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 .
Application Status
Applicant’s response filed July 7, 2026 is acknowledged. Claims 1-23 are pending.
Restriction/Election
Applicant’s election without traverse of Group I (claims 1-5, and 14-23) in the response filed July 7, 2026 is acknowledged. Claims 6-13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Claims 1-5, and 14-23 are under consideration hereinafter.
Priority
Applicant’s priority claims to Application Nos. JP2021-078507, JP2021-151543, and PCT/JP2022/019561 are acknowledged. The certified copies of Application Nos. JP2021-078507 and JP2021-151543 have been received. Claims 1-5, and 14-23 find support in Application No. JP2021-078507. The effective filing date of the claims under examination is May 6, 2021.
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 defective. See item 1) a) or 1) b) above. Specifically, USPTO records indicate that the title and size of the sequence listing of record is “18558056_1_1.txt” and “6,128 bytes,” respectively.
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.
Specification
The specification is objected to because it contains an embedded hyperlink and/or other form of browser-executable code in paragraph [0007] (“https://doi.org/10.1101/2021. 02.14.431096”). 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 specification is also objected to because the structures and text set forth in paragraphs [0049] and [0062] are illegible due to poor resolution. Applicant should provide higher resolution structures and text, so that the structures and text are legible.
Appropriate correction is required.
Claim Objections
Claim 14 is objected to because of the following informalities:
Claim 14 recites “(2) a step of synthesizing the oligonucleotide designed in step (1).” It is reasonably clear that step (2) of claim 14 intends to refer to step (1) of claim 14, not step (1) of claim 1. It would be preferable to amend claim 14 to recite the following, accordingly: “(2) a step of synthesizing the oligonucleotide designed by the method according to claim 1
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-5, and 14-23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “reduced central nervous system toxicity.” The claim does not define “reduced central nervous system toxicity.” The specification provides that “reduced central toxicity” “means that the central toxicity of [a designed oligonucleotide] is low, or expected to be low, compared to the central toxicity of the [parent phosphorothioate oligonucleotide]” ([0037]). This definition provides a reference point for the reduction (i.e., relative to the parent phosphorothioate oligonucleotide). However, the definition does not provide a standard for ascertaining the requisite degree of central nervous system toxicity which would be considered “reduced,” because the definition includes relative language (i.e., “is low, or expected to be low”) for which there is also no standard; the central nervous system toxicity of the designed oligonucleotide must be “low, or expected to be low” compared to the parent phosphorothioate oligonucleotide, not simply “lower” than the parent phosphorothioate oligonucleotide. The skilled artisan would not be reasonably apprised of the scope of the claimed invention.
Claims 2-5, and 14-23 are rejected for depending from claim 1 and failing to remedy the indefiniteness.
Claim 14 recites “low central nervous system toxicity.” The term “low” is a relative term. The term “low” is not defined by the claim, and the specification does not provide a standard for ascertaining the requisite degree of central nervous system toxicity which would be considered “low.” The skilled artisan would not be reasonably apprised of the scope of the claimed invention.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-5, and 15-23 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. Claim 1 recites “A method for designing an oligonucleotide having reduced central nervous system toxicity, comprising: (1) a step of replacing the 5’-position carbon atom of the sugar of at least one nucleoside of an oligonucleotide having phosphorothioate modification, with a structure represented by the following formula I… or the following formula I’… and optionally, (2) a step of replacing at least one phosphorothioate bond of the oligonucleotide with a phosphodiester bond.” The specification states that to carry out the design method of the invention, “it is not necessary to actually synthesize the oligonucleotide, as imagining it is sufficient” ([0038]).
MPEP 2106.04(a)(2)(III) states that “the courts consider a mental process… to be an abstract idea.” “Examples of mental processes include observations, evaluations, judgements, and opinions.” Based on the specification, the design method of claim 1 could be performed entirely in the human mind, i.e., by “imagining” the replacements in step (1) and optional step (2). The method of claims 2-5, and 16-23 recite further limitations to step (1) and optional step (2) of claim 1. Claims 2-5, and 16-23 could also be performed entirely in the human mind, i.e., by “imagining” the replacements in a gapmer parent oligonucleotide and at particular positions therein in the wings and/or gap region, or by “imagining” a number of nucleoside replacements, etc.
Claim 15 recites “(3) a step of confirming the reduction in central nervous system toxicity of the designed oligonucleotide or evaluating the degree of reduction in central nervous system toxicity of the designed oligonucleotide.” The specification does not provide a definition which limits the means of “confirming” or “evaluating” the reduction in central nervous system toxicity. This step could also be performed entirely in the human mind, e.g., by evaluating gathered data, or confirming a certain value was achieved in gathered data.
