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 .
Election/Restrictions
Applicants’ election without traverse of Group I (i.e., claims 1-2, 4, 7, 9, 11-12, 16, 20, 24, 26-30 and 31, drawn to a glycosylated cyclic peptide) and of Species A (i.e., a single and specific glycosylated cyclic peptide indicating, single and specific peptide formula, single and specific amino acid substitution for each variable in the formula, and single and specific SEQ ID NO, Applicant’s election: Tyr for A1, D-Lys for A2, Trp for A3, Phe for A4, Glu for A5 and L-Ser for A6) in the reply filed on 02/16/2026 is acknowledged.
Applicants’ representative Jolene S. Fernandes was contacted on 03/11/2026 regarding the elected species and incomplete response to the restriction mailed on 11/14/2025. Applicants’ representative submitted a supplemental response to the reply filed on 02/16/2026. The supplemental response was filed on 03/12/2026 and a complete response to the species election (i.e., Applicants’ election: Formula I, SEQ ID NO: 1, and Tyr for A1, D-Lys for A2, Trp for A3, Phe for A4, Glu for A5 and L-ser for A6), the supplemental response also included amendments to claims 1 and 16.
Claims 32-33 and 36-38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, and claims 9, 12, 16 and 29-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 03/12/2026.
Please note that the Examiner has expanded the search of elected sequence (i.e., SEQ ID NO: 1), to include SEQ ID NO: 5 and SEQ ID NO: 10. Accordingly, for purposes of compact prosecution, the election of species is modified only to the extent of examining these additional species. Otherwise the election of species requirement is still retained.
Priority
The present application claims status as a 371 (National Stage) of PCT/US23/23879 filed May 30th, 2023 and claims the benefit under 35 U.S.C 119 (e) to U.S. Provisional Application No. 63/347,182 filed May 31st, 2022. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C 119 (e) or under 35 U.S.C 120, 121, or 365 (c ) is acknowledged.
Claim Status
Claims 1-44 were originally filed on 11/26/2024.
The amendment filed on 08/12/20253, cancelled claims 5-6, 8, 10, 13-15, 17-19, 21-23, 25, 34-35, and 39-44; and amended claims 1-2, 4, 7, 9, 12, 16, 20, 24, 26-31 and 33.
The amendment filed on 03/12/2026, amended claims 1 and 16.
The amendment filed on 06/23/2026, amended claim 1.
Claims 1-2, 4, 7, 11, 20, 24, 26, 28 and 31 are currently pending and under consideration.
Information Disclosure Statement
The Information Disclosure Statement (IDS) filed on 06/23/2026 has been considered by the Examiner.
Sequence Interpretation
Regarding claim 28, please note that the Examiner is interpreting the scope of a glycosylated cyclic peptide of Formula (I) as requiring 100% identity to SEQ IDNO: 1 with any N-/C-terminal additions, per Applicants’ election of species.
Response to Arguments
Applicants’ arguments, see Remarks filed 06/26/2023, with respect to the 35 U.S.C. 112(b) rejection, have been fully considered and are persuasive. The 35 U.S.C 112(b) rejection of claims 1-2, 4, 7, 11, 24, 26 and 31 has been withdrawn.
Applicants' arguments, see Remarks filed 06/26/2023, with respect to the 35 U.S.C. 103 rejection, have been fully considered but they are not persuasive. The 35 U.S.C. 103 rejection of claims 1-2, 4, 7, 11, 20, 24, 26 and 31 has been maintained.
Maintained/Modified Rejections
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
1. Claim 1-2, 4, 7, 11, 20, 24, 26, 31 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0222940 A1 Pub. Date: Aug. 9, 2018 (herein after “Zadina et al.”) in view of US 2020/0270318 A1 Pub. Date: Aug. 27, 2020 (cited in the IDS filed on 02/19/2026) (herein after “Polt et al.”).
Regarding claims 1 and 26, Zadina et al. are in the field of cyclic peptide agonist that bind to the mu (morphine) opioid receptor (see Abstract). In particular Zadina et al.’s Fig. 1 depicts the molecular and structural formula of Tyr-c[D-Lys-Trp-Phe-Glu]-NH2 (SEQ ID NO: 1) which is described as “Compound 1” (see pg. 2, para[0022] and Fig. 1).
