DETAILED ACTION
Receipt of Arguments/Remarks filed on July 16 2026 and July 23 2026 are acknowledged. Claims 20 and 29 were/stand cancelled. Claims 1, 14, 21 and 23 were amended. Claims 1-19 and 21-28 are pending. Claims 24-28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on January 7 2026. Claims 1-19 and 21-23 are directed to the elected invention.
Applicants are reminded that pursuant to MPEP 608.01(m): The claim or claims must commence on a separate physical sheet or electronic page and should appear after the detailed description of the invention. Any sheet including a claim or portion of a claim may not contain other parts of the application or other material. The claim set filed July 23 2026 contains other “material” other than just the claims.
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 .
Withdrawn Objections/Rejections
The amendments filed July 23 2026 are sufficient to overcome the objection of claim 1. The acronym is spelt out the first time it occurs.
The amendments filed July 23 2026 are sufficient to overcome the rejection of claims 1-23 and 29 under 35 USC 112(b). Regarding claim 1, while Applicants are reciting 2’-OMe in a manner that is not consistent with the ordinary meaning, the claim clearly recites that 2’-OMe is 2’-O-methoxethyl and the remarks make it clear this is the intended scope. While 2’-O-methoxyethyl is the exact same structure as 2’-methoxyethyl (MOE) and therefore redundant, MPEP 2173.05(h) makes it clear redundancy does not make a claim indefinite. The amendment to claim 14 clarifies the scope as the claim was amended to make it clear that the gapmer sequence is selected from the Markush grouping of SEQ ID No. The cancellation of claims 20 and 29 renders those rejections moot.
Modified Rejections Based on amendments in the reply filed on July 23 2026
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 of this title, 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 1-19 and 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Rungta et al. (Trends in Carbohydrate Research, 2015) in view of Dalla et al. (USPGPUB No. 20190338280) and Fanucchi et al. (Nature Genetics, 2019, cited on PTO Form 1449).
Applicant Claims
The instant application claims a gapmer compound comprising a modified oligonucleotide having 12 to 29 linked nucleosides in length, wherein the gapmer compound has a 5' wing sequence having from about 3 to about 7 modified nucleosides, a central gap region sequence having from about 6 to about 15 2'-deoxynucleosides, and a 3' wing sequence having from about 3 to about 7 modified nucleosides; wherein the 5' wing and 3' wing modified nucleosides each comprise a sugar modification selected from the group consisting of a 2'-methoxyethyl (MOE) modification, a locked nucleic acid (LNA) modification, a 2'F-ANA modification, a 2'-O-methoxyethyl (2'OMe) modification, and combinations thereof; wherein the linked nucleosides are linked with phosphorothioate internucleoside linkages, phosphorothiolate internucleoside linkages, or combinations thereof; and wherein the modified oligonucleotide has a nucleobase sequence that is at least 91% complementary over its entire length to Region A nucleotides 256-282, Region B nucleotides 511- 540, Region C nucleotides 523-547, Region D nucleotides 441-469, Region E nucleotides 88-107, or Region F nucleotides 547-567 of Upstream Master Lnc RNA Of The Inflammatory Chemokine Locus (UMLILO) long non-coding RNA SEQ ID NO: 231.
The instant application claims a gapmer compound comprising a modified oligonucleotide having 12 to 29 linked nucleosides in length, wherein the gapmer compound has a 5' wing sequence having from about 3 to about 7 modified nucleosides, a central gap region sequence having from about 6 to about 15 2'-deoxynucleosides, and a 3' wing sequence having from about 3 to about 7 modified nucleosides; wherein the 5' wing and 3' wing modified nucleosides each comprise a sugar modification selected from the group consisting of a 2'-methoxyethyl (MOE) modification, a locked nucleic acid (LNA) modification, a 2'-fluoro-arabino nucleic acid (2'F-ANA) modification, a 2'-O-methoxyethyl (2'OMe) modification, and combinations thereof; wherein the linked nucleosides are linked with phosphorothioate internucleoside linkages, phosphorothiolate internucleoside linkages, or combinations thereof; and wherein the gapmer sequence is selected from the group consisting of SEQ ID Nos. 223, 12, 21, 35-42, 55-56, 88, 100-102, 123-124, 127-128, 151- 153, 155-162, and 224-227.
