DETAILED ACTION
Receipt of Arguments/Remarks filed on June 4 2026 is acknowledged. Claims 1-34, 44, 47-48, 50 and 52-53 were/stand cancelled. Claims 35, 39-41, 43, 45 and 54 were amended. Claims 35-43, 45-46, 49, 51 and 54 are pending. Claims 51 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made with traverse in the reply filed on December 30 2025. Claims 35-43, 45-46, 49 and 54 are directed to the elected invention.
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 .
Withdrawn Objections/Rejections
The amendments filed June 4 2026 are sufficient to overcome the objection to the drawings. Figure 5 has been corrected. The drawings are accepted.
The amendments filed June 4 2026 are sufficient to overcome the objection to the specification. The embedded hyperlink has been removed from the specification.
The cancellation of claim 48 in the response filed June 4 2026 renders the objection moot.
The amendment filed June 4 2026 is sufficient to overcome the objection of claim 45. The word “of” has been inserted clarifying the grammar of the claim.
The amendments filed June 4 2026 are sufficient to partially overcome the rejection of claims 35-50 and 54 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. The amendments clarify the scope when the parameter recites A and L, K and R, D and E in claims 35 and 41. The amendments partially clarify the scope of claim 40. The amendments clarify the scope of claim 41. The cancelation of claim 44 renders the rejection moot. The recitation other intracellular delivery moiety was removed from the claims. The amendments clarify the scope of the flexible linker. The cancellation of claim 44 renders the rejection moot. The amendments to claims 45 and 54 clarify the scope.
The amendments filed June 4 2026 are sufficient to overcome the rejection of claims 35-41, 46 and 48-49 under 35 U.S.C. 103 over Jarver et al. (Nucleic Acid Ther. 2015, cited on PTO Form 1449) in view of Lundberg et al.; and the rejection of claim 50 under 35 USC 103 over Jarver et al. in view of Lundberg et al. or Del ‘Guidice and in further view of Pattanayak et al. The rejected claims now exclude (B) as a choice for the shuttle agent and specifically claims the synthetic peptide shuttle agent does not comprise a cell penetrating domain, a cell-penetrating peptide or a protein transduction domain and claim 50 was cancelled.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on June is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
New and Modified Rejections Necessitated by the Amendments filed June 4 2026
Claim Rejections - 35 USC § 112-Indefiniteness
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 35-50 and 54 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 35 as currently written is vague and indefinite. The claim recites “wherein at least six of the following parameters (5) to (15) are respected”. Parameter (8) recites the peptide is composed of 35% to 65% of any combination of the amino acids: A, C, G,I, L, M, F, P, W, Y, and V; parameter (10) recites the peptide is composed of 35% to 85% of any combination of the amino acids: A, L, K, or R; parameter (11) recites the peptide is composed of 15% to 45% of any combination of the amino acids: A and L, provided there being at least 5% of L in the peptide; parameter (12) recites the peptide is composed of 20% to 45% of any combination of the amino acids: K and R; and parameter (15) recites the peptide is composed of 10% to 45% of any combination of the amino acids: Q, Y, W,P, I, S, G, V, F, E, D, C, M, N, T and H. When taken together the lower limit of all of these parameter is greater than 100 (i.e. corresponds to 115%). This creates uncertainty as to 1) how many parameters can actually be chosen from 5 to 15 and which ones can be selected. Since these parameters dictate the structure of the peptide, they are critical to understanding the scope of what can and cannot be included in the peptide. Claim 40 and 41 are also indefinite for the same reasons.
Claims 36-39, 42-43, 45-46 and 49 are included in the rejection as they depend on a rejected base claim and they do not clarify the issues.
Response to Arguments
Applicants’ arguments filed June 4 2026 have been fully considered but they are not persuasive.
Applicants argue that a person skilled in the art would understand that parameters (8), (10), (11), (12) and (15) are to be evaluated independently, rather than a closed system composed of non-overlapping lists.
Regarding Applicants’ arguments, if Applicants are correct, parameter (11) states that the peptide is composed of 15 to 45% of A, L, or a combination of A and L provided there being at least 5% L. This means at most for this parameter the peptide is composed of 40% A. However, parameter (8) states the peptide is composed of 35% to 65% A, C, G, I, L, M, F, P, W, Y and V. Therefore, A and L could also be the only amino acids selected for this parameter. That means this parameter allow for 65% of the peptide to be A and L, which is significantly different than the 45% in parameter 11. It isn’t clear which parameter would control. If at least 6 of the parameters (out of a total of 10) have to be followed, and these parameters dictate the structure of the corresponding peptide. Then the scope of the multiple parameters need to be clear because as stated above, would a peptide that has 65% A and L which clearly falls within the scope of parameter (8) but not parameter (11) fall within the scope of the claim. Parameter 10 allows up to 85% A and L which is significantly higher than the 45% of parameter 11. Therefore, the examiner is still of the position that the metes and bounds of the claim are not clear especially in light of the parameters being required to define the structure of the peptide encompassed by the scope.
Claim Rejections - 35 USC § 112-Written Description
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 35-43, 45-46, 49 and 54 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.
