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 .
Applicant’s submission filed on May 29, 2026 has been entered and considered. Rejections and/or objections not reiterated from the previous action mailed January 29, 2026 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 18-19, and 25 have been amended to recite wherein the peptide is a “derivative of SEQ ID NO: 1 wherein the peptide comprising the derivative of SEQ ID NO: 1 comprises an amino acid sequence in which at least one D-arginine residue of SEQ ID NO: 1 is substituted with an alanine residue”. Claim 3 has been amended to update claim dependency. Claims 11 and 13 have been amended to remove SEQ ID NOs. Claim 27 has been amended to correct antecedent basis. Claim 2 has been canceled. Based on Applicant’s amendment to remove the elected species of SEQ ID NO: 3 in claim 11, claim 11 has been withdrawn.
Claims 1 and 3-10, and 12-27 are pending and examined on the merits.
Election/Restrictions
Applicant’s election of SEQ 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. It is noted that the elected species of SEQ ID NO: 3 in claim 11 has been removed in Applicant’s amendment to claim 11.
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 June 1, 2026 is in compliance with the provisions of 37 CFR 1.97 based on payment of the timing fee as is being considered by the examiner. The IDS submitted on November 10, 2025 is in compliance with the provisions of 37 CFR 1.97 and was previously 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.
New Claim Rejections - 35 USC § 103
This is a new rejection necessitated by Applicant’s amendment of claim 1. However, this rejection shares substantial similarity to the rejection as previously set forth in the office action dated January 29, 2026. Any aspect of Applicant’s traversal that pertains to the rejection as newly set forth will be provided following the new statement of rejection.
Claims 1, 3-10, and 14-27 are rejected under 35 U.S.C. 103 as being unpatentable over Jakymiw and Alexander-Bryant (US 20160271258, found in IDS, hereafter “Jakymiw”) 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 1 and 3-5, 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 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 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). Thus, Jakymiw discloses both a derivative of 599 peptide which comprises all L-amino acids and derivative of 599 peptide which comprises D-arginines. Additionally, Jakymiw teaches peptide variants (Para. [0077]-[0078]) and 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, Jakymiw discloses both a derivative of 599 peptide (SEQ ID NO: 1) which comprises L-amino acids (including the arginine tail) and derivative of 599 peptide which comprises D-arginines (Paras. [0008], [0064]). Jun teaches that substitution of the 3rd arginine in a nine arginine CPP with alanine results 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 a L-arginine residue 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. Although Jun teaches use of CPPs comprising D-arginine, a skilled artisan could easily envision use of a CPP comprising all L-amino acids based on the teachings of Jakymiw. 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. Furthermore, considering the limited genus of D or L residues, the option of an L-alanine would have been immediately envisioned by one of ordinary skill.
With regard to claims 9 and 10, as detailed above and similar to the rejection of claims 6-8, the combination of Jakymiw and Jun teach a derivative of SEQ ID NO: 1 comprising a nine-arginine sequence and having an arginine, which can be D-arginine, substituted by an alanine. Jakymiw discloses both a derivative of 599 peptide (SEQ ID NO: 1) which comprises all L-amino acids (including the arginine tail) and derivative of 599 peptide which comprises D-arginines (Paras. [0008], [0064]). Although Jun teaches use of CPPs comprising D-arginine, a skilled artisan could easily envision use of a CPP comprising where the 3rd arginine is substituted by alanine and comprising substitution of all remaining D-arginines with L-arginines based on the teachings of Jakymiw. This is considered to reasonably read on at least one or at least 3 D-arginines are substituted with L-arginines.
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, as detailed above, Jakymiw teaches a composition for delivery of an agent, comprising a peptide and an agent (Para. [0061]) and that the peptide can be a derivative of SEQ ID NO: 1 and the combination of Jakymiw and Jun teach a composition comprising a peptide comprising a derivative of SEQ ID NO: 1 in which at least one D-arginine is substituted with an alanine. 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 SEQ ID NO: 1 and an agent (Para. [0014], claim 19, Example 1).
