DETAILED 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 .
Claim Status
Claims 1-86 and 88-226 have been cancelled; claim 87 has been amended; and claims 227-243 have been newly added, as requested in the amendment filed on 07/22/2026. Following the amendment, claims 87 and 227-243 are pending in the instant application.
New claims 234-235 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species of invention in the Response filed 02/09/2026, there being no allowable generic or linking claim.
Claims 87, 227-233, and 236-243 are under examination in the instant office action.
Priority - Updated
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Furthermore, it is noted that the certified copy of the foreign priority document is in English, and therefore that claim to foreign priority has been perfected.
Claims 87 and 227-243 have an effective filing date of August 21, 2020 corresponding to PCT/CN2020/110607.
Drawings - Objection Withdrawn
Applicant has submitted replacement drawing sheets, wherein the text/labels are clearer. As such, the objection to the drawings is withdrawn.
Specification - Objection Withdrawn
Applicant has submitted a substitute abstract, wherein the substitute abstract does not comprise legal phraseology. As such, the objection to the specification is withdrawn.
Claim Objections - Withdrawn
Claim 87 was objected to for a minor informality. Applicant has amended the language of claim 87, and as such the objection to claim 87 is withdrawn.
Claims 122, 129, 152, and 154 were objected to for a minor informality. Claims 122, 129, 152, and 154 have been canceled, rendering their objection moot. As such, the objection to claims 122, 129, 152, and 154 is withdrawn.
Claim Rejections - 35 USC § 112 - Withdrawn
Claims 87, 98, 122, 129, 152, 154, 171, 174, 179, 181, 194, and 199 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite. Claims 98, 122, 129, 152, 154, 171, 174, 179, 181, 194, and 199 have been canceled, rendering their rejection moot. Claim 87 has been amended such that Q is now explicitly defined. As such, the rejection of claims 87, 98, 122, 129, 152, 154, 171, 174, 179, 181, 194, and 199 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
Claim Rejections - 35 USC § 102 - Withdrawn
Claims 87 and 179 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by non-patent literature by Wu et. al. (Glycobiology, May 2020, 30(12), 970-980; previously cited on PTO-892; herein after referred to as "Wu").
It is noted that claim 179 has been canceled, rendering its rejection moot. Furthermore, Applicant has amended claim 87 such that the claim explicitly defines the claimed protein conjugate by structure, wherein such a structure is not taught by Wu. As such, the rejection of claims 87 and 179 under 35 U.S.C. 102(a)(1) as being anticipated by Wu is withdrawn.
Claim Rejections - 35 USC § 103 - Withdrawn
Claims 87, 98, 122, 129, 179, 181, and 194 were rejected under 35 U.S.C. 103 as being unpatentable over Wu et. al. (Glycobiology, May 2020, 30(12), 970-980; previously cited on PTO-892; herein after referred to as "Wu") in view of non-patent literature by Remon van Geel et. al. (Bioconjugate Chem., 2015, 26, 2233-2242; previously cited on PTO-892; herein after referred to as “Geel”), non-patent literature by Boeggeman et. al. (Bioconjugate Chem., 2009, 20, 1228-1236; previously cited on PTO-892; herein after referred to as "Boeggeman"), and non-patent literature by Boune et. al. (Antibodies, June 2020, 9(22), 1-20; previously cited on PTO-892; herein after referred to as “Boune”).
Claims 98, 122, 129, 179, 181, and 194 have been canceled, rendering their rejection moot. As such, and in view of the instant claim amendments, the rejection of claims 87, 98, 122, 129, 179, 181, and 194 under 35 U.S.C. 103 as being unpatentable over Wu, Geel, Boeggman, and Boune is withdrawn.
Claims 152, 154, 167, 171, and 174 were rejected under 35 U.S.C. 103 as being unpatentable over Wu et. al. (Glycobiology, May 2020, 30(12), 970-980; previously cited on PTO-892; herein after referred to as "Wu"), non-patent literature by Remon van Geel et. al. (Bioconjugate Chem., 2015, 26, 2233-2242; previously cited on PTO-892; herein after referred to as “Geel”), non-patent literature by Boeggeman et. al. (Bioconjugate Chem., 2009, 20, 1228-1236; previously cited on PTO-892; herein after referred to as "Boeggeman"), and non-patent literature by Boune et. al. (Antibodies, June 2020, 9(22), 1-20; previously cited on PTO-892; herein after referred to as “Boune”) in further view of non-patent literature by Srivastava et. al. (The Journal of Biological Chemistry, 1992, 267(31), 22356-22361; previously cited on PTO-892; herein after referred to as “Srivastava”) and WO 2016/192528 A1 (previously cited on PTO-892; herein after referred to as “Han”).
Claims 152, 154, 167, 171, and 174 have been canceled, rendering their rejection moot. As such, the rejection of claims 152, 154, 167, 171, and 174 under 35 U.S.C. 103 as being unpatentable over Wu, Geel, Boeggman, Boune, Srivastava, and Han is withdrawn.
Claim 199 is rejected under 35 U.S.C. 103 as being unpatentable over Wu et. al. (Glycobiology, May 2020, 30(12), 970-980; previously cited on PTO-892; herein after referred to as "Wu"), non-patent literature by Remon van Geel et. al. (Bioconjugate Chem., 2015, 26, 2233-2242; previously cited on PTO-892; herein after referred to as “Geel”), non-patent literature by Boeggeman et. al. (Bioconjugate Chem., 2009, 20, 1228-1236; previously cited on PTO-892; herein after referred to as "Boeggeman"), and non-patent literature by Boune et. al. (Antibodies, June 2020, 9(22), 1-20; previously cited on PTO-892; herein after referred to as “Boune”) in further view of non-patent literature by Vainauskas et. al. (Scientific Report, 2018, 8(9504), 1-8; previously cited on PTO-892; herein after referred to as “Vainauskas”).
Claim 199 has been canceled, rendering its rejection moot. As such, the rejection of claim 199 under 35 U.S.C. 103 as being unpatentable over Wu, Geel, Boeggman, Boune, and Vainauskas is withdrawn.
