DETAILED ACTION
The examiner for your application at the USPTO has changed. Examiner Abigail VanHorn can be reached at 571-270-3502.
Election/Restrictions
Applicant’s election without traverse of Group I, the first structure in claim 163, Ac-PKKKRKV-PEG₂-K(cyclo[FGFGRGRQ)-PEG₁₂-OH, SEQ ID NO: 345 in the reply filed on April 28 2026 is acknowledged.
The examiner notes that the structure in the response filed on April 28 2026 as to the election for claim 163 was unclear. The examiner spoke with Nicole Tepe, on June 24 where she confirmed that the selection is the first structure recited in claim 163.
Claims 156-172 are pending in the application. Claims 168 and 172 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on April 28 2026. Accordingly, claims 156-167 and 169-171 are being examined on the merits herein.
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
This application is a 371 of PCT/US2022/028357 (05/09/2022) which claims benefit of 63/186,664 (05/10/2021); 63/210,866 (06/15/2021); 63/210,882 (06/15/2021); 63/239,671 (09/01/2021; ABN 12/20/21); 63/298,587 (01/11/2022; ABN 3/10/22); 63/318,201 (03/09/2022); 63/321,921 (03/21/2022); and 63/362,295 (03/31/2022) as reflected in the filing receipt issued on October 28 2024.
Applicant’s claim for the 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) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. US63186664, US63210866, US63210882, US63239671, US63298587, US63362295 and US63318201 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
US63186664, US63210866, US63210882 fails to provide support for the claimed linker and the claimed cargo. The closest structure associated with the instant claimed linker is found on page 110 of ‘664 or page 127 of ‘866 or page 104 of ‘882 but it has an additional NH when conjugated to the AC and doesn’t teach combination with an exocyclic peptide. Additionally the AC is not taught as DUX4 but instead IRF-5 or GYS1.
US63239671 while providing support for the claimed linker, the claimed exocyclic peptide, the claimed cyclic cell penetrating peptide and teaches an oligonucleotide can be attached, ‘671 does not teach DUX4 as a target.
US63298587 fails to provide support for the claimed oligonucleotide target as ‘587 teaches IRF-5. The claimed linker is also not expressly taught for linking a ccp, oligonucleotide and exocyclic peptide.
US63362295 fails to provide support for the claimed oligonucleotide target. It merely teaches a target (e.g. pre-RNA). The exocyclic peptide, cpp and linker are taught.
US63318201 fails to provide support for the claimed oligonucleotide target. DUX4 is merely mentioned in the title of a reference in paragraph 294 (page 76) which paragraph is directing the reader’s attention to method for identifying polyadenylation sites. The exocyclic peptide, cpp and linker are taught.
The first instance of support for the scope of claim 156 (the cCPP, the linker, the oligonucleotide and the exocyclic peptide) is US63321921.
Therefore, the effective filing date of claims 156-157 and 169-171 is March 21 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on May 24 2024, July 23 2024, July 10 2025, September 12 2025, March 6 2026 and July 1 2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.831(a) and 1.831(b). However, this application fails to comply with the requirements of 37 CFR 1.831-1.834. The examiner has noted that claims 160, 163, 164, 168, 169 and 170 each contain amino acid sequences with more than 4 enumerated amino acids but these structures are not associated with a SEQ ID NO. Specifically peptide PKKKRKV in claim 160; the cyclic sequences (at a minimum) include FGFG or GFGF or FFFG or FFXGRGR or REFF in claim 163 In claim 164 both the PKKKRKV sequence and the cyclo sequences are present and each contain at least 4 enumerated amino acids. In claim 168 the cyclo amino acid has more than 4 specifically enumerated amino acids. In claim 169-170 it is both the PKKKRKV peptide as well as the cCPP peptide. It is noted that under ST.26 D-amino acids are considered specifically enumerated . Applicant must provide:
Specific deficiency - Sequences appearing in the claims and specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c).
In the specification, see at least pages 5-7, 11-14, 55, 90-94, 97-103, 124-126, 128-133 and 147-149 contain structures with more than 4 specifically enumerated amino acids and are not associated with a SEQ ID NO.
