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 claims 1-15 in the reply filed on 8 June 2026 is acknowledged.
Claim 16 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 8 June 2026.
Information Disclosure Statement
The information disclosure statements (IDS) filed 4 March 2024, 19 March 2025, and 17 October 2025 are considered, initialed, and attached hereto. Non-Patent Literature Document Cite No 4 in the IDS filed 19 March 2025 is lined through and is not considered because this document is not in the English language and no concise explanation of the relevance or translation provided for this, see 37 CFR 1.98(a)(3).
The listing of references in the specification (on page 3 of the clean substitute specification filed 19 July 2024) 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 or in a proper IDS, they have not been considered.
Claim Status
Claims 1-16 are pending.
Claim 16 is withdrawn.
Claims 1-15 are under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the drawings (Fig. 10A, Fig. 10D, Fig. 11A-B, Fig. 11E-F, Fig. 12A-B, Fig. 12E-F, Fig. 13A contains 2 sequences that are identical, Fig. 13C contains 2 sequences that are identical, Fig. 14A top strand only, Fig. 14C top strand only, Fig. 15A-B top strand only, Fig. 15E-F top strand only, Fig. 16A-B top strand only, Fig. 17A, Fig. 17C, and Fig. 25 top and bottom strands) are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, 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 disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on lines 4-5 of [0109] in the clean substitute specification filed 19 July 2024. 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 use of terms including, but not limited to, Cy, Bodipy, and CryoLoop, which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Interpretation
Claims 1-15 are for a product, specifically “An artificial nucleic acid” (claim 1, line 1). Paragraph [0017] of the clean substitute specification filed 19 July 2024 defines artificial nucleic acids as “nucleic acids molecules that are artificially synthesized by biological or chemical synthesis methods”. Since this recitation limits the method by which the nucleic acid is synthesized, the limitation of the claimed nucleic acid as being artificial is a product-by-process limitation which only limits the product to the structure implied by the process and does not limit the structure to those structures obtained specifically by the recited process (see MPEP §2113 I.). Therefore, “an artificial nucleic acid” reads on any nucleic acid with a structure that could be artificially synthesized by biological or chemical synthesis methods, regardless of the actual method used to synthesize it.
The recitation in claim 1 lines 1-3 “for inducing a specific functional three-dimensional structure by hybridizing with a nucleic acid of interest that does not form a functional three-dimensional structure” is an intended use of the claimed artificial nucleic acid in the preamble of the claim. This intended use does not structurally limit the artificial nucleic acid because it only limits the structure of the nucleic acid of interest instead of the claimed artificial nucleic acid and therefore is not a limiting intended use. Were the intended use interpreted as limiting, an artificial nucleic acid capable of fulfilling the intended use would anticipate the intended use. See MPEP §2111.02 II.
Claims 1-15 are for a product, the artificial nucleic acid, but are limited by limitations that describe a property of the artificial nucleic acid, its ability to form a sequence motif composed of double strands forming a specific three-dimensional structure with a nucleic acid of interest, and further limitations regarding the complementarity or lack thereof between the artificial nucleic acid and the nucleic acid of interest (see all limitations from “that forms a three-dimensional structure together with a target domain in said nucleic acid of interest” in lines 4-5 of claim 1 through the end of claim 1 and all limitations of claims 2-6 and 8). Examiner notes that the ability for a nucleic acid to form a three-dimensional structure when hybridized with another nucleic acid is an inherent property of its sequence (see clean substitute specification [0046-0061] and associated Figures for various sequences that inherently form the described functional three-dimensional structures when nucleic acids with the sequences are hybridized, such as [0060] and Figure 6 demonstrating that the sequences 5’-NGAN-3’ and 5’-NGAN-3’ hybridized together in respective alpha and beta chains inherently form a tandem GA structure). Therefore, claims 1-6 and 8 will be anticipated by any prior art that teaches an artificial nucleic acid (claim 1 line 1) comprising a three-dimensional structure formation-inducing domain (claim 1 lines 4-5) that has a sequence capable of fulfilling the limitations of the respective claims as discussed above. Since the capability of fulfilling the limitations is inherent to the sequence of the artificial nucleic acid, so long as there is a possible sequence of a nucleic acid of interest that, when hybridized to the artificial nucleic acid of the prior art, would fulfill the limitations as claimed then the sequence of the artificial nucleic acid will be considered to have said capability. Importantly, the prior art is not required to teach the nucleic acid of interest, as only the artificial nucleic acid is claimed and its capability to interact with a nucleic acid of interest is inherent to its sequence.