Double Patenting
Claims 87, 98, 122, 129, 179, 181, 194, and 199 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20, 22, 25, 40, 43, 50, 69, 70-71, and 73-75 of copending Application No. 18/697,675 (herein after referred to as "reference patent").
Claims 98, 122, 129, 179, 181, 194, and 199 have been canceled, rendering their rejection moot. Furthermore, with the amendment of claim 87 it is noted that the reference application no longer reads directly on the instant claims. As such, the rejection of claims 87, 98, 122, 129, 179, 181, 194, and 199 on the ground of nonstatutory double patenting over copending App. No. 18/697,675 is withdrawn.
Claims 98, 122, 129, 154, 167, 171, 174, 179, 181, 194, and 199 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20, 22, 25, 40, 43, 50, 69, 70-71, and 73-75 of copending Application No. 18/697,675 (herein after referred to as "reference patent") in view of non-patent literature by Remon van Geel et. al. (Bioconjugate Chem., 2015, 26, 2233-2242; herein after referred to as “Geel”), non-patent literature by Srivastava et. al. (The Journal of Biological Chemistry, 1992, 267(31), 22356-22361; herein after referred to as “Srivastava”) and WO 2016/192528 A1 (herein after referred to as “Han”).
Claims 98, 122, 129, 154, 167, 171, 174, 179, 181, 194, and 199 have been canceled, rendering their rejection moot. As such, the rejection of claims 98, 122, 129, 154, 167, 171, 174, 179, 181, 194, and 199 on the ground of nonstatutory double patenting over copending App. No. 18/697,675 in view of Srivastava and Han is withdrawn.
Claim Interpretation
With regard to claim 243, it is noted that the recitation of “the fucosyltransferase comprises an amino acid sequence as set forth in GenBank Accession No, AAD07710.1” is being interpreted as open sequence language, wherein in order to meet the limitation a reference fucosyltransferase need only comprise two consecutive amino acid residues comprised within the full-length sequence of GenBank Accession No, AAD07710.1 to meet the limitation; a reference sequence may be mutated and/or truncated in any way relative to GenBank Accession No, AAD07710.1 so long as the reference fuscosyltransferase comprises two consecutive amino acid residues comprised within the full-length sequence of GenBank Accession No, AAD07710.1.
Claim Objections - New as Necessitated by Amendment
Claim 243 is objected to because of the improper recitation of a Genbank Accession No. An incorporation by reference of essential material to an unpublished U.S. patent application, a foreign application or patent, or to a publication is improper under 37 CFR 1.57(d). See MPEP 608.01(p)(I)(A)(2).
Claim Rejections - 35 USC § 112 - New as Necessitated by Amendment
Claim 243 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
Claim 243 is drawn to a fucosyltransferase comprising an amino acid sequence as set forth in GenBank Accession No. AAD07710.1, or a functional variant or fragment thereof. Thus, the claim identifies the fucosyltransferase by function (transfer of a fucosyl group), and a partial sequence structure that comprises an amino acid sequence as set forth in GenBank Accession No. AAD07710.1 or a functional variant or fragment thereof wherein the sequence corresponding to the recited GenBank Accession No. may be mutated and/or truncated in any possible way so long as the sequence comprises two or more consecutive amino acid residues from the recited GenBank Accession No. and function is maintained. Thus, the claim encompasses a vast genus of fucosyltransferase variants.
The instant specification discloses five structurally distinct, full-length fucosyltransferases derived Helicobacter pylori: GenBank Accession No. AF008596.1, GenBank Accession No. AAD07447.1, GenBank Accession No. AAD07710.1, GenBank Accession No. AAF35291.2, or GenBank Accession No. AAB93985.1 (see Page 13).
Thus, the instant specification discloses five structurally distinct fucosyltransferases defined by their full-length sequences. The specification fails to disclose any sequence variants and/or fragments of the above-recited fucosyltransferases having as few as two consecutive amino acids as set forth in the Genbank Accession No. amino acid sequences, wherein such variants and/or fragments retain function.
To provide adequate written description and evidence of possession of the claimed antibody genus, the instant specification can structurally describe representative fuscosyltransferase variants and/or fragments that retain function, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
In this case, the only factor present in the claims is a recitation of function and partial sequence structure as stated above. The instant specification fails to describe structural features common to the members of the antibody genus, which features constitute a substantial portion of the genus because the instant specification fails to disclose representative fucosyltransferase variant and/or fragment sequences that function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the enzyme does, rather than what it is. Other than for the fucosyltransferases identified above, the specification fails to provide the structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of fucosyltransferase sequence variants and/or fragments for the genus of fucosyltransferases that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to make/use the claimed genus of fucosyltransferases.
The claims broadly encompass any sequence variant and/or fragment having as few as two consecutive amino acids from GenBank Accession No. AAD07710.1 that retains function. Applicants have not established any reasonable structure-function correlation with regards to the sequences in the recited fucosyltransferase sequence that can be altered and still maintain function. The skilled artisan would not have been in possession of the vast repertoire of fucosyltransferases encompassed by the claimed invention. One could not reasonably or predictably extrapolate the structure of a single tfucosyltransferase comprising an amino acid sequence as set forth in GenBank Accession No. AAD07710. to the structure of any variants and/or fragments required to function as broadly claimed. Therefore, one could not readily envision members of the broadly claimed genus.
Although Applicants may argue that it is possible to screen for fucosyltransferase variants and/or fragments that function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future fucosyltransferases yet to be discovered that may function as claimed.
Given the lack of representative examples to support the full scope of the claimed variant antibodies, and lack of reasonable structure-function correlation with regards to the unknown variable sequence(s) in the recited fucosyltransferase that confers function, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of a fucosyltransferase comprising an amino acid sequence as set forth in GenBank Accession No. AAD07710.1, or a functional variant or fragment thereof, that is required to practice the claimed invention.
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 87, 227-233, and 240-243 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 broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 87 recites: (i) the broad recitation of “the Fuc*’” at line 9, and the narrower recitation at line 12 wherein Fuc*’ is defined by a particular structure; (ii) the broad recitation of “the Q-Fuc*’ at line 11, and the narrower recitation at lines 19-25 wherein Q-Fuc*’ is defined by particular structural elements; and (iii) the broad recitation of “the protein” at line 18, and the narrower recitation at lines 27-37 wherein the protein is defined by specific structure(s). The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Claims 227-233 and 240-243 are included in the rejection as they depend from claim 87 and do not clarify the intended claim scope with regard to all of the broad/narrow limitations recited in claim 87.