Claims 160, 163, 164, 168, 169 and 170 each contain amino acid sequences with more than 4 enumerated amino acids but these structures are not associated with a SEQ ID NO. Specifically peptide PKKKRKV in claim 160; the cyclic sequences (at a minimum) include FGFG or GFGF or FFFG or FFXGRGR or REFF in claim 163 In claim 164 both the PKKKRKV sequence and the cyclo sequences are present and each contain at least 4 enumerated amino acids. In claim 168 the cyclo amino acid has more than 4 specifically enumerated amino acids. In claim 169-170 it is both the PKKKRKV peptide as well as the cCPP peptide. It is noted that under ST.26 D-amino acids are considered specifically enumerated .
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
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 156-167 and 171 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 156 as currently written is vague and indefinite. Claim 156 claims a compound comprising a linker but the claim never indicates what the linker is linking. The * is indicated as point of attachment to the AAsc of the cCPP and M is indicated as a bonding group but the claim clearly shows three squiggly lines which typically stand for points of attachment. But the claim never clearly sets forth what the linker is linking other than to indicate the point of attachment to the cCPP. Claim 169-170 are not indefinite as they clearly indicates what groups are being linked by the linker.
Claim 164 as currently written is vague and indefinite. Focusing on the elected species: Ac-PKKKRKV-PEG₂-K(cyclo[FGFGRGRQ)-PEG₁₂-OH, this structure recites both K and Q. K is the amino acid symbol for Lysine which has the following structure:
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Q is the amino acid symbol for glutamine which has the following structure:
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. The instant specification teaches that this species is also PKKKRKVAEEA-K(cyclo[FGFGRGRQ])-PEG12-OH (Ac-SEQ ID NO: 132—K(cyclo[SEQ ID NO:82])-PEG12-OH) (page 126 of the specification). SEQ ID NO: 82 is taught in the instant specification as FGFGRGRQ. The K (lysine) corresponds to the portion of the linker which connects the cCPP but this structure as claimed doesn’t include the N from the side which is present in lysine. Ultimately to connect lysine and glutamine only one nitrogen is present in the formula below:
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. This creates confusion on the actual structure because K(cyclo[FGFGRGRQ]) suggests two nitrogens N-N (one from lysine and one from glutamine) but that is not what is shown in drawn out structure. It is noted that the instant specification does not describe a synthetic scheme for making the above compound to indicate how the final compound is formed. In order to form the B-4 structure above, the NH of lysine could be coupled to a C(O)OH with standard coupling procedures to form the amide bond. But without an actual discussion on how the compounds are made, the scope is unclear.
Claim 164 as currently written is additionally vague and indefinite. The claim recites wherein the EEV prior to conjugation comprises a sequence selected from….each species starts with Ac. The claim never defines what Ac means. AC is mentioned in claim 156 as corresponding to the antisense compound but the claim recites this is the sequence prior to conjugation which is presumably the conjugation to the oligonucleotide. Therefore, it isn’t clear what Ac is corresponding to.
Claims 156-163, 165-167 and 169are included in the rejection as they depend on a rejected base claim and they do not clarify the issues.
Claim Rejections - 35 USC § 112
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 156-167 and 169-171 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for attachment of the cCPP to the linker when the AAsc has reactive functionality like an amine or acid, does not reasonably provide enablement for attaching the cCPP to the linker when the AAsc is any amino acid. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims. This is a scope of enablement rejection.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Formal, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) the quantity of experimentation necessary,
2) the amount of direction or guidance provided,
3) the presence or absence of working examples,
4) the nature of the invention,
5) the state of the prior art,
6) the relative skill of those in the art,
7) the predictability of the art, and
8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The breadth of the claims, nature of the Invention, the amount of direction or guidance provided and the presence or absence of working examples
The claim is very broad insofar as it recites attachment of the cCPP to the linker at the AASc wherein the AAsc is any amino acid side chain. The instant specification provides no protocol for how the cCPP is connected to the linker except by showing an amide bond. Example 1 of the instant specification teaches that the cell-penetrating peptide is formulated using Fmoc chemistry and conjugated to the AC, for example, as described in PCT/US20/66459. This PCT corresponds to WO2021127650 (cited on PTO Form 1449). WO ‘650 discusses coupling between a terminal lysine and a CPP containing a glutamine through an amide bond (paragraph 0255). WO ‘650 repeatedly teaches that the linker comprises an amino acid (e.g. lysine) to facilitate chemical conjugation to the side chain of an amino acid on the cCCP (paragraph 0533). Looking at the instant claims, claim 164 in every conjugation it is lysine (K) to a glutamine (Q).