The specification and prior art discloses chemicals, such as SEQ ID NO: 35, HA2-penetratin, EB1 and other specific sequences as set forth, for example, in (i) of claim 45 which meet the written description and enablement provisions of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. However, claim(s) 35-50 and 54 is(are) directed to encompass either (A) any synthetic peptide shuttle agent that the features of (1)-(4) and also has at least six of the parameters of (5) to (15) which only correspond in some undefined way to specifically instantly disclosed chemicals. None of these peptide shuttle agents meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, due to lacking chemical structural information for what they are and chemical structures are highly variant and encompass a myriad of possibilities. The specification provides insufficient written description to support the genus encompassed by the claim. Note: MPEP 2163.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, (Fed. Cir. 1991), makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Univ. of Rochester v. G.D. Searle, 69 USPQ2d 1886, 1892 (CAFC 2004), further supports this by stating that:
The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. A description of an anti-inflammatory steroid, i.e., a steroid (a generic structural term) described even in terms of its functioning of lessening inflammation of tissues fails to distinguish any steroid from others having the same activity or function. A description of what a material does, rather than of what it is, usually does not suffice…. The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described. (Emphasis added).
With the exception of the above specifically disclosed chemical structures, the skilled artisan cannot envision the detailed chemical structure of the encompassed peptide shuttle agents, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The chemical structure itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Circ. 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016, (Fed. Cir. 1991). In Fiddes v. Baird, 30 USPQ2d 1481, 1483, (Bd. Pat. App. & Int. 1993), claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 (Fed. Cir. 1997) held that:
...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
Furthermore, to the extent that a functional description can meet the requirement for an adequate written description, it can do so only in accordance with PTO guidelines stating that the requirement can be met by disclosing “sufficiently detailed, relevant identifying characteristics,” including “functional characteristics when coupled with a known or disclosed correlation between function and structure.” Univ. of Rochester v. G.D. Searle, 68 USPQ2d 1424, 1432 (DC WNY 2003).
Looking to the instant specification, example 1 just generically mentions “synthetic peptide shuttle agent” but it does not appear where the specific peptide shuttle agent is recited. But looking to Figure 1/5 there are several peptides disclosed which correspond to the sequences set forth in claim 45 (i). But the claims are much broader than that. Even claim 45 allows for changes to the amino acids in the sequences set forth in (i) as well as at least 50% identity to those sequences. While conservative amino acid substitution typically do not alter the function of the polypeptide, there are exceptions. Nothing in the specification makes it clear what residues are required to be maintained for the peptide to serve as a shuttle agent. The specification fails to describe the common attributes or characteristics that identify all the members of the genus or even a substantial portion thereof.
Therefore, only the above chemically structurally defined chemicals, but not the full breadth of the claim(s) meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The species specifically disclosed are not representative of the genus because the genus is highly variant. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC § 112 is severable from its enablement provision. (See page 1115.)
Response to Arguments
Applicants’ arguments filed June 4 2026 have been fully considered but they are not persuasive.
Applicants argue that the presently claimed invention builds on the disclosure of Applicant’s prior patent publication which is incorporated by reference into the instant specification and is thoroughly discussed throughout the specification as filed and specifically in example 2. It is argued that WO ‘135 thoroughly describes the rational design parameters of the genus of synthetic peptide shuttle agents useful or the intracellular delivery of polypeptide cargoes. The presently claimed invention stems from the surprising discovery that the same genus of synthetic peptide shuttle agents is useful for intracellular delivery. The results in Fig. 1 show that sixteen different randomly selected rationally designed synthetic peptide shuttle agents which respect the parameters recited in claim 35 are able to transduce non-anionic polynucleotide cargoes (i.e. fluorescently labeled PMOs). Fig. 5 of the instant specification presents cargo transduction activity for several hundred rationally designed synthetic peptide shuttle agents in a side-by-side screen.
Regarding Applicants’ arguments, while the examiner acknowledges that in Fig. 5 there are numerous peptides shown. However, the examiner cannot agree the claims are limited to a scope that these peptides represented or even limited to those which show an “unexpected effect”. Firstly, the arguments indicate the instantly claimed shuttle agents can effectively delivery non-anionic polynucleotide cargo and that the first generation peptides cannot. However, the instant claims include within the scope of these first generation shuttle agents as both claims 45 and 54 include SEQ ID No: 1-6 which are taught in Figure 1 and 5 as first generation (see also original claim 18). Additionally, nothing in the remarks makes it clear what it is specifically within the structure of the peptide shuttle agents that provide for the “surprising discovery” that the peptides can effectively deliver non-anionic polynucleotide cargo especially in light of claim 35 recitation of broad scope with regards to the amino acids which can be present and claim 35 or 54 which recite that the peptide shuttle agent merely have to have 50% identity with the claimed species. In Fig. 1 one of the controls is an FSD10 scramble peptide which has a mean delivery score of 0.01. However, this sequence has 53.2% identity with instantly claimed SEQ ID No: 50 (see alignment below). The examiner has not compared this sequence to others as there could be other claimed sequences with higher % identity. Therefore, the sequence falls within the scope claimed but is a sequence which Applicants allege the instant composition shows an unexpected effect over.
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Therefore, the examiner cannot agree that the instant specification provides written description support for the scope of peptide shuttle agents claimed, especially in light of the arguments that the peptide shuttle agents have an unexpected effect and that many peptides, including numerous claimed, would not be expected to deliver the claimed oligonucleotide.
Claim Rejections - 35 USC § 112-failture to further limit
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 45 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 45 as written includes various amino acids sequence. One group of sequences claimed, for example, are SEQ ID No: 1-6, which is taught in Fig. 1 as CM18-Penetratin-cy, TAT-KALA, His-CM18-PTD4, His-LAH4-PTD4, PTD4-KALA and EB1-PTD4 which are peptide sequences which include a cell penetrating peptide or protein transduction domain and are the so-called first-generation shuttle agents (see for example Fig. 1, original claim 18). Claim 45 depends from claim 35 which states that the synthetic peptide shuttle agent does not comprise a cell penetrating domain, a cell-penetrating peptide or a protein transduction domain. Therefore, claim 45 is broader in scope than the claim from which it depends as it specifically claims sequence which include domains/peptides excluded by the claim from which is depends.
