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 .
Claim Status
Claims 1-17 are pending. Claims 5-6, 12, and 17 are withdrawn. Claims 1-4, 7-11, and 13-16 are presently considered.
Election/Restriction
Applicant’s election without traverse of Group I (claims 1-16) and the species of Example 7-5, condition B at paragraphs [0364], and [0367]-[0372] in the reply filed on 3/12/2026 is acknowledged.
The originally elected species is understood to be a method for producing a peptide by solid-phase comprising at least the three steps set forth at claim 1 as filed 6/28/2023, as follows:
The originally elected species of Example 7-5, condition B1.
Examiner notes that a solid phase peptide synthesis methodology typically comprises seven basic steps, namely (1) resin swelling and preparation; (2) loading the first amino acid; (3) Fmoc deprotection (Deblocking); (4) Activation and Coupling (i.e., Condensing Step or Elongation Step); (5) Washing; (6) Cycle Repetitions of steps 3-5 until full peptide is assembled; and finally (7) Cleavage and Global deprotection.
In the instant claim, the basic steps (1)-(2) are essentially skipped by claim 1 at step 1, which begins by providing an existing, resin bound peptide of Compound 1-2-11; furthermore, steps (5)-(7) are left unspecified at claim 1.
The originally elected species of Example 7-5, condition B2, is understood to be a “condition with solvent bubbled with CO2” 3. The summary of this reaction is provided at Table 15, which is reproduced in part below:
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Critically, Example 7-5, condition B (see, e.g., Spec. filed 4/28/2023 at ¶¶[0364], [0367]-[0372], Table 15 at Run 2 at [0371]) appears to be incorrectly described by the Applicant in the Response, because Applicant identifies the solvent at Step (2) (i.e., deblocking step) to be “DCM (a halogen solvent)” (see, e.g., Reply filed 3/12/2026 at page 4-5); however, Example 7-5, condition B, explicitly utilizes 2% DBU or 1,8-diazabicyclo[5.4.0]-7-undecene in CO2-DMF4, wherein the step is described as “using a solvent bubbled with CO2 as a carbonate source”5, and therefore the elected species is reasonably inferred to utilize a “base having a pKa of 23 or more in acetonitrile. . . . in a solvent containing . . . a carbonate solvent” of 2% DBU or 1,8-diazabicyclo[5.4.0]-7-undecene in CO2-DMF. This is reasonable because the elected example does not teach or disclose DBU in DCM6 as alleged in the Reply.
Accordingly, the originally elected species is understood as follows: The elected species is understood to be a method for producing a peptide, comprising the steps of
(1) providing the peptide bound to a resin of Compound 1-2-11
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This peptide contains an “Fmoc skeleton” (i.e., Fmoc) and is supported on a solid-phase synthesis resin (i.e., chlorotrityl resin) (see, e.g., Spec. filed 4/28/2023 at ¶¶[0364], [0367]-[0372]; see also Spec. filed 4/28/2023 at ¶¶[0214]-[0219] and [0226], discussing synthesis of Compound 1-2-11, and identifying resin); The resin bound “first peptide” was treated with DCM to swell the resin and then washed twice with DMF (see, e.g., id. at ¶[0367]).
(2) [Deblocking Step] Then, “after the step(1)”, resin-bound compound 1-2-11 is then treated in a deblocking step with a solvent comprising the base of DBU (which has a pKa of 23 or more in acetonitrile) in CO2-DMF (i.e., 2% DBU or 1,8-diazabicyclo[5.4.0]-7-undecene in CO2-DMF7), and then washed with DMF (see, e.g., Spec. filed 4/28/2023 at ¶[0367])..
(3) [Activation and Coupling (Condensing step)] Then, “after the step(1)”, and in step (3), the deblocked, washed resin was combined with a “carboxylic acid or a carboxylic acid analog”, namely an amino acid having a protecting group, and specifically Fmoc-MeIle-OH in DMF, with PyOxim (typical counter anion is PF6-) and DIPEA (see, e.g., Spec. filed 4/28/2023 at ¶[0368]). Following mixing for 2 hours, the mixture is discharged and the resin is washed with DMF and then DCM (see id), in order to obtain the third peptide of compound 4-1-6:
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The originally elected species, therefore, is understood to read upon claims 1-4, 7-11, and 13-16 (wherein the donor number of DMF-CO2 would be approximately zero); but to not read upon instant claims 5-6 or 12 as explained below. Regarding instant claim 5, the CO2 in CO2-DMF is what acts “as a carbonate source”8, but CO2 is not reasonably present at 25 v/v% or higher, and this limitation is not actually addressed in the disclosure of the originally elected species. Regarding claim 6, neither DMF-CO2 or CO2 is enumerated with claim 6. Regarding instant claim 12, the Applicant identified that it did not read upon the originally elected species in the reply filed on 3/12/2026.
Following extensive search and examination, the originally elected species has been deemed free of the prior art in view of the combination of specific elements,
Per MPEP § 803.02(III)
If the examiner determines that the elected species is allowable over the prior art, the examination of the Markush claim will be extended. If prior art is then found that anticipates or renders obvious the Markush claim with respect to a nonelected species, the Markush claim shall be rejected; claims to the nonelected species would still be held withdrawn from further consideration. The prior art search will not be extended unnecessarily to cover all nonelected species.
