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
Claims 1-12 are pending in the present application.
Claims 1-12 have been examined on the merits as detailed below:
Specification
The disclosure is objected to because of the following informalities: After careful review of the present application, it is noted that the Specification discloses:
“Histological analysis of the distribution of fluorescent AONs in the retina demonstrated the presence of fluorescence in the photoreceptor nuclear layer (FIG. 4B).”
However, there does not appear to be a Figure 4B associated with the present application. Applicant can either delete the reference to Figure 4B from the Specification or provide Figure 4B to add as an amendment to the Drawings. NOTE: If Applicant chooses the latter, this may introduce new matter since priority document 13305968.3 also references Figure 4B, however, the actual figure/drawing is similarly absent.
Appropriate correction is required.
Drawings
The Drawings filed April 24, 2023 are acknowledged and have been accepted by the Examiner.
Information Disclosure Statement
Applicant’s information disclosure statement (IDS) filed April 19, 2024 is acknowledged. The submission is in compliance with the provisions of 37 CFR §1.97. Accordingly, the Examiner has considered the information disclosure statement, and a signed copy is enclosed herewith.
Applicant’s IDS filed May 22, 2023 is acknowledged. The submission is in compliance with the provisions of 37 CFR §1.97. Accordingly, the Examiner has considered the information disclosure statement, and a signed copy is enclosed herewith.
Priority
Acknowledgment is made of applicant's claim for foreign priority based on European Application 13305968.3, filed 07/08/2013. The certified copy is found in parent application USSN 14/903,477.
Nucleotide Sequence Disclosures
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 C.F.R. §1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 C.F.R. §1.821-1.825 for the reason(s) set forth below or on the attached Notice To Comply with Requirements for Patent Applications Containing Nucleotide Sequence and/or Amino Acid Sequence Disclosures. The disclosure contains sequences which fall under the purview of 37 CFR 1.821 through 1.825 as requiring SEQ ID NOs., but which are not so identified. For example, see pages 17, 18 and 22. Also, see Figures 1A and 1B. This is an example and does not indicate that the Examiner has made an exhaustive review of the application. Applicant must fully comply with the sequence rules for any response to this action to be considered fully responsive.
Claim Rejections - 35 USC § 112
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.
Claims 1-12 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is an enablement rejection.
There are many factors to be considered when determining whether there is sufficient evidence to support determination that a disclosure does not satisfy the enablement requirements and whether any necessary experimentation is undue. These factors have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include:
(1) the quantity of experimentation necessary,
(2) the amount of direction or guidance presented,
(3) the presence or absence of working examples,
(4) the nature of the invention,
(5) the state of the prior art,
(6) the relative skill of those in the art,
(7) the predictability or unpredictability of the art, and
(8) the breadth of the claims.”
The nature of the invention and the breadth of the claims:
Claims 1-6 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. Claims 7-12 are drawn to a method of treating 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 a photoreceptor cell, in a subject in need thereof, comprising the step of injecting into the vitreous of the subject an amount of a naked antisense oligonucleotide targeting the gene which mutation causes LCA, 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 a photoreceptor cell of the subject, and wherein the antisense oligonucleotide is chronically administered by intravitreal injections at least 10 days apart.
The amount of direction or guidance and presence/absence of working examples:
In their Specification, Applicants disclose:
Leber congenital amaurosis (LCA) is a severe hereditary retinal dystrophy responsible for congenital or early-onset blindness. The most common disease-causing mutation (>10%) is located deep in CEP290 intron 26 (c.2991+1655 A>G) where it creates a strong splice donor site and leads to the insertion of a cryptic exon encoding a premature stop codon.
Applicant’s Specification also discloses:
“Histological analysis of the distribution of fluorescent AONs in the retina demonstrated the presence of fluorescence in the photoreceptor nuclear. However, 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”.
Applicants confusedly report that histological analysis showed a large distribution of antisense oligonucleotides (AON) through-out retinal sections, however, (histological analysis of whole mount retinas are scheduled). Applicants also confusedly report that histological analysis of the distribution of fluorescent AONs in the retina demonstrated the presence of fluorescence in the photoreceptor nuclear layer (FIG. 4B), however, there is not a Figure 4B associated with the present application. For further explanation, see the objection to the Specification discussed above.
As it relates to Cep290, Applicants teach splice modulation of Cep290 mRNA in which mice were injected into the vitreous with Cep290 AON and RT-PCR analyses was performed on eyes dissected to isolate the neuroretina. It should be noted that the neuroretina is layered tissue composed of six types of neuronal cells (two types of photoreceptors (cones and rods); horizontal, bipolar, amacrine and ganglion cells) as evidenced by Behar-Cohen et al. (MED SCI, pages 594-599 Vol. 36, No. 6-7, 2020, only Abstract provided).
Since Cep290 is ubiquitously expressed, experimental evidence of splice modulation of Cep290 mRNA on eyes dissected to isolate the neuroretina does not support that exon skipping occurred in the nucleus of photoreceptor cells. In fact, Applicants 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.” Therefore, it is clear that at the time of invention, Applicant had not confirmed that splice-modulation of the Cep290 mRNA occurred in the nucleus of photoreceptor cells.
