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 .
DETAILED ACTION
Response to Election/Restriction filed on December 19, 2025 is acknowledged. Claims 1-16 are pending in the instant application.
Election/Restrictions
Applicant initially elected without traverse formula III-B with two arginine residues, two hydrophobic residues, each hydrophobic residue selected from glycine and phenylalanine, that arginine is adjacent to a hydrophobic reside, Xn comprises a linker, a therapeutic and a targeting moiety and attached to the side chain of a Gln in the reply filed December 19, 2025. On January 16, 2025 the Examiner placed a telephone call to clarify the species election as Applicant did not fully elect the peptide of formula III-B as required. On January 16, 2025, Applicant further elected without traverse wherein Au is Gln, AA1 is Arg, AA2 is Gly, Aa3 is Arg, Aa4 is gly, AAz is phe-Gly-Phe and the linker is found in instant claim 10.
The restriction is deemed proper and is made FINAL in this office action. *Please note that the elected species of peptide is free of the prior art. However, the search was extended to other species and art was found.
Claims 1-16 are examined on the merits of this office action.
Priority
The application claims priority to multiple provisional applications. The earlier-filed provisional applications provide written-description support for cyclic cell-penetrating peptides comprising multiple arginine residues, hydrophobic amino acids, and a cargo moiety conjugated to the peptide, including side-chain attachment to glutamine, as demonstrated by explicit examples (Application 62/425438 in particular, filing date of 11/22/2016). The priority documents further support Formula III-B–type architectures defining cargo attachment to the cyclic peptide.
However, the priority disclosures do not provide clear and consistent written-description support for an interpretation in which glycine is considered a hydrophobic amino acid until the priority document 62/507438 (filed 5/17/2017). Accordingly, to the extent the claims rely on glycine to satisfy the recited “hydrophobic amino acid” limitation, such subject matter is not entitled to priority to the earlier provisional applications but entitled to the priority date of 5/17/2017.
Claim Rejections - 35 USC § 112, First Paragraph
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
Scope of the claims
The claims are directed to a broad genus of cyclic peptide compounds defined primarily by numerical and functional limitations rather than by specific sequences or narrowly circumscribed structural features. In particular, the claims encompass cyclic peptides that comprise at least two arginine residues;
comprise at least two hydrophobic amino acid residues, without restriction as to identity, position, or spacing; permit all remaining amino acid positions to be occupied by any amino acid, including glycine;
include a cargo moiety conjugated to the side chain of a glutamine residue; and allow substantial variability in peptide length, residue order, residue composition, and cargo attachment location.
As drafted, the claims encompass an exceptionally large and structurally diverse genus of cyclic peptides, including peptides with markedly different charge distributions, hydrophobicity profiles, conformational flexibility, and secondary structure characteristics.
Therefore, to meet the written description requirement of 35 U.S.C. § 112, first paragraph, the specification must disclose a representative number of species that meet both the structural and functional limitations of the genus or the specification and/or the prior art must identify the structural elements that correlate to the claimed function in a manner that demonstrates to one of ordinary skill in the art that Applicant was in possession of the claimed genus at the time the application was filed.
Actual Reduction to Practice
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The specification discloses synthesis and testing of a limited number of cyclic cell-penetrating peptides, primarily characterized by multiple arginine residues; bulky, aromatic hydrophobic residues (e.g., phenylalanine, naphthylalanine, tryptophan); defined turn-forming or β-hairpin motifs; and
cargo moieties attached at positions not limited to glutamine side chains (see Table 4, paragraph 0107, look at delivery efficiency). No examples are provided that demonstrate actual reduction to practice of peptides spanning the full scope of the claims, including peptides that contain only the minimum number of arginine residues recited in the claims; contain only the minimum number of hydrophobic amino acids recited in the claims; include glycine as one or more of the residues within the cyclic peptide; rely on glycine as a hydrophobic residue to satisfy the hydrophobic amino acid requirement; or include a cargo moiety conjugated specifically to the side chain of a glutamine in the context of such broadly defined peptides.
Accordingly, the disclosed examples do not constitute representative species of the claimed genus. Therefore, the instant specification has failed to meet the written description requirement by actual reduction to practice of a representative number of species alone.
Sufficient relevant identifying characteristic
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination thereof.
To satisfy the written description requirement for a genus, the specification must either disclose a representative number of species or identify common structural features sufficient to establish possession of the genus. Here, the specification fails to provide sufficient identifying characteristics applicable across the full scope of the claims. While the claims permit inclusion of glycine at any position within the cyclic peptide, the specification does not identify glycine-containing peptides as representative members of the claimed genus, nor does it provide guidance as to how glycine-rich or glycine-containing peptides would retain the claimed cell-penetrating and cargo-delivery functionality. Moreover, the specification inconsistently characterizes glycine with respect to hydrophobicity. In certain passages, hydrophobic amino acids are defined by reference to hydrophobicity scales or thresholds that exclude glycine or treat glycine as less hydrophobic than alanine or phenylalanine. In other portions of the specification, glycine is not listed among hydrophobic amino acids at all. This inconsistency undermines any assertion that peptides relying on glycine to satisfy the “hydrophobic amino acid” limitation were contemplated or possessed by the inventors.
Physical/Chemical Properties
The specification attributes the functional performance of the disclosed peptides to specific physical and chemical properties, including amphipathicity, high cationic charge density, and the presence of bulky hydrophobic side chains. These properties are repeatedly discussed in connection with aromatic and aliphatic hydrophobic residues of substantial side-chain volume.
However, glycine lacks a side chain and is known to confer increased conformational flexibility rather than hydrophobic stabilization. The specification does not describe how incorporation of glycine—particularly where glycine is relied upon as a hydrophobic residue—would preserve the physical and chemical properties associated with cellular uptake and cargo delivery.
Additionally, the claims require cargo conjugation to the side chain of glutamine, yet the specification does not describe how such conjugation interacts with glycine-containing backbones across the broad range of claimed peptides.
Functional characteristics when coupled with a known or disclosed correlation between function and structure:
The specification discusses structure–function correlations for a narrow subset of peptides, emphasizing that increased hydrophobic residue size and aromaticity correlate with improved cellular uptake. These teachings do not extend to glycine-containing peptides, nor do they suggest that glycine, either alone or in combination with minimal arginine content, would provide equivalent functionality.
The specification provides no experimental data, predictive framework, or structural rationale demonstrating that peptides meeting only the minimal claim requirements (which is two Arginine residues and two hydrophobic amino acids of a possible 8 amino acids), and optionally incorporating glycine, would retain the claimed functional characteristics. Nor does it disclose a structure–function correlation applicable to cargo conjugation at glutamine side chains across such diverse peptide architectures.
