another to obtain the predictable benefit of an alternative site-specific conjugation chemistry. It would also have been obvious to correspondingly substitute DIBO as taught by Li et al. with maleimide in view of Sampathkumar et al. because it is known in the art that thiol is not reactive with DIBO. A skilled artisan would have recognized that thiol react predictably with maleimide to form thioether linkage. It is also known in the art that thiol-maleimide chemistry is routine and widely used bioconjugation method. Therefore, one of the ordinary skill in the art would have had a reasonable expectation of success to substitute the azide-sialic acid moiety as taught by Li et al. with a thiol-containing sialic acid moiety in view of Sampathkumar et al. to provide an alternative reactive functional group for bioconjugation reactions, and to correspondingly substitute DIBO as taught by Li et al. with maleimide in view of Sampathkumar et al. to arrive the method of making an effector moiety conjugated binding polypeptide as claimed because Li et al. explicitly teach that glycosyltransferases tolerate chemical modifications in their sugar nucleotide substrates, enabling installation of reactive functional groups into glycans for site-specific conjugation and thiol-maleimide conjugation is known to yield stable thioether bond as exemplified in Sampathkumar et al.
Claim 39 is rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (Angewandte Chemie International Edition, 2014, Vol. 53, Issue 28, page 7179 – 7182, cited in the previous Office Action mailed February 20, 2025) in view of Sampathkumar et al. (Nature Chemical Biology, 2006, Vol. 2, Issue 3, page 149 – 152, cited in the previous Office Action mailed February 20, 2025) as applied to claims 17 – 19, 22 – 23, 25 – 30, 35, 37 – 38, and 43 – 50 above, and further in view of Chen et al. (WO2013037484A2, cited in the previous Office Action mailed February 20, 2025).
b. Regarding claim 39, Li et al. and Sampathkumar et al. teach the limitations discussed above. Li et al. further teach that ADC have considerable promise as anticancer agents by selectively targeting cytotoxic drugs to cells expressing tumor-associated cell surface proteins. It has been proposed that ADCs are endocytosed after binding a cell-surface protein and degraded in the lysosome to release the cytotoxic drug (page 1, para. 1). The heavy chain of an IgG antibody is modified at Asn297 with a complex biantennary N-linked oligosaccharide, which does not affect antigen binding but influences effector function (page 2, para. 1).
However, these references do not teach the antibody comprises a S298N mutant.
Chen et al. teaches the antibody comprises two or more of mutations N297Q, S298N, T299A and Y300S. For example, Chen et al. disclose a humanized antibody comprising the multiple mutations S298N/T299A/Y300S (page 6, lines 25 – 28). Chen et al. also teaches that one glycosylation site is observed at amino acid 298 with biantennary and tri-antennary complex-type glycans detected as the major species (page 32, lines 14 – 16). S298N/T299A/Y300S H66 mutant also show a stability characteristics (page 33, lines 27 – 30). Furthermore, Chen et al. further disclose a functional analysis of Fc-engineered mutants. The results demonstrate that H66 S298N/T299A/Y300S behaved similarly to the H66 deltaAB in all cell based assays, showing minimal T-cell activation by CD25 expression; binding to abTCR, although with slightly different kinetics to deltaAB; minimal cytokine release at both D2 and D4 time points; the mutant is in fact superior to deltaAB at D4 in respect of several of the cytokines. The S298N/T299A/Y300S mutant thus eliminated effector function as effectively as the deltaAB mutation (page 34, lines 1 – 19).
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 substitute the antibody of Li et al. with the antibody comprising S298N/T299A/Y300S mutant in view of Chen et al. to arrive the method of making an effector moiety conjugated antibody as claimed because Li et al. disclose ADC in which the antibody serves as a delivery vehicle for a cytotoxic payload, and further teach that modification at Asn297 of the antibody influences effector function though not antigen binding and Chen et al. teach antibodies comprising Fc mutations including S298N/T299A/Y300S. Thus, Li et al. indicate that the effector properties are an important design consideration for ADC scaffolds. Chen et al. disclose Fc-engineered antibodies, including S298N/T299A/Y300S mutant, that retain antigen binding while markedly reducing effector functions. One would have been motivated to substitute the antibody of Li et al. with the antibody comprising S298N/T299A/Y300S mutant in view of Chen et al. because Chen et al. disclose that the mutant minimizes T-cell activation and cytokine release while retaining binding, thereby, yielding a safer ADC. Therefore, one of the skills in the art would have had a reasonable expectation of success by substituting the sialic acid moiety of Li et al. with thiol-sialic acid moiety in view of Sampathkumar et al., followed by substitute the antibody of Li et al. with the antibody comprising S298N/T299A/Y300S mutant in view of Chen et al. to arrive the method of making an effector moiety conjugated antibody as claimed because the substitution will improve the safety of the ADC, while maintaining the antibody’s role as a targeting and delivery vehicle.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed December 30, 2025, have been fully considered and are found to be not persuasive.