Claim Rejections - 35 USC § 103 - New as Necessitated by Amendment
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 87, 227-233, and 236-243 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et. al. (Glycobiology, May 2020, 30(12), 970-980; previously cited on PTO-892; herein after referred to as "Wu") in view of non-patent literature by Vainauskas et. al. (Scientific Report, 2018, 8(9504), 1-8; previously cited on PTO-892; herein after referred to as “Vainauskas”), non-patent literature by Remon van Geel et. al. (Bioconjugate Chem., 2015, 26, 2233-2242; previously cited on PTO-892; herein after referred to as “Geel”), non-patent literature by Boeggeman et. al. (Bioconjugate Chem., 2009, 20, 1228-1236; previously cited on PTO-892; herein after referred to as "Boeggeman"), non-patent literature by Boune et. al. (Antibodies, June 2020, 9(22), 1-20; previously cited on PTO-892; herein after referred to as “Boune”), non-patent literature by Li et. al. (ACS Cent. Sci., 2018, 4, 1633-1641; herein after referred to as “Li”), and WO 2016/192528 A1 (previously cited on PTO-892; herein after referred to as “Han”).
Wu teaches the detection of glycans on glycoproteins and in their free forms via enzymatic incorporation of fluorophore-conjugated fucose using FUT2, FUT6, FUT7, FUT8, and FUT9 (i.e., fucosyltransferases); the detection of substrate glycans of these enzymes are detected on, for example, therapeutic antibodies (Abstract). Fluorophore-conjugated GDP-fucoses were prepared by incubating equivalent GDP-Azido-Fucose (GDP-N3-Fuc) and alkyne-conjugated fluorophores via copper (I)-catalyzed azide-alkyne cycloaddition (Page 979, Column 1, Paragraph 5); for a typical labeling reaction, 1-5 μg of a target protein (e.g., therapeutic antibody) was mixed with 0.2 nmol fluorophore-conjugated GDP-fucose and 0.2 μg of a fucosyltransferase in 30 μL 25 mM Tris pH 7.5, 10 mM MnCl2 (Page 979, Column 1, Paragraph 6). Figure 3 is drawn to probing fucosylation on antibodies Cantuzumab, and anti-MUC1 therapeutic antibody, and NIST antibodies by FUT8 and FUT9; it is specifically noted that Figure 3A demonstrates that FUT9 may be utilized to enzymatically conjugate a fluorophore via fucose to terminal -GlcNAc-Gal- (Figure 3A reproduced below, pertinent structures indicated
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As such, Wu discloses a method for preparing a protein conjugate comprising the step of contacting a fucose derivative donor (i.e., fluorophore-conjugated GDP-fucose; reading on Q-Fuc*’ generally) with a protein (e.g., antibody comprising an antigen binding domain and an Fc domain) wherein said protein comprises an oligosaccharide of the structure -GlcNAc(Fuc)b-Gal in the presence of a catalyst (i.e., a fucosyltransferase) to obtain a protein conjugate comprising the structure presented below:
wherein said GlcNAc is indirectly linked to an amino acid of said protein, Gal is galactose, (Fuc) is fucose, b is 0, Fuc*’ comprises fucose and a molecule of interest (e.g., a fluorophore). Furthermore, it is noted that according to the conjugate structures of Wu presented in Figure 3A above, the terminal Gal is linked to the terminal GlcNAc through a Galβ1,4GlcNAc linkage and the core fucose (at position α6 above) is linked to the core GlcNAc though an α1,6 linkage. Thus, Wu demonstrates the fucosyltransferases are useful in the conjugation of molecules of interest to antibodies at accessible (i.e., terminal; b =0) -GlcNAc(Fuc)b-Gal structures in the Fc domain of the antibody.
However, it is noted that Wu does not disclose (i) protein conjugates wherein Q-Fuc*’ is conjugated to a core GlcNAc (i.e., GlcNAc directly linked to an Asn residue of said protein), nor does Wu suggest conjugation to an antibody glycogengineered to comprise a core
-GlcNAc(Fuc)b-Gal, specifically wherein the core fucose has been removed with a fucosidase. These deficiencies are remedied by Vainauskas, Geel, Boeggeman, and Boune.
Vainauskas discloses the identification, cloning, expression and biochemical characterization of an α-fucosidase from Omnitrophica bacterium (termed fucosidase O); the authors show that fucosidase O can efficiently remove α1-6- and α1-3-linked core fucose from N-glycans and demonstrate that fucosidase O is able to efficiently hydrolyze core α1-6-linked fucose from N-glycans labeled with any of the existing NHS-carbamate activated fluorescent dyes (Abstract). Thus, Vainauskas discloses a core-α1,6 fucosidase capable of removing α1,6-linked core fucose.
