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Application Status and Withdrawn Rejections
Applicant’s amendments filed August 19, 2026, amending claims 5, 6, 8 and 30, and adding new claim 139 is acknowledged. Claims 5-17, 22, 24, 26, 28-31, 36-37, 114-116 and 134-139 are pending and under examination.
The amendments to claims 5, 6 and 8 overcome the §112 and §101 rejections. The amendment to claims 5 and 6 requiring the limitation that the oligomeric compound be capable of reducing human DUX4 expression in vitro and Applicant’s arguments regarding the predictability of a specific antisense oligonucleotide reducing expression of DUX4 overcomes the §103 and nonstatutory double patenting rejections.
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 Objections
Claim 114 is objected to because it recites “claim 5and a…” There needs to be a space between “claim 5” and “and”.
Claim Rejections - 35 USC § 112(a)
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 5-16, 22, 24, 26, 28-31, 36-37, 114-116 and 134-139 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. This is a new rejection necessitated by amendment.
MPEP 2163.II.A3.(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.II.A3.(a).(ii) states, “written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species” where “representative number of species' means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.”
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Claims 5 and 6 recite an oligomeric compound comprising a modified oligonucleotide consisting of 12-50 nucleosides having a sequence comprising 8-20 nucleobases complementary to positions 4503-4522 of SEQ ID NO 1. According to the Specification, SEQ ID NO 1 is GenBank Accession NC_000004.12, which is the genomic sequence of the last DUX4 open reading frame in the DUX4 array at the end of human chromosome 4 (See FIG. 3 of Belayew, US 20120225034 A1, of record). Positions 4503-4522 are in the middle of intron 2. An annotated version of FIG. 31 from Belayew is provided below with claimed targeted position and previously disclosed antisense oligonucleotides indicated. DUX4 intron 2 is spliced out in all major transcript variants, as indicated by the slanted lines. Intron 2 is the plain text between the bolded (exon 2) and bolded italics (exon 3) sequences.
The claimed oligonucleotide must have at least one modified sugar moiety or one modified internucleoside linkage. The modified sugar moiety must be one of a variety of moieties that are known in the art for oligonucleotides. Therefore, the claims encompass a genus of modified oligonucleotides. The oligonucleotides need only have 8 nucleotides that are complementary to the sequence of DUX4 intron 2 but can be as long as 50 nucleotides. The genus of 12-50-mers having 8-20 nucleotides complementary to a 20-mer sequence encompasses over 1026 different sequences. Each of those >1026 sequences can have different patterns of sugar modifications and internucleoside linkage modifications. As such the genus of possible oligonucleotide structures is extremely large and potentially limitless given that some of the recited modifications are not a specific structure (i.e., a sugar surrogate).
Finally, claims 5-6 require that the oligomeric compound must be capable of reducing DUX4 expression in vitro, i.e., in cell culture. For the reasons explained below, Applicant has not sufficiently described the structure of oligomeric compounds that target/hybridize the claimed DUX4 intron 2 sequence and are capable of reducing human DUX4 expression in cells commensurate in scope of the claimed genus.
The Specification describes screening a class of oligonucleotides called “gapmers” that are targeted to various sequences of the DUX4 pre-mRNA and mature transcripts (Tables 1-13). Applicant specifically tests 5-10-5 MOE gapmers, (tables 1-2) and 3-10-3 cEt gapmers (Tables 3-4). Gapmers comprise a central DNA region of 10 nucleosides with 5’ and 3’ “wings”, which range from 1-6 RNA nucleosides. In the case of the MOE gapmers, the RNA wing nucleosides have a methoxy group in place of the -OH on the 2’ carbon of ribose (page 2). The cEt gapmers have a bicyclic sugar in which a bridge is formed connecting the 4’ carbon and the 2’ carbon of the ribosyl sugar in the RNA wing nucleosides (page 5). Applicant only reports screening and knockdown percentages of the 3-10-3 cEt gapmers targeting the claimed intron II sequence (Tables 3 and 12), which showed 25-66% DUX4 mRNA level compared to untargeted control (UTC) (Table 3, compounds 1098903-1098909; Table 12, compounds 1098912). In follow-up screening, Applicant demonstrated up to 93% knockdown (i.e., 7% of UTC) for compounds 1098904 and 1098907 (Tables 8 and 9).
