DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1, 3-4, 7, 11-14, 16-17, and 25 are pending. Claims 14 and 16 were amended and claims 26-27, 40-41, 43, 45-46, 52, and 54 (directed to Groups II-III) were canceled in the Reply filed 11/14/2025.
Election/Restriction
Applicant’s election without traverse of Group I (claims 1, 3-4, 7, 11-14, 16-17, and 25, directed to products) and the species of Example 4 (PMO-P7, a.k.a. PMO-MACH 20, comprising SEQ ID NO: 75) in the reply filed on 11/14/2025 is acknowledged.
The originally elected species is understood to be the species of PMO-P7 as disclosed at Example 4 (see, e.g., Spec. filed 07/22/2022 at 66 at line 34 to page 67 at line 27). However, neither the Applicant nor the Specification appear to unambiguously identify the additional chemical moieties, bond orientations, etc. of the species of PMO-P7 (i.e., A’, R1, R2, R3, R4, R5, R6, R7, R8, Q, z, E’, L, G, L1, S, M, R10, etc. are not unambiguously identified in the response or in the originally filed disclosure with respect to PMO-P7 as used at Example 4). Accordingly, no single, unique species was actually identified, but rather it is understood that the Applicant has chosen to elect a narrow subgenus of patentably indistinct variants (i.e., obvious variants). However, Examiner notes that Applicant did identify that the species read upon claims 1, 3-4, 7, 11-13, 17, and 25, but did not read upon claims 14 or 16 (see, e.g., Reply filed on 11/14/2025 at 17). Accordingly, L is understood to be a “C(O)(CH2)1-6-C7-15-heteroaromatic-(CH2)1-6C(O)- moiety (see, e.g., instant claims 1 and 12); G is limited to H, C(O)(CH3), benzoyl, or stearoyl (see, e.g., instant claim 17), and wherein the peptide-oligonucleotide conjugate must have the general formula of either
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Wherein E’ is either H, C1-6 alkyl, -C(O)CH3, benzoyl, or stearoyl (see, e.g., instant claim 7); and wherein J is SEQ ID NO: 75 (KKKKKQBKKKHRWPKXXC, P7 or “MACH 20”). Accordingly, M, Q, R7, R8, etc. are absent from the originally elected, narrow subgenus of patentably indistinct species. The targeting sequence (i.e., nucleotide sequence) utilized in the originally elected subgenus is not specified, and is therefore understood to be generic (no SEQ ID NOs corresponding to nucleotides appear to be in the sequence listing). Accordingly, the originally elected subgenus of patentably indistinct species is understood to read upon instant claims 1, 3-4, 7, 11-13, 17, and 25, but to not read upon claims 14 or 16 (see, e.g., Reply filed on 11/14/2025 at 17).
Following extensive search and consideration, the originally elected subgenus of patentably indistinct species was deemed free of the prior art, wherein CAS NO. 2676914-13-7 (18-mer, KKKKKQBKKKHRWPKXXC; instant SEQ ID NO: 75) was deemed to be a point of novelty. Per MPEP § 803.02(III)
If the examiner determines that the elected species is allowable over the prior art, the examination of the Markush claim will be extended. If prior art is then found that anticipates or renders obvious the Markush claim with respect to a nonelected species, the Markush claim shall be rejected; claims to the nonelected species would still be held withdrawn from further consideration. The prior art search will not be extended unnecessarily to cover all nonelected species.
