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 using N-methylmorpholine as the base, Fmoc as the protecting group strategy, Isobutyl chloroformate as the acid halide, and N, O, -bis(trimethylsilyl)acetamide as the silating agent with traverse in the reply filed on 22 May, 2023. In the response of 10 July, 2025, applicants amended the claims so they no longer read on this species.
Claims Status
Claims 1-3, 8, 9, 11, and 13-15 are pending.
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) 1-3, 8, 9, 11, and 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over Callens et al (US 20100298537, previously cited) in view of Fuse et al (Angew. Chem. Int. Ed. (2014) 53 p851-855, previously cited), Hinkel et al (WO 2009144175), the Organic chemistry portal web page for flow chemistry (https://www.organic-chemistry.org/topics/flowchemistry.shtm, available 2016 previously cited) and Gobert et al (Org. Process. Res. Dev. (2017) 21 p531-542, previously presented). Note that Hinkel et al is in German. A machine translation of this reference is provided, and all references to locations in this reference refer to the machine translation unless otherwise noted.
Applicants are claiming a method of making a peptide, comprising reacting a derivative of a peptide fragment with an acid chloride in the presence of at least one defined base in a flow reactor, reacting a separate amino acid/fragment derivative with a silyating agent, and reacting these two compounds together.
Callens et al discusses a process for the manufacture of a peptide (title). An amino acid or peptide fragment with a protected N-terminus and an activated carboxylic acid group is reacted with a persilyated peptide (paragraph 6). A number of sequences using α-amino acids are mentioned as candidates for this reaction (paragraph 17). Persilylating the peptide uses a silylatating agent that does not contain a cyano group, such as N, O, bis(trimethylsilyl)acetamide (paragraph 19), applicant’s elected silating agent. A preferable activating group for the carboxylic acid is an acid chloride, with a more preferable agent selected from a small group including isobutyl chloroformate (paragraph 31), applicant’s elected activating species. This reaction can be conducted in the presence of a base, with typical bases used being N, N, diisopropylamine, triethylamine, or N-methylmorpholine (paragraph 32). Amino protecting groups that can be used include Fmoc (paragraph 29), applicant’s elected protecting strategy. Note that at least one proposed reaction system uses an Fmoc protecting group (paragraph 27). An example was run where a hexapeptide was reacted with MSA in NMP, a Boc protected 4 amino acid peptide was reacted with IBCF with NMM, followed by mixing the two solutions (paragraph 54).
The difference between this reference and the instant application is that Callens et al does not use a flow reactor, nor does it specify the base.
Fuse et al discuss generating an amide bond using a microflow reactor (title). There is a tradeoff between reactivity and side reactions; coupling with a high reactivity chemistry, such as acid chlorides and anhydrides will allow for forming amide bonds with less nucleophilic amines, but will have more side reactions (p851, 2nd column, 1st paragraph). However, using a flow system, with a short residence time, allowed for reduced racemization (a side reaction) compared to bulk solution phase chemistry, while still allowing for reaction with less nucleophilic amines (p851, 2nd column, 2nd paragraph). A protected peptide was reacted in a flow system with triphosgene, with the product of the reaction continuing in the flow system to react with a C-terminal protected sequence (fig 1, p852, 1st column, top of page). The three different ingredients were added at 2 mL/min, 1.2 mL/min, and 2 mL/min, totalling 5.2 mL/min product (table 1, p852, 2nd column, top of page). By modifying the solvents used, the base, and the ratio of the base to the triphosgene, the yield and the amount of racemization could be varied (tables 1 and 2, p852, 2nd column). Note that MeCN was the most commonly used solvent in these experiments. Using different peptides under flow conditions always gave improved yield and racemization profiles compared to the same reaction run as a batch reaction (table 3, p853, 1st column, top of page). A tetrapeptide with a depsipeptide link was synthesized using this system (scheme 2, p854, 1st column, top of page). This reference discusses the advantage of peptide coupling with a flow system.
Hinkel et al discuss the synthesis of amides from a reaction of amines with carboxylates (paragraph 2), the same reaction that both Callens et al and Fuse et al (and applicants) are conducting. This reaction is conducted using an amide coupling agent (paragraph 42), such as a chloroformate (paragraph 50); the same chemistry as used by Callens et al (and similar to that of Fuse et al). A base is used in the reaction, with methydiethylamine explicitly mentioned (paragraph 107).
The organic chemistry portal web page discusses flow systems in the context of chemistry (title). There are a number of well defined advantages to flow chemistry compared to batch chemistry, including reproducibility, scale up, multistep systems, in line downstream processing, automation, and improved safety (2nd page, 1st paragraph).
Gobert et al discuss the relationship between mixing efficiency and residence time distribution (title). An increase in Reynolds number (related to both the flow rate and the tubing diameter) decreases the mixing time (p538, 2nd column, 3d paragraph). For fast reactions (note that Fuse states that the reaction is fast), the mixing rate is very important (p531, 1st column, 1st paragraph), making it an obvious parameter to optimize.