With regard to claim 19, as detailed above, Jakymiw teaches a composition for delivery of an agent, comprising a peptide and an agent (Para. [0061]) and that the peptide can be a derivative of SEQ ID NO: 1 and the combination of Jakymiw and Jun teach a composition comprising a peptide comprising a derivative of SEQ ID NO: 1 in which at least one D-arginine is substituted with an alanine. 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 (i.e., SEQ ID NO: 1) 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, as detailed above, Jakymiw teaches a composition for delivery of an agent, comprising a peptide and an agent (Para. [0061]) and that the peptide can be a derivative of SEQ ID NO: 1 and the combination of Jakymiw and Jun teach a composition comprising a peptide comprising a derivative of SEQ ID NO: 1 in which at least one D-arginine is substituted with an alanine. Jakymiw discloses wherein the composition also 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, as detailed above, Jakymiw teaches a composition for delivery of an agent, comprising a peptide and an agent (Para. [0061]) and that the peptide can be a derivative of SEQ ID NO: 1 and the combination of Jakymiw and Jun teach a composition comprising a peptide comprising a derivative of SEQ ID NO: 1 in which at least one D-arginine is substituted with an alanine. 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 (i.e., SEQ ID NO: 1) and an agent (Para. [0145]).
With regard to claim 25, as detailed above, Jakymiw teaches a composition for delivery of an agent, comprising a peptide and an agent (Para. [0061]) and that the peptide can be a derivative of SEQ ID NO: 1 and the combination of Jakymiw and Jun teach a composition comprising a peptide comprising a derivative of SEQ ID NO: 1 in which at least one D-arginine is substituted with an alanine. Additionally, Jakymiw discloses that the agent may be plasmid DNA (Para. [0007]).
With regard to claim 26, as detailed above, the combination of Jakymiw and Jun teach a composition comprising a peptide comprising a derivative of SEQ ID NO: 1 in which at least one D-arginine is substituted with an alanine. Jakymiw discloses a method of administering an agent, which can be plasmid DNA (Para. [0007]) to a cell comprising contacting the cell with an effective amount of the composition comprising a derivative of 599 peptide (i.e., SEQ ID NO: 1) and an agent (Para. [0014], claim 19).
With regard to claim 27, the combination of Jakymiw and Jun teach a composition comprising a peptide comprising a derivative of SEQ ID NO: 1 in which at least one D-arginine is substituted with an alanine. 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 derivative of 599 peptide (i.e., SEQ ID NO: 1) and an agent (Para. [0145], claim 20) which can be plasmid DNA (Para. [0007]) and a method of administering an agent , which can be plasmid DNA (Para. [0007]) 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).
Response to Arguments
Applicant's arguments filed May 29, 2026 have been fully considered but they are not persuasive.
With regard to the rejection of claims 2-8 under 35 U.S.C. 103 based on the combination of Jakymiw and Jun, Applicant traverses, first, that the cited art does not teach or suggest each element of the claimed invention. Specifically, Applicant asserts on Pg. 9-10 that Jakymiw does not teach or suggest a peptide comprising an amino acid sequence in which at least one D-arginine residue of SEQ ID NO: 1 is substituted with an alanine and Jun does not cure these deficiencies as Jun does not teach or suggest a peptide comprising SEQ ID NO: 1 in which at least one D-arginine is substituted with an alanine as Jun teaches use of an IL-4 receptor targeting peptide for CPP design.
