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 .
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 04/14/2026 is acknowledged.
Claims 77-86 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 04/14/2026.
STATUS OF CLAIMS
Claims 1-69 are cancelled.
Claims 70-86 are pending.
Claims 70-76 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application, 63/391,161, under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c), with filing date 07/21/2022 is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/13/2024 and 02/19/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings are objected to because the drawings submitted on 07/21/2023 are in color. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 70 is rejected under 35 U.S.C. 103 as being unpatentable over Leventhal L. et. al., (WO2021108602A1, in IDS) in view of Hua Y. et. al., (Methods Mol Biol. 867:307-23, published 2012), Bloom, A. et. al., (WO2022197941A2, effective filing date 03/17/2021), and Swayze; E. et. al., (US20170037410A1).
Levanthal teaches “compositions and methods for treating neurodegeneration and neurodegenerative diseases associated with axonal degeneration,” such as “amyotrophic lateral sclerosis,” using “therapies comprising SARM1 inhibitors such as SARM1 antisense oligonucleotides,” see abstract and [0017]. Levanthal teaches the antisense oligonucleotide may comprise “a sequence selected from a group consisting of SEQ ID NO: 3-2412,” which span the entire SARM1 transcript, see [0004], figure 1 (which shows a map of antisense oligonucleotides complementary to human SARM1 mRNA), Table 2, Table 3, EXEMPLARY SEQUENCES, SEQ ID NO: 2, and [0143 and 0146]. Levanthal further teaches the target nucleic acid is a SARM1 transcript in the form of either a “ a pre-mRNA” or “a mature RNA,” see [0067]. “Levanthal teaches the antisense oligonucleotide “comprises one or more modifications” including “phosphorothioate internucleotide linkages” and may be a gapmer, see [0044] and [0071]. Levanthal further teaches the “modified oligonucleotides … are formulated as a prodrug,” see [0135].
Levanthal further teaches “pharmaceutical compositions comprising antisense oligonucleotides” and that “a pharmaceutical composition comprises a pharmaceutically acceptable carrier,” and that a pharmaceutically acceptable carrier “means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material,” which may be “pH buffered solutions,” see [0007] and [0050]. Levanthal further teaches the composition comprises a “pharmaceutically acceptable salt,” see [0051] and “Pharmaceutical Compositions” section.
Levanthal does not teach the specific antinucleotide sequence and modified structure of SEQ ID NO: 344.
Hua teaches “a two-step ASO-tiling method involving ASO walks to systematically screen hundreds of MOE ASOs targeting a gene of interest.” Hua and co-workers “successfully applied this method to target SMN2 exon 7 and its flanking introns in spinal muscular atrophy (SMA),” see introduction, paragraph 4. Specifically, Hua teaches the first step is a course walk involving a series of overlapping ASOs, and the second step is a high-resolution walk in 1-nucleotide steps focused on regions of interest identified in the first walk to identify optimal ASOs, see introduction paragraph 4. Hua further teaches that “the efficacy of ASOs can be tested in several splicing assays: cell-free splicing with in vitro transcribed pre-mRNA; splicing of minigenes transfected into cultured cells; and splicing of RNA expressed from the endogenous genes in cultured cells, patient fibroblasts, or animal models,” see introduction, paragraph 4. Hua further teaches that “MOE ASOs with a phosphorothioate backbone show superior antisense activities,” introduction, paragraph 5. Lastly, Hua teaches the MOE ASOs are efficient in “both peripheral tissues and the CNS,” see abstract.
Bloom teaches “isolated nucleic acid molecules,” including antisense RNAs, that “hybridize to SARM1 variant nucleic acid molecules (such as genomic nucleic acid molecules, mRNA molecules, and/or cDNA molecules),” and provides the SARM1 reference sequence as SEQ ID NO: 1, see claim 4 and [0074 and 0076]. SEQ ID NO: 344 of the instant case maps with 100% to the SARM1 reference sequence SEQ ID NO: 1 of Bloom. Bloom further teaches that the antisense RNAs may comprise “modified phosphate moieties” including but not limited to “a phosphorothioate, chiral phosphorothioate,” among many others, and that they may be in the form of a salt or mixed salt, see [0088].