In claim 1 line 8, claim 2 line 2, claim 4 line 2, and claim 6 lines 2, 3, 4, 5, 6, and 7 the phrase “composed of” is recited. This phrase is interpreted as closed claim language equivalent to the transitional phrase “consisting of”, see MPEP §2111.03 IV.: “The transitional phrase "composed of" has been interpreted in the same manner as either "consisting of" or "consisting essentially of," depending on the facts of the particular case”.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
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 1-15 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 the limitation “a nucleic acid of interest that does not form a functional three-dimensional structure” in lines 2-3. The metes and bounds of this claim are unclear because this limitation and the similar definition of a nucleic acid of interest in the clean substitute specification filed 19 July 2024 (“the nucleic acid of interest herein is a nucleic acid that does not form a functional three-dimensional structure” [0063]) could be interpreted either (A) as being an immutable property of the nucleic acid of interest, which would appear to be contradictory to a specific functional three-dimensional structure being induced when it hybridizes with the artificial nucleic acid, or (B) is a property of the nucleic acid of interest specifically when it is not hybridized with the artificial nucleic acid. For the purpose of examination, interpretation (B) is used. Claims 2-13 are also rejected based on their dependency on claim 1; claims 14-15 are also rejected because they recite agents “comprising the artificial nucleic acid of claim 1” and thereby import the unclear limitation.
Claim 1 recites the limitation "the specific three-dimensional structure" in line 8. There is insufficient antecedent basis for this limitation in the claim, since it is unclear whether this limitation refers to the recited “a specific functional three-dimensional structure” in lines 1-2, “a functional three-dimensional structure” in lines 2-3, or “a three-dimensional structure” in line 5. Claims 2-13 are also rejected based on their dependency on claim 1; claims 14-15 are also rejected because they recite agents “comprising the artificial nucleic acid of claim 1” and thereby import the unclear limitation.
Claim 5 recites the limitation "said specific three-dimensional structure" in line 2. There is insufficient antecedent basis for this limitation in the claim for the same reason as “the three-dimensional structure” in line 8 of claim 1 lacks sufficient antecedent basis, as discussed above. Claim 6 is also rejected based on its dependency on claim 5.
Claim 11 recites the limitation "the ribose" in line 2. There is insufficient antecedent basis for this limitation in the claim. For the purpose of examination, the modified nucleotide is interpreted as comprising a ribose with a fluoro group-modification at the 2’ position of the ribose.
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 1-10 and 12-15 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a without significantly more. The claims are directed to a product, and therefore meet step 1 of the subject matter eligibility test (see MPEP §2106.03).
Step 2A of the subject matter eligibility test requires a two-pronged analysis. Prong One asks: does the claim recite an abstract idea, law of nature or natural phenomenon? As discussed in MPEP §2106.04(II)(A)(1), the meaning of “recites” is “set forth” or “describes”. That is, a claim recites a judicial exception when the judicial exception is “set forth” or “described” in the claim. The markedly different characteristics analysis (MPEP §2106.04(c)) is applied to determine whether the recitation of a nature-based product (“an artificial nucleic acid” claim 1 line 1) is the recitation of a product of nature exception.
The claims broadly encompass artificial nucleic acids comprising a three-dimensional structure formation-inducing domain that is capable of forming a specific three-dimensional structure when hybridized to a target domain wherein there are complementary regions and a non-complementary-containing region when the three-dimensional structure formation-inducing domain and target domain hybridize. As discussed in the Claim Interpretation section above, “an artificial nucleic acid” only limits the nucleic acid to nucleic acids that are structurally identical to nucleic acids that can be artificially synthesized by biological or chemical synthesis methods.
