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 1-20 are pending. Claims 1-8 and 14-20 are withdrawn as directed to non-elected Groups I and III. Claim 12 is withdrawn as directed to a non-elected species. Claims 9-11 and 13 are presently considered.
Election/Restrictions
Applicant’s election without traverse of Group II (original claims 9-13, directed to peptide conjugates) and the species of Example 1 at ¶¶[0124]-[0130] and Figure 1 of the Specification filed 5/23/2023, in the reply filed on 5/05/2026 is acknowledged.
The originally elected species is understood to correspond to Example 1 at ¶¶[0124]-[0130] and Figure 1 of the Specification filed 5/23/2023, and is understood to have a diazaborine structure of
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wherein PP (polypeptide) is a serum protein; L1 (linker connecting PP to the tether) is -(CH2)4-NH-C(=O)-; R’ is hydrogen; L2 (linker connecting tether to M) is -O-(CH2)6-triazole- (i.e., a hexyloxy linker with trizole formed via azide-DBCO click chemistry); and M (cargo moiety) is a DBCO-modified oligonucleotide. An illustrated version of this species is understood to be shown at Figure 1, reproduced-in-part below:
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Although Applicant indicated that Example 1 read upon claim 12, this appears to be erroneous as no point of attachment to solid support was actually identified as present in the enumerated components. Furthermore, upon review, Example 1 does not pertain to conjugates attached to solid supports, but rather such solid supports are disclosed at non-elected Example 2 (compare Spec. filed 5/23/2023 at Example 1 at ¶¶[0124]-[0130] and Figure 1, with Spec. filed 5/23/2023 at Example 2 at ¶¶[0131]-[0134], noting that although Example 1 mentions “solid support (beads)”, it clearly identifies that such “solid support” was “explored” in Example 2 at ¶[0129], but no such solid support was disclosed at Example 1). Accordingly, the originally elected species is understood to read upon instant claims 9-11 and 13, but not original claim 12.
Following extensive search and examination, the originally elected species has been deemed free of the prior art in view of the specific combination of all present limitations being simultaneously present. Per MPEP § 803.02(III)
If the examiner determines that the elected species is allowable over the prior art, the examination of the Markush claim will be extended. If prior art is then found that anticipates or renders obvious the Markush claim with respect to a nonelected species, the Markush claim shall be rejected; claims to the nonelected species would still be held withdrawn from further consideration. The prior art search will not be extended unnecessarily to cover all nonelected species.
Accordingly, no species are recited in the claims, and therefore examination has been extended to a non-elected species of Laminin-DAB31-SN-38. Following extensive search and examination, the non-elected species was deemed anticipated and/or obvious in view of the prior art as applied below. Per MPEP § 803.02(III), claims directed to other nonelected species have been withdrawn.
Claims 1-8 and 14-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/05/2026.
Claim 12 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/05/2026.
Accordingly, claims 9-11 and 13 are presently considered.
Priority
The priority claim to US Provisional 63/345192 (filed 5/24/2022) is acknowledged.
Information Disclosure Statement
The IDS filed 1/26/2024 is acknowledged and presently considered.
Claim Interpretation
For purposes of examination, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
Claim 9 is representative of the pending claim scope, and the applicable claim interpretations are discussed below.
“Comprising” is an open-ended transitional term (see, e.g., MPEP § 2111.03(I)), wherein additional steps or components are not excluded. However, “‘[c]omprising’ is a term of art used in claim language which means that the named elements are essential” (see, e.g., id.; see also Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997)).
Diazaborine is interpreted consistent with the description provided in the specification (see, e.g., Spec. filed 5/23/2023 at ¶[0050], discussing alternative resonance forms).
“Cargo moiety or a reactive functional moiety” is given the broadest reasonable interpretation, and is reasonably understood to encompass any molecule reasonably deemed “cargo” or otherwise any molecule comprising a “reactive functional moiety”, wherein “reactive” is given the broadest reasonable interpretation to include reactivity under any chemical or biochemical assay.
Additional claim interpretations are set forth below.
Claim Objections
Claim 11 is objected to because of the following informalities:
Claim 11 contains a grammatical error, namely “is connection of the polypeptide to a carbonyl group”, which should be “is the connection of the polypeptide to the carbonyl group”.
Appropriate correction is required.
