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 .
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because the application does not contain a statement that the CRF is identical to the "Sequence Listing" part of the disclosure, as described above in item 1), as required by 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii).
Required response - Applicant must provide such statement.
Application Status
This action is written in response to applicant’s correspondence received on 07/28/2026. Claims 189-209 are currently pending. Claims 195, 198-201, 205-208 are withdrawn from prosecution as being drawn to nonelected subject matter. Accordingly, claims 189-194, 196, 197, 202-204, and 209 are examined herein. The restriction requirement mailed on 04/29/2026 is still deemed proper. Applicant elected Group I without traverse in the reply filed on 07/28/2026.
Election/Restrictions
Applicant elects compound MOE-307 as the species without traverse. MOE-307 comprises the following ASO design: a. Length: 18 nucleotides; b. Sequence: 5'-CCGAAAGAAGTATGAACC-3' (SEQ ID NO:252); c. Complementary sequence in the CD33 pre-mRNA: SEQ ID NO:218; d. Nucleotide modification scheme: 2'-O-MOE modified ribonucleotides and a hydroxyl group at the 5' end; e. Internucleotide linkage modifications: the non-natural linkages are all stereopure phosphorothioate internucleotide linkages; f. Stereochemistry: SSOSSSSSSSSSSOSSS; g. Nucleobase modifications: none.
Claims 195, 198-201, 205-208 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected Group II, there being no allowable generic or linking claim.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
This application is a 371 of PCT/US2022/026760 filed on 04/28/2022, claims priority to PRO 63/334,496 filed on 04/25/2022, PRO 63/320,651 filed on 03/16/2022, PRO 63/181,023 filed on 04/28/2021. However, under 35 U.S.C. §119(e), a claim is entitled to the benefit of an earlier-filed provisional only to the extent that Provisional’s disclosure provides §112(a) written description support for that claim, and where supporting subject matter first appears in a later-filed provisional, the claim is accorded that later filing date for all purposes, including prior art available under 35 U.S.C. §102 (See MPEP §211.05). Claims 189-194, 196-197, 204, and 209 are supported by provisional No. 63/181,023 and are accorded an effective filing date of April 28, 2021; claims 202 and 203, reciting the elected species MOE-307 (SEQ ID NO:252, stereopattern SSOSSSSSSSSSSOSSS), are first supported across the full claim scope by the stereopure MOE data of Table 14/FIG. 28 in provisional No. 63/334,496, and are accordingly entitled to an effective filing date April 25, 2022.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on pages 47-48, ¶[0183]-¶[0184], page 87, ¶[0259]. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The disclosure is objected to because of the following informalities: Several recitations of a “U-188 MG” cell line on pages 34-35, ¶[0099]-[0101], page 71, ¶[0242], which appear to be likely typographical errors because no such cell line exists. The disclosure also recites several “U-118 MG”s, which is an art recognized cell line. These recitations of “U-188 MG” occur in the definitions of what constitutes the Standard Exon-Skipping Efficiency Assays for ASOs.
Appropriate correction is required.
Claim Rejections - 35 USC § 112 Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 189-194, 196, 197, 202-204, and 209 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
The independent claim 189 is directed to an extremely broad genus of ASO of 16-30 nucleotides complementary to a portion of SEQ ID NO:1, functionally defined by having ≥30% Exon-2 skipping efficiency, whereas no common structure that underlies the functional limitation is disclosed. In another word, it claims what the product does instead of what the product is.
Claims 190 & 191 recite “complementary to a portion of…”, and claims 202 & 203 recite “or a portion of…”. However, the specification does not describe any ASO variant that only comprises a less than 100% portion of any claimed SEQ ID NOs. Given that the limited ASO species with different lengths and chemistry have unpredictable CD33 Exon-2 skipping efficiency across variant attributes (Tables 3-6, 16-22; FIGs.18, 19, 22-31), the CD33 Exon-2 skipping efficiency of ASOs that only comprise “a portion of” specific ASOs with different lengths, sequences, and stereochemistry are unpredictable, thus lack written description support in the specification.
Claim 193 is also directed to a broad genus of ASOs by reciting "at least one non-natural sugar moiety, at least one non-natural internucleotide linkage, or... both", with no limitation to a particular chemistry for the claimed ASOs.