The examiner notes that claim 54 is interpreted different. Claim 54 while reciting, for example, SEQ ID No: 1-6, does not exclude the shuttle agent from containing a cell penetrating domain, a cell-penetrating peptide or a protein transduction domain. Claim 54 requires that the cargo is not covalently linked to a CPP or octa-guanidine dendrimer.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 35-43, 45-46, 49 and 54 are rejected under 35 U.S.C. 103 as being unpatentable over Jarver et al. (Nucleic Acid Ther. 2015, cited on PTO Form 1449) in view of Del’ Guidice et al. (WO 2018068135, cited on PTO Form 1449).
Applicant Claims
A composition comprising a non-anionic polynucleotide analog cargo for intracellular delivery and a synthetic peptide shuttle agent that is independent from, or is not covalently linked to, said non-anionic polynucleotide analog cargo, wherein: as elected the peptide shuttle agent is SEQ ID No: 35.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Jarver et al. is directed to peptide nanoparticle delivery of charge-neutral splice-switching morpholino oligonucleotides. Cellular entry and bioavailability is low for most therapeutic oligonucleotides (ON) and their ability to reach a desired organ or tissue is often very limited. Commonly used ON analogs include phosphorodiamidate morpholino (PMO). In order to carry out their functions, the ability to cross biological membranes is essential to all therapeutic ONs that have intracellular targets. However, all ONs suffer from inefficient delivery into cells and tissues. Most common methods to increase cellular uptake of therapeutic Ons are based on cationic polymers. One such system involves cationic peptide delivery vehicles, often referred to as cell-penetrating peptides or peptide transduction domains (page 65). ON analogs such as PMO have a hydrophobic nature and are charge-neutral. These ON types have not been thought to be compatible with commonly used cationic nanoparticle delivery systems (page 66, left column, first paragraph). The PMO backbone, on the other hand, is based upon
morpholine rings instead of deoxyribose and is linked through phosphorodiamidate groups instead of phosphates. PMO ONs are very promising for therapeutic purposes (page 66, left column, second paragraph). Tested whether the addition of a hydrophobic moiety, such as a lipid, might also help the lipid-CPP hybrid to interact and form complexes with other more hydrophobic structures such as PMO ONs (page 66, right column, last paragraph). Table 1 shows the sequences of selected lipopeptides and phosphorodiamidate morpholino oligonucleotides included in the study (Table 1). KL sequences are designed as secondary amphipathic peptides that might be expected to fold into an alpha helical structure. The STR peptides have histidine residues incorporated into the sequence, which are mainly uncharged at physiological pH. However, the histidines are protonated at lower pH (e.g. in maturing endosomes) and hence increase the net positive charge of the CPP (pointing to Lundberg et al.) (page 67, right column, first paragraph). Tested whether the addition of a hydrophobic moiety, such as a lipid, might also help the lipid-CPP hybrid to interact and form complexes with other more hydrophobic structures such as PMO ONs. It was shown well-established lipopeptides and novel lipopeptides can form nanoparticles readily with PMOs. Such nanoparticles are efficiently taken up by cultured patient fibroblasts and mouse muscle cells, and the PMO is delivered into the cell nucleus with retained biological activity (page 75, left column, first paragraph). Low and high doses of nanoparticles (1 and 10 µM) are taught (Fig. 1). Working concentrations of 5 µM is taught (page 73; Fig. 8).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Jarver et al. teaches cationic peptides to deliver the PMO, Jarver et al. does not expressly teach the instantly claimed synthetic peptide shuttle agent. However, this deficiency is cured by Del ‘Guidice et al.
Del ‘Guidice et al. is directed to rationally-designed synthetic peptide shuttle agents for delivering polypeptide cargos from an extracellular space to the cytosol and/or nucleus of a target eukaryotic cell, uses thereof, methods and kits relating to same. Cell delivery technologies to transport large molecules inside eukaryotic cells have a wide range of applications, particularly in the biopharmaceutical industry. While some soluble chemical substances (e.g., small molecule drugs) may passively diffuse through the eukaryotic cell membrane, larger cargos (e.g., biologies, polynucleotides, and polypeptides) require the help of shuttle agents to reach their intracellular targets (page 1).The shuttle agents are taught as “improved” specifically capable of increasing the transduction efficiency of polypeptide cargos and delivery the cargos to the cytosol and/or nuclease of target eukaryotic cells. Claimed is a synthetic peptide shuttle agent (claim 17) which 1) a peptide at least 20 amino acids in length comprising (2) an amphipathic alpha-helical motif having a positively-charged hydrophilic outer face, and (3) a hydrophobic outer face, wherein at least five of the following parameters (4) to (15) are respected:(4) the hydrophobic outer face comprises a highly hydrophobic core consisting of spatially adjacent L, I, F, V, W, and/or M amino acids representing 12 to 50% of the amino acids of the peptide, based on an open cylindrical representation of the alpha-helix having 3.6 residues per turn; (5) the peptide has a hydrophobic moment (μ) of 3.5 to 11 ; (6) the peptide has a predicted net charge of at least +4 at physiological pH;(7) the peptide has an isoelectric point (pi) of 8 to 13;(8) the peptide is composed of 35% to 65% of any combination of the amino acids: A, C, G, I, L, M, F, P, W, Y, and V;(9) the peptide is composed of 0% to 30% of any combination of the amino acids: N, Q, S, and T; (10) the peptide is composed of 35% to 85% of any combination of the amino acids: A, L, K, or R; (11) the peptide is composed of 15% to 45% of any combination of the amino acids: A and L, provided there being at least 5% of L in the peptide; (12) the peptide is composed of 20% to 45% of any combination of the amino acids: K and R;(13) the peptide is composed of 0% to 10% of any combination of the amino acids: D and E; (14) the difference between the percentage of A and L residues in the peptide (% A+ L), and the percentage of K and R residues in the peptide (K + R), is less than or equal to 10%; and (15) the peptide is composed of 10% to 45% of any combination of the amino acids: Q, Y, W, P, I, S, G, V, F, E, D, C, M, N. T and H.
