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 with traverse of group I (Claims 1-5, 7, 16 and 19) and species (SEQ ID NO:1) in the reply filed on 11/24/25 is acknowledged. The traversal is on the ground(s) that the amended claims have unity because they are all directed to a product, produces specifically adapted for the manufacture of the product and a use of said product. More specifically, the special technical feature of the claims is a product comprising at least one o8G among the 1st to 9th nucleotide from the 5’ end of the at least one single strand of double strands thereof, wherein the product has a sequence of a microRNA selected from miR-1, miR-122, let-7, and miR-124. This is not found persuasive because the amendment to claim 1 results in a new special technical feature for the claimed invention. The new special technical feature appears to be a double stranded nucleic acid comprising at least one 8-oxoguanine (o8G) among the 1st to 9th nucleotide from the 5’ end of at least one strand of the double stranded nucleic acid, wherein the strand is a microRNA selected from miR-1, miR-122, let-7, and miR-124. A search of the prior art indicates that groups I-III lack unity of invention because even though these groups require the technical feature, this technical feature is not a special technical feature as it does not make a contribution over the prior art of Burrows (WO 2010111290, cited on an IDS) taken with Duan et al. (Mol. Biosyst, 2014, 10,2775-2782, cited on an IDS). Burrows teaches incorporating at least one o8G into a siRNA (also known as double stranded nucleic acid) for reduced or complete abrogation of off-target effects (page 2). Burrows teaches that siRNA mimicking miRNAs can be added to mammalian cells and reduce expression of gene in the cells. Burrows does not specifically teach incorporating at least one o8G into the miRNA set forth in instant claim 1. However, Duan teaches studying miR-1 in heart disease since it might be a possible therapeutic target. Thus, it would have been obvious to one of ordinary skill in the art before the filing date of the instant application to make the claimed product to reduce the off-target effect of the siRNA for targeting miR-1 expression in a cell. Thus, the restriction is still applicable to the amended claims.
The requirement is still deemed proper and is therefore made FINAL.
Claims 9-13, 15, 21 and 23-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 11/24/25.
Upon further review of the sequences in claim 5, SEQ ID NOs: 2 and 3 are miR-1 sequences and are rejoined with the elected species and searched.
NOTE: in the response filed on 11/24/25, applicant indicates that claims 16 and 19 in group I read on the elected species, however, the elected species (miR-1) is not recited in these two claims.
The microRNA, miR-122, let-7, and miR-124 in claim 1 and SEQ ID NOs: 65-67 in Claim 5 and claims 16 and 19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 11/24/25.
Information Disclosure Statement
The references cited in the PCT international search report by the PCT/KR2020/017341 have been considered, but will not be listed on any patent resulting from this application because they were not provided on a separate list in compliance with 37 CFR 1.98(a)(1). In order to have the references printed on such resulting patent, a separate listing, preferably on a PTO/SB/08 form, must be filed within the set period for reply to this Office action. NOTE: Seok et al. (Nature August 2020 Vol. 584, 279-285) was cited on the search report, but does not appear to be listed on an IDS. The Office cited the reference on a PTO-892 so the applicant does not need to file an IDS with this reference.
The listing of references in the PCT international search report is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, “the list ... must be submitted on a separate paper.” Therefore, the references cited in the international search report have not been considered. Applicant is advised that the date of submission of any item of information in the international search report will be the date of submission of the IDS for purposes of determining compliance with the requirements for the IDS with 37 CFR 1.97, including all timing statement requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Drawings
The drawings were received on 11/24/25. These drawings for figures 2d-2j, 3a, 5f, 6a-6e are acceptable.
However, several drawings are objected to because the view numbers for Figures 1A-H, 2a-c, 3b-3p, 5a-5e, 6f-6n, 7a-d and 8a-e are preceded by the word “Figure” instead of the abbreviation “FIG”. See 37 CFR 1.84(u)(1). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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 – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). see page 49.
