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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/21/2025 has been entered.
Application Status
This action is written in response to applicant’s correspondence received 05/25/2025. Claims 1-3, 6, 8-10, 13-20, 22 and 24-26 are currently pending. Claims 14, 16, 24 and 26 are withdrawn from prosecution as being drawn to non-elected subject matter. Accordingly, claims 1-3, 6, 8-10, 13, 15, 17-20, 22 and 25 are examined herein. The restriction requirement mailed 01/03/2024 is still deemed proper. Applicant elected the invention of group I (claims 1-3, 6, 8-10, 13-22 and 25); the species of a substituted or unsubstituted polyglycol as the covalent, first, and second spacers; a monophosphate as the first and second terminal moiety, and a TLR as a Toll-like receptor; without traverse in the reply filed 03/04/2024.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
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, 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:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
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, 6, 9-10, 13, 15, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over WIPO Publication 2015/077657 A1 to Kortylewski (published 05/28/2015, hereinafter ‘Kortylewski’) in view of Moreira (Moreira et al. Eliminating TLR9+ Prostate Cancer Stem Cells In Vivo Using NF-kB/RELA- or STAT3-Targeting CpG-siRNA Conjugates. Molecular Therapy Volume 23, Supplement 1, May 2015.) and Hecker & Wagner (Transcription factor decoy technology: A therapeutic update. Biochemical Pharmacology 144 (2017) 29-34.).
Regarding claim 1:
Kortylewski teaches a compound comprising a nucleic acid sequence capable of binding a TLR protein (TLR9) (p. 1 ln. 27-29):
We previously demonstrated that ligand for the intracellular receptor TLR9 (CpG ODN) allows for the delivery of oligonucleotides, such as siRNA, specifically to TLR9-positive target cells
Please see also FIG. 1A, which shows the nucleic acid compound comprising both the CpG ODN and STAT3 ODN.
In FIG. 1A, Kortylewski further teaches that the CpG ODN is covalently bound to another nucleic acid through a covalent spacer, x, which is a “single unit of a C3 carbon chain” (para [0234]). Kortylewski also teaches that the spacer
Kortylewski further teaches that the other nucleic acid to which the CpG ODN is bound is a decoy oligodeoxynucleotide capable of binding the transcription factor STAT3 (STAT3 dODN) (pp. 136-137, paras [0270-0271]).
Kortylewski further states that, “the limiting factor in the clinical application of dODNs is difficulty in their targeted delivery” (p. 1 ln 24-25). Their solution to the problem is the conjugation of the CpG ODN to the STAT3 dODN for delivery of the STAT3 dODNA to TLR9-positive cells (see above).
The difference between Kortylewski’s teachings and the claimed invention is that Kortylewski teaches a STAT3 dODN conjugated to a CpG ODN, while the claims encompass a NF-κB dODN conjugated to a CpG ODN.
Moreira teaches the TLR9-targeted delivery of CpG-siRNA conjugates targeting STAT3 or NF-κB:
We further demonstrated the feasibility of targeting prostate cancer-propagating potential in vivo by TLR9-targeted siRNA delivery using CpG-siRNA conjugates. Local administration of CpG-RELAsiRNA or CpG-STAT3siRNA but not control conjugates, inhibited tumor growth and cancer cell clonogenic potential in two xenotransplanted prostate cancer models. Selective elimination of tumor-propagating cells using TLR9-targeted blockade of NF-κB/RELA and STAT3 signaling has potential for clinical translation to benefit patients with late-stage prostate cancers.
Therefore, Moreira teaches that TLR9 is a target for delivery of nucleic acid therapeutics against STAT3 and/or NF-κB.
Moreira does not teach a nucleic acid capable of binding a NF-κB protein.
Hecker & Wagner teach that, “Inhibiting target gene expression (e.g., in oncogenes) or overexpression of target genes (e.g., tumour suppressor genes) in cancer is achieved through E2F, NF-κB, or STAT3 TFD ODNs” (p.32 §Preclinical and current therapeutic options) and teaches that several STAT3 and NF-κB ODNs were known in the art (Table 2).
Hecker & Wagner also teach that polyglycol (polyethylene glycol) linkers are a common structural modification that confers thermal stability and exonuclease resistance when conjugated to ODNs (Table 1).