MPEP §2106.04(c) provides as an example of products lacking markedly different characteristics:
“In Ambry Genetics, the court identified claimed DNA fragments known as "primers" as products of nature, because they lacked markedly different characteristics. University of Utah Research Foundation v. Ambry Genetics Corp., 774 F.3d 755, 113 USPQ2d 1241 (Fed. Cir. 2014). The claimed primers were single-stranded pieces of DNA, each of which corresponded to a naturally occurring double-stranded DNA sequence in or near the BRCA genes. The patentee argued that these primers had markedly different structural characteristics from the natural DNA, because the primers were synthetically created and because "single-stranded DNA cannot be found in the human body". The court disagreed, concluding that the primers’ structural characteristics were not markedly different than the corresponding strands of DNA in nature, because the primers and their counterparts had the same genetic structure and nucleotide sequence. 774 F.3d at 760, 113 USPQ2d at 1243-44” (emphasis added)
Based on the decision in Ambry Genetics, the distinction between a nucleic acid as being synthetically created or artificially synthesized in comparison to the synthesis of a natural counterpart nucleic acid in nature does not make the artificial nucleic acid markedly different from its natural counterpart. Natural counterpart nucleic acids are known to exist that fulfill the limitations of the claimed artificial nucleic acid (see Figure 2D-F of Bartel teaching natural miRNAs that form a three-dimensional structure with target nucleic acids wherein there is at least one non-complementary-containing region and multiple complementary regions, as annotated in Exemplary Figure 1; Bartel “MicroRNA Target Recognition and Regulatory Functions” Cell 136(2), pages 215-233 (2013)). Therefore, based on the decision in Ambry Genetics, artificially synthesized versions of these miRNAs that possess identical sequences are encompassed by the claim but are not markedly different from their natural counterparts, so claims 1-10 and 12-15 are directed toward the judicial exception of a product of nature.
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Exemplary Figure 1: naturally occurring miR-2 miRNA forms a three-dimensional structure (a structure other than the double helix formed by completely complementary double-stranded nucleic acid molecule, per instant specification [0039]) with complementary regions and a non-complementary-containing region when hybridized to a target domain; annotated from Figure 2E of Bartel.
Note that claim 11 is not rejected under 35 U.S.C. 101. Claim 11 does not recite a product of nature because modified nucleotides comprising a fluoro group-modification at the 2’ position of the ribose are not found in nature, so an artificial nucleic acid comprising such modified nucleotides is markedly different from a natural counterpart with an identical sequence lacking a modified nucleotide comprising a fluoro-group modification at the 2’ position of the ribose.
Prong Two of the analysis under step 2A asks: does the claim recite additional elements that integrate the judicial exception into a practical application of the judicial exception? As discussed in MPEP §2106.04(II)(A)(2):
Because a judicial exception is not eligible subject matter, Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)), if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017) ("Adding one abstract idea (math) to another abstract idea (encoding and decoding) does not render the claim non-abstract"); Genetic Techs. Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016) (eligibility "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself."). For a claim reciting a judicial exception to be eligible, the additional elements (if any) in the claim must "transform the nature of the claim" into a patent-eligible application of the judicial exception, Alice Corp., 573 U.S. at 217, 110 USPQ2d at 1981, either at Prong Two or in Step 2B.
The considerations to be used are set forth in MPEP §2106.04(d)(2) and MPEP §2106.05(a) through (c) and (e) through (h). Turning to those sections of the MPEP:
MPEP §2106.05(a) has to do with improvements to the functioning of a computer or to any other technology or technical field. The claims at issue do not improve the functioning of a computer or a technical field.
MPEP §2106.05(b) has to do with whether the claims involve the use of a particular machine. In this case, the claims do not involve the use of a particular machine.
MPEP §2106.05(c) has to do with whether the claims involve a particular transformation. Here, the claims do not involve a particular transformation as the nucleic acid is not transformed by the claims.
MPEP §2106.05(e) has to do with “other meaningful limitations”. The additional limitations imposed upon the product of nature is the length and orientation of the complementary regions and non-complementary containing region (A, claims 2-4), the three-dimensional structure formed when the three-dimensional structure formation-inducing domain of the claimed artificial nucleic acid hybridizes with the target domain of the nucleic acid of interest (B, claims 5-6), the type of the nucleic acid of interest (C, claims 7 and 12-13), the hybridization conditions (D, claim 8), the inclusion of modified nucleotides in the three-dimensional structure formation-inducing domain (E, claim 9-10), and the intended use of the nucleic acid of interest (F, claims 14-15). As limitations B, C, D, and F do not structurally limit the claimed product, they are not meaningful limitations that integrate the judicial exception. As limitation A is found in nature (see Exemplary Figure 1 above, the non-complementary-containing region is between the complementary regions, there is a hybridizable domain composed of 6 to 120 bases, and the non-complementary-containing region is composed of 2 to 7 bases), it does not restrict the claim to nucleic acids that are not directed to a judicial exception and therefore is not a meaningful limitation. As limitation E is found in nature as taught by Dimitrova et al. (“2′-O-methylation (or Nm, where N stands for any nucleotide) […] Nm is also present […] at the 3′- end of small non-coding RNAs (sncRNAs), such as microRNAs (miRNAs) and small-interfering RNAs (siRNAs) in plants, on Ago2 loaded si- and miRNAs in flies”, page 1 Introduction paragraph 1 of Dimitrova et al. “RNA 2′-O-Methylation (Nm) Modification in Human Diseases” Genes (Basel) 10(2), 117 (2019)), it does not restrict the claim to nucleic acids that are not directed to a judicial exception and therefore is not a meaningful limitation.
