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
This Office Action is a response to Applicant’s Amendment and Remarks filed May 27, 2026 and January 29, 2026.
Claims 1-12 are pending in the present application.
Claims 1-12 have been examined on the merits as detailed below:
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Specification
In the previous Office Action mailed October 27, 2025, the disclosure was objected to because it referenced FIG. 4B, however, there is no FIG. 4B associated with the present application. This objection is withdrawn in view of Applicant’s Amendment to the Specification to remove any reference to FIG. 4B.
Nucleotide Sequence Disclosures
In the previous Office Action mailed October 27, 2025, it was noted that this application failed to comply with the requirements of 37 C.F.R. §1.821-1.825. In Applicant’s Amendment filed January 29, 2026, appropriate and respective sequence identifiers (e.g. SEQ ID NOs.) were added in the Specification. The present application is fully compliant with the sequence rules of 37 C.F.R. §1.821-1.825.
Claim Rejections - 35 USC § 112
In the previous Office Action mailed October 27, 2025 claims 1-12 were rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. This rejection is maintained for the reasons of record set forth in the previous Office Action mailed October 27, 2025.
Response to Arguments
In response to this rejection, Applicants traverse with a threefold argument. First, Applicants argue that The Rozet Declaration dated August 20, 2020, filed in the parent application, USSN 14/903,477, now US Patent 11,667,913 establishes the unpredictability before the invention, not an inherent flaw in the disclosed method. For example, Applicants argue that The Declaration explicitly describes the state of the art and the prevailing technical prejudice prior to the filing date of the application, then explains precisely how the Inventors overcame this prejudice.
Second, Applicants argue that the Abca4 example provided in Example 2 and Figure 5 provides a clear and enabling proof of concept. For example, Applicants submit that Example 2 and Figure 5 provide a clear, operative example demonstrating successful AON-mediated exon skipping in vivo in photoreceptor cells (targeting the Abca4 gene). This working example serves as a powerful proof of principle, validating the Applicants' hypothesis and providing the person skilled in the art with a "reasonable expectation of success" for applying this validated method to other relevant genes, such as CEP290.
Applicant’s third argument suggests that the combined evidence for CEP290 is sufficient and enabling in light of the clear teaching provided by the Abca4 proof of concept. Applicants argue that the data shows successful exon skipping of the CEP290 pre-mRNA in retinal tissue containing photoreceptors. Applicants point the Examiner to Figures 3A and 3B as presently filed. Applicants also argue that histological analysis of the distribution of fluorescent AONs in the retina were also performed on dissected retinas from animals, although images of the histological analyses were eventually not shown in the patent application.
Applicants conclude that a person of ordinary skill, armed with the knowledge from the Abca4 example that the AONs efficiently target photoreceptors, would logically and directly conclude that the CEP290 exon skipping observed in the neuroretina is indeed occurring in the photoreceptor cells.
For these reasons, Applicant respectfully submits that the claims are fully enabled and respectfully requests withdrawal of the rejection under 35 U.S.C. § 112(a).
Applicant’s traversals have been fully considered by the Examiner, however they are not found persuasive. Regarding the first traversal, the Examiner relied on The Rozet Declaration to provide evidence that, at the time of invention, the claims as presented in the application as filed were unpredictable. While Applicants argue that The Declaration explicitly describes the state of the art and the prevailing technical prejudice prior to the filing date of the application, then explains precisely how the Inventors overcame this prejudice, the Examiner disagrees as detailed below:
The claims are drawn to a method for performing antisense oligonucleotide-mediated exon skipping in a photoreceptor cell of a subject in need thereof comprising the step of injecting into the vitreous of the subject an amount of a naked antisense oligonucleotide, wherein the subject suffers from Leber congenital amaurosis (LCA) caused by a mutation which modifies the splicing and/or creates a premature termination in a gene important to the functioning and/or the survival of the photoreceptor cell, wherein the antisense oligonucleotide comprises a sequence that is complementary to a splice donor site, splice acceptor site, or a branch site within the pre- mRNA of the gene which mutation causes LCA, wherein the naked antisense oligonucleotide performs antisense oligonucleotide-mediated exon skipping in the pre-mRNA from the gene which mutation causes LCA, in the nucleus of the photoreceptor cell of the subject, and wherein the antisense oligonucleotide is chronically administered by intravitreal injections at least 10 days apart. The Inventors did not overcome the unpredictability associated with performing antisense oligonucleotide-mediated exon skipping in a photoreceptor cell of a subject in need thereof comprising the step of injecting into the vitreous of the subject an amount of a naked antisense oligonucleotide, wherein the subject suffers from Leber congenital amaurosis (LCA) caused by a mutation which modifies the splicing and/or creates a premature termination in a gene important to the functioning and/or the survival of the photoreceptor cell, wherein the antisense oligonucleotide comprises a sequence that is complementary to a splice donor site, splice acceptor site, or a branch site within the pre- mRNA of the gene which mutation causes LCA.
