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 .
DETAILED ACTION
This Office Action is a response to Applicant’s Amendment and Remarks filed July 29, 2026.
New claim 49 is acknowledged. Claim 29 has been amended.
Claims 29-39 and 41-49 are pending in the instant application.
Accordingly, claims 29-39 and 41-49 have been examined on the merits as detailed below:
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Non-Statutory Double Patenting
In the previous Office Action mailed July 2, 2026, claim 29 was rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 11, 15, 16, and 25-45 of copending U.S. Application 17/914,307. This rejection is maintained for the reasons of record set forth in the previous Office Action mailed July 2, 2026.
Response to Applicant’s Arguments
In response to this rejection, Applicant note that the rejection is provisional in nature and will address the obviousness-type double patenting rejection upon indication that the claims are otherwise allowable.
The Examiner acknowledges Applicant’s note and maintains that the claims of copending U.S. Application 17/914,307 overlaps in scope and fully embraces that which is claimed in the instant invention. The rejection is maintained.
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In the previous Office Action mailed July 2, 2026, claim 29 was rejected on the ground of nonstatutory double patenting as being unpatentable over claim 31 of copending U.S. Application 17/920,769. This rejection is maintained for the reasons of record set forth in the previous Office Action mailed July 2, 2026.
Response to Applicant’s Arguments
In response to this rejection, Applicant note that the rejection is provisional in nature and will address the obviousness-type double patenting rejection upon indication that the claims are otherwise allowable.
The Examiner acknowledges Applicant’s note and maintains that the claim of copending U.S. Application 17/920,769 overlaps in scope and fully embraces that which is claimed in the instant invention. The rejection maintained.
Claim Rejections - 35 USC § 102
In the previous Office Action mailed July 2, 2026, claims 29, 30, 37, 41, 42, 43, 45 and 46 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2011126937 A1 as evidenced by Google AI Overview, how many daltons is anisamide? - Google Search downloaded on January 22, 2026. This rejection is withdrawn in view of Applicant’s Amendment to the claims filed July 29, 2026.
Claim Rejections - 35 USC § 103
In the previous Office Action mailed July 2, 2026, claims 29-31, 37-39 and 41-48 were rejected under 35 U.S.C. 103 as being unpatentable over WO 2011126937 A1. This rejection is withdrawn in view of Applicant’s Amendment to the claims filed July 29, 2026.
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In the previous Office Action mailed July 2, 2026, claims 29 and 32 were rejected under 35 U.S.C. 103 as being unpatentable over WO 2011126937 A1 as evidenced by Hong et al. (Cancer Res. 2023 Mar 15;83(6):845-860). This rejection is withdrawn in view of Applicant’s Amendment to the claims filed July 29, 2026.
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In the previous Office Action mailed July 2, 2026, claims 29 and 33-36 were rejected under 35 U.S.C. 103 as being unpatentable over WO 2011126937 A1 in view of Sardar et al. (J Hematol. 2019;8(1):1-10). This rejection is withdrawn in view of Applicant’s Amendment to the claims filed July 29, 2026.
Applicant’s Amendment filed July 29, 2026 necessitated a new grounds of rejection as presented below:
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.
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 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 29-31, 37-39 and 41-49 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2011126937 A1 (hereinafter, “’937”) (submitted and made of record in the Office Action filed January 29, 2026) in view of Aartsma-Rus et al. (Molecular Therapy, Volume 17, Issue 3, March 2009, Pages 548-553, plus Supplemental Data) or Shao et al. (Nucleic Acids Research, 2006, Vol. 34, No. 19, pages 5660-5669).
The claims are drawn to a synthetic bifunctional molecule comprising: a first domain comprising an antisense oligonucleotide (ASO), wherein the first domain specifically binds to an RNA sequence of a target ribonucleic acid (RNA); a second domain comprising a small molecule having a molecular weight of 900 daltons or less, wherein the second domain specifically binds to a target polypeptide; and a linker that conjugates the first domain to the second domain, wherein the ASO comprises a sequence comprising 36% to 56% GC content.
‘937 teaches targeted intracellular delivery of antisense oligonucleotides (AON) via conjugation with small molecule ligands. See Abstract, pages 1-4, 23, and 59-66 and Figure 1, for example. The ligand is coupled to the antisense oligonucleotide through a linking group, wherein the linker is conjugated at the 5’ end of the AON. A particular antisense oligonucleotide (Oligo 623) having 2’-O-methyl RNA with a phosphorothioate backbone was conjugated (via diethylene glycol linker) to an anisamide, high affinity ligand for sigma receptors. See page 49. NOTE: Anisamide is 151 daltons as evidenced by Google AI Overview, how many daltons is anisamide? - Google Search downloaded on January 22, 2026. AONs of ‘937 are 20 nucleotides in length. See Oligo 623, for example.
‘937 also teaches that upon adequate delivery of Oligo 623 to the nucleus, the intron is spliced out and luciferase is expressed.
‘937 teaches several dozen embodiments in which the antisense oligonucleotide of their invention silences targeted genes (e.g. Erb-B; JNK; JUN; EGFR; Cyclin E; PKC; NFKB, Ras, MEKK, Raf, MYB, etc.), and mutations in tumor suppressor genes, thus treating a subject having a disease or disorder.
