DETAILED ACTION
Applicant’s amendment submitted on 7/14/2025 and 1/30/2026 are acknowledged. In the amendment filed 7/14/2025, claims 1-3, 7, and 17 were amended and Claims 10-11 and 15-16 were canceled. In the amendment filed 1/30/2026, claims 1 and 14 are currently amended and Claims 18-19 are newly added.
Claims 1-9, 12-14, and 17-19 are pending and the subject of this office action.
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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/31/2025 has been entered.
Priority
The instant application claims foreign priority to JP2021-061693 filed 3/31/2021 and a receipt of a certified copy of that document is acknowledged. However, no English translation of the foreign priority document has been provided to perfect priority, therefore the effective filing date of the instant claims is considered to be the filing date of the international application, 3/31/2022. See 37 CFR 1.55.
Response to Amendment
Applicant’s amendment to claim 1 overcomes the 35 U.S.C. 112(a) new matter rejection of claims 1-9 and 12-17 as previously set forth in the Final Rejection mailed on 5/12/2025. Accordingly, the rejection is withdrawn.
Claim Objections
Claim 2 is objected to because of the following informalities:
Claim 2 recites “glycan homogenized” in line 3 and should instead recite “glycan-homogenized” for consistency within the claims.
Appropriate correction is required.
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:
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 1-9, 12, 14, 17, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Manabe et al. (Bioconjugate Chem., 2019, Vol. 30, p.1343-1355; of record in the IDS filed 12/28/2023).
Regarding claims 1-3, 9 and 19, Manabe teaches enzymatic preparation methods of a homogeneous glycan-linked antibody-drug conjugate via glycan remodeling using endo-β-N-acetlyglucosaminidase mutants and glycan oxazoline (see Abstract, Fig. 1, paragraph bridging p.1345-1346, and p.1349, paragraph bridging left and right columns, right column, 1st paragraph). Manabe performs the method using the endo-β-N-acetlyglucosaminidase mutant EndoS D233Q, which the originally-filed specification in paragraph [0020] discloses corresponds to SEQ ID NO: 11 - reading on element (d) in claim 3, and the auristatin drug monomethyl auristatin E (MMAE) – reading on claim 9 (see Fig. 1 and p.1349, paragraph bridging left and right columns, right column, 1st paragraph). The Manabe antibody-drug conjugation method arrives at the same antibody-drug conjugate produced by the claimed method. The Manabe antibody-drug conjugate taught by Manabe comprises a 12 unit PEG (PEG12) and thus the linker of Manabe has a length greater than PEG4, reading on claim 19.
The difference between the method of conjugation taught in Manabe and the claimed invention is that in Manabe the drug is glycosylated after conjugating a glycan-homogenized antibody and a glycan having an oxazolinated end via a linker. It would have been obvious, however, to change the sequence of the reaction steps in the method disclosed by Manabe by performing the bio-orthogonal reaction as disclosed in Figure 1 of Manabe to produce a glycosylated drug with an oxazolinated reducing end via a linker prior to conjugation with a glycan-homogenized antibody, to arrive at the claimed invention. According to MPEP § 2143 (I)(F), which states that examples of rationales that may support a conclusion of obviousness include known work in one field of endeavor that may prompt variations of it for use in either the same field or a different field, based on design incentives or other market forces, if the variations are predictable to one of ordinary skill in the art, and MPEP § 2144.04 (IV)(C), which recites that changes in the selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results. Thus, it would have been obvious for one of ordinary skill in the art to rearrange the order of the steps for producing antibody-drug conjugates, as taught by Manabe, because they would be rearranging the order of performing process steps, in a predictable manner, and in the same field of endeavor for producing antibody-drug conjugates. One of ordinary skill in the art would have had a reasonable expectation of success because the Manabe method uses the same biochemical reactants (e.g. glycan-homogenized antibody and glycan oxazoline), the same technique of glycan engineering of antibodies (e.g. by modifying N-glycan at Asn297 of Fc that is located far from the antigen-binding region so as not to affect antigen-binding ability), and the same enzyme of SEQ ID NO: 11 – EndoS D233Q for site specific conjugation of oligosaccharides with Fc antibody. The method as modified above necessarily requires preparing a mixture of the glycan-homogenized antibody, the glycosylated drug, and EndoS, and incubating the mixture to conjugate the glycan-homogenized antibody and glycosylated drug, reading on claim 2 (see Manabe p.1352, right column, 1st paragraph).
Regarding claims 4 and 5, Manabe teaches the linker comprises a cathepsin-cleavable Val-Cit, peptide linker (see Figure 1 and p.1349, right column, 1st paragraph).
Regarding claims 6-8, the linker disclosed in Figure 1 of Manabe as depicted below follows the -E-D-C-B-A- formula of claim 6, wherein A is a single bond that is bound to the glycan of the antibody, B is the second compound of Formula 2 as depicted in claim 8 (also depicted as the final compound of Formula I in claim 7), C is under the formula -C(O)-(CH2)n=12-C(O)-NH-(CH2CH2O)n=1-(CH2)n=2-C(O)-, D is the peptides Val-Cit, and E is an aminobenzylalcohol bound to MMAE (see Figure 1). While C varies in that n1 is equal to 12 and is not 1 to 6 as claimed, this is not a critical aspect of the linker as Manabe states PEG, which corresponds to this part of the formula, is added to enhance pharmacodynamics of the linker. Thus, an ordinarily skilled artisan could have optimized the units of PEG in the structure to arrive within that of the claimed invention and yield predictable results.