Swayze teaches compounds comprising modified antisense oligonucleotides, see entire reference. More specifically, Swayze teaches that the modified antisense oligonucleotides comprising 20-nucleotides comprising “a gap segment consisting of 8 linked deoxynucleosides, a 5′ wing segment consisting of 5 linked nucleosides, and a 3′ wing segment consisting of 7 linked nucleosides; wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar,” see [0168][0028]. Swayze teaches that “wings may include several modified sugar moieties, including, for example 2′-MOE,” see [0407], and that “such sugar modified nucleosides may impart enhanced nuclease stability, increased binding affinity, or some other beneficial biological property to the antisense compounds,” see [0448]. Swayze further teaches that the modified antisense oligonucleotide may comprise a modified nucleobase such as 5-methylcytosine, see claims 14-15. Furthermore, Swayze teaches that “all cytosine residues throughout each gapmer are 5-methylcytosines,” see [0674]. Swayze teaches that chemically modified nucleobases are employed “to increase the binding affinity of a shortened or truncated oligonucleotide for its target nucleic acid,” see [0443]. Swayze also teaches antisense oligonucleotides with phosphorothioate internucleoside linkages (see claims and [0091][0136][0625]), and that “antisense compounds having one or more modified, i.e. non-naturally occurring, internucleoside linkages are often selected over antisense compounds having naturally occurring internucleoside linkages because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for target nucleic acids, and increased stability in the presence of nucleases,” see [0444]. Swayze further teaches that the modified antisense oligonucleotides (optionally as a salt) are part of a composition, which may be a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent (which may be a liquid such as phosphate buffered saline), see claim 58 and [0045][0519].
It would have been obvious to one of ordinary skill in the art (PHOSITA) before the effective filing date to prepare a modified antisense oligonucleotide 5-8-7 MOE gapmer targeting the SARM1 transcript comprising the sequence and structure set forth in SEQ ID NO: 344.
A PHOSITA would have been motivated because Levanthal teaches antisense oligonucleotides targeting different regions of the SARM1 transcript, including the 5’-UTR, the coding region, and the 3’-UTR can reduce SARM1 expression, and further teaches that effective antisense oligonucleotides may be complementary to either pre-mRNA or mature mRNA of the SARM1 transcript. Bloom provides the reference SARM1 nucleic acid sequence, thereby defining the target sequence space for antisense design. Furthermore, antisense oligonucleotides are routinely designed using systematic “tiling” of “walking” approaches in which overlapping oligonucleotides are generated across a target RNA and evaluated/screened to identify effective sequences. For example, Hua teaches a two-step ASO-tiling method involving “ASO walks” to systematically screen hundreds of MOE-modified antisense oligonucleotides targeting a gene of interest, including overlapping oligonucleotides with high-resolution mapping using single-nucleotide positional shifts to identify optimal sequences. Thus. In view of Bloom’s disclosure of the SARM1 reference sequence and Hua’s teaching of systematic ASO tiling methodologies, a PHOSITA would have been motivated to generate and evaluate a series of overlapping antisense oligonucleotides across the SARM1 transcript, including sequences complementary to regions of the SARM1 nucleic acid such as the region corresponding to SEQ ID NO: 344. Taken together, a PHOSITA would have understood that systematic evaluation of overlapping antisense oligonucleotides across the known SARM1 sequence was a standard and reliable approach to identify effective inhibitors.
With respect to the 5-8-7 gapmer architecture, a PHOSITA would have been motivated to design the antisense oligonucleotide with such a configuration because Swayze and Hua teach that gapmer antisense oligonucleotides comprising chemically modified flanking regions and a DNA gap provide functional advantages including enhanced nuclease resistance, increased binding affinity to the target RNA, and improved cellular uptake and biological activity. Swayze teaches that incorporation of modified sugars such as 2’-MOE in the flanking regions and modified nucleobases such as 5-methylcytosine can improve hybridization properties and stability of antisense oligonucleotides, while the central DNA gap facilitates RNase H-mediated cleavage of the target RNA. Swayze further teaches that antisense oligonucleotides having the 5-8-7 wing-gap-wing structure represent suitable configurations for achieving these combines properties. Accordingly, A PHOSITA would have been motivated to employ a 5-8-7 gapmer architecture with MOE-modified wings, a central DNA gap, and wherein each cytosine is a 5-methylcytosine as a predictable and effective design choice to enhance antisense performance.
A PHOSITA would have had a reasonable expectation of success because antisense oligonucleotide development involved designing multiple candidate oligonucleotides complementary to a target transcript and screening them to identify effective inhibitors, and the SARM1 transcript was known to be targetable across multiple regions throughout its length. Given the routine use of tiling approaches to generate 1-nt resolution overlapping candidate sequences and the established benefits of gapmer architectures with chemical modifications, a PHOSITA would have reasonably expected that antisense oligonucleotides constructed using these principles would yield functional inhibitors of SARM1 expression. The claimed oligonucleotide represents one of a finite number of predictable antisense nucleotides constructed using known gapmer design principles, including routine variation of segment lengths, sequence position, and chemical modifications.
