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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission of RCE on 2/3/26 and the amendment of claims has been entered.
Election/Restrictions
Applicant’s election without traverse of Group I, claimed in claims 1-16 and 18-19 was previously acknowledged. Election was made of Formula I, S1 is present and S2 is absent, S1 is a single amino acid Ahx, part (i) of part (c) of claim 1, L1 is Bpg and L2 is bAla, CPP is SEQ ID NO: 1, oligonucleotide is SEQ ID NO: 13 and Duchenne Muscular Dystrophy.
After further consideration, the species election between the CPPs was withdrawn.
In the reply filed 7/24/25, Applicants amended claims 1,3, 15 and 19. Claims 12-14 were canceled.
In the RCE filed 2/3/26, Applicants amended claims 1-2, 6 and 19.
Claims 1-11 and 15-19 are pending.
Claims 7 and 17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim.
Claims 1-6, 8-11, 15-16, 18 and 19 read on Group I and elected species and are under consideration.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 2/3/26 was considered by the examiner.
Claim Rejections -Withdrawn
The rejection of claims 1-6, 8-11, 15-16, 18 and 19 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn due to amendment of the claims.
The rejection of claims 1-4, 8-11, 15-16 and 18-19 under 35 U.S.C. 103 as being unpatentable over Uhlmann et al. (WO2013/040429,cited on IDS) in view of Wood et al. (WO 2009/144481,cited on IDS) and LifeTein (<https://www.lifetein.com/Peptide_Modifications_Pegylation_Linker.html?srsltid=AfmBOooYB4PzPAyhHF6IPK1QKG6LeqO0dw4Q_DMlI6Nza-fRFSJnIx8G>10/21/2014).
The rejection of claims 1-6, 8-11, 15-16 and 18-19 under 35 U.S.C. 103 as being unpatentable over Uhlmann et al. (WO2013/040429, cited on IDS), Wood et al. (WO 2009/144481, cited on IDS) and LifeTein (<https://www.lifetein.com/Peptide_Modifications_Pegylation_Linker.html?srsltid=AfmBOooYB4PzPAyhHF6IPK1QKG6LeqO0dw4Q_DMlI6Nza-fRFSJnIx8G>10/21/2014) in view of ThermoFisher Scientific (https://www.thermofisher.com/us/en/home/life-science/protein-biology/protein-biology-learning-center/protein-biology-resource-library/pierce-protein-methods/peptide-design.html> cited on IDS).
Claim Rejections - 35 USC § 112-Maintained
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.
The rejection of claims 1-6, 8-11, 15-16, 18 and 19 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 is maintained. 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This rejection has been maintained but modified necessitated by amendment of the claims.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. 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.
Scope of the claimed genus
Claim 1 is drawn to a molecule having the structure of Formula I, wherein the oligonucleotide specifically hybridizes to a target sequence and comprising (i), (ii) or (iii), wherein the target sequences are within exon 23 of the murine dystrophin gene. Claim 10 is drawn to the molecule of claim 1, wherein the oligonucleotide comprises DNA, RNA…etc. Claim 19 is drawn to the molecule of claim 1, wherein S1 and/or S2 are independently a spacer moiety of 1 or 2 amino acids, CPP is Pip6a or B peptide, L1 is Bpg.., S1 and/or S2 comprise alanine…or any combination.
The instant specification states (pg. 15):
The oligonucleotide may comprise a sequence which is substantially complementary > to the target sequence. Typically, the oligonucleotides are 100% complementary. However, lower levels of complementarity may also be acceptable, such as 95%, 90%, 85% and even 80%. Complementarity below 100% is acceptable as long as the oligonucleotides specifically hybridize to the target sequence. An oligonucleotide may therefore have 1, 2, 3, 4,5, 6, 7, 8, 9, 10 or more mismatches across a region of 5, 10, 15, 20, 21, 22, 30, 40 or 50 ) nucleotides. Thus, two oligonucleotides which each comprise a different sequence may nonetheless specifically hybridize to the same target sequence due to differing levels of complementarity with the target sequence, or due to specifically hybridizing to target sequences which overlap with each other. The extent of the overlap may be at least 5, 10, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45 or more nucleotides.
The oligonucleotide is therefore designed to be complementary to the RNA (although the oligonucleotide does not have to be 100% complementary to the target sequence as discussed above). By way of illustration, where the RNA molecule is messenger RNA (mRNA, discussed further below), the oligonucleotide may be considered to be equivalent to a section of cDNA, but need not be 100% identical to the cDNA sequence.
The instant specification also states that the RNA molecule to which the oligonucleotide is complementary may have been transcribed from a coding element of the genome of a cell and may be a messenger RNA, pre-mRNA. Alternatively, the RNA molecule to which the oligonucleotide is complementary may have been transcribed from a non-coding element of the genome (i.e. ribosomal RNA, tRNA, Piwi-interacting RNA, microRNA, lncRNA).