Regarding the rejection, Applicant argues that the rejection is improper because the Office treats the invention as merely substituting one functional group with another rather than the specific process steps required by the claimed method. However, the argument is not persuasive. The rejection does not rely solely on a general substitution of functional groups, but rather on the teachings of the cited references which disclose the claimed process steps and provide motivation to modify the prior art methods. Li et al. teach methods for preparing ADC by enzymatically remodeling antibody glycans using modified CMP-sialic acid donors in the presence of ST6Gal1 to install reactive functional groups on the antibody glycan. Li et al. further teach that the installed functional group will subsequently be reacted with a conjugation partner to attach a payload, such as biotin, FITC, or a cytotoxic drug. Thus, Li et al. teach the enzymatic transfer of a modified sialic acid derivative to an antibody glycan followed by conjugation with an effector moiety, which corresponds to the process steps recited in the claims.
Regarding Li et al., Applicant argues that Li et al. only discloses azide-modified CMP-sialic acid donors installed on antibody glycans using ST6Gal1 and Li et al. do not disclose thiol-modified CMP sialic acid donors. Thus, Li et al. provide no suggestion that ST6Gal1 would tolerate thiol-containing CMP-sialic acids. However, the argument is not persuasive. Li et al. demonstrate that chemically modified CMP-sialic acid derivative bearing reactive functional groups may be enzymatically transferred to antibody glycans using ST6Gal1 to enable subsequent conjugation reactions. Thus, Li et al. teach that the enzymatic glycan remodeling platform tolerates modified sialic acid donors containing reactive handles for conjugation chemistry. The substitution of one known reactive functional group with another known reactive functional group suitable for bioconjugation would have been within the ordinary skill in the art.
Regarding Sampathkumar et al., Applicant argues that Sampathkumar et al. concerns metabolic glycoengineering in living cells, not in vitro antibody modification and there is no teaching, suggestion, or reasonable expectation that a thiol functionality can be substituted into CMP donor disclosed by Li et al. for the reaction workflow. However, the argument is not persuasive. Sampathkumar et al. teach that thiol-modified sialic acid analogs may be incorporated into cell surface glycans and that the resulting thiol groups serve as reactive handles for chemical conjugation reactions. Sampathkumar et al. further demonstrate that thiol groups displayed on sialic acid residues can react with maleimide-containing reagents to form stable thioether linkages. Thus, Sampathkumar et al. teach that thiol-functionalized sialic acid derivative provide a useful reactive functionality for bioconjugation. One of ordinary skill in the art would have recognized that the reactive azide moiety used by Li et al. illustrates one example of a conjugation handle that may be introduced through a modified sialic acid donor, and that other known reactive handles suitable for bioconjugation, such as thiol groups taught by Sampathkumar et al., may be used to enable attachment of effector moiety. Therefore, substituting azide-functionalized sialic acid as taught by Li et la. with a thiol-functionalized sialic acid in view of Sampathkumar et al. would have demonstrated the use of one known conjugation-enabling functional group in place of another to obtain predictable results in conjugation reactions.
Applicant further argues that none of the cited references provides roadmap for generating a thiol-bearing CMP-sialic acid donor or for ensuring its enzymatic transfer and the conclusion of predictable results is unsupported. In response to 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., the thiol-bearing CMP-sialic acid generation) are not recited in the rejected claim(s). 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).
Regarding Chen et al., Applicant argues that Chen et al. fails to cure the deficiencies of Li et al. and Sampathkumar et al. because Chen et al. do not teach or suggest any of the missing steps and supplying only an Fc mutation does not fill the gaps regarding thiol-CMP donor, sialyltransferase-mediated installation, or thioether formation via that installed thiol. However, this argument is not persuasive. Chen et al. is not relied upon to remedy the glycan remodeling and the conjugation steps. As discussed above, Li et al. and Sampathkumar et al. teach the enzymatic installation of modified sialic acid residues on antibody glycans and the use of thiol functional groups for subsequent conjugation chemistry forming thioether linkages. Chen et al., instead, is relied upon for teaching antibodies comprising Fc mutations including S298N/T299A/Y300S. Thus, Chen et al. provide the additional teaching of the claimed antibody mutation, while the remaining process steps are taught or suggested by Li et al. and Sampathkumar et al. The combination of Li et al., Sampathkumar et al., and Chen et al. renders the claims obvious.
Regarding claims 43 – 50, Applicant argues that the claims are non-obvious for the reasons discussed above. The arguments are not persuasive and they have been addressed above.
Conclusion
No claim is found to be allowable.
Applicant's amendment necessitated the maintained / modified / 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.
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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693