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 sequence identifiers, 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. 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. For example, see pages 41, 56 and 76, please review entire specification for any other hyperlinks or codes.
The use of the term RNAiMax and Lipofectamine on page 39; Qubit on page 40; Qiazol on page 45 and TaqMan on page 51, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Please review the specification for any additional trade name or marks used by commerce.
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 Objections
Claims 1 and 5 are objected to because of the following informalities: the term Group 1(2): [group 1(2)] is redundant. Appropriate correction is required.
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 1, 4-5 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Seok et al. (Nature Vol. 584, pages 279-285, pages 1-31, August 2020) taken with Burrows (WO 2010111290, cited on an IDS).
NOTE: the applicant claims priority to a Korean application filed on 11/28/19, but the applicant has not provided a certified English copy of the foreign application. Thus, the effective filing date is 11/30/20.
Applicant cannot rely upon the certified copy of the foreign priority application to overcome this rejection because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Seok et al. sequenced o8G in a rat model of redox-associated condition cardiac hypertrophy (abstract). Seok et al. teaches:
We find that position-specific o8G modifications are generated in seed regions (positions 2–8) of selective miRNAs, and function to regulate other mRNAs through o8 G•A base pairing. o8G is induced predominantly at position 7 of miR-1 (7o8 G-miR-1) by treatment with an adrenergic agonist. Introducing 7o8 G-miR-1 or 7U-miR-1 (in which G at position 7 is substituted with U) alone is sufficient to cause cardiac hypertrophy in mice, and the mRNA targets of o8 G-miR-1 function in affected phenotypes; the specific inhibition of 7o8 G-miR-1 in mouse cardiomyocytes was found to attenuate cardiac hypertrophy. o8 G-miR-1 is also implicated in patients with cardiomyopathy. Our findings show that the position-specific oxidation of miRNAs could serve as an epitranscriptional mechanism to coordinate pathophysiological redox-mediated gene expression (abstract).
Seok et al. teaches the miR-1 sequences set forth in instant claim 5 (see figures 2 and 3 and extended data Fig. 3g and 10a). O8G miR-1 redirected target repression via o8G-A base pairing (figure 3). Seok et al. further teaches that miR-1 has been found to function as negative regulator of cardiac hypertrophy (page 279). Expression of mir-1 exacerbates arrhytmogenesis and injury during ischaemia reperfusion (page 279). Seok further teaches using an antioxidant (N-acetylcysteine, NAC) to treat and study hypertrophy (page 279).
Seok et al. do not specifically teach a double stranded oligonucleotide comprising a strand comprising a miR-1, wherein the strand has at least one o8G among the 1st to 9th nucleotides from the 5’ end.
The term ‘RNA interference inducing nucleic acid’ in the pending claims broadly reads on a double stranded RNA comprising a sense and antisense strand, wherein one strand comprises a miR-1 sequence.
However, Burrows teaches incorporating at least one o8G into a siRNA for reduced or complete abrogation of off-target effects (page 2). Burrows teaches that siRNA mimicking miRNAs can be added to mammalian cells and reduce expression of gene in the cells. Burrows does not specifically teach incorporating at least one o8G into the miRNA set forth in instant claim 1.
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of Seok taken with Burrows to substitute at least guanine with o8G in the 5’ end of a miR-1 sequence in a double stranded RNA to reduce the off-target effect of the siRNA for targeting miR-1 expression in a cell, namely to arrive at the claimed invention. Seok et al. teaches instant SEQ ID NO: 1 is the sequence for miR-1 (Figure 2). Seok et al. teach that o8G miR-1 redirected target repression via o8G-A base pairing (figure 3). There are a finite number of guanines in the miR-1 sequence comprising SEQ ID NO: 1, it would have been obvious for one of ordinary skill in the art to try o8G at each guanine to determine the optimal sequence for reducing the off-target effect of the siRNA in a cell. See MPEP 2143(I)E. Thus, the sequences in instant claim 5 would be considered obvious variants. One of ordinary skill in the art would have been motivated to combine the teaching to combine the nucleic acid with NAC to study the potential for an additive effect for treating a cardiac disease (hypertrophy) in a subject.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Claims 1 and 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Burrows (WO 2010111290, cited on an IDS) taken with Duan et al. (Mol. Biosyst, 2014, 10,2775-2782, cited on an IDS).