‘937 does not necessarily teach the AON of their invention comprises a sequence comprising 36% to 56% GC content.
Aartsma-Rus et al. teach guidelines for antisense oligonucleotide design. Aartsma-Rus et al. teach antisense are usually designed as 18-22 mers with a 40%-60% GC content. See Tables, plus Supplemental Data.
Shao et al. teach a rational design and rapid screening of antisense oligos. Shao et al. teach for stability of the oligo or the oligo:target duplex, the GC content ranges from 40 to 65%, with an average of 55%.
Also, ‘937 teach the diethylene glycol linker, but does not teach the linker comprising the structures in present claim 31. However, a person of ordinary skill in the art would have been motivated to substitute the diethylene glycol linker of ‘937 with the linker comprising the structures in present claim 31 as presently claimed since they are functional equivalents of each other, and it is obvious to substitute one functional equivalent for another, particularly when they are to be used for the same purpose. See MPEP 2144.06.
Furthermore, KSR forecloses that the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. See Board Decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d). Also, see M.P.E.P. §2144.07 which states, "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06.
‘937 teach AONs comprising 2’-O-methyl RNA with a phosphorothioate backbone, but does not teach locked nucleosides as recited in present claims 38 and 39. However, a person of ordinary skill in the art would have been motivated to substitute the ASO chemical modifications which confer oligonucleotide stability of ‘937 with the ASO chemical modifications which confer oligonucleotide stability recited claims 38 and 39 as presently claimed since they are functional equivalents of each other, and it is obvious to substitute one functional equivalent for another, particularly when they are to be used for the same purpose. See MPEP 2144.06.
Furthermore, KSR forecloses that the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. See Board Decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d). Also, see M.P.E.P. §2144.07 which states, "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06.
Before the effective filing date of the claimed invention, it would have been prima facie obvious to devise a synthetic bifunctional molecule comprising: a first domain comprising an antisense oligonucleotide (ASO), wherein the first domain specifically binds to an RNA sequence of a target ribonucleic acid (RNA); a second domain comprising a small molecule having a molecular weight of 900 daltons or less, wherein the second domain specifically binds to a target polypeptide; and a linker that conjugates the first domain to the second domain as taught and suggested by ‘937.
Starting from Oligo 623 and looking to further stabilize the oligonucleotide, a person of ordinary skill in the art would have been motivated to modify the teachings of ‘937 to have the AON comprise a sequence comprising 36% to 56% GC content as Aartsma-Rus et al. and Shao et al. teach, for stability of the oligo or the oligo:target duplex, the optimum GC content for an antisense oligonucleotide generally ranges between 40% and 60%, with an average of 55%.
It would have been obvious and one of skill in the art would have expected reasonable success to chemically modify the ASO for the purpose of increasing stability of the ASO and for the purpose of increasing delivery of the oligonucleotide as taught by ‘937.
Therefore, the subject matter of claims 29-31, 37-39 and 41-49 is obvious over WO 2011126937 in view of Aartsma-Rus et al. or Shao et al.
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Claims 29 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2011126937 A1 (hereinafter, “’937”) in view of Aartsma-Rus et al. (Molecular Therapy, Volume 17, Issue 3, March 2009, Pages 548-553, plus Supplemental Data) or Shao et al. (Nucleic Acids Research, 2006, Vol. 34, No. 19, pages 5660-5669) and evidenced by Hong et al. (Cancer Res. 2023 Mar 15;83(6):845-860). NOTE: ‘937 and Hong et al. have been submitted and made of record in the Office Action filed January 29, 2026.
‘937 is relevant and relied upon in its entirety as discussed supra. Specifically, ‘937 teaches targeted intracellular delivery of antisense oligonucleotides (AON) via conjugation with small molecule ligands.
Also, Aartsma-Rus et al. and Shao et al. are relevant and relied upon in their entirety as discussed supra.
‘937 teach an exemplary small organic molecule includes tegaserod, for example. NOTE: Tegaserod targets the YTHDF1 polypeptide as evidenced by Hong et al. Also NOTE: Tegaserod has a molecular weight of 302 daltons as evidenced by Wikipedia – Tegaserod, downloaded from Tegaserod - Wikipedia on June 30, 2026.
Before the effective filing date of the claimed invention, it would have been prima facie obvious to devise a synthetic bifunctional molecule comprising: a first domain comprising an antisense oligonucleotide (ASO), wherein the first domain specifically binds to an RNA sequence of a target ribonucleic acid (RNA); a second domain comprising a small molecule having a molecular weight of 900 daltons or less, wherein the second domain specifically binds to a target polypeptide; and a linker that conjugates the first domain to the second domain as taught and suggested by ‘937.
Starting from Oligo 623 and looking to further stabilize the oligonucleotide, a person of ordinary skill in the art would have been motivated to modify the teachings of ‘937 to have the AON comprise a sequence comprising 36% to 56% GC content as Aartsma-Rus et al. and Shao et al. teach, for stability of the oligo or the oligo:target duplex, the optimum GC content for an antisense oligonucleotide generally ranges between 40% and 60%, with an average of 55%.