Accordingly, Examination was extended to a non-elected species of peptide-oligonucleotide conjugate falling withing the subgenera of compounds having either the general formula of
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Or
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wherein E’ is either H, C1-6 alkyl, -C(O)CH3, benzoyl, or stearoyl (see, e.g., instant claim 7); G is H, C(O)(CH3), benzoyl, or stearoyl (see, e.g., instant claim 17), L is “-C(O)(CH2)1-6-DBCO-(CH2)1-6C(O)-, and wherein J is either CAS NO. 2676914-07-9 (12-mer, KXKKQQGKKKHR; instant SEQ ID NO: 69); CAS NO. 2676914-08-0 (16-mer, KKKKKQBKKKHRWPMG; instant SEQ ID NO: 70); CAS NO. 2676914-09-1 (20-mer, KKKKNQBKKKHRWPMKXCPQ; instant SEQ ID NO: 71); CAS NO. 2676914-10-4 (14-mer, HKKKKQBKKKHRWP; instant SEQ ID NO: 72); CAS NO. 2676914-11-5 (9-mer, KXKHQQQXK; instant SEQ ID NO: 73); CAS NO. 2676914-12-6 (5-mer, KXKXT; instant SEQ ID NO: 74); CAS NO. 2676914-13-7 (18-mer, KKKKKQBKKKHRWPKXXC; instant SEQ ID NO: 75); CAS NO. 2676914-14-8 (18-mer, KKKKKCBKKKHRWPKXXQ; instant SEQ ID NO: 76); CAS NO. 2676914-15-9 (18-mer, KKKXKQBKKKHRWPKKXC; instant SEQ ID NO: 77); CAS NO. 2676914-16-0 (18-mer, KCHKXKWKKPKRXKQKBK; instant SEQ ID NO: 78); CAS NO. 2676914-17-1 (18-mer, KKKKKQCKKKHRWPKXXC; instant SEQ ID NO: 79); CAS NO. 2676914-18-2 (18-mer, KKKKKQBKKKHRWPKXXG; instant SEQ ID NO: 80); CAS NO. 2676914-19-3 (20-mer, KKKKKQBKKKHRWPMGKXXC; instant SEQ ID NO: 81); CAS NO. 2676914-20-6 (18-mer, HKKKKQBKKKHRWPKXXC; instant SEQ ID NO:82); CAS NO. 2676914-21-7 (13-mer, KXKHQQQXKKXXC; instant SEQ ID NO:83); CAS NO. 2676914-22-8 (9-mer, KXKXTKXXC; instant SEQ ID NO:84); CAS NO. 2676914-23-9 (24-mer, ALWKTLLKKVLKAPKKKRKVKXXC; instant SEQ ID NO:85); CAS NO. 2676914-24-0 (20-mer, RQIKIWFQNRRMKWKKKXXC; instant SEQ ID NO: 86); CAS NO. 2676914-25-1 (14-mer, KKKKKQBKKKHRWP; instant SEQ ID NO: 87); CAS NO. 2676914-26-2 (20-mer, KKKKKQBKKKHRWPKXXCCC; instant SEQ ID NO: 88); CAS NO. 2676914-27-3 (18-mer, KKKKKQBKKKHRWAKXXC; instant SEQ ID NO:89); CAS NO. 2676914-28-4 (8-mer, KXKHQQGP; instant SEQ ID NO: 90); CAS NO. 2676914-29-5 (10-mer, KXKHQQGKKT; instant SEQ ID NO: 91); CAS NO. 2676914-30-8 (13-mer, HKKKQQGKKKHRW; instant SEQ ID NO:92); CAS NO. 2676914-31-9 (15-mer, KKKKKQBKKKHRWPM; instant SEQ ID NO: 93); CAS NO. 2676914-32-0 (16-mer, KKKKKQGKKHRWPMGG; instant SEQ ID NO:94); CAS NO. 2676914-33-1 (19-mer, KKKKNQBKKK HRWPMKXCP; instant SEQ ID NO: 95); CAS NO. 2676914-34-2 (18-mer, KKKKKQBKKK HRWPKXXA; instant SEQ ID NO: 96); CAS NO. 2676914-35-3 (18-mer, KKKKKQBKKK HRWPKXAC; instant SEQ ID NO: 97); CAS NO. 2676914-36-4 (18-mer, KKKKKQBKKK HRWPKAXC; instant SEQ ID NO: 98); CAS NO. 2676914-37-5 (18-mer, KKKKKQBKKK HRWPAXXC; instant SEQ ID NO: 99); CAS NO. 2676914-38-6 (18-mer, KAKKKQBKKKHRWPKXXC; instant SEQ ID NO: 100); CAS NO. 2676914-39-7 (18-mer, KKKKKQBKAKHRWPKXXC; instant SEQ ID NO: 101); CAS NO. 2676914-40-0 (18-mer, KKKAKQBKKKHRWPKXXC ; instant SEQ ID NO: 102); CAS NO. 2676914-41-1 (18-mer, KKKAKQBKAKHRWPKXXC; instant SEQ ID NO: 103); CAS NO. 2676914-42-2 (18-mer, KAKAKQBKKK HRWPKXXC; instant SEQ ID NO: 104); or CAS NO. 2676914-43-3 (18-mer, KAKAKQBKAK HRWPKXXC; instant SEQ ID NO: 105). Following extensive search and consideration, these non-elected subgenera of patentably indistinct species were each deemed free of the prior art, wherein SEQ ID NOs: 69-105) were deemed to be a point of novelty. Examination was then extended to a non-elected species of
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wherein E’ is either H, C1-6 alkyl, -C(O)CH3, benzoyl, or stearoyl (see, e.g., instant claim 7); G is H, C(O)(CH3), benzoyl, or stearoyl (see, e.g., instant claim 17), L is “-C(O)(CH2)1-6-DBCO-(CH2)1-6C(O)-, and wherein J is “ALWKTLLKKVLKAPKKKRKV” (i.e., instant SEQ ID NO: 26, CAS NO. 714248-44-9). Following extensive search and consideration, this subgenera was deemed anticipated and/or obvious in view of the prior art as applied below.
