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
Applicants elected group I (compounds) and o-nitrobenzyl citrulline without traverse in the reply filed on 14 March, 2026.
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.
response to applicant’s arguments
Applicants state that fig 4a can be interpreted without color with a detailed description, and that they are in compliance with all regulations regarding sequences.
Applicant's arguments filed 15 Aug, 2026 have been fully considered but they are not persuasive.
Applicants argue that color is not necessary for the heatmap, because of detailed description. However, if the description is detailed enough that the drawing is unnecessary, there is no need for the drawing. The point of a heat map is to use two colors to graphically show relationships in an intuitive manner. In greyscale, all this information is lost.
Applicants argue that they are in compliance with all regulations regarding sequences. However, without an explanation of how their lack of SEQ ID numbers associated with the various sequences in the drawings still meets all the appropriate regulations, this is argument is merely a statement of disagreement, which is insufficient to overcome the rejection.
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.
response to applicant’s arguments
Applicants argue that they are in compliance with all regulations regarding sequences.
Applicant's arguments filed 15 Aug, 2026 have been fully considered but they are not persuasive.
Applicants argue that they are in compliance with all regulations regarding sequences. However, without an explanation of how their lack of SEQ ID numbers associated with the various sequences in the specification still meets all the appropriate regulations, this is argument is merely a statement of disagreement, which is insufficient to overcome the rejection.
Claims Status
Claims 1-18 are pending.
Claims 1-4 have been amended.
Claims 17 and 18 are new.
Claims 2, 3, and 5-18 are withdrawn from consideration due to an election/restriction requirement.
It is noted that applicants state that they have added claims 17-28, but only the first two of those claims are found in the submitted claim set.
Withdrawn Rejections
The rejection of claim(s) 1 under 35 U.S.C. 102(a)(1) as being anticipated by Pryyma et al (Bioconj. Chem. (Dec, 2020) 31 p2685-2690) is hereby withdrawn due to amendment.
Maintained/Modified Rejections
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 and 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 1 and 4.
response to applicant’s arguments
Applicants point to differences between each reference and their claims, imply that Weiboldt et al use a different nitrobenzyl derivative, imply there is no rationale to combine, argue no reasonable expectation of success, and argue synergy (presumably an argument of unexpected results).
Applicant's arguments filed 15 Aug, 2026 have been fully considered but they are not persuasive.
Applicants have demonstrated that none of the references cited in the rejection anticipate the claims. However, this is not a rejection under 35 USC 102, but rather, 35 USC 103; there is no requirement in that statute that all limitations of a claim be found in a single reference.
Applicants imply that Weiboldt et al uses a different nitrobenzyl group, showing figures where the carbon between the aromatic ring and the urea is substituted with a carboxylate. However, the reference also discusses variants unsubstituted at that position, note scheme I, p8828, 1st column, top of page.
Applicants imply that there is no rationale to combine, but do not explain why the rationales given, various substitutions and to protect the citrulline side chain from side reactions, is improper or invalid.
Applicants argue no reasonable expectation of success. Yet Weiboldt et al shows that ureas can be modified and protected with these protecting groups, which would lead to a reasonable expectation of success with the substituted urea compounds of applicants, as noted in the rejection.
Applicants argue synergy. It is not clear what they are discussing; the arguments do not describe where synergy is to be found, a search of the specification did not find it, and there is no declaration with data supporting their argument..
Conclusion
THIS ACTION IS MADE FINAL. 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.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melissa Fisher can be reached at 571-270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658
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