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 and 3-17 are pending. Claim 2 was canceled; no claims were added; and claims 1, 2, 7, 9, 11, 13, and 16-17 were amended in the Reply filed 8/14/2026. Claims 5-6, 12, and 17 remain withdrawn. Claims 1, 3-4, 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 was previously acknowledged.
The originally elected species was 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 original 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 within 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 was previously 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 functional equivalent of 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’839 in view of Hachmann et al. 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 remain 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, 3-4, 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 8/14/2026 is acknowledged and presently considered.
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. 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 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, a phosphoric acid ester solvent, and mixtures thereof, 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), and
wherein the method does not comprise the step of treating the first peptide with piperidine as a single base before 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 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, a phosphoric acid ester solvent, and mixtures thereof” 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 substitute specification filed 8/14/2026 is acknowledged.
Claim Objections
Claim 7 objected to because of the following informalities:
Amended claim 7 recites “wherein any of the solvent in the step (2) has a donor number…”, which is grammatically incorrect. Claim 7 is understood to mean “wherein any one of the solvents in step (2) has a donor….”. 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.
Appropriate correction is required.
Withdrawn Claim Rejections
The rejections of claims 3, 7, 11, 13, and 16 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, are withdrawn in view of the amendments filed 8/14/2026. The amendments have necessitated new or revised rejections, which are set forth below.
The rejection of claims 1, 3-4, 7-11, and 13 under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by US20180319839A1 (Nov. 8, 2018), is withdrawn in view of the amendment to claim 1, adding the prior limitation of claim 2 into claim 1. The amendments have necessitated new or revised rejections, which are set forth below.
The rejection of claim 14 under 35 U.S.C. 103 as being unpatentable over US20180319839A1 (Nov. 8, 2018) is withdrawn in view of the amendment to claim 1, adding the prior limitation of claim 2 into claim 1. The amendments have necessitated new or revised rejections, which are set forth below.
The rejection of claims 15-16 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.12 is withdrawn in view of the amendment to claim 1, adding the prior limitation of claim 2 into claim 1. The amendments have necessitated new or revised rejections, which are set forth below.
Maintained or Revised Claim Rejections as Necessitated by Applicant Amendment
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 is 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 base”, but claim 1 recites multiple bases (i.e., “one or more bases”, and refers to “piperidine as a single base”. Therefore, 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), and any base present is neutralized.
Accordingly, 3 is rejected.
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.
[Revised Prior Art Rejection 01]
Claim 1, 3-4, 7-11, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over US20180319839A1 (Nov. 8, 201813) in view of Hachmann et al.14
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.
Regarding instant claim 1, step (1), US’839 discloses Example 12 (see, e.g., US’839 at ¶¶[0166]-[0168]). Example 12 of US’839 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’839 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’839 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’839 at ¶[0167]). Regarding instant claim 1 step (3), and claims 11 and 13, at Example 12, US’839 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-alanine15, which is attached in the presence of DIC/DMF and OxymaPure®16 (see, e.g., US’839 at ¶[0167]). Regarding instant claim 3, US’839 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’839 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’839. 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’839 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’839 at ¶[0167]). Regarding instant claim 10 and “the step of bringing the solvent into contact with CO2” at step (2), US’839 discloses Example 12 (see, e.g., US’839 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.
The teachings of US’839 differ from the amended claims as follows: US’839 at Example 12 differs from the scope of amended claim 1 because it utilizes piperidine “as a single base before step (2)”, namely US’839 utilizes 20% piperidine in DMF (see, e.g., US’839 at ¶[0167]), but amended claim 1 as filed 8/14/2026 now recites “wherein the method does not comprise the step of treating the first peptide with piperidine as a single base before the step (2)”. Therefore, the issue is whether or not the limitation precluding the use of piperidine as a single base in deblocking steps, renders the pending claim scope patentably distinct in view of the prior art.
Hachmann pertains to art-recognized 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, claims 1, 3-4, 7-11, and 13 are rejected.