Claims 14 and 16 are 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 without traverse in the reply filed on 11/14/2025.
Claims 1, 3-4, 7, 11-13, 17, and 25 are presently considered.
Information Disclosure Statement
The IDS filed 7/22/2022; 12/16/2024; 04/01/2025; 06/26/2025; and 11/14/2025 are acknowledged and presently considered.
Denial of Priority
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. 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) 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, US Provisional 62/965555 (filed 1/24/2020) 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.
The MPEP states that "[w]hile there is no in haec verba requirment, . . . . claim limitations must be supported in the specification through express, implicit, or inherent disclosure." See MPEP § 2163.
Lack of Express Support
Claim 1 is representative of the pending claim scope. Claim 1 does not literally appear in US Provisional 62/965555 (filed 1/24/2020), and therefore the claims lack literal support in the Pro’555.
More specifically, Pro’555 does not teach, disclose, nor identify SEQ ID NOs: 90-105 (i.e., P24 to P39) as recited at instant SEQ ID NO: 1.
Accordingly, Pro’555 fails to provide literal support for the pending claim scope that is synonymous or equivalent in scope.
Lack of Implicit or Inherent Support
The MPEP states that "[w]hile there is no in haec verba requirment, . . . . claim limitations must be supported in the specification through express, implicit, or inherent disclosure." See MPEP § 2163. In the absence of express support, the relevant issue is whether or not the claimed invention is supported by the priority document through implicit or inherent disclosures.
Upon review, zero inherent or implicit support commensurate in scope with the metes and bounds of the instant claims is found in Pro’555, at least because SEQ ID NOs: 90-105 (i.e., P24 to P39) do not literally, implicitly, or inherently appear in Pro’555 using either synonymous or equivalent language.
Accordingly, Pro’555 fails to provide implicit or inherent support for the pending claim scope that synonymous or equivalent in scope, or otherwise commensurate in scope with the pending claims.
Conclusion
Accordingly, priority to US Provisional 62/965555 (filed 1/24/2020) is denied for claim 1 and all of the dependents of those claims; these claims have been accorded a priority date of 1/06/2021, which corresponds to the filing date of US Provisional 63/134405 (filed 1/06/2021)
Claim Interpretation
For purposes of examination, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
Claim 1 is representative of the pending claim scope. Applicable claim interpretations are set forth below.
The limitations regarding “C” and “another C” have raised issues under 35 USC 112(b) as set forth below, and have necessitated an objection to claim 1 as set forth below. For purposes of applying prior art, the recitations of “C” and M are reasonably inferred to only be applicable to embodiments comprising SEQ ID NOs: 67-68.
Additional claim interpretations are set forth below.
Claim Objections
Claims 1 and 12 are objected to because of the following informalities:
Claim 1 recites underlined C’s (i.e., “C”) at claim 1 (see, e.g., SEQ ID NO: 67, 68, and page 10 of the claim set filed 11/14/2025 stating “C is covalently bound to another C by L1”). However, underlining is reserved for making amendments (see, e.g., 37 CFR §§ 1.121(b)(1)(ii)-(iii), 1.121(c)(2)-(3)), and any new or added claims “must be . . . presented in clean version, i.e., without any underlining” (see, e.g., 37 CFR § 1.121(c)(2)-(3)). Accordingly, claim 1 is not amended but not shown in a “clean version . . . without any underlining”, and is therefore objected.
Claim 12 recites the acronym “DBCO”, which should be completely spelled out at least once in the pending claim set.
Appropriate correction is required.
