Notice of Pre-AIA or AIA Status
The Examiner prosecuting the application has changed.
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 response and claim amendments filed on 5/22/2026 are received and entered.
In response to the most recent action, claims 3, 7, 9-11, 17-18, and 20-25 are cancelled, without prejudice. Claims 2, 5, 8, 12, 14-16, and 19 are amended. Claims 26-35 are new.
Claims 2, 5-6, 8, 12-16, 19, and 26-35 are currently under examination on the merits.
Any rejections/objections NOT repeated/presented here are withdrawn.
Maintained Rejections
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 2-3, 5-6, 12-16, and 26-35 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.
Independent claims 2 and 6 are drawn to AAV vector compositions that comprise the genus of nucleotide sequences that encode a functional RDH12 protein comprising the amino acid sequence of SEQ ID NO: 2, where the nucleotide sequence is at least 95% identical to nucleotides 1-948 of SEQ ID NO: 5, and wherein “the nucleotide sequence is a codon optimized sequence for enhanced expression in a human cells as compared to a wildtype RDH12 sequence and the composition comprising the AAV is configured for delivery to host cell.”
The claims are interpreted as requiring that the nucleotide sequences provide for enhanced expression in human cells as compared to a wildtype RDH12 sequence. There is a failure to meet the written description requirement because the specification as filed fails to disclose a representative number of species that have both the structural and functional attributes the claimed genus.
Applicant is referred to MPEP 2163(II)(A)(3)(a) which indicates 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,
reduction to drawings, 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 variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure indicates that the patentee has invented species sufficient to constitute the genus. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. An applicant may show possession of an invention by disclosure of drawings or structural chemical formulas that are sufficiently detailed to show that applicant was in possession of the claimed invention as a whole.
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.
In the instant case, one of skill could envision all sequences that are at least 95% identical to SEQ ID NO: 5 and which encode the amino acid sequence of SEQ ID NO: 2. However, one could not immediately envision the claimed subgenus of those sequences that provide for enhanced expression in a human cells as compared to a wildtype RDH12 sequence due to unpredictability in the art as discussed further below.
The specification as filed discloses only one variant of SEQ ID NO: 5 (i.e. SEQ ID NO: 3) and this variant differs from SEQ ID NO: 5 only by the addition of terminal sequences to SEQ ID NO: 5 (12 nucleotides at the 5’ end and 16 to the 3’ end). Nucleotides 1-949 of SEQ ID NO: 5 are contained within SEQ ID NO: 3. The specification does not disclose a single variant of SEQ ID NO: 5 that provides for enhanced expression in a human cell as compared to a wildtype RDH12 sequence. In fact, the specification provides no evidence that SEQ ID NO: 5 itself provides for enhanced expression in any human cell as compared to a wildtype RDH12 sequence.
Mauro et al., (Trends Mal Med. 2014 Sep 25;20(11):604-613) taught that unpredictable structural and functional consequences may arise from synonymous codon changes: " ... synonymous codon changes can have unanticipated effects. Synonymous codon changes may affect protein conformation and stability, change sites of post-translational modifications, and alter protein function." See page 1, left column. Mauro taught that codon-optimization strategies for increasing protein expression are based on the assumptions that: (i) rare codons are rate-limiting for protein synthesis; (ii) synonymous codons are interchangeable without affecting protein structure and function; and (iii) replacing rare codons with frequently used codons increases protein production. However, Mauro indicated that “there is little evidence to substantiate the notion that rare codons limit protein production in mammalian cells”, and that “it seems likely that codons designated as ‘rare’ may be rate-limiting for translation.” See page 606, last full sentence, and page 607, last sentence of paragraph bridging columns. Mauro further indicates that there are many studies that indicate that assumption (ii) above is false (first sentence of first full paragraph of right column on page 607). Mauro points to evidence that protein folding is influenced by translation rate, and to further evidence that synonymous codon changes can affect protein function (page 607, last full paragraph through paragraph bridging columns on page 608). Regarding assumption (iii), Mauro indicates that there is anecdotal data in support of this assumption, but that these studies do not account for numerous variables that may inadvertently affect expression, or indicate whether other codon-optimized variants were tested. “Without additional data, it is impossible to determine whether the reported effects were due to altered codon bias or other mechanisms.” Moreover, Mauro states that “[o]ther studies do not support the postulated effects of rare codons on protein expression. See paragraph bridging pages 608 and 609. Thus, Mauro provides evidence that the behavior of codon-optimized genes and mRNAs, with regard to enhancing expression in mammalian cells, was known to be unpredictable in the prior art. As noted above, for inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. In this case, the genus of sequences that encode SEQ ID NO: 2 and are 95% identical to SEQ ID NO: 5 is quite broad, and it is not clear that a single member of that genus has been disclosed that actually provides enhanced expression in human cells relative to a wild type RDH12 sequence.