Geel teaches that the vast majority of ADCs in the clinic are based on conjugation of payload to naturally available amino acid side-chains (lysine, cysteine), leading to a stochastic distribution of drug-antibody ratio (DAR) between 0 and 8 (or even higher), and that it has been demonstrated that random conjugation has a negative impact on efficacy, and as a consequence the therapeutic index remains low (Page 2233, Column 1, First Paragraph). Two main strategies can enhance the therapeutic index of a given mAb-payload combination: (a) site-specific conjugation and (b) enhancing stability; site-specific conjugation is typically achieved by engineering of a specific amino acid (or sequence) into an antibody, serving as the anchor point for payload attachment (Page 2233). However, re-engineering of protein sequence and site optimization is a laborious exercise and expression yields may be compromised (typically ∼50% yield reduction for a cysteine-engineered mAb, while expression yields for genetic encoding of an unnatural amino acid typically reach 1 g/L maximally), which has a significant impact on the cost of goods of the ADC (Page 2233, Column 2, First Partial Paragraph). Additionally, it has been amply demonstrated that ADCs obtained by conjugation to cysteine side chains often display limited stability in circulation, leading to premature disconnection of the cytotoxic payload before the tumor site is reached (Id.). The authors report a unique and robust chemoenzymatic technology for efficient mAb-to-ADC conversion by anchoring a payload to the antibody’s glycan at precisely one azide, a unique anchor point is introduced for copper-free click conjugation with a payload wherein the versatility of this technology, termed GlycoConnect, is demonstrated across a range of different mAb isotypes and linker-payload combinations both in vitro and in vivo; seamless upscaling of GlycoConnect corroborated manufacturability, whereas the superiority of the native glycosylation site for conjugation was demonstrated through in vivo efficacy assessment of a series of ADCs based on glycosylation mutants (Pages 2233-2234). The authors disclose a chemoenzymatic ligation strategy to generate DAR2 ADCs, based on the strategy depicted in Figure 1 (Fig. 1A reproduced below): (1) trimming of all glycan isoforms (complex, hybrid, high-mannose) with an endoglycosidase, thereby liberating the core GlcNAc; (2) enzymatic transfer of a galactose residue harboring a reactivity-enhanced azide to reduce conjugation stoichiometry and incubation time; and (3) copper-free click conjugation with bicyclononyne (BCN), a cyclooctyne with minimal
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lipophilicity to reduce aggregation.
Specifically with regard to the transfer of a galactose residue to the core GlcNAc, it is noted that incubation of trimmed trastuzumab (II) with GalNAz 2 (0.4 mM) in the presence of only 1% (w/w) of GalT(Y289L) and MnCl2 (10 mM) led to complete labeling after overnight incubation (Page 2235, Column 1, Galactosyl Transferase). The conditions and conjugation efficiencies of azido-modified trastuzumab variants with various BCN-linker-payload constructs are provided in Table 1 (see Page 2236). Thus, Geel discloses glycan trimming via endoglycosidase to make the core GlcNAc available for modification (i.e., the GlcNAc directly linked to Asn297), after which a glycosyltransferase may be used to attach an azido-modified sugar (e.g., UDP-GalNAz) that can be reacted with BCN to conjugate various linker-payloads to said azido-modified galactose residue. It is further noted that the payloads (i.e., corresponding to MOI’ of the instant claims) are biologically and/or pharmaceutically active (i.e., anti-tumor agents) and comprise various spacer/linker components (e.g., PEG groups, cleavable Val-Cit dipeptide, and/or self-immolative PABA). The advantage of glycan-remodeled ADCs versus randomly labeled ADCs becomes apparent in vivo; PDX mice with an average tumor size of 100 mm3 were intravenously injected with one of three different GlycoConnect ADCs (cleavable/noncleavable with maytansine or cleavable with MMAF) and compared to Kadcyla at 9 mg/kg (single dose bolus injection), followed by twice weekly tumor sizes measurements (Figure 5) (Page 2237, Column 1, First Full Paragraph). The results were as follows: (i) during the first week, all groups showed significant tumor shrinkage or even complete regression; (ii) after 1 week, tumor sizes gradually increased for mice treated with Kadcyla but not for any of the GlycoConnect ADCs; (iii) only after approximately 3 weeks, reappearance and regrowth of tumors became apparent for mice treated with trastuzumab-vc-PABA-MMAF, while both ADCs based on maytansine (cleavable or noncleavable) showed complete tumor regression for the whole length of the study (60 days) (Id.). This study clearly demonstrates the superiority of GlycoConnect conjugation technology versus a randomly conjugated ADC based on the same components, wherein the latter observation becomes particularly interesting in view of the higher drug loading of Kadcyla (average DAR3.5) versus GlycoConnect ADCs (DAR2; the modified N297 site of each heavy chain in the antibody is conjugated to a drug-linker) (Id.). The authors also note that no difference in blood clearance was observed (Page 2237, Column 1, Second Full Paragraph). Thus, the resulting ADCs were found to be homogeneous and highly hydrolytically stable, while displaying negligible aggregation, and benchmark in vitro and in vivo efficacy studies against the marketed product Kadcyla, based on the same antibody and payload components, generated strong biological data in favor of the GlycoConnect ADCs, despite the lower DAR (Page 2238, Column 2). GlycoConnect technology is readily applicable to any off-the-shelf monoclonal antibody (turnaround in <1 week), while delivering site-specific, stable, and highly efficacious ADCs, and therefore GlycoConnect shows high promise as the next generation ADC generation technology for targeted therapy with improved therapeutic index (Id.). Thus, Geel discloses antibody modification at Asn297 via the core GlcNAc, wherein each antibody heavy chain is modified to comprise, generally, GlcNAc(Fuc)GalNAc-Azide which may be reacted with a cyclooctyne group (e.g., BCN) via ligation reaction with various payload-linkers (e.g., PEG groups, cleavable Val-Cit dipeptide, and/or self-immolative PABA).
Boeggeman discloses that the mutant β1,4Gal-T1-Y289L enzyme, in contrast to the wild-type enzyme β1,4Gal-T1, exhibits both β1,4Gal transferase and β1,4GalNAc transferase activities, and using chemoenzymatic methods, it was shown that the mutant enzyme can transfer the C2-keto-Gal from its UDP-derivative to the GlcNAc residue on the N-glycan chain of an asialo-agalacto IgG molecule (Page 1231, Column 2, Reglycosylation of G0 Glycoform of mAbs Using Either UDP-Gal or UDP-GalNAc as Sugar Donors). The authors investigated the transfer of UDP-sugars to the protein A purified G0 glycoform of Herceptin by the wildtype and a mutant β1,4-galactosyltransferse; Figure 3 shows the MALDI-TOF profile of the oligosaccharide after the transfer of galactose by the wild-type β1,4Gal-T1 (Figure 3A) and the transfer of N-acetylgalactosamine (Figure 3B) by the mutant enzyme β1,4Gal-T1-Y289L to the free GlcNAc residues on the G0 glycoforms of Herceptin (Figure 2D′) (Id.). Under the conditions of the study, the transfer of galactose and of GalNAc to both GlcNAc residues on each arm of the N-linked structure is observed (Page 1232, Column 1, First Partial Paragraph). Thus, Boeggeman demonstrates that UDP-galactose derivatives may be used in reactions with galactosyltransferases to add galactose (or a derivative thereof) to GlcNAc.