Claim Rejections
Claim Rejections - 35 USC § 112(b)
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.
Claim 9-11 and 13 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.
Claims 9 and 11 are rendered indefinite in view of the linkage of -L2-M to the remainder of the conjugate because it is unclear if the linkage is limited to a single, direct bond, or if any form of linkage (e.g., 2 points of contact, forming a tricyclic compound) is encompassed by the claim scope. Here, the description for the linkage at claim 9 is simply that L2 is a “linker connecting the tether to M”, which reasonably suggests that any structure “connecting” the tether to M satisfies the claim scope regardless of the points of contact. However, all example of record appear to have a single point of contact (see, e.g., Spec. filed 5/23/2023 at Fig. 1, Fig. 4, Fig. 6), which suggests that the claim scope is limited to a single point of contact. Accordingly, it is unclear what the metes and bounds of the recited structures may be, and clarification is required. For purposes of examination in view of the prior art, it is understood that the claim scope at least encompasses -L2-M moieties having a single point of contact with the ring; clarification is required.
Claims 10-11 and 13 depend directly or indirectly from an indefinite base claim, and fail to clarify the indefiniteness of the base claim. Accordingly, claims 10-11 and 13 are rejected as indefinite for depending upon an indefinite base claim.
Accordingly, claims 9-11 and 13 are rejected.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
[Prior Art Rejection 01]
Claims 9-10 and 13 are rejected under 35 U.S.C. 102(a)(2) as being clearly anticipated by Antonio et al1.
Claim interpretation: The applicable claim interpretation has been discussed in a separate section above, and those discussions are incorporated herein. Additional claim interpretations are set forth below.
Antonio pertains to a crosslinker suitable for linking thiols and N-Cys peptides (see, e.g., Antonio at 6222 at col II at last ¶), wherein the reaction schemes are understood to demonstrate “the crosslinking of different thiol-bearing peptides or payloads with N-terminal cysteine peptides” (see, e.g., Antonio at title, abs). Regarding instant claims 9-10, and 13, Antonio teaches and discloses a generic peptide-conjugate having the generalized form of
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(see, e.g., Antonio at Scheme 2 on 6223). This structure is understood to correspond to the structure at instant claim 9 as follows: R’ is hydrogen, L2 is the linker corresponding to
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, M is a cargo moiety corresponding to
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, and L1-PP is the linker-polypeptide corresponding to
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(see, e.g., Antonio at Scheme 2 on 6223). In view of the disclosure, it is understood that
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is a thiol-bearing polypeptide capable of reacting with the maleimide of the 2-FPBA-maleimide crosslinker (see, e.g., Antonio at abs, 6222 at col II at 1st to 2nd ¶, Scheme 3 on 6223), and that
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represents a polypeptide with a hydrazine handle reacted to from a diazaborine (see, e.g., Antonio at abs, Scheme 1(B) at 6222)
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Accordingly,
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is understood to necessarily satisfy the claimed limitations of claims 9, wherein L1 is arbitrarily the residual hydrazine handle after reaction and arbitrarily a portion of the polypeptide, and wherein PP is the remaining polypeptide (see, e.g., Antonio at abs, 6222 at col II at 1st to 2nd ¶, Scheme 1(B) at 6222, Scheme 3 on 6223).
Accordingly, claims 9-10 and 13 are anticipated by the prior art.
[Prior Art Rejection 02]
Claims 9-10 and 13 are rejected under 35 U.S.C. 102(a)(2) as being clearly anticipated by Gois et al2.
Claim interpretation: The applicable claim interpretation has been discussed in a separate section above, and those discussions are incorporated herein. Additional claim interpretations are set forth below.
Gois pertains diazaborine-based linkers (see, e.g., Gois at title, abs). Regarding instant claims 9-10 and 13, Gois discloses the a peptide conjugate having the structure of
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(see, e.g., Gois at Figure 13 at page 18), and the structure of
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(see, e.g., Gois at Figure 14 at page 19), wherein the circle represents a spacer molecule (see, e.g., Gois at Figure 13 at page 18, noting that the spacer is -(CH2)2-(NH)-(C=O)-(CH2)2-(O-CH2-CH2)4-(NH)-(C=O)-(CH2)2-). Accordingly, relative to instant claim 9, such structures satisfy the claim scope wherein R’ is hydrogen, L1 is
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, PP is the polypeptide shown (i.e., either Laminin or the antibody “VL”), L2 is
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, and M is the cargo of
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(see, e.g., Gois at Figure 13 at page 18, Figure 14 at page 19).