As indicated in the indefiniteness above,
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. This structure shows an amide bond between the linker and the cCPP. This could easily be formed between the NH of lysine and an amino acid with a side chain of C(O)OH which would create the NH-C(O). While the instant specification does not teach the specific reaction, the state of the art, Mindt et al. (Bioconjugate Chemistry, 2007) teaches that transglutaminases can be utilized to connect lysine and glutamine to form a C(O)-NH bond (fig. 1).
The Relative Skill Level, the State of the Prior Art and The Level of
Predictability in the Art
The invention relates to a compound in which a linker is covalently bonded to a cCPP. The relative skill of those in the art is high, that of an MD or PHD, a peptide chemist with experience in synthesizing chemical compounds. When the amino acid side is one that possessing a NH or a C(O)OH, OH or SH one skilled in the art would recognize that the cCPP could be coupled to a corresponding coupling group which is supported in WO ‘650. But the instant claims encompass the side chain of all amino acids. This scope includes glycine which just has a side chain of H, alanine which just has a methyl side chain, isoleucine which just has an alkyl side chain, etc. The specification does not teach one skilled in the art how to connect the cCPP which could have any amino acid chain, to the instantly claimed linker as claimed. One skilled in the art would readily recognizes that an NH and C(O)OH can be readily coupled as this is the chemistry that is utilized to connect two amino acids. But the state of the art does not teach how the side chain of amino acid such as glycine which is just a H can be coupled or otherwise covalently bonded to the linker as claimed.
The quantity of experimentation necessary
Because of the known unpredictability of the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that the instantly claimed cCPP with any amino acid side chain could be predictably used make the compound by covalently linking or coupling to the linker as inferred by the claim and contemplated by the specification. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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 156-167 and 169-171 are rejected under 35 U.S.C. 103 as being unpatentable over Qian et al. (WO2021127650, cited on PTO Form 1449) in view of Belayew et al. (USPGPUB No. 20120225034) and Wickstrom et al. (WO2009154804).
Applicant Claims
The instant application claims a compound comprising an endosomal escape vehicle comprising (1) a cyclic cell penetrating peptide or a protonated form or salt thereof; (b) an exocyclic peptide; (c) a linker and (d) a cargo which is an antisense compound which targets double homeobox 4 (DUX4) transcript. As elected the antisense compound is 345. The exocyclic peptide is PKKKRKV. As elected the cCPP is:
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which based on the election of claim 164, the AAsc is interpreted as glutamine.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Qian et al. is directed to compositions for delivery of antisense compounds. Claimed is a compound comprising (a) a cyclic cell penetrating peptide (cCPP) sequence and (b) an antisense compound (AC) that is complementary to a target sequence in a pre-mRNA sequence (claim 1). Claimed is a linker which conjugates the cCPP to the AC (claim 5) wherein the linker is covalently bound to the side chain of an amino acid on the cCPP (claim 6). As claimed the linker comprises one or more D or L amino acids which is optionally substituted (claim 8). The compound further comprises a nuclear localization signal (NLS) (claim 42). Coupling the NLS to the AC and the CPP is taught. The NLS can be attached to the CPP through a side chain of lysine which is conjugated to a side chain of glutamine in the CPP. The NLS can be coupled to a linker (paragraph 0255). Non limiting examples of nuclear localization sequences is the seven amino acid sequence PKKKRKV (paragraph 0188). Target nucleic acid include cellular gene whose expression is associated with a particular disorder or disease state (paragraph 0206). In some embodiments L comprise a polyethylene glycol moiety having from 1 to 50 ethylene glycol units and a lysine residue (paragraph 0262).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Qian et al. suggest the target nucleic acid includes a cellular gene whose expression is associated with a particular disorder or disease state, Qian et al. does not expressly teach SEQ ID NO: 345 or targeting DUX4 as claimed. However, this deficiency is cured by Belayew et al.
Belayew et al. is directed to agents useful in treating facioscapulohumeral muscular dystrophy. Claimed is an antisense agent capable of binding to the double homeobox 4 (DUX4) and/or double homeobox 4c (DUX4c) genes (claim 1). The antisense agent is between about 10 and about 100 nucleotides in length which is configured to bind at least about 10 bases of the DUX4 sequences (SEQ ID NO: 2, 4, 5, 6, 8) (claim 48). The antisense agent may be conjugated to a cell penetrating peptide to enhance the cellular uptake of the antisense agents (paragraph 0034; claim 43). Instantly claimed SEQ ID No:34 is complementary to SEQ ID NO: 2 of Belayew et al. as set forth below.
