DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s Response to Election/Restriction Filed with Arguments/Remarks, filed 23 September 2025, have been entered. Claims 1, 3-4, 6-13, 16-19, 22-24, and 26-27 are currently pending. Claims 1, 9, 11, 12, 19, 22, 24, 26, and 27 are independent claims. Applicant’s election of the invention 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, is acknowledged.
Additionally, Applicant’s election of the following species:
Heterologous nucleic acid sequences: c. SEQ ID NO: 7,
in a reply filed 23 September is acknowledged.
While Applicant has not indicated whether the election of Group I and the election of species SEQ ID NO: 7 have been made with or without traverse, Applicant has not provided any arguments traversing the restriction and election of species requirement(s). Therefore, the election of Group I and SEQ ID NO: 7 is considered to have been made without traverse.
Upon further consideration, Examiner has withdrawn the election of species requirement for 1) Heterologous nucleic acid sequences.
Claims 12-13, 16-19, and 27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1, 3-4, 6-11, 22-24, and 26 are currently pending in the application and under examination to which the following grounds of rejection are applicable. An action on the merits follows.
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.
Information Disclosure Statement
The information disclosure statement filed 08 May 2023 has been considered by the Examiner.
Specification
The disclosure is objected to because of the following informalities: the Brief Description of the Drawings does not include a description of each panel. Specifically, the descriptions of Figure 3A-D does not include individual descriptions of panels A through D. See MPEP 608.01(f), which states, “When there are drawings, there shall be a brief description of the several views of the drawings and the detailed description of the invention shall refer to the different views by specifying the numbers of the figures, and to the different parts by use of reference letters or numerals”. Further, MPEP 608.01(f) instructs Examiners such that “If the drawings show Figures 1A, 1B, and 1C and the brief description of the refers only to Figure 1, the examiner should object to the brief description, and require applicant to provide a brief description of Figures 1A, 1B, and 1C.” Appropriate correction is required.
The use of the terms “Hamilton” in [00136], “Scancope FL” in [00138], “Image-Scope” in [00138], “Positive Pixel Counter FL v1” in [00138], “Odyssey Infrared Imaging systems” in [00139], “GraphPad Prism 6” in [00140], which are trade names or a marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Note that the specification has not been inspected sufficiently to identify all instances of trade names and/or marks used in commerce. It is Applicant’s responsibility to ensure complete compliance.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112(b)
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 1, 3-4, 6-11, 22-24, and 26 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim 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.
The term “a variant thereof” in independent claims 1 and 24 is a relative term which renders the claim indefinite. The term “a variant thereof” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The specification teaches a number of AAV8 variant options in [0036-0037], however, the specification does not provide a limiting definition of an AAV8 variant which would apprise the ordinarily skilled artisan of the metes and bounds of the term “variant”.
Claims 3-4, 6-11, 22-23, and 26 are included in this rejection due to their dependence on or encompassing of independent claims 1 or 24.
Claim Rejections - 35 USC § 112(a)
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 1, 3-4, 6-11, 22-24, and 26 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 claim 1 recites, “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. Additionally, dependent claim 4 recites, “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 recites, “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.
The specification teaches that the nucleotide sequence of the human N-acetylglucosaminidase alpha (NAGLU) is set out in SEQ ID NO: 1 [0043-0044]. Additionally, the specification teaches that SEQ ID NO: 7 is a sequence encoding human NAGLU which has been codon optimized for human expression [0046-0047]. The specification also 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 additionally teaches generally, as claimed, that the nucleotide sequences have at least 80% identity, at least 85% identity, at least 90% identity, at least 92.5% identity, at least 95% identity, at least 98%, and/or at least 99% identity to the sequences specified in SEQ ID Nos: 1, 2, or 7 [0043, 0046, 0052]. The specification further teaches a definition for percent identity [0055] and writes out example numbers of nucleotides which could differ relative to the NAGLU sequence set forth in SEQ ID NO: 1 or 7 [0056] or the vector according to SEQ ID NO: 2 [0057]. The specification does not teach any specific sequences out to 80% or 85% identity with the recited sequences for NAGLU (i.e., SEQ ID NOs: 1 or 7) or a vector comprising NAGLU (e.g., SEQ ID NO: 2) beyond the 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: 1, 2, or 7 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 15% or 20% of the sequence of SEQ ID NOs: 1, 2, or 7 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 NOs: 1, 2, or 7, and particularly variants of SEQ ID NO: 1, 2, or 7 which comprise up to 15% or up to 20% sequence differences.
