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 .
Priority
Acknowledgment is made of applicant’s claim for priority based on a provisional application filed as 63/104,340 on 10/22/2020.
All claims are given the priority date of 10/22/2020.
Application Status
Receipt is acknowledged of amendment, filed 02/13/2026. Claims 92-111 are currently pending.
Election/Restriction
Applicant’s election without traverse of Group II, drawn to claims 85-88 and 92 as well as newly added claims 93-111 in the reply filed on 02/13/2026 is acknowledged.
The previous species election is withdrawn in view of the cancellation of the claims in which the species election was relied upon. Therefore, the current claims are interpreted as written.
The amendment filed on 02/13/2026 cancelling claims 1-91 as either not drawn to the elected invention or not pursuing examination is acknowledged.
Claims 92-111 are currently under examination.
Information Disclosure Statement
Receipt of acknowledgment of the information disclosure statements filed on 05/29/2024, 10/11/2024 and 02/13/2026 have been received and all references have been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Rejections - 35 USC § 112
Claim 92 is vague and indefinite in that the metes and bounds of the phrase “or in the presence of DNA and/or RNA” are unclear. The phrase is unclear in that it is not known whether the transduction of the cargo occurs in the presence of “the DNA and/or RNA” or if the “DNA and/or RNA are in the cargo.
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.
(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 92-111 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Krishnamurthy et al (Nat Commun. 2019 Oct 28; 10(1):4906; Pgs. 1-12) as evidenced by Kulhankova et al (Nucleic Acids Research, Volume 52, Issue 19, 28 October 2024, Pages 11911–11925).
Regarding claim 92, Krishnamurthy teaches a method of delivering compositions comprising a Cas9-RNP (non-anionic cargo) and, separately, an S10 synthetic peptide shuttle agent (which corresponds in sequence and structure to instant FSD10-15 synthetic peptide shuttle agent shown in Fig. 1; Page 6) to epithelial cells of the large and small airways (Page 4, Column 1). Krishnamurthy teaches successful and efficient transduction of the synthetic peptide shuttle agent as well as the Cas9-RNP to ciliated, non-ciliated and goblet cells of the human airway epithelial as compared to the synthetic peptide shuttle agent administered independently (Page 5, Column 1 and Column 2). Krishnamurthy teaches the S10 synthetic peptide shuttle agent (which corresponds in sequence and structure to instant FSD10-15 synthetic peptide shuttle agent shown in Fig. 1; Page 6) comprising six cationic residues and five highly hydrophobic residues as well as a “GGSGGGS” linker attached to the C-terminal end (Page 3, Figure 1a).
The instant specification teaches for FSD 10-15, GFP transduction efficiency slightly increased from 21 % to 24 % in the presence of Cas9-RNP (Fig. 3) and FSDl0-15 is a 15-amino acid fragment of several longer shuttle agents, including FSD375, FSD422, FSD424, FSD432, FSD241, FSD231, FSDl0, and FSD210, as well as, adding flanking glycine/serine-rich residues to FSDl0-15 (see FSD375 and FSD424) retained the peptide's resistance to Cas9-RNP while improving GFP transduction activity over FSDl0-15 (Page 45, Lines 26-30).
Therefore, Krishnamurthy teaching the same structure of instantly claimed FSD10-15 as S10 as well as the same results as disclosed in the instant specification on Page 45, Krishnamurthy also teaches a central core amphipathic alpha helical region having shuttle agent activity, flanked N- and C-terminally by flexible linker domains, wherein one or both of the flexible linker domains comprises or consists essentially of a sufficient number of non-cationic hydrophilic residues such that cargo transduction activity of the synthetic peptide shuttle agent across the mucus-producing membrane, or in the presence of DNA and/or RNA, is increased relative to that of the central core amphipathic alpha helical region lacking the flexible linker domains, wherein the central core amphipathic alpha helical region is an endosomolytic peptide 15 amino acids in length having both a positively- charged hydrophilic outer face and a hydrophobic outer face.
Kulhankova is cited only to show that the S10 synthetic peptide shuttle agent forms an alpha-helical structure (Page 11912, Column 2).
Regarding claim 93, Krishnamurthy teaches the S10 synthetic peptide shuttle agent which consists of 15 amino acids in length (Page 3, Figure 1a).