Accordingly, claims 9-10 and 13 are anticipated by the prior art.
[Prior Art Rejection 03]
Claims 9-10 and 13 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being clearly anticipated by US2015/0329568.
Claim interpretation: The applicable claim interpretation has been discussed in a separate section above, and those discussions are incorporated herein. Additional claim interpretations are set forth below.
Regarding instant claims 9-10 and 13, US’568 discloses compounds comprising a diazaborine tether (see, e.g., US’568 at Figs. 1, 15, 25A-25B, 44, ¶¶[0071], [0226], [0231]-[0232], [0248]). Specifically, these figures show the compounds of
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,
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and
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(see, e.g., US’568 at Figs. 15, 25B, 44, each reproduced in part above). Each of these substances satisfy the requirements of instant claims 9-10 and 13 as follows: R’ that is hydrogen (compare instant claims 9-10 and 13 with US’568 at Figs. 15, 25A-25B, and 44); an L2 linker (compare instant claims 9-10 and 13 with US’568 at Figs. 15, 25A-25B, and 44, noting that the linker is indicated by either “X” or a wavy line, wherein it is understood that the structure of the wavy line is a design choice per US’568 at Fig. 1 and ¶[0071]); M is cargo comprising a “substance of interest”, taxol (“TAX”), or a nanoparticle (“NP”) (compare instant claims 9-10 and 13 with US’568 at Figs. 15, 25A-25B, and 44); L1 is a linker (compare instant claims 9-10 and 13 with US’568 at Figs. 15, 25B, and 44, noting that the linker is indicated by an amino acid side chain at Fig. 15, at least an alkyl repeat at Figure 25A-25B, and a wavy line at Fig. 44); and wherein PP is a polypeptide (compare instant claims 9-10 and 13 with US’568 at Figs. 15, 25A-25B, and 44, noting that the polypeptide at Fig. 15 is generically any protein with a modified amino acid side-chain, that Fig. 25A-B shows an antibody with a modified side-chain, and wherein Fig. 44 exemplifies a C-terminally modified hydrazide protein or peptide). Regarding Figure 44 and instant claim 13, although Figure 44 shows a cargo (a.k.a., M relative to instant claim 9) that is a nanoparticle (“NP”), an artisan would at once envisage that the nanoparticle shown may be viral nanoparticles (VNP) as detailed by US’568 (see, e.g., US’568 at ¶¶[0039], [0261]), wherein such a VNP or VLP would necessarily and inherently comprise proteins, nucleotides, and/or polysaccharides as recited by claim 13.
Accordingly, claims 9-10 and 13 are anticipated by the prior art.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, 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.
[Prior Art Rejection 04]
Claims 9-11 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over US2015/0329568 as applied to claims 9-11 and 13 above, and further in view of Antonio et al3, Bhat4, and Miyatake5, and in view of US10435418.
Claim interpretation: The applicable claim interpretation has been discussed in a separate section above, and those discussions are incorporated herein. Additional claim interpretations are set forth below.
The teachings of US’568 as applied to instant claims 9-10 and 13 have been discussed above, and those teachings are incorporated herein. Additional teachings pertinent to additional embodiments within the scope of claims 9-10 and 13 are discussed below.
The teachings of US’568 differ from the scope of claim 11 as follows: Although US’568 teaches and exemplifies embodiments within the scope of instant claims 9-10 and 13, US’568 does not explicitly reduce to practice a compound wherein PP-L1- may be written as “PP-(CH2)4-NH-(C=O)-”, and is a “connection of the polypeptide to a carbonyl group on the diazaborine through a lysine residue of the polypeptide” as required by claim 11.