Applicant also tested siRNA compounds having a sense and an antisense strand with modified 2’-sugars (Tables 22 and 24). However, none of the siRNAs are designed to target a sequence in intron 2, which spans position 4290-4644 of SEQ ID NO 1. Applicant does not explain why they chose gapmer inhibitory oligonucleotides targeted to various sequences of the DUX4 primary and mature transcripts, but only chose to screen siRNAs targeted to sequences of the mature Dux4 transcripts. Applicant also failed to test other antisense oligonucleotide architectures to determine what oligonucleotide lengths, mismatch nucleotide positions, and modifications are useful for knocking down gene mRNA levels when targeted to an intronic region. As such, it is not predictable from the Specification what additional structures other than the 3-10-3 cEt gapmers can function to reduce expression by targeting an intron region. Thus, in view of the Specification, the skilled artisan would have reasonably concluded that Applicant did not possess genus of oligomeric compounds having the claimed function.
There have been many reports of designing and screening inhibitory oligonucleotides that generically target DUX4, but only a few that target intronic regions. Harper lists targeting sequences for DUX4 intron 2 region, including the claimed region, but does not test the inhibitory oligonucleotides (US 20140322169 A1, of record). Harper only tests microRNAs (miRNAs) which are unmodified, genetically encoded antisense RNAs, targeted to cDNA transcripts (i.e., no intronic sequences). Applicant pointed out in their Remarks filed August 19, 2026, that the miRNAs had differing knockdown efficiencies and argue that there is not a reasonable expectation that changing the targeting sequence would result in the function of reducing DUX4 expression. Thus, although Harper teaches targeting the claimed intron 2 region with an antisense oligonucleotides, and teaches that inhibitory RNAs can be siRNAs, which often have modified nucleotides, Harper’s working example does not support the conclusion that targeting any generic sequence would necessarily result in target expression knockdown.
The only other prior art reference that targets intronic regions is Lim (Lim et al., Human Molecular Genetics (2015), 24: 4817-4828). Lim designs a series of siRNAs targeted to promoter, exon, intronic, a polyA signal (PAS) sequences of the DUX4 primary transcript (Fig 1). The targeting sequences of Lim’s two intron 2-targeting siRNAs, +1741 and +1676, are indicated on the diagram above and are near the exon2-intron 2 junction. Lim’s data suggests that targeting the intron II sequence with an siRNA has no effect on DUX4 expression (Figure 1B), whereas targeting exonic sequences with siRNA reduced DUX4 expression by over 50% (Fig 1C). Thus, it was not predictable that siRNAs having modified nucleotides as produced by Dharmacon and Life Technologgies (page 4825, last ¶) and targeted to intronic regions were capable of reducing human DUX4 expression. Lim also tested MOE-gapmer oligonucleotides targeted to various DUX4 promoter sequences. Interestingly, Lim found that for some targeted sites, the MOE-gapmers had limited effect on DUX4 expression where siRNAs had a high reduction effect (Figure S6). siRNAs reduce gene expression through a Dicer and Ago2-mediated pathway, wherein gapmers degrade RNNA through a RNAaseH pathway (page 4818, ¶3). The prior art would suggest that given the complex regulation of DUX4 expression, different classes of inhibitory oligonucleotides targeting different DUX4 transcript sequences would have different capabilities of reducing mRNA levels of DUX4.