Applicant’s traversal has been fully considered but is not persuasive.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
First, to address Applicant’s assertion that Jakymiw and Jun do not teach each and every element of the instant invention, Jakymiw teaches a derivative of SEQ ID NO:1 (an endosome disruptive peptide) which comprises a nine-arginine sequence at the C-terminus and which aid serves as a carrier for siRNA (Para. [0166]). Jakymiw also teaches variants of SEQ ID NO: 1 which can include amino acid alterations (Paras. [0077], [0078]) as well as co-delivery of a derivative of SEQ ID NO: 1 with a targeting peptide for binding to a cellular membrane receptor which also comprises nine-arginine sequence and is able to deliver siRNA (Para. [0006], [0009], [0064]). Jakymiw teaches that the targeting moiety can be any receptor present on a cell membrane (Para. [0067]-[0068]). Therefore, although Jakymiw does not teach the specific arginine to alanine substitution as instantly claimed, that specific substitution in the nine-arginine CPP sequence is found in the art of Jun which teaches a targeting peptide (an IL-4 receptor targeting peptide) comprising a nine-arginine CPP which is complexed with siRNA (Abstract). Jun further teaches that the targeting peptide comprising a nine-arginine CPP can be blended with an endosomolytic peptide to form a multicomponent nanocomplex (Abstract) and that the endosomolytic peptide also comprises a nine-arginine CPP (Pg. 6, last para.). Although Jun is silent as to an arginine to alanine substitution in the endosomolytic peptide, Jun’s arginine to alanine substitution in the targeting peptide resulted in increased siRNA delivery and gene silencing (Pg. 9, last para. and Pg. 10, 1st para.). Therefore, one of ordinary skill in the art could easily find each element of the instantly claimed invention in the cited prior art and would have been motivated to combine the arginine to alanine substitution as taught by Jun with the endosome disrupting peptide which is a derivative of SEQ ID NO: 1 as taught by Jakymiw.
Second, Applicant traverses on Pg. 10-13 that the cited art does not provide a reasonable expectation of success and that there is no motivation to combine the teachings of Jakymiw and Jun to produce the instantly claimed invention. Applicant asserts that as the length of the peptides and linkers taught by Jakymiw and Jun differ, a skilled artisan would not have been able to predict or have any expectation of success in arriving at the instant invention because, even though Jun discloses a substitution of arginine to alanine in the nine arginine CPP, the peptides of Jakymiw and Jun would form drastically different three-dimensional structures. Applicant asserts that Jun is silent to peptide 599 and therefore a skilled artisan would not combine Jakymiw and Jun as Jun states there are drawbacks to using CPPs which lack tumor-homing peptides.
Applicant’s traversal has been fully considered but is not persuasive.
A skilled artisan would also have had a reasonable expectation of success. As a first matter, the 9R cell penetrating peptide was well-known in the art, and in a free aqueous solution does not adopt a fixed or regular secondary structure. Furthermore, as acknowledged by Applicant, there is a fair degree of similarity between the 9R conjugated peptide of Jakymiw and the 9R conjugated peptide of Jun. Jakymiw teaches use of a nine-arginine CPP attached to both a derivative of SEQ ID NO: 1 having 22 amino acids as well as a targeting moiety having 12 amino acids both of which comprise a four glycine linker and are able to successfully deliver siRNA to cells. Similarly, Jun teaches use of a nine-arginine CPP attached to a nine amino acid targeting moiety as well as a 15 amino acid endosomolytic peptide (Pg. 3, Peptides and siRNAs) both of which comprise a two glycine linker and were also able to successfully able to deliver siRNA to cells (Fig. 2A). Therefore, it appears that the nine-arginine CPP as instantly claimed and taught by Jakymiw and Jun is able to be successfully linked to peptides of various lengths without affecting functionally delivery ability. Although Jun does not specifically teach peptide 599, Jun teaches use of a endosomolytic peptide (i.e., sHGP-9r) in conjunction with the targeting peptide for releasing siRNA from endosomes after delivery (See Fig. 2A). Jakymiw also teaches use of endosome-disrupting peptide 599 and a targeting moiety for delivery of siRNA which is better able to deliver/release siRNA from endosomes (See Example 1). Both Jakymiw and Jun teach that effective delivery of siRNA requires cell-specific targeting (i.e., the targeting moiety of Jakymiw and the IL-4 receptor targeting peptide of Jun) as well as a peptide which mediates siRNA release from endosomes (i.e., the derivative of 599 peptide of Jakymiw and the sHGP-9r peptide of Jun). Therefore, although the endosome-disrupting and targeting peptides differ, a skilled artisan could have easily combined the prior art of Jakymiw and Jun with a reasonable expectation of success. One would have been motivated to do so as Jun teaches that an arginine to alanine substitution of the 3rd arginine in the nine-arginine CPP is beneficial for enhanced siRNA release to the cytosol after delivery and, as a result, improves gene silencing ability (Pgs. 9-10, bridging para. and Pg. 10, last para.) when compared to the non-modified peptide comprising an all arginine CPP. Although Jun’s modification is to the targeting peptide rather than the endosome-disrupting peptide, Jun teaches that the arginine to alanine substitution alters electrostatic interactions (Pg. 8, last para.) which results in more rapid dissociation of the siRNA in the cytosol (Pg. 11, 1st para., indicated by Fig. 5C) which a skilled artisan would also expect to occur if the arginine to alanine substitution were made on a different peptide. Jun teaches that targeting moieties comprising variant CPPs were still able to encapsulate siRNA at ratios of 20:1 and 30:1 peptide to siRNA (Pg. 8, last para.) and deliver siRNA to cells (Pg. 9, 1st para.). Therefore, a skilled artisan looking to improve delivery and therapeutic effect of siRNA could easily envision use of a modified CPP comprising an arginine to alanine substitution at the 3rd position as taught by Jun for the derivative of 599 peptide as taught by Jakymiw.