[Revised Prior Art Rejection 02]
Claim 14 rejected under 35 U.S.C. 103 as being unpatentable over US20180319839A1 (Nov. 8, 201817) in view of Hachmann et al.18 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 in view of Hachmann 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.
[Revised Prior Art Rejection 03]
Claims 15-16 is rejected under 35 U.S.C. 103 as being unpatentable over US20180319839A1 (Nov. 8, 201819) in view of Hachmann et al.20 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 in view of Hachmann 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, 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.
Response to Arguments
Applicants’ arguments filed 8/14/2026 have been fully considered but they are not persuasive. Examiner notes that multiple arguments have been rendered moot in view of the revised or new rejections, necessitated by Applicant’s amendments. Remaining applicable arguments are addressed below.
Arguments Regarding Obviousness
Applicants raise applicable arguments pertaining to US’839 in view of Hachmann at pages 10-13 (see, e.g., Reply filed 8/14/2026 at 10 at 1st ¶ to 13 at 1st full ¶), which are addressed below.
It is the Examiner’s understanding that Applicant quotes caselaw (see, e.g., Reply filed 8/14/2026 at 10 at 2nd full ¶). The holdings of such cases are neither disputed nor dispositive of obviousness in the instant case, and Examiner notes that Applicant has failed to identify how the specific fact patterns and holdings of such cases weigh in favor of a determination of non-obviousness, or otherwise rebut the rationales supporting a determination of obviousness relied upon by the Examiner.
It is the Examiner’s understanding that Applicant acknowledges that the single difference between the prior art of US’839 at Example 12 and the claimed invention is the specific substitution of a known, art-recognized equivalent for piperidine, in place of piperidine in the US’839 methods (see, e.g., Reply filed 8/14/2026 at 10-11 at bridging ¶, 11 at 1st full ¶).
Examiner provided rationales supporting a determination of obviousness, specifically MPEP § 2143(I)(B) and MPEP § 2144.06(II): It is the Examiner’s understanding that Applicant is alleging that an artisan “would not have had reason to modify US’839 in a specific way so as to arrive at the claimed invention” (see, e.g., Reply filed 8/14/2026 at 11 at 1st full ¶ to 2nd full ¶, alleging no “reason to modify”, “no reason to specifically remove piperidine treatment”, no “expectation of advantages in doing so”, “Hachmann …. Does not teach or suggest that the deprotecting step in Example 12 of US’839 should be modified…”). In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the Examiner’s rationale supporting a determination of obviousness is explicitly recited in the rejection. Namely, 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 (see, e.g., Hachmann at title “Alternative to Piperidine in Fmoc Solid-Phase Synthesis”), 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)). Critically, Applicant does not dispute that US’839 differed from the claimed invention by the single substitution of an art-recognized piperidine equivalent, and Applicant provides no objective evidence that such piperidine alternatives were inoperable or would not be usable by artisans in place of piperidine, exactly as taught and suggested in view of the secondary reference (see, e.g., MPEP § 2143(I)(B)(1)-(4)). Accordingly, all elements required to support a determination of obviousness under a simple substitution rationale are not disputed, and therefore the claimed invention is obvious per MPEP § 2143(I)(B). In addition, or alternatively, per MPEP § 2144.06(II), it is obvious to simply substitute equivalent known in the art, and here the secondary reference establishes that piperidine and piperidine equivalents are art-recognized equivalents. Accordingly, the claims are obvious in view of the prior art of record. This determination is in accord with the Courts, which have stated
"[W]hen a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious."
KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 , 417 , 127 S. Ct. 1727 , 167 L. Ed. 2d 705 (2007) (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273 , 282 , 96 S. Ct. 1532 , 47 L. Ed. 2d 784 (1976));
and have emphasized that
“If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.”
KSR Int'l v. Teleflex Inc., 550 U.S. 398, 415 (2007), at 417.
Here, all elements at issue are “old elements with each performing the same function it had been known to perform”, and they “yield[] no more than one would expect” to date, because 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 (see discussion below regarding allegations of unexpected results).