MPEP §2106.04(d)(2) has to do with whether the additional elements apply or use the judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition. The additional elements do not apply the judicial exception to a particular treatment or prophylaxis.
MPEP §2016.05(f) raises the question as to whether the additional elements recited in the claim represent “mere instructions to apply an exception”. The additional limitation F discussed above applies the artificial nucleic acid as an active ingredient in a gene expression inhibiting agent or a nucleic acid detecting agent, which does not amount to more than a mere instruction to apply the judicial exception.
MPEP §2106.05(g) has to do with whether the additional elements of the claim amount of insignificant extra-solution activity. The additional limitations A-F discussed above do not integrate the judicial exception with an activity.
MPEP §2106.05(h) has to do with whether the additional elements amount to more than generally linking the use of a judicial exception to a particular technological environment or field of use. The recitation of the judicial exception being applied to gene expression inhibition and nucleic acid detection in additional limitation F represents “field of use” limitations. However, as MPEP §2106.05(h) indicates, such limiting to a particular “field of use” does not confer patentability to otherwise ineligible subject matter.
In addition, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception (as set forth in step 2B of the subject matter eligibility test) because additional limitations B, C, and D do not structurally limit the claimed product, additional limitations A and E do not limit the claimed nucleic acid sufficiently to exclude it from being directed toward natural products as discussed above, and additional limitation F merely uses the nucleic acid as a gene expression inhibiting or nucleic acid detection agent, both of which are well-understood, routine, and conventional uses of nucleic acids in the art.
Having considered the factors discussed in MPEP §2106.05, it is clear that the additional elements recited in the claims, whether considered individually or as a whole, do not integrate the judicial exception into a practical application of the exception in such a way as to provide meaningful limits on the use of the judicial exception and do not amount to significantly more than the judicial exception. Therefore, claims 1-10 and 12-15 are rejected here under 35 U.S.C. 101.
Claim Rejections - 35 USC § 102
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 1-10 and 12-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Peacey et al. (Non-Patent Literature Document Cite No 1 in IDS filed 17 October 2025)(“Targeting a pre-mRNA structure with bipartite antisense molecules modulates tau alternative splicing” Nucleic Acids Res 40(19), 9836-9849 (2012)), herein Peacey.
Regarding claim 1, Peacey teaches an artificial nucleic acid (“we designed bipartite antisense oligonucleotides (ASOs)” page 9836 right column paragraph 3). As discussed in the second paragraph of the Claim Interpretation second above, the intended use recited in claim 1is not interpreted as being limiting. Peacey further teaches said artificial nucleic acid comprising a three-dimensional structure formation-inducing domain that forms a three-dimensional structure together with a target domain in said nucleic acid of interest (Figure 1A), said target domain and said three-dimensional structure formation-inducing domain form a sequence motif composed of double strands forming the specific three-dimensional structure (Figure 1A), in said sequence motif, said three-dimensional structure formation-inducing domain and said target domain comprises complementary regions consisting of mutually complementary sequences (Figure 1A, regions of ASO hybridizing with the nucleic acid of interest), in said sequence motif, said three-dimensional structure formation-inducing domain and/or said target domain further comprises a non-complementary-containing region with 1 or more bases comprising a mutually non-complementary sequence (this limitation is interpreted as encompassing either the three-dimensional structure formation-inducing domain or target domain comprising a region of 1 or more bases that does not have a complementary sequence in the other domain; Figure 1A, hairpin region of the nucleic acid of interest does not have a complementary region in the ASO), and said non-complementary-containing region comprises non-complementary sequences at its both ends (Figure 1A).
Regarding claim 2, Peacey teaches the artificial nucleic acid of claim 1 (see 35 U.S.C. 102 rejection of claim 1 above), further comprising a hybridizable domain(s) composed of 6 to 120 bases, adjacent to one or both sides of said three-dimensional structure formation-inducing domain (Figure 1A, the A-linker-C from 5’ to 3’ of the ASO is considered the three-dimensional structure formation-inducing domain, it is adjacent on its 5’ end to a hybridizable domain of 9 bases and on its 3’ end to a hybridizable domain of 8 bases).