Zadina et al.’s “Compound 1” is a peptide of Formula I (i.e., H-Tyr-c[X1-X2-X3-X4]-X5) (see pg. 2, para[0009]) wherein the peptide is cyclic and is shown as "c[X1-X2-X3-X4]" or "cyclo[X1-X2-X3-X4]" which by virtue of an amide linkage between the carboxylic acid and amino substituents of the side chains of amino acid residues X1 and X4 forms a cyclic peptide (see pg. 2, para[0010]). Zadina et al. teach that each variable of Formula I an acidic amino acid (i.e., an amino acid comprising a carboxylic acid-substituted side-chain) or a basic amino acid (i.e., an amino acid comprising an amino substituted side-chain), with the proviso that if X1 is an acidic amino acid (e.g., D-Asp or D-Glu), then X4 is a basic amino acid ( e.g., Lys, Om, Dpr, or Dab), and vice versa (see pg. 1, para[0009]). Preferably, X1 is D-Asp, D-Glu, D-Lys (i.e., corresponding to instant A2), D-Om, D-Dpr or D-Dab; while X4 preferably is Asp, Glu (i.e., corresponding to instant A5), Lys, Orn, Dpr or Dab (see pg. 1, para[0009]).
X2 and X3 each independently are an aromatic amino acid, for example X2 preferably is Trp (i.e., corresponding to instant A3) and X3 preferably is Phe (i.e., corresponding to instant A4); and wherein X5 is selected from the group consisting of -NHR, Ala-NHR, Arg-NHR, Asn-NHR, Asp-NHR, Cys-NHR, GluNHR, Gln-NHR, Gly-NHR, His-NHR, Ile-NHR, Leu-NHR, Met-NHR, Om-NHR, Phe-NHR, Pro-NHR, Ser-NHR, ThrNHR, Trp-NHR, Tyr-NHR, and Val-NHR; where R is H or an alkyl group (e.g. a (C1 to C10) alkyl group, where R is H or an alkyl group (see pg. 3, para[0009]). Additionally, the peptides of Formula I are cyclic pentapeptide and hexapeptide analogues of endomorphin-1 (Tyr-ProTrp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2) (see pg. 3, para[0032]).
Moreover, Zadina et al. teach that the solubility of the peptides of Formula I (e.g., in saline or physiologic buffer) typically is enhanced relative to the prior art tetrapeptide analogs of the endomorphins (see pg. 4, para[0040]). For instance, addition of a hydrophilic amino acid and amidated C-terminus to the relative hydrophobic tetrapeptide sequence Tyr-cyclo[D-Lys-Trp-Phe] (SEQ ID NO:10), resulted in an unexpectedly high improvement in solubility while maintaining or improving functionality (see pg. 4, para[0040]). Thereby, Zadina et al.’s “Compound 1” corresponds to a cyclic peptide wherein A1 is Tyr, A2 is D-Lys, A3 is Trp, A4 is Phe, A5 is Glu, and A6 is Ser-HN2 as recited in instant claim 1.
However Zadina et al.’s compound 1 does not correspond to a glycosylated cyclic peptide of formula (I): A1-cyclo[A2-A3-A4- A5]-A6-O-Carb, wherein A6 is an amino acid residue or an oligopeptide comprising 2 to 5 amino acid residues, and wherein the amino acid or the oligopeptide comprising 2 or 5 amino acid residues comprises at least one hydroxy-substituted amino acid residue; and Carb is a carbohydrate group bonded to a sidechain oxygen of the HO-AA by a P-D-glycosidic bond as recited in instant claims 1 and 26.
Polt et al. are in the field of glycosylated peptides and teach that glycosylation at or near the C-terminal domain of the peptide has an enhanced ability to cross the blood brain barrier (BBB) and/or enhanced half-lives (see Abstract). Polt et al. that glycosylation modifies the amphipathicity of the glycopeptides, and not just the hydrophilic or hydrophobic nature alone; which greatly influences interaction with biological membranes, such as increasing their ability to cross membrane barriers like the blood-brain barrier; and that the native peptide remains intact with similar or better receptor binding (see pg. 2, para[0015]). Thus, Polt et al.’s invention features a peptide chain modified by the addition of glycosides to specific residues (see pg. 2, para[0015]).