The design methods of claims 1-5, and 15-23 are directed, in their entirety, to abstract idea(s), which is a judicial exception. The abstract idea(s) recited in claims 1-5, and 15-23 is not integrated into a practical application, and does not include additional elements that are sufficient to amount to significantly more than the judicial exception, because there are no additional elements recited in the claims.
Claim Rejections - 35 USC § 102 - Vasquez
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 5, 14, 16, and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Vasquez (Vasquez et al., 5 February 2021, Nucleic Acids Research, Vol. 49, No. 4).
The design methods of claims 1-5, and 15-23 could be performed entirely in the human mind as described above. For the purposes of prior art, the methods are interpreted as requiring the synthesis step recited in claim 14. The phrases “reduced central nervous system toxicity” and “low central nervous system toxicity” in claims 1 and 14 are interpreted hereinafter as properties which result from the design step(s). This interpretation is supported by the Examples in the specification (see at least Examples 3-4, [0124]-[0125]). The phrases do not impose any additional limitations on the methods. See MPEP 2112.02(II).
Regarding claims 1 and 14, Vasquez teaches a method of designing an oligonucleotide comprising (1) replacing the 5’-position carbon atom of the sugar of at least one nucleoside of an oligonucleotide having phosphorothioate modification, with a structure represented by formula I’, and synthesizing the designed oligonucleotide (“We evaluated the effect of replacing each PS deoxynucleotide in the gap region of ION 558807… with R- and S- 5’-methyl DNA monomers. The R- and S-5’-methyl DNA phosphoramidites were incorporated into gapmer ASOs using standard automated chemistry and the resulting ASOs were evaluated… for effects on antisense activity and cytotoxicity,” pg. 1831, right col.; Fig. 1; Fig. 3-5).
Regarding claim 2, Vasquez’s oligonucleotide is a gapmer oligonucleotide (pg. 1831, right col.; Fig. 3-5).
Regarding claim 3, the term “gap region” is interpreted as an internal region having one or more nucleosides recognized by RNase H, which is positioned between “wing regions” having one or more nuclease resistant nucleosides ([0040]). The replacement of step (1) is located in the gap region of Vasquez’s oligonucleotide (“red indicate 5’-alkyl DNA nucleotides,” Fig. 3-5 and description, pg. 1833-1835).
Regarding claim 5, the term “crosslinked nucleoside” is interpreted as a nucleoside comprising a linkage (e.g., via a bridging group) between two or more nucleoside elements, e.g., a nucleoside comprising a linkage between the 2’- and 4’-position of the sugar ([0061]-[0062]). Constrained Ethyl (cET) is a crosslinked nucleoside (see Fig. 1, Vasquez). Thus, Vasquez’s oligonucleotide comprises at least one crosslinked nucleoside (i.e., cET nucleoside) in the 3’ wing region and 5’ wing region (“Blue letters indicate constrained Ethyl (cET),” Fig. 3-5 and description, pg. 1833-1835).
Regarding claims 16 and 20, the number of nucleosides with the replacement of step (1) is 1 (“red indicate 5’-alkyl DNA nucleotides,” Fig. 3-5, pg. 1833-1835).
Notice to Joint Inventors
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 Rejections - 35 USC § 103 – Vasquez
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.
Claims 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Vasquez (Vasquez et al., 5 February 2021, Nucleic Acids Research, Vol. 49, No. 4) as applied to claims 1-3, 5, 14, 16, and 20 above.
The teachings of Vasquez are described above and applied as to claims 1-3, 5, 14, 16, and 20 therein.
Vasquez’s oligonucleotides comprise a single replaced nucleoside at each position in the gap region (see Figs. 3-4). Vasquez does not teach replacing 2, 3, or 4 nucleosides as recited in step (1).
Vasquez teaches that “site-specific incorporation of 2’ modifications… in the deoxynucleotide gap region of toxic phosphorothioate (PS) gapmer antisense oligonucleotides (ASOs) can enhance the therapeutic index and safety” (pg. 1828, right col.). Vasquez teaches that “all the structural changes which mitigate toxicity cluster near nucleotides 2, 3, 4 on the 5’-side of the DNA gap suggesting that this region is an important structural recognition site of proteins that are involved in cellular toxicities” (pg. 1837, right col.). Vasquez teaches that their work “ushers a new era of chemical optimization with a focus on optimizing the therapeutic profile of the ASO” (pg. 1837, right col.).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have replaced 2, 3, or 4 nucleosides in the gap region of Vasquez’s oligonucleotides with 5’-methyl, to arrive at the method of instant claims 21-23. It would have amounted to preparing an oligonucleotide comprising two, three, or four separate nucleoside replacements which are taught by Vasquez, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success in preparing an oligonucleotide comprising two, three, or four separate nucleoside replacements because means of preparing the oligonucleotides were known and “standard” as evidenced by Vasquez (pg. 1831), and the replacements were also “well-tolerated” (pg. 1837). Vasquez teaches a “toxicity [mitigating] cluster near nucleotides 2, 3, 4 on the 5’ side of the DNA gap,” that, when combined with Vasquez’s statement that efforts should “focus on optimizing the therapeutic profile of the ASO,” would have motivated the skilled artisan to prepare an oligonucleotide comprising two, three, or four separate nucleoside replacements near toxicity mitigating nucleosides 2, 3, and 4 in the gap region, e.g., replacements at nucleosides 1 and 2, or 1, 2, and 3, or 2, 3, and 4, etc., in the gap region.
