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 .
DETAILED ACTION
Applicant’s amendments and remarks filed on February 16, 2026 are acknowledged. Claims 3, 7, 8, 11-14, and 16 have been canceled. Claims 1 and 15 were amended. Claims 1, 2, 4-6, 9, 10, and 15 are pending and are examined on the merits herein.
It is noted that the status identifier for claim 15 indicates that the claim is currently amended and the claim contains markings; however, the claim has not been amended relative to the immediate prior version of the claim.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 filed on February 16, 2026 has been entered.
Withdrawn Rejections
In view of Applicant’s amendments and response, the 35 U.S.C 112(a) written description, 35 U.S.C 103, and nonstatutory double patenting rejections are withdrawn.
Specification
The substitute specification filed on September 5, 2024 has been entered.
Claim Objections
Claims 1 and 5 are objected to because of the following informalities:
To improve the grammar of the claim, claim 1 should be amended to recite “wherein the pharmaceutical composition is for intraocular delivery” (emphasis added).
Claim 5 is missing a space before “wherein” and also before “2’-O alkyl”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 15 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 15 recites the following:
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. Claim 1 is drawn to a pharmaceutical composition comprising an antisense oligonucleotide. Claim 15 only requires the antisense oligonucleotide of claim 1 not the pharmaceutical composition of claim 1; therefore, claim 15 does not incorporate all of the limitations of the claim which it depends on.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Written Description
Claims 1, 2, 4-6, 9, 10, and 15 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.
Claim 1 is drawn to the provision of a genus of antisense oligonucleotides that has a length of 16 to 24 nucleotides defined solely by function to redirect splicing. The specification as filed discloses
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[page 2, second paragraph]. The specification discloses that the terms “modulate splicing” and “redirect splicing” encompass AON-based splice modulation therapy for the c.768G>T mutation [page 3, lines 31-32]. Thus, the claims encompass a broad genus of antisense oligonucleotides that has a length of 16 to 24 nucleotides defined solely by function to modulate splicing for the c.768G>T mutation.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification envisions the following
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The specification also discloses that it is preferred that an AON for redirecting splicing comprises one or more residues that are modified to increase nuclease resistance and/or to increase the affinity of the antisense oligonucleotide for the target sequence [page 4, second full paragraph – fourth full paragraph]. Further, the specification envisions on pages 6 through 9 that in various embodiments, an AON for redirecting splicing comprises or consists of SEQ ID NOS: 6, 10, 14, 18, 22, 26, 30, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, or 77 and comprises a 2’-O-methyl modified ribose (RNA) or a 2’-O-methoxyethyl modified ribose (RNA) and a phosphorothioate backbone.
The specification discloses in working example 1 that oligonucleotides of approximately 20 nucleotides in length were designed and all oligonucleotides were subjected to in silico RNA structure prediction. Eight AONs that showed differences in predicted structure and/or had the best accessibility were designed and ordered in different chemistries as shown in Table 2 (reproduced below)
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[page 22]. The SEQ ID NOS. listed in Table 2 above all range from 19 to 21 nucleotides in length.
The specification discloses in working example 2, an expansion of working example 1, using more AONs which were different in terms of sequence and chemistry. Specifically, 26 AONs each 21 nucleotides in length were designed with a 2’-O-methyl or 2’-O-methoxyethyl chemistry. Then, 5 more AONs with 2’-O-MOE chemistry were designed. All antisense oligonucleotides have a phosphorothioate backbone.
The specification does not disclose antisense oligonucleotides that are less than 19 nucleotides in length or greater than 21 nucleotides in length.
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims with regard to structure and function, the examples are only representative of a small group of antisense oligonucleotides that modulate splicing. The results are not necessarily predictive of other antisense oligonucleotides that modulate splicing falling within the broadly claimed genus not limited to any particular structure. Thus, it is impossible for one to extrapolate from the limited examples described herein those antisense oligonucleotides that modulate splicing that would necessarily meet the structural/functional characteristics of the rejected claims.