Finally, Applicant asserts that the variant peptide of Jun comprising the arginine to alanine substitution decreased “certain functions” of the parent peptide such as siRNA binding affinity and reduced expression by only 42%. Further, Applicant asserts that Jun “may” teach away from the instantly claimed peptides with enhanced nucleic acid binding and uptake. Applicant traverses that a skilled artisan would not have been able to predict the efficacy of the instantly claimed peptide in view of Jun as Jun’s CPP is different from the CPP in SEQ ID NO: 1. Further, Applicant asserts Jun does not disclose chirality of the alanine substitution and therefore, a skilled artisan would not be able to predict effects of chirality on CPP design. Applicant traverses that a skilled artisan would not have expected the enhanced delivery functions of the instantly claimed peptide derivatives based on the teachings of Jakymiw and Jun and the instant invention provides a superior peptide carrier with improved function.
Applicant’s traversal has been fully considered but is not persuasive.
It is noted that the features upon which applicant relies (i.e., enhanced nucleic acid binding and uptake, enhanced delivery) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant cites instant Figure 1 to show instantly claimed derivative peptides having enhanced nucleic acid binding and uptake. It is noted that instant Fig. 1 shows no differences in binding affinity between peptides at ratios of 30:1. It is difficult to determine which specific peptide variants exhibit enhanced or reduced siRNA binding at various ratios, however binding affinity appears to depend significantly on peptide to siRNA ratio. Additionally, the instant specification, indicates that peptides RD456 and RD19 (corresponding to SEQ ID NOs: 2 and 4, respectively) exhibited the most binding enhancement and peptides RD123789 and All-L (corresponding to SEQ ID NOs: 5 and 3 respectively) exhibited no binding enhancement (bridging para., Pg. 67-68). The variant CPP peptide taught by Jun having an alanine substitution at position 3 of the nine arginine CPP corresponds to instant SEQ ID NO: 20 (i.e., peptide RD3AD) and instant SEQ ID NO: 21 (i.e., peptide RD3AL), neither of which Applicant’s instant specification indicate show significantly superior siRNA binding affinity at ratios below 30:1. Further, based on the instant specification, improved siRNA uptake was only examined at ratios of 30:1 and 50:1, which correspond to ratios at which binding affinity was not found to be different between any of the instant peptides. At ratios of 30:1, all peptides were able to deliver siRNA to CAL27 cells with no differences, except peptide INF7D (instant SEQ ID NO: 8) which had significantly reduced delivery. At ratios of 50:1, only peptide RD3AD (instant SEQ ID NO: 20) exhibited significantly increased delivery while peptides RD13579 (instant SEQ ID NO: 6) and INF7D exhibited significantly reduced delivery (See Pg. 68 and Fig. 2). Thus, Applicant’s alleged enhanced nucleic acid binding and uptake is also not exhibited by all of the instantly claimed peptides and appears to depend heavily on the particular ratio of siRNA to peptide. As a 50:1 concentration is well above that which was tested in Jun (20:1, See Pg. 3, 3rd para.), it is not possible to evaluate whether the variant CPP of Jun would exhibit superior delivery at a 50:1 ratio. However, Jun does indicate that the variant peptide comprising an arginine to alanine substitution at the 3rd position results in improved gene silencing. In regard to Applicant’s argument that Jun only demonstrates 42% inhibition with the 3rd position arginine to alanine, it must be noted that this % inhibition was normalized to the wild-type peptide. Thus, Jun’s results actually demonstrate a significant improvement with the 3rd position substitution which is comparable to Applicant % inhibition. Applicant’s instant specification also indicates that a variant peptide comprising an arginine to D-alanine substitution at the 3rd position, RD3AD, exhibits improved gene silencing (Pg. 72, last para.) and that a variant peptide comprising an arginine to L-alanine substitution at the 3rd position, RD3AL, also exhibits improved gene silencing (Pg. 82, 2nd para.). Therefore, the results of the instant specification regarding arginine to alanine substitution at position 3 of a nine arginine CPP are what would be expected by a skilled artisan based on the teachings of the prior art of Jun.