Claim Rejections - 35 USC § 103 – Vasquez in view of Moazami and Tran
Claims 4, 15, and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Vasquez (Vasquez et al., 5 February 2021, Nucleic Acids Research, Vol. 49, No. 4) as applied to claims 1-3, 5, 14, 16, and 20-23, in view of Moazami (Moazami et al., 15 February 2021, bioRvix, pg. 1-26) and Tran (Tran et al., 5 February 2021, Research Square, pg. 1-30).
As stated above, the term “gap region” is interpreted as an internal region having one or more nucleosides recognized by RNase H, which is positioned between “wing regions” having one or more nuclease resistant nucleosides ([0040]). With respect to bonds between nucleosides in the oligonucleotide, the phrase “in the gap region” is interpreted as referring to a bond between a nucleoside of the gap region and another nucleoside.
The teachings of Vasquez are described above and applied as to claims 1-3, 5, 14, 16, and 20-23 therein. As stated above, Vasquez renders obvious preparing an oligonucleotide comprising two, three, or four separate nucleoside replacements near toxicity mitigating nucleosides 2, 3, and 4 in the gap region, e.g., replacements at nucleosides 1 and 2, or 1, 2, and 3, or 2, 3, and 4, etc., in the gap region.
Vasquez’s oligonucleotide is “fully phosphorothioate (PS) modified” (Figs. 3-5 and description). Accordingly, Vasquez does not teach replacement of at least one phosphorothioate bond in the gap region, with a phosphodiester bond (claim 4). Vasquez also does not teach that the at least one replaced bond is 5’ of the replaced nucleoside (claim 17), or that the at least one replaced bond is located between the 5’ wing region and the gap region (claim 18), and 5’ of the replaced nucleoside (claim 19).
Moazami teaches that “[i]n early trials, gapmer ASOs were fully PS modified… while current variants of the compounds use a mixed backbone where up to six linkages are substituted back to phosphodiester” (pg. 2). Moazami teaches that while in some cases reducing PS content reduces gapmer ASO efficacy, “[r]educing the PS content of gapmer ASOs, which contain a stretch of PS-DNA, improves their toxicity profile… [and] improved the acute tolerability of ASOs in both mice and sheep” (pg. 1).
Moazami teaches replacing PO linkages adjacent to the gap region with phosphodiester linkages (“our lead backbone design… contains a single PS linkage at each end of the ASO, followed by three PO linkages and then PS linkages throughout the remaining (central) portion of the ASO,” pg. 5; Table 2). Moazami teaches that gapmer ASOs require a stretch of “8-10 non-sugar-modified DNA nucleotides in the middle to enable RNase H recruitment” (pg. 2), and that other mixed backbone designs are functional, and in clinical development (pg. 5). Moazami references Tran et al., which teaches an oligonucleotide wherein a phosphorothioate linkage in the gap region, specifically, a linkage between the last nucleoside of the 5’ wing region and the first nucleoside of the gap region, is replaced by a phosphodiester linkage (“ASO5-1,” Fig. 3A, pg. 24)
Regarding claims 4, and 17-19, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have replaced at least one phosphorothioate bond in the gap region of Vasquez’s fully phosphorothioated oligonucleotide with a phosphodiester bond, such that the replaced bond is between the 5’ wing region and the gap region, and 5’ of the replaced nucleoside. It would have amounted to applying a known design technique (i.e., reducing PS linkage content) to a known oligonucleotide comprising nucleoside replacement(s) near toxicity mitigating nucleosides in the gap region, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success because Moazami teaches that gapmer ASOs require a stretch of “8-10 non-sugar-modified DNA nucleotides in the middle to enable RNase H recruitment,” and the skilled artisan would know, therefore, that the replaced phosphorothioate bond would not affect the ability of the designed oligonucleotide to recruit RNase H. This expectation would be further supported by the design features of Moazami’s and Tran’s oligonucleotides, which comprise replacements in the 5’ wing region adjacent to the gap region, and in the gap region, at the bond between the 5’ wing region and the gap region. The skilled artisan would have been motived to replace at least one phosphorothioate bond of Vasquez’s fully phosphorothioated oligonucleotide in an effort to improve the toxicity profile of Vasquez’s oligonucleotides.
