DETAILED ACTION
Applicant’s amendment and Arguments/Remarks received on 11 May 2026 have been entered. Claims 1, 3-4, 6-13, 16-19, 22-24, and 26-27 were previously pending in the application. No claims have been cancelled, and new claims 28 has been added by Applicant. Claims 1, 3-4, 6-13, 16-19, 22-24, and 26-28 are currently pending in the application. Claims 1, 9, 11, 12, 19, 22, 24, 26, and 27 are independent claims.
The election of Group I, drawn to a recombinant adeno-associated viral (rAAV) vector, an rAAV particle comprising the rAAV vector, a pharmaceutical composition comprising the rAAV particle, a host cell, a second rAAV vector, and a second rAAV particle comprising the second rAAV vector, remains in effect in the instant application.
Claims 12-13, 16-19, and 27 remain withdrawn from consideration as being directed to a nonelected invention, there being no allowable generic or linking claim.
Claims 1, 3-4, 6-11, 22-24, 26, and 28 are currently pending and under examination in the instant application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2021/031863, filed 11 May 2021, which claims priority to U.S. Provisional Application No. 63/023,224, filed 11 May 2020.
Thus, the earliest possible priority for the instant application is 11 May 2020.
Specification
The objection to the specification of the disclosure for the brief description of the drawings not specifically describing each panel of Figure 3 and for reciting trade names and/or marks used in commerce without the corresponding signals and/or generic terminology, is withdrawn in view of the amendment to the specification. The amendment to the specification of the disclosure filed 11 May 2026 has been entered.
Claim Rejections - 35 USC § 112(b)
The rejection of amended, previously presented, and original claims 1, 3-4, 6-11, 22-24, and 26 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for reciting “a variant thereof” in claims 1 and 24 is withdrawn in view of Applicant’s amendments to the claims such that claims 1 and 24 now specifically recite “a variant of AAV8 having an amino acid substitution at one or more of positions Y444, Y447, T494, E533, and Y733.
Claim Rejections - 35 USC § 112(a)
The rejection of amended, previously presented, and original claims 1, 3-4, 6-11, 22-24, and 26 under 35 U.S.C. 112(a) for failing to comply with the written description requirement for Independent claim 1 reciting, “a sequence having at least 85% identity, at least 90% identity, at least 92.5% identity, at least 95% identity, at least 98%, or at least 99% identity to the sequence of SEQ ID NO: 1” in lines 3-5; dependent claim 4 reciting, “a sequence having at least 80% identity, at least 85% identity, at least 90% identity, at least 92.5% identity, at least 95% identity, at least 98%, or at least 99% identity to the sequence of SEQ ID NO: 2” in lines 2-4; independent claim 24 reciting, “a sequence having at least 85% identity, at least 90% identity, at least 92.5% identity, at least 95% identity, at least 98%, or at least 99% identity to the sequence of SEQ ID NO: 7” in lines 2-4, and claims 1 and 24 reciting “wherein the rAAV vector is of serotype AAV8, or a variant thereof”, is maintained and newly applied to new claim 28.
Applicant amendment the claims such that amended independent claim 1 now recites “at least 95% identity to the sequence of SEQ ID NO: 1”, amended dependent claim 4 now recites, “at least 90% identity to the sequence of SEQ ID NO: 2”, and amended independent claim 24 now recites, “at least 95% identity to the sequence of SEQ ID NO: 7”.
Additionally, Applicant amended independent claims 1 and 24 to recite “a variant of AAV8 having an amino acid substitution at one or more of positions Y444, Y447, T494, E533, and Y733.”
Although the amendments to the claims narrow the scope of the claimed invention to partially address the issues identified in the prior action, they do not sufficiently align with the teachings in the specification to comply with the written description requirement. The claim(s) still contain 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.
Specifically, regarding Applicant’s amendment to dependent claim 4 to recite, “at least 90% identity to the sequence of SEQ ID NO: 2, as discussed in the prior action, the specification teaches that SEQ ID NO: 2 is the vector sequence AAVtcm8-coNAGLU, which comprises the sequence of SEQ ID NO: 7 [0052-0053]. The specification does not teach any specific sequences out to 90% identity with the recited sequence of a vector comprising NAGLU (e.g., SEQ ID NO: 2) beyond two alternatives encoding NAGLU (i.e., SEQ ID NOs: 1 or 7). Example 1 discloses the administration of a single AAVtcm8 vector expressing codon-optimized NAGLU (AAVtcm8-coNAGLU) to NAGLU-/- mice [00107-00115]. Example 2 discloses assessment of transduction of AAV8 double and triple capsid mutants packaged with nucleic acids encoding a fluorescent reporter gene (e.g., GFP) in brain tissues, and does not disclose additional or alternative NAGLU nor vector sequences for expressing NAGLU [00116-00140].