The specification demonstrates chemistry attributes of a limited subset of species of the claimed genus of ASOs targeting the CD33 pre-mRNA target sequence set forth in SEQ ID NO: 1. Regarding ASO chemistry, all efficacy data (Tables 3-6, 16-22; FIGs. 18, 19, 22-31) is limited to PMO (sugar modified to a morpholine ring and phosphorodiamidate-based modified internucleotide linkages) and MOE (sugar modified with a 2'-O-methoxyethyl substituent, phosphorothioate linkages). The specification discloses no working example, structural or functional, for any other chemistry falling within claim 193's scope, including other established, art-recognized non-natural sugar-moiety modifications such as locked nucleic acid (LNA), constrained ethyl (cEt), 2'-fluoro, tricyclo-DNA, and glycol nucleic acid (GNA), each of which is a chemically distinct sugar modification from those of PMOs and MOEs.
Regarding the state of the art, Khvorova (Nat Biotechnol. 2017;35(3):238-248) describes the evolution of diverse ASO chemistry modification strategies that led to improvements in performance and potency (Page 241, Figure 3). Bennett (Annu Rev Pharmacol Toxicol. 2010;50:259-93) highlights that “both the intrinsic binding affinity and pharmacokinetics of natural oligonucleotides are insufficient for their use as systemic drugs. Oligonucleotides, akin to small-molecule drugs, are amenable to medicinal chemistry efforts that can improve their attributes” (Page 272, last ¶, first 3 lines). Iwamoto (Nat Biotechnol. 2017;35(9):845-851; Listed on IDS filed on 10/27/2023) teaches that stereochemical purity impacts ASO function such that the link between stereochemistry of ASOs and their functions are not predictable a priori and required dedicated empirical study (Page 845, Abstract). These are strong evidence that there is a high degree of unpredictability in the art in predicting ASO functions simply based on attributes such as length, sequence, or chemical modifications.
The disclosure of insufficient species of a broad genus, the high degree of variation in the art, and the failure to disclose correlation between structure in the specification and the claimed function led to the determination that claims 189-191, 193, 202, and 203 are overly broad with insufficient evidence of possession at the time of filing to one skilled in the art. Thus, claims 189-191, 193, 202, and 203 do not meet the written description requirement, and the specification demonstrates a clear lack of possession of the full genus as claimed.
Claims 192, 194, 196-197, 204, 209 are also rejected for depending from the rejected claims 189 and/or 193 and failing to remedy the lack of written description therein.
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.
Claims 189-194, and 209 are rejected under 35 U.S.C. 103 as being unpatentable over Malik (J Neurosci. 2013;33(33):13320-5), in view of Hua (PLoS Biol. 2007;5(4):e73), further in view of NCBI (NCBI_2002_Homo sapiens CD33 gene, complete cds.pdf listed on PTO-892 form), claim 193 is as evidenced by Lind (Nucleic Acids Res. 1998;26(16): 3694-799).
Malik (2013) teaches that the rs3865444-A allele modulates CD33 pre-mRNA splicing to cause Exon-2 skipping, and that this splicing outcome is associated with reduced full-length CD33 and protection against late-onset Alzheimer's disease/AD (Page 13320, Abstract), thus identifying CD33 Exon-2 skipping as a known, disease-relevant, therapeutically desirable splicing outcome that reduces AD risk. Malik does not teach an antisense oligonucleotide (ASO) of 16-30 nucleotides in length, wherein the ASO is complementary to a portion of SEQ ID NO:1, and wherein the ASO has a CD33 Exon-2 skipping efficiency of 30% or greater according to a Standard Exon-Skipping Efficiency Assay for the ASO.