As mentioned above, Applicant does not explain the mechanism behind intron 2-targeted gapmer-mediated DUX4 down regulation. Applicant also does not explain why they screened gapmers targeting the length of the DUX4 primary transcript and limited siRNA screening to exonic sequences. However, in the art, siRNAs are used to mediate RNA degradation through RISC in the cytoplasm. However, gapmers are used for RNAseH-mediated cleavage in the nucleus where they can degrade primary transcripts that have not been spliced. Additionally, gapmers have been used to block the splicing machinery to alter splicing. It is possible that the compounds discovered by Applicant block a branch-point nucleotide necessary for splicing out intron 2, which then triggers nonsense mediated decay of the DUX4 transcript (Feng et al., eLife (2015), 4:e04996). However, the branch points and other sequences for splicing out intron 2 from the DUX4 primary transcript have not been reported in the prior art. As such was not predictable that an intron 2-targeted antisense oligonucleotide would have any effect on DUX4 expression. Thus, in view of the prior art, it was not predictable how to design/modify an antisense oligonucleotide that targets an intron 2 sequence such that it could reduce DUX4 expression.
In summary, given 1) the lack of evidence in the Specification that oligonucleotides other than gapmers can knockdown DUX4 expression when targeted to intron 2, and 2) the complete lack of any evidence in the prior art that antisense oligonucleotides targeted to intron 2 are capable of inhibiting DUX4 expression, the skilled artisan would have reasonably concluded that Applicant did not possess the large genus of 12-50-mer oligonucleotides having 8-20 nucleotides complementary to the 20-mer sequence in DUX4 intron 2 with nearly limitless combinations of modifications that are capable of reducing expression of DUX4 expression in cell culture as claimed.
Claims 7, 9-16, 22, 24, 26, 28-29, 36-37, 114-116 and 134-139 do not substantially limit the size of the genus of possible modified oligonucleotides. It is noted that siRNAs can also be designed with bicyclic sugars, but they are still not predicted to have any effect on DUX4 expression when designed to target intron 2, since intron 2 is spliced out before export to the cytoplasm where siRNAs function.
Claims 8 and 30-31 limit the length of the oligonucleotide to 16-21 and 18-21 nucleosides. Although the size of the genus of oligonucleotides is much smaller – 1013 different sequences – it still encompasses siRNAs that are not predicted to have any effect when targeted to an intron region.
Allowable Subject Matter
Claim 17 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim 17 recites the structure of the oligonucleotide as having a central DNA region of 6-10 nucleosides with 5’ and 3’ “wings”, which range from 1-6 RNA nucleosides, which is the structure of a gapmer. Applicant provides evidence that 5-10-5-MOE gapmers and 3-10-3 cEt gapmers targeting regions of the intron 2 are capable of reducing DUX4 expression in cell culture (Table 1 and 2). Although Applicant did not specifically test the 5-10-5-MOE design on the 4503-4522 region, gapmers with the 5-10-5-MOE architecture targeted just upstream (4481-4500) and downstream (4535-4554) of the claimed region had modest reduction of DUX4 expression. As such, it would have been entirely predictable that the generic gapmer architecture recited in claim 17 and targeted to the claimed Intron 2 region would be capable of reducing DUX4 expression in culture cells.
The closest art prior art is Belayew (US 20120225043 A1) in view of Harper (US 20140322169 A1) whose teachings are recited above and in the previous office action (pages 10-12). As noted above, neither Belayew nor Harper demonstrate that targeting a DUX4 intron 2 sequence would be effective at knocking down DUX4 expression. Given the unpredictability of targeting intronic DUX4 sequences for knockdown expression, it would not have been obvious to use the theoretical targeting sequence reported in Harper to design a gapmer for knocking down DUX4 expression.
Conclusion
Claims 17 and 114 are objected to. Claims 5-16, 22, 24, 26, 28-31, 36-37, 114-116 and 134-139 are rejected.
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 CATHERINE KONOPKA whose telephone number is (571)272-0330. The examiner can normally be reached Mon - Fri 7- 4.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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