DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Status of Application/Amendment/Claims
This Office action is in response to the communications filed on May 12, 2026.
Currently, claims 2, 9-11, and 14-20 are pending in the instant application. Claim 10 is withdrawn from further consideration as being drawn to a nonelected invention, there being no allowable generic or linking claim. Accordingly, claims 2, 9, 11, and 14-20 are under examination on the merits in the instant application.
The following rejections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
Response to Arguments and Amendments
Withdrawn Rejections
Any rejections/objections not repeated in this Office action are hereby withdrawn.
New Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 2, 9, and 14-20 are 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 instant claims are now strictly directed to a 26-mer PMO comprising SEQ ID NO:37 (a 19-mer sequence) or SEQ ID NO:38 (a 23-mer sequence that comprises SEQ ID NO:37) and a pharmaceutical composition thereof, wherein the 26-mer PMO “induces skipping of exon 44 of human dystrophin pre-mRNA” and is coupled to a targeting ligand.
The instant specification does not disclose the instantly claimed 26-mer PMOs that induce skipping of exon 44 of the human dystrophin pre-mRNA and have a pharmaceutical function, nor does the specification disclose the claimed 26-mer PMOs conjugated/coupled to any targeting ligand, wherein the targeting ligand-conjugated 26-mer PMOs have the required, claimed activity.
The instant specification identifies the 19-mer oligonucleotide of SEQ ID NO:37 as “PS 187” and the 23-mer oligonucleotide of SEQ ID NO:38 as “PS 194”, wherein the two oligonucleotides are fully modified with 2’-O-methyl RNA and phosphorothioate backbones and show DMD exon 44 skipping in patient cells in vitro. See Table 1A; Figures 1A-1B; paragraph 0112. Hence, not only is the claimed 26-mer comprising SEQ ID NO:37 or SEQ ID NO:38 undisclosed in the instant specification, but the specifically claimed PMO-modified 26-mer is not disclosed in the instant specification.
The instant specification generically discloses length ranges encompassing 26 and enumerates “26” in paragraph 0048. The specification also generically discloses “Phosphorodiamidate morpholino oligomers” (PMO) and “Morpholino oligonucleotides”. See paragraphs 0059-0060 and 0063. However, such generically disclosed embodiments are far from adequately describing the specifically claimed 26-mer PMO comprising a non-26-mer sequence (SEQ ID NO:37 and SEQ ID NO:38) in such a manner to reasonably convey that the instant co-inventors had possession of the claimed PMO as exactly claimed as of the filing date sought in the instant application. In fact, a 25-mer PMO comprising an 18-mer of SEQ ID NO:37 (nucleotide positions 2-19) or a 22-mer of SEQ ID NO:38 (nucleotide positions 2-23) was not deemed effective in inducing exon 44 skipping by relevant artisans shortly after the earliest filing date sought in the instant application. See Sazani et al. (US 2010/0130591 A1, applicant’s citation) who report that the 25-mer PPMO (transport peptide conjugated PMO) of SEQ ID NO:7 (5’-CCATTTCTCAACAGATCTGTCAAAT) comprising the entirety of SEQ ID NO:37 or SEQ ID NO:38 except one nucleotide (position 1) was not selected as an effective exon-skipping PPMO for further evaluation. See paragraph 0294 that discloses “a series of PPMOs, each 25 bases in length, were made (SEQ ID NOS:1-20) as shown in FIG. 5A. The PPMOs were evaluated for exon skipping efficacy by treating RD cells at various concentrations as described above in the Materials and Methods. Five PPMOs (SEQ ID NOS:4, 8, 11, 12 and 13) were identified as effective in inducing exon-skipping and selected for additional evaluation.” As such, it is clear that a 19-mer or 23-mer oligonucleotides fully modified with 2’-O-methyl with phosphorothioate backbone cannot represent a PMO composition that is 26 nucleotides in length having the intended exon 44 skipping activity, which is claimed and necessary for the claimed pharmaceutical composition. Therefore, the instant specification fails to adequately describe the required structure-function correlation for the undisclosed 26-mer PMO and its recited function in the rejected claims.