However, US’568 teaches and discloses the general chemical mechanism shown at Figure 1 (see, e.g. US’568 at Fig. 1, reproduced below):
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Wherein, the -X-R4 moieties within H2N-X-R4 are understood to be: X is -NH-, and R4 is virtually unlimited (see, e.g., US’568 at Figs. 1, 15, 25A-25B, 44, ¶¶[0071], [0226], [0231]-[0232], [0248]; see esp. id. at ¶[0071], [0119], [0122]). Therefore, the difference between US’568 and instant claim 11 appears to be that claim 11 requires that that the H2N-X-R4 compound utilized in the US’568 reactions and structures have the structure of H2N-NH-C(O)-NH-(CH2)4-[polypeptide]. Accordingly, a remaining issue is whether such reactants (e.g., H2N-NH-C(O)-NH-(CH2)4-[polypeptide]) were either already known or otherwise obvious to make using any chemical reaction known in the prior art (i.e., a product is being examined, which is not limited to the process methodology at instant claim 1.
Similarly, Antonio discloses that the general mechanism for reacting any polypeptide containing a hydrazine handle to from a diazaborine (see, e.g., Antonio at abs, Scheme 1(B) at 6222, reproduced below; see also id. at col II at 1st to 2nd ¶, Scheme 1(B) at 6222, Scheme 3 on 6223):
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Additional teachings of Antonio have been discussed above under 35 USC 102, and those teachings are incorporated into the instant rejection. Accordingly, the issue is whether or not an artisan could place a hydrazide handle at a lysine (e.g. H2N-NH-C(O)-NH-(CH2)4-[polypeptide]).
The addition of a hydrazide handle to a lysine moiety is understood to have been well-within the ordinary skill in the art as taught and suggested in view of US’568 and Antonio, and the full scope of hydrazide handles on amino acids side chains referenced by Antonio are presumed fully enabled absent objective evidence to the contrary (see, e.g., Antonio at abs, Scheme 1(B) at 6222). For example, Bhat pertains to hydrazide mimics for protein lysine acylation, and discloses that similar reactants were already known in the prior art. More specifically, Bhat discloses that polypeptides comprising acetyl-hydrazido-Lys (shown below), were known:
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(e.g., an R-NH-NH-C(O)-CH3; see, e.g., Bhat at Fig. 1 on 9479); and Miyatake discloses that methods of deacetylation of proteins, wherein an acetyl moiety at an α-amino group could be removed without impacting the remainder of the side chain, were already known (see, e.g., Miyatake at abs, Fig. 1 on 786, 788 at col I-II at § Results) and “under these conditions, peptide-bond cleavage or modification of the constituent amino acid residues does not occur” (see, e.g., Miyatake at abs; see also id. at Fig. 1 on 786, 88 at col I-II at § Results). In addition, US’418 is an issued US patent, wherein claim 1 encompasses hydrazides of all amino acids (see, e.g., US’418 at claim 1, 8-9, col. 19 at lines 50-65, col 33 at lines 25-56), and as an issued patent the full scope of the claims is presumed fully enabled absent objective evidence to the contrary. Accordingly, making and using a lysine modified to contain a hydrazide handle is understood to be fully enabled and well-within the ordinary skill in the art.
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): The usage of any amino acid, including lysine, modified with a hydrazide handle as taught and suggested by US’568 and Antonio to predictably yield the exact outcome and structures taught by US’568 and Antonio is obvious because it is the combination (or simple substitution, or variation) of known compounds according to known methods to yield only the predicted and expected results (i.e., polypeptide compounds conjugated to cargo molecules via a diazaborine structure as taught by the primary and secondary references); furthermore, the full scope of the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses or reasonably suggests (see, e.g., MPEP §§ 2123(I)-(II)), and the unclaimed intermediate (i.e., a lysine with a hydrazide handle) is presumed fully within the abilities of one of ordinary skill in the art to make in view of Bhat, Miyatake, and US’418 (see, e.g., MPEP §§ 2143(I)(A), (B), (C), (D), (F), and (G)). The selection of lysine relative to other amino acid side chains is therefore a design choice well-within the ordinary skill in the art.
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses and reasonably suggests (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the art to make and use reagents necessary to practice the full scope of polypeptide compounds conjugated to cargo molecules via a diazaborine structure as taught by the primary and secondary references, including via a modified lysine hydrazide handle intermediate.
Accordingly, claims 9-11 and 13 are rejected.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US20180065993 pertains to related methods of labeling proteins with a substance of interest via an azaborine tether (see, e.g., id. at title, abs, figures, claims). The reference is substantially cumulative with US’568 as applied above.
US9758533 pertains to related methods of labeling proteins with a substance of interest via an azaborine tether (see, e.g., id. at title, abs, figures, claims). The reference is substantially cumulative with US’568 as applied above.
