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
The action is written in response to the applicant’s correspondence received on 7/1/2026. Claims 1-20 are currently pending.
The examiner reviewing the application has changed.
Priority
The instant application claims priority to US Provisional Application 62/226,617, with an effective filing date of 7/28/2021.
Election/Restriction
Applicant's election with traverse of the inventions of Group I (Claims 1-9), drawn to a process for making an antisense oligonucleotide product, in the reply filed on 7/1/2026 is acknowledged. The traversal is on the grounds that each of the claims in the group is linked by a common inventive concept and that as a result, a search into the prior art with regard to the invention of different groups is so related that separate significant search efforts should not be necessary. Applicant further states there is no serious burden on the examiner to collectively examine the different claim groups of the subject application. This is not found persuasive because the instant application is a 371 of PCT/US22/38037, wherein search burden is not a criteria for a restriction. The restriction is proper as the inventions lack unity under PCT Rule 13.2, as the technical feature present is not a special technical feature, in view of the prior art as discussed in the lack of unity requirement mailed on 5/1/2026.Furthermore, there is a search burden for examining the invention of group II as they are drawn to antisense oligonucleotide targeting specific genes and specific nucleotide sequences.
The requirement is still deemed proper and is therefore made FINAL.
Claims 10-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/1/2026.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Claims 1-9 are under examination on the merits.
Specification
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:
Regarding the drawings, Fig. 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 21, 22, 23, 24, 25, 26, and 27A-D all contain nucleotide sequences present with no identifying SEQ ID NOs. Looking to the instant specification for guidance, the brief description of the drawings do not provide appropriate or corresponding SEQ ID NOs with the sequences presented in the drawings.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated 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 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.
Drawings
The drawings are objected to under 37 CFR 1.83(a) because they fail to show:
The legends and data points of Fig. 3C-D
The structures of Fig. 5
The structures of Fig 6 and modifications present on the sequences
The structure and modifications present in Fig. 8
The legends and data points present in Fig. 9
The structures of Fig. 11
The legends and data points of Fig. 12A-B
The modification and sequences of Fig. 13
The structures and sequences of Fig. 15
The structures of Fig. 16
The structures of Fig. 18
The structures of Fig. 19
The structures and sequence modifications of Fig. 21
The structures and sequence modifications of Fig. 22
The structures of Fig. 23
The sequences and modifications of Fig. 24
The sequences and modifications for Fig. 25
The sequences of Fig. 26
The sequence of Fig. 27C
The structures of Fig. 28
as described in the specification. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). 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.
Claim Objections
Claim 6 objected to because of the following informalities: Claim 6, as written, is directed to a product (the antisense oligonucleotide of claim 2), while the base claim (claim 1 and 2) are drawn to a process.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 6 is 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 6 recites the broad recitation “a modification of the 2’ sugar position of a ribose moiety”, and the claim also recites “a 2’-MOE methoxyethyl moiety, a 2-flouro moiety, or a 2’-hydroxy moiety” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim Interpretation
Regarding claim 1, applicant recites “wherein the antisense oligonucleotide product is constructed by: forming an antisense oligonucleotide product by selecting a plurality of nucleotides”. Looking to the specification for guidance, applicant discloses plurality as “a plurality of nucleotides such that when covalently coupled together the plurality of nucleotides form an antisense oligonucleotide product having a segment of polynucleotides that is complementary to the ribonucleotide target sequence (as occurs with conventional ASOs). However, this methodology further includes selecting for this ASO such that: (a) one or more nucleotides within the antisense oligonucleotide product are selected to form a bonding interaction with a major-groove RNA triplex structure or minor-groove RNA triplex structure within the naturally occurring ribonucleotide molecule…” (see page 15 of the instant specification). Therefore, plurality is interpreted as multiple nucleotide sequences that can form the antisense oligonucleotide product as well as segments that may be designed for RNA interactions. Claim 1 also recites the word “comprising” which examiner interprets that the antisense oligonucleotide product can comprise multiple antisense oligonucleotides. This is evidenced by page 18, line 11 of the specification, wherein embodiments of the invention also include antisense oligonucleotides having the properties that occur when an ASO is made by a process disclosed herein.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-6, 8-9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Uhlmann et al. (US 2017/0211065 A1, published 7/27/2017) as evidenced by Dhuri (Antisense Oligonucleotides: An Emerging Area in Drug Discovery and Development, Journal of Clinical Medicine, Volume 9, Issue 6, all pages, published 6/26/2020).