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However, Hua (PLoS Biol. 2007;5(4):e73) teaches: 1) Tiered coarse and high resolution ASO walk strategies to identify ASOs with a 2’-O-methoxy-ethyl ribose (MOE; Page 0729, Abstract, line 4) backbone with different effects on exon skipping or retention based on any target pre-mRNA sequence. Hua also discloses: 2) ASOs of 12nt, 15nt, 16nt, 18nt nucleotides in length (Page 0732, right col, 2nd ¶, lines 5-9), with at least some embodiments falling within the claimed 16-30nt range. Given the discovery of Malik discussed above, Hua teaches: 3) that “Antisense oligonucleotides (ASOs) that target an exon or its flanking splice sites usually promote exon skipping” (Page 0729, Abstract), hence the target sequence should encompass the Exon-2 coding sequence and its flanking regions of adjacent introns. Hua further teaches: 4) A standardized and quantitative exon splice modulation efficiency assay that led to the precise identification of ASOs targeting an Exon with either promoting skipping effect or promoting inclusion effect within the same Exon (Page 0740, Figure 9), which provides a standard assay measuring the effects of ASOs on Exon inclusion or skipping percentages based on RT-PCR and radiograph densitometry with detailed protocols (Page 0742, left col, last ¶, right col, first ¶; Figures 1-6, 7B, 8A,B). Since Exon Skipping is the inversion of Exon Inclusion based on Hua’s calculation formula, % Inclusion = [included mRNA X 100 / (included mRNA + skipped mRNA)] (Page 0742, left col, 3rd ¶, last 4 lines), % Exon Skipping = [100 – (% Inclusion)], thus some ASOs tested by Hua show numerous ASOs with strong exon skipping effect for over 60% (Page 0735, e.g. ASOs 04-15, 8-22, 12-23, 11-22, and many others over 30% skipping in Figure 5A,B), reflecting the identical formula defined in the instant specification: Skipping % = (Skipped Value) / [(Skipped Value) + (Unskipped Value)] X 100% (Page 72, ¶[0244]). Neither Malik nor Hua teaches the exact sequence of CD33 Exon-2 and its flanking sequences.
However, NCBI (2002) teaches the complete CDS, and its mRNA sequence of human CD33 joins all exons (1667-1715, 1778-2158, 2363-2641, 2869-2916, 11716-11812, 12154-12235, 16077-16575). Based on the alignment above, the claimed SEQ ID NO: 1 (530nt) encompasses 6nt of the 3’ end of Exon-1 (1710-1715), Intron-1 (1716-1777), Exon-2 (1778-2158), and the 5’ end of Intron-2 (2159-2239).
Regarding claim 189, it would have been obvious to persons having ordinary skills in the art (PHOSITAs) before the effective filing date of the claimed invention to have further combined the potential therapeutic targeting and mechanism of reducing AD risk by promoting CD33 Exon-2 skipping taught by Malik (2013) with the CD33 CDS sequence taught by NCBI (2002), then would have applied the ASO walk strategies taught by Hua (2007) to search for effective 12nt, 15nt, 16nt, 18nt MOE modified ASOs to target the sequence of CD33 Exon-2 and its flanking sequences, based on a standardized exon splice modulation efficiency assay taught by Hua. At least some embodiments of the ASOs tested would fall within the claimed 16-30nt ASOs complementary to a portion of SEQ ID NO: 1 because the alignment above indicates that SEQ ID NO: 1 encompasses Exon-2 and its flanking sequences. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. One would have been motivated to do so because Malik (2013) teaches that CD33 Exon-2 skipping associated with human SNPs underlines reduced AD risks. One would have reasonable expectations of success because Hua demonstrates effective ASO identification using the tiered ASO walk strategies to support quantitative candidate selections for ASOs with an Exon Skipping efficiency of 30% or greater according to a standardized splice modulation efficiency assay that measures Exon Skipping. Since the strategy of identifying ASOs with 30% or greater exon skipping efficiency is routine optimization at the time of filing, PHOSITAs can apply this strategy and evaluation criteria to select ASOs with 30% or greater CD33 Exon-2 skipping efficiency to arrive at the claimed invention with reasonable expectations for success.
Regarding claim 190 and 191, SEQ ID NO: 218 aligns to part of SEQ ID NO: 1 and the Exon-2 of CD33, at least some embodiments of ASO candidates based on the combined teachings of Malik, Hua, and NCBI would have targeted this section of the Exon-2 sequence designed for the ASO walk assays.
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Query: SEQ ID NO: 218; Sbjct: AY040541.1.
Regarding claim 192, Hua teaches 18nt ASOs (Page 0732, Table 1; right col, 2nd ¶, lines 5-9).
Regarding claims 193 and 194, Hua recites “Oligonucleotides with a 2’-O-methoxy-ethyl ribose (MOE) phosphodiester backbone were used. This backbone modification imparts a very high affinity for targeted mRNA, resistance to both exo- and endonucleases, and does not support cleavage of hybridized mRNA by RNase H…” (Page 0732, last ¶, lines 8-13). As evidenced by Lind (1998), which recites “improved binding affinity of MOE-substituted duplexes, but does not explain the improved stability seen compared with natural RNA:RNA duplexes” (Page 3699, left col, 2nd ¶, lines 6-8), MOE modification is a non-natural sugar moiety-based modification. PHOSITAs are motivated to combine the teachings of Malik, Hua, and NCBI to arrive at ASOs with 30% or greater CD33 Exon-2 skipping efficiency to arrive at the claimed invention with reasonable expectations for success, as discussed above.