Harding et al. (Molecular Therapy 2007) discloses that one of the challenges for splicing blockade is to design antisense oligonucleotides that efficiently remove targeted exons across the dystrophin pre mRNA. Although no single motif has been implicated in the consistent induction of exon skipping, the length of the AO has emerged as an important parameter in designing compounds that redirect dystrophin pre-mRNA processing. Data from in vitro studies in murine and human cells show that appropriately designed AOs of 25–31 nucleotides are generally more effective at inducing exon skipping than shorter counterparts; however, there appears to be an upper limit in optimal length, which may have to be established on a case-by-case basis [abstract]. Harding et al. also discloses that simply designing an antisense oligonucleotide of 30 nucleotides will not guarantee induction of exon skipping, and in some cases may be counter productive [page 164, right column, first full paragraph].
Wu et al. (PLoS ONE 2011) discloses that splice switching oligonucleotides have a range of nucleotide length that are efficient and also varies based on the system tested. As demonstrated in Table 1, Wu et al. tested 15-32 base pair length and the results show that increasing or decreasing the length of the antisense oligonucleotide affects the efficiency of the splice switching oligonucleotide [page 4]. For example, if the oligonucleotide is too short (e.g., 15 or 16 bp) or is too long (e.g., >30 bp), the efficiency decreases or there is no splice switching.
Thus, as evidenced by Harding et al. and Wu et al., the art is unpredictable regarding the length of splice switching oligonucleotides and its effect on the efficiency of the oligonucleotide. The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of antisense oligonucleotides that has a length of less than 19 nucleotides in length or greater than 21 nucleotides that could result in modulating splicing.
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 1, 2, 4-6, 9, 10, and 15.
Scope of Enablement
Claim 15 is 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 a method for the treatment of Stargardt disease caused by the c.768G>T mutation in the ABCA4 gene comprising administering to the eye of an individual in need thereof by intravitreal injection a pharmaceutical composition comprising an antisense oligonucleotide for redirecting splicing that is at least 90% complementary to a polynucleotide with the nucleotide sequence as shown in SEQ ID NO: 80 wherein the antisense oligonucleotide comprises a 2’-O alkyl phosphorothioate antisense oligonucleotide and has a length from 19 to 21 nucleotides, does not reasonably provide enablement for a method for the treatment of Stargardt disease caused by any other mutation in any other gene comprising administering a pharmaceutical composition comprising an antisense oligonucleotide for redirecting splicing that is at least 90% complementary to a polynucleotide with the nucleotide sequence as shown in SEQ ID NO: 80 wherein the antisense oligonucleotide comprises a 2’-O alkyl phosphorothioate antisense oligonucleotide and has a length 16, 17, 18, 22, 23, or 24 nucleotides by any other route of administration or route of delivery. 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.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue". These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Breadth of claims and nature of the invention:
Claim 15 is drawn to a method for the treatment of Stargardt disease, the method comprising contacting a cell of an individual in need thereof with the antisense oligonucleotide for redirecting splicing according to claim 1. The broadest reasonable interpretation of claim 15 is that the method encompasses treatment of Stargardt disease caused by any mutation in any Stargardt gene comprising administering the pharmaceutical composition of claim 1 by any route of administration.
Amount of direction provided by the inventor and existence of working
examples:
Working example 1 discloses that oligonucleotides of approximately 20 nucleotides in length were designed and all oligonucleotides were subjected to in silico RNA structure prediction. Eight AONs that showed differences in predicted structure and/or had the best accessibility were designed and ordered in different chemistries as shown in Table 2 (reproduced below)
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[page 22]. The SEQ ID NOS. listed in Table 2 above all range from 19 to 21 nucleotides in length. A skin biopsy from an STGD1 patient homozygously carrying the c.768G>T mutation was obtained and a fibroblast cell line was generated. The fibroblast cell line was transfected with AON1 through AON8 and the transfected cells were then subjected to RT-PCR analysis. The results demonstrated that AON8 was able to block the alternative splice site in intron 6 and redirect the splice site back to the original splice donor site that, albeit is weakened due to the c.768G>T mutation, still can be employed. Thus, as a result, ABCA4 pre-mRNA splicing can be restored.