Method of Making
Although general peptide synthesis and cyclization techniques are disclosed, the ability to make peptides within the claim scope does not establish written description. The specification does not describe or exemplify methods directed to producing peptides that include glycine in positions relevant to hydrophobicity or function, nor peptides that rely on glycine to satisfy the hydrophobic amino acid limitation of the claims.
Conclusion
In view of the foregoing, the specification does not reasonably convey to one of ordinary skill in the art that the inventors were in possession of the full scope of the claimed genus at the time of filing. The claims encompass a vast array of cyclic peptides defined only by minimal residue counts and a cargo conjugation site, including peptides incorporating glycine as a structural or functional component. The specification, however, discloses and characterizes only a narrow subset of peptides and provides inconsistent treatment of glycine with respect to hydrophobicity and function. Accordingly, the claims are rejected under 35 U.S.C. §112(a) for lack of adequate written description.
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.
Claims 1-16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “the cargo moiety is conjugated to the side chain of a glutamine”. There is no prior recitation of “a glutamine” in the peptide sequence. The claim defines the sequence using generic variables AAu, AA1-AA4, AAz. It is unclear whether the glutamine is intended to be one of the previously recited AA variables or if it is an additional residues not accounted for in Formula III-B. If it is one of the AA variables, it is unclear which one (AAu or AAz). Without a clear antecedent basis, the boundaries of the claim cannot be determined. Furthermore, the claim is internally inconsistent regarding the identity of AAu. Formula III-B depicts the cargo moiety Xn bonded directly to (AAu)m. However, the claim further requires the cargo moiety be conjugated specifically to a “glutamine”. The claim describes AAu as a variable that can be any amino acid (subject to the Arginine/hydrophobic proviso). Yet, because Formula III-B shows Xn attached to AAu, and the text requires that attachment point to be a glutamine, AAu is not actually “any amino acid”, it is restricted to glutamine. A claim that purports to allow “any” amino acid simultaneously mandating a specific amino acid (glutamine) via a structural limitation is ambiguous. A person of ordinary skill in the art would not know if AAu is truly a variable or a fixed residue. Given the broadest reasonable interpretation of claim 1, for apply art purposes, the cyclic peptide AAu variable can be any amino acid as long as the cyclic peptide has at least two arginine residues, two hydrophobic amino acids and one glutamine with a cargo attached.
Claims 2-16 are also rejected due to their dependence on claim 1 and not further clarifying these points of confusion.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 3, 6, 11, 16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Qian (ACS Chem. Biol, 2013, 8, 423-431, cited in IDS).
Given the broadest reasonable interpretation of claim 1, for applying art purposes, the cyclic peptide AAu variable can be any amino acid as long as the cyclic peptide has at least two arginine residues, two hydrophobic amino acids and one glutamine with a cargo attached. Furthermore, regarding claim interpretation, Applicant’s specification states that a detection label can be a therapeutic (see paragraph 0142) and the targeting moiety can be part of the CPP sequence itself (see paragraph 0210, CPP moiety can be part of the sequences that forms targeting moiety). Furthermore, the limitation of “natural stereo configuration” refers to the L-stereochemistry of amino acids as found in naturally occurring peptides and protein.
Qian discloses cyclic cell penetrating peptide compounds comprising all of the limitations recited in claim 1. Specifically, Qian teaches cyclic peptides (see e.g., Table 1 and associated discussion) that comprise multiple arginine residues, including peptides containing three or more arginine residues (e.g. sequence such as AFΦRRRRQ). Qian further teaches that these cyclic peptides comprise multiple hydrophobic amino acids, including Phenylalanine, napthyalanine, and alanine, thereby satisfying the limitation of at least two hydrophobic amino acids found in instant claim 1. Qian further discloses a cargo moiety in the form of a detectable/labeling moiety (e.g. FITC). As described in Qian (see Table 1 footnote), the detectable moiety is conjugated to the side chain of an invariant glutamine residue of the cyclic peptide. Thus, Qian expressly discloses a cargo moiety conjugated to the side chain of glutamine, as required by instant claim 1. Qian further teaches that the cargo moiety is attached via a lysine residue, which functions as a linker moiety between the cyclic peptide and the detectable moiety (i.e. CPP-Gln-Lys-FITC). Accordingly, Qian discloses a cargo moiety comprising both a linker and a detectable (therapeutic) moiety.
With respect to the targeting moiety, applicants define the targeting moiety as optionally being part of, or overlapping with, the cell-penetrating peptide sequence itself. Qian teaches that the arginine and hydrophobic residues-rich cyclic peptide mediates cellular binding and uptake (see Abstract), thereby functioning as a targeting element. Accordingly, under Applicants own definition, the cyclic peptide of Qian constitutes a targeting moiety. Regarding claim 3, Qian teaches wherein at least one amino acid is a Phe (see Table 1, peptide 13).
Regarding claim 6, Qian teaches wherein arginine is adjacent to a hydrophobic amino acid (see Table 1, peptide 13, arginine next to napthylalanine
Regarding claim 16, Qian teaches that all of the amino acids are in the natural stereo configuration (“L amino acid”) thus meeting the limitations of instant claim 16.
Regarding claim 11, Qian teaches wherein arginine is adjacent to a hydrophobic amino acid (see Table 1, peptide 13, arginine next to napthylalanine).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-9, 11-14, 16 are rejected under 35 U.S.C. 103 as being unpatentable over Qian (ACS, Chem. Biol, 2013, 8, pages 423-431, cited in IDS) in view of Rothbard (J. Med. Chem. 2002, 45, 3612-3618).
Given the broadest reasonable interpretation of claim 1, for applying art purposes, the cyclic peptide AAu variable can be any amino acid as long as the cyclic peptide has at least two arginine residues, two hydrophobic amino acids and one glutamine with a cargo attached. Furthermore, regarding claim interpretation, Applicant’s specification states that a detection label can be a therapeutic (see paragraph 0142) and the targeting moiety can be part of the CPP sequence itself (see paragraph 0210, CPP moiety can be part of the sequences that forms targeting moiety).
Qian discloses cyclic cell penetrating peptide compounds comprising all of the limitations recited in claim 1. Specifically, Qian teaches cyclic peptides (see e.g., Table 1 and associated discussion) that comprise multiple arginine residues, including peptides containing three or more arginine residues (e.g. sequence such as AFΦRRRRQ). Qian further teaches that these cyclic peptides comprise multiple hydrophobic amino acids, including Phenylalanine, napthyalanine, and alanine, thereby satisfying the limitation of at least two hydrophobic amino acids found in instant claim 1. Qian further discloses a cargo moiety in the form of a detectable/labeling moiety (e.g. FITC). As described in Qian (see Table 1 footnote), the detectable moiety is conjugated to the side chain of an invariant glutamine residue of the cyclic peptide. Thus, Qian expressly discloses a cargo moiety conjugated to the side chain of glutamine, as required by instant claim 1. Qian further teaches that the cargo moiety is attached via a lysine residue, which functions as a linker moiety between the cyclic peptide and the detectable moiety (i.e. CPP-Gln-Lys-FITC). Accordingly, Qian discloses a cargo moiety comprising both a linker and a detectable (therapeutic) moiety.
