DETAILED CORRESPONDENCE
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 .
This action is in response to the papers filed July 25, 2022. Currently, claims 22-35, 60-65 are pending. Claims 60-62, 65 have been withdrawn as drawn to non-elected subject matter.
All arguments have been thoroughly reviewed but are deemed non-persuasive for the reasons which follow. This action is made FINAL.
Any objections and rejections not reiterated below are hereby withdrawn.
Election/Restrictions
Applicant’s election without traverse of Group I, TUG1 in the reply filed on May 5, 2025 is acknowledged.
Priority
This application claims priority to
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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.
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 22, 25, 27-29, 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Surana et al. (US2019/0309302, October 10, 2019) in view of Krishna et al. (WO2019/060522, March 28, 2019) or Paul et al. 254th National Meeting (August 17-24, 2017, Thiophosphoramidate morpholino: A new class of antisense oligonucleotides).
Surana teaches methods of introducing into a cell a composition that specifically hybridizes to a target region and sterically inhibits RNA splicing. Surana teaches introducing antisense morpholino oligonucleotides. The antisense oligonucleotides are complementary to target region on a target RNA that includes a splice site that specifically hybridize to an exon, intron or exon-intron boundary target region (para 10)(limitations of Claims 23-24). The intron-exon boundary is an antisense polynucleotide that specifically and predominantly hybridizes to intronic sequence and only hybridizes to two or more nucleotides of an adjoining exon (para 16)(limitations of Claims 25-26). The antisense oligonucleotide may comprise a modified polynucleotide backbone (para 17-18). The modified backbone may comprise phosphorodiamidate morpholino oligomer (PMO), for example)(para 18). Surana teaches the methods may be used for the purpose of analysis and treatment of cancers (para 22, for example).
Surana does not teach the oligonucleotide comprises a thiomorpholino nucleotide.
However, Krishana teaches administration of a thiomorpholino antisense compound may require lower doses and/or less frequent dosing regimens to obtain desired results (page 6, para 2).
Further Paul teaches thiophosphoramidate morpholino (TMO) are prepared on DNA synthesizers using phosphoramidate chemistry. Paul teaches TMO had higher melting temperatures when compared to natural DNA/DNA or DNA/RNA duplexes. Paul intron retention ASO TMO teaches the simplistic synthesis procedures render the TMO analogues readily available and useful for antisense methods.
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention to have modified the ASO oligonucleoitdes used in Surana to include a thiophosphoramidate morpholino as taught by Krishana or Paul. Surana specifically teaches the ASO’s may be modified, specifically modified the backbone may comprise phosphorodiamidate morpholino oligomer (PMO), for example)(para 18). It would have been obvious to modify the backbone with an alternative morpholino such as thiophosphoramidate morpholino because the art teaches the compound may require lower doses, less frequent dosing regimens or require more simplistic synthesis procedures to obtain.
Response to Arguments
The response traverses the rejection. The response asserts neither Krishna nor Paul teaches targeting of an RNA with a TMO to induce nuclear retention of unspliced RNA. This argument has been considered but is not convincing because the nuclear retention of the unspliced RNA is an inherent property. The claim does not require anything more than introducing to a cell a TMO that is configured to be complementary to a target region on a target RNA. The “thereby” clause is an inherent property that occurs upon the hybridization. There are not further active method steps required. As provided by MPEP 2112 (II), the inherent property need not be recognized at the time of the invention. Thus, the substitution of TMO for the ASO would have been obvious at the time the invention was made for the reasons above.
Furthermore, as provided in MPEP 2144, Examiner has supplied a different reason to support combining the art’s teachings, which is detailed above. And, it is well settled that these reasons need not be the same in an obviousness analysis. KSRInt’l Co. v. Teleflex Inc., 550 U.S. 398, 419 (2007) (“In determining whether the subject matter of a patent claim is obvious, neither the particular motivation nor the avowed purpose of the patentee controls.”); In re Kemps, 97 F.3d 1427, 1430 (Fed. Cir. 1996) (“[T]he motivation in the prior art to combine the references does not have to be identical to that of the applicant to establish obviousness.”); Outdry Tech. Corp. v. Geox S.P.A., 859 F.3d 1364, 1370-71 (Fed. Cir. 2017) (“Any motivation to combine references, whether articulated in the references themselves or supported by evidence of the knowledge of a skilled artisan, is sufficient to combine those references to arrive at the claimed process . . . [, which] need not be the same motivation articulated in the patent for making the claimed combination.”). Thus, while the response argues that the substitution or combination of TMOs for the standard ASO would be desirable to enter the nucleus and prevent exit from the nucleus, this is merely a different reason for making the substitution. Krishna teaches TMOs have a longer ½ life, are less complicated to product and are less expensive. Thus, the ordinary artisan would have been motivated to have used TMOs rather than ASOs for these benefits taught in the art.
