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 Ile coupling in 2-methyltetrahydrofuran followed by extraction with DMAP in potassium carbonate without traverse in the reply filed on 1 July, 2025 and the phone call with Xiaoxiang Liu on 17 July, 2025.
Applicants argue that claims 5 and 7 were improperly withdrawn. Claim 5 requires a non-natural amino acid in the peptide; this was not elected. Claim 7 specifies the relative concentration of the amine compounds. In the 17 July, 2025 phone call with Xiaoxiang Liu, applicant’s representative, the office was instructed to use the peptide and extraction base of example 2. No mention was given of the relative concentrations in this phone call or applicant’s 1 July, 2025 response, indicating that this is a non-elected parameter. Thus, both claims are properly withdrawn.
Claims Status
Claims 1 and 4-15 are pending.
Claim 1 has been amended.
Claims 5 and 7 have been withdrawn from consideration due to an election/restriction requirement.
Withdrawn Rejections
The rejection of claim 3 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite due to uncertainty as to measuring stearic hinderance is hereby withdrawn due to amendment.
The rejection of claim 2 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite due to uncertainty as to various considerations about nucleophilicity is hereby withdrawn due to amendment.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, 4, 6, and 8-15 are rejected under 35 U.S.C. 103 as being unpatentable over Isidro-Llobet et al (J. Org. Chem (March 2019) 84 p4615-4628) in view of Mergler et al (Bachem sales literature (2005)), Schneider et al (Int. J. Peptide Protein Res. (1980) 15 p411-419), and Anderson (US 8,709,166) with evidentiary support from Pace et al (Encyclopedia of reagents for organic synthesis (2014) ISBN 978041936237).
Isidro-Llobet et al discuss peptide synthesis and purification (title). Most coupling protocols use benzotriazole derivatives such as HATU, as these reagents provide high coupling efficiency with low racemization (p4615, 2nd column, 2nd paragraph). 2-Methyltetrahydrofuran (applicant’s elected coupling solvent) is mentioned as a green solvent that can be used for peptide synthesis (p4617, 1st column, 5th paragraph). Liquid-liquid extraction is mentioned as a method of purification of the reaction mixtures (p4621, 2nd column, 2nd paragraph).
The difference between this reference and the examined claims is that this reference does not discuss the bases in the reaction and the extraction, nor does it discuss reaction conditions.
Mergler et al is a guide to peptide synthesis (title). HATU is listed as a more potent coupling reagent, useful for bulky amino acids (p42, 3d paragraph). The reaction is run with a base, usually DIPEA or collidine (“recommended standard procedure” p42, 4th paragraph). Washing steps with appropriate solvents ensures the complete elimination of reagents, byproducts, etc (p10, 2nd paragraph). This reference teaches a base in the coupling reaction, and paired with Isidro-Llobet et al teach every limitation of step A of the examined claims.
Schneider et al discuss liquid liquid extraction in peptide synthesis (title). Among the sequences synthesized using these methods are at least one with an Ile residue (applicant’s elected amino acid to couple) (table 1, p413, top of page). Routine extraction with aqueous acid and base in water are used, with basic decomposition of active esters (p414, 2nd column, 2nd paragraph). This can be done as a rapid routine workup procedure (p417, 1st column, 2nd paragraph, continues to 2nd column, 1st paragraph). Volumes of potassium carbonate (applicant’s elected solvent) needed to extract half of various protected amino acids is discussed (table 2, p416, top of page). This reference discusses some of the details of liquid liquid extraction in peptide synthesis.
Anderson also discusses extraction to remove organic compounds (title). This extraction requires a base to extract the undesired material from a polymer substrate (column 6, line 32-38). In some embodiments, the base is potassium carbonate or N,N-dimethylaminopyridine (applicant’s elected solvent and base) (column 8, line 38-52). This reference discusses using potassium carbonate and N,N dimethylaminopyridine as bases in extraction of organic compounds.
Therefore, it would be obvious to use the di-isopropyl ethyl amine in the reaction of Isidro-Llobet et al, as a standard part of the coupling reaction, as described by Mergler et al. As this is a standard protocol, an artisan in this field would attempt this reaction with a reasonable expectation of success.
