DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on January 7 2026 is acknowledged. Claims 1-29 are pending in the application. Claims 24-28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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. Accordingly, claims 1-23 and 29 are being examined on the merits herein.
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 .
Priority
This application is a 371 of PCT/IB2021/060676 (11/17/2021) which claims benefit of 63/235,890 (08/23/2021) and claims benefit of 63/115,448 (11/18/2020) as reflected in the filing receipt issued on September 20 2023.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on May 16 2023, June 13 2025 and January 14 2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 1 is objected to because of the following informalities: The acronym “F-ANA” is not defined in the claims. When an acronym is used in a claim set, it should be defined the first time it appears in the claims. For the purposes of examination, the term “F-ANA” is interpreted to mean fluoro-arabino nucleic acid. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-23 and 29 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 as currently written is vague and indefinite. Claim 1 recites 2’-methoxyethyl (MOE) which is NOT indefinite and MOE is the abbreviation for 2’-methoxyethyl. However, claim 1 also recites 2’-O-methoxyethyl (2’ OMe). This recitation is indefinite. OMe typical stands for O-Methyl. But the claim indicates it means 2’-O-methoxyethyl which is of a different scope and already recited in the claim. Therefore, the scope of the claim is indefinite.
Claims 14 and 20 as currently written are vague and indefinite. Claims 14 and 20 depend from claim 1. Claim 1 recites a gapmer compound comprising a modified oligonucleotide…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.
Claim 14 recites the gapmer is selected from a group of specific sequences which include, for example, SEQ ID No 128, 42, 88, 101, 102, 123 and 124.
Claim 20 recites the modified oligonucleotide consists of the nucleobase sequence of SEQ ID NO: 150.
However, as shown in the instant specification (page 36-52) SEQ ID No: 128 (page 44) corresponds to 443 to 462 of human UMLILO position SEQ ID No: 231. SEQ ID NO: 42 corresponds to 461-480 (which does not result in 91% complementary over its entire length), SEQ ID No: 88 corresponds to 331-346, SEQ ID NO: 101 corresponds to 203-218, SEQ ID NO: 102 corresponds to 345-360, SEQ ID NO: 123 corresponds to 69-84 (which does not result in 91% complementary over its entire length), SEQ ID NO: 124 corresponds to 483-498 and SEQ ID NO: 150 corresponds to 493-508. None of these sequences meet the requirements as set forth in claim 1 for the regions of SEQ ID NO: 231 the sequence must complementary. This creates confusion as to the scope of the claim because it isn’t clear what is controlling, is it the wherein clause or the SEQ ID No.
Claim 29 as currently written is vague and indefinite. The claim depends from any one of claims 1-23. However, the claim recites “wherein the locked nucleic acid modification”. However, for example, claim 15 would exclude locked nucleic acid as the claim requires 2’-O-methoxyethyl modified nucleosides in the wings. This creates confusion since the claim depends from any of the recited claims 1-23 but many of the claims do not require locked nucleic acids.
Claims 2-13, 15-19 and 21-23 are included in the rejection as they depend on a rejected base claim and they do not clarify the issues.
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 1-23 and 29 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 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, 224-227, and 230 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, specifically for example SEQ ID No: 150. 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 claimed SEQ ID NO: 150 (Qy) and 230 (Qy) as shown below:
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305
680
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318
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Dalla et al. teach siRNA which are complementary to SEQ ID No; 54. This sequence, SEQ ID NO: 54 is complementary to Instantly claimed SEQ ID NO: 150 (Qy).
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304
691
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Thus, these reference teach expressly claimed SEQ ID NO: 150 and 230. 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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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.
Conclusion
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/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636