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 .
Priority
Applicant’s claim to priority from PCT/US2019/052223 filed 09/20/2019 and from Provisional Application No. 62/734,196 filed 09/20/2018.
Application Status
This Application is a National Stage entry of International Application No. PCT/US2019/052223 under 35 U.S.C. § 371.
This Office Action is in response to amendments and arguments filed 05/06/2026.
Claim amendments filed 05/06/2026 are hereby acknowledged. Claims 1-3 are currently amended. Claims 52 and 69-71 are cancelled.
Claims 45-47, 51 and 53-68 are withdrawn as they are drawn to nonelected inventions and species. Claims 1-51 and 53-68 are currently pending.
Claims 1-44 and 48-50 are under examination in this Office Action.
Any objection or rejection not reiterated herein has been overcome by Applicants’ arguments and amendments and are withdrawn.
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 follows.
The following rejections are maintained from Office Action dated
11/07/2025, but are modified as necessitated by Applicant’s amendments:
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 non-obviousness.
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 and 2 are rejected under 35 U.S.C. §103 as being unpatentable over Hakonarson (Hakonarson, H. et al. US 8,575,120 B2; published November 5, 2013; previously cited) and Deleavey (Deleavey, G.F. et al. "Designing chemically modified oligonucleotides for targeted gene silencing". Chemistry & Biology, Vol. 19 (2012), pp: 937-954; previously cited).
Regarding claim 1 reciting “An oligomeric compound comprising
a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 contiguous nucleobases complementary to an equal length portion of nucleobases 24759-24791 of SEQ ID NO: 1…”, Hakonarson teaches a sequence, SEQ ID NO: 1206 (see Table 7, lines 60-65, column 57) that is 21 nucleotides in length, that comprises 13 nucleotides that are complementary to nucleotides 24759-24791 of SEQ ID NO: 1 of instant application.
SEQ ID NO: 1206 is: 5’ GAUCUAAGAGAGAAAA 3’
Alignment of nucleotides 24759-24791 of SEQ ID NO: 1 (Qy: query) with complementary of Hakonarson’ s SEQ ID NO: 1206 (Db: database) is shown below:
Query Match 43.6%; Score 14.4; DB 1; Length 16;
Best Local Similarity 93.8%;
Matches 15; Conservative 0; Mismatches 1; Indels 0; Gaps 0;
Qy 3 TTTTCTCTCTTAGAGC 18
|||||||||||||| |
Db 16 TTTTCTCTCTTAGATC 1
Regarding claim 2 reciting “An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 12, at least 14, at least 15, or at least 16 any of the nucleobase sequences of SEQ ID Nos: 14-157”, Hakonarson teaches a sequence that consists of 21 nucleotides and that has 13 of the nucleobases of SEQ ID NO: 133. See column 57, Table 7, between lines 60 and 65, SEQ ID NO: 1206.
Alignment of SEQ ID NO: 1206 (Db) with instant application’s SEQ ID NO: 133 (Qy) is shown below:
Query Match 90.0%; Score 14.4; Length 21;
Best Local Similarity 81.2%;
Matches 13; Conservative 2; Mismatches 1; Indels 0; Gaps 0;
Qy 1 GCTCTAAGAGAGAAAA 16
| :|:|||||||||||
Db 3 GAUCUAAGAGAGAAAA 18
Therefore, an oligonucleotide with a sequence that is 16 nucleotides in length comprising 13 contiguous nucleobases complementary to nucleotides 24759-24791 of SEQ ID NO: 1 is taught by Hakonarson.
Regarding claims 1 and 2 reciting “wherein the oligomeric compound is an antisense compound”, Hakonarson teaches oligonucleotides for gene targeting for therapeutic use against Type 1 diabetes, i.e. siRNA (see column 2, lines 40-43; Lines 60-67; column 3, lines 1-25). Hakonarson teaches that the terms “agent” and “test compound” are used to denote a chemical compound, a mixture of chemical compounds, a biological macromolecule that includes siRNA, shRNA, antisense oligonucleotides which exhibits the capacity to modulate the activity of the SNP containing nucleic acids described or their encoded proteins” (see column 10, lines 49-61).
Hakonarson teaches the use of vectors to carry the sequences encoding siRNAs (see column 5, lines 9-16).
However, Hakonarson also teaches an embodiment of the invention wherein the siRNAs are delivered naked, or conjugated, or with a carrier, therefore, siRNAs are taught within an oligomeric compound in pharmaceutically acceptable formulations (see column 18, lines 25-35).
Hakonarson does not teach an oligomeric compound comprising a modified oligonucleotide. However, Deleavey teaches modifications of oligonucleotides designed for targeted gene silencing (see title).