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Jarver et al. and Del ‘Guidice et al. and utilize the peptide shuttle agents of Del ‘Guidice to deliver the PMO of Jarver et al. One skilled in the art would have been motivated to utilize the peptide shuttle agents of Del ‘Guidice as Jarver et al. expressly teaches the use of cationic peptides to enhance delivery and Del ‘Guidice teaches that the “improved” peptide shuttle agents can effectively deliver large cargo which as recognized by Del ‘Guidice includes polynucleotides and polypeptides as these require the help of shuttle agents to reach their intracellular targets and are positively charged.
Regarding claims 35-37, 39 and 49, the PMO of Jarver et al. is taught as a charge-neutral PMO reading on non-anionic polynucleotide analog. The synthetic peptide shuttle agent claimed by Jarver et al. (claim 1; 17) has the same/similar requirements and parameters. Regarding the claimed concentration, Jarver et al. suggest concentrations overlapping the instant claims. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05. The PMO of Jarver et al. is not linked to anything other molecule.
Regarding claim 38, as shown in table 1 of Jarver et al. the oligonucleotides have lengths of 18-mer to 25-mer.
Regarding claims 40-43 and 46, Del ‘Guidice et al. teaches the same limitations of the shuttle peptide agent (claims 1-8).
Regarding claims 45 and 54, firstly, the examiner notes that no prior art expressly teaches a sequence with 100% identity to instantly claimed SEQ ID NO: 35. However, the claims are not limited to such a sequence. Seq ID No: 113 of Del ‘Guidice et al. has 51.2% identity to instantly claimed SEQ ID No: 35 which falls within the scope instantly claimed. Claims 45 and 50 allow for an amino acid sequence that different from, for example SEQ ID NO: 358, by no more than 10 amino acids. Since SEQ ID No: 358 is 12 amino acids long, this means there needs to only be a 2 amino acid match. SEQ ID No: 121 of Del ‘Guidice et al. has 53.8% identity. Both sequence alignments are shown below.
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Regarding claim 49, as set forth above Jarver et al. teaches an overlapping range.
Response to Arguments
Applicants’ arguments filed June 4 2026 have been fully considered but they are not persuasive.
Applicants argue that (1) first each and every peptide disclosed in Jarver that shows activity for delivery PMOs are in fact cell-penetrating peptides conjugated to lipid moieties. As amended claim 35 does not include a CPD, CPP or PTD. Thus, the skilled person would have to go against the teachings of Jarver to arrive at the claimed invention.
Regarding Applicants’ first argument, while Jarver does teach cell penetrating peptides, Jarver does not teach that other cationic or amphipathic peptides would not be expected to work. In fact, throughout Jarver, discussion of the cationic nature is what is taught as being useful in delivery of the charge-neutral PMOs. Jarver teaches that the relative ratio of lipopeptide to PMO seems to affect uptake differently depending on the primary sequence of the peptide. At higher ratios, less cationic peptides such as amphipathic St-KL4 promote a greater activity, while the delivery seems to plateau or even decrease somewhat when using peptides, with a higher amount of cationic amino acids. It can be ruled out that unwanted toxic side effects influence the activities since none of the peptides shown any toxicity. Depending on the type of peptide used, there might be a threshold value of cationic charges needed to induce endosomal release. At higher concentration, the less cationic peptides might have a greater impact on the endosomal escape and more PMO is released into the cytoplasm/nuclease. Therefore, while Jarver does expressly teach cell penetrating peptides, the teachings of Jarver that it isn’t the sequence specifically of the cell penetrating peptides but the concentration and amount of cationic amino acids that have an effect on the PMO delivery. Therefore, the examiner cannot agree that Jarver teaches that the use of other peptides would not be obvious.
Applicants argue that (2) the skilled person would not seek to combine the teachings of Jarver with those of Del ‘Guidice. Del ‘Guidice is for the delivery of polypeptide cargoes as discussed in example 2. Jarver teaches incubating cells with PMO cargo for 4 hours for intracellular delivery. In contrast Applicants’ synthetic peptide shuttle agents were designed and screened for the rapid transduction of polypeptide cargoes and thus were designed to lack a CPD.
Regarding Applicants’ second argument, these arguments are directed to the use of the invention. The examined claims are directed to a composition. The length of transduction does not make the formation of the claimed composition unobvious in view of Jarver and Del ‘Guidice because nothing in the product claim requires a particular rate of transduction. Additionally, the examiner cannot agree that the instant claims include polypeptides without a CPD. While claim 35 does recite this limitation, claim 45 specifically includes peptide sequences which include a CPD same with claim 54, this claim specifically includes peptides with sequences which include a CPD. Therefore, Applicants arguments are not commensurate with the claim, even as amended.