Boune teaches that recombinant mAbs and the human endogenous IgG Fc region have biantennary complex oligosaccharides with either zero, one, or two terminal galactose moieties, which are the three major glycoforms (G0, G1, or G2); the terminal Gal residue has been shown to play an important role in CDC activity of IgG (Page 9, Section 4.2). With regard to IgG1 proteins specifically, it is noted that: (i) by degalactosylation of Rituxan and generating mAbs with various Gal content, it has been demonstrated that CDC activities and antibody binding to C1q increase as Gal content increases; (ii) lower affinity to C1q is due to hydrophobic and hydrophilic interactions between terminal Gal residue and protein, which alter the conformation of the CH2 domain; (iii) galactosylation can induce a positive impact on the binding affinity of the IgG1 to FcRIIa and FcRIIIa receptors and ADCC activity; and (iv) Fc-galactosylation of rituximab enhances CDC activities compared to the degalactosylated glycoform and improvement of C1q binding eventually leads to tumor cell lysis (Id.). Thus, Boune indicates that terminal Gal may promote/enhance critical functions of therapeutic antibodies, specifically with regard to CDC and/or ADCC.
However, it is noted that none of the above-cited references teach/suggest using a α1,3-fucosyltransferase to conjugate a MOI’ comprising F and an active moiety selected from Y1 or P, wherein said Y1 is a functional group capable of participating in a ligation reaction and wherein said P is a pharmaceutically active substance, nor (iii) Q-Fuc*’ corresponding to Q-Fuc-(F)m-(L)n-Y1 or Q-Fuc-(F)m-(L)n-P, as structurally defined by claim 87, wherein Q-Fuc*’ corresponds to:
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These deficiencies are remedied by Li and Han.
Li discloses a chemoenzymatic approach that exploits a fucosyltransferase to transfer bio-macromolecules, such as an IgG antibody (MW∼ 150 KD), to the glycocalyx on the surfaces of live cells when the antibody is conjugated to the enzyme’s natural donor substrate GDP-Fucose (Abstract). To develop the enzyme-based glycan modification as a general method for cell-surface engineering, a practical and scalable approach for the preparation and transfer of nucleotide sugar donors equipped with new functional groups is required; the authors discovered that GDP-L-6-ethynylfucose (GF-Al) or GDP-L-6-azidofucose (GF-Az) produced in situ can be coupled directly with a wide variety of probes using the ligand accelerated copper(I) catalyzed alkyne−azide cycloaddition (CuAAC) (Figure 1C), wherein these probes include biotin, a fluorescent probe Cy3, a bioorthogonal reaction handle tetrazine (Tz), and a dye labeled (fluorescein amidite, FAM), single-strand DNA (ssDNA) (Supporting Information, Figure S1) (Page 1634, Column 2, First Paragraph). All reactions attained near quantitative yields (>90%), and the crude products were rendered biocompatible for direct transfer by α1,3 FucT onto the cell surface after quenching the reaction with the FDA-approved copper chelator bathocuproine sulfonate (BCS); compared to the conventional two-step labeling protocol, i.e., enzymatic transfer followed by cell-surface click chemistry, the one-step enzymatic labeling using the substrate of one-pot product was significantly more efficient and biocompatible (Page 1634-1635). The remarkable efficiency of fucosylation to transfer small-molecule probes with diverse structures to the cell surface combined with the previous known plasticity of mammalian sialyltransferases for protein PEGylation suggests the possibility that FucT may tolerate even larger molecules conjugated to the fucose C6 position; to assess this possibility, the authors conjugated GDP Fucose with monoclonal antibodies (mAbs, full-length IgG), the fastest growing class of protein drugs, wherein the bioorthogonal handle trans-cyclooctene (TCO) with a PEG linker was installed onto mAbs or their isotype controls via standard amine-coupling procedures and subsequently, mAbs bearing TCO moieties were reacted with GF-Az-Tz via the highly efficient inverse electron-demand Diels−Alder reaction (IEDDA) to generate GDP-Fucose-conjugated IgG molecules (GF-IgG) (Figure 2A) (Page 1635, Column 2, Furst Paragraph). The one-pot product of GDP-Fucose-conjugated rat IgG (GF-rIgG) was then incubated with Lec2 CHO cells that express abundant terminal LacNAc units in the presence of FucT (Figure 2B); remarkably, the signal of rIgG conjugated onto the cell surface was detectable after a 2-min incubation with FucT (60 mU) and GF-rIgG (0.1 mg/mL) (Figure 2C) and the labeling efficiency was concentration-dependent (GF rIgG), which reached saturation at 0.1 mg/mL during a 30-min reaction course (Page 1636, Column 1, First Paragraph). ACCs can also be constructed using other human fucosyltransferases, such as FucT 6 and 9 (Supporting Information, Figure S10A), and sialyltransferases (Supporting Information, Figure S10B) despite with much lower efficiency compared with H. pylori 26695 α1,3FucT (Page 1637, Column 1, First Paragraph). It is specifically noted that H. pylori 26695 α1,3FucT corresponds to GenBank Accession No. AAD07710.
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Han discloses trimaleimide linkers and uses thereof are disclosed. The trimaleimide linkers can be applied for preparation of antibody-drug conjugate as shown by formula I: L- (T-A-D)n wherein L is an antibody, antibody fragment or protein; T is a trimaleimide linker; A is a cleavable linker group or a noncleavable linker; D is a drug; n is an integer ranging from 1 to 8 (Abstract). Exemplary trimaleimide linkers are shown on Pages 3-5, wherein one such linker is designated as trimaleimide linker No. 3, shown below:
Han discloses that enzyme-liable linkers are an approach to achieve better control of drug release and self-immolative linker undergo self-structural rearrangement to release active drug when the cleavable/enzyme-liable linkers are cleaved, and provides the below cleavable linker structure comprising a maleimide group:
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Example 11 of Han discloses the preparation of a drug-linker comprising reacting trimaleimide linker No. 5 with Val-Cit-PAB-MMAE:
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Thus, if the trimaleimide linker No. 3 were reacted in a similar manner, one of ordinary skill in the art would recognize that the structure below could be achieved:
It is specifically noted that above structure, absent the trimaleimide group, comprises the instantly elected -(F)m-(L)n-P structures wherein m and n are both 1, P is MMAE, and the structures of F and L are as presented above.