Regarding claims 94-99 and 103, Krishnamurthy teaches the S10 synthetic peptide shuttle agent central core amphipathic alpha helical region as “KWKLARAFARAIKKL” which when produced in Schiffer-Edmundson’s wheel representation, shows a cluster of hydrophobic amino acid residues on one side of the helix defining a hydrophobic angle of 220º and a cluster of positively charged residues on the other side of the helix defining a positively charged angle of 100º in the Schiffer-Edmundson’s wheel representation (Page 3, Figure 1a provides the sequence of the central core amphipathic alpha helical region; See below the Schiffer-Edmundson’s Wheel representation which is compared with the instant Fig. 1 comprising FSD10-15 sequence in Schiffer-Edmundson’s Wheel representation along with calculations). The calculations below show the hydrophobic angle of 220º, the positively charged angle of 100º and the hydrophobic moment as 4.27 µH. Kulhankova is cited only to show that the S10 synthetic peptide shuttle agent forms an alpha-helical structure (Page 11912, Column 2).
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Regarding claims 100 and 101, Krishnamurthy teaches the S10 synthetic peptide shuttle agent central core amphipathic alpha helical region as “KWKLARAFARAIKKL” which when produced in Schiffer-Edmundson’s wheel representation, shows a cluster of hydrophobic amino acid residues on one side of the helix defining a hydrophobic angle of 220º and a cluster of positively charged residues on the other side of the helix defining a positively charged angle of 100º in the Schiffer-Edmundson’s wheel representation (Page 3, Figure 1a provides the sequence of the central core amphipathic alpha helical region; See below the Schiffer-Edmundson’s Wheel representation which is compared with the instant Fig. 1 comprising FSD10-15 sequence in Schiffer-Edmundson’s Wheel representation along with calculations). Further, when calculating the percentages in the hydrophobic cluster that are phenylalanine, isoleucine, tryptophan and leucine, the percentage is 20%. Kulhankova is cited only to show that the S10 synthetic peptide shuttle agent forms an alpha-helical structure (Page 11912, Column 2).
Regarding claim 102, Krishnamurthy teaches the S10 synthetic peptide shuttle agent central core amphipathic alpha helical region as “KWKLARAFARAIKKL” which when produced in Schiffer-Edmundson’s wheel representation, shows a cluster of hydrophobic amino acid residues on one side of the helix defining a hydrophobic angle of 220º and a cluster of positively charged residues on the other side of the helix defining a positively charged angle of 100º in the Schiffer-Edmundson’s wheel representation (Page 3, Figure 1a provides the sequence of the central core amphipathic alpha helical region; See below the Schiffer-Edmundson’s Wheel representation which is compared with the instant Fig. 1 comprising FSD10-15 sequence in Schiffer-Edmundson’s Wheel representation along with calculations). Further, when calculating the percentages in the positively charged cluster that are lysine and arginine, the percentage is 40%. Kulhankova is cited only to show that the S10 synthetic peptide shuttle agent forms an alpha-helical structure (Page 11912, Column 2).
Regarding claims 104 and 105, Krishnamurthy teaches the S10 synthetic peptide shuttle agent (which corresponds in sequence and structure to instant FSD10-15 synthetic peptide shuttle agent shown in Fig. 1; Page 6) comprising six cationic residues and five highly hydrophobic residues as well as a “GGSGGGS” linker attached to the C-terminal end (Page 3, Figure 1a). Kulhankova is cited only to show that the S10 synthetic peptide shuttle agent forms an alpha-helical structure (Page 11912, Column 2).
Regarding claim 106, Krishnamurthy teaches the S10 synthetic peptide shuttle agent (which corresponds in sequence and structure to instant FSD10-15 synthetic peptide shuttle agent shown in Fig. 1; Page 6) comprising six cationic residues and five highly hydrophobic residues as well as a “GGSGGGS” linker attached to the C-terminal end (Page 3, Figure 1a). Kulhankova is cited only to show that the S10 synthetic peptide shuttle agent forms an alpha-helical structure (Page 11912, Column 2). Therefore, in the alpha-helical structure the amino acids would be in the D-configuration.