Looking to the instant specification, there does not appear to be a specific definition of cell penetrating peptide. Therefore the BRI of this recitation is the known definition which is short peptides that facilitate cellular intake and uptake of molecules see for example Zorko et al. (Advanced Drug Delivery Reviews, 2005). Based on Applicants arguments with regards to the instantly claimed shuttle agents, aren’t these agents doing the same function as the cell penetrating peptide, specifically facilitating cellular intake and uptake of molecules? Therefore, the examiner cannot agree that the teachings of Jarver would exclude the combination with Del ‘Guidice. Especially since Del ‘Guidice teaches the peptides include a positively-charged hydrophilic outer face.
Applicants argue that (3) it was surprising that Applicants’ second generation synthetic peptide would outperform Applicants first-generation shuttles as evidenced by Fig. 1 of the specification.
Regarding Applicants’ third argument, firstly, this argument is not persuasive because as set forth above, those “first-generation” shuttles are still encompassed by the instant claims either by claiming a specific SEQ ID No: or in light of the claimed % identity to one of the claimed sequences. Furthermore, while the rationally designed shuttle agents recited in Fig. 1 show a mean delivery score which is significantly better than the domain-based shuttle agent, Figure 5 shows numerous FSD peptides which have the same or similar mean delivery score, see for example FSD5 (SEQ ID NO: 12), FSD129 (SEQ ID No: 21), FSD250D (SEQ ID No: 36), etc. all of which are specifically claimed. Therefore, while some of the peptides do show significantly higher delivery scores, the examiner cannot agree that these “unexpected results” are commensurate in scope with the claims.
Applicants argue that (4) Del ‘Guidice explicitly dissuades the skilled person from using synthetic peptide shuttle agents for the cytosolic delivery of polynucleotide cargos. Example 7 of Del ‘Guidice states that the results show that peptides which are suitable for delivery polypeptide cargos may not be suitable for delivery plasmid DNA. A peptide which effective transduce polypeptide cargoes displays only a DNA plasmid transfection efficiency of 0.34%. Example 10 and Fig. 8A and 8B of the specification as filed shows that DNA and RNA exhibit a dominant negative effect on the cargo transduction activity of synthetic peptide shuttle agents. Thus, a person of ordinary skill would not seek to substitute the polypeptide cargoes of Del ‘Guidice with the polynucleotide cargoes let alone with non-anionic polynucleotide cargoes.
Regarding Applicants’ fourth argument, firstly, the rejection is based on using the peptide shuttle agents of Del ‘Guidice with the PMO of Jarver not replacing the cargo of Del ‘Guidice. Even if this were the rejection, while the efficiency of DNA plasmid transfection is only 0.34%, it still possess some efficiency and would still meet the claim limitation of “sufficient to increase transduction efficiency and cytosolic delivery of the non-anionic polynucleotide analog cargo as compared to the absence of the shuttle agent”. Jarver teaches that it is surprising that cationic peptides can be used to deliver PMO. Therefore, the examiner is of the position, one skilled in the art based on the teachings of Jarver which clearly suggest the effect concentration and cationic charge amount can be used to effect the delivery of PMO.
Regarding example 10, this examples states: RH-30 cells (150,000 cells/well in 24-well dish) were contacted with a delivery mix of 6 μM of a PMO-FITC and of 5 μM of the synthetic peptide shuttle agent FSD250 for 2 minutes in RPMI, in the presence of increasing amounts of a DNA oligonucleotide or an sgRNA spiked in medium. Cells were then washed, incubated in growth medium and then collected for analysis by flow cytometry after 1 h. The results in FIG. 8 show that reduced PMO-FITC transduction efficiency was observed in the presence of 1.5 lag of DNA oligo (3 μg/mL) (FIG. 8A) and 2 μg of sgRNA (4 μg/mL) (FIG. 8B). Therefore, this example shows that naked DNA or RNA (i.e. DNA oligo or sgRNA) when spiked into a mixture of PMO and peptide shuttle agent reduced transduction efficiency. It is not clear to the examiner how this shows an unexpected effect. This clearly shows that naked DNA or RNA have an effect the transduction efficiency of the instantly claimed composition, but it is not clear to the examiner how this shows an unexpected effect. If anything this shows that the claimed shuttle agents have decreased transduction efficiency of PMO when non non-anionic polynucleotide analog cargo is present. However, the instant claims do not exclude non non-anionic (aka anionic) polynucleotide cargo, the claims merely require that the composition contains non-anionic polynucleotide analog cargo.
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 35-41, 43, 45, 49 and 54 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 12428447 (cited on PTO Form 1449) in view of Jarver et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
A composition comprising a non-anionic polynucleotide analog cargo for intracellular delivery and a synthetic peptide shuttle agent that is independent from, or is not covalently linked to, said non-anionic polynucleotide analog cargo, wherein: as elected the peptide shuttle agent is SEQ ID No: 35.
