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 .
Applicant’s response of 04/22/2026, including a substitute specification, has been received and entered into the application file.
Claims 1, 24, 30, 53, 60, and 97 were amended in the claim set filed 04/22/2026.
Claims 15, 19, 33, 43, 44, 51, and 98-100 were canceled in the claim set filed 04/22/2026.
Claims 101-109 were added in the claim set filed 04/22/2026.
Claims 1, 22, 24, 30, 53, 60, 70, 74, 75, 77, 84, 87, 88, 94, 97, and 101-109 are pending, of which claims 77, 84, 87, 88, 94, 108, and 109 were previously withdrawn.
Election/Restrictions
Applicant’s previous election without traverse of Group I (claims 1, 5, 6, 12, 15, 19, 22, 24, 30, 33, 43, 44, 51, 53, 60, 70, 74, and 75) in the reply filed on 09/19/2025 is acknowledged. Claims 5, 6, 12, and 93 were canceled in the amended claim set filed 09/19/2025. Claims 97-100 were added in the amended claim set filed 09/19/2025. Claims 15, 19, 33, 43, 44, 51, and 98-100 were canceled in the claim set filed 04/22/2026. Claims 101-109 were added in the claim set filed 04/22/2026.
Claim 1 is directed to an allowable product. Pursuant to the procedures set forth in MPEP § 821.04(B), claims 77, 84, 87, 88, 94, 108, and 109, directed to the process of making or using an allowable product, previously withdrawn from consideration as a result of a restriction requirement, are hereby rejoined and fully examined for patentability under 37 CFR 1.104.
Because all claims previously withdrawn from consideration under 37 CFR 1.142 have been rejoined, the restriction requirement as set forth in the Office action mailed on 03/21/2025 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Prior Grounds of Objection/Rejection
RE: Specification
►The disclosure was previously objected to because it contained an embedded hyperlink and/or other form of browser-executable code.
The amendments to the instant specification received 04/22/2026 have obviated the basis of the objection of record. The objection of record is hereby withdrawn.
RE: Nucleotide and/or Amino Acid Sequence Disclosures
►It was previously set forth that nucleotide and/or amino acid sequences appearing in the specification at least at Tables 13 and 14 are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
The substitute specification received 04/22/2026 has obviated the basis of the prior noted sequence compliance issues. However, the newly filed sequence listing received 04/30/2026 has introduced new sequence compliance issues, as set forth below.
RE: Claim Objections
►Claims 1, 15, and 100 were previously objected to for minor informalities.
The cancellation of claims 15 and 100 renders the objection thereof moot.
The amendments to instant claim 1 have obviated the basis of the objection of record. The objection of record is hereby withdrawn.
RE: Claim Rejections - 35 USC § 102
►Claims 1, 15, 19, 22, 24, 30, 51, 60, 74, 75, and 97 were previously rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by US 2018/0305689 A1 (hereinafter Sætrom).
The cancellation of claims 15, 19, and 51 renders the rejection thereof moot.
The amendments to instant claim 1 (from which all other claims directly or indirectly depend) have obviated the basis of the rejection of record. The rejection of record is hereby withdrawn.
RE: Claim Rejections - 35 USC § 103
►Claims 33, 43, 44, 53, and 98-100 were previously rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0305689 A1 (hereinafter Sætrom) as applied to claims 1 and 51 above (see section Claim Rejections - 35 USC § 102), and further in view of US 2015/0197746 A1 (hereinafter Rajeev) and US 2016/0376591 A1 (hereinafter Manoharan).
The cancellation of claims 33, 43, 44, and 98-100 renders the rejection thereof moot.
The amendments to instant claim 1 (from which all other claims directly or indirectly depend) have obviated the basis of the rejection of record. The rejection of record is hereby withdrawn.
New/Maintained Grounds of Objection/Rejection
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 - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825. This application contains a “Sequence Listing” as a PDF file (37 CFR 1.821(c)(2)) or as physical sheets of paper (37 CFR 1.821(c)(3)). A copy of the "Sequence Listing" in computer readable form (CRF) has been submitted; however, the content of the CRF does not comply with one or more of the requirements of 37 CFR 1.822 through 1.824, as indicated in the "Error Report" that indicates the "Sequence Listing" could not be accepted. Refer to attachment or document "Computer Readable Form (CRF) for Sequence Listing – Defective" dated 04/30/2026.
Required response – Applicant must provide:
A replacement "Sequence Listing" part of the disclosure, as described above in item 1); together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the replacement "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also 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 and
An amendment to the specification to remove the “Sequence Listing previously submitted as a PDF file (37 CFR 1.821(c)(2)) or as physical sheets of paper (37 CFR 1.821(c)(3))
If the replacement "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, Applicant must also provide:
A CRF in accordance with 1.821(e)(1) or 1.821(e)(2) as required by 37 CFR 1.825(b)(6)(ii); and
Statement according to item 2) a) or b) above.