The specification does not disclose which variants of the sequence of SEQ ID NO: 2 would encode an amino acid sequence which would retain the essential functional properties of the NAGLU or the other vector elements nor which variants would disrupt such functions. The specification additionally does not disclose any % identity which would retain the necessary identity and functionality in the encoded NAGLU polypeptide and other vector elements. As such, the specification fails to provide any specific guidance as to which up to 10% of the sequence of SEQ ID NO: 2 could be changed to allow for a functional NAGLU polypeptide and additional vector components (e.g., ITRs, promoter, or terminator sequences) of the instant invention. Therefore, the description is not sufficient to adequately describe and demonstrate possession of any variants of SEQ ID NO: 2, and particularly variants of SEQ ID NO: 2 which comprise up to 10% sequence differences.
The specification, as discussed above and in the prior action, provides guidance for only two disclosed species of sequence encoding NAGLU (e.g., SEQ ID NOs: 1 or 7), which each encode the same polypeptide sequence with some alternative codon usage, without providing sufficient detailed descriptions of the various variants which would encode a polypeptide with sufficient structural and functional properties of NAGLU. As such, the specification fails to provide a 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 possession of any of the claimed genus of variants of SEQ ID NO: 2 comprising up to 10% differences in nucleic acid sequence.
At the time of filing, codon optimization was well known in the art; however, the claim as written does not require that any variants within the 90% identity limitation encode the same amino acid sequence as encoded by SEQ ID NOs: 2 beyond the requirement to encode a full-length human NAGLU protein from a coding sequence at least 95% identical to SEQ ID NO: 1. There is not a disclosure of regions or domains of the protein that are essential to NAGLU activity. There is no disclosure of what amino acids are in the active site, the binding pocket, or the hydrophobic core of the protein. There is no structure/function relationship taught at all for SEQ ID NOs: 1, 2, or 7. The specification mentions only the full length of two disclosed species of NAGLU (non-codon optimized and codon optimized versions) corresponding to nucleotides of SEQ ID NOs: 1 and 7. The scope of the claims as written encompasses any variation in the nucleic acid sequences, which include variations which change the amino acid sequence at any position to any other amino acid. As such, the claim as written, encompasses variations which may change the structure sufficiently to adversely affect the function and/or alter the function of the NAGLU polypeptide or of the vector sequences (e.g., UTRs, promoter, and terminator) themselves.
As discussed in the prior action, Filocamo teaches at least 166 mutations have been identified in the NAGLU gene of mucopolysaccharidosis type IIIB (MPS IIIB) patients [Filocamo et al. 2018, Italian Journal of Pediatrics, 44, 129, 1-11, cited in a prior action, column 11 ¶ 3, Table 2]. Filocamo further teaches that the extensive NAGLU mutational heterogeneity is likely responsible for the wide clinical spectrum of MPS IIIB, wherein certain mutations (e.g., p.Phe48Lys, p.Gly69Ser, and p.Ser612Gly) appear to be related to a less severe clinical phenotype [column 11 ¶ 3]. Filocamo also teaches that the defect of NAGLU enzyme causes the pathological accumulation of heparin sulfate in organs and tissues, leading to the disease [abstract, column 1 ¶ 1- column 2 ¶ 1, column 11 ¶ 3]. Accordingly, given the dramatic effects single missense or small indel mutations within the coding sequence for NAGLU can have on the function of the alpha-sarcoglycan protein function, sufficient to induce MPS IIIB [abstract, column 1 ¶ 1- column 2 ¶ 1, column 11 ¶ 3], the scope of the claim encompasses variants of the NAGLU coding sequence which would result in non- or dys-functional NAGLU polypeptides. As such, variations of the NALGU coding sequences of up to 5% non-identities relative to the sequence of SEQ ID NO: 1 (within the up to 10% non-identities relative to the sequence of SEQ ID NO: 2), such that a functional NAGLU protein is still encoded, were neither conventional nor predictable at the time of filing, and the knowledge and level of skill in the art at the time of filing would not have permitted the ordinary artisan to immediately envisage all the variations of the sequence of SEQ ID NOs: 1 (within the up to 10% non-identities relative to the sequence of SEQ ID NO: 2), up to 5% variation relative the sequence of SEQ ID NO: 1, which would still produce a functional NAGLU protein from the generic description provided by the specification. In view of these considerations, an ordinarily skilled artisan would not have viewed the teachings of the specification as sufficient to show that the applicant was in possession of the claimed invention.
