DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-10, 20-22, 27-32 and 41 are pending.
Applicant’s amendment to the claims filed 06/04/2026 is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Election
Applicant’s election with traverse of
Group I, claims 1-10 and 20-22, drawn to the technical feature of a method of restoring one or more reduced or degraded para-azido-phenylalanine (pAzF) residues in a polypeptide in need thereof comprising contacting the polypeptide with an effective amount of imidazole-1-sulfonyl azide (ISAz) to restore one or more of the reduced or degraded pAzF residues to pAzF therein,
in the reply filed 06/04/2026 is acknowledged. The traversal is on the grounds that there is no undue examination and search burden for searching methods of restoring one or more reduced or degraded pAzF residues in a polypeptide according to claims 27-32 and the restored polypeptides manufactured according to claim 41. Applicant further states the claims have unity because Wang et al. (Angew Chem Int, 2012, 57:1; cited on the IDS filed 01/14/2025) does not teach or suggest restoring one or more reduced or degraded pAzF residues in a polypeptide in need thereof comprising contacting the polypeptide with an effective amount of (ISAz) to restore one or more of the reduced or degraded pAzF residues to pAzF therein. Applicant additionally states the International Search Authority (ISA) did not find a lack of unity, and the International Search Report (ISR) found claims 1-40 to be novel and inventive.
Applicant’s arguments are considered and not found convincing. The instant application is a national stage filing under 35 U.S.C. 371, and the Requirement for Restriction mailed 12/04/2025 cites 35 U.S.C. 121 and 372 for the basis of restriction as the application contains inventions or groups of inventions which are not so linked as to form a single general inventive concept under PCT Rule 13.1, and as such search burden and examination burden are not factors considered in the requirement for restriction.
Regarding unity, as stated in the Requirement for Restriction mailed 12/04/2025, the inventions of Groups I, II and III require the technical feature of a polypeptide comprising a para-azido phenylalanine (pAzF) residue. Applicant states claim 27 of Group II and claim 41 of Group III each depend from claim 1, and implies therefore that the shared technical feature among the inventions of Groups I, II and III is the method of claim 1. However, claim 41 recites “a polypeptide manufactured according to the method of claim 41”, and therefore is a product-by-process claim wherein the product (e.g., a polypeptide) is not limited to the manipulations of the recited steps (e.g., the method of claim 1), but only the structure implied by the steps (e.g., a polypeptide comprising a pAzF residue) (see MPEP 2113.I). This technical feature of a polypeptide comprising a pAzF residue is not a special technical feature as it does not make a contribution over the prior art in view of Wang which discloses a GFP polypeptide with a pAzPhe residue [p 1, col 1, para 1; and Scheme 1].
Regarding Applicant’s statement of the findings of the ISR and ISA, this is not found persuasive because the United States Patent and Trademark Office is not bound by the lack of unity determination by another ISA. 37 C.F.R. 1.484 states the international preliminary examination is a non-binding opinion. Additionally, 37 C.F.R. 1.499 states that, if the Examiner finds that a national stage application lacks unity of invention under 37 C.F.R. 1.475, the Examiner may in an Office action require the applicant in the response to that action to elect the invention to which the claims shall be restricted. Thus, the determination of lack of unity made in the Requirement for Restriction mailed 12/04/2025 is proper under the PCT treaty.
The requirement is still deemed proper and is therefore made FINAL.
Applicant’s election without traverse of
Species A1) modifying the pAzF residue by copper-catalyzed azide-alkyne cycloaddition,
in the reply filed 06/04/2026 is acknowledged.
Claims 27-32 and 41 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 with traverse in the reply filed on 06/04/2026.
Claims 1-10 and 20-22 are being examined on the merits only to the extent they read on the elected subject matter.
Priority
The instant application is a national stage filing under 35 U.S.C. 371 of international application PCT/US2022/027885 filed 05/05/2022, which claims domestic priority to U.S. Provisional Application No. 63/184,646 filed 05/05/2021.