The present Specification teaches that LCA is associated with a mutation affecting the centrosomal protein 290 (CEP290) gene. As it relates to CEP290, the present Specification is explicit in disclosing:
To confirm that skipping occurred in photoreceptors, we have set up collaboration with M.P. Felder (Institute of Cellular and Integrative Neurosciences, CNRS UPR 3212, University of Strasbourg) to isolate the photoreceptor layer of non-injected and injected eyes using vibratome. This will be performed in the following weeks.
Given this disclosure, the Inventors have not overcome the prejudice associated with performing antisense oligonucleotide-mediated exon skipping in a photoreceptor cell of a subject in need thereof comprising the step of injecting into the vitreous of the subject an amount of a naked antisense oligonucleotide, wherein the subject suffers from LCA caused by a mutation which modifies the splicing and/or creates a premature termination in a gene important to the functioning and/or the survival of the photoreceptor cell, wherein the antisense oligonucleotide comprises a sequence that is complementary to a splice donor site, splice acceptor site, or a branch site within the pre- mRNA of the gene which mutation causes LCA as presently claimed.
The Examiner has not found Applicant’s second or third traversals persuasive because the results reported for the Abca4 gene cannot be extrapolated to the CEP290 gene. According to the present Specification, Abca4 expression is confined to the photoreceptor cells (rods and cones), while CEP290 is more ubiquitously expressed in cells including the ganglion cell layer, the inner nuclear layer and the photoreceptors cell layer. Also, the present Specification teaches Stargardt disease is caused by mutations in the gene encoding Abca4, a photoreceptor ATP binding cassette (ABC) transporter, while CEP290 is the most frequently involved in Leber's congenital amaurosis (LCA). Further, the Abca4 protein intervenes as a flippase that facilitates the removal of potentially toxic retinal compounds from photoreceptors following photoexcitation.
Example 2 and Figure 5 of the present invention discloses exon skipping in photoreceptors specific for the Abca4 transcript. Abca4 is photoreceptor-specific gene, CEP290 is not. Abca4 and CEP290 are not functionally or structurally related genes – they encode very different proteins and mutations in their transcripts cause different diseases. Data regarding exon skipping in photoreceptors with antisense-induced modification on the Abca4 mRNA in photoreceptors would not lend any information towards results with antisense-induced modification on CEP290, an entirely different gene. While the Examiner acknowledges that the present Specification teaches histological analysis of the distribution of fluorescent CEP290 AONs in the retina demonstrated the presence of fluorescence in the photoreceptor nuclear layer, any evidence to confirm that exon skipping occurred in photoreceptors in lacking and absent. Furthermore, Abca4 expression is confined to the photoreceptor cells (rods and cones), while CEP290 is expressed in the inner nuclear photoreceptors cell layer. As noted in the present Disclosure:
To confirm that skipping occurred in photoreceptors, we have set up collaboration with M.P. Felder (Institute of Cellular and Integrative Neurosciences, CNRS UPR 3212, University of Strasbourg) to isolate the photoreceptor layer of non-injected and injected eyes using vibratome. This will be performed in the following weeks.
Therefore, a person of ordinary skill in the art would not logically and directly conclude that the CEP290 exon skipping observed in the neuroretina is indeed occurring in the photoreceptor cells based on data related to the Abca4 example.
In the present invention, confirmation that exon skipping occurred in photoreceptor cells was only shown for the Abca4 transcript and not any other gene. Applicants do not show that direct injection into the vitreous delivers naked antisense oligonucleotides to perform exon skipping in vivo in the nucleus of photoreceptor cells for any other gene, other than the photoreceptor-specific gene, Abca4. Further review of the instant application finds prophetic examples for a method for performing antisense oligonucleotide-mediated exon skipping in a photoreceptor cell of a subject in need thereof comprising the step of injecting into the vitreous of the subject an amount of a naked antisense oligonucleotide, wherein the subject suffers from Leber congenital amaurosis (LCA) caused by a mutation which modifies the splicing and/or creates a premature termination in a gene important to the functioning and/or the survival of the photoreceptor cell, wherein the antisense oligonucleotide comprises a sequence that is complementary to a splice donor site, splice acceptor site, or a branch site within the pre- mRNA of the gene which mutation causes LCA, wherein the naked antisense oligonucleotide performs antisense oligonucleotide-mediated exon skipping in the pre-mRNA from the gene which mutation causes LCA, in the nucleus of the photoreceptor cell of the subject, and wherein the antisense oligonucleotide is chronically administered by intravitreal injections at least 10 days apart as presently claimed.
In view of the breadth of the claims, the lack of guidance, and the lack of working examples, the instant specification is not found to be enabling. Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention. Therefore, it is appropriate to reject the claims under 35 USC 112(a) for not being enabled.
The Wands factors have been weighed and still favor undue experimentation. The rejection under 35 U.S.C. § 112(a) is maintained.
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 Terra C. Gibbs whose telephone number is 571-272-0758. The Examiner can normally be reached from 8 am - 5 pm M-F.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Ram Shukla can be reached on 571-272-00735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/TERRA C GIBBS/Primary Examiner, Art Unit 1635
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