Regarding recitation of “a variant of AAV8 having an amino acid substitution at one or more of positions Y444, Y447, T494, E533, and Y733” in independent claims 1 and 24, the specification generally teaches, “In particular embodiments, the capsids of the disclosed rAAV vectors and particles have one or more non-native amino acid substitutions relative to the wild-type AAV8 capsid protein sequence. In some embodiments, the capsid comprises non-native amino acid substitutions at one or more of the amino acid residues 447, 494, and 733 of a wild-type AAV8 capsid.” [0035]. The specification additionally teaches specific mutations Y444F, Y447F, T494V, E533K, and Y733F [0035-0036]. The specification does not teach any other specific amino acids at positions Y44, Y447, T494, E533, and Y733 other than the wildtype amino acids or the Y444F, Y447F, T494V, E533K, and Y733F substitutions. As such, the specification fails to provide any specific guidance as to which amino acids could be substituted at positions Y44, Y447, T494, E533, and Y733 to allow for a functional capsid polypeptide to form the AAV8 variant of the instant invention. Therefore, the description is not sufficient to adequately describe and demonstrate possession of any amino acid variants of AAV8 at positions Y44, Y447, T494, E533, and Y733 other than AAV8(Y447F, Y733F) , AAV8(Y447F,Y733F,T494V), and AAV8(E533K, Y733F).
At the time of filing, various capsid protein sequences were well known in the art; however, claims 1 and 24 as written does not require that any variants comprise any specific amino acids at the indicated positions such that a functional or desirable capsid protein is produced. The scope of the claims as written encompasses any variation in the amino acid sequence at the indicated positions, which includes variations which change the amino acid sequence to any other amino acid. As such, the claims as written, encompass variations which may change the structure sufficiently to adversely affect the function and/or alter the function of the AAV8 capsid protein in unpredictable ways.
As discussed in the prior action, Agbandje-McKenna teaches that human and nonhuman primate AAVs are clustered into serologically distinct genetic clade and serotype groups, which have distinct cellular/tissue tropisms and transduction efficiencies, which are highly dependent upon the AAV capsid amino acid sequence, their capsid structure, and their interactions with host cell factors, including cell surface receptors and co-receptors, among others [Agbandje-McKenna & Kleinschmidt 2011, Adeno-Associated Virus: Methods and Protocols, in Methods in Molecular Biology, 807, 47-92, published online 01 January 2011, cited in a prior action, abstract], such that the specific structure of the AAV capsid protein is critical for both basic functions of the AAV vector, such as assembly, as well as the tropism of the vector in targeting particular cell and/or tissue types.
The scope of claims 1 and 24 as written encompass an AAV8 having capsid proteins that comprises any variant amino acid at the indicated positions. Accordingly, the scope of the claims encompasses variants of the AAV8 capsid protein sequence which could result in non- or dys-functional capsid proteins. Without any guidance from the specification to teach which amino acid residues of the AAV8 capsid protein sequence could be incorporated at the indicated positions without loss of basic function or undesirable alterations to/ loss of receptor interactions and tropisms, it is unclear which such sequences would constitute an AAV8 variant to maintain the “AAV8 variant” capsid identity/ functionality. As such, any variations of the AAV8 capsid sequence at the indicated positions, such that a functional capsid protein is still produced, were neither conventional nor predictable at the time of filing, and the knowledge and level of skill in the art at the time of filing would not have permitted the ordinary artisan to immediately envisage the variations of AAV8 which would still produce a functional capsid protein from the generic description provided by the specification. In view of these considerations, an ordinarily skilled artisan would not have viewed the teachings of the specification as sufficient to show that the Applicant was in possession of the claimed invention.