Specification
The disclosure is objected to because of the following informalities:
The Specification incorrectly identifies that colors are shown in the drawings (see, e.g., Spec. filed 4/01/2025 at 9 at lines 5-6, referring to “blue dots” at Figure 2; see id. at 10 at lines 33-35, referring to “blue” at Figure 14; see id. at 9 at line 10-11, referring to “green”). No colors are shown.
The instant disclosure is objected to for not complying with 37 C.F.R. 1.821 as detailed in MPEP §§ 2421–2424. Specifically, the instant application does not comply with 37 C.F.R. 1.821(b)-(e). The instant claims and/or disclosure contain references or disclosures of amino acid sequences that should be accompanied by a sequence listing and identified using "SEQ ID NOs” as prescribed (see, MPEP §§ 2421–2424). Specifically, the instant application discloses a sequence at page 61 at lines 15-16, which is not accompanied by a SEQ ID NO.
The specification recites underlined C’s (i.e., “C”) (see, e.g., Spec. filed 4/01/2025 at Table on 34, and Table 2 on 42). However, underlining is reserved for making and showing amendments (see, e.g., 37 CFR §§ 1.121(b)(1)(ii)-(iii), 1.121(c)(2)-(3), 1.125(c)), and the clean version of a specification should be “without markings” (see, e.g., 37 C.F.R. 1.125(c)), wherein “the full text” is shown “without underlining” (see, e.g., 37 CFR §§ 1.121(b)(1)(ii)-(iii)). Accordingly, the specification is objected because the clean specification continues to show underlining.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Appropriate correction is required.
Drawings
The drawings are objected to under 37 CFR 1.83(a) because they fail to show colors as described in the specification (see, e.g., Spec. filed 4/01/2025 at 9 at lines 5-6, referring to “blue dots” at Figure 2; see id. at 10 at lines 33-35, referring to “blue” at Figure 14; see id. at 9 at line 10-11, referring to “green”) and because Figure 16 is illegible. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Rejections
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-4, 7, 11-13, 17, and 25 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 1 recites “and C is covalently bound to another C” at page 10 of the claims filed 11/14/2025, and this renders the claim scope indefinite because “another C” lacks antecedent basis in the claims. Accordingly, there is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites “and C is covalently bound to another C” at page 10 of the claims filed 11/14/2025, and this renders the claim scope indefinite because it is unclear
(i) if the phrase “C is covalently bound to another C” at page 10 is only applicable to embodiments containing SEQ ID NOs: 67 or 68, which are shown as having one “C” residue at claim 1; or
(ii) if “C” if the phrase “C is covalently bound to another C” at page 10 is Applicable to all sequences at claim 1 (i.e., SEQ ID NOs: 26, 45, 57-105), sequences comprising at least one cysteine (e.g., SEQ ID NOs: 67-68, 71, 75-79, 81-86, 88-89, 95, and 97-105), only sequences having at least two cysteines (e.g., SEQ ID NOs: 67-68, 88), or sequences having three cysteines (e.g., SEQ ID NO: 88).
The relevant issue is that “C” is shown in an unamended claim as underlined, but underlining is reserved for amended claims (see, e.g., 37 CFR § 1.121(c)(2)-(3)), and therefore it is unclear if “C” refers only to some cysteines or to all cysteines. Clarification is required. For purposes of applying prior art, the limitations regarding “M” and “another C” are reasonably inferred to only be applicable to embodiments comprising SEQ ID NOs: 67-68.
Claim 1 recites “A peptide-oligonucleotide conjugate comprising a compound of Formula II”, which renders the claim scope indefinite because Formula II is explicitly defined within the body of claim 1, but “comprising” is open-ended, which raises concerns regarding the metes and bounds of the claim scope, because Formula II is fully defined. Accordingly, this usage of “comprising” renders the claim scope ambiguous because it is unclear if modified derivatives of Formula II (e.g., derivatives having additional modified positions, derivatives altering the ranges or lengths of enumerated variables, etc., etc. relative to Formula II) that do not satisfy the explicitly limitations, bond arrangements, and other specifically recited structural limitations within the body of claim 1, are excluded or included from the scope of the claims. Clarification is required. For purposes of applying prior art, claim 1 is limited to peptide-oligonucleotides of Formula II.
Claims 3-4, 7, 11-13, 17, and 25 are rejected as depending upon an indefinite base claim but failing to clarify or reconcile the indefiniteness of the base claim.