Working example 2, an expansion of working example 1, used more AONs which were different in terms of sequence and chemistry and employed HEK293T cells and patient-derived fibroblasts. Specifically, 26 AONs each 21 nucleotides in length were designed with a 2’-O-methyl or 2’-O-methoxyethyl chemistry. Following the first results, 5 more AONs with 2’-O-MOE chemistry were designed. All antisense oligonucleotides have a phosphorothioate backbone. The working example demonstrated that when using the ABCA4 midigene system combined with an oligo-walk, almost all AONs were able to redirect splicing to some extent although significant differences were observed. Specifically, the most efficacious AONs had 2’-OMe chemistry (SEQ ID NO: 51, 52, 53, 56, 59, and 60) and SEQ ID NO: 72 which had 2’-O-MOE chemistry but outperformed all the AONs with 2’-OMe chemistries. Similar observations were made with SEQ ID NOS: 73-77 which all had 2’-O-MOE chemistry but with different efficacies between AON sequences. In addition, AONs in the fibroblast cells were not as effect compared to the HEK293T cells. Thus, it was shown that AONs with the 2’-O-MOE chemistry appear to be more effective compared to those with the 2’-OMe chemistry.
State of the prior art, level of predictability in the art, and level of one of
ordinary skill:
Schulz et al. (IOVS 2017) discloses that autosomal recessive STGD1 is caused by mutations in the ABCA4 gene [page 394, left column, second paragraph]. To date, more than 900 different mutations including missense, splicing, truncating, and frameshift alterations have been reported in the ABCA4 gene and shown to be associated with retinal degeneration. Of these, 72% were identified in STGD1 patients [page 395, left column, first full paragraph].
Although post-filing, Ghenciu et al. (International Journal of Molecular Sciences 2024) teaches that Stargardt disease is one of the most common forms of inherited retinal diseases and affects individuals worldwide. The primary cause is mutations in the ABCA4 gene, leading to the accumulation of toxic byproducts in the retinal pigment epithelium (RPE) and subsequent photoreceptor cell degeneration [abstract]. Ghenciu et al. also teaches that other genes such as the elongation of very-long-chain fatty acids protein 4 (ELOVL4) and prominin-1 (PROM1), have also been associated with the disease, although they are less common [page 2, first paragraph].
Harding et al. (Molecular Therapy 2007) discloses that one of the challenges for splicing blockade is to design antisense oligonucleotides that efficiently remove targeted exons across the dystrophin pre mRNA. Although no single motif has been implicated in the consistent induction of exon skipping, the length of the AO has emerged as an important parameter in designing compounds that redirect dystrophin pre-mRNA processing. Data from in vitro studies in murine and human cells show that appropriately designed AOs of 25–31 nucleotides are generally more effective at inducing exon skipping than shorter counterparts; however, there appears to be an upper limit in optimal length, which may have to be established on a case-by-case basis [abstract]. Harding et al. also discloses that simply designing an antisense oligonucleotide of 30 nucleotides will not guarantee induction of exon skipping, and in some cases may be counter productive [page 164, right column, first full paragraph].
Wu et al. (PLoS ONE 2011) discloses that splice switching oligonucleotides have a range of nucleotide length that are efficient and also varies based on the system tested. As demonstrated in Table 1, Wu et al. tested 15-32 base pair length and the results show that increasing or decreasing the length of the antisense oligonucleotide affects the efficiency of the splice switching oligonucleotide [page 4]. For example, if the oligonucleotide is too short (e.g., 15 or 16 bp) or is too long (e.g., >30 bp), the efficiency decreases or there is no splice switching.