Direct substitution is not the test for obviousness: It is the Examiner’s understanding that Applicant is suggesting that a direct substitution of piperidine alternatives into the exact method of Example 12 of US’839 would not be optimized for the particular timing and steps utilized and taught by US’839 (see, e.g., Reply filed 8/14/2026 at 11 at 1st full ¶, arguing that US’839 treats the resin “in a much longer duration”). This line of arguments is not persuasive because "It is well-established that a determination of obviousness based on teachings from multiple references does not require an actual, physical substitution of elements" (see In re Mouttet, 686 F.3d 1322, 1332, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012) (citing In re Etter, 756 F.2d 852, 859, 225 USPQ 1, 6 (Fed. Cir. 1985); see also In re Keller, 642 F.2d 413, 425, 208 USPQ 871, 881 (CCPA 1981); explaining that "The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference.... Rather, the test is what the combined teachings of those references would have suggested to those of ordinary skill in the art."). Accordingly, all arguments suggesting a direct physical combination of prior art elements is not persuasive, because that is not the test for obviousness. Rather, it is well-within the ordinary skill in the art, to simply substitute an art-recognized equivalent for piperidine in place of piperidine, to predictably obtain an equivalent method that does not utilize piperidine. Furthermore, even assuming arguendo that direct substitution was required, Hachmann discloses that 4-methylpiperidine “had identical efficiency in Fmoc group removal, as compared to piperidine”, and identifies that his lab had used it “the last two years” and “synthesized thousands of peptide sequences” (see, e.g., Hachmann at title, Tables 1-2 on 149, 149 at col I at penultimate ¶, 149 at col II at final ¶), which is pertinent because prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Accordingly, physical substitution is not the test for obviousness, and even if it were, Hachmann informs artisans that it can be utilized in place of piperidine.
Recitations of intended and expected results of performing prior art methods does not establish obviousness: It is the Examiner’s understanding that Applicant’s position is that a proper rejection under 35 USC 103 requires verbatim teachings of recitations of the Applicant’s unclaimed intended or expected results (see, e.g., Reply filed 8/14/2026 at 11 at 1st full ¶). This position is not persuasive or tenable because, if instant claim 1 is fully enabled, then such results would necessarily and inherently be obtained from performing the active method steps positively recited in the body of the claim. Accordingly, recitations of intended and expected results obtained from performing methods taught or otherwise rendered obvious by the prior art do not weigh in favor of non-obviousness because the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). As explained below, Applicant has provided no evidence of any benefit relative to the closest, existing prior art of record (i.e., US’839), but even if such benefit were established commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02, it would need to be weighed in view of the prior art’s teachings and guidance regarding the relative benefits of utilizing 4-methylpiperidine in place of piperidine in Fmoc Solid-Phase synthesis methods28.
Acknowledging that individual references used in a combination do not independently and separately support a rejection under 35 USC 103 is neither disputed nor dispositive of the rejection: It is the Examiner’s understanding that Applicant addresses the teachings of individual references in isolation (see, e.g., Reply filed 8/14/2026 at 11 at 1st full ¶, alleging that “US’839 does not teach or suggest removing the initial step of treatment with piperidine would have any benefit”; see id. at 11 at 2nd full ¶, alleging that “Hachmann also does not teach…”; see also id. at 13 at 2nd full ¶, addressing the teachings of Manne individually). In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Examiner is permitted to establish obviousness using any rationale set forth at MPEP §2143 and §2144: It is the Examiner’s understanding that Applicant identifies that their rationale for arriving at the claimed invention differs from the rationale relied upon by the Examiner to establish obviousness (see, e.g., Reply filed 8/14/2026 at 11 at 1st full ¶ to 13 at 2nd full ¶¶, referring to Applicant’s alleged discovery of diketopiperazine or cyclic amidine formation during the Fmoc deprotection step, or reactions carried out “under conditions that do not include an amid solvent”). Examiner notes that this is not persuasive because an examiner may support a determination of obviousness by relying upon a rationale that differs from the Applicant’s rationale (see, e.g., MPEP § 2144(IV)). Here, the Examiner’s rationales are explicitly identified in the rejection (i.e., MPEP § 2143(I)(B) and MPEP § 2144.06(II))29, but Applicant fails to address or specifically dispute these rationales supporting a determination of obviousness. Accordingly, it is neither disputed nor dispositive of obviousness that the Examiner did not support a determination of obviousness based upon the Applicant’s rationale for arriving at the claimed invention, because the Examiner has established prima facie obviousness based upon a different rationale.