Accordingly, claims 1, 3-4, 7, 11-13, 17, and 25 are rejected.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-4, 7, 11-13, 17, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over WO2019/079386A1 (April 25, 2019; cited in IDS filed 7/22/2022) in view of Kim et al.1.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding rejection above, and also in a separate section above, and those discussions and interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
Regarding instant claims 1, 3-4, 7, 11-13, 17, and 25, WO’386 teaches, discloses and claims peptide-oligonucleotide conjugates having the general form of
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(see, e.g., WO’386 at claims 4-6; compare id. with instant claims 1, 3-4, and 7). Such prior art formulas are identical to those disclosed at instant claim 7, except that in the instant claims “J” is an entire peptide wherein in WO’386 “(J)t” represents individual amino acids (compare WO’386 at claims 4-6 with instant claim 7, noting that Formulas (Ia) and (Ib) are equivalent in both claim sets). Regarding “G” in Formulas (Ia) and (Ib), WO’386 identifies that “G” may be is H, C(O)(CH3), benzoyl, or stearoyl (compare WO’386 at claims 1 and 13 with instant claims 1 and 17). Regarding “E’” in Formulas (Ia) and (Ib), WO’386 identifies that E’ is either H, C1-6 alkyl, -C(O)CH3, benzoyl, or stearoyl (compare WO’386 at claims 1 and 4 with instant claims 1 and 7). Regarding “L” in Formulas (Ia) and (Ib), WO’386 identifies that L is any “C(O)(CH2)1-6-C1-6-heteroaromatic-(CH2)1-6C(O)- moiety (see, e.g., WO’386 at claims 1, 4, 11-12). Regarding J or (J)t in Formulas (Ia) and (Ib), WO’386 identifies that J or (J)t may be ALWKTLLKKVLKAPKKKRKV or RQIKIWFQNRRMKWKK (compare WO’386 at claim 1 and 15 with instant claim 1 and SEQ ID NOs: 26 and 45). Regarding “R1” in Formulas (Ia) and (Ib), WO’386 identifies that R1 may be independently selected at each occurrence from OH
-NR3R4, wherein each R3 and R4 are, independently at each occurrence, -C1-6-alkyl, and wherein R1 may specifically be N(CH3)2 (see, e.g., WO’386 at claims 1 and 9; compare id. with instant claim 1 at instant R1). Regarding “R2” and “z” in Formulas (Ia) and (Ib), WO’386 provide the same definitions for each of R2 and z (compare WO’386 at claim 1 with instant claim 1), wherein WO’386 specifically identifies that z may be 8-40 (compare WO’386 at claim 1 with instant claim 1), and wherein WO’386 specifically identifies that R2 is a nucleobase, independently selected at each occurrence, selected from adenine, guanine, cytosine, 5-methyl-cytosine, thymine, uracil, and hypoxanthine (compare WO’386 at claims 1 and 10 with instant claims 1 and 11). Regarding instant claim 25, WO’386 explicitly teaches and claims pharmaceutical compositions comprising the disclosed compounds suitable for use in in vivo and in vitro applications (see, e.g., WO’386 at claims 17-18).
The primary reference of WO’386 differs from the instant claims as follows: The prior art genera, subgenera, and species only differ from instant claims 1 and 12-13, namely they differ with respect to a subcomponent of the variable “L” in Formulas (Ia) and (Ib). Specifically, WO’386 identifies that L is any “-C(O)(CH2)1-6-C1-6-heteroaromatic-(CH2)1-6C(O)-” moiety (e.g., Triazole), but the instant claims require that L is “-C(O)(CH2)1-6-C7-15-heteroaromatic-(CH2)1-6C(O)-” (e.g., DBCO), and therefore the scope of claims WO’386 differs from instant claim 1 because the range of sizes of heteroaromatic groups differ by a single carbon moiety or otherwise the substitution of DBCO in place of Triazole. Therefore, the relevant issue is whether or not a single carbon difference between C1-6 and C7-15 heteroaromatic moieties in the middle of a linker (or otherwise the simple substitution of DBCO in place of Triazole) is sufficient to patentably distinguish the disclosure of WO’386 from the instant claims.
The difference in heteroaromatic moiety size does not appear to relate to functionality: WO’386 does not teach that the size limitation of the heteroaromatic moiety within “L” serves any critical function, but rather exemplifies C1-9 heteroaryl moieties among others (see, e.g., WO’386 at 6 at line 14 to page 7 at line 8). Accordingly, the claimed compounds appear to be substantially identical, structurally and functionally to the prior art compounds disclosed by WO’386 (see, e.g., MPEP § 2144.05(I), explaining that “a prima facie obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close”, and noting that here the prior art range of C1-6 is as close as possible to C7-15 without actually overlapping; see also MPEP § 2144.09(I)-(II), explaining that “a prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities”, such as when compounds merely differ by the “successive addition of the same chemical group, e.g., by -CH2- groups)”).