Accordingly, Examination was extended to a non-elected species, namely a method of peptide synthesis wherein a first-peptide bound to 2-chlorotrityl resin is treated with a mixture of piperidine/DBU/toluene/DMF (5:5:20:70), and then coupled to Fmoc-N-L-alanine in the presence of DIC/DMF and OxymaPure®9. Following search and examination, the non-elected species has been deemed anticipated and/or obvious in view of the prior art of US’893 as applied below. Per MPEP § 803.02(III), claims directed to other nonelected species have been withdrawn.
Claim 17 is 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 without traverse in the reply filed on 3/12/2026.
Claims 5-6 or 12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3/12/2026.
Claims 1-4, 7-11, and 13-16 are presently considered.
Priority
The priority claim PCT/JP2021/039586 (filed 10/27/2021) is acknowledged.
Examiner notes that no certified translation of the Foreign Application JP2020-184839 (filed 11/05/2020) has been placed on record. If applicant wants the application to be accorded benefit of the non-English language application, a certified translation is required (see 35 U.S.C. 119(b)(3), 37 CFR 1.55(g)(1)-(4)). Applicant is advised that any showing of priority that relies on a non-English language application is prima facie insufficient if no certified translation of the application is on file. See 37 CFR 41.154(b).
Information Disclosure Statement
The IDS filed 3/12/2026 is acknowledged and presently considered.
Applicant should note that one or more documents disclosed on the IDS form submitted on 3/12/2026 were not considered since they did not conform to 37 CFR 1.98(b) by providing a proper date, as 37 CFR 1.98(b) requires that each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue. See MPEP 609.04(a). Here, the earliest priority claim is to JP2020-184839, filed 11/05/2020; therefore, all documents published in 2019 or later must be accompanied by both month and date of publication.
References that were not considered have been indicated by strike-though on the attached IDS forms. Although not considered, these documents have been placed in the application file, but the information referred to therein has not been considered as to the merits. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Claim Interpretation
For purposes of examination, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
Claim 1 is representative of the pending claim scope and presently recites:
1. (Original) A method for producing a peptide by a solid-phase method, comprising the steps of:
(1) providing a first peptide having a protective group containing an Fmoc skeleton and supported on a solid-phase synthesis resin;
(2) treating the first peptide with one or more bases including at least a base having a pKa of 23 or more in acetonitrile as a conjugate acid in a solvent containing at least one selected from the group consisting of an aromatic hydrocarbon solvent, a halogen solvent, an ether solvent, an ester solvent, a ketone solvent, a carbonate solvent and a phosphoric acid ester solvent after the step (l); and
(3) condensing the first peptide with a carboxylic acid or a carboxylic acid analog in a solvent in the presence or absence of a condensation agent to obtain a third peptide after the step (2).
Applicable claim interpretations are set forth below.
“Comprising” is an open-ended transitional term (see, e.g., MPEP § 2111.03(I)), wherein additional steps or components are not excluded. However, “‘[c]omprising’ is a term of art used in claim language which means that the named elements are essential” (see, e.g., id.; see also Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997)).
“Consisting of” excludes any elements, step, or ingredient not specified (see, e.g., MPEP § 2111.03(II)). When the phrase "consists of" appears in a clause of the body of a claim, rather than immediately following the preamble, the "consisting of" phrase limits only the element set forth in that clause; other elements are not excluded from the claim as a whole (see, e.g., MPEP § 2111.03(II)).
“Fmoc skeleton” is interpreted consistent with the specification (see, e.g., Spec. filed 4/28/2023 at ¶[57]), which identifies that an Fmoc skeleton includes any species represented by formula (1):
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Wherein, R1 to R8 are independently selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 fluoroalkyl, halogen, sulfo and trimethylsilyl; and wherein R9 to R10 are independently hydrogen or methyl (see, e.g., Spec. filed 4/28/2023 at ¶[57]).
At claim 1, the phrase requiring a base “having a pKa of 23 or more in acetonitrile as a conjugate acid” is understood to encompass at least the bases recited at claim 9 (i.e., “DBU, MTBD, TMG, PltBu, P2Et and HPI (dma)”) (see also Spec. filed 4/28/2023 at ¶¶[25]-[29]). The phrase “as a conjugate acid” is understood to be a recitation of intended and expected use, which would be necessarily satisfied by the present of a base as identified at claim 9.
At step (2), the phrase “solvent containing at least one selected from the group consisting of an aromatic hydrocarbon solvent, a halogen solvent, an ether solvent, an ester solvent, a ketone solvent, a carbonate solvent and a phosphoric acid ester solvent” is understood to read upon at least a halogen solvent (DCM), an aromatic hydrocarbon solvent (toluene or cumene), an ether solvent (THF, DME, 1,3-dioxo1ane or 2-methyltetrahydrofuran), a phosphoric acid ester solvent (tributyl phosphate), an ester solvent (methyl propionate or butyl acetate), a ketone solvent (diethyl ketone or methyl ethyl ketone), and a carbonate solvent (dimethyl carbonate) (see, e.g., Spec. filed 4/28/2023 at ¶[0261], Table 5 at [0259], [18]-[24]), and all solvents explicitly recited at claim 6. Notably, DMF (or N,N-dimethylformamide) alone is identified as an “amide solvent” (see id.)10 and is therefore excluded, meaning that if DMF is present, then another solvent in addition to DMF must be present. However, it is noted that DMF-CO2 is utilized in the originally elected species, and therefore DMF bubbled with CO2 as described in the originally elected species is understood to satisfy step (2), wherein DMF-CO2 is “a solvent bubbled with CO2 as a carbonate source”11.
