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 . 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.
Election/Restrictions
Applicant’s election without traverse of group I (compounds) and o-nitrobenzyl citrulline in the reply filed on 14 March, 2026 is acknowledged.
The requirement is deemed proper and is therefore made FINAL.
Applicants have elected o-nitrobenzyl citrulline. A search was conducted for this invention, and references rendering it obvious were found. As a result, claims 1-4 were examined and claims 5-16 were withdrawn from consideration. Applicants have stated that they believe claims 5-7 and 9 read on their elected species, but claims 5 and 6 require a different protecting group, claim 7 requires additional components not elected (the additional amino acids in the sequence), as does claim 9 (the excipient, carrier, or diluent). Thus, these claims are properly withdrawn.
Drawings
The drawings are objected to because fig 4a requires color. Applicants are required to amend the drawings so that they do not require color. Should it be impossible to show important information without color, applicants can petition for color drawings. In addition, figs 10a, 16, and 17 show sequences, but do not give the associated SEQ ID numbers. The MPEP states that "It should be noted that when a sequence is presented in a drawing, regardless of the format or the manner of presentation of that sequence in the drawing, the sequence must still be included in the sequence listing and the sequence identifier ("SEQ ID NO:X") must be used, either in the drawing or the brief description of the drawings” (MPEP 2422.02). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities: the specification gives sequences without the associated SEQ ID numbers, note paragraphs 30 and 31, for example. The MPEP states that "37 CFR 1.821(d) requires the use of the assigned sequence identifier in all instances where the description or claims of a patent application discuss sequences regardless of whether a given sequence is also embedded in the text of the description or claims of an application” (MPEP 2422.03).
Appropriate correction is required.
Claims Status
Claims 1-16 are pending.
Claims 5-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 14 March, 2026.
Examiner’s Note
Prosecution of this application has been transferred to Fred Reynolds from Brendan Oliss.
Carbamate groups, a very common pH labile linker in protecting groups, are photolabile by applicant’s definition (note Yuan et al, J. Haz. Mat. (2025) 489 I37648, graphical abstract). This means that just about any side chain protected Cit residue will read on applicant’s independent claim.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Pryyma et al (Bioconj. Chem. (Dec, 2020) 31 p2685-2690), with evidentiary support from D’Souza et al (Science (1968) 160 p882-883) and Lun et al (CN 106831536A (2017)). Note that Lun et al is in Chinese. An English language machine translation is used; all citations to this reference are to the machine translation unless otherwise noted.
Pryyma et al discuss synthesis of the Val-Cit cathepsin B cleavable linker (abstract). Direct synthesis on resin using standard methodology gave very low yield, presumably because of the Cit side chain reacting with the resin to form a lactam that cleaved from the resin (p2687, 1st column, 2nd paragraph). The authors discuss the possibility of a PBF side chain protected Cit building block, but, as it is an uncommon amino acid, it appears to be a poorly explored area (p2687, 2nd column, 4th paragraph). Note that the PBF protecting group is an aromatic sulfonamide (2,2,4,6,7-pentamethyldihydrobenzo-furan-5-sulfonyl, p2687, 2nd column, 4th paragraph). As evidenced by D’Souza et al, the sulfonamide bond can be photolytically cleaved (abstract), making PBF a photolabile group. While Pryyma et al does not discuss how to synthesize such a compound, Lun et al discuss the synthesis of gliclazide, with the structure
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(title). Prior art methods using hydrazine to couple the sulfonylurea to the azabicyclo compound are discussed as prior art (p2, 5th paragraph, continues to p3, 2nd paragraph), and their inventive method, using phosgene to link both the sulfonamide and the azabicyclo compound together (3d page 5th paragraph). Note that this is forming an asymmetric disubstituted urea, with an aromatic sulfonamide on one side, the same chemistry necessary to generate Cit(PBF), showing that a person of ordinary skill in the art could synthesize the compound suggested by Pryyma et al without undue experimentation.
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.
Claim(s) 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Pryyma et al (Bioconj. Chem. (Dec, 2020) 31 p2685-2690) in view of Bochet (J. Chem. Soc. Perkin Trans. 1 (2002) 125-142) and Wieboldt et al (J. Org. Chem. (2002) 67 p8827-8831).
Pryyma et al discuss synthesis of the Val-Cit cathepsin B cleavable linker (abstract). Direct synthesis on resin using standard methodology gave very low yield, presumably because of the Cit side chain reacting with the resin to form a lactam that cleaved from the resin (p2687, 1st column, 2nd paragraph). The authors discuss the possibility of a side chain protected Cit building block, but, as it is an uncommon amino acid, it appears to be a poorly explored area (p2687, 2nd column, 4th paragraph). Note that this reference anticipates claim 1.
The difference between this reference and the remaining claims is that, while this reference mentions protecting Cit residues, it does not actually discuss an o-nitrobenzyl protecting group.
Bochet discusses photolabile protecting groups (title). Different protecting groups need to be orthogonal to each other to be useful if they are to be removed at different times (p125, 1st column, 1st paragraph). Or, the final product can still have the photolabile protecting group, which inactivates it, which is removed with light as it is used to provide in situ activation (p127, 2nd column, 3d paragraph). A number of o-nitrobenzyl derivatives as protecting groups are discussed (p125, 2nd column, 4th paragraph, continues to p128, 1st column, 1st paragraph). This reference discusses photolabile protecting groups, including o-nitrobenzyl protecting groups.
Wieboldt et al discuss photolabile o-nitrobenzyl derivatives of urea (title). Note that applicant’s elected species is a substituted o-nitrobenzyl urea. By using a photoactive protecting group, where and when the protecting group is removed can be controlled (p8827, 1st column, 1st paragraph), similar to the rationale of Bochet. Examples of various experiments taking advantage of such derivatives are discussed (p8827, 2nd column, 1st paragraph). The o-nitrobenzyl group is discussed for carbamates, amines, carboxylates, phosphates, and amides (p8828, 1st column, 1st paragraph). The direct o-nitrobenzylurea has the highest quantum yield of all the derivatives tested (table 1, p8829, 2nd column, 1st paragraph). There is a suggestion to make other o-nitrobenzylurea derivatives, with a suggestion of a derivative where the other urea amine is substituted (p8830, 2nd column, 5th paragraph).
Therefore, it would be obvious to use a o-nitrobenzyl protecting group for the synthesis of Pryyma et al, as this is a common protecting group for a variety of functional groups, and Wieboldt et al show it works for the urea of the citrulline of Pryyma et al. As Wieboldt et al suggest using it for other substituted urea derivatives, an artisan in this field would attempt this protecting group with a reasonable expectation of success. Note that this is a substitution of one known element (the PBF protecting group) for another (the o-nitrobenzyl group) yielding expected results (protected citrulline).
Alternatively, it would be obvious to use a photolabile protecting group, such as the o-nitrobenzyl group of Weiboldt et al, to allow for temporal and spatial resolution of activating the resulting construct, as described by both Bochet and Weibold et al. As this protecting group has been used for similar functional groups, an artisan in this field would attempt this process with a reasonable expectation of success.
Pryyma et al discusses a side chain protected Cit residue. Bochet and Weibold et al render obvious an o-nitrobenzyl protecting group. Thus, the combination of references renders obvious claims 2-4.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658
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