Regarding instant claims 1, 12-13, and the usage of DBCO in place of triazole in the linker of “L” in Formulas (Ia) and (Ib), WO’386 exemplifies that the linker “L” may be “-C(O)(CH2)1-6-triazole-(CH2)1-6C(O)-” (see, e.g., WO’386 at 19 at lines 19-23, claims 1, 4, 11-12). In view of Kim, an artisan would readily appreciate that a triazole moiety results from click chemistry reactions, namely copper-catalyzed [3+2]azide-alkyne cycloaddition (see, e.g., Kim at title, abs, Table 1 at 7836). However, Kim identifies that such reactions have art-recognized problems, namely that such reactions require a “toxic copper catalyst” (see id), which “restricts the in vitro or in vivo application of CuAAC reactions” (see, e.g., Kim at 7835-7836 at § Introduction; see esp. id. at 7836 at col I at 1st full ¶ to col II at final ¶). Kim identifies an art-recognized solution, namely strain-promoted azide–alkyne cycloaddition reactions (SPAAC) that permit azide-alkyne reactions “without the need for a cytotoxic copper catalyst” (see, e.g., Kim at 7836 at Table 1, 7836 at col I at 4th full ¶ to col II at final ¶). Kim identifies and discloses that “Dibenzocyclooctyne (DBCO)” is “representative of strained cyclic ring-containing alkynes for SPAAC” (see id).
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(Table above modified from Table 1 of Kim). Kim reasonably informs artisans that a representative CuAAC reaction, utilizing cytotoxic copper catalyst, would form a trizole-containing linkage:
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(see, e.g., Kim at Table 1 at 7836), as present in the exemplified linkers of WO’386 (see, e.g., WO’386 at 19 at lines 19-23, claims 1, 4, 11-12). Kim reasonably informs artisans that an equivalent click chemistry reaction results in a DBCO-containing linkage:
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(see, e.g., Kim at Table 1 at 7836), which are present in the instantly claimed embodiments (see, e.g., instant claims 12-13). Accordingly, an artisan would readily appreciate that such linkers were functional equivalents for the purpose of linking moieties via “click chemistry reactions”, and readily understand that triazole and DBOC moieties result from different click chemistry reactions (CuAAC vs SPAAC), wherein each such click chemistry reaction has different pros and cons known in the prior art (see, e.g., Kim at Table 1 at 7836, listing out pros and cons of each approach). Specifically, an artisan wanting to make and utilize the compounds of WO’386 for use in in vitro or in vivo applications would simply substitute a CuAAC reaction for a SPAAC reaction, which would avoid the usage of a cytotoxic copper catalyst, and would predictably and expectedly result in the same exact compounds claimed and taught by WO’386, except wherein the triazole within linker “L” was simply substituted for DBOC.
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): The claimed invention results the simple substitution of an equivalent “click chemistry reaction” (SPAAC in place of CuAAC) to create the compounds of WO’386, wherein such simple substitution would predictably and expectedly result in compounds of WO’386 having an “L” moiety of “-C(O)(CH2)1-6-DBOC-(CH2)1-6C(O)-” rather than “-C(O)(CH2)1-6-Triazole-(CH2)1-6C(O)-” (see, e.g., MPEP §§ 2144.06(II), 2143(I)(B)), and wherein such compounds would advantageously and predictably be usable in in vivo and in vitro applications since SPAAC reactions do not require a cytotoxic copper catalyst (see, e.g., MPEP §§ 2143(I)(G)). Furthermore, such compounds are the combination of only known components according to known methods (i.e., click chemistry methods and methods of making conjugates per WO’386), wherein each individual component merely performs its art-recognized function in combination as it does separately (see, e.g., MPEP §§ 2143(I)(A)).
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the art to utilize known reactions and known reagents to form known compounds having DBOC in place of triazole, because such click chemistry reactions were well-understood in the prior art.
Claims 1, 3-4, 7, 11-13, 17, and 25 are rejected.