Claims 9-10 and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Jakymiw and Jun as applied to claim 1 above and in further view of Cantini et al (2013, Fusogenic-oligoarginine peptide-mediated delivery of siRNAs targeting the CIP2A oncogene into oral cancer cells. PloS one, 8(9), e73348, found in IDS dated 11/10/2025, hereafter “Cantini”).
This is a new rejection necessitated by Applicant’s amendment. However, this rejection shares substantial similarity to the rejection as previously set forth in the office action dated January 29, 2026. Any aspect of Applicant’s traversal that pertains to the rejection as newly set forth will be provided following the new statement of rejection.
With regard to claims 9 and 10, as detailed above, 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 derivative of SEQ ID NO: 1 and can comprise nine “densely packed” cationic amino acids which can be arginines as well as an embodiment wherein the arginines are D-arginine residues (Paras. [0008], [0064], [0166] and Example 1). Jakymiw teaches peptide variants (Para. [0077]-[0078]) and peptide analogs (Para. [0087]) which can be used to optimize peptide function. Jun teaches that substitution of arginine to alanine at the 3rd position of a nine-arginine sequence can increase dissociation of delivered siRNA thereby increasing gene silencing (i.e., therapeutic effect) (Pg. 13, lines 5-6). Thus, the combination of Jakymiw and Jun teach a peptide comprising a derivative of SEQ ID NO: 1 in which at least one D-arginine is substituted with an alanine.
While Jakymiw and Jun teach alteration of amino acid sequences in a nine-arginine sequence to substitute an arginine with alanine, they are silent as to alterations in the chirality of the other amino acids in the sequence.
Cantini teaches use of a 599 peptide comprising a cationic cell-penetrating nine D-arginine sequence for use in delivering siRNA (Abstract). The 599 peptide as taught by Cantini appears to share 100% sequence identity with the 599 peptide which can comprise a nine-arginine sequence as taught by Jakymiw (See Pg. 8, right col., Peptide Synthesis). Cantini teaches that cells exhibit preferential uptake of L versus D amino acid CPPs and that chirality is important for determining CPP uptake (Pg. 6, right col., 1st para.). Further Cantini suggests that changing the chirality of the D-arginines in the 599 peptide to L-arginines could enhance peptide uptake and result in stronger RNA interference in the presence of serum (Pg. 8, left col., 1st para., approx. half way down). This is considered to reasonably read on substituting at least one or at least three D-arginines with an L-arginine.
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 derivative of SEQ ID NO: 1 as taught by the combination of Jakymiw and Jun to substitute D-arginines with L-arginines as taught by Cantini with a reasonable expectation of success. A skilled artisan would have been motivated to make this modification because Cantini suggests that changing the chirality of the D-arginines to L-arginines in the 599 peptide could enhance uptake of the 599/siRNA complex, which one would recognize is critical for gene silencing. A skilled artisan would have had a reasonable expectation of success as Jakymiw, Jun, and Cantini all teach use of CPPs comprising a nine arginine sequence for delivery of siRNA and Jun and Cantini both teach that alterations of the CPP sequence can increase delivery effectiveness.