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 01/14/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS has been considered by the examiner.
Non-Patent Literature Document Foreign Patent Documents 90 and 133 of the IDS filed 01/14/2025 have been lined through because there is no copy of a reference with the author “Myffeler et al.” or a reference with the author “Zhnag et al.” in the application file.
Objections to Specification
The disclosure is objected to because of the following informalities.
The use of the terms GE HEALTHCARE, STRATAGENE, QIAGEN, SIGMA-ALDRICH, CHEMAXON, PERKINELMER, FISHER SCIENTIFIC, J.T. BAKER, EMD MILLIPORE, BIO-RAD, PROMEGA, AGILENT, NEB, BOSTON BIOCHEM, PIERCE, PICOFRIT, WATERS, CHARLES RIVER, BRUKER, NEW ENGLAND BIOLABS, KAPA BIOSYSTEMS, KAPA HIFI PCR, KAPA HOTSTART READYMX, GENEWIZ, BACHEM, ABCAM, and ADDGENE, which are trade names or marks used in commerce, have been noted in this application in pages 38, 69-72, 81-82, 87-89, 100-101, 103-105 and 109. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
Objections to Drawings
The drawings are objected to for the following reasons:
Figure 4A contains a marking "C" with no corresponding description in the specification;
Figures 6D-6G contain markings ELP(0FA)GFP, ELP(1FA)GFP, ELP(5FA)GFP, and ELP(10FA)GFP that do not correspond to the description in the specification;
Figure 7B contains X-axis labels which are illegible on the right side;
Figures 7C and 7D are presented without color and contain reference to red intensity;
Figures 7F-7I contain legends which are illegible;
Figures 8B and 8C contain series labels within the legend which are illegible;
Figures 9A-9G contain X- and Y-axis labels which are illegible.
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.
Claim Objections
Claim 5 is objected to as not ending with a period. See MPEP 608.01(m).
Claim 10 is objected to for the phrase “The method of claim 9, at least 95 … percent of the … residues are pAzF after the contacting”. In the interest of improving claim form, Applicant should consider an amendment to recite “The method of claim 9, wherein at least 95 … percent of the … reduced or degraded pAzF residues are restored to pAzF after the contacting”.
Claim 22 is objected to for the phrase “wherein the moiety is a lipid”. In the interest of improving claim form and consistency with claim 20, Applicant should consider an amendment to recite “where in the one or more moieties comprise a lipid”.
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.
Claims 4-7 and 10 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 4 is rejected for the recitation of “the conditions”. There is no antecedent basis for this limitation in the claim. Applicant may consider amending the claim to depend from claim 2.
Claims 5-7 are indefinite for the recitation of the phrase “about”. The term “about” is a term of approximation that renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. As such, the limitations of pH recited in claim 5, of the amount of ISAz recited in claim 6, and of contact time recited in claim 7 are is rendered indefinite by the use of the term. See MPEP 2173.05(b).III.A regarding the term “about.”
Claim 10 is indefinite for the recitation of the phrase “at least 95 … percent of the between 1 and 500 residues are pAzF after the contacting”, as the phrase encompasses a polypeptide with less than 1 residue of pAzF resulting from the method of claim 1 (from which claim 10 ultimately depends). It is unclear how carrying out the method of claim 1, which requires the restoration of one or more reduced or degraded pAzF residues to pAzF, can result in less than 1 residue of pAzF as encompassed by claim 10.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-10 and 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015/120287 A2 (cited on the IDS filed 01/14/2025; herein Isaacs) in view of Wang et al. (Nat Chem, 2014, 6:393; cited on the IDS filed 01/14/2025; herein Wang) and Schoffelen et al. (Chem Sci, 2011, 2:701; cited on the IDS filed 01/14/2025; herein Schoffelen).
Claim 1 is drawn to a method of restoring one or more reduced or degraded para-azido-phenylalanine (pAzF) residues in a polypeptide in need thereof, comprising
contacting the polypeptide with an effective amount of imidazole-1-sulfonyl azide (ISAz) to restore one or more of the reduced or degraded pAzF residues to pAzF therein.