With respect to the targeting moiety, applicants define the targeting moiety as optionally being part of, or overlapping with, the cell-penetrating peptide sequence itself. Qian teaches that the arginine and hydrophobic residues-rich cyclic peptide mediates cellular binding and uptake (see Abstract), thereby functioning as a targeting element. Accordingly, under Applicants own definition, the cyclic peptide of Qian constitutes a targeting moiety. Regarding claim 3, Qian teaches wherein at least one amino acid is a Phe (see Table 1, peptide 13).
Regarding claim 6, Qian teaches wherein arginine is adjacent to a hydrophobic amino acid (see Table 1, peptide 13, arginine next to napthylalanine
Regarding claims 9 and 16, Qian teaches that all of the amino acids are in the natural stereo configuration (“L amino acid”) thus meeting the limitations of instant claims 9 and 16.
Regarding claim 11, Qian teaches wherein arginine is adjacent to a hydrophobic amino acid (see Table 1, peptide 13, arginine next to napthylalanine).
Qian is silent to wherein the cyclic peptide comprises are least one glycine residue in the sequence.
However, Rothbard introduces glycine residue into a polyarginine CPP (see abstract). Rothbard teaches that “The differential uptake of the peptides supported the view that increasing the spacing between the arginines would result in greater cellular uptake. Glycine has a single methylene between the amino and this increased space between the arginine residues and resulted in improved cellular uptake (see page 3615, right hand column, first paragraph, Figure 3, Figure 5, see also discussion, page 3616, right column, second to last paragraph). Rothbard concluded that “By increasing the conformational freedom of the backbone of peptides through the addition of methylene units, a significant enhancement in the rate of cellular uptake of the transporter was seen. Even though the structural basis for the conformational flexibility of peptoids and peptides is very different, addition of methylenes in either the backbone or the side chain results in enhanced cellular uptake”.
Regarding claims 2, 4, 5, 7-8, 12-13, It would have been obvious before the effective filing date of the claimed invention to substitute a glycine residue for an arginine residues (or two) in the peptide of Qian. Rothbard teaches that introducing glycine into arginine rich cell penetrating peptides increases spacing between arginine residues, enhances back bone conformational flexibility, and improves cellular uptake. A person of ordinary skill in the art would have been motivation to make this substitution to modulate arginine spacing while mainlining/improving cell penetrating functionality. There is a reasonable expectation of success given Rothbard demonstrates incorporation of glycine predictably enhances cellular uptake by increasing backbone flexibility and teaches that addition of methylene units to the peptide results in enhanced uptake.
Regarding claims 8 and 13, which requires that both arginine residues are adjacent to glycine residues, Rothbard teaches introducing glycine residues into arginine rich CPPs to increase spacing between arginine residues and enhance uptake. A person of ordinary skill in the art would have found it obvious to substitute or introduce multiple glycine residues adjacent to arginine residues in the cyclic peptides of Qian to achieve the taught increase in arginine spacing and backbone flexibility. A person of ordinary skill in the art would have had a reasonable expectation of success, as Rothbard demonstrates that incorporation of glycine predictability enhances cellular uptake without disrupting CPP function. With two arginine substitutions, the resulting peptide would be AFΦRGRGQ or AFΦGGRRQ or AFΦGRRGQ or AFΦRRGGQ. However, AFΦRGRGQ would result in the greatest separation of the arginine residues.
Furthermore, selection of the number and placement of glycine residues adjacent to arginine residues constitutes routine optimization of known result effective variables, namely arginine spacing and peptide flexibility, to enhance cellular uptake. A person of ordinary skill in the art would have been motivated to introduce multiple glycine residues adjacent to arginine residues in the cyclic peptides of Qian to optimize uptake while retaining function.
Claim(s) 1-16 are rejected under 35 U.S.C. 103 as being unpatentable over Qian (ACS, Chem. Biol, 2013, 8, pages 423-431) in view of Rothbard (J. Med. Chem. 2002, 45, 3612-3618) as applied to claims 1-9, 11-14, 16 above, in further view of Qian* (Biochemistry 2014, 53, 4034−4046).
The teachings of Qian and Rothbard in provided in the above rejection. The combined teachings are silent to wherein the linker is mini-peg, or 8-amino-3,6-dioxaoctaonic acid. Qian* teaches that the cargo moiety comprises 8-amino-3,6-dioxaoctanoic acid. Specifically, Qian defines “miniPEG” as 8-amino-3,6-dioxaoctanoic acid (see Table 1 abbreviations) and discloses multiple cyclic cell-penetrating peptides in which miniPEG is conjugated between the cyclic peptide and a detectable or therapeutic moiety (see Table 1, peptides 8–12). Qian further teaches that the cargo is conjugated to the cyclic peptide via the side chain of an invariant glutamine residue.
Regarding claims 10 and 15, It would have been obvious before the effective filing date of the claimed invention, to modify the cyclic peptide conjugates of Qian to include the miniPEG (8-amino-3,6-dioxaoctanoic acid) linker as taught by Qian*. Qian* teaches that miniPEG is a suitable linker for conjugating cargo moieties to cell-penetrating peptides while maintaining cellular uptake. A person of ordinary skill in the art would have been motivated to substitute the linker of Qian with the miniPEG linker of Qian* as a predictable design choice to provide spacing between the cyclic peptide and the cargo (Substituting one known element for another to obtain predictable results, KSR v. Teleflex; MPEP2143, I(B)). A reasonable expectation of success would have existed because Qian* demonstrates that miniPEG-linked CPP conjugates remain functional and Qian already teaches cargo attachment to the side chain of glutamine.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of Copending Application No. 19329358 (reference application) in view of Qian* ((Biochemistry 2014, 53, 4034−4046).
Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims A cyclic peptide structure comprising Formula IIIB.
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wherein: Xn is a cargo moiety comprising a linker moiety, a therapeutic moiety, and a targeting moiety;m is1;n is 3;each AA1, AA2, AA3, and AA4, are independently selected from an amino acid; AAu and AAz, at each instance, are independently selected from an amino acid; wherein:two amino acids selected from AA1 AA2, AA3, AA4, AAu, and AAz are arginine with the remaining amino acids being an amino acid other than arginine; and at least two amino acids selected from AA1, AA2, AA3, AA4, AAu, and AAz are independently a hydrophobic amino acid; and the cargo moiety is conjugated to the side chain of a glutamine in the cyclic peptide. The instant application further claims glycine 9see claim 2, 4, 7-8, 12-13), L-configuration (claims 9, 14, 16) and miniPEG as the linker (claims 10, 15).