Even more, with respect to the response argument there is no reasonable expectation of success to use TMO chemistry, this argument has been reviewed but is not persuasive. Krishna teaches the similarity of TMO to ASO. Krishna explicitly states “these thiomorpholino-containing nucleotides (TMOs) may cause exon skipping in exons (including exon 51) of the transcripts of the dystrophin gene during RNA processing, similar to the antisense oligonucleotide eteplirsen, but with longer serum half-life, with substantially less complicated production methods, and ultimately with less expensive therapeutic compositions and administration regimens.” (page 4, lines 1-5). Thus, the art teaches the similarity and the expectation the TMO will function similar to the ASO.
Applicant provides numerous arguments about what was known in the art and what an ordinary researcher would have expected. These arguments are attorney arguments that are not supported by evidence of record. The evidence of record does not establish the art taught multiple challenges for using TMO.
Thus, for the reasons above and those already of record, the rejection is maintained.
Claims 30-32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Surana et al. (US2019/0309302, October 10, 2019) in view of Krishna et al. (WO2019/060522, March 28, 2019) or Paul et al. 254th National Meeting (August 17-24, 2017, Thiophosphoramidate morpholino: A new class of antisense oligonucleotides) as applied to claims 22-29, 33, 35 above and further in view of Kondo et al. (US 2018/0163208, June 14, 2018).
Neither Surana, Krishna nor Paul teaches introducing to a cell a composition comprising a TMO to TUG1 target region.
However, Kondo teaches a method of treating cells with antisense oligonucleotides to TUG1 gene to treat a subject having a tumor. Kondo teaches TUG1, the taurine upregulated gene 1 is a spliced and polyadenylated RNA that was identified as non-coding RNA with a role in cancer and tumors (para 2-3). Kondo teaches TUG1 is aberrant in many different cancers including NSCLC, osteosarcoma, urothelial cancer etc (para 3). TUG1 targeting nucleic acids are effective for significant regression of such tumors (para 11).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention to have designed TMO’s as taught by Surana, Krishna or Paul to target lncRNA to TUG1 to treat tumors that express the TUG1 gene at high levels. The ordinary artisan would have been motivated to have designed the TMO to known aberrant sequences to target nucleic acids effective to significantly regress tumors.
Response to Arguments
The response traverses the rejection. The response asserts Kondo does not disclose or suggest the use of TMOs targeting an exon-intron junction. This argument has been reviewed but is not persuasive. The combination of references teaches designing TMOs to intron/exon junctions. The ordinary artisan would have been motivated to design these TMO to the TUG1 region that are known to be associated with tumors to regress tumors.
Conclusion
No claims allowable over the art.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Havens et al. (Nucleic Acids Research, Vol. 44, No. 14, pages 6549-6563, June 2016) teaches splice-switching antisense oligonucleotides as therapeutic drugs. Havens teaches splicing modulation allows alteration of splicing in a therapeutic manner. The ASOs create a steric block to the binding of splicing factors to the pre-mRNA (page 6550, col. 2). Havens teaches chemical modifications have improved oligonucleotide binding affinity, stability and pharmacodynamic properties (page 6551, col. 1). The ASOs can move into the nucleus to affect pre-mRNA splicing (page 6552, col. 1). Figure 3 illustrates the Splice switching antisense oligonucleotides in the nucleus (page 6554).
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 JEANINE ANNE GOLDBERG whose telephone number is (571)272-0743. The examiner can normally be reached Monday-Friday 6am-3:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng (Winston) Shen can be reached on (571) 272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JEANINE A GOLDBERG/Primary Examiner, Art Unit 1682
December 9, 2025