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the instant invention was filed to make a protein conjugate wherein the method of making the protein conjugate comprises the step of contacting a fucose derivative donor (i.e., Q-Fuc*’) with a protein (e.g., antibody comprising an antigen binding domain and an Fc domain) wherein said protein comprises an oligosaccharide of the structure -GlcNAc(Fuc)b-Gal in the presence of a catalyst (i.e., α1,3-fucosyltransferase) to obtain a protein conjugate comprising the structure
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presented below:
wherein: (i) said GlcNAc is directly or indirectly linked to an amino acid of said protein, Gal is galactose, (Fuc) is fucose, b is 0, Fuc*’ comprises fucose and a molecule of interest (e.g., an anti-tumor agent), and Q-Fuc*’ comprises said Fuc*’; (ii) the Gal is linked to the GlcNAc through a Galβ1,4GlcNAc linkage and (Fuc) is linked to the GlcNAc though an α1,6 linkage; (iii) said molecule of interest further comprises (a) an active moiety wherein said active moiety comprises P, wherein P is a biologically and/or pharmaceutically active substance (e.g., an anti-tumor agent); and (iv) wherein Q-Fuc*’ is of the formula Q-Fuc-(F)m-(L)n-Y1 or Q-Fuc-(F)m-(L)n-P wherein F is a connector, L is a linker, and m and n are each independently 0 or 1.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, it is noted that:
(1) Wu discloses a method for preparing a protein conjugate comprising the step of contacting a fucose derivative donor with a protein (e.g., antibody comprising an antigen binding domain and an Fc domain) wherein said protein comprises an oligosaccharide of the structure
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-GlcNAc(Fuc)b-Gal in the presence of a catalyst (i.e., a fucosyltransferase) to obtain a protein conjugate comprising the structure presented below:
wherein said GlcNAc is directly or indirectly linked to an amino acid of said protein, Gal is galactose, (Fuc) is fucose, b is 0, Fuc*’ comprises fucose and a molecule of interest (e.g., a fluorophore), and Q-Fuc*’ comprises said Fuc*’. Furthermore, it is noted that according to the conjugate structures of Wu presented in Figure 3A above, the terminal Gal is linked to the terminal GlcNAc through a Galβ1,4GlcNAc linkage and the core fucose (at position α6 above) is linked to the core GlcNAc though an α1,6 linkage; furthermore the fucosyltransferases specifically transfer the fucose derivative donor group to GlcNAc(Fuc)b-Gal wherein b = 0 (i.e., free and accessible GlcNAc-Gal).
(2) Vainauskas discloses a core-α1,6 fucosidase capable of removing α1,6-linked core fucose.
(3) Geel discloses antibody modification at Asn297 via the core GlcNAc, wherein each antibody heavy chain is modified to comprise, generally, GlcNAc(Fuc)GalNAc-Azide which may be reacted with a cyclooctyne group (e.g., BCN) via ligation reaction with various payload-linkers (e.g., PEG groups, cleavable Val-Cit dipeptide, and/or self-immolative PABA).
(4) Boeggeman discloses that UDP-galactose derivatives may be used in reactions with galactosyltransferases to add galactose (or a derivative thereof) to GlcNAc.
(5) Boune discloses indicates that terminal Gal may promote/enhance critical functions of therapeutic antibodies, specifically with regard to CDC and/or ADCC.
(6) Li discloses that α1,3-fucosyltransferases derived from H. pylori are capable of transferring GDP-Fuc donors conjugated to sterically bulky groups (e.g., drug-linkers, full IgG molecules) to cell surfaces at a GlcNAc-Gal in a single step.
(7) Han discloses the preparation of a drug-linker comprising reacting a trimaleimide linker with Val-Cit-PAB-MMAE, wherein the trimaleimide is used to conjugate the drug-linker to an antibody.
Thus, to one of ordinary skill in the art, it would have been obvious to try a method of making a protein conjugate wherein the method comprises: (i) contacting an antibody with an endoglycosidase to free the core GlcNAc directly linked to Asn297 (as suggested by Geel); (ii) contacting the antibody of step (i) with a core α1,6-fucosidase to remove the core fucose (i.e., Fuc, as suggested by Vainauskas); (iii) contacting the glycan-trimmed antibody produced from (i) and/or (ii) with UDP-Gal (or a derivative thereof) in the presence of a catalyst (i.e., a galactosyltransferase) to add a terminal Gal to the now free core GlcNAc (as suggested by Geel and Boeggeman), which may or may not comprise a core fucose (linked to the GlcNAc though an α1,6 linkage) wherein the addition of the terminal Gal (linked to the GlcNAc through a Galβ1,4GlcNAc linkage) would be expected to enhance CDC and/or ADCC activities of the antibody (as suggested by Boune); and (iv) contacting the antibody produced by (iii) with Q-Fuc*’ in the presence of a fucosyltransferase to attach Fuc*’ to the core GlcNAc wherein said Fuc*’ comprises a molecule of interest that further comprises (a) an active moiety wherein said active moiety comprising P, wherein P is a biologically and/or pharmaceutically active substance (e.g., an anti-tumor agent) wherein Q-Fuc*’ is of the formula Q-Fuc-(F)m-(L)n-Y1 or Q-Fuc-(F)m-(L)n-P wherein F is a connector, L is a linker, and m and n are each independently 0 or 1 as suggested by Han (wherein the trimaleimide is replaced with GDP-fucose for fucosyltransferase conjugation) wherein it would reasonably expected that step (iv) could be performed in a single step because Li demonstrates the one-step conjugation of GDP-fucose linked to sterically bulky agents is possible and efficient with fucosyltransferases. One of ordinary skill in the art would have been motivated to try such a method to produce a protein conjugate (i.e., antibody conjugate) that would reasonably be expected to be useful diagnostic and/or therapeutic methods and would be expected to be homogeneous and serum stable and therefore have an improved therapeutic index, as suggested by the cited prior art references.
