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 action is in response to papers filed on August 21, 2026. A response to the restriction requirement filed on August 21, 2026, is acknowledged. Claims 1-19 are currently pending as per claims filed May 9, 2024.
Applicants’ election without traverse of Group II, e.g. claims 14-19, directed to the transgene comprising the polynucleotide of SEQ ID NO: 1 (claim 14) recombinant adeno-associated viruses comprising said transgene is acknowledged. Moreover, Applicants’ election of the transgene of SEQ ID NO: 4 (claim 15) said sequence including the P546 MeCP2 promoter (See Applicants’ remarks) is acknowledged.
Claims 1-13 have been withdrawn from further consideration by Applicants, pursuant to 37 CFR 1.142(b), as being drawn to a non-elected invention, there being no allowable generic or linking claim. The restriction requirement is deemed proper, maintained and made FINAL.
Therefore, claims 14-19 are under examination to which the following grounds of rejection are applicable.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US22/79756, filed 11/11/2022, which claims priority to US Provisional Application 63/278,905 filed 11/12/2021.
Therefore, the earliest effective filing date for the instant application is November 12, 2021.
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 14-19 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling
a rAAV comprising the transgene of SEQ ID NO: 4, which includes the P546 MeCP2 promoter, and the rAAV comprising the transgene of SEQ ID NO: 1
does not reasonably provide enablement for other recombinant adeno-associated viruses comprising any variants thereof of SEQ ID NOS 1 and 4, e.g, a polynucleotide at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
Further, claims 14-19 are rejected under 35 U.S.C. 112, 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(s), at the time the application was filed, had possession of the claimed invention.
While the written description and enablement requirements are separate and generally separable requirements, the instant application fails to meet either requirement for essentially the same reasons, as set forth below.
Applicants claim a recombinant adeno-associated virus (rAAV) with a genome comprising a transgene comprising the polynucleotide of SEQ ID NO 4, which comprises SEQ ID NO: 1 (sets out the polynucleotide sequence of a SLC6A1 cDNA encoding a GAT-1 protein with GABA transporter activity, para [0031]) , alongside the p546 MeCP2 promoter which encode the GAT-1 protein having GABA transporter activity (para [0064] of the published application). While the claims are enabling for the full length of the nucleotides of SEQ ID NOS 1 and 4, there is no support for a polynucleotide at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the full length of the polynucleotides of SEQ ID NOS: 1 and 4 encoding the GAT-1 protein from the human SLC6A1 cDNA under the control of the P546 MeCP2 promoter (a ubiquitous promoter). The disclosure does not provide sufficient guidance regarding which nucleotide positions or substitutions can be permitted, and which sequence variants will retain the required gamma-aminobutyric acid (GABA) transporter activity.
The written description requirement for a genus may be satisfied by sufficient description of a representative number of species by actual reduction to practice 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 structure and function, or by a combination of such identifying characteristics, sufficient to show that applicant was in possession of the claimed invention. The court and the Board have repeatedly held (Amgen Inc. v. Chugai Pharmaceutical Co. Ltd.,18 USPQ2d 1016 (CA FC, 1991); Fiers v. Revel, 25 USPQ2d 1601 (CA FC 1993); Fiddes v. Baird, 30 USPQ2d 1481 (BPAI 1993) and Regents of the Univ. Calif. v. Eli Lilly & Co., 43 USPQ2d 1398 (CA FC, 1997)) that an adequate written description of a nucleic acid requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it, irrespective of the complexity or simplicity of the method; what is required is a description of the nucleic acid itself.
Thus, It is not sufficient to define DNA solely by its principal biological property (e.g. nucleic acid that encodes GAT-1 with GABA transporter activity), because disclosure of no more than that, as in the instant case, is simply a wish to know the identity of any DNA with that biological property. Naming a type of material generically known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material. Thus, claiming all DNA's that achieve a result without defining what means will do so is not in compliance with the description requirement. Rather, it is an attempt to preempt the future before it has arrived. Also, where a claim purports to cover all nucleic acids that encode a specific protein and the specification discloses but a single DNA known to do so, the situation is analogous to a single means claim and does not meet the enablement requirement under para. 1 of §112.
In terms of the structural requirements of the nucleic acid molecules, claims 14-19 recite an arbitrary structural relationship between the claimed nucleic acid sequence(s) and the single disclosed species of nucleotide sequence of SEQ ID NOS 1 and 4 and the encoded amino acid sequence, respectively. The Specification does not provide a representative number of sequence variants falling throughout the claimed 90-99% homology genus having a gamma-aminobutyric acid (GABA) transporter activity , nor does it identify structural characteristics or a structure-function relationship sufficient to demonstrate which nucleotide substitutions, deletions or alterations may be made while still maintaining GABA transporter activity under the control of the P546 MeCP2 promoter (a ubiquitous promoter). The Specification only provides one example of an rAAV comprising transgene with SEQ ID NO: 4 (para 0062-0066) encoding the GAT-1 protein from the human SLC6A1 cDNA under the control of the P546 MeCP2 promoter, but is silent on variants with different additions, deletions, and/or substitutions with as little as 90% homology to SEQ ID NOS 1 and 4, and whether they can achieve the same intended effect as the working examples. Thus, the recited structural relationship is arbitrary since neither the specification, nor the prior art discloses any definitive relationship between protein function and % identity or homology at the nucleotide level; and the specification does not describe a single species of nucleic acid that encodes a functional GAT-1 protein that is not either 100% identical to SEQ ID NO: 1 or 4.
