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 .
The examiner prosecuting this application has changed.
The amendment and response filed on 07/02/2025 have been received and entered.
Claim 4 has been cancelled. Claims 2, 3, and 5-25 are pending.
A new non-final rejection is set forth.
New rejections:
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 15 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
Claim 15 recites “ a host cell comprising the rAAV of claim 2”. While claims immediately considered on merits recite a composition, compositions comprising pharmaceutically acceptable excipient for delivery to ocular cells of a subject (claims 21-22) have been claimed and claim 25 recites where the subject is a human. Furthermore, the specification describes therapeutic compositions and methods useful in the treatment of ocular disorders by delivering optimized sequences to a subject with an ocular disease (see summary of inventio on page 2). Furthermore, instantly withdrawn claims 15 and 16 recite a method of treatment. Accordingly, when the claimed AAV vectors and compositions comprising the AAV vectors are delivered to a human subject, cells of the subject will comprise AAV vectors claimed. Therefore, the claim 15 would encompass cells in a human organism and the human organism itself.
Amending the claim to an isolated host cell or a host cell in vitro will be remedial.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 17 and 23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth the subject matter which the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the applicant regards as the invention.
Claims 17 and 23 recite the limitation "the host cell" in line 2 of each claim.
It is noted that there is no prior recitation of the term “a host cell” in these claims or claims they depend on (claims 16 and 22).
There is insufficient antecedent basis for this limitation in these claims.
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.
Claim 17 and 23 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.
Claims 17 and 23 were amended in the response filed on 01/31/2024 by adding the limitation “configured for delivery”. However, the phrase is not disclosed in the originally filed specification nor in the originally filed claims. Searching for the term “configured for delivery” does not find any occurrence of the phrase. Applicants did not indicate where the support for the phrase was present in the specification.
This is a new matter rejection.
Claims 2-3 and 5-25 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, 6 and 19 are drawn 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 90% 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 90% 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: 23 and are 90% 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.
Applicants canceled claim 4 in response to previous written description rejection. However, rejection as set forth above is applied to all claims.
Maintained rejections:
Claim Rejections - 35 USC § 103
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.
Claim(s) 2-3, 5-10 and 12-18 remain rejected under 35 U.S.C. 103 as being unpatentable over Chalberg et al (US 20150259395, of record) and Fotin-Mleczek et al., (US 20190241633) for reasons of record set forth in the previous office action of 04/02/2005 and reiterated below.
Chalberg taught polynucleotide cassettes, expression vectors, pharmaceutically acceptable carriers comprising the vectors, and methods for the expression of a gene in cone cells (see abstract and e.g. [0175]). The vectors may be introduced into cells through the use of liposomes ([0064]). In one embodiment, the polynucleotide cassette comprises a sequence encoding RDH12 (SEQ ID NO: 47). See [0016]. 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). The polynucleotide sequence may be linked to a promoter active in cone cells ([0011]), and to a polyadenylation signal such as a bovine growth hormone polyadenylation signal ([0162]). The resulting construct may be inserted into a recombinant AAV vector (claim 24) such as rAAV, 2, 5, 7, or 8 ([0039]) and flanked by AAV inverted terminal repeats ([0043]). Chalberg also taught that the coding region of the polynucleotide sequences of the invention (such as Chalberg SEQ ID NO: 46) could be codon-optimized to enhance expression by replacing infrequently represented codons with more frequently represented codons for a particular species. See [0160].
Chalberg did not teach a nucleic acid comprising the sequence of nucleotides 1-948 of instant SEQ ID NO: 5. However, Chalberg taught that different cell types and different animal species utilize tRNAs (each bearing an anticodon) coding for the same amino acids at different frequencies, therefore the coding region of the polynucleotide sequences of the invention (such as Chalberg SEQ ID NO: 46) could be codon-optimized to enhance expression by replacing codons that are infrequently represented by the corresponding tRNA with more frequently represented codons. See [0160].