Therefore, it would be obvious to use the system of Fuse et al for the synthesis of Callens et al, to reduce the epirimization rate and to improve the yield of the reaction. As Fuse et al discusses a very similar set of reactions, an artisan in this field would attempt this process with a reasonable expectation of success.
Furthermore, it would be obvious to plumb the silyation reaction of Callens et al into the flow system of Fuse et al, to gain the advantages of reproducibility, scale up, in line downstream processing, automation, and improved safety discussed by the organic chemistry portal web page. As these improvements are general for chemical processes using flow chemistry, an artisan in this field would attempt this process with a reasonable expectation of success.
In addition, it would be obvious to use the methydiethylamine of Hinkel et al, as a simple substitution of one known element (the base of Callens et al) for another (the base of Hinkel et al) yielding expected results (amide coupling). As the two references discuss the same reaction (amide coupling), an artisan in this field would attempt this substitution with a reasonable expectation of success.
Finally, it would be obvious to optimize the tubing diameter for the flow rate and mixing characteristics required for the reaction, as discussed by Gobert et al. As optimization of the tubing diameter is common in flow chemistry, an artisan in this field would attempt this process with a reasonable expectation of success.
Callens et al describe the chemistry used by applicants, including the acid chloride activation with isobutylchlroformate, a base that meets the limitations of claim 1, and silylation of the C-terminal fragment using N,O-bis(trimethylsilyl) acetamide. Fuse et al discusses the advantages of flow chemistry. Hinkel et al renders obvious methydiethylamine as the base. Gobert et al render obvious optimizing the tubing diameter. Thus, the combination of references renders obvious claim 1.
The cited references discuss a number of bases, including methyldiethylamine and diisopropylethylamine. The MPEP states that “it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose. . .the idea of combining them flows logically from their having been individually taught in the prior art" (MPEP 2144.06). Fuse et al show that the amount of the base will affect the percent yield and the amount of side reactions, making this a result oriented variable. 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). In other words, it would be obvious to optimize the amount of base used to optimize the yield and level of difficult to remove side reactions. This renders obvious combinations of these bases and the amount used, rendering obvious claims 2, 3, and 8
The peptides described by Callens et al and Fuse et al all contain α-amino acids. Thus, the combination of references renders obvious claim 9.
Both Callens et al and Fuse et al discuss Fmoc protecting groups, rendering obvious claim 11.
Fuse et al discusses reactions in acetonitrile, rendering obvious claims 13 and 14.
Fuse et al runs their reaction with a total flow rate of 5.2 mL/min, rendering obvious claim 15.
response to applicant’s arguments
Applicants argue that the claimed bases give unexpectedly better yields than the non-methyl versions, that the flow reactor of Fuse et al is used for a different reaction, so the conclusions will not transfer, and that the rejection is based on hindsight reasoning.
Applicant's arguments filed 5 Feb, 2026 have been fully considered but they are not persuasive.
Applicants argue that it is unexpected that the claimed bases give much better results compared to non-methyl versions of the same bases. There are a number of issues with this argument. First, unexpected results are compared to the closest prior art (MPEP 716.02(e)), which is typically assumed to be the primary reference used in the rejection. While applicants may propose a closer reference as the basis of comparison (MPEP 716.02(e)(I)), they cannot use an alternative compound not described in the prior art of record as the basis of comparison. Callens et al list their yields as “above 70%” for batch reactions with no optimization described (paragraphs 48-56). As Fuse et al states that flow systems can improve yield, this is not obviously lower than applicant’s experimental results. Second, it was already known in the art that the base can make a difference in yield, (Fuse et al). The base used in the rejection has been used for generating amides from amines and carboxylates (the same reaction as applicants are conducting); in other words, this is optimization, which is not a patentable distinction. Third, it is not clear that applicant’s data is reliable. Callens et al states that their yields (batch, with no mention of optimization) vary from “greater than 70%” to “greater than 75%” (paragraphs 48-56), considerably higher than applicant’s comparative examples. Applicants state that using Fmoc protected compounds and n-methylpiperidine gave a yield of 93% of the Fmoc protected sequence. However, n-methylpiperidine, similar to piperidine, will remove Fmoc protecting groups (Liu et al, Methods Mol. Biol. (2015) 1248 p3-22, fig 5, 16th page, and scheme 1, step I, p18).
Applicants argue that the flow reactor of Fuse et al is for a different reaction, so the expectations will not transfer. This is incorrect; both applicants and Fuse et al react an acid chloride with an amine to generate an amide. Furthermore, it is generally known that flow reactors can improve yields (note Rossetti et al, Chem. Eng. J. (2016) 296 p56-70, p57, 1st column, 2nd paragraph). In other words, this effect is not limited to the specific reaction run by Fuse et al.