Furthermore, it is known in the art that conservative nucleic acid substitutions can adversely affect subsequent protein activity, and the relationship between a polynucleotide sequence of SLC6A1 and its intended function after modifying the sequence is not well understood nor predictable, as discussed in Mermer et al. (Published: October 2022. Neurobiology of Disease, 172, Article 105810.) Mermer discloses that specific variants of the GAT-1 protein had reduced GABA uptake, and were essentially defective (Figure 7D)
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Moreover, Mermer discloses that GAT-1 variants can destabilize the resulting proteins and cause enhanced protein disposal inside the ER (pp. 14, col 1 para 1). Therefore, the prior art establishes that mutations or alterations in the nucleic acid sequence cannot always result in functioning proteins. Consequently, excessive trial and error experimentation would have been required to identify the necessary human SLC6A1 cDNA under the control of the P546 MeCP2 promoter encoding
GAT-1 protein derivatives having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the full length of the polynucleotides of SEQ ID NOS: 1 and 4 since the nucleic acid sequence of such nucleotides could not be predicted - even were the activity known.
As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112, first paragraph requires that scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.
In Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991), the court ruled that a claim to a large genus of possible genetic sequences encoding a protein with a particular function that needs to be determined subsequent to the construction of the genetic sequences may not find sufficient support under 35 USC 112, 1st para., if only a few of the sequences that meet the functional limitations of the claim are disclosed and if undue experimentation would be required of one skilled in the art for determining other genetic sequences embraced by the claim. In regard to the instant claims, the specification discloses only one putative functional nucleic acid sequence, SEQ ID NO: 4, for a GAT-1 protein having the necessary activity and provides no guidance on determining which polypeptide variants of SEQ ID NO: 4 that would have an activity of SEQ ID NO: 4.
While one of skill in the art can readily envision numerable species of nucleic acid sequences that are at least a given % identity to a reference nucleotide sequence and that encode a polypeptide at least a given % identity to a recited reference amino acid sequence, one cannot envision which of these also encode a protein with a specified activity. The fact remains that the actual nucleic acid sequences which encode a protein with a particular activity or the actual amino acid sequences of such a protein cannot be envisioned any better when the possible choices are narrowed from all possible sequences to all possible sequences with an arbitrary structural relationship with a known functional sequence.
To put this situation in perspective, the claims encompass any rAAV that is at minimum 90% similar to the full-length sequence of 3102 nucleic acids of SEQ ID NO: 4, i.e. the transgene expressing SLC6A1, under the control of the p546 MeCP2 promoter. The 10% variance results in a situation in which even if a 310-contiguous nucleic acid region is independently varied among the 4 different naturally occurring nucleic acids, there would be 4.35 x 10186 (4 310) different possible permutations of nucleic acid sequences. In fact, since variations could occur anywhere within the rAAV, the actual number of different permutations is orders of magnitude greater than 4.35 x 10186. Thus, computer software may provide means for identification of such elements, but it is not itself an adequate description of the structure of the claimed invention.
Neither prior art of record nor the as-filed specification provides sufficient guidance to enable a person skilled in the art to make and use a genus of rAAV comprising a polynucleotide having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the full length of the polynucleotides of SEQ ID NOS: 1 and 4, Seq ID NO:4 encoding the GAT-1 protein from the human SLC6A1 cDNA under the control of the P546 MeCP2 promoter for GABA transporter activity. As the result, given the unpredictability of the art and the lack of working example in the instant specification, particularly when taken with the lack of guidance in the specification, it would have required undue experimentation to practice the instant invention to identify an enormous number of to alternative transgenes comprising a functional SLC6A1 gene, specifically exhibiting the biological activity of producing enhanced GABA transporter activity.
Claim Rejections - 35 USC § 102
To the extent that claim 14 encompasses nucleotide fragments of the nucleotide of SEQ ID NO:1, the following rejection applies.
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)(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) 14, 16, 18 and 19 is/are rejected under 35 U.S.C. 102a(2) as being anticipated by Cargill et al. (Published: 2005. US 20060024700 A1)
Regarding claim 14, Cargill teaches SEQ ID NO: 129 with 100% homology to SEQ ID NO: 1 of the instant claims.
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Regarding claim 16, Cargill teaches the transgene comprising a nucleotide sequence having 100% homology to the full length of the polynucleotide SEQ ID NO: 1 of the instant claims, and that the transgene can be present in a adenoviral vectors (AAV) (para 0174, para 0380, para 0245, para 0363-0366)
***
Claim(s) 14, 16, 18 and 19 is/are rejected under 35 U.S.C. 102a(2) as being anticipated by Gray et al. (Published: 2021. US Publication: US 20210139934 A1).
Regarding claim 14, Gray teaches SEQ ID NO: 11 with 99. 2% homology to SEQ ID NO: 1 of the instant claims.
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Regarding claim 16, Gray teaches the transgene comprising a nucleotide sequence having 99. 2% homology to the full length of the polynucleotide SEQ ID NO: 1 of the instant claims, and also that the transgene can be present in a recombinant adeno-associated virus (rAAV) (Abstract, para [0004], para [0007], para [0051], para [0090], para [0094] discusses transgene can be present in an rAAV).
Regarding claim 18, Gray teaches that the rAAV can be a rAAV9 (Abstract, para [0094] discusses transgene can be present in an rAAV, para [0029] discusses embodiments of rAAV, one being AAV9; para [0238]).
Regarding claim 19, Gray teaches that the rAAV can be a rAAV9 (Abstract, para [0094] discusses transgene can be present in an rAAV, para [0029] discusses embodiments of rAAV, one being AAV9; para [0238]).
Therefore, by teaching all the limitations of the claims as written, Gray et al. anticipates the claimed invention.
The examiner notes the polynucleotides comprising the full-length sequence of SEQ ID NO: 4 are free of prior art.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Katriel B Kasayan whose telephone number is (571)272-1402. The examiner can normally be reached 10-4p.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria G Leavitt can be reached at (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KATRIEL BARCELLANO KASAYAN/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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