Quantity of experimentation:
In view of the breadth of the claims which embrace treatment of Stargardt disease caused by any mutation in any Stargardt gene comprising administering the pharmaceutical composition of claim 1 by any route of administration and any route of delivery, the state and level of predictability in the art, the lack of working examples to show treatment of Stargardt disease caused by any mutation besides c.768G>T in any Stargardt gene besides ABCA4, and the failure to provide adequate guidance to overcome the state and level of predictability of the art, one of skill would have to perform undue experimentation in order to practice the invention commensurate in scope with the claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 2, and 4-6 are rejected under 35 U.S.C. 103 as being unpatentable over Sangermano et al. (Genome Research 2017; reference cited by Applicant) in view of Pijnappel et al. (WO 2018/026284) and NCBI NC_000001.11 (NCBI 2016).
Regarding claims 1, 2, and 4-6, Sangermano et al. teaches that sizeable exon elongations in significantly occurring RNA products due to c.160+5G>C, c.768G>T, c.1937+13T>G, c.4538A>G, and c.4538A>C variants were observed. Splice modulation using antisense oligonucleotides (AONs) may be an option to redirect the splicing back to the natural splice sites. Sangermano et al. also teaches that AONs have already demonstrated their therapeutic potential for several eye disease-associated genes and have a great potential as therapeutic molecules for inherited retinal diseases [page 107, left column, fifth full paragraph]. Sangermano et al. shows in Figure 3H (reproduced below) that the Sanger sequencing of RNA extracted from c.768G>T mutant BA4 midigene showed a 35-nt exon 6 elongation.
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Sangermano et al. teaches that the 35-nt elongation is explained by the presence of a cryptic splice donor site 36-nt downstream [page 103, paragraph bridging columns]. Positions 34 through 45 of instant SEQ ID NO: 80 (designated as Qy) matches to the sequence of Sangermano et al. (designated as Db) as shown in the alignment below.
Query Match 16.0%; Score 12; DB 1; Length 12;
Best Local Similarity 100.0%;
Matches 12; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 34 GCCAATTGCAAG 45
||||||||||||
Db 1 GCCAATTGCAAG 12
The sequence of Sangermano et al. (designated as Db) is complementary to positions 9 through 20 of instant SEQ ID NO: 34 (designated as Qy) as shown in the alignment below.
Query Match 57.1%; Score 12; DB 1; Length 12;
Best Local Similarity 66.7%;
Matches 8; Conservative 4; Mismatches 0; Indels 0; Gaps 0;
Qy 9 CUUGCAAUUGGC 20
|::||||::|||
Db 12 CTTGCAATTGGC 1
However, Sangermano et al. does not teach a pharmaceutical composition comprising an antisense oligonucleotide that is at least 90% complementary to a polynucleotide with the nucleotide sequence as shown in SEQ ID NO: 80 wherein the antisense oligonucleotide comprises a 2’-O alkyl phosphorothioate antisense oligonucleotide and has a length of from 16 to 24 nucleotides and wherein the composition is for intraocular delivery. Sangermano et al. also does not teach that the antisense oligonucleotide comprises or consists of the SEQ ID NOS. recited in claims 4 and 6.
Pijnappel et al. teaches repairing aberrant splicing caused by the expression of a natural pseudo exon, by providing a pair of AONs, in which the second AON is directed to the natural cryptic donor splice site of said natural pseudo exon (i.e. the 5' splice site of the natural pseudo exon) [page 30, second full paragraph]. Further, Pijnappel et al. teaches that the antisense oligomeric compound targets the location of the natural cryptic splice site and may also be targeted to a sequence comprising nucleotides upstream and downstream of the location of the splice site. For example, the antisense oligomeric compound targets a sequence comprising 2-50 nucleotides upstream and/or 2-50 nucleotides downstream of the location of the splice site [page 37]. In a preferred embodiment, the antisense oligomeric compound is about 20 nucleotides in length [page 47, line 27]. Pijnappel et al. also teaches that in a preferred embodiment each of said AON or pair of AONs is uniformly modified, preferably wherein the sugar of one or more nucleotides is modified, more preferably wherein the sugar modification is 2'-O-methyl or 2'-O-methoxyethyl [page 6, first full paragraph]. In addition, Pijnappel et al. teaches that in a preferred embodiment the internucleoside linkage is phosphorothioate [page 61, lines 9-10]. Pijnappel et al. teaches a pharmaceutical composition comprising an AON or pair of AONs preferably wherein the composition further provides a pharmaceutical acceptable excipient [page 6, second full paragraph]. Further, Pijnappel et al. teaches that pharmaceutical compositions can be in the form of oil-in-water emulsions [page 87, last paragraph].
