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 .
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 07/30/2026 is acknowledged. Claims 1-18,20 and 21 were cancelled. Claims 19,22 and 25 were amended.
Applicant elected Group I (claims 1-4 and 7-25) without traverse in the reply filed on 03/26/2026. The claims drawn to the non-elected invention have been canceled.
Claims 19 and 22-25 are under examination.
Priority
This application is a 371 of PCT/JP2020/014307, filed 03/27/2020 and claims Foreign priority to JAPAN 2019/067914, filed 03/29/2019 as reflected by the most recent filing receipt.
Withdrawn Objections and Rejections
Applicant’s arguments and amendments, see page 5, filed 07/30/2026, with respect to the objections to claims 1,4,14,15 and the 35 U.S.C. 112(d) rejection of claims 18 and 19 have been fully considered and are persuasive due to the cancelation of claims 1-18, and the amendment to claim 19 to an independent claim. The objections and 35 U.S.C. 112(d) rejection have been withdrawn.
Applicant’s arguments and amendments, see page 6 filed 07/30/2026, with respect to the 35 U.S.C. 112(a) Written Description rejection of claims 23-25 have been fully considered and are persuasive due to the amendment to claims 23 and 25 to depend on claim 19 which is now an independent claim and no longer recites a genus of modified oligonucleotides with the recited functions. The 35 U.S.C. 112(a) Written Description rejection have been withdrawn.
Applicant’s arguments and amendments, see page 7, filed 07/30/2026, with respect to the 35 U.S.C. 102(a)(1) rejection of claims 1-4,7-10 and 22-24 as anticipated by Agrawal et al. have been fully considered and are persuasive due to the cancelation of claims 1-4,7-10 and the amendment to claim 22 to now depend on claim 19 rather than claim 1. Therefore, the rejection has been withdrawn.
Applicant’s arguments and amendments, see page 7, filed 07/30/2026, with respect to the 35 U.S.C. 103 rejection of claim 11 as obvious over Agrawal et al. in view of Seth et al., claim 12 as obvious over Agrawal et al., claims 13,14 and 18 as obvious of Agrawal et al. further in view of Swayze et al. have been fully considered and are persuasive due to the cancelation of these claims, and therefore the rejections have been withdrawn.
Applicant’s arguments and amendments, see pages 7-9, filed 07/30/2026, with respect to the Obviousness type double-patenting rejections over claims 21-23 of U.S. Patent 12,338,265 in view of Agrawal et al. and Swayze et al., over claims 21-23 of Application 17/998,463 in view of Agrawal et al. and Swayze et al., and over claims 8 and 19 of Application 18/005,520 in view of Agrawal et al. and Swayze et al. have been fully considered and are persuasive due to the cancelation of claims 1-4,7-15 and 18, as well as the arguments pertaining to claim 19 and therefore the rejections have been withdrawn.
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). Specifically, claim 19 shows the chemical structure of the modified oligonucleotide, which is 16 nucleotides in length, however, does not recite a sequence identifier. It is noted that claim 19 recited “SEQ ID NO: 4” in the claim set filed 11/20/2024, and therefore this SEQ ID NO should be amended back into the claim.
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.
Claim Rejections - 35 USC § 112
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.
Claim Rejections-Scope of Enablement
Claims 23-25 are 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 knockdown of DUX4 in skeletal muscle cells in vitro using Compounds 3 and 123, and being enabling for knockdown of DUX4 in vivo comprising administering an effective amount of Compounds 3 or 123 to a subject in need thereof, does not reasonably provide enablement for treating, preventing or delaying progress of a genus of DUX-4 related diseases in a subject comprising administering by any route of administration an effective amount of the modified oligonucleotide according to claim 19 to a subject in need thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As stated in MPEP §2164.01(a), “there are many factors to consider when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any experimentation is ‘undue’.” These factors include, but are not limited to:
1. The breadth of the claims;
2. The nature of the invention;
3. The state of the prior art;
4. The level of skill in the art;
5. The level of predictability in the art;
6. The amount of direction provided by the inventor;
7. The presence or absence of working examples;
8. The quantity of experimentation necessary needed to make or use the invention based on the disclosure.
See In re Wands USPQ 2d 1400 (CAFC 1988).