The USPTO provides claim terms with broadest reasonable interpretation in light of the specification. Therefore, the broadest reasonable interpretation of the claim includes oligonucleotides that are complementary to an exon of dystrophin. The molecule can comprise any CPP, between 0-2 spacer moieties, a first linker and a second linker and oligonucleotides attached to L1 and L2, wherein the target sequences are within exon 23 of the murine dystrophin gene.
Assessment of whether species are support in the original specification
Two embodiment of the invention of claims were reduced to practice at the time of filing. Applicants disclosed SEQ ID NO: 13-14 which hybridize to exon 23 of human dystrophin.
There was no disclosure of other oligonucleotides that specifically hybridized to exon 23 of murine dystrophin.
In summary, for these reasons, the skilled artisan would reasonably conclude that the inventor(s), at the time the application was filed, had possession of the oligonucleotides 13-14.
Assessment of whether disclosed species are representative of the claimed genus
MPEP § 2163 states that 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.
In the instant case, the disclosure of SEQ ID NOs: 13-14 are not representative of the of the target sequence genus. The genus of all oligonucleotides that are complementary to exon 23 of dystrophin is quite large. Dystrophin gene is one of the largest in the mammalian genome, spanning approximately 2.3 metabases. Much of the sequence is noncoding with 79 exons (Hilyard et al. Biomedicines. 2023 Jul 24; 11(7):2082). Dystrophin has a large central domain formed by 24 spectin like repeats. Each repeat is encoded by two exons with the homology between most repeats in ranges from 10-25%. Each repeat is encoded by two exons (Leiden Muscular Dystrophy pages, DMD (dystrophin) modified Feb. 2004). Graham et al. (The Journal of Gene Medicine 2004;6:1149-1158) discloses an array analysis of oligonucleotide hybridization to dystrophin exon 23 (Fig. 1). Fig. 1 discloses certain species in the array are bound more favorably to the RNA than others and those that perform best are located very close to the exon 23/intron 23 boundary and are predicted to be suitable ASOS for modulation of pre-mRNA splicing. Therefore, there is variability of oligonucleotide hybridization based on sequence.
Therefore, the disclosure of two oligonucleotides is not representative of the entire genus because the specification does not identify common structural features, motifs of other defining characteristics that would allow one of ordinary skill in the art to recognize the applicants had full possession of the claimed subject matter.
Identifying characteristics and structure/function correlation
In the absence of a reduction to practice of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. To meet this requirement in the instant case, the specification must describe the structural, physical and/or chemical properties of an oligonucleotide that specifically hybridizes to a target sequence.
The data do not suggest the physical basis for the claimed activity. Understanding the physical basis for the claimed activity is critical to determining which of the sequences that meet the structural requirements of the genus also meet the functional requirements of the genus. The claims cover numerous possible target sequences anywhere within exon 23 and each target yields a fully distinct oligonucleotide. The specification provided two examples, however there is no teaching why those two examples are representative of the broad class.
The specification fails to provide description is in the structure of the oligonucleotide to make. For all of the reasons presented above, one of ordinary skill in the art would not know which of the countless oligonucleotides that meet the structural requirements of the claims would also be able to specifically hybridize to a target sequence, because the target sequence is not known. This is an issue of written description. The specification does not make clear which oligonucleotides and target sequences are in the genus and which are not because it does not describe the physical basis for the claimed activity. In other words, the specification does not describe which molecules to make.
In conclusion, for the reasons presented above, the skilled artisan would reasonably conclude that the inventors, at the time the application was filed had full possession of the oligonucleotides, SEQ ID NO: 13 and 14.
Response to Arguments
Applicant's arguments filed 2/3/26 have been fully considered but they are not persuasive. Applicants argue that the claim was amended to specify that the target sequence or sequences are within exon 23 of murine dystrophin. Applicants argue that PHOSITA would understand that Applicants had possession in view of the examples provided in the specification.
These arguments were considered but are not persuasive because the specification does not convey to one of ordinary skill in the art that the inventor has possession of the claimed invention. T disclosure of two oligonucleotides is not representative of the entire genus because the specification does not identify common structural features, motifs of other defining characteristics that would allow one of ordinary skill in the art to recognize the applicants had full possession of the claimed subject matter. MPEP §2163 states that 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. In the instant case, there is substantial variation within the genus, which is open to any target sequence within exon 23. Please note that this rejection could be overcome if SEQ ID NO: 13 and SEQ ID NO: 14 are incorporated into claim 1.
For the reasons presented above the rejection is maintained.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TARA L MARTINEZ whose telephone number is (571)270-1470. The examiner can normally be reached Mon-Fri 8:00-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached on (571)270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/TARA L MARTINEZ/Examiner, Art Unit 1654
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