The phrase “carboxylic acid or a carboxylic acid analog” is understood to encompass at least all embodiments recited at instant claims 11-13. For purposes of applying prior art, the phrase is understood to includes at least
(i) amino acids with any protective group,
(ii) active esters of amino acids with any protective group,
(iii) acid halides of amino acids with any protective group,
(iv) peptides having any protective group,
(v) active esters of peptides having any protective group,
(vi) acid halides of peptides having any protective group,
(vii) any C1-C8 alkylcarboxylic acid,
(viii) active esters of any C1-C8 alkylcarboxylic acid,
(ix) acid halides of any C1-C8 alkylcarboxylic acid,
(x) any C6-C10 arylcarboxylic acid,
(xi) active esters of any C6-C10 arylcarboxylic acid,
(xii) acid halides of any C6-C10 arylcarboxylic acid;
wherein (vii)-(xii) may be optionally substituted with one or more substituents independently selected from the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, halogen, nitro, dialkylamino, cyano, alkoxycarbonyl, and dialkylaminocarbonyl.
The term “peptide” includes peptides containing at least “2 to 30” amino acid residues (see, e.g., Spec. filed 4/28/2023 at ¶¶[43]-[49]; see esp. id. at ¶[46]).
The term “condensation reagent” is understood to include all agents discussed in the Specification (see, e.g., Spec. filed 4/28/2023 at ¶¶[51]-[53]) and utilized in the examples of record (see, e.g., Spec. filed 4/28/2023 at ¶¶[0259] at Table 5), including is present in all examples (oxyma, PyOxim, TATU, HATU, TOTU, HOTU, PyBOP, and COMU (see id).
At claim 1, and the recitation of “in the presence or absence of a condensation agent” is understood to mean that the presence of a condensation agent is optional. However, Examiner notes that all examples of record utilized condensation reagents (see, e.g., Spec. filed 4/28/2023 at ¶¶[51]-[53], Table 5 at [0259]).
Additional claim interpretations are set forth below.
Specification
The disclosure is objected to because of the following informalities:
The disclosure contains illegible content, such as structures at pages 36 and 38; Mobile phases at Table 1; and Abbreviations, Compound Numbers, CAS Nos, etc. at Tables 2-3; Tables 5-6, Table 8; and Table 10 of the Specification as filed 4/28/2023. For example,
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Is not fully legible. This example is exemplary only and not exhaustive.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see, e.g., Spec. filed 4/28/2023 at ¶¶[0009], [0136]). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the terms PYOXIM12, PYBOP13, and COMU14, which are trade names or a marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. 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.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Appropriate correction is required.
Claim Objections
Claims 1, 9, and 16 are objected to because of the following informalities:
Claim 1 recites “a solvent containing at least one selected from the group consisting of an aromatic hydrocarbon solvent, a halogen solvent….”. This should presumably be “a solvent selected from the group consisting of…”.
Claims 9 and 16 recites multiple acronyms, which should be completely spelled out at least once in the pending claim set.
Appropriate correction is required.
Claim Rejections
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3, 7, 11, 13, and 16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 3 recites the phrase “neutralizing the residual base”, but claim 1 does not recite a “residual base”. There is insufficient antecedent basis for this limitation in the claim. For purposes of applying prior art, it is presumed that the phrase refers to an intermediate, unclaimed step of claim 1, wherein the mixture of step (2) is removed prior to step (3), thereby forming a “residual base” on the resin prior to commencement of step (3). Clarification is required (e.g., Applicant may amend by adding a step of removing the base and solvent of step (2), thereby creating resin comprising a “residual base”).
Claim 7 recites “wherein the solvent in the step (2) has a donor number value of 26 or less”, but claim 1 at step (2) identifies that there is an overall “solvent” that comprises “at least one” solvent from the enumerated list at claim 1. Accordingly, it is unclear if the reference to a donor number at claim 7 is referring to the overall mixture of solvents (i.e., an average, overall property) or if claim 7 is referring only to only a single solvent within the enumerated list. There is insufficient antecedent basis for this limitation in the claim. For purposes of applying prior art, it is reasonably inferred that claim 7 refers to any individual solvent within the scope of enumerated solvents (e.g., claim 7 may be any solvent within the scope of claim 6), including toluene.
Claim 11 recites the limitation "wherein the C1-C8 alkylcarboxylic acid and the C6-C10 arylcarboxylic acid are optionally substituted" starting at line 7. There is insufficient antecedent basis for this limitation in the claim as C1-C8 alkylcarboxylic acid and C6-C10 arylcarboxylic acid are referenced more than once, and it is unclear if the “wherein” clause limits all or less than all uses.