Vasquez teaches evaluating the degree of reduction in toxicity of the designed oligonucleotide (“the resulting ASOs were evaluated… for effects on antisense activity and cytotoxicity,” pg. 1831, right col.; Fig. 1; Fig. 3-5). However, Vasquez does not teach evaluating the degree of reduction in central nervous system toxicity of the designed oligonucleotide (claim 15).
Moazami teaches that ASOs are promising therapeutics for neurological disease, but that gapmer ASOs can exhibit central nervous system toxicity (pg. 1-2). Moazami teaches evaluating the degree of reduction in central nervous system toxicity of designed oligonucleotides (pg. 3-8; Fig. 1).
Regarding claim 15, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the method rendered obvious above with a step of evaluating the degree of reduction in central nervous system toxicity of the designed oligonucleotide. It would have amounted to combining a known step which evaluates ASO therapeutic potential, with an obvious method of producing potentially therapeutic gapmer ASOs, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success in combining the evaluating step with the obvious method, because as evidenced by both Vasquez and Moazami, evaluating steps were well-known steps which were combinable with production of potentially therapeutic gapmer ASOs, and means to evaluate central nervous system toxicity of ASOs were known as evidenced by Moazami. The skilled artisan would have been motivated to combine the evaluating step with the obvious method because the step would allow the skilled artisan to determine the therapeutic potential of a gapmer ASO produced by the obvious method.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Application No. 19/493,539
Claims 1-5, 14, and 16-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-7, 9, 11-18, 20-22, and 24-25 of co-pending Application No. 19/493,539 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other for the reasons that follow. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Co-pending claim 1 recites a method of designing an antisense oligonucleotide with reduced central toxicity comprising “designing a second antisense oligonucleotide based on a first antisense oligonucleotide,” wherein the first oligonucleotide is a gapmer oligonucleotide comprising a gap region which “does not include a 5’-CP nucleic acid,” comprises a 3’ wing region and 5’ wing region, and nucleosides bonded by a phosphate and/or a modified phosphate group, and the second oligonucleotide comprises “at least one 5’-CP nucleic acid” in the gap region. Based on the co-pending claims, the “modified phosphate group” encompasses phosphorothioate, and therefore, the method encompasses phosphorothioate oligonucleotides. Based on the co-pending specification, a “5’-CP nucleic acid” is a species of nucleoside comprising instant Chemical Formula I (see at least [0161]). Thus, the method of co-pending claim 1 anticipates instant claims 1-3, 16 (i.e., “at least one 5’-CP”), and 20.
Co-pending claim 21 anticipates instant claims 4 and 17. Co-pending claim 6 anticipates instant claim 5. Co-pending claim 24 anticipates instant claim 14. Co-pending claims 11-12 anticipate instant claim 21-23.
Regarding instant claims 18-19, co-pending claim 15 recites that the “5’-CP nucleic acid is located on the 5’ end side in the gap region,” and co-pending claim 21 recites that “a bond between the 5’-CP nucleic acid and a nucleoside located adjacent to a 5’ end of the 5’-CP nucleic acid is a phosphodiester bond.” These claims encompass the limitations of instant claims 18-19.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have designed an oligonucleotide in which a nucleoside comprising 5’-CP was positioned at the 5’ end side of the gap region, and the bond between the nucleoside 5’ of the 5’-CP nucleoside and the 5’-CP nucleoside in the gap region, was a phosphodiester bond. It would have amounted to combining co-pending design features which are compatible together, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success in combining the design features of the co-pending claims, and would have been motivated to do so, because the co-pending claims are compatible together, as they are part of the same design method.
Claim 15 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-7, 9, 11-18, 20-22, and 24-25 of co-pending Application No. 19/493,539 (reference application) as applied to claims 1-5, 14, and 16-23 above, in view of Moazami (Moazami et al., 15 February 2021, bioRvix, pg. 1-26). Although the claims at issue are not identical, they are not patentably distinct from each other for the reasons that follow. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The co-pending claims do not recite step (3) of instant claim 15. The teachings of Moazami are described above and applied hereinafter. The obviousness of combining the co-pending method with a step of evaluating the degree of reduction in central nervous system toxicity of the designed oligonucleotide is described above and applied hereinafter.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNA L PERSONS whose telephone number is (703)756-1334. The examiner can normally be reached M-F: 9-5pm.
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/JENNA L PERSONS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
Prosecution Insights