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While Qian et al teaches that in some embodiments L comprise a polyethylene glycol moiety having from 1 to 50 ethylene glycol units and a lysine residue and that lysine can be used to connect to glutamine on a CPP, Qian et al. does not expressly teach the claimed linker. However, this deficiency is cured by Wickstrom et al.
Wickstrom et al. is directed to twin fluorophore peptide nucleic acid hybridization probes. Taught are conjugates comprising a peptide nucleic acid oligomer connected at both ends through a peptidic linker linked to the same fluorophore (paragraph 0013). Peptidic linkers taught include AEEA-LYS-AEEA (paragraph 0020; claim 16). AEEA is 2-(2-aminoethoxy)ethoxyacetic acid (paragraph 0018).
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 Qian et al., Belayew et al. and Wickstrom et al. and utilize PKKKRKV as the NLS peptide. One skilled in the art would have been motivated to utilize this sequence as it is a specifically taught NLS peptide in Qian et al. and a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007).
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 Qian et al., Belayew et al. and Wickstrom et al. and utilize antisense oligonucleotide comprising about 10 and about 100 nucleotides in length which is configured to bind at least about 10 bases of the DUX4 sequences of SEQ ID NO: 2. One skilled in the art would have a reasonable expectation of success as Qian et al. teaches the oligonucleotide can target a gene with a particular disease state and Belayew et al. teaches oligonucleotide which targets DUX4 useful in treating facioscapulohumeral muscular dystrophy. As taught by Belayew et al. SEQ ID No: 2 is 100% complementary to instantly claimed SEQ ID No: 345.
Regarding the claimed linker, Wickstrom et al. teaches a linker of AEEA-LYS-AEEA. AEEA would have the structure:
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. The use of AEEA-LYS-AEEA would result in a linker of the instant claims wherein X’ of 1, Z’ of 1 and y of 4 and a M of C(O). Qian et al. teaches that the length of the PEG chains (i.e. the OCH2CH2O) can be varied from 1 to 50. 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 Qian et al., Belayew et al. and Wickstrom et al. and utilize an AEEA-LYS-AEEA linker as Qian et al. teaches the linker can comprise PEG and lysine and this linker is known for linking amino acids as taught by Wickstrom et al. In light of the teachings of Qian et al. one skilled in the art would have been motivated to manipulate the number of ethylene glycols. 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.
Regarding the claimed cyclic cell penetrating peptide, firstly, Qian et al. teaches that the CPP can be connected via a glutamine to a lysine, clearly providing motivation to utilize glutamine in the CPP. Qian et al. teaches that In some embodiments, the cCPP used in compounds described herein has a structure comprising Formula III:
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III wherein: each of AA1, AA2, AA3, and AA4, are independently selected from a D or L amino acid, each of AAu and AAz, at each instance and when present, are independently selected from a D or L amino acid, and m and n are independently selected from a number from 0 to 6; and wherein: at least two of AAu, when present, AA1, AA2, AA3, AA4, and AAz, when present, are independently arginine, and at least two of AAu, when present, AA1, AA2, AA3, AA4, and AAz, when present, are independently a hydrophobic amino acid (paragraph 0300). Hydrophobic amino acids include glycine and phenylalanine (paragraph 0301). It is taught that the presence of hydrophobic amino acids on the N- or C-terminal of a D- or L-Arg has found to improve the cytosolic uptake of the cCCP (paragraph 0311). The size of the hydrophobic amino acid on the N- or C-terminal of the D-Arg or an L-Arg, or a combination thereof (i.e., AAH1), may be selected to improve cytosolic delivery efficiency of the CPP. For example, a larger hydrophobic amino acid on the N- or C-terminal of a D-Arg or L- Arg, or a combination thereof, improves cytosolic delivery efficiency compared to an otherwise identical sequence having a smaller hydrophobic amino acid (paragraph 0312). This suggest including a larger hydrophobic amino acid such as phenylalanine (F) at the end. As taught Qian et al. at least two arginine are included. Based on the teachings of Qian et al. one skilled in the art would manipulate the remaining amino acids in order to achieve the desired hydrophobicity and consequently the desired cytosolic delivery efficacy of the CPP. Since the selection of the hydrophobic amino acid is to improve cytosolic delivery, one skilled in the art would have been motivated to choose from smaller and larger hydrophobic groups as taught by Qian et al. This would result in a cCPP of FGFGRGRQ which is the elected species.
