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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 14 April, 2026 has been entered.
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.
Claims Status
Claims 1, 4-7, and 9-15 are pending.
Claims 1, 11, 14, and 15 have been amended.
Claims 5 and 7 have been withdrawn from consideration due to an election/restriction requirement.
Withdrawn Rejections
The rejection of claim(s) 1, 4, 6, and 8-15 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evidentiary support from Pace et al (Encyclopedia of reagents for organic synthesis (2014) ISBN 978041936237) is hereby withdrawn due to amendment.
New 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 9-15 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), Anderson (US 8,709,166), Vrettos et al (RSC Adv. (2017) 7 p50519-50526), Bender et al (J. Am. Chem. Soc. (1957) 79 p1656-1662), and Essery et al (J. Chem. Soc. (1961) 164 p3939-3953), 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.
Vrettos et al discusses side reactions of guanidine peptide coupling agents (title). The mechanism of coupling is that the HATU forms an activated ester with the carboxyl group of the reacting amino acid (p50525, 1st column, 2nd paragraph, and scheme 3, p50525, 2nd column, top of page). This reference teaches that the C-terminal activated substance generated with HATU is an active ester.
Bender et al discuss basic catalyst of ester hydrolysis (title). The activity of a basic catalyst is strongly correlated with the basicity of the catalyzing amine, absent steric effects (abstract). The compounds tested had pKa values varying from 5.2 to 9.7 (table 1, p1657, 2nd column, center of page). For most amine catalysts, a log-log plot of the reaction constant vs the Ka of the catalyst is linear (fig 4, p1660, 1st column, top of page), in other words, the larger the pKa, the more effective the catalyst. This reference correlates pKa of an amine catalysts with reaction rate for hydrolysis of esters.
Essery et al discuss properties of aminopyridine derivatives (title). At 20°C, the pKa of N,N dimethylaminopyridine is 9.7 (table 2, p3944, top of page). This reference shows that the dimethylaminopyridine of Anderson, given the teachings of Bender et al and Vrettos et al, would be expected to very efficiently decompose the active esters formed by HATU in the synthesis of Isidro-Llobet et al.
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. As shown by Vrettos et al, the HATU of Isidro-Llobet et al will form an active ester. Bender et al states that amine bases will decompose esters with a constant that increases with pKa of the conjugate acid. Essery et al teaches that the N,N dimethylaminopyridine of Anderson has a high pKa, so would reasonably be expected to rapidly decompose this ester. Thus, the combination of references renders obvious claims 1, 4, and 10.
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). Note the combination of Vrettos et al, Bender et al, and Essery et al strongly suggest that the catalytic hydrolysis of the active ester will be very fast. 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
While this is a new rejection, it is similar to the withdrawn rejection, and many of applicant’s arguments apply. In the interest of compact prosecution, those arguments are answered here.
Applicants argue that they have explicitly added limitations of hydrolysis of the activated ester, that the mechanism of reaction of the compounds of Schneider et al are different than that of applicants, that Anderson is non-analogous art, and claim unexpected results of rapid hydrolysis.
Applicant's arguments filed 14 April, 2025 have been fully considered but they are not persuasive.
Applicants argue that they have added limitations of hydrolysis of the activated specie. The rejection has been amended to make this explicit.
Applicants argue that the mechanism of removal of the active specie by Schneider et al is different than that of applicants. It is not clear how this overcomes the rejection. The reference makes it clear that removal of this activated compound is desirable. The combination of Vrettos et al, Bender et al, and Essery et al make clear a person of skill in the art would expect the dimethyl aminopyridine of Anderson to catalyze hydrolysis of the activated ester.
Applicants argue that Anderson is not analogous art. The test of analogous art is if the reference from the same field of endeavor as the claimed invention, or if the reference is reasonable pertinent to the problem faced by the inventor. Applicants are purifying a peptide; Anderson discuss a purification technique. That makes the reference reasonably pertinent to the problem faced by the inventors.
Applicants argue that it is unexpected that the active specie is rapidly hydrolyzed. It is not clear why this would be unexpected. As noted above, the combination of Vrettos et al, Bender et al, and Essery et al make it clear that a person of skill in the art would have expected rapid hydrolysis.
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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