Instant SEQ ID NO: 5 is about 78% identical to the wild type cDNA (instant SEQ ID NO: 1 or SEQ ID NO: 46 of Charlberg). 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). Thus, it was routine in the art to arrive at codon optimized versions of RDH12 that were of a similar level of identity to instant SEQ ID NO: 1 as is instant SEQ ID NO: 5.
While there is a very large number of sequences that can encode the amino acid sequence of instant SEQ ID NO: 2, all of these sequences could have been determined by one of ordinary skill prior to the invention since all codons were known. Moreover, not all of these sequences are adapted for expression in human cone cells, and one of ordinary skill in the art prior to the effective filing date of the claims would have been motivated by the teachings of Charlberg to optimize a native RDH12 cDNA for expression in cone cells. To the extent that the various possible codon optimized versions of such a cDNA all encode the same polypeptide, they are considered to be obvious equivalents or alternatives of each other absent evidence of secondary considerations, such as evidence that one sequence provides superior expression to another. That is, absent evidence of secondary considerations, sequences that are 90 or 95% identical to nucleotides 1-948 of instant SEQ ID NO: 5 are considered to be obvious equivalents or alternatives of Chalberg SEQ ID NO: 46, and of Fotin-Mleczek SEQ ID NOS: 35585, 48642, 61699, 22528, and 74756. Similarly, a recombinant AAV8 comprising an expression cassette comprising those sequences under the control of a promoter active in a human photoreceptor cell, and its use in a host cell, were obvious in view of the disclosures of Chalberg and Fotin-Mleczek.
Claims 11 and 19-25 are rejected under 35 U.S.C. 103 as being unpatentable over Chalberg et al (US 20150259395, of record) and Fotin-Mleczek et al., (US 20190241633) as applied to claims 2-10 and 12-18 above, and further in view of Boye et al., (US 20130210895).
The teachings of Chalberg and Fotin-Mleczek are discussed above and can be combined to render obvious an rAAV comprising an AAV8 capsid and an expression cassette comprising a 5' AAV ITR, a promoter active in cone cells, a nucleotide sequence at least 90% identical to nucleotides 1 to 948 of SEQ ID NO: 5, and a 3' AAV ITR, wherein the nucleotide sequence encodes a functional retinal dehydrogenase 12 (RDH12) protein comprising the amino acid sequence set forth in SEO ID NO: 2.
These references did not teach a rhodopsin kinase promoter.
Boye taught recombinant AAV vectors for expression of therapeutic gene products in the eye ([0005]). Boye chose a human rhodopsin kinase (hGRK1) promoter to drive expression of a therapeutic gene because of its ability to specifically target robust transgene expression in rod and cone photoreceptors when used in conjunction with AAV (see [0193] as well as [0037], [0038], Figs 1-6, 11-15, and 17-24.
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claims to have used the rhodopsin kinase promoter of Boye in the rAAV vector rendered obvious by Chalberg and Fotin-Mleczek. Doing so would have been no more than the combination of prior art elements according to known methods to yield predictable results, or the simple substitution of one known element for another to obtain predictable results. See MPEP 2143(I)(A) and (B).
Response to arguments:
Applicants argued:
“Due to the degeneracy of the genetic code, sequences sharing low levels of sequence identity can encode the same protein. Codon optimization of coding sequences was widely known at the time of filing of the instant application. However, there are a myriad of techniques, algorithms, and services for optimizing a given sequence, including making manual changes to the coding sequences. Even then, codon optimization is not merely a routine task but involves a complex and nuanced process that requires a deep understanding of the target organism's codon usage preferences, mRNA stability, secondary structure, and translational efficiency. The optimization process must consider various factors such as GC content, rare codon avoidance, and regulatory elements, which are not straightforward and require significant expertise….
However, these arguments are not persuasive. Applicants used examiners rational in supporting their arguments. However, the referenced rational was used for analyzing the possession issue. The issue is whether the claimed invention is obvious over the art cited and as discussed in the rejection above the invention as a whole was obvious over the combined teachings of the cited prior art. The rejection is maintained.
Conclusion
No claim is allowed.
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RAM R. SHUKLA
Supervisory Patent Examiner
Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635