Patent ‘447 claims a synthetic peptide shuttle agent having transduction activity for both proteinaceous and non-proteinaceous cargoes in target eukaryotic cells, the synthetic peptide shuttle agent comprising: an amino acid sequence at least 70% identical to SEQ ID NO: 35, calculated excluding the linker domain set forth in SEQ ID NO: 354; or an amino acid sequence that differs from SEQ ID NO: 35 by no more than 6 amino acids excluding the linker domain set forth in SEQ ID NO: 354, wherein the synthetic peptide shuttle agent is a peptide at least 17 amino acids in length comprising an amphipathic alpha-helical motif comprising a positively-charged hydrophilic outer face and a hydrophobic outer face, and the synthetic peptide shuttle agent comprises at least five of the following parameters: (a) the hydrophobic outer face comprises a highly hydrophobic core consisting of spatially adjacent L, I, F, V, W, and/or M amino acids representing 12 to 50% of the amino acids of the peptide, based on an open cylindrical representation of the alpha-helix having 3.6 residues per turn; (b) the peptide has a hydrophobic moment (μ) of 3.5 to 11; (c) the peptide has a predicted net charge of at least +4 at physiological pH; (d) the peptide has an isoelectric point (pI) of 8 to 13; (e) the peptide is composed of 35% to 65% of any combination of the amino acids: A, C, G, I, L, M, F, P, W, Y, and/or V; (f) the peptide is composed of 0% to 30% of any combination of the amino acids: N, Q, S, and/or T; (g) the peptide is composed of 35% to 85% of any combination of the amino acids: A, L, K, and/or R; (h) the peptide is composed of 15% to 45% of any combination of the amino acids: A and/or L, provided there being at least 5% of L in the peptide; (i) the peptide is composed of 20% to 45% of any combination of the amino acids: K and/or R; (i) the peptide is composed of 0% to 10% of any combination of the amino acids: D and/or E; (k) the difference between the percentage of A and L residues in the peptide (% A+L), and the percentage of K and R residues in the peptide (% K+R), is less than or equal to 10%; and/or (l) the peptide is composed of 10% to 45% of any combination of the amino acids: Q, Y, W, P, I, S, G, V, F, E, D, C, M, N, T and/or H, wherein the synthetic peptide shuttle agent increases the transduction efficiency of propidium iodide or other membrane-impermeable fluorescent DNA intercalating agents by at least 3-fold over a corresponding negative control lacking said synthetic peptide shuttle agent, and/or enables a transduction efficiency of at least 10% of propidium iodide or other membrane-impermeable fluorescent DNA intercalating agents, in a eukaryotic cell line model suitable for assessing cargo transduction in said target eukaryotic cells; wherein the synthetic peptide shuttle agent increases the transduction efficiency of GFP-NLS by at least 3-fold over a corresponding negative control lacking said synthetic peptide shuttle agent, and/or enables a transduction efficiency of at least 7% of GFP-NLS, in a eukaryotic cell line model suitable for assessing cargo transduction in said target eukaryotic cells (claim 1). Linker domains include GSGGGS (claim 6-9).
The difference between the instant claims and Patent ‘447 is that Patent ‘447 does not claim a non-proteinaceous cargo which is a non-anionic polynucleotide analog cargo. However, this deficiency is cured by Jarver et al.
Jarver et al. is directed to peptide nanoparticle delivery of charge-neutral splice-switching morpholino oligonucleotides. Cellular entry and bioavailability is low for most therapeutic oligonucleotides (ON) and their ability to reach a desired organ or tissue is often very limited. Commonly used ON analogs include phosphorodiamidate morpholino (PMO). In order to carry out their functions, the ability to cross biological membranes is essential to all therapeutic ONs that have intracellular targets. However, all ONs suffer from inefficient delivery into cells and tissues. Most common methods to increase cellular uptake of therapeutic Ons are based on cationic polymers. One such system involves cationic peptide delivery vehicles, often referred to as cell-penetrating peptides or peptide transduction domains (page 65). ON analogs such as PMO have a hydrophobic nature and are charge-neutral. These ON types have not been thought to be compatible with commonly used cationic nanoparticle delivery systems (page 66, left column, first paragraph). The PMO backbone, on the other hand, is based upon
morpholine rings instead of deoxyribose and is linked through phosphorodiamidate groups instead of phosphates. PMO ONs are very promising for therapeutic purposes (page 66, left column, second paragraph). Tested whether the addition of a hydrophobic moiety, such as a lipid, might also help the lipid-CPP hybrid to interact and form complexes with other more hydrophobic structures such as PMO ONs (page 66, right column, last paragraph). Table 1 shows the sequences of selected lipopeptides and phosphorodiamidate morpholino oligonucleotides included in the study (Table 1). KL sequences are designed as secondary amphipathic peptides that might be expected to fold into an alpha helical structure. The STR peptides have histidine residues incorporated into the sequence, which are mainly uncharged at physiological pH. However, the histidines are protonated at lower pH (e.g. in maturing endosomes) and hence increase the net positive charge of the CPP (pointing to Lundberg et al.) (page 67, right column, first paragraph). Tested whether the addition of a hydrophobic moiety, such as a lipid, might also help the lipid-CPP hybrid to interact and form complexes with other more hydrophobic structures such as PMO ONs. It was shown well-established lipopeptides and novel lipopeptides can form nanoparticles readily with PMOs. Such nanoparticles are efficiently taken up by cultured patient fibroblasts and mouse muscle cells, and the PMO is delivered into the cell nucleus with retained biological activity (page 75, left column, first paragraph). Low and high doses of nanoparticles (1 and 10 µM) are taught (Fig. 1). Working concentrations of 5 µM is taught (page 73; Fig. 8).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘477 and Jarver et al. and utilize a PMO as the cargo. One skilled in the art would have been motivated to utilize these as the non-proteinaceous cargoes in Patent ‘477 as Jarver et al. teaches that cationic peptides can be utilized to delivery PMO.
Regarding the claimed peptide shuttle agent, Patent ‘477 specifically claims SEQ ID NO: 35 which has 100% identity to instantly claimed SEQ ID NO: 35
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Regarding claims 35-37, 39 and 49, the PMO of Jarver et al. is taught as a charge-neutral PMO reading on non-anionic polynucleotide analog. The synthetic peptide shuttle agent claimed by Jarver et al. (claim 1; 17) has the same/similar requirements and parameters. Regarding the claimed concentration, Jarver et al. suggest concentrations overlapping the instant claims. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05. The PMO of Jarver et al. is not linked to anything other molecule.
