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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 filed on 16 December 2025 has been entered.
Application Status
This action is written in response to applicant’s correspondence received 16 December 2025. Claims 84-85, 87-88, 90-105, 107, and 113-114 are currently pending. Claims 84, 93, and 112 are amended. Claims 86 and 93 are canceled. Accordingly, claims 84-85, 87-88, 90-105, 107, and 113-114 are examined herein. The restriction requirement mailed 4 October 2024 is still deemed proper. Applicant's elected Group I, claims 84-114, alongside SEQ ID NOs: 67, and 28 without traverse in the reply filed 4 December 2024.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant' s amendments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 84-85, 87-88, 90-94, 107, and 114 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Collin (PG Pub No. US 2018/0228829 A1, published 16 August 2018, filed 3 September 2015).
Regarding claims 84 and 114, Collin is drawn towards an invention concerned with novel antisense oligonucleotides that may be used in the treatment, prevention and/or delay of Leber congenital amaurosis (Abstract). Collin teaches that the expression of a target CEP290 peptide that is encoded by an endogenous CEP290 pre-mRNA can be modulated through the use of an antisense oligonucleotide ([0002], [0097]-[0099], [0202]; see FIGs. 1A-1C). Collin teaches that the antisense oligonucleotide can be about 12-30 nucleotides in length ([0024]). Collin teaches that mutant endogenous CEP290 pre-mRNA comprises, 5’ to 3’, a first start codon present in exon 26, an aberrant exon (i.e., encoded by intron 26) comprising a premature start codon that is expressed in the mutated non-spliced CEP290 mRNA (i.e., the aberrant exon comprises a second start codon) such that an incorrect CEP290 protein that expresses the aberrant exon is generated, followed by exon 27 ([0002], [0097]-[0099], [0202]; see FIGs. 1A-1C). Collin teaches that the antisense oligonucleotide can bind to a targeted region of intron 26 in the mutant CEP290 pre-mRNA such that the splicing of the aberrant exon is modulated and a first protein comprising only exons 26-27 (i.e., a first processed mRNA that is processed from the endogenous pre-mRNA that is devoid of the premature stop codon and second start codon) is produced and a correct CEP290 protein is encoded ([0002], [0097]-[0099], [0202]; see FIGs. 1A-1C). Collin teaches that when the antisense oligonucleotide is utilized, the first protein has a higher translation efficiency than a second protein that would otherwise be produced by the mutant endogenous CEP290 pre-mRNA and is identical to the first protein but comprises the aberrant exon comprising the premature stop codon and second start codon ([0002], [0097]-[0099], [0202]; see FIGs. 1A-1C).
Regarding claim 85, Collin teaches that the region comprising the premature stop codon and the second start codon generates an aberrant exon that is present in the mutant non-spliced mRNA and generates an incorrect CEP290 protein that expresses the aberrant exon ([0002], [0097]-[0099], [0202]; see FIGs. 1A-1C).
Regarding claims 87-88, Collin teaches that a portion of the region targeted by the antisense oligonucleotide is upstream and within the region comprising the premature stop codon and start codon ([0136]; see FIG. 3A).
Regarding claim 90, Collin teaches that the antisense oligonucleotide can bind to a targeted region of intron 26 in the mutant CEP290 pre-mRNA such that the splicing of the aberrant exon is modulated and a first protein comprising only exons 26-27 (i.e., a first processed mRNA that is processed from the endogenous pre-mRNA that is devoid of the premature stop codon and second start codon) is produced and a correct CEP290 protein is encoded ([0002], [0097]-[0099], [0202]; see FIGs. 1A-1C). Collin teaches that when the antisense oligonucleotide is utilized, the first protein has a higher translation efficiency than a second protein that would otherwise be produced by the mutant endogenous CEP290 pre-mRNA and is identical to the first protein but comprises the aberrant exon comprising the premature stop codon and second start codon ([0002], [0097]-[0099], [0202]; see FIGs. 1A-1C).
Regarding claim 91, Collin teaches that the CEP290 protein encodes 2479 amino acids total across 54 exons (i.e., the target peptide sequence comprises at least 100 amino acids) ([0187]).
Regarding claims 92-93, Collin teaches that the antisense oligonucleotide may be delivered to a cell via the use of a vector that encodes the antisense oligonucleotide ([0049]).
Regarding claim 94, Collin teaches that the antisense oligonucleotide can comprise a modified backbone ([0037]).
Regarding claim 107, Collin teaches that the target peptide sequence produced when the aberrant exon is spliced out via the antisense oligonucleotide is a fully functional CEP290 protein ([0002], [0097]-[0099], [0202]; see FIGs. 1A-1C).
