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
Applicant’s election of SED ID NOs: 20 (claim 5), 35 (claim 8), 3 (claim 11), and 14 (claim 13) without traverse in the reply filed on November 10, 2025 is acknowledged.
Priority
The present application is a 35 U.S.C. 371 national stage filing of the International Application No. PCT/US21/53379, filed on October 4, 2021. The instant application claims benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) to U.S. provisional application 63/086,823, filed on October 2, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on November 10, 2025 is in compliance with the provisions of 37 CFR 1.97 and is being considered by the examiner.
Applicant is reminded that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
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, 18-19, 25 and 27 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.
With regard to claims 1, 18-19, and 25, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, instant claims recite the broad recitation “a derivative of 599 peptide”, and the claim also recites in parenthesis “SEQ ID NO: 1” which is the narrower statement of the limitation in so far that positions 27-35 are D chirality.
With regard to claim 27, which depends from claims 25 and 26, claim 27 recites the limitations “a composition”, "a peptide", and “an agent” in lines 2-3. There is insufficient antecedent basis for these limitations in the claim. As claim 27 depends from claims 25 and 26, claim 25 recites a composition which comprises a 599 peptide and an agent which is plasmid DNA or mRNA. As instantly claimed, it is unclear whether claim 27 is intended to refer to the composition, peptide, and agent of claim 25 or to a different composition, peptide, and agent. Appropriate correction is required.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 9-11, and 14-27 are rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by Jakymiw and Alexander-Bryant (US 20160271258, found in IDS, hereafter “Jakymiw”).
With regard to claim 1, Jakymiw discloses a “dual peptide” composition for delivery of an agent comprising a peptide and an agent (Para. [0061]) and that the peptide can be an analog or derivative of 599 (SEQ ID NO: 2) (Para. [0089]). SEQ ID NO: 2 as disclosed by Jakymiw shares 100% homology to instantly claimed SEQ ID NO: 1 (See sequence listing on Pg 16 of Jakymiw and search results dated 01/06/2025, SEQ ID NO: 1, .rapbm file, result 1).
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Additionally, Jakymiw discloses that the 599 peptide can comprise nine “densely packed” cationic amino acid which can be arginines as well as an embodiment wherein the arginines are D-arginine residues (Paras. [0008], [0064], 0166] and Example 1). Thus, Jakymiw discloses both a derivative of 599 peptide which comprises all L-amino acids and derivative of 599 peptide which comprises D-arginines.
With regard to claims 9-11, as stated supra Jakymiw discloses an all L-amino acid version of the 599 peptide, which is 100% identical to instant SEQ ID NO: 3. In regard to the product-by-process language that the 599 peptide is a derivative in which at least one or three D-arginine residue(s) are substituted with L-arginine residue(s), these limitations encompass an all L-amino acid version of the 599 peptide that is structurally indistinguishable from the 599 peptide of Jakymiw.
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With regard to claim 14, Jakymiw discloses that the agent may be a nucleic acid (Paras. [0007], [0065]).
With regard to claim 15, Jakymiw discloses that the agent may be siRNA (Paras. [0007], [0065]).
With regard to claim 16, Jakymiw discloses a preferred embodiment wherein the ratio of the 1st (targeting) peptide to 2nd (endosome-disruptive) peptide to agent is 60:30:1. As Jakymiw discloses that the 599 derivatives are the “2nd peptide” comprising endosome-disruptive activity (Paras. [0006], [0011]), this is considered to reasonably read on a molar ratio of 599 derivate peptide to agent of 30:1.
With regard to claim 17, Jakymiw discloses that the peptide may comprise chemical modifications such as conjugation to a polymer such as PEG which slows renal clearance (Para. [0141]).
With regard to claim 18, Jakymiw discloses a method of administering an agent to a cell comprising contacting the cell with an effective amount of the composition comprising a derivative of 599 peptide and an agent (Para. [0014], claim 19).
With regard to claim 19, Jakymiw discloses a method of treating a disease of disorder in a subject comprising administration of a therapeutically effective amount of the composition comprising one or more components of the dual peptide system, wherein components are a derivative of 599 peptide and an agent (Para. [0145], claim 20).
With regard to claim 20, Jakymiw discloses that the therapeutic agent can be used to treat a variety of diseases and disorders (Para. [0061]) and that treat means to reduce the frequency or severity of at least one sign or symptom of a disease or disorder (Para. [0058]).
With regard to claim 21, Jakymiw discloses an embodiment wherein the peptides may be administered to a subject to treat or prevent a disease or disorder which is cancer (Para. [0116]).
With regard to claim 22, Jakymiw discloses wherein the composition comprises a peptide comprising a targeting moiety and a stretch of densely packed cationic amino acids (Para. [0006]).