The genomic sequence NC_000001.11 (designated as Query) matches to the sequence of Sangermano et al. (designated as Sbjct) as shown in the alignment below.
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The genomic sequence NC_000001.11 (designated as Query) matches to instant SEQ ID NO: 80 (designated as Sbjct) as shown in the alignment below.
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It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to design an antisense oligonucleotide targeting the cryptic splice donor that becomes used as a result of a c.768G>T mutation at the end of exon 6 because the sequence immediately following the alignment of Sangermano et al.’s c.768G>T 35-nt exon 6 elongation with the genomic sequence (NC_000001.11) is the cryptic splice donor. One of ordinary skill in the art would want to target the specific mutation because Sangermano et al. taught that the c.768G>T mutation causes an extension to exon 6 and suggests the use of antisense oligonucleotides to modulate splicing and Pijnappel et al. taught the design of oligonucleotides to cryptic 5’ and 3’ splice sites to repair aberrant splicing. Although Pijnappel et al. targeted a different disease, there is a suggestion to design antisense oligonucleotides to repair aberrant splicing resulting from the use of a cryptic splice donor present in the intron. Piinappel et al. designed AON5 to target the cryptic splice donor site of the pseudo exon wherein the AON promoted exon 2 inclusion and repressed inclusion of the pseudo exon thus suggesting that the pseudo exon competes with exon 2 splicing and that pseudo exon skipping by AONs promotes exon 2 inclusion [page 101, last paragraph bridging to page 102].
Claims 9, 10, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Sangermano et al. (Genome Research 2017; reference cited by Applicant) in view of Pijnappel et al. (WO 2018/026284) and NCBI NC_000001.11 (NCBI 2016) as applied to claims 1, 2, and 4-6 above, and further in view of Collin et al. (WO 2018/109011, published June 21, 2018; reference cited by Applicant).
Regarding claims 9, 10, and 15, the teachings of Sangermano et al., Pijnappel et al., and NCBI NC_000001.11 are discussed above.
However, Sangermano et al., Pijnappel et al., and NCBI NC_000001.11 do not teach a method for the treatment of Stargardt disease (claim 15) or the dosing range of total antisense oligonucleotides (claims 9 and 10).
Collin et al. teaches a method for the treatment of an ABCA4-related disease or condition requiring modulating splicing of ABCA4 of an individual in need thereof, said method comprising contacting a cell of said individual with an antisense oligonucleotide for redirecting splicing [page 3, lines 28-32]. Further, in all embodiments, the ABCA4-related disease or condition is preferably Stargardt disease [page 42, lines 13-14]. Collin et al. also teaches that a suitable intravitreal dose wherein each or the total amount of AON’s for redirecting splicing used comprises between 0.05 mg and 5 mg, preferably between 0.1 and 1 mg per eye [page 41, last paragraph bridging to page 42].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the antisense oligonucleotide of Sangermano et al. and Pijnappel et al. in a pharmaceutical composition for intraocular delivery doseable in an amount ranged from 0.05 mg to 5 mg because Sangermano et al. taught that the c.768G>T mutation causes an extension to exon 6 and suggests the use of antisense oligonucleotides to modulate splicing, Pijnappel et al. taught the design of oligonucleotides to cryptic 5’ and 3’ splice sites to repair aberrant splicing, and Collin et al. taught a pharmaceutical composition comprising an antisense oligonucleotide for redirecting splicing and a pharmaceutically acceptable excipient. One of ordinary skill in the art would have been motivated to do so for the purposes of treating an ABCA4-related disease or condition requiring modulating splicing of ABCA4 such as Stargardt disease as taught by Collin et al.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA TRAN whose telephone number is (571)270-0550. The examiner can normally be reached M-F 7:30 - 5:00pm.
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/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637