Response to Arguments - 35 USC § 103
Applicant's arguments filed 07/22/2026 have been fully considered but they are not persuasive. Furthermore, the declaration under 37 CFR 1.132 filed 07/22/2026 is insufficient to overcome the new grounds of rejection as set forth above.
Specifically, Applicant argues the following:
With regard to the prior art, Applicant argues that one step enzymatic conjugation is unpredictable and fraught with technical barriers. Wu does not provide a workable solution for ADC manufacturing, and the art provides no predictable pathway to improve the efficiency required for protein engineering. The additionally cited secondary references do not provide a reasonable expectation of success.
The declaration demonstrates unexpected and profound efficacy corresponding to the instantly claimed F structure, wherein Applicant points to improved conjugation efficiencies and higher conversion after 24 hours for ADCs produced using the F groups encompassed by the instant claims. Applicant also argues further unexpected improvements when the instantly claimed F structure is employed with an antibody engineered to comprise non-natural core GlcNAc(Fuc)b-Gal and wherein ADCs comprising the instantly claimed F structure have improved plasma stability. The specific glycosidic structure and connector design instantly claimed overcome the documented failures of generalized enzymatic transfers, conferring unexpected conjugation efficiency and plasma stability.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). Additionally, obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988).
In this case, the obviousness rejection relies solely on teachings, suggestions, and/or motivations provided by the cited art references themselves and/or in the knowledge generally available to one of ordinary skill in the art. Notably, as provided above, to one of ordinary skill in the art, it would have been obvious to try a method of making a protein conjugate wherein the method comprises: (i) contacting an antibody with an endoglycosidase to free the core GlcNAc directly linked to Asn297 (as suggested by Geel); (ii) contacting the antibody of step (i) with a core α1,6-fucosidase to remove the core fucose (i.e., Fuc, as suggested by Vainauskas); (iii) contacting the glycan-trimmed antibody produced from (i) and/or (ii) with UDP-Gal (or a derivative thereof) in the presence of a catalyst (i.e., a galactosyltransferase) to add a terminal Gal to the now free core GlcNAc (as suggested by Geel and Boeggeman), which may or may not comprise a core fucose (linked to the GlcNAc though an α1,6 linkage) wherein the addition of the terminal Gal (linked to the GlcNAc through a Galβ1,4GlcNAc linkage) would be expected to enhance CDC and/or ADCC activities of the antibody (as suggested by Boune); and (iv) contacting the antibody produced by (iii) with Q-Fuc*’ in the presence of a fucosyltransferase to attach Fuc*’ to the core GlcNAc wherein said Fuc*’ comprises a molecule of interest that further comprises (a) an active moiety wherein said active moiety comprising P, wherein P is a biologically and/or pharmaceutically active substance (e.g., an anti-tumor agent) wherein Q-Fuc*’ is of the formula Q-Fuc-(F)m-(L)n-Y1 or Q-Fuc-(F)m-(L)n-P wherein F is a connector, L is a linker, and m and n are each independently 0 or 1 as suggested by Han (wherein the trimaleimide is replaced with GDP-fucose for fucosyltransferase conjugation) wherein it would reasonably expected that step (iv) could be performed in a single step because Li demonstrates the one-step conjugation of GDP-fucose linked to sterically bulky agents is possible and efficient with fucosyltransferases when GlcNAc-Gal is free/accessible for conjugation. One of ordinary skill in the art would have been motivated to try such a method to produce a protein conjugate (i.e., antibody conjugate) that would reasonably be expected to be useful diagnostic and/or therapeutic methods and would be expected to be homogeneous and have an improved therapeutic index, as suggested by the cited prior art references.
It is noted that, with regard to the above-presented arguments and data in the submitted declaration, MPEP 716.02b indicates that the evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c). Applicant has not provided any statistical analysis to demonstrate that the differences and improvements as argued are of practical and statistical significance. Furthermore, it is noted that the data presented is not fully commensurate in scope with the instant claims. It is acknowledged that the data presented is drawn to a variety of F structures encompassed by the instant claims, however all of the data presented drawn to species encompassed by the instant claims are drawn to structures wherein s = 1 and n = 1, such that both FL and L are required components of Q-Fuc*’; Applicant provides no data to demonstrate that when s = 0 and/or when n = 0 that the same trends and improvements are maintained. As such, the data as currently presented is not fully commensurate in scope with the instant claims.
Double Patenting - Updated as Necessitated by Amendment
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 87, 227-233, and 236-243 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20, 22, 25, 40, 43, 50, 69, 70-71, and 73-75 of copending Application No. 18/697,675 (herein after referred to as "reference patent") in view of non-patent literature by Vainauskas et. al. (Scientific Report, 2018, 8(9504), 1-8; herein after referred to as “Vainauskas”), non-patent literature by Remon van Geel et. al. (Bioconjugate Chem., 2015, 26, 2233-2242; previously cited on PTO-892; herein after referred to as “Geel”), non-patent literature by Li et. al. (ACS Cent. Sci., 2018, 4, 1633-1641; herein after referred to as “Li”), and WO 2016/192528 A1 (previously cited on PTO-892; herein after referred to as “Han”).