Regarding claim 165, Qian et al. teaches that the AC is a phosphorodiamidate morpholino oligomer (PMO) (paragraph 0081). Belayew et al. also teaches a morpholino phosphorodiamidate-backbone nucleic acid (PMO) (paragraph 0160).
Regarding claim 166, Qian et al. teaches that hybridization of the AC with its target results in exon skipping and the skipped exon sequence comprises a frameshift mutation (paragraph 0033; 0345).
Regarding claim 171, Qian et al. teaches the compounds can be formulated into pharmaceutically acceptable composition which include a suitable carrier in order to facilitate effective administration (paragraph 0609).
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.
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Claims 156-167 and 169-171 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 141-162 of copending Application No. 18289944 (USPGPUB No. 20240247259) in view of Belayew et al. (USPGPUB No. 20120225034). 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 application claims a compound comprising an endosomal escape vehicle comprising (1) a cyclic cell penetrating peptide or a protonated form or salt thereof; (b) an exocylic peptide; (c) a linker and (d) a cargo which is an antisense compound which targets double homeobox 4 (DUX4) transcript.
Copending ‘944 claims a compound comprising an EEV comprising (a) a cyclic cell penetrating peptide; (b) an exocyclic peptide; (c) a linker and (d) an oligonucleotide which targets at least a portion of DUX4. The same cyclic penetrating peptide, the same exocyclic peptide and the same linker is claimed. Ac-PKKKRKV-PEG₂-K(cyclo[FGFGRGRQ)-PEG₁₂-OH is also claimed (claim 149).
While copending ‘944 claims targeting DUX4, copending ‘944 does not expressly claim SEQ ID NO: 345 as instantly claimed. However, this deficiency is cured by Belayew et al.
Belayew et al. is directed to agents useful in treating facioscapulohumeral muscular dystrophy. Claimed is an antisense agent capable of binding to the double homeobox 4 (DUX4) and/or double homeobox 4c (DUX4c) genes (claim 1). The antisense agent is between about 10 and about 100 nucleotides in length which is configured to bind at least about 10 bases of the DUX4 sequences (SEQ ID NO: 2, 4, 5, 6, 8) (claim 48). The antisense agent may be conjugated to a cell penetrating peptide to enhance the cellular uptake of the antisense agents (paragraph 0034; claim 43). Instantly claimed SEQ ID No:34 is complementary to SEQ ID NO: 2 of Belayew et al. as set forth below.
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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 ‘944 and Belayew et al. and utilize antisense oligonucleotide comprising about 10 and about 100 nucleotides in length which is configured to bind at least about 10 bases of the DUX4 sequences of SEQ ID NO: 2. One skilled in the art would have a reasonable expectation of success as copending ‘944 expressly claims an oligonucleotide which targets DUX4 and as taught by Belayew et al. SEQ ID No: 2 is 100% complementary to instantly claimed SEQ ID No: 345.
Claims 156-167 and 169-171 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of copending Application No. 18506057 (USPGPUB No. 20240245790) in view of Belayew 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 ‘057 claims a compound comprising (a) a cyclic cell penetrating peptide; (b) an exocyclic peptide; and (c) a linker. The same cyclic penetrating peptide, the same exocyclic peptide and the same linker is claimed. The compound is conjugated to a therapeutic moiety selected from an oligonucleotide, a peptide and a small molecule (claim 9). Ac-PKKKRKV-PEG₂-K(cyclo[FGFGRGRQ)-PEG₁₂-OH is also claimed (claim 18).
While copending ‘057 claims conjugating an oligonucleotide to the compound, copending ‘057 does not expressly claim SEQ ID NO: 345 as instantly claimed. However, this deficiency is cured by Belayew et al.
The teachings of Belayew 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 ‘057 and Belayew et al. and utilize antisense oligonucleotide comprising about 10 and about 100 nucleotides in length which is configured to bind at least about 10 bases of the DUX4 sequences of SEQ ID NO: 2 as the oligonucleotide conjugated to the compound. One skilled in the art would have a reasonable expectation of success as copending ‘057 expressly claims an oligonucleotide and as taught by Belayew et al. SEQ ID No: 2 is 100% complementary to instantly claimed SEQ ID No: 345 and these oligonucleotides can be conjugated to a cell penetrating peptide.