Burrows teaches incorporating at least one o8G into a siRNA (also known as double stranded nucleic acid) for reduced or complete abrogation of off-target effects (page 2). Burrows teaches that siRNA mimicking miRNAs can be added to mammalian cells and reduce expression of gene in the cells.
Burrows does not specifically teach incorporating at least one o8G into the miRNA set forth in instant claim 1.
However, Duan teaches studying miR-1 in heart disease since it might be a possible therapeutic target. The nucleotide sequence for miR-1 (miR-1-1 and mir-1-2) taught by Duan reads on an unmodified nucleotide sequence (SEQ ID NOs: 1-3) set forth in instant claim 5 (page 2278, Fig 3).
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of Burrows taken with Duan to make the claimed product to reduce the off-target effect of the siRNA for targeting miR-1 expression in a cell, namely to arrive at the claimed invention. The term ‘RNA interference inducing nucleic acid’ in the pending claims broadly reads on a double stranded RNA comprising a sense and antisense strand, wherein one strand comprises a miR-1 sequence. The broadest reasonable interpretation of instant claim 4 embraces either the other strand of the RNA interference nucleic acid having a adenine (A) opposite the o8G (structural limitation) or the target miR-1 sequence in the cell has an A at a position complementary to the position of o8G in the strand of the nucleic acid (functional limitation). The product made obvious by Burrows and Duan would inherently possess the functional limitation in instant claim 4 because it has at least one o8G. Duan et al. teaches instant SEQ ID NO: 1 is the sequence for miR-1 (Figure 3). There are a finite number of guanines in the miR-1 sequence comprising SEQ ID NO: 1, it would have been obvious for one of ordinary skill in the art to try o8G at each guanine to determine the optimal sequence for reducing the off-target effect of the siRNA in a cell. See MPEP 2143(I)E. Thus, the sequences in instant claim 5 would be considered obvious variants.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Burrows taken with Duan et al. as applied to claims 1 and 4-5 above, and further in view of Agrawal et al. (Pharmacological Research 61, 2010, 269-280, cited on an IDS).
Burrows and Duan do not specifically making a composition comprising the nucleic acid of claim 1 and an antioxidant.
However, Agrawal teaches high doses of vitamin C/superoxide dismutase can be used to treat heart failure in a subject (page 276).
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of Burrows and Duan taken with Agrawal to add an antioxidant to a composition comprising the instant nucleic acid, namely to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to combine the teaching to combine the agents in a composition to study the potential for an additive effect for treating a cardiac disease in a subject.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Conclusion
See attached PTO-326 for disposition of claims.
While oxidation of a nucleotide can happen to a nucleotide sequence (including a miR-1 molecule, single stranded mature miRNA sequence) in nature (Seok et al. Nature Vol. 584, pages 279-285, pages 1-31, 2020), cited on an IDS), a search of the prior art does not result in a double stranded sequence (e.g., pre-miRNA) comprising a miR-1 sequence having at least one o8G among the 1st to 9th nucleotides from the 5’ end of a sequence of a microRNA. The prior art teaches that a miRNA sequence in a cell has to be processed into a mature single stranded RNA before oxidation occurs. Thus, the product claims are patent eligible.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. US 20160289675 discloses that incorporating an 8-oxoguanine into an oligomer can result in loss or decrease of TLR9 stimulation (page 18).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brian Whiteman whose telephone number is (571)272-0764. The examiner can normally be reached on Monday thru Friday; 6:00 AM to 3:00PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at (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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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636