Copending Application No. 19329358 claims “A compound comprising; i. a cyclic cell penetrating peptide that contains a) one arginine within two amino acids of another arginine ;b) an amino acid with a hydrophobic side chain within two amino acids of another amino acid with a hydrophobic side chain; and ii) an exocyclic cargo moiety conjugated to a side chain of the cell penetrating peptide wherein the conjugation is through glutamine and wherein the cargo comprises an amino acid sequence that targets an enzyme” (see claim 1). Copending Application No. 19329358 further claims wherein the cargo moiety comprises a therapeutic moiety and a linker moiety (see claims 5-6); glycine as a hydrophobic amino acid (claim 9); phenylalanine as the hydrophobic amino acid (claim 10); wherein the CPP comprises 8 amino acids (claim 19) and L-amino acids (claim 14).
Co-pending Application No. 19329358 is silent to minipig linker.
However, Qian* teaches that the cargo moiety comprises 8-amino-3,6-dioxaoctanoic acid. Specifically, Qian* defines “miniPEG” as 8-amino-3,6-dioxaoctanoic acid (see Table 1 abbreviations) and discloses multiple cyclic cell-penetrating peptides in which miniPEG is conjugated between the cyclic peptide and a detectable or therapeutic moiety (see Table 1, peptides 8–12). Qian* further teaches that the cargo is conjugated to the cyclic peptide via the side chain of an invariant glutamine residue.
It would have been obvious before the effective filing date of the claimed invention, to modify the cyclic peptide conjugates of o-pending Application No. 19329358 to include the miniPEG (8-amino-3,6-dioxaoctanoic acid) linker as taught by Qian*. Qian* teaches that miniPEG is a suitable linker for conjugating cargo moieties to cell-penetrating peptides while maintaining cellular uptake. A person of ordinary skill in the art would have been motivated to substitute the linker of Co-pending Application No. 19329358 with the miniPEG linker of Qian* as a predictable design choice to provide spacing between the cyclic peptide and the cargo (Substituting one known element for another to obtain predictable results, KSR v. Teleflex; MPEP2143, I(B)). A reasonable expectation of success would have existed because Qian* demonstrates that miniPEG-linked CPP conjugates remain functional.
Claims 1-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of Copending Application No. 19329410 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims A cyclic peptide structure comprising Formula IIIB.
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wherein: Xn is a cargo moiety comprising a linker moiety, a therapeutic moiety, and a targeting moiety;m is1;n is 3;each AA1, AA2, AA3, and AA4, are independently selected from an amino acid; AAu and AAz, at each instance, are independently selected from an amino acid; wherein:two amino acids selected from AA1 AA2, AA3, AA4, AAu, and AAz are arginine with the remaining amino acids being an amino acid other than arginine; and at least two amino acids selected from AA1, AA2, AA3, AA4, AAu, and AAz are independently a hydrophobic amino acid; and the cargo moiety is conjugated to the side chain of a glutamine in the cyclic peptide. The instant application further claims glycine 9see claim 2, 4, 7-8, 12-13), L-configuration (claims 9, 14, 16) and miniPEG as the linker (claims 10, 15).
Copending Application No. 19/329410 claims “a cyclic peptide comprising A1-A8 conjugated to a cargo moiety via a side chain, wherein the peptide comprises two arginine, two hydrophobic amino acids and the cargo is couple to side chain of glutamine (claim 1). Co-pending Application No. 19329410 further claims the cargo moiety comprise mini-peg (claim 10), the peptide comprise L-configuration (Claim 12), arginines adjacent to glycines (Claim 9), phenylalanine and glycine (claim 11).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of Copending Application No. 19329427(reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims A cyclic peptide structure comprising Formula IIIB.
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wherein: Xn is a cargo moiety comprising a linker moiety, a therapeutic moiety, and a targeting moiety;m is1;n is 3;each AA1, AA2, AA3, and AA4, are independently selected from an amino acid; AAu and AAz, at each instance, are independently selected from an amino acid; wherein:two amino acids selected from AA1 AA2, AA3, AA4, AAu, and AAz are arginine with the remaining amino acids being an amino acid other than arginine; and at least two amino acids selected from AA1, AA2, AA3, AA4, AAu, and AAz are independently a hydrophobic amino acid; and the cargo moiety is conjugated to the side chain of a glutamine in the cyclic peptide. The instant application further claims glycine (see claim 2, 4, 7-8, 12-13), L-configuration (claims 9, 14, 16) and miniPEG as the linker (claims 10, 15).
Copending Application No. 19/329427 claims “a cyclic peptide comprising A1-A8 conjugated to a cargo moiety via a side chain, wherein the peptide comprises two arginine, two hydrophobic amino acids and the cargo is couple to side chain of glutamine (claim 1). Co-pending Application No. 19329427 further claims the cargo moiety comprise mini-peg (claim 16), the peptide comprise L-configuration (Claim 15), arginines adjacent to glycines (Claim 14), phenylalanine and glycine (claim 19).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 74, 82-83, 88-89 of Copending Application No. 18/688096(reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims A cyclic peptide structure comprising Formula IIIB.
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wherein: Xn is a cargo moiety comprising a linker moiety, a therapeutic moiety, and a targeting moiety;m is1;n is 3;each AA1, AA2, AA3, and AA4, are independently selected from an amino acid; AAu and AAz, at each instance, are independently selected from an amino acid; wherein:two amino acids selected from AA1 AA2, AA3, AA4, AAu, and AAz are arginine with the remaining amino acids being an amino acid other than arginine; and at least two amino acids selected from AA1, AA2, AA3, AA4, AAu, and AAz are independently a hydrophobic amino acid; and the cargo moiety is conjugated to the side chain of a glutamine in the cyclic peptide. The instant application further claims glycine (see claim 2, 4, 7-8, 12-13), L-configuration (claims 9, 14, 16) and miniPEG as the linker (claims 10, 15).
Copending Application No. 18/688096 claims a cyclic peptide attached to a therapeutic moiety via a linker (see claims 74, 83). Copending Application No. 18/688096 claims wherein the CPP has a glutamine as the AAsc (site of attachment, see claim 88); two arginine residues (see claim 83); glycine adjacent to the arginine residues (claim 83), phenylalanine (claim 83) and wherein the linker is PEG2 (minipig) and wherein all amino acids are in L-configuration.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-35 of U.S. Patent No. 11168310 in view of Qian* and Rothbard (cited above). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims A cyclic peptide structure comprising Formula IIIB.