Regarding claim 3, Peacey teaches the artificial nucleic acid of claim 1 (see 35 U.S.C. 102 rejection of claim 1 above), wherein said three-dimensional structure formation-inducing domain and/or said target domain comprises a plurality of said complementary regions, and wherein said non-complementary-containing region is located between said plurality of the complementary region (Figure 1A).
Regarding claims 4-6, Peacey teaches the artificial nucleic acid of claim 1 (see 35 U.S.C. 102 rejection of claim 1 above). As discussed in the third paragraph of the Claim Interpretation section above, the artificial nucleic acid taught by Peacey anticipates the claimed artificial nucleic acid of claims 4-6 so long as there is a possible sequence of a nucleic acid of interest that, when hybridized to the artificial nucleic acid of the prior art, would form a three-dimensional structure as claimed in claims 4-6. For example, when the 9-1A-10 RNA 5’-GCGCAUGGGAACCGCCUCCC-3’ ASO of Table 1, which is the ASO of Figure 1A modified to be made of RNA instead of DNA to do have the linker be a single adenosine, hybridizes with a possible nucleic acid of interest sequence 5’-GGGAGGCGGUGACCAUGCGC-3’, there is a non-complementary-containing region composed of 2 bases and a specific three-dimensional structure comprising a tandem GA structure is formed wherein the tandem GA structure is composed of 5’-NGAN-3’ and 5’-NGAN-3’, see Exemplary Figure 2 below. Also, regarding the intended use of claim 1, even if the intended use were interpreted as limiting, this exemplary nucleic acid of interest clearly does not form a functional three-dimensional structure when not hybridized to the artificial nucleic acid but does when hybridized to the artificial nucleic acid, so the artificial nucleic acid taught by Peacey is capable of performing the intended use.
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Exemplary Figure 2: example nucleic acid of interest such that an ASO taught by Peacey hybridizes to form a tandem GA structure and wherein the non-complementary-containing region is 2 bases.
Regarding claim 7, Peacey teaches the artificial nucleic acid of claim 1 (see 35 U.S.C. 102 rejection of claim 1 above), wherein the nucleic acid of interest is mRNA (“Our first designed bipartite ASOs were DNAs with up to 10 bases on either side, complementary to their respective partner regions that flank the stem–loop (or hairpin) structure at the tau pre-mRNA exon 10–intron 10 junction” page 9838 right column paragraph 3; Figure 1A; note that pre-mRNA is a type of mRNA, as the clean substitute specification filed 19 July 2024 states in [0088] “Specific examples include mRNAs transcribed from the gene (including, for example, mature mRNAs, mRNA precursors”).
Regarding claim 8, Peacey teaches the artificial nucleic acid of claim 1 (see 35 U.S.C. 102 rejection of claim 1 above), wherein said hybridizing is performed under high stringent conditions (“0.5 µM hairpin-containing RNA was hybridized with 0.5 µM ASO in incubation buffer at 25°C for 30 min (50 mM TRIS–HCl, pH 7.5, 10 mM MgCl 2 , 10 mM NaCl, 0.1 mM EDTA)” page 9837 left column paragraph 2). Examiner notes that this limitation, as discussed in the third paragraph of the Claim Interpretation section above, only limits the artificial nucleic acid insofar as it is capable of forming the structure described in claim 1 with the nucleic acid of interest under high stringent conditions.
Regarding claims 9-10, Peacey teaches the artificial nucleic acid of claim 1 (see 35 U.S.C. 102 rejection of claim 1 above), wherein said three-dimensional structure formation-inducing domain comprises 1 or more modified nucleotides that are 2’-OMe RNA (“RNA ASOs were modified with 2’-OMe groups and a phosphorothioate backbone to confer stability against nucleases […] Like their DNA counterparts, RNA ASOs 9-1A-10, 9-2A-10 and 9-3A-10 hybridized to the tau RNA” page 9839 right column paragraph 2).