Deleavey teaches modifications such as internucleotide linkages, i.e. phosphorothioate, phosphonoacetate, boranophosphate, and peptide nucleic acid modifications (see Figure 4).
Deleavey also teaches sugar modifications on each nucleobase, i.e. 2’-O-Me, 2’-F, 2’-O-MOE and LNA (see Figure 6).
Therefore, it would be obvious to one with ordinary skills before the effective filing date of the claimed invention to have tried and administered the siRNA as a naked formulation as suggested by Hakonarson and modified with the chemical modifications taught by Deleavey. One with ordinary skills in the art motivated in administering to a subject a naked siRNA formulation that can be stable and escape degradation would have been interested in such modifications and could have performed the modifications with a reasonable expectation of success and arrived at the claimed invention.
Response to Arguments
Applicant’s arguments, see Remarks filed 05/06/2026, page 8, with respect to the rejections of claims 1 and 2 under 35 U.S.C. §103 as unpatentable over Hakonarson (US 8,575,120) and Deleavey (Deleavey et al. Chemistry & Biology, Vol. 19(2012), 937-954), have been fully considered but are not persuasive.
Hakonarson teaches an oligonucleotide claimed in claims 1 and 2. Hakonarson also teaches that the oligonucleotides can be therapeutic siRNA (see column 10, lines 49-61, and column 17, lines 29-67). Deleavey teaches modifications of siRNA oligonucleotides, which are routine in the art. The combination of references renders the modified antisense oligonucleotides obvious.
Claims 1-7, 17-22, 24, 28-32, 35-36, 48 and 50 are rejected under 35 U.S.C. §103 as being unpatentable over Lee (Lee, J.M. et al. “Modulation of LMNA splicing as strategy to treat prelamin A diseases”. The Journal of Clinical Investigation. Vol. 126, No. 4 (2016), pp: 1592-1602; previously cited), Genschel (Genschel, J. et al. "Mutations in the LMNA gene encoding Lamin A/C". Human Mutation, Vol. 16 (2000), pp: 451-459; previously cited), NM_001282626 (Exons sequences of GENBANK Accession No. NM_001282626.1 published September 17, 2013, updated under NM_001282626.2 on May 3, 2019; previously cited) and Kole (Kole et al. US 9,066,967 B2; published June 30, 2015, priority date from US2014/0024821 A1 dated January 23, 2014 and Application No. 13/708,708 filed December 7, 2012; previously cited).
Regarding claims 1-4, Lee teaches that alternatively spliced products of LMNA, lamin C and prelamin A are produced in similar amounts in tissues and have redundant functions. Therefore, the redundancy suggests that Lamin A diseases could be rescued via shifting production of one mutated isoform towards a functional non-mutated isoform performing the same function. Lee teaches that Hutchinson-Gilford Progeria Syndrome (HGPS) caused by prelamin A-specific mutation could be treated by shifting the output of LMNA more toward Lamin C production (see abstract and “Introduction” sections). Lee also teaches that most point mutations causing HGPS are located in exon 11. Lee teaches that these point mutations cause an aberrant mRNA splicing which produces a mutant prelamin A protein containing an internal deletion of 50 amino acids (see page 1592, “Introduction” section, right column, third paragraph).
Lee teaches the use of antisense oligonucleotides ASOs complementary to sequence of exon 11, capable of modulating splice-site utilization and leading to Lamin C production (see page 1593, left column, third paragraph; and “Results” section, left column, first paragraph).
Lee shows that sequences in Exons 10 and 11, and therefore sequences in introns between these two exons as well, are necessary to modify alternative splicing and produce prelamin A or Lamin C and contain mutation and binding sites for splicing factors (see page 1596, right paragraph, lines 3-5; see Figure 4 and below).
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Lee states “An exon-10 to exon -12 genomic fragment containing the HGPS point mutation (c.1824;C>T) was subclones into the RHCglo reporter plasmid”.
Lee teaches knocking down each splicing factor binding sites and shows reduction in LMNA mRNA expression using ASOs (see figure 4D).
Lee teaches ASOs E11-31 (Exon 11- nt 31 of exon 11) and similar ASOs with sequences -4 nt or +4 nt relative to E11-31) (see page 1593, left column, “Results” section). Lee teaches ASOs starting at nt 26 to nt 41 of exon 11 (see Figure 1).
Lee teaches that to identify sequences that regulate lamin C/prelamin A splicing, mouse fibroblasts were transfected with a series of 20-nt ASOs corresponding to exon 10, intron 10, and exon 11 sequences and that all ASOs were modified oligonucleotides containing phosphorothioate linkages in the backbone and 2’-O-methoxyethyl substitutions of the sugar moiety (see page 1593, left column, “Results” section).