The Examiner further notes that the replacement sequence listing is inconsistent with the sequences disclosed in the instant specification. For example, SEQ ID NOs: 217 and 218 are respectively disclosed to be 5’-AGCUACCUAUGAUAAACUU-3’ and 5’-GCUACCUAUGAUAAACUCU-3’ and SEQ ID NOs: 627 and 628 are respectively disclosed to be 5’-AAGUUUAUCAUAGGUAGCU-3’ and 5’-AGAGUUUAUCAUAGGUAGC-3’ at Table 2. This is consistent with the prior sequence listing and with the amended claim set filed 04/22/2026. However, the replacement sequence listing discloses that SEQ ID NOs: 217, 218, 627, and 628 are respectively 5’-ccagaaataccaagggtggag-3’, 5’-agaaataccaagggtggagat-3’, 5’-tcaataacttagtcttgtttgac-3’, and 5’-caataacttagtcttgtttgaca-3’. These are examples; Applicant should check the entire specification and sequence listing for any further occurrences and ensure that the sequences listed in the specification and in the sequence listing are consistent.
Claim Rejections - 35 USC § 112(a) - Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 84, 87, 88, 94, 108, and 109 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for reducing the level of both sense- or antisense-containing foci in mice expressing human C9orf72 RNAs with up to 450 GGGGCC repeats, does not reasonably provide enablement for treatment of a subject diagnosed with any RPS25-associated disease such as a nucleotide repeat expansion disease such as C9orf72 ALS/FTD or prevention of the same disease(s). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: Claims 84, 87, 88, 94, 108, and 109 are drawn to a method of treating a subject (i.e. a human subject) diagnosed with an RPS25-associated disease (i.e. a nucleotide repeat expansion disease such as C9orf72 ALS/FTD) by administering a therapeutically effective amount of the dsRNA agent of claim 1, as well as an additional agent suitable for treatment or prevention of an RPS25-associated disorder, thereby treating the subject. The nature of the invention is complex in that one must be able to treat a disease such as C9orf72 ALS/FTD that currently has no documented treatments. Furthermore, the instant claim language is considered to encompass the prevention of such diseases, which is also not documented in the field. All of these requirements must be considered in the context of in vivo usage in human subject, as recited at instant claim 108.
Breadth of the claims: The claims broadly encompass the treatment of any RPS25-associated disease via providing the dsRNA agents targeting RPS25 of the instant claim set. While dependent claims 87 and 88 respectively limit the treated RPS25-associated disease to a nucleotide repeat expansion disease such as C9orf72 ALS/FTD, Huntington-Like Syndrome Due To C9orf72 Expansions, Fragile X syndrome (FXS), Myotonic dystrophy, CAG/polyglutamine disease, Friedreich ataxia, Unverricht-Lundborg myoclonic epilepsy (EPM1), Oculopharyngeal muscular dystrophy (OPMD), and Fuchs endothelial corneal dystrophy (FECD), the instantly claimed method nonetheless encompasses the treatment of any RPS25-associated diseases. The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification and existence of working examples: While the specification envisions a method of treating a subject (i.e. a human subject) having a disorder that would benefit from a reduction in RPS25 expression (i.e. a nucleotide repeat expansion disease such as C9orf72 ALS/FTD) (page 15, lines 6-17; page 28, lines 6-13), it only teaches in vivo reduction of the level of both sense- or antisense-containing foci in mice expressing human C9orf72 RNAs with up to 450 GGGGCC repeats by administering the dsRNA agents of instant claim 1 (Example 2). Crucially, while the data of Example 2 indicate that administration of a single dose of the dsRNA agents targeting RPS25 reduce the level of C9orf72 sense strand- and C9orf72 antisense strand-containing foci in the frontal cortex, hippocampal dentate gyrus, retrosplenial cortex and cerebellar molecular layer of the model mice set forth above, there is nothing disclosed indicating that this reduction has therapeutic benefit in treating nucleotide repeat expansion diseases such as C9orf72 ALS/FTD. Furthermore, no data is presented to identify or support an additional agent suitable for treatment or prevention of an RPS25-associated disorder.