The following guidance provided in MPEP 2163 is informative. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. 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 (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 the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. In other words, describing a composition by its function alone typically will not suffice to sufficiently describe the composition. See for example Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406 (Holding that description of a gene’s function will not enable claims to the gene "because it is only an indication of what the gene does, rather than what it is."); see also Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991)). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that "[w]ithout such disclosure, the claimed methods cannot be said to have been described."). Furthermore, written description issues may also arise if the knowledge and level of skill in the art would not have permitted the ordinary artisan to immediately envisage the claimed product arising from the disclosed process. See, e.g., Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir. 1996). While it has been held that what is conventional or well known to one of ordinary skill in the art need not be disclosed in detail, for inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession.
The specification, as discussed in detail above, 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 (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 variants of SEQ ID NOs: 1, 2, or 7 comprising up to 15% or up to 20% 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 80% or 85% identity limitation encode the same amino acid sequence as encoded by SEQ ID NOs: 1, 2, or 7. 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).
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, 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 sever 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 15% non-identities relative to the sequence of SEQ ID NOs: 1 or 7, 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 or 7, up to 15% variation, 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.
Further, claims 1 and 24 recite, “wherein the rAAV vector is of serotype AAV8, or a variant thereof”. The specification teaches the use of AAV8 capsid variants comprising mutations to amino acid residues associated with ubiquitination of the AAV vector in expression of coNAGLU, particularly a triple-capsid mutant (tcm) modification to the AAV8 capsid designed to reduce ubiquitination and degradation of the AAV vector, which confers further enhanced expression and distribution in brain cells [0009]. The specification teaches four non-native amino acid substitutions (e.g., residues Y444F, Y447F, Y494F, T733V) relative to a wildtype AAV8 capsid, along with different combinations of mutations at those positions, wherein that the tcm modification is the AAV8(Y447F/Y733F/T494V) capsid variant [0035]. The disclosure also teaches that in some embodiments, the rAAV vectors are pseudotyped, e.g., are of an rAAV2/AAV8 pseudotype [0034-0037].
The specification does not disclose which variants of AAV8 (e.g., variants of the AAV8 capsid protein sequence) would have an amino acid sequence which would retain the essential functional properties of the AAV capsid protein or which variants would disrupt such functions. The specification additionally does not disclose any % identity which would retain the necessary identity and functionality in the capsid polypeptide. Example 2 of the specification teaches transduction assessment of AAV8 and AAV8 variants used to deliver GFP transgenes to brain tissue, wherein only the AAV8 variants AAV8(Y447F, Y733F) and AAV8(Y447F,Y733F,T494V) were tested [00116-00141, Figure 9, 10].
The specification does not teach any other variations of the AAV8 capsid protein. All of the examples use the AAV8, AAV8(Y447F, Y733F), and/or AAV8(Y447F,Y733F,T494V) capsid serotype without any disclosed further variation. As such, the specification fails to provide any specific guidance as to which amino acids could be changed 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 variants of AAV8 other than AAV8(Y447F, Y733F) and AAV8(Y447F,Y733F,T494V).
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 mutations 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, which includes variations which change the amino acid sequence at any position 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.
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, abstract]. Agbandje-McKenna also teaches that AAVs have evolved a multifunctional capsid with conserved core regions as is required for efficient capsid trafficking, capsid assembly, and genome packaging, along with disparate surface loop structures which confer different receptor recognition and are involved in antibody recognition [abstract]. As such, 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 sequence. Accordingly, the scope of the claims encompasses variants of the AAV8 capsid protein sequence which would 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 changed 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, 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 two disclosed species of sequence of an AAV8 variant (e.g., AAV8(Y447F, Y733F) and AAV8(Y447F,Y733F,T494V)) 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 does not describe the claimed variants of the nucleotide sequences of SEQ ID NOs: 1, 2, or 7 and AAV8 capsid protein 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.
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.
Claim(s) 1, 3-4, 6-11, 22-24, and 26 are rejected 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].
Regarding claims 1, 3, and 24, Bosch Tubert teaches a rAAV9 vector comprising a heterologous nucleic acid encoding NAGLU (SEQ ID NO: 22) [0027, claim 1], wherein the heterologous nucleic acid comprises a sequence having at least 85% identity to the sequence of SEQ ID NO: 1 of the instant application:
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and at least 85% identity to the sequence of SEQ ID NO: 7 of the instant application:
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[0077].
Bosch Tubert does not teach that the rAAV vector is AAV8.