Lee also teaches that after modulation of expression using ASOs, there is reduction of laminC/prelamin A splicing. However, there is still residual expression of prelamin A (see Figure 6).
Genschel teaches mutations in laminopathies involving Lamin A/C gene. Genschel teaches that Exon 11 and 12 are specific for lamin A, with a sequence coding for the carboxy-terminal CAAX box of prelamin A in exon 12. Genschel teaches that this precursor prelamin A is converted into mature lamin A after incorporation into the lamina structure, this conversion depending upon isoprenylation of prelamin A occurring at a cysteine residue of the CAAX box (see page 452, right column).
Therefore, Genschel’s teachings suggest that conversion of mutated prelamin A into mutated lamin A and incorporation into the lamina structure can still occur, as long as the CAAX box are still present in exons 11 and 12 (see Figure 1).
NM_001282626 exon 12 aligns with the sequences 16-33 of SEQ ID NO: 1, in fragment 24759-24791, i.e. 24,775-24,791. See below (Qy = Query: SEQ ID NO: 1- 24759-24791; Db = database: NM_001282626.2 exon 12).
Query Match 54.5%; Score 18; DB 1; Length 1002;
Best Local Similarity 100.0%;
Matches 18; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 16 AGCCCCCAGAACTGCAGC 33
||||||||||||||||||
Db 1 AGCCCCCAGAACTGCAGC 18
NM_001282626 exon 12 aligns with the sequences 6-23 of SEQ ID NO: 2, in fragment 2176-2198, i.e. 2182-2198. See below (Qy = Query: SEQ ID NO: 2, 2062-2085; Db = database: NM_001282626.2 exon 12).
Query Match 78.3%; Score 18; DB 1; Length 1002;
Best Local Similarity 100.0%;
Matches 18; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 6 AGCCCCCAGAACTGCAGC 23
||||||||||||||||||
Db 1 AGCCCCCAGAACTGCAGC 18
NM_001282626 exon 12 aligns with the sequences 7-24 of SEQ ID NO: 2, in fragment 2062-2085, i.e. 2069-2085. See below (Qy = Query: SEQ ID NO: 2, 2176-2198; Db = database: NM_001282626.2 exon 12).
Query Match 75.0%; Score 18; DB 1; Length 1002;
Best Local Similarity 100.0%;
Matches 18; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 7 AGCCCCCAGAACTGCAGC 24
||||||||||||||||||
Db 1 AGCCCCCAGAACTGCAGC 18
These alignments indicate that the complementary region claimed as targets in claims 1-4 are regions from native LMNA/C gene encompassing exon 11, intron 11 and exon 12. It indicates that the claimed region overlaps in the intronic sequence and the first 18 nt of exon 12 sequence.
NM_001282626 shows that this region of LMNA/C is known, has been sequenced and is published.
Kole also teaches Human Lamin A targeted antisense compounds that are splice-switching oligonucleotides SSOs (see column 1, line 18-19; see same column, lines 44-51).
Kole teaches that SSOs contain 12-40 nucleotide bases and complementary to exon 10, intron 10, exon 11 and/or combinations thereof of a human LMNA pre-mRNA (see column 2, lines 9-12). Kole teaches that in some embodiments, the targeting sequence is complementary to a region that overlaps the splice junction of splice donor (SD) or splice acceptor (SA) sites of exons 10 and 11 of LMNA pre-mRNA, and is complementary to a portion of an exonic region and a portion of an intronic region of the pre-processed mRNA (see column 2, lines 45-50).
Therefore, since Lee teaches that using the ASOs as taught leads to residual expression of prelamin A, Genschel’s teachings suggest that conversion of residual mutated prelamin A into mutated lamin A and incorporation into the lamina structure can still occur, as long as the CAAX box present in exons 11 and 12 are still present (see Figure 1). Kole teaches that SSOs can be designed using target sequences between exons, at the junction of exons and introns.
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have tried and dissected not only the intron 10-exon 11 junction, but also exon 11- intron 11 and intron 11 - exon 12 junctions and designed ASOs specific for this region using the sequence taught by NM_001282626. One with ordinary skills in the art could have substituted the ASOs taught by Lee and Kole, with ASOs targeting exon 11 and 12 and intronic sequences between exons 11 and 12. One motivated in blocking the Splicing junction making the full-length pre-lamin A pre-mRNA encoding a protein with a functional CAAX box specifically, could have performed this substitution with a reasonable expectation of success since the sequence is known and since there is a finite amount of ASOs that can be designed in the region of exon 11, intron-11 and exon 12. One with ordinary skills in the art could have designed these oligonucleotides and used/tested them as directed by Lee and Kole, through routine experimentation, with a reasonable expectation of success and arrived at the claimed invention.