Particular embodiments of Polt et al.’s invention include a glycoside moiety formed by a carbohydrate or a saccharide bound to another reactive functional group via a glycosidic bond, which is a covalent bond formed between the hemiacetal group of the carbohydrate and the reactive functional group, such as the hydroxyl group, of another compound (see pg. 4, para[0033]). Additionally, the saccharide that bounds to the reactive functional group can be a mono-, di-, tri- or poly-saccharide, for instance glucose, maltose, lactose, cellobiose, or any other saccharide as known to one of ordinary skill in the art (see pg. 4, para[0037]). Moreover, the glycoside moiety may further include α and ß forms of the saccharides (see pg. 4, para[0037]). Polt et al. add that glycosylation processes and glycans are well known to one of ordinary skill in the art and that in some embodiments the glycan is an O-linked glycan (see pg. 5, para[0048]).
As per the peptide (i.e., reactive functional group) to be glycosylated, Polt et al. teach that it may be any peptide such as a hormone, an agonist, or an antagonist that can bind to a target receptor (see pg. 4, para[0037]).
With respect to the C-terminal end of instant Formula (I) i.e., A6-O-Carb:
Polt et al. teach embodiments where an amino acid in the C-terminal domain of the peptide is substituted with a different amino acid that is adapted to be glycosylated with the glycan or that a different amino acid (e.g., a glycosylated amino acid) is appended to the C-terminus of a peptide; and that the different amino acid may be selected from the group consisting of: serine, threonine, cysteine, tyrosine, hydroxylysine, hydroxyproline, asparagine, arginine, or tryptophan, and any reasonable alkyl derivative thereof (see pg. 6, para[0051]).
As evidenced by BOC Sciences, serine is a neutral aliphatic amino acid that contains a hydroxyl group (see BOC Sciences, pg. 1, second paragraph retrieved from https://aapep.bocsci.com/resources/serine-definition-structure-benefits-types-and-uses.html, on 03/18/2026). Therefore, after reading Polt et al., an ordinary skilled artisan would have been motivated to append serine at the C-terminal end of a peptide (e.g., any peptide such as a hormone or an agonist that can bind to a target receptor) in order to form a glycosidic bond between the ß form of lactose (i.e., carbohydrate/saccharide) and the hydroxyl group of serine. As such, the teachings of Polt et al. when combined with the teaching of Zadina et al. are suggestive of the claimed limitations recited in instant claims 1 and 26.
Before the effective filing date of the claimed invention, an ordinary skilled artisan would have been motivated with reasonable expectation of success to combine the teachings of Zadina et al. and Polt et al. to arrive at the claimed invention.
One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because it was known that:
- peptides corresponding to Formula I (i.e., H-Tyr-c[X1-X2-X3-X4]-X5), wherein each variable of Formula I is an acidic amino acid (i.e., an amino acid comprising a carboxylic acid-substituted side-chain) or a basic amino acid (i.e., an amino acid comprising an amino substituted side-chain), with the proviso that if X1 is an acidic amino acid (e.g., D-Asp or D-Glu), then X4 is a basic amino acid ( e.g., Lys, Om, Dpr, or Dab), and vice versa, X2 and X3 each independently are an aromatic amino acid (i.e., an amino acid comprising an aromatic group in the side chain thereof), and X5 is NHR, where R is H or an alkyl group, as taught by Zadina et al.;
- the solubility of the hydrophobic tetrapeptide sequence Tyr-cyclo[D-Lys-Trp-Phe] was enhanced by addition of a hydrophilic amino acid and amidated C-terminus, thus resulting in an unexpectedly high improvement in solubility while maintaining or improving functionality, as taught by Zadina et al.;
-glycosylation modifies the amphipathicity of the glycopeptides, and not just the hydrophilic or hydrophobic nature alone; and that the native peptide remains intact with similar or better receptor binding, as taught by Polt et al.;
-glycosylation at or near the C-terminal domain of a peptide has an enhanced ability to cross the blood brain barrier (BBB) and/or enhance the peptide’s half-life, as taught by Polt et al.;
-the ß form of a saccharide/carbohydrate such as lactose (i.e., glycoside moiety) forms a covalent bond between the hemiacetal group of the carbohydrate and the hydroxyl group of serine, as taught by Polt et al.;
One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success given that:
-an analogue (i.e., “Compound 1” Tyr-c[D-Lys-Trp-Phe-Glu]-NH2 ) of endomorphin-1 and endomorphin-2 which corresponds to Formula I (i.e., H-Tyr-c[X1-X2-X3-X4]-X5) binds to the mu (morphine) opioid receptor as taught by Zadina et al.;
- any peptide/reactive functional group such as a hormone, an agonist, or an antagonist that can bind to a target receptor can be glycosylated, as taught by Polt et al.;
- an adapted amino acid to be glycosylated (e.g., serine) can be appended to or substituted at the C-terminus end of the peptide to be glycosylated; and given that the glycan (e.g., ß form of lactose) can be an O-linked glycan as taught by Polt et al.