With regard to claim 23, Jakymiw discloses wherein the peptide comprising the targeting moiety (Jakymiw’s “first peptide”) comprises SEQ ID NO: 1 (Para. [0010]). SEQ ID NO: 1 as disclosed by Jakymiw shares 100% homology to instantly claimed SEQ ID NO: 41 (See sequence listing on Pg 16 of Jakymiw and search results dated 01/06/2025, SEQ ID NO: 41, .rapbm file, result 1).
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With regard to claim 24, Jakymiw discloses a method of treating a disease of disorder in a subject comprising administration of one or more components of the dual peptide composition comprising a derivative of 599 peptide and an agent (Para. [0145]).
With regard to claim 25, Jakymiw discloses a “dual peptide” composition for delivery of an agent comprising a peptide and an agent (Paras. [0006],[0061]) wherein the peptide is SEQ ID NO: 2 (Para. [0011]). SEQ ID NO: 2 as disclosed by Jakymiw shares 100% homology to instantly claimed SEQ ID NO: 1 (See sequence listing on Pg 16 of Jakymiw and search results dated 01/06/2025, SEQ ID NO: 1, .rapbm file, result 1 and as detailed above in claim 1). Jakymiw further discloses that SEQ ID NO: 2 is 599 peptide (Para. [0087]). Additionally, Jakymiw discloses that the agent may be plasmid DNA (Para. [0007]).
With regard to claim 26, Jakymiw discloses a method of administering an agent to a cell comprising contacting the cell with an effective amount of the composition comprising a 599 peptide and an agent (Para. [0014], claim 19).
With regard to claim 27, Jakymiw discloses a method of treating a disease of disorder in a subject comprising administration of a therapeutically effective amount of the composition comprising a 599 peptide and an agent (Para. [0145], claim 20) and a method of administering an agent to a cell comprising contacting the cell with an effective amount of the composition comprising a 599 peptide and an agent (Para. [0014], claim 19).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 2-8 are rejected under 35 U.S.C. 103 as being unpatentable over Jakymiw as applied to claim 1 above, and in view of Jun et al. (2015, Design of a multicomponent peptide-woven nanocomplex for delivery of siRNA. PLoS One, 10(2), e0118310; found in IDS; hereafter “Jun”).
With regard to claims 2-5, as detailed above and incorporated herein, Jakymiw teaches a “dual peptide” composition for delivery of an agent comprising a peptide and an agent (Para. [0061]) and that the peptide can be an analog or derivative of 599 (SEQ ID NO: 2) (Para. [0089]). SEQ ID NO: 2 as taught by Jakymiw shares 100% homology to instantly claimed SEQ ID NO: 1 (See sequence listing on Pg 16 of Jakymiw and search results dated 01/06/2025, SEQ ID NO: 1, .rapbm file, result 1). Jakymiw teaches that the 599 peptide can comprise nine “densely packed” cationic amino acid which can be arginines as well as an embodiment wherein the arginines are D-arginine residues (Paras. [0008],[0064], [0166], and Example 1). Additionally, Jakymiw teaches peptide analogs including peptidomimetics of the taught peptides generated by structural modifications of the peptide sequence, including unnatural amino acids, conformational restraint, isosteric replacement, and similar (Para. [0094]) and that modifications to peptide analogs/derivatives can exhibit improved solubility, half-life, bioavailability, and reduced renal clearance (Para. [0087]). Thus, Jakymiw teaches alternation of peptide properties in order to optimize peptide function.
Jakymiw is silent as to specific modifications which can be made to the derivative of 599 peptide.
Jun teaches an “siRNA nanocomplex” comprising peptides designed for cellular targeting, endosomal escape, and delivery of siRNA to cells wherein a targeting peptide can comprise a nine-arginine peptide and modification of the nine arginine peptide to alter positions of positive charges in order to investigate siRNA release from the nanocomplex (Abstract). Jun teaches that the nine-arginine cell penetrating peptide (CPP) comprises D-arginine (Pg. 3, Peptides and siRNAs) and was modified with different combinations of alanine substitutions in order to determine the optimal nine-arginine CPP variant for siRNA dissociation from the carrier (Pg. 2, last para.). Further, Jun teaches alanine substitutions at the 3rd position of the nine-arginine CPP, which is considered to reasonably read on position 29 as instantly claimed (Table 1) and that modification of arginine to alanine at the 3rd position of the nine-arginine CPP resulted in improved dissociation of siRNA from the complex resulting in improved gene silencing in vitro and in vivo (Pg. 13, lines 5-6). It is noted that based on Applicant’s instant disclosure, the alanine substitution in instant SEQ ID NO: 20 is at position 29, the 3rd position of the nine-arginine sequence. Although Jun is silent as to the alanine modifications being D-alanine, since Jun teaches that the nine-arginine residues are in D-form, one having ordinary skill in the art could reasonably expect that the alanine substitutions are also in D-form. Further, in Table 1 of Jun, all residues of the nine-arginine CPP are capitalized, indicating that there is no stereoisomeric difference between arginine and alanine.
Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to modify the 599 derivative comprising nine D-arginine residues as taught by Jakymiw to replace D-arginine with D-alanine at position 3 as taught by Jun with a reasonable expectation of success as both Jakymiw and Jun teach cellular delivery of an agent via use of peptides comprising a nine-arginine sequence. A skilled artisan would have been motivated to do this as Jun teaches that substitution of D-arginine to alanine at the 3rd position in the nine-arginine CPP results in improved cellular delivery of siRNA and increased gene silencing in vitro and in vivo which a skilled artisan would recognize is critical for targeted delivery of therapeutic compounds such as siRNA.
With regard to claim 6-8, as detailed above and incorporated herein, Jakymiw teaches a “dual peptide” composition for delivery of an agent comprising a peptide and an agent (Para. [0061]) and that the peptide can be an analog or derivative of 599 (SEQ ID NO: 2) (Para. [0089]). SEQ ID NO: 2 as taught by Jakymiw shares 100% homology to instantly claimed SEQ ID NO: 1 (See sequence listing on Pg 16 of Jakymiw and search results dated 01/06/2025, SEQ ID NO: 1, .rapbm file, result 1). As detailed above, Jakymiw discloses a derivative of 599 peptide which comprises all L-amino acids. In regard to the product-by-process language that the 599 peptide is a derivative in which at least one D-arginine residue is substituted with an L-arginine residue, these limitations encompass an all L-amino acid version of the 599 peptide that is structurally indistinguishable from the 599 peptide of Jakymiw. Additionally, Jakymiw teaches peptide analogs including peptidomimetics of the taught peptides generated by structural modifications of the peptide sequence, including unnatural amino acids, conformational restraint, isosteric replacement, and similar (Para. [0094]) and that modifications to peptide analogs/derivatives can exhibit improved solubility, half-life, bioavailability, and reduced renal clearance (Para. [0087]). Thus, Jakymiw teaches alternation of peptide properties in order to optimize peptide function.
Jakymiw is silent as to specific modifications which can be made to the derivative of 599 peptide.
Jun teaches an “siRNA nanocomplex” comprising peptides designed for cellular targeting, endosomal escape, and delivery of siRNA to cells wherein a targeting peptide can comprise a nine-arginine peptide and modification of the nine arginine peptide to alter positions of positive charges in order to investigate siRNA release from the nanocomplex (Abstract). Jun teaches that the nine-arginine cell penetrating peptide (CPP) was modified with different combinations of alanine substitutions in order to determine the optimal nine-arginine CPP variant for siRNA dissociation from the carrier (Pg. 2, last para.). Further, Jun teaches alanine substitutions at the 3rd position of the nine-arginine CPP, which is considered to reasonably read on position 29 as instantly claimed (Table 1) and that modification of arginine to alanine at the 3rd position of the nine-arginine CPP resulted in improved dissociation of siRNA from the complex resulting in improved gene silencing in vitro and in vivo (Pg. 13, lines 5-6). It is noted that based on Applicant’s instant disclosure, the alanine substitution in instant SEQ ID NO: 35 is at position 29, the 3rd position of the nine-arginine sequence.
Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to modify the 599 derivative comprising nine L-arginine residues as taught by Jakymiw to replace L-arginine with L-alanine at position 3 as taught by Jun with a reasonable expectation of success as both Jakymiw and Jun teach cellular delivery of molecules via use of peptides comprising a nine-arginine sequence. A skilled artisan would have been motivated to do this as Jun teaches that substitution of arginine to alanine at the 3rd position in the nine-arginine CPP results in improved cellular delivery of siRNA and increased gene silencing in vitro and in vivo which a skilled artisan would recognize is critical for targeted delivery of therapeutic compounds such as siRNA.
Claims 12 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Jakymiw as applied to claim 1 above, and further in view of Jun and Youngblood et al. (2007, Stability of cell-penetrating peptide− morpholino oligomer conjugates in human serum and in cells. Bioconj. Chem., 18(1), 50-60, found in IDS, hereafter “Youngblood’).