Claims 156-167 and 169-171 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 111-113, 116-117, 119-125, 132-133 and 135 of copending Application No. 18553379 (USPGPUB No. 20250243244) in view of Belayew 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 ‘379 claims a compound comprising (a) a cyclic cell penetrating peptide; (b) an exocyclic peptide; and (c) a linker. The same cyclic penetrating peptide, the same exocyclic peptide and the same linker is claimed. The compound is conjugated to a therapeutic moiety selected from an oligonucleotide, a peptide and a small molecule (claim 119).
While copending ‘379 claims conjugating an oligonucleotide to the compound, copending ‘379 does not expressly claim SEQ ID NO: 345 as instantly claimed. However, this deficiency is cured by Belayew et al.
The teachings of Belayew 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 ‘379 and Belayew et al. and utilize antisense oligonucleotide comprising about 10 and about 100 nucleotides in length which is configured to bind at least about 10 bases of the DUX4 sequences of SEQ ID NO: 2 as the oligonucleotide conjugated to the compound. One skilled in the art would have a reasonable expectation of success as copending ‘379 expressly claims an oligonucleotide and as taught by Belayew et al. SEQ ID No: 2 is 100% complementary to instantly claimed SEQ ID No: 345 and these oligonucleotides can be conjugated to a cell penetrating peptide.
Claims 156-167 and 169-171 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 100-124 of copending Application No. 18560080 (USPGPUB No. 20240358845) in view of Belayew 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 ‘080 claims a compound comprising (a) a cyclic cell penetrating peptide; (b) an exocyclic peptide; (c) a linker and (d) a therapeutic moiety. The same cyclic penetrating peptide, the same exocyclic peptide and the same linker is claimed. The therapeutic moiety is an antisense compound (claim 102). Ac-PKKKRKV-PEG₂-K(cyclo[FGFGRGRQ)-PEG₁₂-OH is claimed (claim 114).
While copending ‘080 claims conjugating an oligonucleotide to the compound, copending ‘080 does not expressly claim SEQ ID NO: 345 as instantly claimed. However, this deficiency is cured by Belayew et al.
The teachings of Belayew 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 ‘080 and Belayew et al. and utilize antisense oligonucleotide comprising about 10 and about 100 nucleotides in length which is configured to bind at least about 10 bases of the DUX4 sequences of SEQ ID NO: 2 as the antisense oligonucleotide conjugated to the compound. One skilled in the art would have a reasonable expectation of success as copending ‘080 expressly claims an oligonucleotide and as taught by Belayew et al. SEQ ID No: 2 is 100% complementary to instantly claimed SEQ ID No: 345 and these oligonucleotides can be conjugated to a cell penetrating peptide.
Claims 156-167 and 169-171 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 46-72 of copending Application No. 18858718 (USPGPUB No. 20250289851) in view of Belayew 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 ‘718 claims a method of making an endosomal escape vehicle comprising a cyclic cell penetrating peptide; an exocyclic peptide; (c) a linker. The same cyclic penetrating peptide, the same exocyclic peptide and the same linker is claimed. Conjugation to an oligonucleotide is claimed (72). Ac-PKKKRKV-PEG₂-K(cyclo[FGFGRGRQ)-PEG₁₂-OH is claimed (claim 68).
While copending ‘718 claims conjugating an oligonucleotide to the compound, copending ‘718 does not expressly claim SEQ ID NO: 345 as instantly claimed. However, this deficiency is cured by Belayew et al.
The teachings of Belayew 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 ‘718 and Belayew et al. and utilize antisense oligonucleotide comprising about 10 and about 100 nucleotides in length which is configured to bind at least about 10 bases of the DUX4 sequences of SEQ ID NO: 2 as the antisense oligonucleotide conjugated to the compound. One skilled in the art would have a reasonable expectation of success as copending ‘718 expressly claims an oligonucleotide and as taught by Belayew et al. SEQ ID No: 2 is 100% complementary to instantly claimed SEQ ID No: 345 and these oligonucleotides can be conjugated to a cell penetrating peptide.
Conclusion
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/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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