Regarding claim 5, Kole teaches that the oligonucleotide analog refers to an oligonucleotide having “(i) a modified backbone structure”, and “(ii) optionally, modified sugar moieties” (see column 11, lines 31-36).
Regarding claims 6-7, Lee teaches a modified sugar moiety on each nucleotide (see column 3, lines 22-24). Lee teaches a modified sugar moiety that is a 2’-methoxyethyl ribosyl sugar moiety. Lee teaches that all ASOs were modified oligonucleotides containing phosphorothioate linkages in the backbone and 2’-O-methoxyethyl substitutions of the sugar moiety (see page 1593, left column, “Results” section). The obviousness of combining the references Lee, NM_00182626 and Kole, is discussed above.
Regarding claims 17 and 18, Kole teaches subunits (subunit referring to one nucleotide), linked with inter-subunit linkage, a phosphorothioate linkage or a cationic linkage (see column 11, lines 57-63).
Regarding claims 19 and 20, Kole teaches compounds where each subunit is linked by a phosphorothioate linkage (see column 27, lines 35-40).
Regarding claim 21, Kole teaches optional linkers comprising phosphorothioate and phosphodiester linkage (see column 27, lines 33-34; column 67, lines 53-57).
Regarding claim 22, Kole teaches either phosphodiester linkage or phosphorothioate linkage in oligonucleotides, stating “typical intersubunit linkers include phosphodiester and phosphorothioate moieties” (see column 27, line 33).
Regarding claim 24, Kole teaches that the base pairing moiety may be a purine or pyrimidine found in native DNA or RNA, or analog (see column 32, lines 39-43). Kole is silent about gapmers.
Regarding claims 28, 29 and 31, Kole teaches “subunits” /nucleobases (adenine, cytosine, guanine, thymine or inosine, see column 11, lines 63-64) being modified, e.g. 5’-methylcytidine etc. (see column 11, lines 63-67; column 12, lines 1-25).
Regarding claims 30 and 32, Kole teaches nucleobase that can be hypoxanthine (see column 27, lines 63-65).
Regarding claim 35, Kole teaches an oligomeric compound consisting of the modified oligonucleotide (see column 27, lines 51-60; see claim 1, column 117).
Regarding claim 36, Kole teaches oligonucleotides conjugated with peptides (see column 85, lines 27-38; see column 86, lines 1-3).
Regarding claim 48, Kole teaches that intersubunit linkage can be a phosphate group (see column 11, lines 61-62), therefore, a conjugate could be attached with a phosphate group as well.
Regarding claim 50, Kole teaches that the oligonucleotides can be either a single-stranded RNA or a single -stranded DNA (see column 11, lines 42-43).
Response to Arguments
Applicant's arguments filed 05/06/2026 have been fully considered but they are not persuasive.
Applicant’s arguments, see Remarks, pages 9-11, with respect to the rejections of claims 1-7, 17-22, 24, 28-32, 35-36, 48 and 50 under 35 U.S.C. § 103 as unpatentable have been fully considered but are not found persuasive.
The rejections are made in view of the combination Lee (Lee, J.M. et al. “Modulation of LMNA splicing as strategy to treat prelamin A diseases”. The Journal of Clinical Investigation. Vol. 126, No. 4 (2016), pp: 1592-1602; previously cited), Genschel (Genschel, J. et al. "Mutations in the LMNA gene encoding Lamin A/C". Human Mutation, Vol. 16 (2000), pp: 451-459; previously cited), NM_001282626 (Exons sequences of GENBANK Accession No. NM_001282626.1 published September 17, 2013, updated under NM_001282626.2 on May 3, 2019; previously cited) and Kole (Kole et al. US 9,066,967 B2; published June 30, 2015, priority date from US2014/0024821 A1 dated January 23, 2014 and Application No. 13/708,708 filed December 7, 2012; previously cited).
In response to applicant's argument that the combination of references does not provide a reasonable expectation of success, Examiner would like to remind that the claims are drawn to a composition, the composition being an oligomeric compound that is an antisense compound. There is a reasonable expectation of success to have considered and tested the same series of oligomeric compounds based on the combined knowledge of the references. The claims are not drawn to a method of use of said compound(s) and its(their) end result.
In response to Applicant’s arguments on page 12, against the combination of
references, that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, Lee teaches that Hutchinson-Gilford Progeria Syndrome (HGPS) caused by prelamin A-specific mutation could be treated by shifting the output of LMNA more toward Lamin C production (see abstract and “Introduction” sections). Lee also teaches that most point mutations causing HGPS are located in exon 11.