Regarding claim 1, Ulhmann teaches a process for making an antisense oligonucleotide product (method of making multimeric oligonucleotide compounds, comprising two or more antisense oligonucleotides, see abstract) comprising: selecting a ribonucleotide target sequence, wherein: the ribonucleotide target sequence is selected as one present in a naturally occurring ribonucleotide molecule, the ribonucleotide target sequence is from 8-30 nucleotides in length (see paragraph 0009), the ribonucleotide target sequence comprises: a segment of ribonucleotides that forms an RNA loop structure in the naturally occurring ribonucleotide molecule, or a segment of ribonucleotides that are from 1 to 25 nucleotides distal to a segment of ribonucleotides that forms a hairpin structure in the naturally occurring ribonucleotide molecule.
Ulhmann teaches where the multimeric compound comprising ASOs can also antagonize miRNA which are single-stranded RNA molecules of about 21-23 nucleotides in length regulating gene expression, target sequence is present in a naturally occurring ribonucleotide molecule, and is from 8-30 nucleotides in length, wherein pre-miRNAs comprise a stem-loop structure, and can be bound and inhibited by ASOs (see paragraph 0072 and 0167).
Furthermore, Ulhmann teaches that for the synthesis of ASOs, this process was done by selecting ASO1 and ASO2 covalently linked together (a plurality of nucleotides such that when covalently coupled together the plurality of nucleotides to form an antisense oligonucleotide product) complementary to a ribonucleotide target sequence, such as miRNA (see paragraphs 0072, 0167, 0212, and 0214, as well as formula 1), wherein at least one targeting oligonucleotide comprises a G-clamp (see paragraphs 0019, 0064, 0072, 0167). This reads on “(b) one or more nucleotides within the antisense oligonucleotide product is selected to form a ‘Watson Crick base pairing with the ribonucleotide target sequence and a Hoogsteen base pairing with the target miRNA sequence” as evidenced by Dhuri (Antisense Oligonucleotides: An Emerging Area in Drug Discovery and Development, Journal of Clinical Medicine, Volume 9, Issue 6, all pages, published 6/26/2020). Dhuri teaches wherein the G-clamp modification contains phenoxazine residues that form a total of five hydrogen bonds with complementary guanine nucleobase in the target sequence by Watson-Crick as well as Hoogsteen-base pairing (see page 4, paragraph 3 and page 5, paragraph 1 of Dhuri).
Furthermore, Ulhmann teaches where it should also be appreciated that a targeting oligonucleotide may hybridize with a target region through Watson-Crick base pairing, Hoogsteen base pairing, etc. (see paragraph 0064).
Regarding claim 2, Uhlmann teaches wherein the targeting ASO oligonucleotide comprises a G-clamp (see paragraph 0019, 0064, 0072, and 0167). It is evidenced by Dhuri where the G-clamp has been used to increase the efficacy of ASOs, wherein the G-clamp modification contains phenoxazine residues that form a total of five hydrogen bonds with complementary guanine nucleobase in the target sequence by Watson-Crick as well as Hoogsteen-base, which can increase the binding affinity by 23 degrees Celsius, thereby indicating an increase in free energy of ASO binding (see page 4, paragraph 3 and page 5, paragraph 1 of Dhuri).
Regarding claim 3, Ulhmann teaches where the targeting oligonucleotides are 8 to 100 nucleotides in length (se paragraph 0009 and 0083).
Regarding claim 4, Ulhmann teaches where the ASO targeted to miRNA has a region of complementarity of 4 to 20 nucleotides, wherein the region of complementary may have one or more mismatches compared with the nucleotide sequence of the miRNA target region (see abstract, paragraph 0064).