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wherein: Xn is a cargo moiety comprising a linker moiety, a therapeutic moiety, and a targeting moiety;m is1;n is 3;each AA1, AA2, AA3, and AA4, are independently selected from an amino acid; AAu and AAz, at each instance, are independently selected from an amino acid; wherein:two amino acids selected from AA1 AA2, AA3, AA4, AAu, and AAz are arginine with the remaining amino acids being an amino acid other than arginine; and at least two amino acids selected from AA1, AA2, AA3, AA4, AAu, and AAz are independently a hydrophobic amino acid; and the cargo moiety is conjugated to the side chain of a glutamine in the cyclic peptide. The instant application further claims glycine (see claim 2, 4, 7-8, 12-13), L-configuration (claims 9, 14, 16) and miniPEG as the linker (claims 10, 15).
US Patent No. 11168310 B claims a cyclic peptide comprising instant formula IIIB conjugated via a linker to a therapeutic agent (see claim 1). US Patent No. 11168310 B claims wherein the CPP comprises amino acids 14-101, 108, 110, 124-127 which comprises sequences that falling within instant claims 1-14 and 16 (two arginine, glutamine, phenylalanine). US Patent No. 11168310 B further claims the complex comprising PEG (see claim 32).
US Patent No. 11168310 is silent to wherein the peptides comprising a glycine or two glycines. However, Rothbard introduces glycine residue into a polyarginine CPP. Rothbard teaches that “The differential uptake of the peptides supported the view that increasing the spacing between the arginines would result in greater cellular uptake. Glycine has a single methylene between the amino and this increased space between the arginine residues and resulted in improved cellular uptake (see page 3615, right hand column, first paragraph, Figure 3, Figure 5, see also discussion, page 3616, right column, second to last paragraph). Rothbard concluded that “By increasing the conformational freedom of the backbone of peptides through the addition of methylene units, a significant enhancement in the rate of cellular uptake of the transporter was seen. Even though the structural basis for the conformational flexibility of peptoids and peptides is very different, addition of methylenes in either the backbone or the side chain results in enhanced cellular uptake”.
It would have been obvious before the effective filing date of the claimed invention to substitute a glycine residue for an arginine residues (or two) in one of the peptide of US Patent No. 11168310 (for example SEQ ID NO:32-35. Rothbard teaches that introducing glycine into arginine rich cell penetrating peptides increases spacing between arginine residues, enhances back bone conformational flexibility, and improves cellular uptake. A person of ordinary skill in the art would have been motivation to make this substitution to modulate arginine spacing while mainlining/improving cell penetrating functionality. There is a reasonable expectation of success given Rothbard demonstrates incorporation of glycine predictably enhances cellular uptake by increasing backbone flexibility and teaches that addition of methylene units to the peptide results in enhanced uptake.
Regarding instant claims 8 and 13, which requires that both arginine residues are adjacent to glycine residues, Rothbard teaches introducing glycine residues into arginine rich CPPs to increase spacing between arginine residues and enhance uptake. A person of ordinary skill in the art would have found it obvious to substitute or introduce multiple glycine residues adjacent to arginine residues in the cyclic peptides of US Patent. No. ‘310 to achieve the taught increase in arginine spacing and backbone flexibility. A person of ordinary skill in the art would have had a reasonable expectation of success, as Rothbard demonstrates that incorporation of glycine predictability enhances cellular uptake without disrupting CPP function. Furthermore, selection of the number and placement of glycine residues adjacent to arginine residues constitutes routine optimization of known result effective variables, namely arginine spacing and peptide flexibility, to enhance cellular uptake. A person of ordinary skill in the art would have been motivated to introduce multiple glycine residues adjacent to arginine residues in the cyclic peptides of Qian to optimize uptake while retaining function.
US Patent No. 11168310 is silent to specifically miniPEG
However, Qian* teaches that the cargo moiety comprises 8-amino-3,6-dioxaoctanoic acid. Specifically, Qian* defines “miniPEG” as 8-amino-3,6-dioxaoctanoic acid (see Table 1 abbreviations) and discloses multiple cyclic cell-penetrating peptides in which miniPEG is conjugated between the cyclic peptide and a detectable or therapeutic moiety (see Table 1, peptides 8–12). Qian* further teaches that the cargo is conjugated to the cyclic peptide via the side chain of an invariant glutamine residue.
It would have been obvious before the effective filing date of the claimed invention, to modify the cyclic peptide conjugates of US Patent. No. ‘310 to include the miniPEG (8-amino-3,6-dioxaoctanoic acid) linker as taught by Qian*. Qian* teaches that miniPEG is a suitable linker for conjugating cargo moieties to cell-penetrating peptides while maintaining cellular uptake. A person of ordinary skill in the art would have been motivated to substitute the linker of US Patent. No. ‘310 with the miniPEG linker of Qian* as a predictable design choice to provide spacing between the cyclic peptide and the cargo (Substituting one known element for another to obtain predictable results, KSR v. Teleflex; MPEP2143, I(B)). A reasonable expectation of success would have existed because Qian* demonstrates that miniPEG-linked CPP conjugates remain functional.
Claims 1-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 10626147 in view of Qian* and Rothbard (cited above). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims A cyclic peptide structure comprising Formula IIIB.
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wherein: Xn is a cargo moiety comprising a linker moiety, a therapeutic moiety, and a targeting moiety;m is1;n is 3;each AA1, AA2, AA3, and AA4, are independently selected from an amino acid; AAu and AAz, at each instance, are independently selected from an amino acid; wherein:two amino acids selected from AA1 AA2, AA3, AA4, AAu, and AAz are arginine with the remaining amino acids being an amino acid other than arginine; and at least two amino acids selected from AA1, AA2, AA3, AA4, AAu, and AAz are independently a hydrophobic amino acid; and the cargo moiety is conjugated to the side chain of a glutamine in the cyclic peptide. The instant application further claims glycine (see claim 2, 4, 7-8, 12-13), L-configuration (claims 9, 14, 16) and miniPEG as the linker (claims 10, 15).
US Patent No. 10626147 B claims a cyclic peptide comprising instant formula II-A-IIC conjugated via a linker to a cargo (see claim 7). US Patent No. 106226147 B claims a cyclic peptide comprising at least two arginine residues, hydrophobic amino acids including phenylalanine, wherein m and p are 1, m is 0 (resulting in an 8mer) with a terminal glutamine and wherein the cargo is attached to the glutamine. US Patent No. 106226147 further claims having all L-amino acids (claim 5) and the cargo comprises a detectable moiety, a therapeutic moiety, a targeting moiety, or a combination thereof (claim 6).