Alignments with NM_001282626 indicate that the complementary region claimed as targets in claims 1-4 are regions from native LMNA/C gene encompassing exon 11, intron 11 and exon 12. Genschel’s teachings suggest that conversion of residual mutated prelamin A into mutated lamin A and incorporation into the lamina structure can still occur, as long as the CAAX box present in exons 11 and 12 are still present (see Figure 1). Kole teachings suggest that SSOs can be designed using target sequences between exons, at the junction of exons and introns.
Therefore, the combination of references provides motivation for a systematic dissection of the region using overlapping oligonucleotides to one with ordinary skills in the art and would have arrived at a series of oligonucleotides including the claimed sequences. The end result of a method of using these oligonucleotides and their effectiveness is not the object of the claims, as they are drawn to the compounds.
In response to applicant's argument, on page 13, that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant argues on page 14 that “The Examiner has respectfully not met this burden. Further, a “mere statement that the claimed invention is within the capabilities of one of ordinary skill in the art is not sufficient by itself to establish a prima facie obviousness”.” Applicant cites MPEP § 2143.01, section IV, which specifically states “Rejections on obviousness cannot be sustained by mere conclusory statements; instead, there must be some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness”. Indeed, Examiner cited Lee, Genschel, NM_001282626 and Kole. Lee, Genschel and Kole combination’s teachings lead to knowledge in the field and are testimony of works identifying antisense oligonucleotides interfering with pre-lamin A gene expression. NM_001282626 teaches the sequence comprising the elements claimed by Applicant. These elements/sequences are part of the public domain. Instant rejected claims are not drawn to a specific method using a specific unknown sequence. The claims are drawn to a product that can be envisaged from current knowledge. A systematic dissection of intron/exon 11 and intron/exon 12 that Genschel and Kole pointed to as being a region of interest, can lead to the claimed product(s), regardless of a method of use and its end-result. The prima facie case of obviousness is based on known sequences, and on methods of identifying and isolating such sequences, which are routine knowledge in the art.
Applicant argues that the claims are drawn to “specifically claimed compounds, which comprise specific sequences and modifications”. Examiner respectfully disagrees. The rejected claims as written are drawn to generic compounds (i.e., no specific pattern of modification) based on sequences known in the art. Examiner has listed the claims that are potentially allowable below, because those are the claims drawn to specific compounds.
As far as the rejected claims, Applicant's arguments do not comply with 37 CFR 1.111(c) because they do not clearly point out the patentable novelty which he or she thinks the claims present in view of the state of the art disclosed by the references cited or the objections made. Further, they do not show how the amendments avoid such references or objections.
Claims 8-9, 23, and 26-27 are rejected under 35 U.S.C. §103 as being unpatentable over Lee (Lee, J.M. et al. “Modulation of LMNA splicing as strategy to treat prelamin A diseases”. The Journal of Clinical Investigation. Vol. 126, No. 4 (2016), pp: 1592-1602; previously cited), Genschel (Genschel, J. et al. "Mutations in the LMNA gene encoding Lamin A/C". Human Mutation, Vol. 16 (2000), pp: 451-459; previously cited), NM_001282626.1 (Exons sequences of GENBANK Accession No. NM_001282626.1 published September 17, 2013, updated under NM_001282626.2 on May 3, 2019; previously cited) and Kole (Kole et al. US 9,066,967 B2; published June 30, 2015, priority date from US2014/0024821 A1 dated January 23, 2014 and Application No. 13/708,708 filed December 7, 2012; previously cited), as applied to claim 1 above, and in further view of Bennett (Bennett et al. US 9,856,473 B2; published January 2, 2018, priority date from US 2014/0309282 A1, October 16, 2014 and Application No. 14/315,186 filed June 25, 2014; previously cited).
As described above, the combination of Lee, Genschel, NM_001282626 and Kole renders obvious the elements of claims 1 and 5. The rejections of claims 1 and 5 are discussed above.
Regarding claim 8, the combination of references does not teach a bicyclic sugar moiety having a 2’-4’ bridge. However, Bennett teaches bicyclic nucleic acids having a bridge between the 4’ and the 2’ position of the ribofuranosyl moiety (see column 8, lines 37-43 and lines 49-56).
Regarding claim 9, the combination of references does not teach a 2’-4’ bridge selected from -O-CH2- and -O-CH(CH3)-. However, Bennett teaches methyleneoxy bridge (4’-CH2-O-2’) bicyclic nucleic acid (see column 8, line 55 and column 17, lines 22, 34).
Regarding claim 23, the combination of references does not teach specifically gapmers. However, Bennett teaches gapmers (see column 23, line 3; column 25, line 53).