Claim 13 recites the limitation “the amino acid having a protective group containing an Fmoc skeleton” at the final two lines. There is insufficient antecedent basis for this limitation in the claim. For purposes of examination, the line presumably refers to “an active ester of an amino acid”.
Claim 13 recites the limitation “…; or an active ester of an amino acid or a second peptide having a protective group”, which renders the claim scope indefinite because it is unclear if the phrase “having a protective group” modifies both (i) “an active ester of an amino acid” and (ii) a “second peptide”, or (iii) just modifies “a second peptide”. This alters the applicable claim interpretation and therefore renders the claim scope indefinite.
Claim 13 recites the limitation “…; or an acid halide of an amino acid or a second peptide having a protective group”, which renders the claim scope indefinite because it is unclear if the phrase “having a protective group” modifies both (i) “an acid halide of an amino acid” and (ii) a “second peptide”, or (iii) just modifies “a second peptide”. This alters the applicable claim interpretation and therefore renders the claim scope indefinite.
Claim 13 recites the indefinite “wherein” clause of
wherein the first peptide and/or the second peptide having a protective group containing an Fmoc skeleton contains one or more N-substituted amino acids, and/or the amino acid having a protective group containing an Fmoc skeleton is a N-substituted amino acid.
The “wherein” clause is indefinite in view of the usage of two “and/or” statements, which make it ambiguous what is or is not required. Specifically, in view of two “ands”, the claim scope encompasses (a) a first peptide, (b) a second peptide, and (c) a separate amino acid; this renders the claim scope indefinite because claim 1 recites two reacted components, namely a (i) first peptide and a (ii) “carboxylic acid or a carboxylic acid analog”; this raises material concerns regarding whether or not the method as claimed encompasses two distinct compounds that each independently constitute a “carboxylic acid or a carboxylic acid analog” or not. Additionally or alternatively, the “wherein” clause appears to render claim 13 internally inconsistent because lines 1-4 appear to identify that the “carboxylic acid or a carboxylic acid analog” is a single compound selected from (A) an amino acid; (B) an active ester of an amino acid; (C) an acid halide of an amino acid; (D) a second peptide comprising an Fmoc skeleton, or (E) a second peptide comprising any protective group. Accordingly, the usage of consecutive “and/or” statements raises substantial and material concerns regarding the metes and bounds of the pending claim scope.
Claim 13 recites dangling modifiers that render the scope ambiguous because it is unclear what is or is not being modified. More specifically, claim 13 recites
Wherein the carboxylic acid or carboxylic acid analog is an amino acid or a second peptide having a protective group containing an Fmoc skeleton; or an active ester of an amino acid or a second peptide having a protective group; or an acid halide of an amino acid or a second peptide having a protective group;
The “wherein” clause is indefinite because it is unclear if the claim scope reads upon a single “carboxylic acid or a carboxylic acid analog” selected from
(A) an amino acid; (B) an active ester of an amino acid; (C) an acid halide of an amino acid; (D) a second peptide comprising an Fmoc skeleton; or (E) a second peptide comprising any protective group.
Or, if alternatively, the claim scope reads upon a single “carboxylic acid or a carboxylic acid analog” selected from
(I) an amino acid comprising an Fmoc skeleton; (II) an active ester of an amino acid having any protecting group; (III) an acid halide of an amino acid having any protective group; (IV) a second peptide comprising an Fmoc skeleton; (V) an active ester of a second peptide having a protective group; or (VI) an acid halide of a second peptide having a protective group.
Or, if alternatively, the claim scope reads upon a single “carboxylic acid or a carboxylic acid analog” selected from
(i) an amino acid comprising an Fmoc skeleton; (ii) an active ester of an amino acid; (iii) an acid halide of an amino acid; (iv) a second peptide comprising an Fmoc skeleton; (v) an active ester of a second peptide having a protective group; or (vi) an acid halide of a second peptide having a protective group.
Or some combination of such options. Accordingly, the pending claim scope is indefinite and the indefiniteness impacts the metes and bounds of the pending claim scope. Applicant may overcome this rejection by amending the claim scope such that it is unambiguous what is or is not being claim by, for example, simply providing an enumerated list that completely identifies each individual possibility as exemplified in the lists provided above.
Claim 16 recites the terms PYOXIM15, PYBOP16, and COMU17, which are trade names or a marks used in commerce. Per MPEP § 2173.05 (u), when a trademark/tradename is used in a claim as a limitation to identify or describe a particular material or product the claim does not comply with 35 USC 112(b). Notably, even if expired, the usage of a trademark/trademark is still indefinite in the claim since it designates source and not content. Accordingly, claim 16 is rejected.
Accordingly, 3, 7, 11, 13, and 16 are rejected.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
[Prior Art Rejection 01]
Claims 1, 3-4, 7-11, 13 are rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by US20180319839A1 (Nov. 8, 2018).