As such, appending a serine to the C-terminus end of Zadina et al.’s “Compound 1” (i.e., Formula IH-Tyr-c[X1-X2-X3-X4]-X5), so that a glycoside moiety (e.g., ß form of a lactose) can covalently bond to the hydroxyl group of serine, thus resulting in an O-linked glycan would support the instantly claimed glycosylated cyclic peptide of Formula (I): A1-cyclo[A2-A3-A4-A5]-A6-O-Carb.
The combination of teachings constitutes applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; and/or the use of a known technique to improve similar devices (methods, or products) in the same way; and/or some teaching, suggestion, or motivation in the prior art that would have let one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention, pursuant to KSR.
Regarding claims 2, 4, 7, 11; as previously mentioned, Zadina et al. teach a “Compound 1”, cyclic peptide analogue of endomorphin-1 and endomorphin-2 that follows Formula I (i.e., H-Tyr-c[X1-X2-X3-X4]-X5) and corresponds to Tyr-c[D-Lys-Trp-Phe-Glu]-NH2 (SEQ ID NO: 1); wherein X1 is D-Asp, D-Glu, D-Lys (i.e., corresponding to instant A2), D-Om, D-Dpr or D-Dab; while X4 preferably is Asp, Glu (i.e., corresponding to instant A5), Lys, Orn, Dpr or Dab (see pg. 1, para[0009]). X2 and X3 each independently are an aromatic amino acid, for example X2 preferably is Trp (i.e., corresponding to instant A3) and X3 preferably is Phe (i.e., corresponding to instant A4); and wherein X5 is NHR, where R is H or an alkyl group (see pg. 2, para[0009]). Additionally, the peptides of Formula I are cyclic pentapeptide and hexapeptide analogues of endomorphin-1 (Tyr-ProTrp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2) (see pg. 3, para[0032]). Thereby Zadina et al.’s “Compound 1” reads on the claimed glycosylated peptide of Formula (I) wherein A1 is Tyr, A3 is Trp, and A4 is Phe as recited in instant claims 2, 4, 7 and 11.
Regarding claim 20, Polt et al. teach a peptide chain modified by the addition of glycosides to specific residues (see pg. 2, para[0015]). Additionally that the amino acid that is adapted to be glycosylated with the glycan may be selected from a group consisting of serine (see pg. 6, para[0051]). Polt et al. add that the term "serine" encompasses serine in either its L- or D-configuration, as well as racemate or in various mixtures of its isomers or extended alkyl derivatives (see pg. 4, para[0034]). Therefore, the teachings of Polt et al. when combined with the teachings of Zadina et al. are suggestive of the claimed glycosylated cyclic peptide wherein A6 comprises L-Ser.
Regarding claim 24, as previously mentioned, Polt et al. teach that the saccharide that bounds to the reactive functional group can be a mono-, di-, tri- or poly-saccharide, for instance glucose, maltose, lactose, cellobiose, or any other saccharide as known to one of ordinary skill in the art (see pg. 4, para[0037]). Moreover, the glycoside moiety may further include α and ß forms of the saccharides (see pg. 4, para[0037]). Polt et al. add that glycosylation processes and glycans are well known to one of ordinary skill in the art and that in some embodiments the glycan is an O-linked glycan (see pg. 5, para[0048]). Thereby corresponding to wherein the Carb is ß-D-glucose or ß-D-lactose, as recited in instant claim 24.