Regarding claims 26 and 27, the combination of references is silent about the exact number of linkages throughout the oligonucleotide. Lee teaches that the oligonucleotide is 20 nucleotides in length, and all are linked with phosphorothioate linkages (see page 1593, left column, “Results” section). However, Lee is silent about the numbers of modified linkage in each oligonucleotide.
Bennett teaches that in one embodiment, the antisense compounds further comprise phosphorothioate linkages at each position and throughout the oligonucleotide (see page 2, [0021]; page 13, [0122]).
Therefore, it would have been obvious to one of ordinary skills in the art before the effective filing date of the claimed invention to have combined the teachings of Lee, Genschel, NM_001282626 and Kole, with the teachings of Bennett, and designed/synthesized oligonucleotides targeting exon 11, intron 11 and exon 12, to be more stable to different environmental conditions by incorporating the modifications taught by Bennett. One with ordinary skills in the art, motivated in stability and efficiency of delivery, could have performed these modifications with a reasonable expectation of success and arrived at the claimed invention.
Response to Arguments
Applicant's arguments filed 05/06/2026 have been fully considered but they are not persuasive.
Applicant states in Remarks, page 15, that “Bennett does not cure the deficiencies of Lee, Genschel, NM_001282626 and Kole.”
In response to applicant’s argument, the combination of references Lee, Genschel, NM_001282626 and Kole renders elements of claim 1 obvious, as stated above, since the claims are drawn to structures that can be envisaged from knowledge in prior art. Bennett’s disclosure is also drawn to oligonucleotides for therapeutic treatment of diseases through modulation of expression of LMNA (see title and abstract). Therefore, Bennett’s modifications to oligonucleotides targeting LMNA mRNA are relevant as teachings to implement design of stable oligonucleotides targeting the same mRNA.
Claims 10-12 are rejected under 35 U.S.C. §103 as being unpatentable over Lee (Lee, J.M. et al. “Modulation of LMNA splicing as strategy to treat prelamin A diseases” . The Journal of Clinical Investigation. Vol. 126, No. 4 (2016), pp: 1592-1602; previously cited), Genschel (Genschel, J. et al. "Mutations in the LMNA gene encoding Lamin A/C". Human Mutation, Vol. 16 (2000), pp: 451-459; previously cited), NM_001282626 (Exons sequences of GENBANK Accession No. NM_001282626.1 published September 17, 2013, updated under NM_001282626.2 on May 3, 2019; previously cited) and Kole (Kole et al. US 9,066,967 B2; published June 30, 2015, previously cited), in view of Bennett (Bennett et al. US 9,856,473 B2; published January 2, 2018, priority date from US 2014/0309282 A1, October 16, 2014 and Application No. 14/315,186 filed June 25, 2014; previously cited) as applied to claims 1, 8 and 9 above, and in further view of Crooke ( Crooke, R.M. et al. WO 2014/018930, published January 30, 2014; previously cited).
As described above, the combination (of Lee, Genschel, NM_001282626, Kole and Bennett) renders obvious the elements of claims 1, 8 and 9 obvious. The rejections of claims 1, 8 and 9 are discussed above.
Regarding claims 10-12, the combination of Lee, Genschel, NM_001282626, Kole and Bennett does not teach an oligomeric compound wherein the 2’-4’ bridge is -O-CH(CH3)-.
However, Crooke teaches a methyl (methyleneoxy) (4’-CH(CH3)-O-2’) bridge between the 4’ and the 2’ carbon atoms of a furanosyl sugar of a bicyclic nucleoside (see page 8, lines 15-17; and page 32, line 2).
It would be obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have combined the teachings of Lee, Genschel, NM_001282626, Kole and Bennett with the teachings of Crooke. One with ordinary skills in the art motivated in further enhancing the stability of the oligomeric compound and antisense oligonucleotide could have introduced a 4’-CH(CH3)-O-2’ bridge within the structure of Kole’s nucleotide as taught by Crooke. This 4’-CH(CH3)-O-2’ bridge modification locks the oligonucleotide in a more rigid and therefore stable structure and is now well-known in the art, as taught by Crooke. Therefore, it would be applying a known modification to a well-known and routine tool for gene expression modulation. One with ordinary skills in the art could have performed this modification with a reasonable expectation of success and arrived at the claimed invention.
Response to Arguments
Applicant's arguments filed 05/06/2026 have been fully considered but they are not persuasive.
Applicant states in Remarks, page 15, that “Crooke does not cure the deficiencies of Lee, Genschel, NM_001282626, Kole and Bennett".
The obviousness of structures that can be envisaged from prior art and specifically from the combined references Lee, Genschel, NM_001282626 and Kole, is explained in the response above.