Allegations suggesting “lack of predictability” or “lack of reasonable expectation of success”: It is the Examiner’s understanding that Applicant is alleging a lack of predictability or otherwise a lack of reasonable expectation of success (see, e.g., Reply filed 8/14/2026 at 11 at 1st full ¶ to 12 at 1st full ¶, alleging that “Hachmann does not teach that 4-methyl piperidine is equivalent to piperidine under all circumstances”). This is not persuasive because the Applicant’s assertions do not reflect the proper legal standards for evaluating predictability. MPEP § 2143.02(II) explains that “[o]bviousness does not require absolute predictability”, but instead clarifies that only “at least some degree of predictability is required” (see, e.g., MPEP § 2143.02(II)). Here, as noted in the rejection, Hachmann discloses that 4-methylpiperidine “had identical efficiency in Fmoc group removal, as compared to piperidine”, and identifies that his lab had used it “the last two years” and “synthesized thousands of peptide sequences” (see, e.g., Hachmann at title, Tables 1-2 on 149, 149 at col I at penultimate ¶, 149 at col II at final ¶). Accordingly, Applicant fails to address the explicitly identified predicted and expected results set forth in the rejection and taught by the prior art. Here, the Examiner’s basis for “predictability” is merely based upon the presumption that the prior art is fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)), and Applicant has the burden of rebutting this presumption. As explained at MPEP § 2143.02, predictability and reasonable expectation of success are satisfied when “all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art”. Here zero evidence of unexpected results commensurate in scope with the requirements of MPEP 716.02 have been set forth on record, all elements of the claimed invention were known in the prior art, one of ordinary skill was fully enabled to combined each component using routine methods in the biochemical arts per the guidance of the primary reference, and the elements would have merely performed their art-recognized, respective functions (see Rejection, above, and previous two footnotes). Accordingly, such arguments are not persuasive.
Allegations suggesting “skepticism of experts”: It is the Examiner’s understanding that Applicant’s statements amount to a suggestion that the Examiner’s position would be met with skepticism of experts (see, e.g., Reply filed 8/14/2026 at 11 at 1st full ¶ to 12 at 1st full ¶, alleging what an artisan would or would not have done). If Applicant means to suggest the existence of skepticism of experts, such evidence should be filed per MPEP § 716.05 as evidence is required to establish skepticism of experts. In the absence of such evidence, such statements are understood to be unsupported conjecture of counsel. 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)), including “all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments” (see, e.g., MPEP § 2123(I)), and no objective evidence rebutting this presumption has been placed on record to date.
Allegations suggesting “inoperability” or lack of enabling disclosure regarding a prior art reference: It is the Examiner’s understanding that Applicant’s statements amount to a suggestion that the prior art is not fully enabled or operable (see, e.g., Reply filed 8/14/2026 at 11 at 1st full ¶ to 12 at 1st full ¶, alleging that “Hachmann does not teach that 4-methyl piperidine is equivalent to piperidine under all circumstances”). If Applicant is attempting to allege that the prior art is not enabling or inoperable Applicant is directed to MPEP § 2121(I), which notes that the prior art is presumed fully enabled for all that it discloses, and the burden is on the Applicant to rebut the presumption of operability (see, e.g., MPEP § 2121(I); MPEP § 716.07). No evidence of inoperability commensurate in scope with the requirements of MPEP § 716.07 have been placed on record at this time; critically, arguments of counsel cannot take the place of evidence in the record (see, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965), and evidence is required to rebut the presumption of operability. The Examiner’s position is that 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)), including “all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments” (see, e.g., MPEP § 2123(I)). Accordingly, the Applicant has not satisfied their burden to rebut the presumption of operability of the prior art at this time (see, e.g., MPEP § 2121(I); MPEP § 716.07). Here, in view of the art, an artisan would readily and reasonably appreciate that 4-methyl piperidine is functionally equivalent to piperidine in the relevant methods (see, e.g., Hachmann at title “Alternative to Piperidine in Fmoc Solid-Phase Synthesis”).
