Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Status of Application, Amendments, and/or Claims
2. The Response filed on 27 February 2026 has been entered in full. Claim 2 has been amended, and claims 13-20 remain withdrawn from consideration. Therefore, 1-20 are pending, and claims 1-12 are the subject of this Office Action.
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted on 02 March 2026 has been considered by the examiner.
Withdrawn Objections and/or Rejections
4. The rejection of claims 1-12 for reciting an improper Markush grouping as set forth at pp. 2-4 of the previous Office action (mailed 02 December 2025) is withdrawn in view of Applicants persuasive arguments, and identification that the recited nucleic acid sequences are overlapping (filed 27 February 2026).
5. The rejection of claim 2 under 35 U.S.C. 112(d) as set forth at pg. 4 of the previous Office action (mailed 02 December 2025) is withdrawn in view of Applicants amendment of said claim (filed 27 February 2026).
Maintained and/or New Objections and/or Rejections
Claim Rejections - 35 USC § 112 (Written Description)
6. The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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.
7. Claims 1-2 and 5-12 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The basis for this rejection is set forth at pp. 5-9 of the previous Office action (mailed 02 December 2025).
8. The claims are drawn quite broadly to a phosphorodiamidate morpholino oligonucleotide (PMO) conjugate comprising an anti-transferrin receptor antibody or antigen binding fragment thereof conjugated to a PMO molecule that hybridizes to a pre-mRNA transcript of the DMD gene and induces exon 52 skipping in said pre-mRNA transcript to generate a mRNA transcript encoding a truncated dystrophin protein, wherein the PMO molecule comprises a nucleic acid sequence having at least 90%, 95%, or 100% sequence identity to any one of SEQ ID NOs:100-161. The claims also recite wherein the PMO molecule comprises a nucleic acid sequence having at least 20, 21 23, or 24 nucleotides from a nucleic acid sequence selected from the group consisting of SEQ ID NOs:100-161 with no more than one or two mismatches. Thus, the claims are drawn to a genus of nucleic acid molecules that are defined by a partial structure and a desired function in that they hybridize to a pre-mRNA transcript of the DMD gene, induce exon 52 skipping in said pre-mRNA transcript, and generate a mRNA transcript encoding a truncated dystrophin protein. However, the specification does not provide sufficient written description as to the structural features of the claimed genus of PMO molecules that are encompassed by the claims, nor does it describe a representative number of species that have the recited functions.
9. A "representative number of species" means that the species, which are adequately described, are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004)("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)(Claims directed to PTFE dental floss with a friction-enhancing coating were not supported by a disclosure of a microcrystalline wax coating where there was no evidence in the disclosure or anywhere else in the record showing applicant conveyed that any other coating was suitable for a PTFE dental floss.).
10. In contrast to the breadth of the claims, the specification provides adequate written description for a number of PMO molecules that are defined by particular nucleic acid sequences, it does not provide adequate written description for the genus of variants recited in the claims. The specification provides adequate written description for a number of PMO molecules that are defined by particular nucleic acid sequences that hybridize to a pre-mRNA transcript of the DMD gene, induces exon 52 skipping in said pre-mRNA transcript, generates a mRNA transcript encoding a truncated dystrophin protein, and produces an increase and/or restores dystrophin protein levels in vitro (See Examples 1-4 and 5 at pp. 95-99), and when conjugated to a transferrin receptor antibody exhibited these same activities in vivo (See Examples 6 and 7 at pp. 99-103. However, there does not appear to be an adequate written description in the Specification as filed of the essential structural features of the variants encompassed by the claims that provide the recited functions. In contrast to the constructs described in the Specification, the only factors present in the instant claims is a limited structure and a desired function.
11. It is well known that minor structural differences even among structurally related compounds can result in substantially different biology, expression and activities. While it is known that nucleotide and amino acid substitutions are generally possible in any given nucleic acid molecule or protein, the positions within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of success are limited. Moreover, the art teaches that off-target effects often result from the complimentary binding to an unintended RNA with a sequence similar to the intended target RNA, an unintended consequence from even a single mismatch (See Yoshida et al., Genes Cells. 24:827-835, published 2019).
12. For inventions in an unpredictable art, adequate written description of a genus, which
embraces widely variant species, cannot be achieved by disclosing only one or two species
within the genus. See, e.g., Eli Lilly. Description of a representative number of species does not
require the description to be of such specificity that it would provide individual support for each
species that the genus embraces. If a representative number of adequately described species are
not disclosed for a genus, the claim to that genus must be rejected as lacking adequate written
description under 35 U.S.C. 112, first paragraph.
13. Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
14. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
15. In the instant case, there is insufficient guidance based on the instant disclosure to direct a person of skill in the art to select or to predict particular nucleotides as essential for proper functioning, as evidenced by the art referenced supra. With the exception of a PMO conjugate comprising an anti-transferrin receptor antibody or antigen-binding fragment thereof conjugated to a PMO molecule consisting of a nucleic acid sequence selected from SEQ ID NOs: 100-161, the skilled artisan cannot envision the detailed chemical structure of the encompassed variants, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The product itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
16. Therefore, only a PMO conjugate comprising an anti-transferrin receptor antibody, or antigen-binding fragment thereof, conjugated to a PMO molecule consisting of a nucleic acid sequence selected from SEQ ID NOs: 100-161, meets the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Response to Arguments
17. Applicant’s arguments as they pertain to the rejections have been fully considered but are not persuasive for the following reasons.
18. Applicant argues at pg. 6 of the response (filed 27 February 2026) that the Specification at Example 1 and Table 1 teach the sequence of SEQ ID NOs: 100-147 and their exon skipping activities, and Example 3 and Table 3 teach the sequence of SEQ ID NOs: 148-161 and their exon skipping activities, and thus describes more than one species of PMO molecule.
19. Applicant's arguments have been fully considered but are not found persuasive for the following reasons. While the Examiner acknowledges that the Specification provides adequate written description for PMO conjugates comprising an anti-transferrin receptor antibody, or antigen-binding fragment thereof, conjugated to a PMO molecule consisting of a nucleic acid sequence selected from SEQ ID NOs: 100-161, the claims are not so limited and the Specification does not provide adequate written description for the genus of variants recited in the claims since the art recognizes that function cannot be predicted from structure alone. It is well known that minor structural differences even among structurally related compounds can result in substantially different biology, expression and activities. While it is known that nucleotide and amino acid substitutions are generally possible in any given nucleic acid molecule or protein, the positions within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of success are limited. Moreover, the art teaches that off-target effects often result from the complimentary binding to an unintended RNA with a sequence similar to the intended target RNA, an unintended consequence from even a single mismatch (See Yoshida et al., Genes Cells. 24:827-835, published 2019).
Summary
20. Claims 1-2 and 5-12 stand rejected.
Claims 3-4 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
21. 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.
Advisory Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JON M LOCKARD whose telephone number is (571) 272-2717. The examiner can normally be reached M-F 9-6 EST.
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/J.L/Examiner, Art Unit 1647 March 21, 2026
/Christine J Saoud/ Primary Examiner, Art Unit 1645