However, Dai teaches that AAV8 vectors with capsid mutations, including AAV8 (Y447F/Y733F/T494V) have significantly enhanced transduction efficiency in retinas compared to WT AAV controls, such that AAV8 (Y447F/Y733F/T494V)-treated cpfl5 mouse retinas showed greater preservation of short-term cone electroretinogram (ERG) responses than AAV8 (Y447F/Y733F)-mediated treatments [abstract]. Dai further teaches that transgene expression was primarily detected in the photoreceptor outer segment layer of the cpfl5 retinas [page 6 ¶ 3]. Dai also teaches that AAV8 with capsid Y-F and T-V mutations may be one of the most effective AAV vectors for long-term treatment in a naturally occurring mouse model of CNGA3 achromatopsia [abstract]. Therefore, an ordinarily skilled artisan would have been motivated to deliver a transgene using the AAV8 (Y447F/Y733F/ T494V) serotype variant for enhanced transduction efficiency in retinas, greater preservation of short-term treatment responses, and effective long-term treatment.
Regarding claim 4, Bosch Tubert also teaches an AAV vector comprising a heterologous nucleic acid sequence (e.g., SEQ ID NO: 23 referred to as the plasmid pAAV-CAG-cohNaglu-version3) comprising a sequence having at least 80% identity to the sequence of instant SEQ ID NO: 2:
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Regarding claim 6, Bosch Tubert also teaches that the AAV vectors of their invention further contain a promoter linked to the coding nucleotide sequence to control the expression of NAGLU, and that example suitable promoters include the CAG promoter (which comprises both the cytomegalovirus early enhancer element and the chicken β-actin (CBA) promoter), allowing for long-term expression of NAGLU [0020, 0070-0073, 0078]. Bosch Tubert further teaches that the CAG promoter proved to be more efficient than the CMV promoter usually used in the art [0078].
Regarding claim 7, Bosch Tubert also teaches that the vector comprises inverted terminal repeats (ITRs) from AAV serotype 2 (AAV2) [0079].
Regarding claim 8, Bosch Tubert teaches wherein the heterologous nucleic acid is codon-optimized for human expression [0069, 0077, 0086-0087, 0148].
Regarding claim 9, Bosch Tubert teaches an rAAV particle comprising the rAAV vector as described above [0156, claim 42].
Regarding claims 10 and 26, as described above, Bosch Tubert and Dai teach the limitations of claims 1 and 24. Dai additionally teaches the motivation to deliver a transgene using the AAV8 (Y447F/Y733F/ T494V) variant for enhanced transduction efficiency in retinas, greater preservation of short-term treatment responses, and effective long-term treatment.
Regarding claim 11, Bosch Tubert teaches a pharmaceutical composition comprising the rAAV particle described above and one or more pharmaceutically acceptable excipients [abstract, 0022, 0098, claim 32-35].
Regarding claim 22, Bosch Tubert teaches a host cell comprising the rAAV vector described above [0106, 0110].
Regarding claim 23, Bosch Tubert and Dai teach the limitations of claim 1. Bosch Tubert teaches delivery of the rAAV vector to neurons and glial cells of mice and Beagle dogs [0040, Figure 14, 0179, 0184]. Bosch Tubert also teaches that Beagle dogs is an animal model with a brain size closer to that of humans compared to mice [0184]. Bosch Tubert further teaches a method of increasing NAGLU activity in a living animal body, including a human [0061, 0100, claim 36-40].
As discussed above, Dai teaches that transgene expression following delivery with the AAV8 (Y447F/Y733F/ T494V) variant was primarily detected in the photoreceptor outer segment layer of the cpfl5 retinas [page 6 ¶ 3], thereby teaching a neuron (e.g., photoreceptor) comprising the rAAV vector.
Therefore, in delivering the rAAV taught by Bosch Tubert and Dai to humans, an ordinarily skilled artisan would generate human neurons and/or human glial cells comprising the rAAV vector.
Given the motivation taught by Dai to deliver a transgene using the AAV8 (Y447F/Y733F/ T494V) serotype variant for enhanced transduction efficiency in retinas, greater preservation of short-term treatment responses, and effective long-term treatment; it would have been prima facie obvious to an ordinarily skilled artisan at the time of filing the instant application to modify the rAAV vector of Dai such that the vector is an AAV8 (Y447F/Y733F/ T494V) variant with a reasonable expectation of success.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dr. KATIE L PENNINGTON whose telephone number is (703)756-4622. The examiner can normally be reached M-Th 8:30 am - 5:30 pm, Friday 8:30 am - 12:30 pm CT.
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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