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 95, 100-101, and 103-105 are rejected under 35 U.S.C. 103 as being unpatentable over Collin (PG Pub No. US 2018/0228829 A1, published 16 August 2018) as applied to claims 84-85, 87-94, 107, and 114 above, and further in view of Barrett (PG Pub No. US 2019/0192691 A1, filed 11 April 2017, cited on the IDS filed 21 March 2024).
Regarding claims 95, 100-101, and 103-105, Collin anticipates claims 84-85, 87-94, 107, and 114 as described above.
Collin does not teach or suggest that the antisense oligomer has a sequence that is complementary to a sequence with at least 80% sequence identity to SEQ ID NO: 28 (Claims 95 and 100). Collin does not teach or suggest that the target peptide sequence is translated from a sequence selected from the claimed SEQ ID NO: 32 (Claim 101). Collin does not teach or suggest that the first processed mRNA encodes a protein having at least 80% sequence identity to SEQ ID NO: 8204 (Claim 103). Collin does not teach or suggest that the second processed mRNA encodes a protein having at least 80% identity to SEQ ID NO: 440 (Claim 104). Collin does not teach or suggest that the targeted region of the pre-mRNA comprises at least 10 contiguous bases of SEQ ID NO: 238 (Claim 105).
However, one of ordinary skill in the art would have considered the teachings of Barrett as both references are analogous prior art pertaining to targeted genes of interest.
Barrett is drawn towards an invention concerned with regulatable bio circuit systems (Abstract). Barrett teaches the use of a methyl CpG binding protein 2 pre-mRNA with a sequence that has 100% sequence identity to the claimed SEQ ID NO: 28 and comprises 10 contiguous base pairs of the claimed SEQ ID NO: 238 (see Claim 1 and SEQ ID NO: 153282 in previously attached sequence alignment). Barrett teaches the use of a methyl CpG binding protein 2 that has 100% identity to the claimed SEQ ID NO: 8204 (see Claim 1 and SEQ ID NO: 50826 in previously attached sequence alignment). Barrett teaches the use of a methyl CpG binding protein 2 that has 100% sequence identity to the claimed SEQ ID NO: 440 (see Claim 1 and SEQ ID NO: 50833 in previously attached sequence alignment). Barrett teaches the use of a methyl CpG binding protein 2 pre-mRNA that has a region with 100% sequence identity to the claimed SEQ ID NO: 32 (see Claim 1 and SEQ ID NO: 153279 in previously attached sequence search result).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to try to target the region of the methyl CpG binding protein 2 pre-mRNA comprising 100% sequence identity to the claimed SEQ ID NOs: 28, 32, and 10 contiguous base pairs of the claimed SEQ ID NO: 238, as described in Barrett, with an antisense oligonucleotide, as described in Collin. Collin teaches that there has been a finding that at the relevant time there had been a recognized problem or need in the art to utilize an oligonucleotide that can target a pre-mRNA and modulate its expression such that an aberrant exon is spliced out of the resulting mRNA molecule. Collin teaches that there had been a finite number of identified, predictable potential solutions to the modulation of pre-mRNA expression via the design and creation of the antisense oligonucleotides of length 12-50 nucleotides that bind to specific regions of pre-mRNA while Barrett teaches that the claimed pre-mRNA comprising 100% sequence identity to the claimed SEQ ID NOs: 28, 32, and 10 contiguous base pairs of the claimed SEQ ID NO: 238 is only 261 nucleotides in length. Further, one of ordinary skill in the art would have recognized that the known potential solutions could be pursued with a reasonable expectation of success because Collin teaches that the antisense oligonucleotide can be used to modulate pre-mRNA splicing of other genes of interest.
Further, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the first and second processed mRNA molecule of Collin for the protein having at least 80% sequence identity to SEQ ID NO: 8204 and the protein having at least 80% identity to SEQ ID NO: 440, as described in Barrett. A person of ordinary skill in the art would have had a reasonable expectation of success because Collin teaches the modulation of the splicing of pre-mRNA via the sue of an antisense oligonucleotide that can be targeted to other genes of interest while Barrett teaches the use of a pre-mRNA that encodes mRNA proteins having 100% sequence identity to the claimed SEQ ID NOs: 8204 and 440.
Claim 96 is rejected under 35 U.S.C. 103 as being unpatentable over Collin (PG Pub No. US 2018/0228829 A1, published 16 August 2018) as applied to claims 84-85, 87-94, 107, and 114 above, and further in view of Freier (PG Pub No. US 2018/0036335 A1, published 8 Feb 2018, cited on the IDS filed 19 November 2021).