The Breadth of the Claims and The Nature of the Invention
Claim 23 encompasses a pharmaceutical composition comprising the modified oligonucleotide of claim 19 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, and recites an intended use for therapeutically treating, preventing or delaying progress of a genus of DUX4- related diseases, with claim 24 limiting the disease to facioscapulohumeral muscular dystrophy. Claim 25 encompasses treating, preventing (including 100% prevention) or delaying progress of a genus of DUX-4 related disease in a subject comprising administering an effective amount of the modified oligonucleotide according to claim 19 to a subject in need thereof. The instant specification discloses that a “DUX4-related disease” refers to a disease caused by abnormal expression of DUX4 mRNA or DUX4 protein, or mRNA or protein of a fusion gene due to translocation of the DUX4 gene. Examples thereof include, but are not limited to facioscapulohumeral muscular dystrophy, B-cell acute lymphocytic leukemia, differential round cell sarcoma, fetal rhabdomyosarcoma, and the like (page 29, paragraph 0118).
The State of the Prior Art
Before the effective filing date, Ansseau et al. (Genes 2017,8(3):93) cited on an IDS, taught that no curative treatment for FSHD is available, and that clinical management involves physical therapy, aerobic exercise, respiratory function therapy and orthopedic interventions (page 3, Section 1.4). Ansseau et al. taught that the systematic evaluation in vivo of AOs targeting the DUX4 mRNA has been hampered by the lack of a transgenic mouse model expressing DUX4 and presenting a myopathy, and that the difficulty in generating these mice results from the combination of DUX4 toxicity, frequent leaks in its expression even from an inducible promoter and its normal role in early embryogenesis, however research groups are developing new transgenic mouse models that appear much closer to the pathological presentation of FSHD and could potentially be used to evaluate AOs of different chemistries in vivo for efficacy, specificity and lack of toxicity (Section 3.4 and Conclusions). Ansseau et al. taught that it may be more difficult to target FSHD muscles for which no major membrane alteration has been described, and since DUX4 expression occurs in a low proportion of FSHD myonuclei, PMOs may need to be administered in large and repeated doses to achieve and maintain therapeutic efficacy, and that various chemical moieties have been added to PMOs in order to facilitated their membrane crossing and cell uptake, and some of these structures could be optimized for FSHD muscles (Conclusions, page 15).
The Level of Predictability in the Art
The instant claimed invention is highly unpredictable due to the claims encompassing that the recited method can prevent, which includes 100% prevention, as well as treat or delay the progress of a genus of DUX4-related diseases in a subject (facioscapulohumeral muscular dystrophy, B-cell acute lymphocytic leukemia, differential round cell sarcoma, fetal rhabdomyosarcoma, and the like) by administering an effective amount of the modified oligonucleotide of claim 19. It would be unpredictable that the recited method would be capable of preventing any DUX4-related disease, as if one does not know that the subject will have the DUX4-related disease, how would one know to administer the modified oligonucleotide. In addition, the as shown by Ansseau et al. above, at the time of the effective filing date, there was no curative treatment for FSHD available, and the systematic evaluation in vivo of AOs targeting the DUX4 mRNA has been hampered by the lack of a transgenic mouse model expressing DUX4 and presenting a myopathy.
In addition, as the DUX4-related diseases also encompass various cancers including B-cell acute lymphocytic leukemia, differential round cell sarcoma, and fetal rhabdosarcoma which affect different cells and parts of the body than facioscapulohumeral muscular dystrophy, this adds to the unpredictability of the recited method being carried out. Different routes of administration may affect the ability of the oligonucleotide to reach the affected cells/tissues depending on the DUX4-related disease being treated.
The Amount of Direction Provided by the Inventor and
The Presence or Absence of Working Examples
Regarding claims 23-25, the specification does not enable any person skilled in the art to which it pertains to make and/or use the invention commensurate in scope with the claims. The instant specification discloses specific sequences with modifications patterns, and which target different positions of DUX4. Table 1, Page 122 shows Compound No. 3 which is SEQ ID NO: 4 with specific modifications and that targets position 1480. Compound 123, also SEQ ID NO: 4 and having specific modifications and that targets position 1480 is shown in Table 1 on page 128.