Regarding claims 12-13, Peacey teaches the artificial nucleic acid of claim 1 (see 35 U.S.C. 102 rejection of claim 1 above), wherein said target domain comprises said non-complementary-containing region containing a mutation that is a single nucleotide variant, insertion-deletion mutation, structural variant, or a combination thereof (“Bipartite RNA ASOs can also bind to tau RNA with mutations that remove all complementarity in the hairpin” page 9841 left column paragraph 1; note that the non-complementary-containing region in the target domain is the hairpin, which is 21 bases long, and the clean substitute specification filed 19 July 2024 states in [0034] that “the term "insertion-deletion mutation (in-del mutation)" refers to a type of mutation in base sequence present in the genome of a population of biological species, with a mutation size of 2 bases or more and less than 50 bases”; furthermore, insofar as the intended use recited in claim 1 could be interpreted as limiting, the mutation of the tau hairpin of Figure 1A of Peacey to the nucleic acid of interest of Exemplary Figure 2 above would also be encompassed by this definition of an insertion-deletion mutation).
Regarding claim 14, Peacey teaches a gene expression inhibiting agent comprising the artificial nucleic acid of claim 1 as an active ingredient (“the effect of 9-1A-10 RNA antisense is due to inhibition of splicing” page 9842 right column paragraph 1, note that inhibiting splicing will inherently inhibit gene expression of the spliced form for the splicing event that is inhibited).
Regarding claim 15, Peacey teaches a nucleic acid detecting agent comprising the artificial nucleic acid of claim 1 as an active ingredient (“An EMSA gel (Figure 1B) revealed that DNA with 9 bases complementary to the 5’-flank, a linker of one adenosine, and 10 bases complementary to the 3’-flank (termed 9-1A-10 DNA; Table 1 lists all ASOs used in this study) can hybridize virtually completely to a synthetic 40-nt hairpin-containing RNA at equimolar concentrations as shown by a band of slower mobility (lane 3) compared with tau RNA alone (lane 1)” page 9838 right column paragraph 3, note in Figure 1B that comparing lane 2 with the artificial nucleic acid alone and lane 3 of the artificial nucleic acid plus the nucleic acid of interest the hybrid band is only detected in lane 3, so the artificial nucleic acid is serving as a detection agent that produces the hybrid band when the target nucleic acid is detected).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, 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.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Peacey et al. (Non-Patent Literature Document Cite No 1 in IDS filed 17 October 2025)(“Targeting a pre-mRNA structure with bipartite antisense molecules modulates tau alternative splicing” Nucleic Acids Res 40(19), 9836-9849 (2012)), herein Peacey, as applied to claims 1-10 and 12-15 above, and in view of Chen et al. (“Systematic evaluation of 2′-Fluoro modified chimeric antisense oligonucleotide-mediated exon skipping in vitro” Sci Rep 9(1), 6078 (2019)), herein Chen.
Regarding claim 11, Peacey teaches the artificial nucleic acid of claim 9 (see 35 U.S.C. 102 rejection of claim 9 above). However, Peacey does not teach that the modified nucleotide comprises fluoro group-modification at the 2’ position of the ribose. This deficiency is made up for in the teachings of Chen.
Regarding claim 11, Chen teaches that the substitution of 2’-F modifications of ribonucleotides for 2’-OMe modifications of ribonucleotides in antisense oligonucleotides (AOs) led to similar or greater efficiency in splicing modulation (“Our results showed that all AOs containing 2′-F nucleotides induced efficient exon-23 skipping” Abstract; “In conclusion, 2′-F-PS modified AOs induce higher Dmd exon-23 skipping efficiency than fully 2′-OMe-PS AO […] Collectively, our findings expand the scope of utilizing 2′-F modified AOs in splice modulation application by constructing 2′-OMe and LNA-modified 2′-F-PS chimeras” page 8 paragraph 4).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to perform the simple substitution of the 2’-F modification of antisense oligonucleotides taught by Chen for at least some of the 2’-OMe modifications in the RNA antisense oligonucleotides taught by Peacey (MPEP §2143 I. B.). One of ordinary skill in the art would further be motivated to perform this substitution because Chen teaches that antisense oligonucleotides with 2’-F modifications were advantageous because they had increased efficiency when used to induce exon skipping. One of ordinary skill in the art could have performed this substitution and would have found the results of this substitution predictable because Chen teaches that antisense oligonucleotides using 2’-OMe modifications, 2’-F modifications, or a mix of both modifications have similar functionality. Therefore, the invention as a whole of claim 11 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Conclusion
Claims 1-15 are rejected. Claim 16 is withdrawn. No claims are allowed.
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/JEFFREY BELLAH/Examiner, Art Unit 1683
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683
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