The instant application claims a gapmer compound comprising a modified oligonucleotide having 12 to 29 linked nucleosides in length, wherein the modified oligonucleotide comprises a nucleobase sequence selected from the group consisting of SEQ ID NOs: 223, 12, 21, 35-42, 55-56, 88, 100- 102, 123-124, 127-128, 151-153, 155-162 and 224-227 wherein the gapmer compound has a 5' wing sequence having from about 3 to about 7 modified nucleosides, a central gap region sequence having from about 6 to about 10 2'-deoxynucleosides, and a 3' wing sequence having from about 3 to about 7 modified nucleosides, wherein the 5' wing and 3' wing modified nucleosides each comprise a sugar modification selected from a 2'-methoxyethyl (MOE) modification, a locked nucleic acid (LNA) modification, a 2'F-ANA modification, a 2'-O-methoxyethyl (2'OMe) modification, or combinations thereof, the linked nucleosides are linked with phosphorothioate internucleoside linkages, phosphorothiolate internucleoside linkages, or combinations thereof; and wherein the modified oligonucleotide has a nucleobase sequence that is at least 91% complementary over its entire length to a nucleotide sequence of Upstream Master LncRNA Of The Inflammatory Chemokine Locus (UMLILO) long non-coding RNA wherein the UMLILO long non-coding RNA SEQ ID NO: 231.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Rungta et al. is directed to gapmer oligonucleotides, sugar-modified wings to antisense therapeutics. Antisense oligonucleotides (AONs) have demonstrated a great therapeutic potential towards sequence-specific silencing of selected gene. Inclusion of chemical modifications has imbued AONs with essential drug-like properties. Gapmers are beautifully designed AONs that contain a central ‘gap’ of deoxyribonucleotides which are flanked by ‘wings’ of sugar-modified nucleotides. Central gap is responsible for recruitment of RNase H cleavage, whereas sugar-modified terminal ‘wings’ ensure high affinity for its complementary target and also shield the central gap from nuclease degradation. With gapmer design, it is now possible to achieve high potency with shorter AONs that can avoid ‘irrelevant cleavage’ and have significantly reduced toxicities (abstract; page 29, page 40 conclusions). Polyphosphorothioate (PS) backbone modifications render improved metabolic stability, cellular uptake and can elicit RNase to cleave the target RNA in AON: RNA heteroduplex. Modification in sugar can bias its pucker towards C3’-endo conformation that imparts excellent nuclease resistance, binding affinity, specificity and potency to AONs. Third generation AONs are gapmers that contain a central gap and wings (page 29, Fig. 1). Gapmers are considered as the most advanced chemical modified AONs that can be designed (page 30).
PS internucleoside linkage has several distinct advantages over natural phosphate, such as improved metabolic stability and high cellular uptake and does not interfere with RNase H recruitment mechanism (page 33, last paragraph). 2’-Sugar modifications include 2’-O-methoxyethyl (2’-OMOE), 2’-O-methyl (2’-OMe), locked nucleic acid (LNA) and 2’-F-ANA. Bridged nucleic acids include cEt LNA. Since these sugar modification are unable to trigger RNase H mediated cleavage of target RNA, in gapmers, these sugar-modifications better serve as high-affinity wings to the central deoxyribose gap to allow RNase H recruitment. In order to increase nuclease resistance and bioavailability gapmer AONs are often designed with PS-backbone (page 34; Figure 4). Table 2 discusses Gapmer Design which include 5-10-5, 4-13-4 as well as 4-10-4, etc. (Fig. 6)
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Rungta et al. teaches gapmer design and advantages and that gapmers can target and silence any gene, Rungta et al. does not expressly teach the target is UMLILO RNA of SEQ ID NO: 231. However, this deficiency is cured by Dalla et al. and Fanucchi et al.
Dalla et al. is directed to immunomodulation by controlling elr+ proinflammatory chemokine levels with the long non-coding RNA Umlilo. UMLILO is a long non-coding RNA that regulates expression of the ELR+ proinflammatory chemokines (paragraph 003). Taught are UMLILO IncRNA inhibitor (paragraph 0015) wherein inhibitors may be an antisense oligonucleotide or siRNA (paragraph 0018). The DNA sequence for UMLILO is provided in SEQ ID NO: 1 (paragraph 0076). Taught is siRNA knockdown of UMLILO (Fig. 12) with targeting UMLILO being taught (paragraph 0113). Taught is a pharmaceutical composition comprising a nucleic acid such as a complementary sequence of SEQ ID NO: 54 (claim 1; 4).
Fanucchi et al. is directed to immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments. Taught is the knockdown of UMLILO with either siRNA or LNA GapmeRs (Fig. 3).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Rungta et al., Fanucchi et al. and Dalla et al. and utilize a gapmer that contains a central gap of deoxynucleosides and 5’ and 3’ wing sections with 2’ modified sugars and a phosphorothioate backbone. One skilled in the art would have been motivated to utilize this structure of gapmers as Rungta et al. teaches that the sugar modifications are better in the wings for high-affinity and the phosphonothioate modifications are useful for RNase H mediated cleavage
Regarding the claimed sequence, firstly, Fanucchi et al. teaches a GapmeRs with the following sequence (UMLILO: TCGCCTCTAATTTAAG; supplemental information) which has 100% identity to instantly taught 230 (Qy) as shown below:
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318
701
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which the instant specification corresponds to UMLILO position 444-461 (aka Region D).