Regarding claim 31, Zadina et al.’s invention is also directed to a pharmaceutical composition comprising a peptide of Formula I and a pharmaceutically acceptable carrier (e.g., a diluent or excipient) (see pg. 2, para[0017)]. Polt et al. also teaches that a drug can be designed that exploits the glycopeptide lead structure to produce a bona fide pharmaceutical entity (see pg. 2, para[0018]). As such, the combined teachings of Zadina et al. and Polt et al. are suggestive of a pharmaceutical composition comprising the claimed glycosylated cyclic peptide of Formula (I) or a pharmaceutical acceptable salt thereof in a pharmaceutically acceptable carrier.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Response to Arguments
Applicants' assert that the cited prior art does not teach or suggest a glycosylated cyclic peptide of Applicants’ present claims (see Remarks, filed 06/23/2026, pg. 8, paragraphs 2-3). Applicants add that a detailed explanation of why a person of ordinary skill in the art would be successful at arriving at the claimed invention was not provided (see Remarks, filed 06/23/2026, pg. 8, paragraph 1). These arguments have been fully considered but they are not persuasive.
It is the Examiner’s understanding that Applicants’ statements amount to lack of motivation to combine the teachings of Zadina and Polt; as well as to lack of a reasonable expectation of success to arrive at the claimed invention because the exact glycosylated cyclic peptide is not disclosed by the cited art.
It is acknowledged that there is not a single reference that teaches and/or suggests every claim limitation recited in the examined claims. However, Applicants are respectfully reminded that the 35 U.S.C 103 rejection above is based on obviousness. Pursuant to MPEP 2142, 35 USC 103 authorizes a rejection where, to meet the claim, it is necessary to modify a single reference or to combine it with one or more other references (emphasis added). Since the rejection is based on obviousness, it is unnecessary for every claim limitation to be taught and/or suggested by a single reference. Additionally, 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 the instant case, as discussed above, the teachings of Zadina and Polt are suggestive of the claim limitations as recited in instant claims 1, 2, 4, 7, 11, 24, 26 and 31. Zadina expressly teaches “Compound 1” (i.e., Formula I, H-Tyr-c[X1-X2-X3-X4]-X5), wherein each of Zadina’s variables read on Applicants’ elected species for variables A1-A6 of instant Formula (I). Polt teaches glycosylation at or near the C-terminal domain of a peptide, wherein the glycoside moiety is the ß form of a saccharide/carbohydrate such as lactose. Polt also teaches that glycosylation enhances the ability of the peptide to cross the blood brain barrier and/or enhance the peptide’s half-life. As such, the question is (1) whether a person of ordinary skill in the art would be motivated and/or expected to glycosylate a cyclic peptide, and (2) whether a person of ordinary skill in the art would be motivated and/or expected to use the ß form of a saccharide/carbohydrate such as lactose as the glycoside moiety. The Examiner maintains that the answers to these questions are yes in light of the teachings of Zadina for question one and Polt for question two.
Regarding the alleged lack of reasonable expectation of success. Pursuant to MPEP 2143.02(II), obviousness does not require absolute predictability, however, at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976). As discussed in the rejection above, the combination of teachings constitute applying a known technique (i.e., glycosylation) to a known product (i.e., a cyclic peptide) ready for improvement to yield predictable results and/or the use of a known technique (i.e., glycosylation) to improve similar devices (methods, or products) (i.e., a cyclic peptide) in the same way. Thus, a person of ordinary skill in the art would recognize that glycosylation of a cyclic peptide would improve the peptide’s half-life and ability to cross the brain blood barrier. Therefore, contrary to Applicants’ argument, the Examiner maintains that a person of ordinary skill in the art would correlate the benefits and advantages of combining both teachings, thereby rendering the claim invention obvious with a reasonable expectation of success.
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., reduced peptide stability, deleterious effects on numerous pharmacodynamic properties and potency) are not recited in the rejected claims. 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). Therefore, Applicants’ arguments pertaining to greater reduction in potency for receptor mediated in vitro signaling are not pertinent to the claimed cyclic peptide because the scope of the examined claims do not encompass any structure-function limitations.
In response to Applicants’ arguments that the claimed glycosylated cyclic peptides despite having reduced affinity resulting from glycosylation exhibited MOR IC50 values ranging from 0.81 to 1.71, which translates to an unexpected 10- to 20- fold increase in potency relative to the non-glycosylated cyclic peptide control ZH853 potency of 37.1 (see Remarks, filed 06/23/2026, pg. 10, second paragraph); and the unexpected beneficial antinociception properties (see Remarks, filed 06/23/2026, pg. 11, second paragraph). These arguments have been fully considered but are not persuasive.