Claim 20 of the reference patent is drawn to a method for preparing a protein conjugate, comprising contacting a donor Q-Fuc* with a protein having a glycan chain comprising a structure of formula (I), corresponding to GlcNAc(Fuc)b-GalX, in a presence of the isolated polypeptide of claim 1 to obtain a protein conjugate, wherein said protein conjugate comprises a structure of formula (II):
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wherein GlcNAc is a N-acetylglucosamine, Fuc is a fucose, b is 0 or 1, GalX is an optionally substituted galactose, MOI is a molecule of interest comprising an active substance (AM), Q is a guanosine diphosphate (GDP), a uridine diphosphate (UDP), and/or a cytidine diphosphate (CDP), said protein conjugate comprises a Fc domain and/or an antigen-binding moiety, said GalX and said GlcNAc are linked via a β-1,4 glycosidic linkage, said Fuc and said GlcNAc are linked via an α-1,6 glvcosidic linkage, said Fuc* and said GlcNAc are linked via an α-1,3 glycosidic linkage, Fuc* comprises a structure of Fuco-MOI wherein the structure of Fuco is represented by formula (III) wherein said MOI is linked to the left terminus of formula (III):
Claims 22 and 25 further limits claim 20 wherein, respectively: (i) said GalX is a galactose (i.e., is not substituted) and/or (ii) said GalX is a monosaccharide. Claim 40 further limits claim 20 wherein said active substance AM is a functional group X1, and the X1 comprises a functional group capable of participating in a bioorthogonal ligation reaction. Claim 43 further limits claim 20 wherein said active substance AM is a biologically active substance and/or a pharmaceutically active substance P1, wherein P1 comprises one or more substances selected from the group consisting of a cytotoxin, an agonist, an antagonist, an antiviral agent, an antibacterial agent, a radioisotope, a radionuclide, a metal chelator, an oligonucleotide, and a polypeptide. Claim 50 further limits claim 20 wherein said MOI further comprises a linker L used for linking said AM to said Fuco, said linker L has a structure of J-(Sp)ₙ, wherein n is 0 or 1, J is a binder, Sp is a spacer, and said J is directly linked to said Fuco, said Q-Fuc* is a Q-Fuco-J-(Sp),-AM, wherein n is 0 or 1, said J is a structure selected from the group of recited structures wherein the left terminus of J is directly linked to said Fuco and said spacer Sp optionally comprises a cleavable moiety. Claim 69 further limits claim 20 wherein the structure of said protein conjugate is represented by formula (IV):
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Claim 70 further limits claim 69 wherein the method further comprises contacting the Fc domain-containing antibody and/or Fc fusion protein with a UDP-GalX in the presence of a suitable catalyst to obtain a protein having a glycan chain comprising a structure of formula (I) wherein the Fc domain-containing antibody and/or Fc fusion protein has a G0(F)0,1, G1(F)0,1, and/or G2(F)0,1 glycoform wherein the structure of the protein having a glycan chain is represented by formula (V):
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Claim 71 further limits claim 69, wherein the method further comprises contacting the Fc domain-containing antibody and/or Fc fusion protein with a UDP-GalX in the presence of a suitable catalyst to obtain a protein having a glycan chain comprising a structure of formula (I) wherein the Fc domain-containing antibody and/or Fc fusion protein has a G0(F)0,1 glycoform wherein the structure of the protein having a glycan chain is represented by formula (V):
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Claim 73 further limits claim 20, wherein the structure of said protein conjugate is represented by formula (VI):
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Claim 74 further limits claim 73 wherein the method further comprises treating the Fc domain-containing antibody and/or Fc fusion protein with an endoglycosidase to obtain a treated antibody and/or Fc fusion protein and contacting said treated antibody and/or Fc fusion protein with a UDP-GalX in the presence of a suitable catalyst to obtain a protein having a glycan chain comprising a structure of formula (I), the structure of the protein having a glycan chain being represented by formula (VII):
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Claim 75 further limits claim 73, wherein the method further comprises treating the Fc domain-containing antibody and/or Fc fusion protein with an endoglycosidase and an α1,6 fucosidase to obtain a treated antibody and/or Fc fusion protein and contacting said treated antibody and/or Fc fusion protein with a UDP-GalX in the presence of a suitable catalyst to obtain a protein having a glycan chain comprising a structure of formula (I), the structure of the protein having a glycan chain being represented by formula (VII):
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However, it is noted that the reference application does not explicitly claim a method of making a protein conjugate wherein the structure of Q-Fuc*’ corresponds to:
This deficiency is remedied by Geel, Vainauskas, Li, and Han, whose teachings are provided in the 103 section above.
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the instant invention was filed to try and further modify the method(s) of preparing protein conjugates claimed by the reference application such that the method comprises: (i) contacting an antibody with an endoglycosidase to free the core GlcNAc directly linked to Asn297 (as suggested by the reference application); (ii) contacting the antibody of step (i) with a core α1,6-fucosidase to remove the core fucose (i.e., Fuc, as suggested by Vainauskas); (iii) contacting the glycan-trimmed antibody produced from (ii) with UDP-Gal (or a derivative thereof) in the presence of a catalyst to add a Gal to the now free core GlcNAc (as suggested by the reference application) wherein the Gal is linked to the GlcNAc through a Galβ1,4GlcNAc linkage (as suggested by the reference application); and (iv) contacting the antibody produced by (iii) with the instantly elected Q-Fuc*’ structure in the presence of a fucosyltransferase in a single step (as suggested by Li) to attach Fuc*’ to the GlcNAc wherein said Fuc*’ comprises a molecule of interest that further comprises (a) an active moiety wherein said active moiety comprises a reactive group Y1 capable of participating in a ligation reaction and/or (b) a P, wherein P is a biologically and/or pharmaceutically active substance (e.g., a cytotoxic agent) wherein Q-Fuc*’ is of the instantly elected formula Q-Fuc-(F)m-(L)n-Y1 or Q-Fuc-(F)m-(L)n-P wherein Q-Fuc is GDP-L-Fucose (as suggested by the reference application and Srivastava) and wherein F is a connector, L is a linker, and P is MMAE and m and n are each independently 1 (i.e., the structure of F-L-P corresponds to the linker-payload structure suggested by Han). It would be within the purview of one having ordinary skill in the art to modify and/or combine linker elements with reactive moieties and/or methods known in the art to arrive at ADC structures having desired features and/or properties. Notably, replacing the trimaleimide portion of the Han linker-payload structures with GDP-L-Fucose would allow for antibody conjugation site-specifically at a GlcNAc residue of an antibody. One of ordinary skill in the art would have been motivated to try such a method to produce a protein conjugate (i.e., antibody conjugate) that would reasonably be expected to be useful diagnostic and/or therapeutic methods and would be expected to be homogeneous and serum stable and therefore have an improved therapeutic index, as suggested by the reference application, Geel, Srivastava, and Han.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 87 and 227-243 pending. Claims 234-235 are withdrawn. Claims 87, 227-233, and 236-243 are rejected. No claims are allowed.
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.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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