Since the 25-mer PMO comprising nucleotides 2-19 of SEQ ID NO:37 conjugated to a targeting ligand (transport peptide) was deemed ineffective in inducing dystrophin exon 44 skipping in a post-filing reference having a priority date of October 24, 2008, which reflects the complete lack of prior art knowledge pertaining to an exon skipping function of a 26-mer PMO (or PPMO) comprising the instantly claimed shorter oligonucleotide sequences of SEQ ID NOs:37-38 that are tested with a completely different, non-PMO chemical modification, and since the instant specification is completely silent regarding an actual exon skipping 26-mer PMO comprising the 19-mer SEQ ID NO:37 or the 23-mer SEQ ID NO:28, a person of ordinary skill in the art would reasonably conclude that the instantly claimed 26-mer PMO compositions are not adequately described by the instant specification in a manner to reasonably convey to the person of ordinary skill in the art that the instant co-inventors had possession of the instantly claimed 26-mer PMO compositions as of the filing date sought in the instant application.
Response to Arguments
Applicant's arguments filed on May 12, 2026 have been fully considered but they are not persuasive. Applicant argues that the instant claims as currently amended are limited to only “26” nucleotides in length and Sazani’s oligonucleotides pertain to only 25 nucleotides in length thus outside the scope of the amended claims, thereby failing to support the previous ground of rejection. Contrary to applicant’s argument, Sazani’s 25-mer PPMO of SEQ ID NO:7 that was found ineffective to induce exon skipping reasonably and fairly reflects the complete lack of the relevant prior art knowledge as well as the high level of unpredictability pertaining to the instantly claimed subject matter because a 26-mer PPMO having one additional base to the 25-mer PPMO comprising 18 consecutive nucleotides (positions 2-19) of SEQ ID NO:37 or 22 consecutive nucleotides (positions 2-23) of SEQ ID NO:38 would have been reasonably deemed to be also ineffective as there is only one base difference between the actual PPMO of Sazani and the instantly claimed 26-mer PMO. That is, Sazani’s actually tested 25-mer PMO of SEQ ID NO:7 and the claimed 26-mer PMO shares about 96% sequence identity, whereas applicant’s claims are directed to a 26-mer PMO comprising a 19-mer 2’-O-methyl/phosphorothioate-modified oligo of SEQ ID NO:37 (thus having about 73% sequence identity) or a 23-mer 2’-O-methyl/phosphorothioate-modified oligo of SEQ ID NO:37 (thus having about 88% sequence identity). Since applicant asserts that such undisclosed, untested 26-mer PMO compositions having far lower sequence identity levels with completely different chemical modifications (see “PS 187” and “PS 194”) is described to have the claimed function by the instant specification, the examiner finds that Sazani’s 25-mer PPMO having satisfying a higher level of structural requirements (both the nucleotide sequence and the chemical modification including PMO and the targeting ligand) should also represent the instantly claimed PMO.
Applicant points out a post-filing reference by Etxaniz et al. (2025) and argues that “a 26-nucleotide PMO oligonucleotide targeting exon 44 of human dystrophin pre-mRNA effectively reduces exon 44 skipping”. As an initial matter, it is noted that applicant did not submit a legible copy of the 2025 reference, nor is it recorded in an IDS of record. Hence, the examiner cannot verify the statement provided by applicant. However, it appears from applicant’s brief summary of the 2025 reference that the 26-mer PMO comprises the 19-mer or any fragment of SEQ ID NO:37 claimed in the instant case, whereas Sazani provided objective evidence that a longer oligonucleotide (25-mer) PMO comprising an 18-mer fragment of SEQ ID NO:37 failed to provide the intended exon skipping activity. As such, the preponderance of evidence against the non-utility of the instantly claimed subject matter is established by Sazani’s teachings, unless the 2025 reference’s 26-mer PMO does comprise the entirety of the 19-mer sequence of SEQ ID NO:37 or the same 18-mer fragment of SEQ ID NO:37 as contained in Sazani’s 25-mer PMO.