Allegations suggesting the references “teach away”: It is the Examiner’s understanding that Applicant is suggesting that the references “teach away” from the claimed invention in view of the statements alleging that an artisan would not utilize alternatives to piperidine in the prior art methods (see, e.g., Reply filed 8/14/2026 at 11 at 1st full ¶ to 12 at 1st full ¶, alleging what an artisan would or would not have done). Examiner notes that this argument is not persuasive because none of the cited prior art references at issue “teach away” from the claimed invention since they do not actually “criticize, discredit, or otherwise discourage the solution claimed” (see, e.g., MPEP § 2141.02(VI)). Applicant has not identified any disclosure that “criticizes, discredits, or otherwise discourages the solution claimed”. Accordingly, no “teaching away” has been identified on record.
Allegations regarding benefits and results not explicitly taught by the prior art: It is the Examiner’s understanding that Applicant is alleging that they have obtained benefits and results not explicitly taught by the prior art (see, e.g., Reply filed 8/14/2026 at 11 at 1st full ¶ to 13 at 2nd full ¶¶, referring to diketopiperazine or cyclic amidine formation during the Fmoc deprotection step, and other advantages). In response to applicant's argument regarding benefits and results not contemplated by the prior art, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Here, the simple substitution of one known piperidine equivalent in place of piperidine is obvious because the piperidine equivalent would perform the same basic function as piperidine in Fmoc Solid Phase Synthesis (see, e.g., Hachmann at title “Alternative to Piperidine in Fmoc Solid-Phase Synthesis”), and would therefore predictably yield the expected results, namely the Fmoc-solid Phase Synthesis method of US’839 at Example 12 with a reasonable expectation of success30, wherein a piperidine alternative is utilized in place of piperidine, which would yield predicted and expected results. If applicant means to allege unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02, then that is addressed in a separate section below.
Unclaimed limitations do not distinguish the claimed invention from the prior art: It is the Examiner’s understanding that Applicant references unclaimed limitations and attempts to import portions of the Specification into the instant claim scope (see, e.g., Reply filed 8/14/2026 at 11 at 1st full ¶ to 13 at 2nd full ¶¶, referring to diketopiperazine or cyclic amidine formation, referring to “the use of a weaker base”, “byproducts of diketopiperazine elimination”, “enabled suppression”, “using a stronger base having a pKa of 23 or more” is notably not the same or equivalent to “with one or more bases including at least a base having a pKa of 23 or more” since 0.1% total Base present having a pKa of 23 or more and 99.9% total Base present having a pKa of much less than 23 has not been tested or shown to have any advantages but is presently claimed, “byproducts are significantly reduced”, Table 5, “much reduced formation of DKP byproduct and Amidine byproduct”, etc.). In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., such as those limits discussed above) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). If applicant means to allege unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02, then that is addressed in a separate section below.