Isaacs relates to polypeptides having non-standard amino acids and methods of use thereof [title].
Regarding claim 1, Isaacs teaches polypeptides with multiple instances of pAzF [p 60, lines 22-25], and that these polypeptides allow for the highly efficient copper-catalyzed azide-alkyne addition click chemistry reaction with alkyne-containing molecules to allow said polypeptides to be functionalized with molecules such as small molecule drugs, imaging agents and molecular linkers [p 60, lines 10-21]. Isaacs further teaches examples of alkyne-bearing molecules to be added to pAzF-containing proteins through in vivo click reactions such as Cy5.5 fluorophores to improve in vivo cell imaging [p 141, lines 16-25] as well as the fatty acid palmitic acid, which is understood to be a lipid, to improve in vivo pharmacokinetics profile via albumin binding [p 142, lines 15-25]. Regarding the degradation of pAzF, Isaacs teaches the analysis of non-standard amino acid-containing polypeptides, including those containing pAzF via mass spectroscopy, comprising the identification of pAzF degradation products [p 125, lines 10-30], which is considered to correspond to a polypeptide with one or more reduced or degraded pAzF residues. In view of Isaacs, One of skill in the art would recognize the applications of pAzF-containing proteins as taught by Isaacs depend on the presence of the azide group of pAzF, and would additionally recognize that polypeptides bearing degraded pAzF residues would not be capable of participating in the copper-catalyzed azide-alkyne addition click chemistry reaction used for functionalization of the proteins with alkyne-containing molecules.
Isaacs does not teach contacting the polypeptide with an effective amount of ISAz to restore one or more of the reduced or degraded pAzF residues to pAzF.
Wang relates to polypeptides containing unnatural amino acids [title] and discusses methods of incorporating various unnatural amino acids into peptides [p 393, top, Structures 1-8], wherein one of the unnatural amino acids is pAzF [p 393, top, Structure 4]. Regarding pAzF degradation, Wang teaches the evaluation of amino acid incorporation via mass spectroscopy and discloses the detection of additional peaks in samples that were intended to show incorporation of pAzF, wherein the additional peak corresponds to the reduction of the azide in pAzF to an amine [Figure 4, top row, and Figure 4 legend]. Wang further teaches that the reacting of azides with alkynes is an example of labeling proteins comprising unnatural amino acids, but unfortunately azides are known to degrade via in vivo reduction [p 398, col 1, para 1].
Schoffelen relates to pH-controlled introduction of azides in proteins [title] and discusses the use of azide-alkyne cycloaddition as a chemoselective ligation strategy for modification of proteins [p 701, col 1, para 1].
Regarding claim 1, Schoffelen teaches a method of converting amines to azides in proteins using imidazole-1-sulfonyl azide (ISAz) as a diazotransfer reagent [abstract]. One of ordinary skill in the art would have reasonably concluded that the diazo transfer reaction of Schoffelen can be used to replace the amine from the degraded pAzF, as taught by Wang, with an azide, in order to recover the lost potential for functionalization of the pAzF-containing polypeptide with alkyne-containing molecules, as taught by Isaacs and Schoffelen.
In view of Isaacs, Wang and Schoffelen, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Isaacs by treating the degraded pAzF-containing polypeptides with ISAz, as taught by Schoffelen, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the method of Isaacs by treating the degraded pAzF-containing polypeptides with ISAz because Isaacs teaches the functionalization of pAzF-containing polypeptides with alkyne-containing molecules is dependent on the azide group, Wang teaches the azide group of pAzF is known to degrade to an amine, and Schoffelen teaches a method of replacing an amine with an azide group to allow for azide-alkyne click chemistry reactions for the functionalization of proteins. One of ordinary skill in the art would have had a reasonable expectation of success because Isaacs and Wang relate to pAzF-containing polypeptides, and Isaacs and Schoffelen relate to the functionalization of proteins containing azide molecules via azide-alkyne click chemistry reactions.