Claims 71-76 are rejected under 35 U.S.C. 103 as being unpatentable over Leventhal L. et. al., (WO2021108602A1, in IDS) in view of Hua Y. et. al., (Methods Mol Biol. 867:307-23, published 2012), Bloom, A. et. al., (WO2022197941A2, effective filing date 03/17/2021), and Swayze; E. et. al., (US20170037410A1) as applied to claim 70 above, and further in view of Just G. et. al., (WO2000000499A1).
As discussed above, with respect to claim 70, while Levanthal, Hua, Bloom, and Swayze collectively teach the modified antisense oligonucleotide can be part of a composition, optionally in the form of a salt, and that the composition may be a pharmaceutical composition comprising a pharmaceutically acceptable carrier and may be delivered as a liquid, neither artisan explicitly teaches: 1) for each chiral linkage phosphorus, the percentage of the Rp configuration is independently about 20%-80%, or 2) the composition comprises one or more diastereomers of the oligonucleotide.
Just teaches that “since they exist as diastereomers, phosphorothioate, methylphosphonate, phosphotriester, phosphoramidate and other phosphorus and boranophosphate oligonucleotides synthesized using known, automated techniques result in mixtures of Rp and Sp diastereomers at the individual phosphorothioate, methylphosphonate, phosphotriester, phosphoramidate or other phosphorus linkages,” and thus, further teaches that, for example, “a 15-mer oligonucleotide containing 14 asymmetric linkages has 214, i.e. 16,384, possible stereo- isomers.” Just further teaches that “it is possible that oligomers having diastereomerically enriched linkages could possess advantages in hybridizing to a target mRNA or DNA,” and “accordingly, there is a need for such oligomers,” see pg. 4 lns. 3-14. Just further teaches that oligomers having diastereomerically enriched linkages may possess advantageous hybridization properties, including reports that oligonucleotides enriched in Rp configurations formed thermodynamically more stable hybrids than corresponding Sp-configured oligonucleotides, see pg. 5 lns 8-25. Just additionally teaches separation and preparation of Rp and Sp stereoisomers, including isolation of stereoisomerically enriched diastereomers such as “Sp-86” and “Sp-87,” demonstrating that phosphorus stereochemistry was recognized and controllable using known methods, see pgs. 122-123. Just further teaches preferred embodiments in which about 85%, about 95%, or substantially all phosphorothioate or boranophosphate linkages are present in a single stereoisomeric form, see pgs. 12-13.
It would have been obvious to one of ordinary skill in the art (PHOSITA) before the effective filing date to prepare the modified antisense oligonucleotide compositions of claims 71-76 comprising phosphorothioate linkages having Rp and Sp stereochemical configurations and one or more diastereomeric forms. Just teaches that phosphorothioate oligonucleotides synthesized using conventional automated methods inherently exist as mixtures of Rp and Sp stereoisomers at individual phosphorus linkages due to the chiral nature of phosphorothioate internucleotide linkages. Thus, a PHOSITA would have understood that preparation of phosohorothioate antisense nucleotides using known synthetic techniques would inherently produce oligonucleotides comprising stereochemical mixtures and diastereomeric forms. Furthermore, Just teaches that stereochemical configuration affects oligonucleotide hybridization properties and that stereoisomerically enriched oligonucleotides may exhibit improved thermodynamic stability and target binding characteristics. Just additionally teaches methods for separating and enriching Rp and Sp stereoisomers and further teaches preferred embodiments in which phosphorothioate linkages are present in defined stereochemical proportions or substantially enriched stereoisomeric forms. Accordingly, a PHOSITA would have recognized phosphorous stereochemistry as a result-effective variable and would have been motivated to optimize or control Rp and Sp stereochemical distributions to obtain desirable antisense properties.
A PHOSITA would have had a reasonable expectation of success because the prior art already recognized that phosphorothioate oligonucleotides inherently comprise Rp and Sp stereoisomers, that such stereochemical configurations influence hybridization and biological properties, and that stereoisomeric forms could be separated, enriched and characterized using known synthetic and purification methods. Just teaches both the preparation of stereochemically enriched oligonucleotide linkages and the functional significance of Rp and Sp configurations, including improved hybrid stability associated with certain stereochemical forms. Accordingly, a PHOSITA would have reasonably expected that preparing antisense oligonucleotides comprising mixtures or enriched proportions of Rp or Sp phosphorothioate linkages, including stereochemical distributions within the claimed ranged, could be achieved using routine oligonucleotide synthesis and optimization techniques while maintaining functional antisense activity.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to COREY LANE BRETZ whose telephone number is (571)272-7299. The examiner can normally be reached M-F 7:30am - 6:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at (571) 272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/COREY LANE BRETZ/Patent Examiner, 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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