Pursuant under MPEP 716.02(d), whether the unexpected results are the results of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” As previously mentioned, the scope of the claimed glycosylated cyclic peptide of Formula (I) encompasses a generic formula wherein each variable in the formula includes at least one amino acid substitution, and does not encompass structure-function correlation. The specification does not provide details pertaining to the specific variants as recited in instant claim 1, exhibiting the unexpected increase in potency and the unexpected beneficial antinociception properties. The specification provides evidence relative to potency for compounds A2 (i.e., SEQ ID NO: 1), A7 (i.e., SEQ ID NO: 10) and A1 (i.e., SEQ ID NO: 5) (see instant specification, pg. 39 and Figs. 1-3 and 7). Additionally, it is noted that Table 3, included in with the Remarks (see remarks, filed 06/23/2026, pg. 10) is not part of the instant specification. Accordingly, the specification does not support that the unexpected results of increase potency are commensurate in scope with the examined claims.
Furthermore, the Federal Circuit found, “[t]o be particularly probative, evidence of unexpected results must establish that there is a difference between the results obtained and those of the closest prior art, and that the difference would not have been expected by one of ordinary skill in the art at the time of the invention.” Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014).
MPEP 716.02(b) also states that evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). See In re Blondel, 499 F.2d 1311, 1317, 182 USPQ 294, 298 (CCPA 1974) and In re Fouche, 439 F.2d 1237, 1241-42, 169 USPQ 429, 433 (CCPA 1971) for examples of cases where indirect comparative testing was found sufficient to rebut a prima facie case of obviousness.
The remarks filed on 06/23/2026 include arguments pertaining to Zadina’24 and Szabo 2023. However, these references are not prior art. Thus Applicants’ comparison of the alleged unexpected results achieved with the claimed invention to the art published after the effective filing date of the claimed invention (i.e., Zadina 2024 and Szabo 2023) are not sufficient to rebut a prima facie case of obviousness.
With respect to Applicants’ arguments pertaining to the unexpected long duration of antinociception and reasonable expectation of success in the absence of experimental evidence (see Remarks, filed 06/23/2026, pg. 11). These arguments have been fully considered, but are not persuasive.
Pursuant to MPEP 2143.02(II), obviousness does not require absolute predictability, however, at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976). MPEP 716.02(c)(II), also states that expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967).
In other words, the prior art has already demonstrated that glycosylating a peptide with a glycoside moiety such as the ß form of a lactose at or near the C-terminal domain enhances the peptide’s ability to cross the blood brain barrier (BBB) and/or can enhance the peptide’s half-life.
Therefore, the standard for determining whether a person of skill in the art has the requisite expectation of success does not depend on absolute expectation of success (i.e., achieving the glycosylated cyclic peptide as claimed). Rather the standard depends on whether there is reasonable expectation of success (i.e., enhancing peptide’s activity and/or improving its properties and functions). Furthermore, the alleged unexpected prolonged duration of antinociception (a property and/or a function of the claimed peptide) would have been expected, because glycosylation enhances the peptide’s half-life. Thereby, if the peptide’s function/property is blocking the detection of a painful stimulus by sensory neurons, then it would be expected that the peptide’s function/property is prolonged because the time it takes for the peptide’s to be cleared from a subjects system would increase. Thus, the alleged unexpected prolongation of antinociception is obvious and thereby expected.
Accordingly, claims 1-2, 4, 7, 11, 20, 24, 26, 31 are rejected under 35 U.S.C. 103.
Examiner’s Comment
Claims 1-2, 4, 7, 9, 11, 20, 24, 26 and 31 are rejected.
It is noted that there is no teaching in the art for instant SEQ ID NO: 1 (i.e., Tyr-c[D-Lys-Trp-Phe-Glu]-Ser(ß-Lac)-NH2). The closest prior art is Zadina et al. which teaches Tyr-c[D-Lys-Trp-Phe-Glu]-SerNH2. Therefore, claim 28 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CLAUDIA E ESPINOSA whose telephone number is (703)756-4550. The examiner can normally be reached Monday-Friday 9:30-5:30 EST.
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 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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CLAUDIA ESPINOSA/Patent Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654
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