Regarding claims 107-109, Krishnamurthy teaches a method of delivering compositions comprising a Cas9-RNP (non-anionic cargo) and, separately, an S10 synthetic peptide shuttle agent (which corresponds in sequence and structure to instant FSD10-15 synthetic peptide shuttle agent shown in Fig. 1; Page 6) to epithelial cells of the large and small airways (Page 4, Column 1). Krishnamurthy teaches successful and efficient transduction of the synthetic peptide shuttle agent as well as the Cas9-RNP to ciliated, non-ciliated and goblet cells of the human airway epithelial as compared to the synthetic peptide shuttle agent administered independently (Page 5, Column 1 and Column 2).
Regarding claim 110, Krishnamurthy teaches a method of delivering compositions comprising a Cas9-RNP (non-anionic cargo) and, separately, an S10 synthetic peptide shuttle agent (which corresponds in sequence and structure to instant FSD10-15 synthetic peptide shuttle agent shown in Fig. 1; Page 6) to epithelial cells of the large and small airways (Page 4, Column 1). Krishnamurthy teaches successful and efficient transduction of the synthetic peptide shuttle agent as well as the Cas9-RNP to ciliated, non-ciliated and goblet cells of the human airway epithelial as compared to the synthetic peptide shuttle agent administered independently (Page 5, Column 1 and Column 2). Krishnamurthy teaches the S10 synthetic peptide shuttle agent (which corresponds in sequence and structure to instant FSD10-15 synthetic peptide shuttle agent shown in Fig. 1; Page 6) comprising six cationic residues and five highly hydrophobic residues as well as a “GGSGGGS” linker attached to the C-terminal end (Page 3, Figure 1a).
The instant specification teaches for FSD 10-15, GFP transduction efficiency slightly increased from 21 % to 24 % in the presence of Cas9-RNP (Fig. 3) and FSDl0-15 is a 15-amino acid fragment of several longer shuttle agents, including FSD375, FSD422, FSD424, FSD432, FSD241, FSD231, FSDl0, and FSD210, as well as, adding flanking glycine/serine-rich residues to FSDl0-15 (see FSD375 and FSD424) retained the peptide's resistance to Cas9-RNP while improving GFP transduction activity over FSDl0-15 (Page 45, Lines 26-30).
Therefore, Krishnamurthy teaching the same structure of instantly claimed FSD10-15 as S10 as well as the same results as disclosed in the instant specification on Page 45, Krishnamurthy also teaches a central core amphipathic alpha helical region having shuttle agent activity, flanked N- and C-terminally by flexible linker domains, wherein one or both of the flexible linker domains comprises or consists essentially of a sufficient number of non-cationic hydrophilic residues such that cargo transduction activity of the synthetic peptide shuttle agent across the mucus-producing membrane, or in the presence of DNA and/or RNA, is increased relative to that of the central core amphipathic alpha helical region lacking the flexible linker domains, wherein the central core amphipathic alpha helical region is an endosomolytic peptide 15 amino acids in length having both a positively- charged hydrophilic outer face and a hydrophobic outer face.
Kulhankova is cited only to show that the S10 synthetic peptide shuttle agent forms an alpha-helical structure (Page 11912, Column 2).
Regarding claim 111, Krishnamurthy teaches the S10 synthetic peptide shuttle agent central core amphipathic alpha helical region as “KWKLARAFARAIKKL” which when produced in Schiffer-Edmundson’s wheel representation, shows a cluster of hydrophobic amino acid residues on one side of the helix defining a hydrophobic angle of 220º and a cluster of positively charged residues on the other side of the helix defining a positively charged angle of 100º in the Schiffer-Edmundson’s wheel representation (Page 3, Figure 1a provides the sequence of the central core amphipathic alpha helical region; See below the Schiffer-Edmundson’s Wheel representation which is compared with the instant Fig. 1 comprising FSD10-15 sequence in Schiffer-Edmundson’s Wheel representation along with calculations). The calculations below show the hydrophobic angle of 220º, the positively charged angle of 100º and the hydrophobic moment as 4.27 µH. Kulhankova is cited only to show that the S10 synthetic peptide shuttle agent forms an alpha-helical structure (Page 11912, Column 2).
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Conclusion
No claims are allowed.
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/ALEXANDRA ROSE LIPPOLIS/Examiner, Art Unit 1637
/CELINE X QIAN/Primary Examiner, Art Unit 1637