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have substituted the STAT3 dODN in the CpG-ODN/STAT3-dODN construct, as taught by Kortylewski, with a NF-κB dODN with PEG spacers connecting the components, as taught by Hecker & Wagner. Based on Hecker & Wagner’s teachings that dODNs for these and other targets were well-known in the art, ne having ordinary skill could have substituted one dODN for the other, and the results would have been predictable . The ordinary artisan would have been motivated to make this substitution so by the combined teachings of all three references: Kortylewski teaches that the conjugation of a decoy ODN to a CpG ODN allows targeted delivery of the dODN to TLR9-positive cells; Moreira teaches that that delivery methods targeting TLR9-positive cells can be used to deliver therapeutics inhibiting STAT3 and/or NF-κB; and Hecker & Wagner teach that both NF-κB and STAT3 dODNs (comprising PEG spacers to confer increased stability) were well-known in the art for inhibiting STAT3 and NF-κB.
Regarding claim 2, Kortylewski and Hecker & Wagner render obvious substitution of Kortylewski’s spacers, including the first spacer between the two NF-κB binding sites, with a PEG spacer (linker), as discussed above.
Regarding claim 3, Kortylewski teaches wherein the TLR is TLR9, as discussed above.
Regarding claim 6, Kortylewski teaches that the second nucleic acid sequence comprises an unmethylated CpG motif, as discussed above (see also claim 19).
Regarding claims 9-10, FIG. 1A shows a plurality of phosphorothioate linkages in both ODNs.
Regarding claims 13 and 15, para [0193] of Kortylewski shows the following compound:
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Please note that the covalent and first spacers in the above compound comprise the claimed compound with a three-carbon alkyl chain.
Regarding claim 25, Kortylewski teaches a pharmaceutical composition comprising the nucleic acid of claim 1 (para [0006]).
Claims 8, 17-20 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Kortylewski, Moreira and Hecker & Wagner, as applied to claims 1-3, 6, 9-10, 13, 15, and 25 above, further in view of WIPO Publication WO 2017/181128 A1 to Guiducci (hereinafter Guiducci).
Kortylewski, Moreira and Hecker & Wagner render obvious the nucleic acid of claim 1, from which claim 8 depends.
Kortylewski, Moreira and Hecker & Wagner do not teach that the nucleic acid capable of binding a TLR comprises a polyglycol spacer.
Guiducci teaches CpG ODNs comprising multiple CpG motifs linked by hexaethylene glycol (HEG) spacers. Please refer to Table SI-1, para [0144], and in particular the D61 series of polynucleotide/chimeric compound structures (“referred to herein interchangeably as CpGs or CpG-ODNs (Id.)). As seen in e.g., FIG. 4, intratumoral administration of compounds comprising D61-01 successfully resulted in a reduction in tumor growth (para [0220]), giving the ordinary artisan a reasonable expectation that such a structure could be successfully synthesized and administered therapeutically.
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the nucleic acid construct of Kortylewski, Moreira and Hecker & Wagner, which comprises a CpG ODN, according to Guiducci’s teachings regarding the efficacy of CpG ODNs with multiple CpG motifs linked with HEG spacers, to predictably produce a CpG ODN with greater therapeutic efficacy.
Regarding claims 17 and 22, in para [0193], Kortylewski teaches a first terminal moiety covalently bound through a third spacer to the first nucleic acid sequence (the sequence capable of binding NF-kB), wherein the moiety is the alkyl-amino depicted in claim 22. The relevant portion is reproduced and annotated below:
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Please note that Kortylewski also teaches an alternative embodiment in which the first terminal moiety is a monophosphate (para [0303]).
Regarding claim 18, the third spacer comprises an embodiment of the claimed compound (see the structure reproduced above).
Regarding claim 19, Kortylewski teaches a second terminal moiety (-OH) covalently bound to the second nucleic acid sequence through a fourth spacer (covalent bond):
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Regarding claim 20, Kortylewski teaches wherein the fourth spacer has the claimed formula wherein z13 is 0 (para [0283)]:
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Response to Arguments
Applicant’s arguments with respect to claim(s) 1-3, 6, 8-10, 13, 15, 17-20, 22 and 25 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
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.
Claim 1-3, 6, 8-9, 17, and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12, 15-16, 18-20 and 24 of U.S. Patent No. 9,976,147 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because it would have been obvious to substitute the STAT-binding nucleic acid substituent with a NF-kB (substituent) dODN, with the same reasoning as that presented in the above rejection of the claims under 35 U.S.C. 103, mutatis mutandis. It is noted that claim 8 is considered obvious over the patented claims for the same reasoning presented in the rejection of that claim and its dependents, also above.