No evidence of unexpected results commensurate in scope with the requirements of MPEP §716 have been placed on record: It is the Examiner’s understanding that Applicant is alleging the existence of unexpected results commensurate in scope with the requirements of MPEP §716, §716.01, and §716.02, wherein such results are sufficient to rebut prima facie obviousness (see, e.g., Reply filed 8/14/2026 at 12 at 1st full ¶ to 13 at 2nd full ¶¶, referring to results and data at Table 5, and alleging that “the data in this application establishes that the claimed invention provides superior results”). However, to establish such unexpected results, the allegations must be timely and supported by objective evidence (see, e.g., 37 C.F.R. 1.132; see MPEP §§ 716.01, 716.01(a), 716.01(c)); to be of probative value the proffered evidence must be related to the claimed invention (see MPEP §§ 716.01(b), discussing nexus requirement and noting that "[w]here the offered secondary consideration actually results from something other than what is both claimed and novel in the claim, there is no nexus to the merits of the claimed invention"); the evidence must establish that the expected results occur to an unexpected extent (see, e.g., MPEP § 716.02(a)(I)), on the basis of statistically and practically significant evidence (see, e.g., MPEP § 716.02(b)(I)), which is fully explained (see, e.g., MPEP § 716.02(b)(II)), commensurate in scope with the claimed invention (see, e.g., MPEP § 716.02(d)), and wherein a comparison of the claimed invention with the closest prior art of record is provided (see, e.g., MPEP § 716.02(e)). Furthermore, even if evidence satisfying MPEP §§ 716.02, 716.02(a), 716.02(b), 716.02(d), and 716.02(e) is set forth on record, such evidence may not be sufficient to rebut prima facie obviousness because the evidence of expected and unexpected results must be weighed (see, e.g., MPEP § 716.02(c)(I)) and the totality of the record considered (see, e.g., MPEP §§ 716.01(d), 716.02(f)), including teachings in the prior art and evidence of expected results which weigh in favor of a determination of obviousness (see, e.g., MPEP § 716.02(c)(II)). Here, the allegations of unexpected results are understood to be premised upon the data shown at Table 5 (see, e.g., Reply filed 8/14/2026 at 12 at 1st full ¶ to 13 at 2nd full ¶¶), which has been fully reviewed, but deemed insufficient to establish unexpected results for the following reasons: First, the proffered evidence is not commensurate in scope with the claimed invention as required by MPEP § 716.02(d), because the claim scope is vast, highly varied, and substantially broader with respect to multiple parameters relative to the specific conditions set forth at Table 5. Second, the proffered data is of unknown statistical significance, and therefore does not satisfy Applicant’s burden under MPEP § 716.02(b)(I), because it is unclear if the reported differences are statistically significant, or well-within the range of experimental variability. Third, the proffered data fails to provide a comparison with the closest, existing prior art of record as required by MPEP § 716.02(e), because the closest prior art of record is Example 12 of US’839 (previously applied under 35 USC 102, and differing from the instantly claimed invention by a single parameter, namely the substitution of piperidine with a 4-methylpiperidine); accordingly, to date, zero evidence of unexpected results relative to the closest existing prior art has been shown on record. In sum, for at least the reasons discussed above, the proffered data is insufficient to establish unexpected results commensurate in scope with the requirements of MPEP §716, §716.01, and §716.02, and therefore such proffered data is not sufficient to rebut prima facie obviousness. Accordingly, zero evidence of any unexpected results commensurate in scope with the requirements of MPEP § 716.02 have been placed on record at this time.
Arguments Regarding Nonstatutory Double Patenting Rejections
It is the Examiner’s understanding that Applicant traverses the Provisional Nonstatutory Double Patenting Rejections at page 13 (see, e.g., Reply filed 8/14/2026 at 13 at § “Claim Rejections – Double Patenting”).
It is the Examiner’s understanding that Applicant requests that the provisional rejection be held in abeyance (see, e.g., Reply filed 8/14/2026 at 13 at § “Claim Rejections – Double Patenting”). Regarding abeyance, while a request may be made that objections or requirements as to form not necessary to further consideration of the claims be held in abeyance until allowable subject matter is indicated, the present is a rejection and will not be held in abeyance (see MPEP § 714.02), and requires a proper response. A proper response includes a Terminal Disclaimer approved by the Office, amendment to distinguish from the reference patent, or persuasive arguments as to why the rejection is incorrect. Accordingly, the provisional rejection is maintained.