US Patent No. 10626147 is silent to wherein the peptides comprising a glycine or two glycines. However, Rothbard introduces glycine residue into a polyarginine CPP. Rothbard teaches that “The differential uptake of the peptides supported the view that increasing the spacing between the arginines would result in greater cellular uptake. Glycine has a single methylene between the amino and this increased space between the arginine residues and resulted in improved cellular uptake (see page 3615, right hand column, first paragraph, Figure 3, Figure 5, see also discussion, page 3616, right column, second to last paragraph). Rothbard concluded that “By increasing the conformational freedom of the backbone of peptides through the addition of methylene units, a significant enhancement in the rate of cellular uptake of the transporter was seen. Even though the structural basis for the conformational flexibility of peptoids and peptides is very different, addition of methylenes in either the backbone or the side chain results in enhanced cellular uptake”.
It would have been obvious before the effective filing date of the claimed invention to substitute a glycine residue for an arginine residues (or two) in one of the peptide of US Patent No. 10626147. Rothbard teaches that introducing glycine into arginine rich cell penetrating peptides increases spacing between arginine residues, enhances back bone conformational flexibility, and improves cellular uptake. A person of ordinary skill in the art would have been motivation to make this substitution to modulate arginine spacing while mainlining/improving cell penetrating functionality. There is a reasonable expectation of success given Rothbard demonstrates incorporation of glycine predictably enhances cellular uptake by increasing backbone flexibility and teaches that addition of methylene units to the peptide results in enhanced uptake.
Regarding instant claims 8 and 13, which requires that both arginine residues are adjacent to glycine residues, Rothbard teaches introducing glycine residues into arginine rich CPPs to increase spacing between arginine residues and enhance uptake. A person of ordinary skill in the art would have found it obvious to substitute or introduce multiple glycine residues adjacent to arginine residues in the cyclic peptides of US Patent. No. ‘147 to achieve the taught increase in arginine spacing and backbone flexibility. A person of ordinary skill in the art would have had a reasonable expectation of success, as Rothbard demonstrates that incorporation of glycine predictability enhances cellular uptake without disrupting CPP function. Furthermore, selection of the number and placement of glycine residues adjacent to arginine residues constitutes routine optimization of known result effective variables, namely arginine spacing and peptide flexibility, to enhance cellular uptake. A person of ordinary skill in the art would have been motivated to introduce multiple glycine residues adjacent to arginine residues in the cyclic peptides of Qian to optimize uptake while retaining function.
US Patent No. 10626147 is silent to specifically miniPEG
However, Qian* teaches that the cargo moiety comprises 8-amino-3,6-dioxaoctanoic acid. Specifically, Qian* defines “miniPEG” as 8-amino-3,6-dioxaoctanoic acid (see Table 1 abbreviations) and discloses multiple cyclic cell-penetrating peptides in which miniPEG is conjugated between the cyclic peptide and a detectable or therapeutic moiety (see Table 1, peptides 8–12). Qian* further teaches that the cargo is conjugated to the cyclic peptide via the side chain of an invariant glutamine residue.
It would have been obvious before the effective filing date of the claimed invention, to modify the cyclic peptide conjugates of US Patent. No. ‘147 to include the miniPEG (8-amino-3,6-dioxaoctanoic acid) linker as taught by Qian*. Qian* teaches that miniPEG is a suitable linker for conjugating cargo moieties to cell-penetrating peptides while maintaining cellular uptake. A person of ordinary skill in the art would have been motivated to substitute the linking of the cargo moiety of US Patent. No. ‘147 with the miniPEG linker of Qian* as a predictable design choice to provide spacing between the cyclic peptide and the cargo (Substituting one known element for another to obtain predictable results, KSR v. Teleflex; MPEP2143, I(B)). A reasonable expectation of success would have existed because Qian* demonstrates that miniPEG-linked CPP conjugates remain functional.
Claims 1-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 6, 8, 10, 13-19, 23, 26, 30, 35, 46, 50-53 of Copending Application No. 18278259 (reference application) in view of Qian* and Rothbard (cited above). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims A cyclic peptide structure comprising Formula IIIB.
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wherein: Xn is a cargo moiety comprising a linker moiety, a therapeutic moiety, and a targeting moiety;m is1;n is 3;each AA1, AA2, AA3, and AA4, are independently selected from an amino acid; AAu and AAz, at each instance, are independently selected from an amino acid; wherein:two amino acids selected from AA1 AA2, AA3, AA4, AAu, and AAz are arginine with the remaining amino acids being an amino acid other than arginine; and at least two amino acids selected from AA1, AA2, AA3, AA4, AAu, and AAz are independently a hydrophobic amino acid; and the cargo moiety is conjugated to the side chain of a glutamine in the cyclic peptide. The instant application further claims glycine see claim 2, 4, 7-8, 12-13), L-configuration (claims 9, 14, 16) and miniPEG as the linker (claims 10, 15).
Copending Application No. 18/278259 claims a cyclic peptide comprising at least 4 arginine residues, at least three hydrophobic amino acids (see claim 1). Copending Application No. 18/278259 further claims sequences falling within the scope of instant claims 1-16 (see claim 46, two arginines, terminal Gln, phenylalanine); conjugation to a cargo moiety via a glutamine side chain (claims 50-53); cargo moiety comprising targeting, therapeutic and detectable moiety (see claim 50).
Co-pending Application No. 18/278259 is silent to glycine and minipig linker.
However, Rothbard introduces glycine residue into a polyarginine CPP. Rothbard teaches that “The differential uptake of the peptides supported the view that increasing the spacing between the arginines would result in greater cellular uptake. Glycine has a single methylene between the amino and this increased space between the arginine residues and resulted in improved cellular uptake (see page 3615, right hand column, first paragraph, Figure 3, Figure 5, see also discussion, page 3616, right column, second to last paragraph). Rothbard concluded that “By increasing the conformational freedom of the backbone of peptides through the addition of methylene units, a significant enhancement in the rate of cellular uptake of the transporter was seen. Even though the structural basis for the conformational flexibility of peptoids and peptides is very different, addition of methylenes in either the backbone or the side chain results in enhanced cellular uptake”.
It would have been obvious before the effective filing date of the claimed invention to substitute a glycine residue for an arginine residues (or two) in one of the peptide of Copending Application No. 18/278259. Rothbard teaches that introducing glycine into arginine rich cell penetrating peptides increases spacing between arginine residues, enhances back bone conformational flexibility, and improves cellular uptake. A person of ordinary skill in the art would have been motivation to make this substitution to modulate arginine spacing while mainlining/improving cell penetrating functionality. There is a reasonable expectation of success given Rothbard demonstrates incorporation of glycine predictably enhances cellular uptake by increasing backbone flexibility and teaches that addition of methylene units to the peptide results in enhanced uptake.
