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 .
Application Status
This action is written in response to applicant’s correspondence received 01/15/2026. Claims 1, 21-22, 24-25, 31-32 and 39-51 are currently pending. Claims 21-22, 24-25, 31-32 and 43 are withdrawn from prosecution as being drawn to the non-elected method. Claims 39-40 and 44-51 have been amended to recite the nucleic acid according to claim 1. Accordingly, claims 1, 39-40 and 44-51, drawn to the elected product, are examined herein.
Any rejection or objection not reiterated herein has been overcome by amendment. The rejections of claim 1 under 35 U.S.C. § 101, as set forth on pages 7-8 of the office action of 07/16/2025, is withdrawn in light of the amendments to the claims, which limit the nucleic acid to non-naturally-occurring nucleic acids such as siRNAs, shRNAs, ribozymes, aptamers, LNAs, etc., as opposed to naturally-occurring miRNAs.
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.
Examiner’s Note
Applicant’s remarks, received 01/15/2026, regarding the IDS filed 03/07/2022 are acknowledged. A copy of this IDS was re-submitted, and was received on 01/27/2026 along with the electronic filing receipt of the original submission. This submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner
Claim Rejections - 35 USC § 112(a) – Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 39-40, and 44-51 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 1 recites a nucleic acid comprising an antisense nucleotide sequence complementary to a target region of the PIAS2β mRNA, wherein the binding of the nucleic acid to its target sequence causes the specific inhibition of the expression of PIAS2β mRNA, wherein the nucleic acid is selected from siRNA, shRNA, an antisense oligonucleotide, gapmer, PNA, LNA, INA, HNA, morpholino, ribozyme and an aptamer. While antisense nucleic acid technologies comprising siRNA, shRNA, antisense oligonucleotides, gapmers, morpholinos, and antisense LNA/PNA/INA/HNA nucleic acid sequences share the structural feature of antisense complementarity to a target, the ability to base pair with a target sequence, and the ability to inhibit expression of the target mRNA neither the specification nor the art provide a description of any aptamer or ribozyme that binds to a complementary target sequence in PIAS2β mRNA and causes the specific inhibition of its expression. In fact, the specification explicitly states that aptamers do not have that function: “As used herein, an “aptamer” refers to a nucleic acid ligand which binds to more than one site in a target molecule, wherein the binding is not “complementary”, i.e., not due to the formation of base pairs between a nucleic acid ligand and a target nucleic acid sequence.” (p. 23 ln 12-14). Similarly, a ribozyme is described as, “a RNA molecule which catalyses a chemical reaction” which catalyses “the hydrolysis of their own phosphodiester bonds or the hydrolysis of bonds in other RNAs; but they have also been observed to catalyse the aminotransferase activity of a ribosome, the ligase activity of a DNA ligase…” (p. 23 ln 6-10). While the specification states that aptamers can be synthesized by means known in the art (p. 23 ln 21-25), neither the specification nor the prior art describes aptamers or ribozymes comprising antisense sequences to a target and with the function of complementary binding of the nucleic acid to its target sequence and causing the specific inhibition of the expression of PIAS2B mRNA, nor do they provide a correlation between the structure of the broad genus of aptamers and ribozymes and that function.
Based on the breadth of the claims, the limited amount of guidance provided by the specification and the art, the high degree of variation among members of the claimed genus, and further the unpredictability in the art, that one of ordinary skill in the art would conclude that Applicant was not in possession of the invention as broadly claimed.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 40 and 44-48 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ali et al. (PIASxβ is a key regulator of osterix transcriptional activity and matrix mineralization in osteoblasts. J Cell Sci (2007) 120 (15): 2565–2573.).
Applicant regards the term, “a nucleic acid comprising an antisense nucleotide sequence" to mean, “a nucleic acid comprising, substantially comprising,or consisting of an antisense sequence which is single-stranded or double-stranded.” (p. 10 ln 1-3)
Applicant regards the term, “functionally equivalent sequence” to mean, “sequence/sequences resulting from the insertion, deletion and/or substitution of one or more nucleotides in the reference sequences, i.e., in the sequences to which the sequence/sequences is/are functionally equivalent.” (p. 18 ln 20-24). Please note that the definition is silent as to how much, if any, function must be retained. Instead, the definition describes only structural information. Please note, as well, that by this definition, and given the exemplary embodiments on p. 18 (ln 24-26) in which least 1-25 nucleotides may be inserted/deleted/substituted, a completely different sequence which shares no nucleotides in common with a 19-21 nt reference may still be considered a functional equivalent. Therefore, effectively any sequence is encompassed by the claims. For purposes of comparison to the prior art, the prior art will be searched according to a narrower interpretation wherein the nucleic acid must perform the same recited function in the reference (i.e., causing specific inhibition of PIAS2β mRNA), However, the special definition in the specification leads to a much broader interpretation which effectively encompasses any nucleotide sequence.
