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Claims 32-33 and 36-38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, and claims 9, 12, 16 and 29-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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.
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 02/19/2026 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.
Claim Rejections - 35 USC § 112
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.
1. Claims 1-2, 4, 7, 11, 24, 26, and 31 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 1 is drawn 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 A6 comprises at least one hydroxy-substituted amino acid residue”. However, the phrase “A6 comprises at least one hydroxy-substituted amino acid residue” is ambiguous because it has not been clearly stablished whether an oligopeptide comprising 2 to 5 amino acid residues is limited by at least one hydroxy-substituted amino acid residue, or whether the amino acid residue that represents A6 comprises a hydroxyl group that can be substituted, or whether the limitation “at least one hydroxy-substituted amino acid residue” only applies to when A6 is an oligopeptide comprising 2 to 5 amino acid residues. In order to advance prosecution, A6 will be interpreted as an amino acid residue that comprises a hydroxyl group that can be substituted. Please note that claims20 and 28 are not included in this rejection because the claim limitations recited thereof include an amino acid residue at position A6 (i.e., L-Ser/Ser) which comprises a hydroxyl group that can be substituted.
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 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]).
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 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 A6 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-live, 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.
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]-NH2. 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.
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.
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/CLAUDIA ESPINOSA/Patent Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654