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and in preceding rejections, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
Regarding instant claim 1, step (1), US’893 discloses Example 12 (see, e.g., US’893 at ¶¶[0166]-[0168]). Example 12 of US’893 discloses a peptide synthesis methodology including a synthesis step wherein a first peptide bound to a 2-chlorotrityl resin is provided prior to a deblocking step (compare instant claim 1 at step (1) with US’893 at ¶[0167], noting the existence of a resin-bound peptide present prior to usage of the deblocking step using piperidine/DBU/toluene/DMF (5:5:20:70)). Regarding instant claim 1 step (2), and claims 8-9, at Example 12, US’893 discloses a method wherein a first peptide (resin-bound) is treated with DBU (i.e., a base having a pKa of 23 or more in acetonitrile) in a solvent containing toluene (i.e., an aromatic hydrocarbon solvent), namely the mixture of piperidine/DBU/toluene/DMF (5:5:20:70) (see, e.g., US’893 at ¶[0167]). Regarding instant claim 1 step (3), and claims 11 and 13, at Example 12, US’893 discloses that the synthesis includes an activation and coupling step (i.e., a condensing or elongation step), wherein the first-peptide (i.e., resin bound) is coupled to a “carboxylic acid or a carboxylic acid analog”, namely Fmoc-N-L-alanine18, which is attached in the presence of DIC/DMF and OxymaPure®19 (see, e.g., US’893 at ¶[0167]). Regarding instant claim 3, US’893 does not disclose a step of neutralizing any residual base by adding any acid between the steps of deblocking with piperidine/DBU/toluene/DMF (5:5:20:70) and then coupling with Fmoc-N-L-alanine in the presence of DIC/DMF and OxymaPure® (see, e.g., US’893 at ¶[0167]). Regarding instant claim 4 and the presence of a carbamic acid salt of a peptide, this limitation is understood to be inherently and necessarily satisfied by the presence of DBU in a deprotecting step (see, e.g., Spec. filed 4/28/2023 at ¶¶[6]-[8]), and therefore this limitation is understood to be necessarily and inherently satisfied by Example 12 of US’893. Regarding instant claim 7 and a solvent in step(2) having a donor number of 26 or less, toluene is present in the piperidine/DBU/toluene/DMF (5:5:20:70) solvent, and would be understood by an artisan to have a low or negligible donor number (e.g., <1) (see, e.g., US’893 at ¶[0167]). Regarding claims 8-9 and the selection of an amidine base in step (2), DBU is a base present in the piperidine/DBU/toluene/DMF (5:5:20:70) solvent, which is an amidine base (see, e.g., US’893 at ¶[0167]). Regarding instant claim 10 and “the step of bringing the solvent into contact with CO2” at step (2), US’893 discloses Example 12 (see, e.g., US’893 at ¶¶[0166]-[0168]), which is not disclosed as being performed in a sealed, non-atmospheric environment, and therefore an artisan would either conclude the reaction was performed open to the atmosphere, or otherwise at once envisage such reaction; wherein the atmosphere contains CO2.
Accordingly, instant claims 1, 3-4, 7-11, and 13 are anticipated by the prior art.
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.
[Prior Art Rejection 02]
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over US20180319839A1 (Nov. 8, 2018) as applied to claims 1, 3-4, 7-11, and 13 above, in further view of Hachmann et al.20
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
The teachings of US’839 as applied to claims 1, 3-4, 7-11, and 13 has been discussed above, and those teachings are incorporated into the instant rejection but not repeated. Regarding instant claim 2, US’839 at Example 12 differs from the scope of instant claim 5 because it utilizes piperidine “as a single base before step (2)”, namely US’839 utilizes 20% piperidine in DMF (see, e.g., US’893 at ¶[0167]).
The teachings of US’839 differ from instant claims 5 as follows: Accordingly, Example 12 of US’839 differs from instant claim 5 because it utilizes piperidine “as a single base before step (2)”. Therefore, the issue appears to be one of finding an alternative for piperidine in deblocking steps, such as those disclosed by US’839.
Hachmann pertains to alternatives for Piperidine in Fmoc Solid-Phase synthesis, and Hachmann identifies that 3- and 4-methylpiperidine “had identical efficiency in Fmoc group removal, as compared to piperidine” (see, e.g., Hachmann at title, Tables 1-2 on 149, 149 at col I at penultimate ¶, 149 at col II at final ¶).
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): The claimed invention is the simple substitution of piperidine in the Fmoc solid phase synthesis methodology of the primary reference for an art-recognized piperidine alternative usable in Fmoc solid phase synthesis protocols as disclosed by Hachmann, wherein such substitution would yield predictable results, namely an equivalent Fmoc solid phase synthesis methodology lacking piperidine (see, e.g., MPEP § 2143(I)(B); see also MPEP § 2144.06(II)).
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the art to utilize and substitute a compound with an equivalent compound known and disclosed in the prior art.
Accordingly, claim 2 is rejected.
[Prior Art Rejection 03]
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over US20180319839A1 (Nov. 8, 2018) as applied to claims 1, 3-4, 7-11, and 13 above.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
The teachings of US’839 as applied to claims 1, 3-4, 7-11, and 13 has been discussed above, and those teachings are incorporated into the instant rejection but not repeated.