Regarding instant claims 8 and 13, which requires that both arginine residues are adjacent to glycine residues, Rothbard teaches introducing glycine residues into arginine rich CPPs to increase spacing between arginine residues and enhance uptake. A person of ordinary skill in the art would have found it obvious to substitute or introduce multiple glycine residues adjacent to arginine residues in the cyclic peptides of Co-pending Application No. 18/278259 to achieve the taught increase in arginine spacing and backbone flexibility. A person of ordinary skill in the art would have had a reasonable expectation of success, as Rothbard demonstrates that incorporation of glycine predictability enhances cellular uptake without disrupting CPP function. Furthermore, selection of the number and placement of glycine residues adjacent to arginine residues constitutes routine optimization of known result effective variables, namely arginine spacing and peptide flexibility, to enhance cellular uptake. A person of ordinary skill in the art would have been motivated to introduce multiple glycine residues adjacent to arginine residues in the cyclic peptides of Co-pending Application No. 18/278259 to optimize uptake while retaining function.
Furthermore, Qian* teaches that the cargo moiety comprises 8-amino-3,6-dioxaoctanoic acid. Specifically, Qian* defines “miniPEG” as 8-amino-3,6-dioxaoctanoic acid (see Table 1 abbreviations) and discloses multiple cyclic cell-penetrating peptides in which miniPEG is conjugated between the cyclic peptide and a detectable or therapeutic moiety (see Table 1, peptides 8–12). Qian* further teaches that the cargo is conjugated to the cyclic peptide via the side chain of an invariant glutamine residue.
It would have been obvious before the effective filing date of the claimed invention, to modify the cyclic peptide conjugates of Copending Application No. 18/278259 to include the miniPEG (8-amino-3,6-dioxaoctanoic acid) linker as taught by Qian*. Qian* teaches that miniPEG is a suitable linker for conjugating cargo moieties to cell-penetrating peptides while maintaining cellular uptake. A person of ordinary skill in the art would have been motivated to substitute a linking moiety of Co-pending Application No. 18/278259 with the miniPEG linker of Qian* as a predictable design choice to provide spacing between the cyclic peptide and the cargo (Substituting one known element for another to obtain predictable results, KSR v. Teleflex; MPEP2143, I(B)). A reasonable expectation of success would have existed because Qian* demonstrates that miniPEG-linked CPP conjugates remain functional.
Claims 1-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of Copending Application No. 19329353 (reference application) in view of Qian* and Rothbard (cited above). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims A cyclic peptide structure comprising Formula IIIB.
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wherein: Xn is a cargo moiety comprising a linker moiety, a therapeutic moiety, and a targeting moiety;m is1;n is 3;each AA1, AA2, AA3, and AA4, are independently selected from an amino acid; AAu and AAz, at each instance, are independently selected from an amino acid; wherein:two amino acids selected from AA1 AA2, AA3, AA4, AAu, and AAz are arginine with the remaining amino acids being an amino acid other than arginine; and at least two amino acids selected from AA1, AA2, AA3, AA4, AAu, and AAz are independently a hydrophobic amino acid; and the cargo moiety is conjugated to the side chain of a glutamine in the cyclic peptide. The instant application further claims glycine see claim 2, 4, 7-8, 12-13), L-configuration (claims 9, 14, 16) and miniPEG as the linker (claims 10, 15).
Copending Application No. 19/329353 claims a cyclic peptide comprising at least 2 arginine residues, at least three hydrophobic amino acids (see claim 1) at least three hydrophobic amino acid residues attached to a cargo moiety coupled to a side chain of the amino acid comprising a linker, therapeutic and targeting moiety (see claim 1). Co-pending Application No. 19/329353 further claims glycine residue (see claim 3); 8 amino acids (claim 2).
Co-pending Application No. 19/329353 is silent to minipeg linker, two glycine residues adjacent to arginines and attached to a side chain of glutamine.
However, Rothbard introduces glycine residue into a polyarginine CPP. Rothbard teaches that “The differential uptake of the peptides supported the view that increasing the spacing between the arginines would result in greater cellular uptake. Glycine has a single methylene between the amino and this increased space between the arginine residues and resulted in improved cellular uptake (see page 3615, right hand column, first paragraph, Figure 3, Figure 5, see also discussion, page 3616, right column, second to last paragraph). Rothbard concluded that “By increasing the conformational freedom of the backbone of peptides through the addition of methylene units, a significant enhancement in the rate of cellular uptake of the transporter was seen. Even though the structural basis for the conformational flexibility of peptoids and peptides is very different, addition of methylenes in either the backbone or the side chain results in enhanced cellular uptake”.
It would have been obvious before the effective filing date of the claimed invention to substitute a glycine residue for an arginine residues (or two) in one of the peptide of Copending Application No. 19/329353. Rothbard teaches that introducing glycine into arginine rich cell penetrating peptides increases spacing between arginine residues, enhances back bone conformational flexibility, and improves cellular uptake. A person of ordinary skill in the art would have been motivation to make this substitution to modulate arginine spacing while mainlining/improving cell penetrating functionality. There is a reasonable expectation of success given Rothbard demonstrates incorporation of glycine predictably enhances cellular uptake by increasing backbone flexibility and teaches that addition of methylene units to the peptide results in enhanced uptake.
Regarding instant claims 8 and 13, which requires that both arginine residues are adjacent to glycine residues, Rothbard teaches introducing glycine residues into arginine rich CPPs to increase spacing between arginine residues and enhance uptake. A person of ordinary skill in the art would have found it obvious to substitute or introduce multiple glycine residues adjacent to arginine residues in the cyclic peptides of Copending Application No. 19/329353 to achieve the taught increase in arginine spacing and backbone flexibility. A person of ordinary skill in the art would have had a reasonable expectation of success, as Rothbard demonstrates that incorporation of glycine predictability enhances cellular uptake without disrupting CPP function. Furthermore, selection of the number and placement of glycine residues adjacent to arginine residues constitutes routine optimization of known result effective variables, namely arginine spacing and peptide flexibility, to enhance cellular uptake. A person of ordinary skill in the art would have been motivated to introduce multiple glycine residues adjacent to arginine residues in the cyclic peptides of Copending Application No. 19/329353 to optimize uptake while retaining function.
Furthermore, Qian* teaches that the cargo moiety comprises 8-amino-3,6-dioxaoctanoic acid. Specifically, Qian* defines “miniPEG” as 8-amino-3,6-dioxaoctanoic acid (see Table 1 abbreviations) and discloses multiple cyclic cell-penetrating peptides in which miniPEG is conjugated between the cyclic peptide and a detectable or therapeutic moiety (see Table 1, peptides 8–12). Qian* further teaches that the cargo is conjugated to the cyclic peptide via the side chain of an invariant glutamine residue.