Regarding claim 209, Hua further teaches MOE-modified ASOs comprising phosphorothioate linkage have been shown by a growing number of studies as valuable tools (Page 0738, last 2 lines). PHOSITAs would have been motivated to create MOE-modified ASOs to comprise at least one phosphorothioate linkage for ASO walk-based screening to identity candidates having 30% or greater CD33 Exon-2 skipping efficiency based on standardized assays.
Claims 196-197, and 202-204 are rejected under 35 U.S.C. 103 as being unpatentable over Malik (2013), in view of Hua (2007) and NCBI (2002), further in view of Butler (WO2017062862A2, published on 04/13/2017) and Vargeese (US20210032620A1, published on 02/04/2021).
The teachings of Malik (2013), Hua (2007), and NCBI (2002) have been discussed above and as applied to claims 189-194, and 209. None of Malik, Hua, and NCBI teaches the stereo form of non-natural internucleotide linkages.
However, Butler (2017) teaches antisense oligonucleotides comprising non-natural internucleotide linkages (Page 8, ¶[0011], last 2 lines), and discloses the stereochemistry of these linkages including embodiments wherein the non-natural internucleotide linkages, such as phosphorothioate linkages, are stereopure (Page 105, ¶[00270]; Page 107, ¶[00287]-[00289]; FIGs. 24-25). Numerous stereopure ASOs are listed on page 380, in Table 3A, with many example ASOs showing stereopure pattern, also in Table 4 starting on page 392, e.g. WAVE ID ONT-395, wherein the non-natural internucleotide linkages are all Sp, which is shown on page 382, Table 2B to also have all phosphorothioate internucleotide linkages because “*S represents an Sp phosphorothioate linkage” (Page 382, ¶[00924], line 2).
Butler further teaches chirally controlled oligonucleotide compositions for altering transcript splicing, including exon-skipping applications, e.g., DMD exon 51 skipping (FIGs 1, 2; Page 105, ¶[00264]-[00265]), comprising a wing-core-wing structure in which Sp-configured phosphorothioate linkages are combined with natural phosphodiester linkages in defined proportions, explicitly disclosing backbone patterns comprising 2, 3, or 4 phosphodiesters combined with 13-19 phosphorothioate linkages, contiguous or non-contiguous (Page 120, ¶[00316]). Butler further discloses that such chirally controlled compositions, relative to stereorandom compositions of the same base sequence and chemical modifications, provide unexpectedly high exon-skipping efficiency, reduced toxicity, and improved protein-binding and pharmacokinetic profiles (Page 516, ¶[001082]; Page 753, ¶[001368]). Butler does not teach the specific stereochemistry of the elected species, SSOSSSSSSSSSSOSSS.
However, Vargeese (2021) teaches “the recognition that structural elements of oligonucleotides, such as base sequence, chemical modifications …, and/or stereochemistry (e.g., stereochemistry of backbone chiral centers (chiral internucleotidic linkages), … can have a significant impact on activities and properties, e.g., stability, toxicity, delivery, etc., of oligonucleotides” (Page 1, ¶[0003], lines 2-9), “wherein the oligonucleotide is capable of decreasing the level, expression and/or activity of a target gene or a gene product thereof via a mechanism involving steric hindrance” (Page 279, Claim 11), which encompasses ASOs with Exon Skipping functional outcome. To support this, Vargeese discloses the same ASO architectural class disclosed by Butler with further specificity: a pattern of backbone chiral centers of the stereopatterns taught in the formula (Np)t[(Op/Rp)n(Sp)m]y:
“oligonucleotides comprises a stereochemistry pattern of (Np)t[(Op/Rp)n(Sp)m]y, wherein each variable is independently as described in the present disclosure. In some embodiments, each Np is Sp. In some embodiments, a pattern comprises at least one Op. In some embodiments, n is 1. In some embodiments, m is at least 2, 3, 4, or 5. In some embodiments, y is 1. In some embodiments, y is 2, 3, 4, or 5. In some embodiments, (Np)t[(Op/Rp)n(Sp)m]y is (Sp)t[(Op/Rp)(Sp)m]y. In some embodiments, (Np)t[(Op/Rp)n(Sp)m]y is (Sp)t[Op(Sp)m]y” (Page 1, ¶[0005], lines 18-27).