The teachings of US’839 differ from instant claims 14 as follows: US’839 at Example 12 is not utilized to synthesize a third peptide by combining a first peptide and a second amino acid (or peptide), such that the “second residue from the N-terminal of the first peptide is a N-substituted amino acid” as required by instant claim 14.
However, Example 12 of US’839 is an exemplary method, and an artisan would readily appreciate that the disclosed method could be utilized to synthesize other disclosed amino acid sequences (see, e.g., US’839 at claim 1), including sequences wherein AA1 and AA2 may be selected from N-methyl amino acids (see, e.g., US’839 at claim 1 at AA1 and AA2); and wherein an artisan would readily appreciate that any deblocking step utilizing “an amino base solution such as piperidine solution in DMF” could be replaced with “a mixture of piperidine/DBU/toluene/DMF” (see, e.g., US’839 at ¶¶[0101], [0103], [0107], [0108]), wherein US’839 identifies that the synthesis would yield an intermediate such that the second amino acid from the N-terminus would be an N-substituted amino acid (see, e.g., US’839 at ¶[0108], structure (XII)).
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): The claimed invention is the simple extension of the exemplified Fmoc synthesis protocol and disclosed deblocking solutions to additional disclosed sequences and structures, which is the combination of only prior art elements (i.e., known reagents, known Fmoc methodologies, known deblocking formulations, known sequences) according to known methods of peptide synthesis as taught by the primary reference, to yield predictable results, namely methods of synthesizing peptides as taught and disclosed by the primary reference (see, e.g., MPEP § 2143(I)(A), (B), (C), (D); see also MPEP § 2144.06(II)).
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the art to utilize and substitute a compound with an equivalent compound known and disclosed in the prior art.
Accordingly, claim 14 is rejected.
[Prior Art Rejection 04]
Claims 15-16 is rejected under 35 U.S.C. 103 as being unpatentable over US20180319839A1 (Nov. 8, 2018) as applied to claims 1, 3-4, 7-11, and 13 above, in further view of Manne et al.21.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
The teachings of US’839 as applied to claims 1, 3-4, 7-11, and 13 has been discussed above, and those teachings are incorporated into the instant rejection but not repeated. Regarding additives, US’839 does identify that the disclosed methods may include the activator of PyBOP (see, e.g., US’839 at ¶¶[0054], [0107]-[0110]), and exemplifies the usage of OxymaPure (see, e.g., US’839 at ¶[0167]).
The teachings of US’839 differ from instant claims 15-16 as follows: US’839 at Example 12 does not utilize PyOxim, COMU, etc. having a counter anion of PF6- as required by instant claims 15-16.
Regarding instant claims 15-16, and additives such as PyOxim, COMU, HOTU, TOTU, etc. having a counter anion of PF6- or BF4- , Manne discloses that additives such as those enumerated at claims 15-16 were known, prior art elements. Specifically, Manne pertains to “OxymaPure” and related coupling reagents usable in solid-phase synthesis techniques (see, e.g., Manne at title, abs), including (i) COMU, which has a PF6- counter anion (see, e.g., Manne at 3190 at col I at 1st partial ¶, 3190 at Fig. 2, 3192 at Scheme 5); (ii) HOTU, which has a PF6- counter anion (see, e.g., Manne at 3195 at col I and at Fig. 3); (iii) TOTU, which has a BF4- counter anion (see, e.g., Manne at 3195 at col I and at Fig. 3); and at least (iv) PyOxim, which has a PF6- counter anion (see, e.g., Manne at 3195 at col II and at Fig. 4), among others. Accordingly, such compounds are prior art elements having known and art-recognized utility. Regarding instant claims 15-16, and the known, desirable, and predicted benefits in solid phase synthesis of utilizing additives such as PyOxim, COMU, HOTU, TOTU, etc. having a PF6- or BF4- counter anion; Manne identifies that such additives were known in the prior art as capable of “increase[ing] coupling efficiency and control epimerization in amide bond formation” and suppress racemization (see, e.g., Manne at 3189 at col II at final ¶, 3195 at col II, 3207 at col I at § “6 Conclusion”). Accordingly, PyOxim, COMU, HOTU, and at least TOTU are understood to be modified and improved variants to OxymaPure (see, e.g., Manne at 3207 at col I at § “6 Conclusion”).
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s):
The claimed invention is the obvious combination of prior art elements (e.g., PyOxim, COMU, HOTU, or TOTU as taught by Manne; and the synthesis methods and reagents exemplified by US’839) to yield predictable results, namely an improved Fmoc solid phase synthesis protocol as taught by the primary reference with the addition of an additive as taught by Manne (i.e., PyOxim, COMU, HOTU, or TOTU), which would yield an improved Fmoc solid phase synthesis protocol relative to US’839, wherein the improved Fmoc solid phase synthesis protocol would predictably and expectedly exhibit increased coupling efficiency, controlled epimerization in amide bond formation, and suppressed racemization exactly as taught and suggested in view of Manne (see, e.g., MPEP § 2143(I)(A), (C), (D), (F), (G)).
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the art to utilize and combine known compounds having known functionalities according to known synthesis methodologies to achieve known and expected results.
Accordingly, claims 15-16 are rejected.
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.