Most importantly, applicant cannot demonstrate inventors’ possession of the claimed DMD exon 44-skipping 26-mer PMO comprising SEQ ID NO:37 or SEQ ID NO:38 as of the effective filing date sought in the instant case, May 14, 2008, by using the 2025 reference published more than about 20 years after the effective filing date sought in the instant case because the written description inquiry occurs as of the filing date sought and within the specification, not outside the specification. That is, even if the 2025 reference is the work of the instant co-inventors (again, the examiner is not supplied with a legible copy of the reference for full consideration), the fact that the instant co-inventors actually made the claimed 26-mer PMO almost 20 years after the filing date sought in the instant case is a far cry from demonstrating that the instant specification itself, not outside of the specification, demonstrates possession of the instantly claimed 26-mer PMO.
“Nor is it sufficient [to comply with the written description requirement], as
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Ariad argues, that “skilled workers actually practiced this teaching soon after the 1989 application was filed.” See Vas-Cath, 935 F.2d at 1563-64 (holding that a written description analysis occurs “as of the filing date sought”)…. Conversely, we have repeatedly stated that actual “possession” or reduction to practice outside of the specification is not enough. Rather, as stated above, it is the specification itself that must demonstrate possession.” (emphasis added). Ariad Pharmaceuticals Inc. v. Eli Lilly & Co. 593 F3d 1336, 94 USPQ2d 1161 (Fed. Cir. 2010).
Moreover, based on applicant’s brief summary of the 2025 reference, it appears that the post-filing reference pertains to a 26-mer PMO “coupled to an anti-transferring receptor (TfR1) antibody.” It is noted that none of the rejected claims in the instant rejection is drawn to the TfR1 antibody-conjugated 26-mer PMO, which is allegedly shown to effectively induce exon 44 skipping and have a potential pharmaceutical function. Hence, even if the 2025 reference is the work of the instant co-inventors, and even if the disclosure of the 2025 reference were to be expressly disclosed in the instant specification, such disclosure would not support the entire genus of the instantly rejected claims.
Double Patenting
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 2, 9, and 14-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 13-14 of copending Application No. 18/179,064 in view of Wilson et al. (US 2008/0200409 A1, of record) and Weisbart et al. (Molecular Immunology, 2003, 39:783-789).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are encompassed by and/or rendered obvious by the ‘064 claims drawn to and require an antisense oligonucleotide comprising one of SEQ ID NOs:20-25, 254-259, and 2070-2080, which comprise SEQ ID NO:37 claimed in the instant case, or one of SEQ ID NOs:2055-2069, which comprise SEQ ID NO:38 claimed in the instant case. It would have been obvious to replace the BNA modification in the ‘064 claims with a 26-mer PMO claimed in the instant case because making 26-mer human dystrophin exon skipping oligonucleotides having “morpholinos” or “phosphoromorpholidates” chemistry was an art-recognized methodology as evidenced by Wilson (see SEQ ID NOs:12, 26, and 29 in Table 1A; paragraphs 0051 and 0079) thus one of ordinary skill in the art would have tried making a 26-mer PMO comprising one of the aforementioned SEQ ID NOs claimed in the ‘064 claims, thereby arriving at the instant claims. It would also have been obvious to conjugate the above-modified 26-mer PMO with a targeting moiety/ligand that facilitates that PMO delivery into a cell or into a skeletal muscle cell because dystrophin exon skipping oligonucleotides were known to be useful as a potential therapeutic agent for treating DMD and thus were tested in muscle cells obtained from human muscle biopsies as evidenced by Wilson (see paragraphs 0012 and 0117), wherein an antibody and the fragment thereof, in particular “mAb 3E10 scFv fragments” comprising amino acid sequence (thus peptides), were known to be “primarily localized in the nucleus of skeletal muscle cells” thus deemed “useful in the design of therapeutic delivery vehicles to target skeletal muscle in vivo.” See page 787 of Weisbart.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 DANA H SHIN whose telephone number is (571)272-8008. The examiner can normally be reached Monday-Thursday: 8am - 6:30pm.
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/DANA H SHIN/Primary Examiner, Art Unit 1635