Claims 1, 3-4, 7, 11-13, 17, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Wolfe et al.2 in view of Pickens et al.3.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding rejection above, and also in a separate section above, and those discussions and interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
Regarding instant claims 1, 3-4, 7, 11-13, 17, and 25, Wolfe teaches and discloses phosphorodiamidate morpholino oligonucleotides (PMOs) conjugated to cell-penetrating peptides (CPPs) using click chemistry (see, e.g., Wolfe at title, abs, Fig. 1(A) on 513, Table 1 on 514-515, Fig. 2A on 515, and 513 at col II at 1st full ¶). Regarding instant claims 1, 3-4, 7, 11-13, 17, and 25, Wolfe teaches and discloses compounds having the general form of:
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(see, e.g., Wolfe at Fig. 2B on 515), wherein the oligonucleotide sequence (shown in boxed letters) is understood to be morpholino having the backbone structure of
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(see, e.g., Wolfe at Fig. 1A on 513). Accordingly, regarding instant claims 1, 3-4, 7, 11-13, and 17, this compound satisfies instant Formula II and Formula Ia wherein: A’ is
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(compare Wolfe at Fig. 1A and 2B on 513-514 with instant claims 1, 3, 7); R1 is -N(CH3)2 (compare Wolfe at Fig. 1A and 2B on 513-514 with instant claim 1); z is 18 (compare Wolfe at Fig. 1A and 2B on 513-514 with instant claim 1); R2 is a nucleobase in each instance as shown in the oligo at Figure 2B (compare Wolfe at Fig. 1A and 2B on 513-514 with instant claims 1, 11); E’ is
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as present in instant Formula I(a) (compare Wolfe at Fig. 1A and 2B on 513-514 with instant claims 1, 4, 7); L is a linker having the structure of “-C(O)(CH2)4-Triazole-(CH2)2C(O)-” (compare Wolfe at Fig. 1A and 2B on 513-514 with instant claims 1, 4, 7, 12-13); J is a Cell-Penetrating Peptide (CPP), namely ALWKTLLKKVLKAPKKKRKV or RQIKIWFQNRRMKWKK (compare Wolfe at Fig. 1A and 2B on 513-514, Table 1 on 514-515 with instant claims 1, 7, and SEQ ID NOs: 26 and 45); and G is hydrogen (compare Wolfe at Fig. 1A and 2B on 513-514 with instant claims 1, 7, 17). Regarding instant claim 25, Wolfe teaches and discloses that the PMO-CPP conjugates were tested in functional in vitro assays, and therefore an artisan would appreciate that the PMO-CPP conjugates were necessarily formulated with pharmaceutically acceptable excipients required for in vitro testing, and therefore an artisan would at once envision such compounds in pharmaceutical formulations (see, e.g., Wolfe at title, abs, 513 at col II at final ¶, Fig. 3A on 516).
The primary reference differs from instant claims 1 and 12-13 as follows: The prior art species only differ from instant claims 1 and 12-13 with respect to the “L” component, because Wolfe discloses compounds comprising a “-C(O)(CH2)4-Triazole-(CH2)2C(O)-” linker, but the instant claims require that L is a species of “-C(O)(CH2)1-6-C7-15-heteroaromatic-(CH2)1-6C(O)” such as “-C(O)(CH2)4-DBCO-(CH2)2C(O)-”. Therefore, the relevant issue is whether or not it would have been obvious to utilize DBCO in place of Triazole in the PMO-CPP conjugates taught by the prior art.