Regarding claim 1, Ali et al. teach a double-stranded nucleic acid comprising an antisense sequence (siRNA) complementary to a target region of PIAS2β and which binds to and causes the specific inhibition of PIAS2β mRNA (§Summary):
Using this experimental system, we identified PIASxβ, a splice isoform of
Pias2…Targeted knockdown of PIASxβ by small interfering RNA (siRNA)
Ali teaches that the inhibition is specific to PIASxβ:
The scrambled siRNA, a nonsilence control, had no effect, demonstrating the PIASxβ siRNA sequence specificity. (p. 2567 § Targeted knockdown of PIASx by siRNA inhibits osteoblast differentiation)
All siRNA sequences were subjected to a BLAST search against mouse genome sequences in GenBank to ensure specificity. (p. 2572 § Small interfering RNA (siRNA) duplex preparation and transfection)
Regarding claim 40, it is noted that SEQ ID NOs: 1-5 are disclosed to be parts of the PIAS2β coding sequence (p. 22 ln 3-9). Insofar as Ali targets PIAS2β, therefore, Ali targets a functionally equivalent sequence to SEQ ID NOs: 1-5.
Regarding claims 44-48, the same rationale applies: while Ali does not teach the exact sequence of the PIAS2β siRNA, Ali does teach a siRNA duplex (i.e., dsRNA with complementary sense and antisense strands, as recited in claim 45) which targets PIAS2β and has the function, equivalent to the instantly claimed invention, of causing inhibition of PIAS2β mRNA.
Response to Arguments
Applicant’s arguments in the remarks of 01/15/2026, with respect to the rejection(s) of claim 1 under 35 U.S.C. 102, have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made over Ali to address the limitations of the amended claims.
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.
Claim 39 is rejected under 35 U.S.C. 103 as being unpatentable over Ali (cited above), as applied to claims 1, 40 and 44-51 above, in view of NCBI Reference Sequences NM_173206.4 (the human PIAS2 alpha transcript, 06/01/2019) and NM_004671.5 (PIAS2 beta, 07/06/2019).
Ali teaches the nucleic acid of claim 1, from which claim 39 depends, as already discussed.
Ali does not teach that the nucleic acid targets exon 14 of PIAS2β.
NM_173206.4 and NM_004671.5, in combination, teach that the PIAS2β has a 14th exon spanning positions 1849-11243, which NM_173206.4 (PIAS2α) lacks. Aligning the two transcripts shows that they have 100% identity from positions 1-1811 (see attached OA appendix). Therefore, positions 1812-11243 of the beta isoform are not present in the alpha isoform. This is further evidenced by the instant specification in FIG. 4B, which shows that PIAS2a differs from PIAS2b in exon 14.
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 designed a siRNA targeting PIAS2β, as taught by Ali, specifically targeting exon 14 of PIAS2β, which is specific to PIAS2β and not present in PIAS2α, as taught by NM_173206.4 and NM_004671.5. One skilled in the art would reasonably have inferred, based on the disclosures of NM_173206.4 and NM_004671.5, that designing a siRNA to target a sequence known to be present in PIAS2β but not in PIAS2α would predictably have resulted, with a reasonable expectation of success, in a siRNA capable of specifically targeting the former and not the latter.
Claims 49-51 rejected under 35 U.S.C. 103 as being unpatentable over Ali (cited above), as applied to claims 1, 40 and 44-48 above, in view of Dharmacon (horizontm inspired cell solutions. siGENOMEtm and ON-TARGETplustm siRNA reagents. 2018).
Ali teaches the nucleic acid of claims 1 and 45, from which claims 49-51 depend, as already discussed.
Ali does not specifically teach the siRNA sequences and therefore does not teach that the sense and/or antisense strand has 3’ UU overhangs.
However, Ali does disclose that, “SMARTpool siRNA duplexes were chemically synthesized by Dharmacon RNA Technologies”, and Dharmacon teaches that SMARTpool siRNAs comprise 3’-UU overhangs on both strands (see Product description, first page).
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 siRNAs specifically targeting PIAS2B mRNA, as taught by Ali, to comprise symmetrical 3’ UU overhangs, as taught by Dharmacon. Dharmacon teaches that these overhangs were not only present in SMARTpool siRNAs, but were also known modifications of siRNAs which were “guaranteed to silence target gene expression by at least 75% at the mRNA level”. Based on Dharmacon’s teachings, the ordinary artisan would have had a reasonable expectation that siRNAs designed using Dharmacon’s approach, including symmetrical 3’ UU overhangs, would have been effective at inhibiting their target gene.
Conclusion
No claim is allowed at this time.
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 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