Regarding claim 96, Collin anticipates claims 84-85, 87-94, 107, and 114 as described above.
Collin does not teach or suggest that the antisense oligomer has a sequence with at least 80% sequence identity to SEQ ID NO: 67 (Claim 96).
However, one of ordinary skill in the art would have considered the teachings of Freier as both references are analogous prior art pertaining to the modulation of MeCP2 expression.
Freier is drawn to a study concerned with the modulation of MeCP2 expression via antisense oligonucleotides (Abstract). Freier teaches the use of an antisense oligonucleotide with 100% sequence identity to the claimed SEQ ID NO: 67 (Claim 96) ([0123]; see SEQ ID NO: 257 in previously attached sequence alignment).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the antisense oligonucleotide of Collin for the antisense oligonucleotide of Freier. A person of ordinary skill in the art would have had a reasonable expectation of success because Collin teaches the successful use of an antisense oligonucleotide to modulate expression of a target peptide while Freier teaches the use of antisense oligonucleotides that can modulate MeCP2. Therefore, substituting the antisense oligonucleotide of Collin for the antisense oligonucleotide of Freier would have resulted in a predictable outcome of success.
Claims 97, 99, and 113 are rejected under 35 U.S.C. 103 as being unpatentable over Collin (PG Pub No. US 2018/0228829 A1, published 16 August 2018) as applied to claims 84-85, 87-94, 107, and 114 above, and further in view of Mnatzakanian (Nature genetics 36.4 (2004): 339-341).
Regarding claims 97, 99, and 113, Collin anticipates claims 84-85, 87-94, 107, and 114 as described above.
Collin further teaches for other genes, including those that encode structural proteins like CEP290, tightly-regulated expression levels might be crucial for cell survival, and overexpression of the therapeutic protein might exert toxic effects; however, using antisense oligonucleotides, the therapeutic intervention occurs at the pre-mRNA level, and hence does not interfere with the endogenous expression levels of the target gene ([0140]).
Collin does not teach or suggest that the pre-mRNA is an MeCP2 pre-mRNA (Claim 97). Collin does not teach or suggest that the target peptide sequence is a portion of an MeCP2 protein isoform (Claim 99). Collin does not teach or suggest that the method treats a subject with Rett Syndrome (Claim 113).
However, one of ordinary skill in the art would have considered the teachings of Mnatzakanian as both references are common fields of endeavor prior art pertaining to the study of the splicing of pre-mRNA.
Mnatzakanian is drawn to a study concerned with new protein isoforms relevant to Rett syndrome (Abstract). Mnatzakanian teaches that Rett syndrome is caused by mutations in the MECP2 gene (Abstract). Mnatzakanian teaches that an unmodified MECP2 gene is comprised of exons 1-4 and encodes a MECP2A splice variant (i.e., a second processed mRNA) that comprises a start codon within exon 2 that results Rett syndrome when expressed in cells (i.e., MECP2A is encoded by exons 2-4 of the MECP2 gene) (pg. 340; see Figure 1A). Mnatzakanian teaches that exon 2 has a number of in-frame stop codons upstream of an out-of-frame ATG start codon (i.e., exon 2 comprises premature stop codons located between a first start codon of exon 1 and a second start codon) (pg. 339). Mnatzakanian teaches that exon 2 can be spliced out in order to generate an MECP2B splice variant (i.e., a first processed mRNA generated from exons 1, 3, and 4 of the MECP2 gene) that had ten times higher expression levels than MECP2A splice variants in adult human brains (pg. 339). Mnatzakanian teaches that when MECP2B is absent or truncated, the loss of the splice variant is sufficient to cause Rett syndrome (i.e., the presence of a functional full-length MECP2B is required in order to prevent Rett syndrome) (pg. 339). Mnatzakanian teaches that MECP2A is translated from the second start codon while MECP2B is translated from the first start codon (pg. 340; see Figure 1A).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the antisense oligonucleotide of Collin such that it targeted exon 2 of an MECP gene and comprised a 3’ PCDS encoding functional exons 3 and 4 of the MECP gene in order to generate a functional MECP2B mRNA spliced from exons 1, 3, and 4, as described by Mnatzakanian. A person of ordinary skill in the art would have been motivated to do so in order to treat Rett syndrome by reducing the amount of MECP2A mRNA and increasing the amount of MECP2B mRNA in a target cell. A person of ordinary skill in the art would have had a reasonable expectation of success because Collin teaches that the antisense oligonucleotide can be targeted to different pre-mRNA sequences comprising exons with premature stop codons and can produce full-length functional target mRNA sequences that do not comprise the exons with premature stop codons while Mnatzakanian teaches that Rett syndrome is caused by MECP2 pre-mRNA’s exon 2 that comprises premature stop codons and that eliminating the exon 2 and splicing the exons 1, 3, and 4 can treat Rett syndrome.