Since the sequences are specifically taught for knockdown of UMLILO and Fanucchi et al. expressly teaches a gapmer, one skilled in the art would have been motivated to utilize the gapmer design taught in Rungta et al. for the advantages taught.
With regards to the additional claimed sequences, Dalla et al. teaches UMLILO of SEQ ID NO: 1 which has 100% identity to instantly claimed SEQ ID No: 231 (Qy):
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948
716
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It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Rungta et al., Fanucchi et al. and Dalla et al. and utilize a gapmer that targets any portion of the UMLILO sequence. Since Rungta et al. teaches gapmers for silencing any target gene and Dalla et al. and Fanucchi et al. both teach knockdown of UMLILO, one skilled in the art would have been motivated design gapmers which target any portion of this gene in order to knockdown/silence the gene absent a demonstration of the criticality. Since the instantly claimed sequences, all target different portions of UMLILO, one skilled in the art would have been motivated to design gapmers, for their advantages, and determine the optimal location for knockdown. One skilled in the art would have a reasonable expectation of success as Fanucchi et al. teaches that gapmers of UMLILO can knockdown expression.
Regarding the claimed length, modifications and pattern, Rungta et al. the same modifications, specifically LNA, 2’F-ANA, O-methoxy and O-methoxyethyl as well as cEt (reading on instant claim 29). Rungta et al. suggest various patterns, 5-10-5 and 4-10-4 can be utilized and these correspond to 20 mer and 18 mer gapmers. Fanucchi et al. exemplifies a gapmer of 16 nt, Dalla et al. teaches sequence lengths of 21 nt. Rungta et al. teaches that the gapmers are short AON and can be lengths of 15 or 20 (page 29). Therefore, these lengths of known sequences designed to silence genes overlap with the instant claims. One skilled in the art would manipulate the length in order to determine the optimal length for gene knockdown. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05. Since these sequences are short, one skilled in the art would manipulate the length of the gap and the length of the wings in order to achieve the desired knockdown effect as suggested by Rungta et al. absent demonstration of the criticality.
Response to Arguments
Applicants’ arguments filed July 23 2026 have been fully considered but they are not persuasive.
Applicants argue that (1) the instant application as presently claimed are gapmer compounds which are structurally and functionally different from siRNA compounds. It is argued that the present invention and disclosure provides a section of specific regions within the target UMLILO sequence and not any part. Table 2 of the instant specification shows that gapmer compounds within the claimed regions but not outside of the claimed regions are active. It is argued that the instant application target six specific regions which is only a small fraction of the possible targeting space.
Regarding Applicants’ first argument, the rejection never equates siRNA and gapmers. The examiner cites to Dalla et al. to teach why knockdown or inhibition of UMLILO would be desired. While Dalla et al. teaches siRNA, Fanucchi et al. teaches both siRNA and Gapmers to knockdown UMLILO. While these two inhibitors have different structures and mechanism of action they both are inhibitors which are used to knock down expression. Looking to the data in the instant specification, the examiner cannot agree that the table shows an unexpected effect commensurate in scope with the instant claims. As set forth in MPEP 716.02: Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). It is the examiners position, that based on the prior art, one skilled in the art would design gapmers which target UMLILO (specifically portions of UMLILO of SEQ ID NO: 1 of Dalla et al.) to afford knockdown for the benefits taught by Dalla et al. One skilled in the art would recognize that not all gapmers would work to the same extent, but one skilled in the art would have been motivated to experiment to determine the optimal gapmer sequence(s) absent demonstration of criticality. While Applicants allege that only sequences falling within the claimed scope work and those outside did not, the examiner cannot agree. Firstly, looking to the specifically claimed sequences (aka those with SEQ ID NO:) those for the most part appear to be active (i.e. have a value of less than <1.0), however, the examiner notes no data is provided for SEQ ID NO: 151-153 and 225-227. Other sequences which fall within the scope claimed have an IL-8 expression level above 1.0. For example, SEQ ID NO: 13 corresponds to UMLILO position 265-284 (aka Region B) but has an IL-8 expression of 1.460; SEQ ID NO: 114 which corresponds to positions 257-272 (aka Region A) has an IL-8 expression of 2.759. Contrast SEQ ID NO: 77 which corresponds to positions 69-84 has an IL-8 expression of 0.342 (i.e. does not fall within the regions claimed but still has activity). Same with SEQ ID NO: 78 which corresponds to positions 44-59 and has an IL-8 expression of 0.244. Therefore, Applicants are not correct when they state only gamers falling within the scope claimed are active as the instant specification shows sequences which fall within the scope are not active and those outside the claimed scope are active. Therefore, the data itself confirms the position of the examiner. One skilled in the art would recognize the desire for inhibition of UMLILO. One skilled in the art would design gapmer inhibitors in order to knockdown expression. One skilled in the art based on the teachings of Rungta et al. would design gapmers because these are specifically taught as having great therapeutic potential towards sequence-specific silencing of a selected gene. As shown in Fanucchi et al. gapmers are designed which are complementary to UMLILO. While the data has shown that some designed gapmers would inhibit and some would not, this is not evidence of an unexpected effect. Applicants merely selected some which were active and claimed them and the BRI of the claims encompass sequence which the instant specification show are not active. Thus, Applicants have not established an unexpected or unobvious effect over the full scope of the claims.