Wolfe teaches and discloses PMOs conjugated to cell-penetrating peptides (CPPs) using click chemistry, which results in the formation of a triazole present in the linker of the PMO-CPP conjugates (see, e.g., Wolfe at title, abs, Fig. 1(A) on 513, Table 1 on 514-515, Fig. 2A on 515, and 513 at col II at 1st full ¶). Pickens informs artisans about different click chemistry approaches (see, e.g., Pickens at title, abs, Table 1 on 687, passim). Pickens identifies that triazole-forming CuAAC reactions have art-recognized problems, namely that CuAAC reactions need toxic copper catalysts that oxidize amino acids and have a “toxic effect” on cells (see, e.g., Pickens at 687 at col II at 1st partial to 1st full ¶¶, Table 1 on 687). Pickens identifies an art-recognized solution, namely a strain-promoted azide–alkyne cycloaddition reactions (SPAAC) that permit azide-alkyne reactions, but without the need for a cytotoxic copper catalyst (see, e.g., Pickens at 687 at col II at 1st partial to 1st full ¶¶, Table 1 on 687). Therefore an artisan would be reasonably directed to make and use SPAAC reactions and reagents in place of CuAAC reactions and reagents in order to predictably and expectedly reduce the toxicity of the compounds produced by “click chemistry”. Pickens teaches that DBCO heterobifunctional linkers were commercially available circa 2018: Pickens teaches that DBCO-COOH was a commercially available heterobifunctional linker suitable for use in SPAAC reactions
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(see, e.g., Pickens at Table 1 on 687, Fig. 3 on 689). Pickens provides general guidance regarding the resulting structural differences between CuAAC and SPAAC reactions: Pickens exemplifies that a DBCO-PEG linker (see, e.g., Pickens at Table 1 on 687, Fig. 3 on 689) would result in a compound of form
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wherein the usage of a CuAAC agent would result in a Triazole containing linker
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(see, e.g., Pickens at Table 1 on 687, Fig. 3 on 689, Fig. 4 on 693; images modified from Fig. 4 on 693). In sum, in view of Pickens, an artisan would readily appreciate that DBCO and Triazole containing linkers were indicative of equivalent “click chemistry” reactions, that DBCO heterobifunctional linkers were commercially available, and that SPAAC reactions forming DBCO containing linkers were advantageous for in vivo and in vitro applications because they avoided the usage of cytotoxic copper catalysts.
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): The claimed invention results the simple substitution of an equivalent “click chemistry reaction” (SPAAC in place of CuAAC) using only known reagents to create the PMO-CPP compounds of the primary reference, wherein such simple substitution would predictably and expectedly result in PMO-CPP compounds advantageously having a “-C(O)(CH2)4-DBCO-(CH2)2C(O)-” linker rather than a “-C(O)(CH2)4-Triazole-(CH2)2C(O)-” linker, (see, e.g., MPEP §§ 2144.06(II), 2143(I)(B)), and wherein such SPAAC formed PMO-CPP compounds would advantageously avoid the usage of cytotoxic copper catalysts and therefore be predicted to be less toxic in in vitro and in vivo applications (see, e.g., MPEP §§ 2143(I)(G)). Furthermore, such PMO-CPP compounds as claimed are the combination of only known components (e.g., known PMOs, CPPs, linkers) according to known methods (i.e., click chemistry methods using SPAAC), wherein each individual component merely performs its art-recognized function in combination as it does separately (see, e.g., MPEP §§ 2143(I)(A)).
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the art to utilize known reactions and known reagents to form known PMO-CPP compounds having different linkers, including linkers utilizing DBOC in place of triazole, because such click chemistry reactions were well-understood in the prior art.
Claims 1, 3-4, 7, 11-13, 17, and 25 are rejected.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US12168059 (corresponding to US Application 17/264,163 and US20210290772) pertains to related trimeric peptide-oligonucleotide conjugates as presently claimed, but require three peptides conjugated by specific linkers resulting in structures that are not presently claimed (compare instant claims with US’059 at claims).
US12370261 pertains to related PMO-CPP conjugates, but requires a different linker L as well as a different CPP sequence relative to the instant claims (compare instant claims with US’261 at claims).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RANDALL L BEANE whose telephone number is (571)270-3457. The examiner can normally be reached Mon.-Fri., 7 AM to 2 PM ET.
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/RANDALL L BEANE/ Primary Examiner, Art Unit 1654
1 Kim et al., Biomedical applications of copper-free click chemistry: in vitro, in vivo, and ex vivo. Chem Sci. 2019 Aug 16;10(34):7835-7851. doi: 10.1039/c9sc03368h. PMID: 31762967; PMCID: PMC6855312; hereafter “Kim”.
2 Wolfe et al., Machine Learning To Predict Cell-Penetrating Peptides for Antisense Delivery. ACS Cent Sci. 2018 Apr 25;4(4):512-520. doi: 10.1021/acscentsci.8b00098. Epub 2018 Apr 5. PMID: 29721534; PMCID: PMC5920612; hereafter “Wolfe”.
3 Pickens et al., Practical Considerations, Challenges, and Limitations of Bioconjugation via Azide-Alkyne Cycloaddition. Bioconjug Chem. 2018 Mar 21;29(3):686-701. doi: 10.1021/acs.bioconjchem.7b00633. Epub 2018 Feb 1. PMID: 29287474; PMCID: PMC6310217; hereafter “Pickens”.