With regard to claims 12 and 13, as detailed above and incorporated herein, Jakymiw teaches a “dual peptide” composition for delivery of an agent comprising a peptide and an agent (Para. [0061]) and that the peptide can be an analog or derivative of 599 (SEQ ID NO: 2) (Para. [0089]). SEQ ID NO: 2 as taught by Jakymiw shares 100% homology to instantly claimed SEQ ID NO: 1 (See sequence listing on Pg 16 of Jakymiw and search results dated 01/06/2025, SEQ ID NO: 1, .rapbm file, result 1). Jakymiw teaches that the 599 peptide has endosome-disruptive activity (Para. [0006]) and can comprise nine “densely packed” cationic amino acid which can be arginines as well as an embodiment wherein the arginines are D-arginine residues (Paras. [0008], [0064], [0166] and Example 1). Additionally, Jakymiw teaches peptide analogs including peptidomimetics of the taught peptides generated by structural modifications of the peptide sequence, including unnatural amino acids, conformational restraint, isosteric replacement, and similar (Para. [0094]) and that modifications to peptide analogs/derivatives can exhibit improved solubility, half-life, bioavailability, and reduced renal clearance (Para. [0087]). Thus, Jakymiw teaches alternation of peptide properties in order to optimize peptide function.
Jakymiw is silent as to specific modifications which can be made to the derivative of 599 peptide.
Jun teaches an “siRNA nanocomplex” comprising peptides designed for cellular targeting, endosomal escape, and delivery of siRNA to cells wherein a targeting peptide can comprise a nine-arginine peptide and modification of the nine arginine peptide to alter positions of positive charges in order to investigate siRNA release from the nanocomplex (Abstract). Jun teaches that the nine-arginine cell penetrating peptide (CPP) comprises D-arginine (Pg. 3, Peptides and siRNAs) and was modified with different combinations of alanine substitutions in order to determine the optimal nine-arginine CPP variant for siRNA dissociation from the carrier (Pg. 2, last para.). Further, Jun teaches alanine substitutions at the 3rd position of the nine-arginine CPP, which is considered to reasonably read on position 29 as instantly claimed (Table 1) and that modification of arginine to alanine at the 3rd position of the nine-arginine CPP resulted in improved dissociation of siRNA from the complex resulting in improved gene silencing in vitro and in vivo (Pg. 13, lines 5-6). It is noted that based on Applicant’s instant disclosure, the alanine substitution in instant SEQ ID NO: 14 is at position 29, the 3rd position of the nine-arginine sequence. Although Jun is silent as to the alanine modifications being D-alanine, since Jun teaches that the nine-arginine residues are in D-form, one having ordinary skill in the art could reasonably expect that the alanine substitutions are also in D-form. Further, in Table 1 of Jun, all residues of the nine-arginine CPP are capitalized, indicating that there is no stereoisomeric difference between arginine and alanine.
Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to modify the 599 derivative comprising nine D-arginine residues as taught by Jakymiw to replace D-arginine with D-alanine at position 3 as taught by Jun with a reasonable expectation of success as both Jakymiw and Jun teach cellular delivery of an agent via use of peptides comprising a nine-arginine sequence. A skilled artisan would have been motivated to do this as Jun teaches that substitution of D-arginine to alanine at the 3rd position in the nine-arginine CPP results in improved cellular delivery of siRNA and increased gene silencing in vitro and in vivo which a skilled artisan would recognize is critical for targeted delivery of therapeutic compounds such as siRNA.
While Jakymiw and Jun do teach CPPs comprising D-amino acids in the nine-arginine sequence, they are silent as to D-amino acid substitutions elsewhere in the peptide sequence.
Youngblood teaches investigation of structural features of arginine-rich CPPs and resultant effect on overall stability, including D- vs. L- amino acid configurations (Abstract). Youngblood teaches that CPPs which were in D- configuration exhibit increased stability in comparison to L- configuration in both serum and HeLa cells (Abstract) and that D-configured CPPs were found to be the most stable out of all various structural modifications investigated (Pg. 58, left col., 3rd full para., lines 3-6 and Pg. 58, left col., 5th full para., lines 3-4). Further, Youngblood teaches that use of D-configured CPPs prevented degradation of the D-CPP conjugates (Pg. 58, left col., 5th full para., lines 5-6).
Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to modify the 599 derivative comprising a D-arginine rich sequence wherein the arginine at the 3rd position is replaced by alanine as taught by Jakymiw and Jun to incorporate all D-amino acids as taught by Youngblood with a reasonable expectation of success as Jakymiw, Jun, and Youngblood all teach cellular delivery of an agent via use of cell permeable peptides comprising an arginine-rich sequence. A skilled artisan would have been motivated to do this as Jun teaches that substitution of D-arginine to alanine at the 3rd position in the nine-arginine CPP results in improved cellular delivery and Youngblood teaches that modification to an all D-amino acid configuration results in increased stability of the CPP. Thus, a skilled artisan would recognize that making modifications to Jakymiw’s derivative of 599 as taught by Jun and Youngblood would result in a more stable CPP which also exhibits improved deliver of a compound which is critical use of CPPs in delivery of therapeutic compounds.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIN V PAULUS whose telephone number is (571)272-6301. The examiner can normally be reached Mon-Fri 8 AM-5 PM.
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/ERIN V PAULUS/Examiner, Art Unit 1631
/ARTHUR S LEONARD/Examiner, Art Unit 1631