Pending Claims
Patented Claims
1. A compound comprising a first nucleic acid sequence capable of binding to Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-kB) protein and a second nucleic acid sequence capable of binding a Toll-like receptor (TLR) protein, wherein said first nucleic acid sequence and said second nucleic acid sequence are covalently bound through a covalent spacer, wherein said covalent spacer is a bond, a substituted or unsubstituted polyglycol, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
1. A compound comprising a toll-like receptor (TLR)-binding nucleic acid substituent conjugated to a signal transducer and activator of transcription (STAT)-binding nucleic acid substituent, wherein said STAT-binding nucleic acid substituent is capable of binding to a STAT transcription factor.
18. The compound of claim 5, further comprising a linker between the TLR9-binding DNA substituent and the STAT3-binding DNA substituent.
19. The compound of claim 18, wherein the linker is a substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
2. The compound of claim 1, wherein the first nucleic acid sequence capable of binding to NF-kBprotein comprises a first NF-kB protein binding site nucleic acid sequence and a second NF-kB protein binding site nucleic acid sequence connected through a first spacer, wherein said first spacer is a substituted or unsubstituted polyglycol, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
11. The compound of claim 5, wherein the STAT3-binding DNA substituent comprises a first STAT3-binding DNA sequence covalently bound to a second STAT3-binding DNA sequence by a spacer; and
said spacer is a substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
12. The compound of claim 11, wherein the spacer is a substituted or unsubstituted C1-C40 alkylene, substituted or unsubstituted 2 to 40 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted C6-C10 arylene, or substituted or unsubstituted 5 to 10 membered heteroarylene.
3. The compound of claim 1, wherein the Toll-like receptor protein is human Toll-like receptor 3, Toll-like receptor 7, Toll-like receptor 8, or Toll-like receptor 9.
6. (Original) The compound of claim 1, wherein the second nucleic acid sequence comprises an unmethylated CpG motif.
2. The compound of claim 1, wherein the TLR-binding nucleic acid substituent is an endosomal TLR-binding nucleic acid substituent.
3. The compound of claim 1, wherein the TLR-binding nucleic acid substituent conjugated to a STAT-binding DNA substituent is a nucleic acid sequence comprising SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, or SEQ ID NO:24.
4. The compound of claim 1, wherein the TLR-binding nucleic acid substituent conjugated to a STAT-binding DNA substituent is a nucleic acid sequence comprising SEQ ID NO:23.
5. A compound comprising a toll-like receptor 9 (TLR9)-binding DNA substituent conjugated to a signal transducer and activator of transcription 3 (STAT3)-binding DNA substituent, wherein said STAT3-binding nucleic acid substituent is capable of binding to a STAT3 transcription factor.
6. The compound of claim 5, wherein the TLR9-binding DNA substituent comprises a CpG motif.
7. The compound of claim 5, wherein the TLR9-binding DNA substituent comprises a Class A CpG DNA sequence, a Class B CpG DNA sequence or a Class C CpG DNA sequence.
8. The compound of claim 7, wherein the TLR9-binding DNA substituent is a Class A CpG DNA sequence.
9. The compound of claim 7, wherein the TLR9-binding DNA substituent is a Class B CpG DNA sequence.
10. The compound of claim 7, wherein the TLR9-binding DNA substituent is a Class C CpG DNA sequence.
9. The compound of claim 1, further comprising a phosphorothioate linkage in the first nucleic acid sequence or the second nucleic acid sequence.
20. The compound of claim 5, further comprising a phosphorothioate linkage
17. The compound of claim 8, further comprising a first terminal moiety that is covalently bound through a third spacer to the first nucleic acid sequence.
15. The compound of claim 5, wherein the STAT3-binding DNA substituent comprises a STAT3-binding DNA sequence covalently bonded to a terminal moiety; and
said terminal moiety is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
16. The compound of claim 15, wherein the terminal moiety is an R1-substituted C1-C40 alkyl, R1-substituted 2 to 40 membered heteroalkyl, R1-substituted C3-C8 cycloalkyl, R1-substituted 3 to 8 membered heterocycloalkyl, R1-substituted C6-C10 aryl, or R1-substituted 5 to 10 membered heteroaryl; and R1 is oxo, oxygen, a detectable moiety, or a therapeutic moiety.
25. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of claim 1.
24. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of claim 1.
Conclusion
No claim is allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA M ZAHORIK whose telephone number is (703)756-1433. The examiner can normally be reached M-F 8:00-16:00 EST.
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/A.M.Z./Examiner, Art Unit 1636
/BRIAN WHITEMAN/Primary Examiner, Art Unit 1636