Examples 6-8 of the instant specification (pages 129-135) disclose in vitro testing of DUX4 knockdown in C2C12 cells, and that some of the compounds that target different position ranges were found to have significantly lower inhibition rates.
Example 9 of the instant specification discloses in vivo DUX4 knockdown activity test in mice, and includes Compound No. 3 (sequence complementary to positions 1480-1495 of DUX4 mature mRNA) results shown in Figures 2 and 3 (page 138). Example 11 shows an in vivo test in mice, and that as shown in Figs. 5 and 6, Compound No. 3 and Compound No. 123 (both target position 1480 and are SEQ ID NO: 4 and differ based on modification pattern see pages 123 and 128) suppressed DUX4 mRNA expression.
However, the examples do not show treatment or prevention of any Dux4-related diseases.
The Quantity of Experimentation Necessary
Regarding claims 23-25, in light of the unpredictability surrounding the breadth of the claimed method, one wishing to practice the presently claimed invention would be unable to do so without engaging in undue experimentation. Additional experimentation would be needed in an in vivo model expressing DUX4 that presents a myopathy in order to determine if the recited method is capable of treating facioscapulohumeral muscular dystrophy, and additional experimentation would be needed in other disease relevant models to determine if the recited method is capable of being carried out and resulting in treatment, prevention or delaying progress of B-cell acute lymphocytic leukemia, differential round cell sarcoma or fetal rhabdomyosarcoma with the modified oligonucleotide, as the instant specification and state of the art does not show that these embodiments are enabled, therefore, further experimentation would be required and would be considered undue.
Conclusion of 35 U.S.C. 112(a) (Enablement) Analysis
After applying the Wands factors and analysis to claims 23-25, in view of the applicant’s entire disclosure, it is concluded that the specification is not enabled for the full scope as discussed above. Therefore, claims 23-25 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to use the invention commensurate in scope with these claims.
Response to Arguments
Applicant's arguments filed 07/30/2026 have been fully considered but they are not persuasive.
Applicant states on page 6, that claims 23-25 have been amended to directly or indirectly depend on claim 19, which identifies a particular modified oligonucleotide, and argues the specification enables of person of ordinary skill in the art to utilize pharmaceutical composition and the method of claims 23-25 with the particular modified oligonucleotide of claim 19 (compound 123) and the specification at paragraphs 0001-0003,0118-0120,0221-0231).
This is not found persuasive. While the amendment to claims 23-25 to directly or indirectly depend on claim 19 which identifies the specific modified oligonucleotide, did narrow the scope from the previous claims for the particular modified oligonucleotide, the amendments and arguments did not address any of the other factors or concerns in the Scope of Enablement rejection such as the genus of DUX-4 related diseases that are encompassed by claims 23 and 25, or that claims 23-25 also encompass 100% prevention of the diseases which is not enabled based on the rejection. The Examiner cited Ansseau et al. in the rejection which brings up valid problems and unpredictability regarding treatment for FSHD including that evaluation in vivo of AOs targeting the DUX4 mRNA has been hampered by the lack of a transgenic mouse model expressing DUX4 and presenting a myopathy, and that the difficulty in generating these mice results from the combination of DUX4 toxicity, frequent leaks in its expression even from an inducible promoter and its normal role in early embryogenesis, and that Ansseau et al. taught that it may be more difficult to target FSHD muscles for which no major membrane alteration has been described, and therefore adds to the unpredictability. As stated in the rejection, the DUX4-related diseases also encompass various cancers including B-cell acute lymphocytic leukemia, differential round cell sarcoma, and fetal rhabdosarcoma which affect different cells and parts of the body than facioscapulohumeral muscular dystrophy, this adds to the unpredictability of the recited method being carried out. As the state of the art and the specification do not enable the full scope of the claims, the Scope of Enablement rejection is maintained.
Conclusion
The modified oligonucleotide in claim 19 is free of the prior art due to not finding art on the ALNA[Ms] sugar modification.
Claims 23-25 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 STEPHANIE L SULLIVAN whose telephone number is (703)756-4671. The examiner can normally be reached Monday-Friday, 7:30-3:30 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram R Shukla can be reached at 571-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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