Finally, applicants argue that the rejection is based on hindsight reasoning, because the cited references have solutions for synthesizing peptides. However, that is not evidence of hindsight reasoning. The courts have decided that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as the reconstruction takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Applicants have not pointed to any element of the rejection that is not described by the cited references.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 8, 9, 11, and 13-15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 13, and 18 of U.S. Patent No. 12,240,871 in view of Fuse et al (Angew. Chem. Int. Ed. (2014) 53 p851-855, cited by applicants), Hinkel et al (WO 2009144175), and Gobert et al (Org. Process. Res. Dev. (2017) 21 p531-542). Note that Hinkel et al is in German. A machine language translation was used for this rejection, and references to locations in the reference refer to the machine translation unless otherwise noted.
Competing claim 1 describes a method of synthesizing a peptide, comprising reacting an amino acid or N-terminal protected fragment with a C5-40 alkyl acid chloride based, activating agent, reacting a second amino acid derivative with a sliylating agent, and mixing the product of these two reactions together. Competing claim 8 specifies that one of the reaction materials is an α-amino acid. Competing claim 13 specifies an activating agent that is patentably indistinct from isobutylchloroformate. Competing claim 18 specifies that the silylating agent be N,O-bis(trimethylsilyl)acetamide.
The difference between the claims of the competing application and this application is that the competing claims do not describe a flow system, protecting groups, or amide bases.
Fuse et al discuss generating an amide bond using a microflow reactor (title). There is a tradeoff between reactivity and side reactions; coupling with a high reactivity chemistry, such as acid chlorides and anhydrides will allow for forming amide bonds with less nucleophilic amines, but will have more side reactions (p851, 2nd column, 1st paragraph). However, using a flow system, with a short residence time, allowed for reduced racemization (a side reaction) compared to bulk solution phase chemistry, while still allowing for reaction with less nucleophilic amines (p851, 2nd column, 2nd paragraph). A protected peptide was reacted in a flow system with triphosgene, with the product of the reaction continuing in the flow system to react with a C-terminal protected sequence (fig 1, p852, 1st column, top of page). The three different ingredients were added at 2 mL/min, 1.2 mL/min, and 2 mL/min, totalling 5.2 mL/min product (table 1, p852, 2nd column, top of page). By modifying the solvents used, the base, and the ratio of the base to the triphosgene, the yield and the amount of racemization could be varied (tables 1 and 2, p852, 2nd column). Note that MeCN was the most commonly used solvent in these experiments. Using different peptides under flow conditions always gave improved yield and racemization profiles compared to the same reaction run as a batch reaction (table 3, p853, 1st column, top of page). A tetrapeptide with a depsipeptide link was synthesized using this system (scheme 2, p854, 1st column, top of page). This reference discusses the advantage of peptide coupling with a flow system.
Hinkel et al discuss the synthesis of amides from a reaction of amines with carboxylates (paragraph 2), the same reaction that both the competing claims and Fuse et al (and applicants) are conducting. This reaction is conducted using an amide coupling agent (paragraph 42), such as a chloroformate (paragraph 50); the same chemistry as used by the competing claimsl (and similar to that of Fuse et al). A base is used in the reaction, with methydiethylamine explicitly mentioned (paragraph 107).
Gobert et al discuss the relationship between mixing efficiency and residence time distribution (title). An increase in Reynolds number (related to both the flow rate and the tubing diameter) decreases the mixing time (p538, 2nd column, 3d paragraph). For fast reactions (note that Fuse states that the reaction is fast), the mixing rate is very important (p531, 1st column, 1st paragraph), making it an obvious parameter to optimize.
Therefore, it would be obvious to use the system of Fuse et al for the synthesis of Callens et al, to reduce the epirimization rate and to improve the yield of the reaction. As Fuse et al discusses a very similar set of reactions, an artisan in this field would attempt this process with a reasonable expectation of success.
Furthermore, it would be obvious to optimize the tubing diameter for the flow rate and mixing characteristics required for the reaction, as discussed by Gobert et al. As optimization of the tubing diameter is common in flow chemistry, an artisan in this field would attempt this process with a reasonable expectation of success.
Finally, it would be obvious to use the base of Hinkel et al as a simple substitution of one known element (the base of the competing claims) for another (the base of Hinkel et al) yielding expected results (formation of an amide bond). As the various references are all discussing the same chemistry, an artisan in this field would attempt this process with a reasonable expectation of success.
response to applicant’s arguments
Applicants argue that the rejection does not describe improved yields of their invention, and that there is no teaching or motivation for amending the competing claims to yield applicant’s claimed invention.
Applicant's arguments filed 5 Feb, 2026 have been fully considered but they are not persuasive.
Applicants argue that the rejection does not discuss improved yield. That is not a claim limitation.
Applicants argue that there is no teaching or motivation to combine the references. However, applicants do not explain why the portions of the rejection discussing a motivation (such as improving epirimization, as taught by Fuze et al) is improper or incorrect. Nor is it legally not correct that every rationale be a teaching-suggestion-motivation rationale (MPEP 2145(X)(c)).
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.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658