It would have been obvious and one of skill in the art would have expected reasonable success to chemically modify the ASO for the purpose of increasing stability of the ASO and for the purpose of increasing delivery of the oligonucleotide as taught by ‘937.
A person of ordinary skill in the art would have expected reasonable success to make and use the synthetic bifunctional molecule comprising ASO and tegaserod as the small molecule since ‘937 teaches synthetic bifunctional molecules have been developed and successfully tested for in vitro or in vivo use.
Therefore, the subject matter of claims 29 and 32 is obvious over WO 2011126937 in view of Aartsma-Rus et al. or Shao et al.
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Claims 29 and 33-36 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2011126937 A1 (hereinafter, “’937”) (hereinafter, “’937”) in view of Aartsma-Rus et al. (Molecular Therapy, Volume 17, Issue 3, March 2009, Pages 548-553, plus Supplemental Data) or Shao et al. (Nucleic Acids Research, 2006, Vol. 34, No. 19, pages 5660-5669) and further in view of Sardar et al. (J Hematol. 2019;8(1):1-10). NOTE: ‘937 and Sardar et al. have been submitted and made of record in the Office Action filed January 29, 2026.
‘937 is relevant and relied upon in its entirety as discussed supra. Specifically, ‘937 teaches targeted intracellular delivery of antisense oligonucleotides (AON) via conjugation with small molecule ligands.
Also, Aartsma-Rus et al. and Shao et al. are relevant and relied upon in their entirety as discussed supra.
‘937 are explicit in teaching:
"Small organic molecule" as used herein refers to organic compounds having a molecular weight of more than about 10 Daltons and less than about 5,000 Daltons, of more than about 40 Daltons and less than about 3,000 Daltons, or of more than about 100 Daltons and less than about 2,500 Daltons”.
‘937 does not teach the small molecule is ibrutinib.
Sardar et al. teach the efficacy of an ibrutinib-based regimen in chronic lymphocytic leukemia. See Abstract, for example. Also, see Table 1. NOTE: Ibrutinib targets the polypeptides EIF4E and BTK as evidenced by Del Papa et al. (Clin Cancer Res (2019) 25 (24): 7540-7553) (submitted and made of record in the Office Action filed January 29, 2026) and Sardar et al., respectively.
Also NOTE: Ibrutinib has a molecular weight of 441 daltons as evidenced by Wikipedia – Ibrutinib, downloaded from Ibrutinib - Wikipedia on June 30, 2026.
The present Specification discloses and identifies that a derivative of Ibrutinib is Ibrutinib-MPEA.
A person of ordinary skill in the art would have been motivated to substitute ibrutinib of Sardar et al. with ibrutinib-MPEA as presently claimed since they are functional equivalents of each other, and it is obvious to substitute one functional equivalent for another, particularly when they are to be used for the same purpose. See MPEP 2144.06.
Furthermore, KSR forecloses that the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. See Board Decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d). Also, see M.P.E.P. §2144.07 which states, "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06.
Before the effective filing date of the claimed invention, it would have been prima facie obvious to devise a synthetic bifunctional molecule comprising: a first domain comprising an antisense oligonucleotide (ASO), wherein the first domain specifically binds to an RNA sequence of a target ribonucleic acid (RNA); a second domain comprising a small molecule having a molecular weight of 900 daltons or less, wherein the second domain specifically binds to a target polypeptide; and a linker that conjugates the first domain to the second domain as taught and suggested by ‘937.
Starting from Oligo 623 and looking to further stabilize the oligonucleotide, a person of ordinary skill in the art would have been motivated to modify the teachings of ‘937 to have the AON comprise a sequence comprising 36% to 56% GC content as Aartsma-Rus et al. and Shao et al. teach, for stability of the oligo or the oligo:target duplex, the optimum GC content for an antisense oligonucleotide generally ranges between 40% and 60%, with an average of 55%.
It would have been obvious and one of skill in the art would have expected reasonable success to chemically modify the ASO for the purpose of increasing stability of the ASO and for the purpose of increasing delivery of the oligonucleotide as taught by ‘937.
It would have been obvious for a person of ordinary skill in the art to modify the teachings of ‘937 to also include ibrutinib as the small molecule for the purpose of additive effects of inhibiting leukemia with ASO targeted to Ras, MEKK, Raf, MYB, etc., for example.
A person of ordinary skill in the art would have expected reasonable success to make and use the synthetic bifunctional molecule comprising ASO and ibrutinib as the small molecule since ‘937 teaches synthetic bifunctional molecules have been developed as and successfully tested for in vitro or in vivo use.
Therefore, the subject matter of claims 29 and 33-36 is obvious over WO 2011126937 in view of Aartsma-Rus et al. or Shao et al. and further in view of Sardar et al.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Terra C. Gibbs whose telephone number is 571-272-0758. The examiner can normally be reached from 8 am - 5 pm M-F.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Ram Shukla can be reached on 571-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/TERRA C GIBBS/ Primary Examiner, Art Unit 1635
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