In response to applicant’s argument, Lee, Genschel, NM_001282626, Kole and Bennett are all focused on LMNA, lamin A and lamin C/progerin genes alterations. Lee, Kole and Bennett are drawn to antisense oligonucleotides to alter pre-laminA mRNA expression. Kole and Bennett are also drawn to modifications to increase stability of ASOs. Genschel teaches that mutations in LMNA gene can lead to cardiomyopathies and lipodystrophy (see abstract), and Crooke is drawn to heart/myocardial disease, hypertension, cardiovascular diseases (see page 1, lines 16-31, and page 2, lines 1-3). Both Genschel and Crooke give motivation to design oligonucleotides for an end target organ susceptible to be damaged in these diseases, i.e. the heart; Crooke states “Hence, an AGT antisense oligonucleotide may be able to reverse organ damage and/or fibrosis caused by hypertension in a subject” (see page 57, lines 25-28). More importantly, Kole, Bennett and Crooke teach methods of modifying antisense oligonucleotides for stable and efficient delivery in subjects to treat diseases.
Claims 37-41 are rejected under 35 U.S.C. §103 as being unpatentable over Lee (Lee, J.M. et al. “Modulation of LMNA splicing as strategy to treat prelamin A diseases”. The Journal of Clinical Investigation. Vol. 126, No. 4 (2016), pp: 1592-1602; previously cited), Genschel (Genschel, J. et al. "Mutations in the LMNA gene encoding Lamin A/C". Human Mutation, Vol. 16 (2000), pp: 451-459; previously cited), NM_001282626 (Exons sequences of GENBANK Accession No. NM_001282626.1 published September 17, 2013, updated under NM_001282626.2 on May 3, 2019; previously cited) and Kole (Kole et al. US 9,066,967 B2; published June 30, 2015, priority date from US2014/0024821 A1 dated January 23, 2014 and Application No. 13/708,708 filed December 7, 2012; previously cited), as applied to claims 1 and 36 above, and in further view of Hvam ( Hvam, M.L. et al. Molecular Therapy, Vol. 25 (2017), pp: 1710-1717; previously cited).
As described above, the combination of Lee, Genschel, NM_001282626, and Kole renders elements of claims 1 and 36 obvious. The rejections of claims 1 and 36 are discussed above.
Regarding claims 37-41, the combination of Lee, Genschel, NM_001282626, and Kole does not teach a modification of the oligonucleotide that involves conjugating with a moiety comprising a lipophilic group, nor a fatty acid, nor a C16 alkyl. Kole is silent/does not teach a conjugate linker that consists of a single bond.
However, regarding claim 37, Hvam teaches an antisense oligonucleotide that is modified using a fatty acid, i.e. a lipophilic group (see title, abstract and Figure 1).
Regarding claim 38, 39 and 40, Hvam teaches a conjugate moiety that is a C16 saturated fatty acid, palmitic acid (see figure 1; “R” is palmitoyl or myristoyl).
Regarding claim 41, Hvam teaches a single bond attachment of palmitic acid (see Table 1, ASO no. 2, 5, 8 and 11).
Hvam teaches that ASOs modified with a Fatty-acid conjugate have better biodistribution, increased half-life and serum stability (see title, abstract, and page 1710, “Introduction” section).
It would have been obvious to one with ordinary skills before the effective filing date of the claimed invention to have modified the oligonucleotides targeting intron 11 and exon 12 of prelamin pre-mRNA, as taught by the combination of Lee/ Genschel/ NM_001282626/ Kole and attached a lipophilic group as taught by Hvam. The lipophilic group improves the delivery and biodistribution of antisense oligonucleotides as taught by Hvam. This modification is well known and is routine in the art, since it allows for obtaining a higher efficiency in delivering the oligonucleotide to tissue besides the liver and kidney where the oligonucleotides are rapidly processed. This modification allows for obtaining a higher half-life for the oligonucleotide and better biodistribution. One with ordinary skills in the art motivated in applying this known modification to a known tool, an antisense oligonucleotide or oligomeric compound comprising an oligonucleotide, for gene therapy, would have performed this modification with a reasonable expectation of success and arrived at the claimed invention.
Response to Arguments
Applicant's arguments filed 05/06/2026 have been fully considered but they are not persuasive.
Applicant argues in Remarks, pages 16, that “Hvam does not cure the deficiencies of Lee, Genschel, NM_001282626, and Kole”.
The obviousness of structures that can be envisaged from prior art and specifically from the combination of references is described above. Lee, Genschle, NM_001282626, Kole and Bennett are all focused on LMNA, lamin A and lamin C/progerin genes alterations. Lee, Kole and Bennett are drawn to antisense oligonucleotides to alter pre-laminA mRNA expression. Kole, Bennett and Hvam are drawn to modifications to increase stability of ASOs. Hvam further teaches how to obtain stability of any ASO and/or gapmer in serum. Hvam teaches method to increase the half-life and biodistribution of ASOs using fatty acids as conjugates.