Claims 35-43, 46 and 49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12286632 (cited on PTO Form 1449) in view of Jarver et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant claims are set forth above.
Patent ‘632 claims a method for synthesizing a peptide having protein transduction activity, the method comprising: (a) designing a peptide which is: (1) a peptide soluble in aqueous solution having an overall length of between 20 and 150 amino acids comprising (2) an amphipathic alpha-helical motif having (3) a positively-charged hydrophilic outer face comprising: (a) at least two adjacent positively-charged K and/or R residues upon helical wheel projection; and/or (b) a segment of six adjacent residues comprising three to five K and/or R residues upon helical wheel projection, based on an alpha helix having angle of rotation between consecutive amino acids of 100 degrees and/or an alpha-helix having 3.6 residues per turn; and (4) a hydrophobic outer face comprising a highly hydrophobic core consisting of spatially adjacent L, I, F, V, W, and/or M amino acids representing 12 to 50% of the amino acids of the peptide, based on an open cylindrical representation of the alpha-helix having 3.6 residues per turn; wherein at least five of the following parameters (5) to (15) are respected: (5) the peptide has a hydrophobic moment (μ) of 3.5 to 11; (6) the peptide has a predicted net charge of at least+4 at physiological pH, calculated from amino acid residues having charged side chains; (7) the peptide has an isoelectric point (pI) of 8 to 13; (8) the peptide is composed of 35% to 65% of any combination of the amino acids: A, C, G, I, L, M, F, P, W, Y, and V; (9) the peptide is composed of 0% to 30% of any combination of the amino acids: N, Q, S, and T; (10) the peptide is composed of 35% to 85% of any combination of the amino acids: A, L, K, or R; (11) the peptide is composed of 15% to 45% of any combination of the amino acids: A and L, provided there being at least 5% of L in the peptide; (12) the peptide is composed of 20% to 45% of any combination of the amino acids: K and R; (13) the peptide is composed of 0% to 10% of any combination of the amino acids: D and E; (14) the difference between the percentage of A and L residues in the peptide (% A+L), and the percentage of K and R residues in the peptide (% K+R), is less than or equal to 10%; and (15) the peptide is composed of 10% to 45% of any combination of the amino acids: Q, Y, W, P, I, S, G, V, F, E, D, C, M, N, T and H, (b) chemically synthesizing the peptide in (a), wherein said peptide is deemed to have protein transduction activity when target eukaryotic cells contacted for five minutes with an independent polypeptide cargo in the presence of at least 2.5 μM of the peptide results in an increase transduction efficiency and cytosolic delivery of the independent polypeptide cargo, as compared to in the absence of the peptide, wherein the peptide and the independent polypeptide cargo comprise independent polypeptide backbones or are not covalently bound, and wherein the peptide lacks a cell penetrating domain (claim 1).
The difference between Patent ‘632 and the instant claims is that Patent ‘532 does not claim a non-anionic oligonucleotide cargo with the peptide. However, this deficiency is cured by Jarver et al.
The teachings of Jarver et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘632 and Jarver et al. and utilize a PMO as the cargo. One skilled in the art would have been motivated to utilize the peptide of Patent ‘632 as Jarver et al. teaches that cationic peptides can be utilized to delivery PMO.
Regarding claims 35-37, 39 and 49, the PMO of Jarver et al. is taught as a charge-neutral PMO reading on non-anionic polynucleotide analog. The synthetic peptide shuttle agent claimed by Jarver et al. (claim 1; 17) has the same/similar requirements and parameters. Regarding the claimed concentration, Jarver et al. suggest concentrations overlapping the instant claims. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05. The PMO of Jarver et al. is not linked to anything other molecule.
Regarding claims 40-43, 46, Patent ‘632 claims the same limitations of the shuttle peptide agent (claims 1-20).
Claims 35-41, 43, 45, 49 and 54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 59-78 of copending Application No. 19312632 in view of Jarver et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
The instant claims are set forth above.
Copending ‘632 claims a synthetic peptide shuttle agent having transduction activity for both proteinaceous and non-proteinaceous cargoes in target eukaryotic cells, the synthetic peptide shuttle agent comprising:- an amino acid sequence at least 70% identical to the full length of SEQ ID NO: 285;or - an amino acid sequence that differs from SEQ ID NO: 285 by no more than 8 amino acids, wherein the synthetic peptide shuttle agent is a peptide at least 17 amino acids in length comprising an amphipathic alpha-helical motif comprising a positively-charged hydrophilic outer face and a hydrophobic outer face, and the synthetic peptide shuttle agent comprises at least five of the following parameters: (a) the hydrophobic outer face comprises a highly hydrophobic core consisting of spatially adjacent L, I, F, V, W, and/or M amino acids representing 12% to 50% of the amino acids of the peptide, based on an open cylindrical representation of the alpha-helix having 3.6 residues per turn; (b) the peptide has a hydrophobic moment ( ) of 3.5 to 11; (c) the peptide has a predicted net charge of at least +4 at physiological pH; (d) the peptide has an isoelectric point (pI) of 8 to 13; (e) the peptide is composed of 35% to 65% of any combination of the amino acids: A, C, G, I, L, M, F, P, W, Y, and/or V;(f) the peptide is composed of 0% to 30% of any combination of the amino acids: N, Q, S, and/or T;(g) the peptide is composed of 35% to 85% of any combination of the amino acids: A, L, K, and/or R;(h) the peptide is composed of 15% to 45% of any combination of the amino acids: A and/or L, provided there being at least 5% of L in the peptide;(i) the peptide is composed of 20% to 45% of any combination of the amino acids: K and/or R;(j) the peptide is composed of 0% to 10% of any combination of the amino acids: D and/or E;(k) the difference between the percentage of A and L residues in the peptide (% A+ L), and the percentage of K and R residues in the peptide (% K + R), is less than or equal to 10%; and/or (1) the peptide is composed of 10% to 45% of any combination of the amino acids: Q, Y, W, P, I, S, G, V, F, E, D, C, M, N, T and/or H, wherein the synthetic peptide shuttle agent increases the transduction efficiency of propidium iodide or other membrane-impermeable fluorescent DNA intercalating agents by at least 3-fold over a corresponding negative control lacking said synthetic peptide shuttle agent, and/or enables a transduction efficiency of at least 10% of propidium iodide or other membrane- impermeable fluorescent DNA intercalating agents, in a eukaryotic cell line model suitable for assessing cargo transduction in said target eukaryotic cells; wherein the synthetic peptide shuttle agent increases the transduction efficiency of GFP- NLS by at least 3-fold over a corresponding negative control lacking said synthetic peptide shuttle agent, and/or enables a transduction efficiency of at least 7% of GFP-NLS, in a eukaryotic cell line model suitable for assessing cargo transduction in said target eukaryotic cells.