It would have been obvious before the effective filing date of the claimed invention, to modify the cyclic peptide conjugates of Copending Application No. 19/329353 to include the miniPEG (8-amino-3,6-dioxaoctanoic acid) linker as taught by Qian* to a side chain of a glutamine. Qian* teaches that miniPEG is a suitable linker for conjugating cargo moieties to cell-penetrating peptides while maintaining cellular uptake and at a glutamine. A person of ordinary skill in the art would have been motivated to substitute the linker of Qian with the miniPEG linker of Qian* as a predictable design choice to provide spacing between the cyclic peptide and the cargo (Substituting one known element for another to obtain predictable results, KSR v. Teleflex; MPEP2143, I(B)). A reasonable expectation of success would have existed because Qian* demonstrates that miniPEG-linked CPP conjugates remain functional.
Claims 1-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of Copending Application No. 19329423 (reference application) in view of Qian*. Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims A cyclic peptide structure comprising Formula IIIB.
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wherein: Xn is a cargo moiety comprising a linker moiety, a therapeutic moiety, and a targeting moiety;m is1;n is 3;each AA1, AA2, AA3, and AA4, are independently selected from an amino acid; AAu and AAz, at each instance, are independently selected from an amino acid; wherein:two amino acids selected from AA1 AA2, AA3, AA4, AAu, and AAz are arginine with the remaining amino acids being an amino acid other than arginine; and at least two amino acids selected from AA1, AA2, AA3, AA4, AAu, and AAz are independently a hydrophobic amino acid; and the cargo moiety is conjugated to the side chain of a glutamine in the cyclic peptide. The instant application further claims glycine see claim 2, 4, 7-8, 12-13), L-configuration (claims 9, 14, 16) and miniPEG as the linker (claims 10, 15).
Copending Application No. 19/329423 claims a cyclic peptide comprising at least 2 arginine residues, at least 2 hydrophobic amino acids (see claim 1, 14) attached a cargo (with therapeutic, targeting moiety and linker) attached to a side chain (see claim 1). Co-pending Application No. 19/329423 further claims glycine residue (see claim 2); 8 amino acids (claim 1); both arginines adjacent to glycines (Claim 7), phenylalanine (claim 10) glutamine for attachment of cargo (claim 12), all L-amino acids.
Co-pending Application No. 19/329423 is silent to minipeg linker.
Qian* teaches that the cargo moiety comprises 8-amino-3,6-dioxaoctanoic acid. Specifically, Qian* defines “miniPEG” as 8-amino-3,6-dioxaoctanoic acid (see Table 1 abbreviations) and discloses multiple cyclic cell-penetrating peptides in which miniPEG is conjugated between the cyclic peptide and a detectable or therapeutic moiety (see Table 1, peptides 8–12). Qian* further teaches that the cargo is conjugated to the cyclic peptide via the side chain of an invariant glutamine residue.
It would have been obvious before the effective filing date of the claimed invention, to modify the cyclic peptide conjugates of Copending Application No. 19/329423 to include the miniPEG (8-amino-3,6-dioxaoctanoic acid) linker as taught by Qian* to a side chain of a glutamine. Qian* teaches that miniPEG is a suitable linker for conjugating cargo moieties to cell-penetrating peptides while maintaining cellular uptake and at a glutamine. A person of ordinary skill in the art would have been motivated to substitute the linker of Qian with the miniPEG linker of Qian* as a predictable design choice to provide spacing between the cyclic peptide and the cargo (Substituting one known element for another to obtain predictable results, KSR v. Teleflex; MPEP2143, I(B)). A reasonable expectation of success would have existed because Qian* demonstrates that miniPEG-linked CPP conjugates remain functional.
Claims 1-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of Copending Application No. 19329440 (reference application) in view of Qian*. Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims A cyclic peptide structure comprising Formula IIIB.
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wherein: Xn is a cargo moiety comprising a linker moiety, a therapeutic moiety, and a targeting moiety;m is1;n is 3;each AA1, AA2, AA3, and AA4, are independently selected from an amino acid; AAu and AAz, at each instance, are independently selected from an amino acid; wherein:two amino acids selected from AA1 AA2, AA3, AA4, AAu, and AAz are arginine with the remaining amino acids being an amino acid other than arginine; and at least two amino acids selected from AA1, AA2, AA3, AA4, AAu, and AAz are independently a hydrophobic amino acid; and the cargo moiety is conjugated to the side chain of a glutamine in the cyclic peptide. The instant application further claims glycine see claim 2, 4, 7-8, 12-13), L-configuration (claims 9, 14, 16) and miniPEG as the linker (claims 10, 15).
Copending Application No. 19/329440 claims a cyclic peptide comprising at least 2 arginine residues, 5 hydrophobic amino acids (see claim 1) attached a cargo (with therapeutic, targeting moiety and linker) attached to a side chain (see claim 1). Co-pending Application No. 19/329440 further claims glycine residue (see claim 4); 8 amino acids (claim 1); both arginines adjacent to glycines (Claim 8-10), phenylalanine (claim 2) , all L-amino acids.
Co-pending Application No. 19/329440 is silent to minipeg linker and a glutamine attached to the cargo.
Qian* teaches that the cargo moiety comprises 8-amino-3,6-dioxaoctanoic acid. Specifically, Qian* defines “miniPEG” as 8-amino-3,6-dioxaoctanoic acid (see Table 1 abbreviations) and discloses multiple cyclic cell-penetrating peptides in which miniPEG is conjugated between the cyclic peptide and a detectable or therapeutic moiety (see Table 1, peptides 8–12). Qian* further teaches that the cargo is conjugated to the cyclic peptide via the side chain of an invariant glutamine residue.
It would have been obvious before the effective filing date of the claimed invention, to modify the cyclic peptide conjugates of Copending Application No. 19/329440 to include the miniPEG (8-amino-3,6-dioxaoctanoic acid) linker as taught by Qian* to a side chain of a glutamine. Qian* teaches that miniPEG is a suitable linker for conjugating cargo moieties to cell-penetrating peptides while maintaining cellular uptake and at a glutamine. A person of ordinary skill in the art would have been motivated to substitute the linker of Copending Application No. 19/329440 with the miniPEG linker of Qian* as a predictable design choice to provide spacing between the cyclic peptide and the cargo (Substituting one known element for another to obtain predictable results, KSR v. Teleflex; MPEP2143, I(B)). A reasonable expectation of success would have existed because Qian* demonstrates that miniPEG-linked CPP conjugates remain functional.
Conclusion
NO claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERINNE R DABKOWSKI whose telephone number is (571)272-1829. The examiner can normally be reached Monday-Friday 7:30-5:30 Est.
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/ERINNE R DABKOWSKI/Examiner, Art Unit 1654