Applicants argue that (2) Fanucchi et al. does not teach or suggest the claimed gapmer. It is argued that there was no specific gapmer chemical structure taught in Fanucchi et al.
Regarding applicants’ second argument, the examiner cannot agree that Fanucchi et al. does not teach a specific chemical structure. Supplementary Table 4 clearly provides the list of siRNA, LNA and oligonucleotide sequences utilized. This table expressly states: UMLILO: TCGCCTCTAATTTAAG. This is a specific chemical structure. While this structure might not expressly anticipate the instant claims because the instant claims require a particular modification pattern, the rejection is not based on Fanucchi et al. alone but in fact is combined with Rungta et al. which expressly teaches the claimed pattern.
Applicants argue that (3) Dalla et al. discloses UMLILO but not the claimed gapmer. It relies on siRNA. Rungta just teaches gapmer design in general.
Regarding Applicants’ third argument, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The rejection is not based on Dalla et al. or Rungta et al. alone nor is it based on replacing siRNA with gapmers. Rungta et al. teaches gapmers and teaches the advantages of gapmers to silence any gene. Dalla et al. provides motivation to silence UMLILO. While Dalla et al. utilizes siRNA to silence, Fanucchi et al. teaches that both siRNA and gapmers can be utilized to silence UMLILO. While Rungta et al. generally teaches gapmer design, it is generic such that one skilled in the art would recognize that it teaching can be applied to any sequence for any target. Therefore, while no single reference teaches all the limitations, the rejection is based on the combination of references and what the combination would suggest to one skilled in the art.
Applicants argue that (4) the prior art combination lacks a reasonable expectation of success for the specific claimed gapmer architecture and regions. It is argued that even if the prior art could be combined there is no reasonable expectation of success that a gapmer targeting the specific regions would successfully knock down UMLILO. It is argued that the art recognizes that gapmer efficacy is highly depending on target accessibility, secondary structure of lncRNA and specific combination of chemical modifications which applicants argue is taught in Rungta et al. which acknowledges that sequence and design optimization is required.
Regarding Applicants’ fourth argument, obviousness does not require absolute predictability, however, at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. NOTE: MPEP 2143.02. None of Applicants arguments establish there was no reasonable expectation of success. Fanucchi et al. teaches LNA gapmers UMLILO: TCGCCTCTAATTTAAG which corresponds to SEQ ID NO: 230 which the instant specification teaches corresponds to positions 444-461 (aka region D) and clearly shows knockdown with this sequence. Therefore, the examiner cannot agree that isn’t’ a reasonable expectation of success. Routine experimentation and optimization does not result in a patentable modification or unobvious effect. Therefore, the examiner cannot agree that Rungta et al. teaches there isn’t a reasonable expectation of success. Sequence and design optimization is not evidence of unpredictability. Note MPEP 2144.05 which specifically discusses that routine optimization and routine experimentation do not support the patentability of subject matter.
Applicants argue that (5) the claimed gapmer compounds demonstrate unexpectedly effective knockdown of UMLILO expression in inflammatory cells. The dependent claims recite specific sequences with specific architecture and specifical chemical modifications which are not taught or suggested by the cited prior art.
Regarding Applicants’ fifth argument, firstly the data in the specification is discussed above. Secondly, instantly claimed SEQ ID NO: 233 does not appear to perform any better than SEQ ID NO: 230 (which is what is taught in Fanucchi et al.) when comparing table 14 (SEQ ID NO: 230) and Table 8-13 (SEQ ID NO: 233). Therefore, the data does not establish any specific chemical modification or architecture results in a better than expected effect. With regard to the specific chemical modification and architecture, Rungta et al. teaches 4-104 and MOE modifications. Therefore, the examiner does not agree that the prior art doesn’t teach the same chemical modifications or architecture.
Conclusion
Applicants’ 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.
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/ABIGAIL VANHORN/ Primary Examiner, Art Unit 1636
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