Summary
All applicable arguments raised in the Reply filed 8/14/2026 have been fully considered, but not found persuasive for the reasons discussed above. Therefore, the claims remain rejected in view of the new or revised rejections of record, wherein all new or revised rejections were necessitated by Applicants’ amendments.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US2014/0088291A1 (cited in previous action) pertains to peptide synthesis methods (see, e.g., id. at title, claims).
Teixido et al31 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.32 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.33, 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)34, 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)35, 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.36, 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.
Applicant's amendment necessitated the new or revised ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RANDALL L BEANE whose telephone number is (571)270-3457. The examiner can normally be reached Mon.-Fri., 7 AM to 2 PM ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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 Manne et al., “OxymaPure Coupling Reagents: Beyond Solid-Phase Peptide Synthesis.” Synthesis 52 (published online 9/30/2020): 3189-3210; hereafter “Manne”; cited in previous action.
13 Cited in previous action.
14 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”; cited in previous action.
15 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.
16 An artisan would appreciate this term refers to Ethyl (2Z)-2-cyano-2-(hydroxyimino)acetate, a.k.a. “oxyma”.
17 Cited in previous action.
18 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”; cited in previous action.
19 Cited in previous action.
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”; cited in previous action.
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 Hachmann identifies a clear benefit and rationale for using 4-methylpiperidine in place of piperidine, namely to avoid the “nuisance” of utilizing the controlled substance of piperidine, because 4-methylpiperidine “costs approximately the same as piperidine”, “no significant differences were found between the use of piperidine and 4-methylpiperidine”, but utilizing 4-methylpiperidine desirably saves the “nuisance” of working with a controlled substance, and negates the need “to fill in any paperwork” (see, e.g., Hachmann at 149 at col I at 1st ¶ to col II at 1st full ¶). Accordingly, the alleged benefits would flow naturally from an artisan modifying the method of the primary reference to avoid a controlled substance exactly as suggested by Hachmann.
29 Examiner also directs Applicant to Hachmann, which identifies a clear benefit and rationale for using 4-methylpiperidine in place of piperidine in peptide synthesis methods, namely to avoid the “nuisance” of utilizing the controlled substance of piperidine, because 4-methylpiperidine “costs approximately the same as piperidine”, “no significant differences were found between the use of piperidine and 4-methylpiperidine”, but utilizing 4-methylpiperidine saves the “nuisance” of working with a controlled substance, and negates the need “to fill in any paperwork” (see, e.g., Hachmann at 149 at col I at 1st ¶ to col II at 1st full ¶). This would support an alternative rationale supporting obviousness under MPEP § 2143(I)(A) and (I)(G), wherein all components were known, combined according to known methods, yielded predictable results, and provided the benefit of avoiding the use of a controlled substance.
30 Hachmann identifies a clear benefit and rationale for using 4-methylpiperidine in place of piperidine, namely to avoid the “nuisance” of utilizing the controlled substance of piperidine, because 4-methylpiperidine “costs approximately the same as piperidine”, “no significant differences were found between the use of piperidine and 4-methylpiperidine”, but utilizing 4-methylpiperidine desirably saves the “nuisance” of working with a controlled substance, and negates the need “to fill in any paperwork” (see, e.g., Hachmann at 149 at col I at 1st ¶ to col II at 1st full ¶). Accordingly, the alleged benefits would flow naturally from an artisan modifying the method of the primary reference to avoid a controlled substance exactly as suggested by Hachmann.
31 Teixidó et al., 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” ; cited in previous action.
32 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” ; cited in previous action.
33 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” ; cited in previous action.
34 Jad et al., Peptide synthesis beyond DMF: THF and ACN as excellent and friendlier alternatives, Org. Biomol. Chem., 2015,13, 2393-2398; hereafter “Jad2015” ; cited in previous action.
35 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” ; cited in previous action.
36 Ran et al., Resin Swelling in Mixed Solvents Analysed using Hansen Solubility Parameter Space, Chem. Eur. J. 2019, 25, 4951; hereafter “Ran”; cited in previous action.
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