Based on the formula embodiment “(Sp)t[Op(Sp)m]y”, t is 2, y is 2 (at least two such interrupting [blocks]), m is independently 10 or 3 for the two separate [blocks] (blocks of at least two consecutive Sp-configured linkages), which would have produced a (Sp)2 [Op(Sp)10] [Op(Sp)3] stereopattern, which is SSOSSSSSSSSSSOSSS without annotation of the phosphate group p. Hence, Vargeese teaches the stereopattern of the elected species MOE-307.
Regarding the elected species, it would have been obvious to PHOSITAs before the effective filing date of the claimed invention to have further engineered the modified ASOs designed for promoting CD33 Exon-2 skipping based on the teachings, strategies, and motivations combining Malik (2013), Hua (2007), and NCBI (2002), and incorporating stereochemistry considerations with various stereopatterns taught by Butler (2017) and Vargeese (2021). At least some embodiments of 18nt MOE modified ASOs, designed by targeting all or a portion of SEQ ID NO: 252, because SEQ ID NO: 252 is reverse complementary to SEQ ID NO: 218, a part of the CD33 Exon-2 sequences (see alignment between SEQ ID NO: 252 and the target sequences SEQ ID NO: 218 and AY040541.1 below) via ASO walk
SEQ ID NO: 252 1 CCGAAAGAAGTATGAACC 18
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SEQ ID NO: 218 18 CCGAAAGAAGTATGAACC 1
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AY040541.1 2097 CCGAAAGAAGTATGAACC 2080
strategies would have comprised a base sequence comprising all or a portion of SEQ ID NO: 252 and modified with a stereo pattern of SSOSSSSSSSSSSOSSS with all non-natural internucleotide linkages as Sp, phosphorothioate linkages, since it is known in the art as a preferred embodiment of ASO modifications that positively impact the performance of ASO candidates, taught by Vargeese. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. One would have been motivated to do so because in addition to Butler’s teaching “that chirally controlled oligonucleotide … demonstrate unexpectedly high exon skipping efficiencies” (Page 8, ¶[0011], last 4 lines), Vargeese (2021) teaches that these stereochemistry properties would improve ASO activity and properties such as stability, toxicity, delivery etc. (Page 1, ¶[0003], lines 2-9). One would have reasonable expectations of success because of Butler’s demonstration of enhanced exon skipping by chirally controlled ASOs (FIGs. 26-29).
This selection reflects routine optimization within an art-disclosed genus, not an unpredictable extension requiring inventive contribution. This conclusion is reinforced by the instant specification's own data (FIG. 28), which shows no statistically significant difference in exon-skipping efficiency among several tested stereopatterns falling within the disclosed genus (MOE-305, 306, 307, 310, 311), thus establishing the absence of criticality attributable to the specific Op gap placement recited in claims 202-203 relative to other members of the same genus encompassed by the formula (Np)t[(Op/Rp)n(Sp)m]y.
Regarding claims 196, 197, Butler teaches ASOs comprising non-natural internucleotide linkages, wherein the non-natural internucleotide linkages are stereopure phosphorothioate linkages, including embodiments wherein all non-natural internucleotide linkages are all Sp.
Regarding claims 202, 203, the elected species MOE-307 (base sequence set forth in SEQ ID NO: 252, complementary to target sequence in CD33 pre-mRNA set forth in SEQ ID NO: 218, Stereopattern: SSOSSSSSSSSSSOSSS) has been rendered prima facie obvious based on the combined teachings, strategies, and motivations of Malik, Hua, NCBI, Butler, and Vargeese above with routine optimization.
Regarding claims 204, both Butler (Page 75, ¶[00179]) and Vargeese (Page 6, ¶[0048]; Claim 46) teach a composition comprising the antisense oligonucleotide of claim 189 and a pharmaceutically acceptable carrier or excipient.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Delphinus D. Yu whose telephone number (571) 272-1576. The examiner can normally be reached Mon-Thr 7:30am to 4:30pm Fri 10am to 2pm ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil P Hammell can be reached on (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DELPHINUS DOU YI YU/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