Furthermore, it would be obvious to use potassium carbonate as the extraction liquid, as a simple substitution of one known element (the unknown extraction fluid of Isidro-Llobet et al) for another (the potassium carbonate of Schneider et al) yielding expected results (removal of acid components). As Schneider et al shows that protected amino acids can be removed by this process, an artisan in this field would attempt this process with a reasonable expectation of success.
Finally, it would be obvious to add the N,N dimethylaminopyridine of Anderson, as a combination of known elements yielding expected results. As the purpose of the dimethylaminopyridine is to act as a base, the same purpose as in Anderson, an artisan in this field would attempt this modification with a reasonable expectation of success.
Iisidro-Llobet et al discuss running reactions in 2methyl tetrahydrofuran. Mergler et al render obvious adding a base to the reaction mix (rendering obvious step a of claim 1). Schneider et al render obvious extraction with a base, and Anderson renders obvious N,N dimethylaminopyridine. Thus, the combination of references renders obvious claims 1, 4, and 10.
This is the same base, so will react in the same way, rendering obvious claim 8.
The references do not discuss heating or cooling with extractions, so it is presumably at room temperature. This overlaps with the temperature range of claim 6, rendering it obvious.
As evidenced by Pace et al, 2 methyltetrahydrofuran is practically immiscible with water (1st page, 1st column, 1st section, “solubility”). This means that the washing steps will be a two phase extraction. Mergler et al mentions removing essentially all the impurities with washing, which is reasonably 1.0% or less remaining. Thus, the combination of references renders obvious claim 9.
Schneider et al mention using potassium carbonate as an extraction medium, rendering obvious claim 11.
Schneider et al mention peptides with isoleucine, applicant’s elected amino acid, and protected amino acid synthesis. Thus, the combination of references renders obvious claims 12 and 13.
The reaction time would reasonably be optimized to trade off extent of reaction vs. time of reaction. The MPEP states that “Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or working ranges by routine experimentation" In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”) (MPEP2144.05.II). Thus, the combination of references renders obvious claim 14.
Both Mergler et al and Isidro-Llobet et al mention HATU as a coupling agent, rendering obvious claim 15.
response to applicant’s arguments
Applicants argue that the claimed method is simplified and more effective than existing methods, that Schneider et al teaches that potassium carbonate solution, while effective for removing N-protected amino acids, is not effective for removing N-protected amino active esters unless decomposed by an organic base, leading to a lack of a reasonable expectation of success, that Anderson et al is non-analogous art, and claim the unexpected result of faster hydrolysis of active esters compared to potassium carbonate solution.
Applicant's arguments filed 13 Nov, 2025 have been fully considered but they are not persuasive.
Applicants argue that the claimed method is simplified and more effective than existing methods. The question is not if the method is better than prior art methods, but rather if it is obvious over the cited references. The mere fact that it is allegedly improved is not sufficient to overcome the rejection.
Applicants argue that Schneider et al does not teach removing N-protected amino active esters with potassium carbonate. The rejection is not necessarily drawn to removing the amino active esters. Note that a rationale different from applicants does not render a rejection invalid (MPEP 2144(IV)).
Applicants argue that Anderson et al is non-analogous art. The test for analogous art is if the reference is from the same field of endeavor as the claimed invention, or if the reference is reasonably pertinent to the problem faced by the inventor. Applicants are purifying a peptide; Anderson et al discusses a purification technique. That makes the reference reasonably pertinent to the problem faced by the inventor.
Applicants argue that the amino active esters are hydrolyzed faster using dimethylaminopyridine in the wash solution than if it only contained potassium carbonate, which they argue is unexpected. In the previous office action, March was referenced as showing that nucleophiles catalyze ester hydrolysis. The logic is that the organic base, able to partition into the organic phase where the amino active ester is, would be expected to be a better catalyst than an inorganic base confined to the aqueous layer and the interface. Applicants argue that March demonstrates nucleophiles decomposing acetic anhydride. Applicants appear to be pointing to the tail end of the previous reaction described by March, not the reaction that the reference was relied upon for. Note that one of the compounds that Schneider et al discusses for catalyzing the decomposition, picolylamine, is not all that different from the dimethylaminopyridine used by applicants; lending support to this being an expected result.
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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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658