Claim(s) 98 and 102 is/are rejected under 35 U.S.C. 103 as being unpatentable over Collin (PG Pub No. US 2018/0228829 A1, published 16 August 2018) in view of Mnatzakanian (Nature genetics 36.4 (2004): 339-341) as applied to claims 97, 99, and 113 above, and further in view of Fichou (Neurogenetics 10 (2009): 127-133).
Reading claims 98 and 102, Collin in view of Mnatzakanian renders obvious claims 86, 97, 99, and 113 as described above.
It is highlighted that, as taught by Mnatzakanian, MECP2A is encoded by exons 2-4 of the MECP2 gene while MECP2B is encoded by exons 1, 3, and 4 of the MECP2 gene (pg. 339-340; see Figure 1A).
Collin in view of Mnatzakanian does not teach or suggest that the meCP2 pre-mRNA comprises a sequence with at least 80% sequence identity to the claimed SEQ ID NO: 2 (Claim 98). Collin in view of Mnatzakanian does not specifically teach that the therapeutic agent decreases the level of an e2 isoform of MeCP2 mRNA and increases a level of an e1 isoform of MECP2 mRNA (Claim 102).
However, one of ordinary skill in the art would have considered the teachings of Fichou as both references are common fields of endeavor pertaining to the study of Rett syndrome.
Fichou is drawn to a study concerned with a missense mutation affecting a MeCP2_e1 isoform that causes Rett syndrome (Abstract). Fichou teaches the use of a methyl-CpG-binding protein 2 (MECP2) gene that has 100% identity to the claimed SEQ ID NO: 2 (pg. 127; see attached sequence alignment). Fichou teaches that MECP2 generates two splice variants each encoding a protein isoform that only differs in the N-terminus, termed MeCP2_e2 and MeCP2_e1 (pg. 127). Fichou teaches that MeCP2_e2 is encoded by exons 2-4 of the MECP2 gene (i.e., the MeCP2_e2 isoform of Fichou is identical to the MECP2A of Mnatzakanian) (pg. 127). Fichou teaches that MeCP2_e1 is encoded by exons 1, 3, and 4 of the MECP2 gene (i.e., the MeCP2_e2 isoform of Fichou is identical to the MECP2B of Mnatzakanian) (pg. 127).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the MeCP2 pre-mRNA rendered obvious by Collin in view of Mnatzakanian for MeCP2 pre-mRNA having 100% sequence identity to the claimed SEQ ID NO: 2, as described by Fichou. A person of ordinary skill in the art would have had a reasonable expectation of success because Collin in view of Mnatzakanian renders obvious a method of modulating expression of a target peptide sequence from MeCP2 pre-mRNA while Fichou teaches that the claimed SEQ ID NO: 2 was well known in the prior art to be MeCP2 pre-mRNA. Further, as evidenced by Fichou, the decreased level of the MECP2A mRNA rendered obvious by Collin in view of Mnatzakanian and the increased level of MECP2B mRNA rendered obvious by Collin in view of Mnatzakanian is structurally identical to a decreased level of an e2 isoform of MeCP2 mRNA and increases a level of an e1 isoform of MECP2 mRNA, as described by Fichou. A person of ordinary skill in the art would have recognized that Collin in view of Mnatzakanian teaches that MECP2A is encoded by exons 2-4 of MeCP2 pre-mRNA while Fichou teaches that MeCp2_e2 isoforms are also encoded by exons 2-4 of MeCP2 pre-mRNA. Similarly, a person of ordinary skill in the art would have recognized that Collin in view of Mnatzakanian teaches that MECP2B is encoded by exons 1, 3, and 4 of MeCP2 pre-mRNA while Fichou teaches that MeCp2_e1 isoforms are also encoded by exons 1, 3, and 4 of MeCP2 pre-mRNA.
Response to Arguments
Applicant's arguments filed 4 December 2024 have been fully considered but they are not persuasive.
It is noted that Applicant’s arguments are directed towards the previously utilized primary reference Dooley. As Applicant’s amendments have necessitated the newly filed 35 USC 102 and 103 rejections above that do not utilize the Dooley reference, Applicant’s arguments are not found persuasive.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KYLE T REGA whose telephone number is (571)272-2073. The examiner can normally be reached M-R 8:30-4:30, every other F 8:30-4:30 (EDT/EST).
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/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636