Therefore, claims are not supported by an adequate written description.
Response to Arguments
Applicant's arguments filed on 5/22/2026 have been fully considered but they are not persuasive. Claims 2-3, and 5-25 were rejected under written description in the previous office action. This rejection incorporates independent claims 2 and 6, as well as all non-cancelled depending claims and newly added claims as they depend on the previously rejected independent claims.
Applicant argues that claims 2 and 6 have been amended to recite “a codon-optimized nucleotide sequence comprising at least 95% sequence identity” and claim 19 has been amended to recites “comprising nucleotides 1 to 948 of SEQ ID NO: 5”.
The specification as filed discloses only one variant of SEQ ID NO: 5 (i.e. SEQ ID NO: 3) and this variant differs from SEQ ID NO: 5 only by the addition of terminal sequences to SEQ ID NO: 5 (12 nucleotides at the 5’ end and 16 to the 3’ end). Nucleotides 1-949 of SEQ ID NO: 5 are contained within SEQ ID NO: 3. The specification does not disclose a single variant of SEQ ID NO: 5 that provides for enhanced expression in a human cell as compared to a wildtype RDH12 sequence. In fact, the specification provides no evidence that SEQ ID NO: 5 itself provides for enhanced expression in any human cell as compared to a wildtype RDH12 sequence.
Mauro provides evidence that the behavior of codon-optimized genes and mRNAs, with regard to enhancing expression in mammalian cells, was known to be unpredictable in the prior art. As noted above, for inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.
Furthermore, applicant’s own arguments acknowledges the unpredictable nature of codon optimization. Applicant recites in their response to the obviousness rejection, presented in the previous office action, that codon optimization is not merely a routine task but involves a complex and nuance process that requires a deep understanding of the target organism’s codon usage preference, mRNA stability, secondary structure, and translational efficiency (see page 10 of applicant’s response). If arriving at a sequence with 95% sequence identity to SEQ ID NO: 5 or a single variant thereof (SEQ ID NO: 3) is not merely routine and requires significant expertise, then a single variant, such as SEQ ID NO: 3, would not fully represent the entire genus that is all sequences with 95% sequence identity to SEQ ID NO: 5 nor would it suggest that applicant or inventors had possession of a number of sequences representative of the entire genus, at the time of filing.
Therefore, claims are not supported by an adequate written description.
Applicant amends claim 19 in response to the previous rejection which satisfies the written description requirement. Claims 26-35 have been newly introduce but depend on the limitations of claim 2 and 6.
Allowable Subject Matter
Claim 19 is allowable.
Claim 19 is free of the prior art as claim 19 recites a recombinant adeno-associated virus (rAAV) comprising an AAV8 capsid and an expression cassette comprising : a) 5’ AAV inverted terminal repeat, b) G-protein-coupled receptor protein kinase 1 (GRK1) promoter operably associated to a codon-optimized nucleotide sequence, c) the codon -optimized nucleotide sequence comprising nucleotides 1 to 948 of SEQ ID NO: 5, d) an intron sequence derived from simian virus 40 (SV40), e) a bovine growth hormone (bGH) polyadenylation (polyA) signal, and f) a 3’ AAV ITR, wherein the codon-optimized nucleotide sequence encodes a functional retinal dehydrogenase 12 (RDH12) protein comprising the amino acid sequence set forth in SEQ ID NO: 2.
A codon-optimized sequence comprising nucleotides 1 to 948 of SEQ ID NO: 5 is free of the prior art. The closest combined teachings would be Chalberg et al (US 20150259395, of record) and Fotin-Mleczek et al., (US 20190241633), wherein Chalberg teaches polynucleotide cassettes, expression vectors, a methods for the expression of a gene in cone cells (see abstract and paragraph 0175). The amino acid sequence of Chalberg SEQ ID NO: 47 is identical to instant SEQ ID NO: 2, and is encoded by instant SEQ ID NO: 5 (and by Chalberg SEQ ID NO: 46).
However, Chalberg did not teach a nucleic acid comprising the sequence of nucleotides 1-948 of instant SEQ ID NO: 5. While Fotin-Mleczek taught codon optimized versions of human RDH12 (SEQ ID NOS: 35585, 48642, 61699, 22528, and 74756) that shared from 75 to 81% identity with instant SEQ ID NO: 1 (and Charlberg SEQ ID NO: 46), it is noted that for a skilled artisan to arrive at specifically nucleotides 1 to 948 of SEQ ID NO: 5, an unreasonable amount of experimentation would be required wherein one skilled in the art would not expect predictable results.
Conclusion
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.
/D.T.Y./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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