Regarding claims 2-3, Schoffelen teaches the diazotransfer reaction occurs in milliQ water containing Na2CO3 and CuSO4 [p 704, col 2, Section “Diazotransfer to proteins”], which is considered to correspond to the method occurring under aqueous conditions and without organic solvent.
Regarding claims 4-5, Schoffelen teaches the diazotransfer reaction when carried out at different pH, such as pH 8.5, can facilitate the replacement of low pKa amines such as the N-terminus of the protein [p 701, col 2, final paragraph].
Regarding claim 6, Schoffelen teaches diazotransfer reactions performed with 1.75, 17.5 or 175 equivalents of diazotransfer reagent per amine [p 704, col 2, Section “Diazotransfer to proteins”].
Regarding claim 7, Schoffelen teaches diazotransfer reactions that are carried out overnight [p 704, col 2, Section “Diazotransfer to proteins”], which is considered to correspond to less than 24 hours. According to MPEP 2144.05, in the case where the claimed ranges overlap or lie inside ranges disclosed by the prior art, a prima facie case of obviousness exists.
Regarding claim 8, Isaacs teaches a polypeptide containing 2 pAzF residues [Table 12].
Regarding claim 9, Schoffelen teaches a method of converting amines to azides in proteins using ISAz as a diazotransfer reagent and Isaacs teaches a polypeptide comprising degraded pAzF molecules as discussed in the rejection of claim 1 above. According to MPEP 2144.05.II.A, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In view of the teachings of Isaacs, Wang and Schoffelen, one of ordinary skill in the art would have been capable of optimizing the combined method of Isaacs, Wang and Schoffelen to include proteins wherein at least 10, 15, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% of the 1-500 pAzF residues are degraded prior to the contacting.
Regarding claim 10, Schoffelen teaches a method of converting amines to azides in proteins using ISAz as a diazotransfer reagent and Isaacs teaches a polypeptide comprising degraded pAzF molecules as discussed in the rejection of claim 1 above. According to MPEP 2144.05.II.A, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In view of the teachings of Isaacs, Wang and Schoffelen, one of ordinary skill in the art would have been capable of optimizing the combined method of Isaacs, Wang and Schoffelen to produce proteins wherein at least 95, 90, 85, 80, 75, 70, 65, 60, 55, or 50% of the 1-500 pAzF residues are pAzF after the contacting.
Additionally, Schoffelen teaches that the number of amines converted to azides decreases with lowering pH and in the absence of Cu(II) [p 702, beginning final paragraph], and therefore identifies pH and Cu(II) to be result-effective variables according to MPEP 2144.05.II.B, which are variables that achieve a recognized result (e.g., yield of amine conversion to azide). In view of the results and teachings of Schoffelen, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the combined method of Isaacs, Wang and Schoffelen to achieve the claimed percent of restored pAzF molecules, as Schoffelen establishes the result-effective variables of pH and Cu(II) that affect the yield of amine conversion in proteins to azide.
Regarding claims 20-22, Isaacs teaches modifying pAzF-containing proteins to include alkyne-containing palmitic acid [p 142, lines 15-25], which is understood to be a lipid, wherein the modification comprises copper-catalyzed azide-alkyne cycloaddition [p 60, lines 10-21].
Therefore, the invention of claims 1-10 and 20-22 would have been obvious to one of ordinary skill in the art before the effective filing date.
Conclusion
Status of the Application:
Claims 1-10, 20-22, 27-32 and 41 are pending.
Claims 27-32 and 41 are withdrawn.
Claims 1-10 and 20-22 are rejected.
No claim is in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH SPANGLER whose telephone number is (571)270-0314. The examiner can normally be reached M-F 7:30 am - 4:30 pm.
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/JOSEPH R SPANGLER/
Examiner
Art Unit 1656
/David Steadman/
Primary Examiner, Art Unit 1656
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