Claim 1-2, 4, 8-11, and 13-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-11, and 14-22 of copending Application No. 18/860,859 (reference application; corresponding to US 20250353875). Although the claims at issue are not identical, they are not patentably distinct from each other as explained below.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
The copending claim sets appear to overlap substantially in scope, such that they cover the substantially overlapping subject matter, and are therefore not patentably distinct. Specifically, instant claim 1 appears to correspond to copending claims 2, 4, and 21 (compare instant claim 1 with App’859 at claims 1-6, and 21); instant claim 2 corresponds to copending claim 9 (compare instant claim 1 with App’859 at claims 9); instant claim 4 corresponds to copending claims 8 and 11 (compare instant claim 4 with App’859 at claims 8 and 11); instant claims 8-9 corresponds to copending claims 14-15, respectively (compare instant claims 8-9 with App’859 at claims 14-15); instant claim 10 is understood to be satisfied by open-air reactions (i.e., CO2 is present naturally in the atmosphere), and is therefore satisfied by the copending claims since all reactions encompass open-air reactions; instant claims 11 and 13 correspond to copending claims 17 (compare instant claims 11 and 13 with App’859 at claim 17); instant claim 14 corresponds to copending claims 17-18 (compare instant claim 14 with App’859 at claims 17-18); instant claim 15 corresponds to copending claim 19 (compare instant claim 15 with App’859 at claim 19); and regarding instant claim 16, the copending claims recite and refer to condensation agents, including those having a counterion of PF6- or BF4- (see, e.g., App’859 at claims 1 and 19-20), which are defined and described in the disclosure as including PyOxim, COMU, HATU, HOTU, TOTU, etc. (see, e.g., App’859 at Spec. filed 10/28/2024 at ¶¶[52]-[53]; )22,23.
The pending claim scope ostensibly differs as follows: The copending claims require a solvent at step (2) that contains a sulfoxide, whereas instant claims require a solvent “selected from the group consisting of an aromatic hydrocarbon solvent, a halogen solvent, an ether solvent, an ester solvent, a ketone solvent, a carbonate solvent and a phosphoric acid ester solvent”.
This difference does not render the copending claims patentably distinct because the claim sets are open-ended and may contain multiple solvents. More specifically, the obvious variants of the instant claims, which may in fact contain sulfoxide solvents in addition to the enumerated solvents, and such combinations are obvious variants within the scope of the instant claims (see, e.g., instant Spec. filed 4/28/2023 at ¶¶[70]-[71]) 24,25; similarly, the copending claims permits additional solvents in addition to a sulfoxide solvent, including obvious variants that also comprise an aromatic hydrocarbon solvent, a halogen solvent, an ether solvent, an ester solvent, a ketone solvent, a carbonate solvent and a phosphoric acid ester solvent (see, e.g., App’859 at Spec. filed 10/28/2024 at ¶¶[0-1] to [16], [17])26,27. Accordingly, both Applications are understood to overlap as such additional solvents are permitted as presently claimed and expressly identified as alternative embodiments. Furthermore, or alternatively, both claim scopes read upon solvents comprising two functional moieties, such as aryl sulfoxides (e.g., diphenyl sulfoxide), which is an aromatic hydrocarbon solvent and also a sulfoxide solvent.
Accordingly, although the two copending claim sets are not identical, the two copending claim sets are directed to overlapping subject matter, and are therefore not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US2014/0088291A1 pertains to peptide synthesis methods (see, e.g., id. at title, claims).
Teixido et al28 discusses solid-phase synthesis of N-methyl rich peptides, and directly discusses issues pertaining to DKP formation (see, e.g., Teixido at title, abs).
Heinlein et al.29 discloses peptide synthesis methods utilizing additives such as PyBOP in NMP, and utilizing DBU/HOBt-mediated Fmoc cleavage (see, e.g., Heinlein at title, abs, 6407 at col II, Scheme 2 on 6407, Scheme 3 on 6408).
Alsina et al.30, discloses and pertains to the use of N-tritylamino acids and PyAOP1 for the suppression of diketopiperazine formation in Fmoc/tBu solid-phase peptide synthesis using alkoxybenzyl ester anchoring linkages, wherein it discloses that “coupling may be carried out without a prior neutralization step using PyAOP as a coupling reagent” (see, e.g., Alsina at title, abs).
Jad et al. (2015)31, discusses alternatives to typical solvents used in solid-phase peptide synthesis, such as DMF (see, e.g., id. at title, abs, passim).
Jad et al. (2017)32, discusses alternatives to typical solvents used in solid-phase peptide synthesis, such as DMF (see, e.g., id. at title, abs, passim).
Ran et al.33, discusses alternatives to typical solvents used in solid-phase peptide synthesis, such as DMF (see, e.g., id. at title, abs, passim).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RANDALL L BEANE whose telephone number is (571)270-3457. The examiner can normally be reached Mon.-Fri., 7 AM to 2 PM ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G. Garyu can be reached at (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/RANDALL L BEANE/Primary Examiner, Art Unit 1654
1 See, e.g., Spec. filed 4/28/2023 at ¶¶[0364], [0367]-[0372], Table 15 at Run 2 at ¶[0371].
2 See, e.g., Spec. filed 4/28/2023 at ¶¶[0364], [0367]-[0372], Table 15 at Run 2 at ¶[0371].
3 See prior footnote.
4 CO2-DMF is distinguished from DMF in the instant Specification, and shown to impact reaction results (see, e.g., Spec. filed 4/28/2023 at ¶¶[0367]-[0373]; see esp. id. at Table 15 at ¶[0371]). “Condition B” as elected, corresponds to “condition with solvent bubbled with CO2”.