Regarding claim 5, Ulhmann teaches where the targeting ASO has a structure of X-N-Y (see paragraph 0124), wherein X or Y are 2 to 3 nt long non-complimentary antisense nucleotides (the first five terminal 5’ or 3’ nucleotides in the ASO) comprising 1 to 5 G-clamp modified nucleotides (see paragraph 0019). As evidenced by Dhuri, G-clamp modified nucleotides form a total of 5 hydrogen bonds with complementary guanine nucleobase in the target sequence by Waston-Crick as well as Hoogsteen-base (see page 4, paragraph 3, and page 5, paragraph 1 of Dhuri).
Regarding claim 6, Ulhmann teaches where the antisense oligonucleotide product comprises at least one of: a pseudouridine nucleotide, a phosphorothioate linkage (see paragraph 0019), a morpholino nucleotide, a modification of the 2’ sugar position of a ribose moiety, etc. (see paragraph 0089 and 0108).
Regarding claim 8, Ulhmann teaches where the antisense targeting oligonucleotide is 8 to 30 nucleotides in length (see paragraph 0009), wherein the ASO targeted to miRNA has a region of complementarity of 4 to 20 nucleotides, and where the targeting ASO oligonucleotide comprises a G-clamp (see paragraph 0019), which enables the formation of Watson-Crick and Hoogsteen base pairing with the target miRNA sequence, as evidenced by Dhuri.
Regarding claim 9, Ulhmann teaches where further provided are pharmaceutical compositions, comprising a compound of the invention and one or more pharmaceutically acceptable excipients (see paragraph 0168).
In view of the foregoing, claims 1-6, and 8-9 are rejected under U.S.C. 102(a)(1) as being anticipated by Uhlmann.
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.
Claims 7 is rejected under 35 U.S.C. 103 as being unpatentable over Uhlmann et al. (US 2017/0211065 A1, published 7/27/2017) in view of Compagno et al. (Antisense Oligonucleotides Containing Modified Bases Inhibit in Vitro Translation of Leishmania amazonensis mRNAs by Invading the Mini-exon Hairpin, The Journal of Biological Chemistry, Volume 274, No. 12, pgs. 8191-8198, published 1999).
Regarding the process of claim 1, which claim 7 recites, the teachings of Uhlmann anticipate the process as described above.
Regarding claim 7, Ulhmann further teaches wherein the antisense oligonucleotide product consists of 8 to 30 nucleotide in length (see paragraph 0009), where the ASO targeted to miRNA has a region of 100% complementarity of 4 to 20 nucleotides (see abstract, paragraphs 0064, 0072, 0167), and where the targeting ASO has a structure of X-N-Y, where X or Y are 2 to 3 nt long non-complimentary antisense nucleotides, representing the 5’ or 3’ terminal nucleotides in the ASOs, where at least 1 modified nucleotide is present (see paragraphs 0019, 0064, 0072, 0124, and 0167).
Regarding claim 7, Ulhmann does not teach where at least 1 nucleotide forms a bonding interaction with a major groove RNA structure or a minor-groove RNA structure in the naturally occurring ribonucleotide molecule.
Regarding claim 7, Compango teaches an antisense oligonucleotide comprising at least 1 nucleotide forming a bonding interaction with a minor groove RNA structure as recited by antisense ODNs that bind the Leishmania exon RNA minor groove (see abstract, page 8197, column 1, paragraph 2).
It would have been obvious to one with ordinary skill in the art, to combine the teachings of Ulhmann and Campango, to arrive at an antisense oligonucleotide product where at least 1 nucleotide forms a bonding interaction with a minor-groove RNA structure in the naturally occurring ribonucleotide molecule.
One would expect a reasonable chance of success as Compango teaches where antisense ODNs are capable of binding to the Leishmania exon RNA minor groove.
One would be motivated to modify the antisense oligonucleotide of Ulhmann as Compango teaches where ASOs that can target the RNA minor groove structure are improved as they provide specific targeting and silencing activity in therapeutic application (see abstract of Compango where SBC phosphorothioate ODNs displayed a modest but significant improvement of leishmanicidal properties compared with NB phosphorothioate ODNs).
In view of the foregoing, claim 7 is rejected under U.S.C. 103 as being prima facie obvious, before the effective filing date.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID YU whose telephone number is (571)272-1118. The examiner can normally be reached Monday-Friday 7:30 am -5 pm.
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/D.T.Y./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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