Predictability and state of the art: While the art discloses that RPS25 is a potential therapeutic target for C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia and other neurodegenerative diseases caused by nucleotide repeat expansions (Yamada et al., 2019: abstract), the potential therapeutic applications of inhibiting RPS25 expression have yet to be realized. Furthermore, while WO 2019/084068 A1 (hereinafter Prevail) also envisions treatment of C9orf72 ALS/FTD by inhibiting RPS25 (page 3, lines 26-30; page 5, lines 13-18) but does not disclose any working examples that establish the therapeutic effect of inhibiting RPS25
Therefore, at the time of filing, the prior art does not support therapeutic intervention for C9orf72-related amyotrophic lateral sclerosis by inhibiting RPS25, although the prior art does teach that RPS25 may be a valuable therapeutic target for treatment of the same. Full realization of such therapeutic intervention would require a large amount of experimentation, as set forth below.
Furthermore, when looking to the prior art for guidance, a search of the prior art did not identify any agents suitable for the prevention of RPS25-associated diseases, as recited at instant claim 109. Therefore, given the lack of knowledge present in the prior art and the lack of guidance provided in the specification with respect to preventing RPS25-associated diseases, further experimentation would be required. Considering that the additional experimentation would require de novo experimentation without a guarantee of success, and further considering that any positive results (i.e., successful prevention of an RPS25-associated disease in a subject) would amount to a significant advancement in the state of the art, the additional experimentation required is considered undue.
Amount of experimentation necessary: The quantity of experimentation needed to carry out the full scope of the claimed method is large. One could not solely rely upon the guidance provided in the instant disclosure or prior art, especially in view of the lack of therapeutic and preventative interventions for RPS25-associated diseases such as nucleotide repeat expansion disease C9orf72 ALS/FTD, as set forth above. One would be required to fully develop a currently theoretical treatment (including considering efficacy and safety), which has not yet been achieved in the field despite a large amount of effort from the research community, underscoring the large amount of experimentation (with no guarantee or reasonable expectation of success) required to treat RPS25-associated diseases such as nucleotide repeat expansion disease C9orf72 ALS/FTD.
Furthermore, as set forth above, given the lack of knowledge present in the prior art and the lack of guidance provided in the specification with respect to preventing RPS25-associated diseases, further experimentation would be required. Considering that the additional experimentation would require de novo experimentation without a guarantee of success, and further considering that any positive results (i.e., successful prevention of an RPS25-associated disease in a subject) would amount to a significant advancement in the state of the art, the additional experimentation required is considered undue.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims 84, 87, 88, 94, 108, and 109 are not considered to be fully enabled by the instant disclosure.
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.
Claim 77 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.
Claim 77 recites the limitation "the mRNA transcript of the RPS25 gene" (bolded emphasis added) in lines 4-5. There is insufficient antecedent basis for this limitation in the claim. It would be remedial to amend the instant claim such that there is sufficient antecedent basis for each and every claim term, for example by reciting “an mRNA transcript of the RPS25 gene” (bolded emphasis added). This is merely an example set forth by the Examiner and is not intended to be limiting.
Allowable Subject Matter
Claims 1, 22, 24, 30, 53, 60, 70, 74, 75, 97, and 101-107 are allowed.
The following is a statement of reasons for the indication of allowable subject matter:
Instant claim 1, from which all other claims directly or indirectly depend, recites a dsRNA agent for inhibiting expression of RPS25, wherein said dsRNA agent requires an antisense strand comprising at least 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NOs: 627 or 628. A search of the prior art did not return any sequences which satisfy the instant claim limitations. Although antisense sequences targeting RPS25 are known in the art, Applicant discloses the efficacy of numerous tested duplexes in reducing RPS25 mRNA levels at Table 15, of which the duplexes of the instant claim set (XD-18347 and XD-18348) were the most effective. In view of these results, it is considered that the dsRNA agent of instant claim 1 (from which all other claims directly or indirectly depend) is free of the art. Furthermore, the amendments to the instant claim set have overcome each and every prior objection and/or rejection of record. Therefore, given that claims 1, 22, 24, 30, 53, 60, 70, 74, 75, 97, and 101-107, are free of the art and comply with statutory requirements (as set forth above), instant claims 1, 22, 24, 30, 53, 60, 70, 74, 75, 97, and 101-107 are allowed.
However, the Examiner notes that the application will not be in condition for allowance until the application complies with sequence requirements, as set forth above. In the event that a reply is received that does not comply with sequence requirements, the response will not be entered.
Conclusion
Claims 1, 22, 24, 30, 53, 60, 70, 74, 75, 97, and 101-107 are allowed.
Claims 77, 84, 87, 88, 94, 108, and 109 are rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sarah E Allen whose telephone number is (571)272-0408. The examiner can normally be reached M-F 8-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at 571-272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SARAH E ALLEN/ Examiner, Art Unit 1637
/J. E. ANGELL/ Primary Examiner, Art Unit 1637
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