5 See, e.g., Spec. filed 4/28/2023 at ¶¶[0364], [0367]-[0372], Table 15 at Run 2 at ¶[0371].
6 See, e.g., Spec. filed 4/28/2023 at ¶¶[0364], [0367]-[0372], Table 15 at Run 2 at ¶[0371].
7 CO2-DMF is distinguished from DMF in the instant Specification, and shown to impact reaction results (see, e.g., Spec. filed 4/28/2023 at ¶¶[0367]-[0373]; see esp. id. at Table 15 at ¶[0371]). “Condition B” as elected, corresponds to “condition with solvent bubbled with CO2”.
8 See, e.g., Spec. filed 4/28/2023 at ¶¶[0364], [0367]-[0372], Table 15 at Run 2 at ¶[0371].
9 An artisan would appreciate this term refers to Ethyl (2Z)-2-cyano-2-(hydroxyimino)acetate, a.k.a. oxyma.
10 see, e.g., Spec. filed 4/28/2023 at ¶[0261], explaining that other amide solvents besides DMG and DMI (e.g., DMA, NMP) did not exhibit a suppressing effect.
11 See, e.g., Spec. filed 4/28/2023 at ¶¶[0364], [0367]-[0372], Table 15 at Run 2 at ¶[0371].
12 PYOXIM (Serial Number 97687669; Filing date 2022-11-22; Abandoned)
13 PYBOP (Serial Number 74548482; Registration number 1921356; Filing date 1994-07-12; Alive)
14 COMU (Serial Number 77661239; Registration number 3909714; Registration date 2011-01-25; Dead)
15 PYOXIM (Serial Number 97687669; Filing date 2022-11-22; Abandoned)
16 PYBOP (Serial Number 74548482; Registration number 1921356; Filing date 1994-07-12; Alive)
17 COMU (Serial Number 77661239; Registration number 3909714; Registration date 2011-01-25; Dead)
18 Fmoc-N-L-alanine is an “amino acid having a protective group” and specifically “an amino acid having a protective group containing an Fmoc skeleton”) as required by claims 11 and 13.
19 An artisan would appreciate this term refers to Ethyl (2Z)-2-cyano-2-(hydroxyimino)acetate, a.k.a. “oxyma”.
20 Hachmann et al., Alternative to piperidine in Fmoc solid-phase synthesis. J Comb Chem. 2006 Mar-Apr;8(2):149. doi: 10.1021/cc050123l. PMID: 16529506; hereafter “Hachmann”.
21 Manne et al., “OxymaPure Coupling Reagents: Beyond Solid-Phase Peptide Synthesis.” Synthesis 52 (published online 9/30/2020): 3189-3210; hereafter “Manne”.
22 See, e.g., MPEP § 804(II)(B)(1), “those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application”/
23 Per MPEP § 804(II)(B)(1), it is permissible to use the specification as a dictionary to learn the meaning of a term in a claim.
24 See prior two footnotes.
25 See prior two footnotes.
26 See prior two footnotes.
27 See prior two footnotes.
28 Teixidó M, Albericio F, Giralt E. Solid-phase synthesis and characterization of N-methyl-rich peptides. J Pept Res. 2005 Feb;65(2):153-66. doi: 10.1111/j.1399-3011.2004.00213.x. PMID: 15705160; cited in IDS filed 3/12/2026 as Cite No. NPL5; hereafter “Teixido”.
29 Heinlein et al., Fragment condensation of C-terminal pseudoproline peptides without racemization on the solid phase. Angew Chem Int Ed Engl. 2011 Jul 4;50(28):6406-10. doi: 10.1002/anie.201101270. Epub 2011 May 31. PMID: 21630399; hereafter “Heinlein”.
30 Alsina et al., “Use of N-tritylamino acids and PyAOP1 for the suppression of diketopiperazine formation in Fmoc/tBu solid-phase peptide synthesis using alkoxybenzyl ester anchoring linkages.” Tetrahedron Letters 37 (1996): 4195-4198; hereafter “Alsina”.
31 Jad et al., Peptide synthesis beyond DMF: THF and ACN as excellent and friendlier alternatives, Org. Biomol. Chem., 2015,13, 2393-2398; hereafter “Jad2015”.
32 Jad et al., Green Solid-Phase Peptide Synthesis (GSPPS) 3. Green Solvents for Fmoc Removal in Peptide Chemistry, Org. Process Res. Dev. 2017, 21, 3, 365–369; hereafter “Jad2017”.
33 Ran et al., Resin Swelling in Mixed Solvents Analysed using Hansen Solubility Parameter Space, Chem. Eur. J. 2019, 25, 4951; hereafter “Ran”.
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