The specification, as discussed in detail above, provides guidance for only three disclosed species of sequence of an AAV8 variant (e.g., AAV8(Y447F, Y733F), AAV8(Y447F,Y733F,T494V), and AAV8(E533, Y733F)) without providing sufficient detailed descriptions of the various variants which would provide a polypeptide with sufficient structural and functional properties of the AAV8 capsid protein. The disclosure provides a single sequence for the AAV8 VP1 capsid protein (e.g., SEQ ID NO: 3 representing AAV8(Y447F,Y733F,T494V)). As such, the specification fails to provide a description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), 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 possession of any of the claimed genus of AAV8 variants.
Therefore, the specification still does not describe the claimed variants of the AAV8 capsid protein positions Y444, Y447, T494, E533, and Y733 and the claimed variants of nucleotides of SEQ ID NO: 2 in such full, clear, concise and exact terms so as to indicate that Applicant has possession of these variants at the time of filing the present application. Thus, the written description requirement has not been satisfied.
Accordingly, Applicant’s amendments have not overcome the written description rejection under 35 U.S.C. 112(a).
Applicant argues that Applicant’s amendment to recite “at least 90% identity to SEQ ID NO: 2” in claim 4 and that the rAAV vector “is of serotype AAV8, AAV7BP2, or a variant of AAV8 having an amino acid substitution at one or more position Y444, Y447, T494, E533, and Y733” in claims 1 and 24 are supported by the description such that the disclosure of the application reasonably conveys to those skilled in the art that the inventor had possession of the claimed invention. Specifically, Applicant asserts that the claimed substitutions were specifically selected to improve transduction, in that the specification teaches that phosphorylation prior to ubiquitination results in substantial number of ubiquitinated virions being recognized and targeted for proteasomal degradation on their way to the nucleus, and inefficient second-strand synthesis, thus leading to inefficient nuclear transport, such that substitution of one or more surface-exposed residues leads to improved transduction.
However, this is not agreed.
As discussed in detail above and in the prior action, Applicant has not described the various sequences and/or functions of the sequence of SEQ ID NO: 2 in sufficient detail to apprise the ordinary skilled artisan of the up to 10% variance which would still allow for a functional rAAV vector encoding a functional full-length human NAGLU protein. The only variants described are 2 variants of the sequence encoding NAGLU which differ is some codon usage.
Although the specification teaches that “mutagenesis of highly conserved exposed tyrosine residues (Y444F, Y500F, or Y730F) on AAV2 capsids enhanced transduction up to tenfold in HeLa cells and 30-fold in mouse liver” and “[i]mproved transduction of mouse skeletal muscle was also obtained with tyrosine mutants of AAV8 in the lungs” [pg 39] and provides working experimental data for three capsids: AAV8, AAV8(Y447F, Y733F) and AAV8(Y447F, Y733F, and T494V) thereby demonstrating that the substitutions selected using the rationale described in the specification improve transduction [Figs 9-11, 13], Applicant has only demonstrated a single amino acid substituted at each position, which was selected to prevent phosphorylation and subsequent ubiquitination while minimizing other structural effects, such that a tyrosine to phenylalanine substitution is the most conservative substitution which removes the OH of tyrosine to prevent phosphorylation without removing the bulky phenyl group. Similarly, a threonine to valine substitution removes the OH of threonine and preserves a similarly sized side chain wherein a methyl group replaces the OH. As such, the specific substitutions taught by the specification do not represent the full range of possible substitutions at each selected position, wherein less conservative substitutions may impact the structural and/or functional properties of the capsid protein to a greater extent than the tested substitutions.
Accordingly, Applicant’s arguments have not overcome the written description rejection under 35 U.S.C. 112(a), and the rejection is maintained.
Claim Rejections - 35 USC § 103
The rejection of amended, previously presented, and original claims 1, 3-4, 6-11, 22-24, and 26 under 35 U.S.C. 103 as being unpatentable over Bosch Tubert [US20170088859A1, published 30 March 2017, cited in a prior action] in view of Dai et al. [2017, PLoS One, 12(11), e0188032, 1-16], is withdrawn in view of Applicant’s claims such that independent claim 1 now recites “at least 95% identity to the sequence of SEQ ID NO: 1”, amended dependent claim 4 now recites, “at least 90% identity to the sequence of SEQ ID NO: 2”, and amended independent claim 24 now recites, “at least 95% identity to the sequence of SEQ ID NO: 7”. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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