Claims 42-44 are rejected under 35 U.S.C. §103 as being unpatentable Lee (Lee, J.M. et al. “Modulation of LMNA splicing as strategy to treat prelamin A diseases”. The Journal of Clinical Investigation. Vol. 126, No. 4 (2016), pp: 1592-1602; previously cited), Genschel (Genschel, J. et al. "Mutations in the LMNA gene encoding Lamin A/C". Human Mutation, Vol. 16 (2000), pp: 451-459; previously cited), NM_001282626 (Exons sequences of GENBANK Accession No. NM_001282626.1 published September 17, 2013, updated under NM_001282626.2 on May 3, 2019; previously cited) and Kole (Kole et al. US 9,066,967 B2; published June 30, 2015, priority date from US2014/0024821 A1 dated January 23, 2014 and Application No. 13/708,708 filed December 7, 2012; previously cited), as applied to claims 1 and 36 above, and in further view of Subramanian (Subramanian, R.R et al. Nucleic Acids Research, Vol. 43 (2015), pp: 9123-9132; previously cited).
The rejections of claims 1 and 36 are described above. The combination of Lee, Genschel, NM_001282626, and Kole renders elements of claims1 and 36 obvious. The rejections of claims 1 and 36 are discussed above.
Regarding claims 42-44, the combination of Lee, Genschel, NM_001282626, and Kole does not teach a conjugate linker that is cleavable, a linker that comprises 1-3 linker nucleosides, nor an oligomeric compound comprising no more than 24 total linked nucleosides including the modified oligonucleotide and the linker nucleosides.
However, Subramanian teaches a linker that is cleavable (claim 42) (see title and “[A]bstract” section; see Table 1 and page 9127, left column, first line). Subramanian teaches that the phosphodiester linker is required for cleavage activity in vivo compared to phosphorothioate linker (see Figures 4A and 4B).
Regarding claim 43, Subramanian teaches linkers with different lengths (see figure 2, “doses were adjusted for linker length”). Figure 1 show examples that comprises 4 nucleosides.
Regarding claim 44, Subramanian teaches oligomeric compounds that vary in sizes in Table 1. Subramanian also teaches oligomeric compounds comprising one linker that are less than 24 total linked nucleosides.
It would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have combined the teachings the combination of Lee, Genschel, NM_001282626, and Kole with the teachings of Subramanian, and optimized the linker length to obtain a cleavable linker within the oligomeric compound. One motivated in designing the optimal and efficient oligomeric compound, using more than one oligonucleotide for efficient knockdown of the gene of interest could have combined the teachings and performed this modification to obtain cleavage and release of the oligonucleotides. The number of nucleosides within the linker is a known variable that would require routine optimization. Creating multiple oligomeric compounds with cleavable linkers comprising 1-3 nucleosides is a result-oriented variable and would be obvious to one skilled in the art as a variation of known elements, which yield a predictable result. One with ordinary skills in the art motivated in delivering multiple oligonucleotides with equal efficiency could have performed this modification with a reasonable expectation of success and arrived at the claimed invention.
Response to Arguments
Applicant's arguments filed 05/06/2026 have been fully considered but they are not persuasive.
Applicant argues in Remarks, page 16, that “Subramanian does not cure the deficiencies of Lee, Genschel, NM_001282626, and Kole”.
In response to applicant’s argument, Lee, Genschle, NM_001282626, and Kole are all focused on LMNA, lamin A and lamin C/progerin genes alterations. Lee and Kole are drawn to antisense oligonucleotides to alter pre-laminA mRNA expression.
Lee makes it obvious that ASOs targeting intron 10 and exon 11 alone are not sufficient to alter dramatically the expression level of pre-laminA pre-mRNA. Therefore, it is more likely that one with ordinary skills in the art would use multiple ASOs, which would target not only the region intron 10-exon 11’s junction, but also exon 11- intron 11 and intron 11-exon 12 junctions to abrogate the ability of residual pre-mRNA to comprise a CAAX box resulting in laminopathies. It is therefore obvious that multiple ASOs be linked and designed in tandem to obtain simultaneous delivery in equal amounts. Modifying the ASOs with linkers to obtain these oligomeric compounds using the teachings of Subramanian is obvious.
Allowable Subject Matter
Claims 13-16, 25, 33-34 and 49 are 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.
Conclusion
Claims 2, 13-16, 25, 33-34 and 49 are objected to.
Claims 1-12, 17-24, 26-32, 35-44, 48 and 50 are rejected.
THIS ACTION IS MADE FINAL. 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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/A.D./Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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