US8058469B2 pertains to methods of making compounds of form X1-C(O)-X2, wherein X1 is NR1R2 and X2 is NR3R4, and wherein R1-4 may independently be any linear, branched, or hetero-atom containing aryl, including wherein the nitrogen of X2 may be part of a ring system (see, e.g., US’469 at claim 1). This is relevant because it is an issued US patent and broadly reads upon structures encompassed by claims 9-11 and 13, and therefore weighs in favor of a determination that such compounds are enabled and within the ordinary skill in the art to make and use, absent objective evidence to the contrary.
US20190145982A1 pertains to methods of conjugating the lysines side-chains of polypeptides to cargo molecules via a tether compound (see, e.g., US’982 at Fig. 2B). Although not reduced to practice, US’982 reasonably informs and directs artisans that such exemplified reactions could be performed using alternative functional groups, including hydrazides (see, e.g., US’982 at ¶[0421]).
Scott et al.7 teaches and discloses intermediates and steps to incorporate hydrazide functionality onto the lysine residues of proteins (see, e.g., Scott at title, abs).
Gu et al.8 pertains to diazaborines (see, e.g., Gu at title, abs, Scheme 1 and 4).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RANDALL L BEANE whose telephone number is (571)270-3457. The examiner can normally be reached Mon.-Fri., 7 AM to 2 PM ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G. Garyu can be reached at (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/RANDALL L BEANE/Primary Examiner, Art Unit 1654
1 Antonio et al., A 2-formylphenylboronic acid (2FPBA)-maleimide crosslinker: a versatile platform for Cys-peptide-hydrazine conjugation and interplay. Org Biomol Chem. 2021 Jul 21;19(28):6221-6226. doi: 10.1039/d1ob00917f.; hereafter “Antonio”.
2 Gois et al., Development of Diazaborines as ROS Sensitive Linkers for the Construction of Stimuli
Responsive Antibody Drug Conjugates, Pre-Print, 27 pages (posted July 5, 2021), Chemrxiv.org, DOI: https://doi.org/10.26434/chemrxiv-2021-qh8zd; hereafter “Gois”.
3 Antonio et al., A 2-formylphenylboronic acid (2FPBA)-maleimide crosslinker: a versatile platform for Cys-peptide-hydrazine conjugation and interplay. Org Biomol Chem. 2021 Jul 21;19(28):6221-6226. doi: 10.1039/d1ob00917f.; hereafter “Antonio”.
4 Bhat et al., Hydrazide Mimics for Protein Lysine Acylation To Assess Nucleosome Dynamics and Deubiquitinase Action. J Am Chem Soc. 2018 Aug 1;140(30):9478-9485. doi: 10.1021/jacs.8b03572. Epub 2018 Jul 24. PMID: 29991262; PMCID: PMC6070418; hereafter “Bhat”.
5 Miyatake et al., Removal of N-terminal formyl groups and deblocking of pyrrolidone carboxylic acid of proteins with anhydrous hydrazine vapor. Eur J Biochem. 1993 Mar 15;212(3):785-9. doi: 10.1111/j.1432-1033.1993.tb17719.x. PMID: 8462549.0l; hereafter “Miyatake”.
6 The image is understood to confusingly show acetylated aza-ornithine (i.e., -(CH2)3-NH-NH-C(O)-CH3), but the image label is for aza-lysine, which would be understood to be -(CH2)4-NH-NH-C(O)-CH3. However, such compounds differ by a single repeated -CH2- moiety, and are therefore homologs. Both compounds would be readily understood by one of skill in the art.
7 Scott et al., Synthesis of reagents for the one step incorporation of hydrazide functionality onto the lysine residues of proteins, and their use as linkers for carbonyl containing molecules, Bio. & Med. Chem. Letters, Vol 6(13):1491-1496 (1996), https://doi.org/10.1016/S0960-894X(96)00265-X.
8 Gu et al., Formation of hydrazones and stabilized boron-nitrogen heterocycles in aqueous solution from carbohydrazides and ortho-formylphenylboronic acids. Org Biomol Chem. 2017 Sep 20;15(36):7543-7548. doi: 10.1039/c7ob01708a. PMID: 28853481; PMCID: PMC6636819.
Prosecution Insights