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Regarding claim 12, the linker has an alkyl group between B and C as shown in the annotated figure above.
Regarding claims 14 and 17, the antibody drug conjugate is prepared in a solution comprising DMSO (see p.1352, right column, 1st paragraph). The glycosylated drug is expected to be dissolved in the solution in the methods according to claims 1 and 15 as obviated in the rejections above.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Manabe et al. (Bioconjugate Chem., 2019, Vol. 30, p.1343-1355; of record in the IDS filed 12/28/2023), as applied to claims 1-9, 12, 14, 17, and 19 above, and further in view of Han (WO2020/146541; of record).
Regarding claim 13, Manabe teaches A is a single bond in the linker.
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Manabe does not teach A is –(CH2CH2O)m1-(CH2)m2-, and m1 is 4 to 12.
Han teaches novel traceless linkers for conjugation to proteins/antibodies (see paragraphs [0002] and [0006]). Han teaches moieties of the following structures which correspond to B of the linker of the claimed invention:
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(see paragraphs [0059], [00257], and [00287]).
Han specifically teaches a structure in which A of the presently claimed invention has a –(CH2CH2O)m1=4-(CH2)m2=2-SO3 group attached:
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(see Table 3d, Q1L1-P1).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have substituted the –(CH2CH2O)m1=4-(CH2)m2=2-SO3 group, as taught by Han, for the single bond A, as taught by Manabe, to arrive at the claimed invention. One of ordinary skill in the art would have been modifying the linker of Manabe according to known teachings in the field of linkers for antibodies and choosing from a finite list of modifications present in Han, yielding predictable results. Therefore, claim 13 is prima facie obvious.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Manabe et al. (Bioconjugate Chem., 2019, Vol. 30, p.1343-1355; of record in the IDS filed 12/28/2023), as applied to claims 1-9, 12, 14, 17, and 19 above, and further in view of Tong et al. (Biochemistry, 2018, Vol. 57(35), pp.5239-5246).
Claim 1 is obvious over Manabe as set forth in the rejection above.
Regarding claim 18, Manabe teaches the conjugation step is done at 25 °C using EndoS D233Q (see Fig. 1, p.1349, paragraph bridging left and right columns, right column, 1st paragraph, and p.1352, right column, 1st paragraph).
Manabe does not teach the conjugation step is done at 30-37 °C.
Tong teaches EndoS D233Q has hydrolytic activity and transglycosylation activity at 30 °C (see Table 1 and p.5241, paragraph bridging left and right columns).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have performed the conjugation reaction in Manabe at 30 °C, as taught by Tong, to arrive at the claimed invention. One of ordinary skill in the art would have been applying known incubation and conjugation temperature parameters for successful hydrolytic activity and transglycosylation activity, yielding predictable results. Thus, claim 18 is prima facie obvious.
Response to Arguments
The Declaration under 37 CFR 1.132 filed 1/30/2026 is insufficient to overcome the rejection of claims 1-9, 12-14, and 17-19 based upon 35 U.S.C. 103 as set forth in the last Office action because:
In statement 5 of the Declaration, Declarant disagrees with the Examiner’s position that a person skilled in the art would find the presently claimed invention obvious in view of Manabe. In statement 8 of the Declaration, Declarant describes that performing the method for producing an antibody-drug conjugate by adding a sugar-conjugated drug to the antibody, rather than a simple sugar chain as disclosed in Manabe, results in a reduction in side reactions that would not have been expected by a person of ordinary skill in the art. In statement 9 of the Declaration, Declarant explains that an experiment was conducted to evaluate the generation of byproducts in Manabe’s methods as compared to those of the claimed invention. In statements 13 and 14 of the Declaration, Declarant describes that no byproducts were observed after 6 hours in the experiment conducted according to the method of the claimed invention while Manabe reports byproducts. In statement 15 of the Declaration, Declarant argues the instant invention involves adding a sugar-conjugated drug to the antibody, whereas Manabe demonstrates adding a simple sugar chain to the antibody. Declarant further argues this difference results in the unexpected reduction of side reactions and modifying Manabe would result in a decrease in non-enzymatic reaction efficiency compared to the present invention. In statement 16 of the Declaration, Declarant discloses that the experiment used the antibody trastuzumab while Manabe used mogamulizumab. Declarant further declares that since both antibodies have the same amount of lysine residues, their reactivity to side reactions at lysine residues is considered equivalent. The Declaration is insufficient to overcome the rejection of record.
The claimed invention broadly embraces the conjugation of any glycan-homogenized antibody to any glycosylated drug using any endo-β-N-acetylglucosaminidase mutant enzyme. The Declarant only demonstrates the reduction of side reactions and formation of byproducts in a single species, i.e., conjugation of trastuzumab-GlcNAc and MMAE-PEG3-conjugated oligosaccharide, in a non-enzymatic method, which is not commensurate in scope with the claimed invention. The reduction of byproducts demonstrated in the single species cannot reasonably be extrapolated to the genus of antibody-drug conjugates produced by the claimed invention. Therefore, the Declaration is not sufficient to overcome the 35 U.S.C. 103 rejection of record.
Applicant's arguments filed 1/30/2026 have been fully considered but they are not persuasive.
In Applicant’s Remarks, Applicant reiterates the arguments with respect to the unexpected results as presented in the Declaration, which are addressed above.
Conclusion
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/J.P.S./ Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651