With regard to claim 12 and 13, based on Applicant’s amendment to claim 1, claims 12 and 13 are understood to refer to alterations of the chirality of the portion of SEQ ID NO: 1 outside of the linker and nine-arginine C terminus. As detailed above, 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 derivative of SEQ ID NO: 1 having nine cationic amino acids which can be arginines as well as an embodiment wherein the arginines are D-arginine residues (Paras. [0008], [0064], [0166] and Example 1). Jun teaches that substitution of arginine to alanine at the 3rd position of a nine-arginine sequence can increase dissociation of delivered siRNA thereby increasing gene silencing (i.e., therapeutic effect) (Pg. 13, lines 5-6). Thus, the combination of Jakymiw and Jun teach a peptide comprising a derivative of SEQ ID NO: 1 in which at least one D-arginine is substituted with an alanine.
While Jakymiw and Jun teach alteration of amino acid sequences in a nine-arginine sequence to substitute an arginine with alanine, they are silent as to alterations in the chirality of the other amino acids in the sequence.
Cantini teaches use of a 599 peptide comprising a cationic cell-penetrating nine D-arginine sequence for use in delivering siRNA (Abstract). The 599 peptide as taught by Cantini appears to share 100% sequence identity with the 599 peptide which can comprise a nine-arginine sequence as taught by Jakymiw (See Pg. 8, right col., Peptide Synthesis). Cantini teaches that the arginine sequence is required for delivery of siRNA but that only D-arginine sequences are incapable of cellular delivery (Pg. 6, right col, last para.) and that a combination of hydrophobic moieties and cationic agents, as seen in the 599 peptide, can produce synergistic effects which can enhance cellular update of nucleic acid cargo (Pg. 6, right col., bottom of para.). Cantini suggests that the INF-7 sequence within the 599 peptide comprises 50% hydrophobic amino acids which allows intracellular delivery despite the presence of the D-arginine sequence (Pg. 7, left col.). The INF-7 sequence is understood to be the portion of the 599 sequence without the glycine linker and nine arginines (See Pg. 8, right col., Peptide Synthesis and Pg. 5, right col., 3rd para. stating that the 616 peptide comprised only the anionic INF-7 sequence). Cantini further suggests that changing the chirality of the INF-7 sequence would make the peptide more protease resistant and more stable in the presence of serum (Pg. 8, left col., 1st para., approx. halfway down). This is considered to reasonably read on alterations of the amino acid residues of SEQ ID NO: 1 which correspond to the sequence of INF-7 (i.e., GLFEAIEGFIENGWEGMIDGWY) from their naturally occurring L-form to a D-form, including alteration of all L-form amino acids with D-forms as is reflected in instant SEQ ID NO: 14.
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 derivative of SEQ ID NO: 1 as taught by the combination of Jakymiw and Jun to change the chirality of the INF-7 portion of SEQ ID NO: 1 by substituting D-forms for naturally occurring L-forms as taught by Cantini with a reasonable expectation of success. A skilled artisan would have been motivated to make this modification because Cantini suggests that changing the chirality of the INF-7 portion of the peptide could make the peptide more protease resistant and more stable which a skilled artisan would recognize would lead to a longer lasting peptide therefore better siRNA delivery. A skilled artisan would have had a reasonable expectation of success as Jakymiw, Jun, and Cantini all teach use of CPPs comprising a nine arginine sequence for delivery of siRNA and Jun and Cantini both teach that alterations of the CPP sequence can increase delivery effectiveness.
Response to Arguments
With regard to the rejection of claims 12-13 under 35 U.S.C. 103 based on the combination of Jakymiw, Jun, and Youngblood, Applicant traverses on Pg. 12-13 that Jakymiw and Jun do not teach each element of claim 1 and Youngblood does not cure the deficiencies as Youngblood does not teach or suggest a peptide comprising an amino acid sequence in which one D-arginine residue of SEQ ID NO:1 is substituted with an alanine residue.
Applicant’s traversal has been fully considered but is not persuasive.
The response to Applicant’s traversal based on the combination of Jakymiw and Jun has been stated in the response to traversal above. Applicant’s traversal of the teachings of Youngblood are considered moot as Youngblood is no longer applied in the prior art rejection based on Applicant’s amendment to claim 1.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ERIN V PAULUS/
Examiner, Art Unit 1631
/ARTHUR S LEONARD/Examiner, Art Unit 1631
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