The state of the prior art and the predictability or unpredictability of the art:
The claimed invention is a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The following is cited herein to illustrate the state of the art of administering naked AON by intravitreal injection for the achievement of exon-skipping in the nucleus of photoreceptor cells: The unpredictability in administering naked AON by intravitreal injection for the achievement of exon-skipping in the nucleus of photoreceptor cells in a subject was discussed and made of record in the § 1.131 Declaration of Inventor, Jean-Michel Rozet filed September 16, 2020 in Application No. 14/903,477. The § 1.131 Declaration details and discusses that at the time of priority of the present application, the general knowledge in the art was that naked oligonucleotides, when injected intravitreally, would not reach the nucleus of photoreceptor cells, or at least not with sufficient efficiency to perform exon skipping.
The claims are so broad to include a method of treating 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 a photoreceptor cell. The Specification only teaches naked antisense oligonucleotide-mediated exon skipping of the Cep290 gene, wherein the LCA is associated with a mutation affecting the Cep290 gene. However, as discussed above, the Specification does not demonstrate that intravitreal administration of antisense targeted to Cep290 allows selective alteration of Cep290 splicing in photoreceptor retinal cells.
Gerard et al. (Molecular Therapy - Nucleic Acids, 2015 4, e250) (submitted on the IDS filed April 19, 2024) teach Cep290 splice-switching oligonucleotide-mediated skipping in photoreceptor cells following a unique intravitreal injection. See Gerard et al., Figure 2a. NOTE: Figure 2a is histological analysis by confocal microscopy on all retinal layers, including photoreceptor cells. Gerard et al. are specific that intravitreal administration of modified oligonucleotides allows alteration of Cep290 splicing in retinal cells, including photoreceptors as shown by successful alteration of Abca4 splicing using the same approach.
The level of skill in the art:
The relative skill of those in the art is considered to be high, being a graduate student or post-doctoral fellow in a biological science.
The quantity of experimentation necessary:
A review of the instant application finds successful alteration of Abca4 splicing in photoreceptor cells. See Figure 5. Also, see Example 2. It is noted that Stargardt disease, the most common macular dystrophy, is caused by mutations in the gene encoding Abca4, a photoreceptor ATP binding cassette (ABC) transporter. Confirmation that skipping occurred in photoreceptor cells was not shown for any other gene, Cep290 or otherwise. 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 the methods as claimed in instant claim 1-6.
Applicants do not exemplify 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 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 or a method of treating 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 a photoreceptor cell, in a subject in need thereof, comprising the step of injecting into the vitreous of the subject an amount of a naked antisense oligonucleotide targeting the gene which mutation causes LCA. As Gerard et al. and the § 1.131 Declaration of Inventor, Jean-Michel Rozet indicate, at the time of invention, naked oligonucleotides, when injected intravitreally, would not reach the nucleus of photoreceptor cells. Accordingly, one skilled in the art, being unable to use the prior art for such guidance, must necessarily find such guidance from the Specification. However, one of skill would not find the prophetic examples in the Specification enough to overcome the unpredictability and challenges of naked oligonucleotides, when injected intravitreally, reaching the nucleus of photoreceptor cells for the treatment of LCA.
Thus, it is determined that the prior art before the effective filing date of the claimed invention would not enable the disclosure of the methods as claimed. This is particularly true based on the teachings of Gerard et al. and the disclosures in the § 1.131 Declaration of Jean-Michel Rozet.
In order to practice the invention using the Specification and the state of the prior art as outlined above, the quantity of experimentation required to practice the invention as claimed in vivo would require the de novo determination of how to intravitreally deliver naked oligonucleotides to the nucleus of photoreceptor cells, wherein the oligonucleotides performs exon skipping resulting in the treatment of LCA. As supported by Gerard et al. and the § 1.131 Declaration of Inventor, Jean-Michel Rozet, such analysis is replete with trial and error experimentation. Such experimentation represents an inventive and unpredictable undertaking in itself, with each of the many intervening steps, not providing any guarantee of success. Given the art recognized unpredictability of intravitreally delivering naked oligonucleotides to the nucleus of photoreceptor cells in vivo, this determination would not be routine and would require undue trial and error experimentation.
Due to the scope of the claims, one of skill in the art would be required to further undertake extensive trial and error experimentation with a large number of subjects and controls, to intravitreally deliver naked oligonucleotides to the nucleus of photoreceptor cells to a subject resulting in the treatment of LCA. Since the specification fails to provide any real guidance for methodologies of intravitreally delivering naked oligonucleotides to the nucleus of photoreceptor cells, wherein the oligonucleotides performs exon skipping and treating LCA, and since resolution of the various complications in regards to intravitreally delivering naked oligonucleotides to the nucleus of photoreceptor cells in vivo is highly unpredictable, one of skill in the art would have been unable to practice the invention, without engaging in undue trial and error experimentation.
Thus, 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 favor undue experimentation.
Conclusion
No claims are allowable at this time.
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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