The difference between the instant claims and copending ‘632 is that copending ‘632 does not claim a non-proteinaceous cargo which is a non-anionic polynucleotide analog cargo. However, this deficiency is cured by Jarver et al.
The teachings of Jarver et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘632 and Jarver et al. and utilize a PMO as the cargo. One skilled in the art would have been motivated to utilize these as the non-proteinaceous cargoes in copending ‘632 as Jarver et al. teaches that cationic peptides can be utilized to delivery PMO.
Regarding the claimed peptide shuttle agent, copending ‘632 specifically claims SEQ ID NO: 285 which has 100% identity to instantly claimed SEQ ID NO: 285:
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Regarding claims 35-37, 39 and 49, the PMO of Jarver et al. is taught as a charge-neutral PMO reading on non-anionic polynucleotide analog. The synthetic peptide shuttle agent claimed by Jarver et al. (claim 1; 17) has the same/similar requirements and parameters. Regarding the claimed concentration, Jarver et al. suggest concentrations overlapping the instant claims. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05. The PMO of Jarver et al. is not linked to anything other molecule.
Claims 35-43, 46 and 49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 92-111 of copending Application No. 18033280 (USPGPUB No. 20230399661, cited on PTO Form 1449) in view of Jarver et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
The instant claims are set forth above.
Copending ‘280 claims a method for delivering a non-anionic cargo across a mucus- producing membrane, the method comprising contacting cells of the mucus-producing membrane with the non-anionic cargo and a synthetic peptide shuttle agent at a concentration sufficient to increase a transduction efficiency and/or cytosolic/nuclear delivery of the non-anionic cargo, as compared to in an absence of the synthetic peptide shuttle agent, wherein the synthetic peptide shuttle agent and the non-anionic cargo are not covalently bound at the time of transduction, and
wherein the synthetic peptide shuttle agent comprises or consists essentially of 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 at least 8 amino acids in length having both a positively- charged hydrophilic outer face and a hydrophobic outer face (claim 92). An overlapping length is claimed (claim 93).
The difference between the instant claims and copending ’280 is that copending ‘280 does not claim a non-anionic cargo which is a non-anionic polynucleotide analog cargo. However, this deficiency is cured by Jarver et al.
The teachings of Jarver et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘280 and Jarver et al. and utilize a PMO as the cargo. One skilled in the art would have been motivated to utilize these as the non-anionic cargo in copending ‘280 as Jarver et al. teaches that cationic peptides can be utilized to delivery PMO.
Regarding claims 35-37, 39 and 49, the PMO of Jarver et al. is taught as a charge-neutral PMO reading on non-anionic polynucleotide analog. The synthetic peptide shuttle agent claimed by Jarver et al. (claim 1; 17) has the same/similar requirements and parameters. Regarding the claimed concentration, Jarver et al. suggest concentrations overlapping the instant claims. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05. The PMO of Jarver et al. is not linked to anything other molecule.
Regarding claims 40-43 and 46, copending ‘280 claims the same limitations of the shuttle peptide agent (claims 92-94, 100-106).
Response to Arguments
Applicants’ arguments filed June 4 2026 have been fully considered but they are not persuasive.
Applicants argue that the deficiencies of the CPP-based peptides of Jarver with respect to the present claims are discussed above. Del ‘Guidice explicitly dissuades the skilled person from using a rationally designed synthetic peptide shuttle agent to deliver polynucleotide cargos. Example 10 shows a dominant negative effect on cargo transduction.
Regarding Applicants arguments, firstly, as set forth above the instant claims not exclude CPP-based peptides as the claims recite specific sequences with that contain expressly taught CPP peptides. Secondly, the examiner cannot agree that Del ‘Guidice explicitly dissuades a skilled person from using a rationally designed synthetic peptide shuttle agent. Del ‘Guidice discusses DNA plasmid which is not the same as PMO. Additionally, there was still a transduction efficiency, while it might be lower than peptides, this does not expressly direct one skilled in the art away from using the shuttle agents with PMO, especially in light of the teachings of Jarver which teaches that peptides, especially those with cationic groups, can be used to effectively deliver PMO. Example 10 is not sufficient for the same reasons set forth above. This example does not appear to establish an unexpected effect with regards to the instantly claimed composition.
Conclusion
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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/ABIGAIL VANHORN/ Primary Examiner, Art Unit 1636
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