DETAILED ACTION
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 .
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 01/05/2026 is acknowledged. Claims 2,10,12,13,15-20,27,29-45,47-81,83-86 and 88-103 were/stand cancelled. Claims 1 and 3-8 were amended. Claims 1,3-9,11,14,21-26,28,46,82 and 87 are pending. Claims 21-23 and 87 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant elected Group I (Claims 1,3-9,11,14,24-26,28,46 and 82) without traverse in the reply filed on 08/12/2025.
Upon further consideration, the species election has been withdrawn.
Claims 1,3-9,11,14,24-26,28,46 and 82 are directed to the elected invention and are under examination.
Priority
This application claims benefit of 63/244,132 filed 09/14/2021 as reflected by the most recent filing receipt.
Response to Arguments
Applicant’s arguments and amendments, see page 7, filed 01/05/2026, with respect to the objection to the specification regarding the abstract using legal phraseology “said”, and the objection to the color drawings have been fully considered and are persuasive due to the amendment to the abstract removing “said”, and the filing of the Petition to Accept Color Drawings, the amendment to the specification regarding the required paragraph as the first paragraph of the brief description of the drawings, and payment of the petition fee. The objections to the specification and drawings have been withdrawn.
Applicant’s arguments and amendments, see page 8, filed 01/05/2026, with respect to the rejection(s) of claim(s) 3-8 under 35 U.S.C. 112(b) and 112(d) have been fully considered and are persuasive due to the amendments to claims 3-8 correcting the indefinite language and also are now further limiting. The 35 U.S.C. 112(b) and 112(d) rejections of claims 3-8 have been withdrawn.
Applicant’s arguments and amendments, see pages 9-13, filed 01/05/2026, with respect to the rejection(s) of claim(s) 1,3-9,14 and 24 under 35 U.S.C. 102(a)(1) as anticipated by GenBank Accession NO: AAO88204.1; claims 11 under 35 U.S.C. 103 as unpatentable over GenBank Accession NO: AAO88204.1 in view of Feiner et al.; and claims 25,28,46 and 82 as unpatentable over GenBank Accession NO: AAO88204.1 in view of During and claim 26 as unpatentable over GenBank Accession NO: AAO88204.1, Feiner and During, have been fully considered and are persuasive due to the amendments to claims 1 requiring the number of amino acid residues that are deleted or substituted to be contiguous, and the amendment to claims 3-8 removing the language “comprising a deletion or substitution of” and requiring a specific range of the AAV9 VP1 protein amino acids to be deleted, substituted or a combination thereof, which the cited art of GenBank Accession NO: AAO88204.1 no longer applies based on that instant claims. Therefore, the rejections have been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the amendments to claim 1. See the new rejections below.
Claim Rejections - 35 USC § 102
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1,9 and 24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by GenBank Accession No: AGA15926.1 (29 March 2013).
Regarding claim 1 (c) and (d), GenBank Accession No. AGA15926.1 teaches the amino acid sequence an adeno-associated virus VP1 capsid protein, shown below, was publicly available before the effective filing date.
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ABSS alignment between instant SEQ ID NO: 109 (Qy) and the above amino acid sequence of GenBank Accession No. AGA15926.1 (Db) shows 6 contiguous amino acids equivalent to positions 663-668 are substituted and therefore teaches limitation c) of claim 1 of five or more contiguous amino acid residues functionally equivalent to amino acids 656-669 of the AAV9 VP1 protein (SEQ ID NO: 1) have been deleted or substituted or a combination thereof. The alignment also shows 5 contiguous amino acids equivalent to positions 706-710 are substituted and thereof teaches limitation d) of claim 1 of five or more contiguous amino acid residues functionally equivalent to amino acids 692-736 of the AAV9 VP1 protein of SEQ ID NO: 109 have been deleted or substituted or a combination thereof. See below.
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Regarding claim 9, GenBank Accession No. AGA15926.1 teaches substitution by a peptide segment. The instant specification discloses that the peptide segment is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12 or 15 amino acids in length (paragraph 0009). Therefore, one or more substituted amino acids within the range of aa positions 656-669 or 692-736 of SEQ ID NO: 1 reads on the instant claims. See the above alignment, showing one or more substituted amino acids within the recited amino acid range, and which would therefore be peptide segments.
Regarding claim 24, the preamble recites a variant adeno-associated virus capsid, and the body of the claim only requires “comprising a variant AAV capsid protein of claim 1”. Therefore, as GenBank Accession No. AGA15926.1 teaches the limitations of claim 1, it also teaches claim 24.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over GenBank Accession No: AGA15926.1 as applied to claims 1,9 and 24 above, and further in view of Feiner et al. (Int. J. Mol. Sci. 14 Nov 2019, 20, 5702), previously cited.
Claim Interpretation: The instant specification discloses “In some embodiments, the peptide segment is a flexible peptide segment. In some embodiments, the flexible peptide segment is a G/S-rich peptide segment. In some embodiments, the flexible peptide segment is a peptide (G/S)n. In some embodiments, n is a position integer that is smaller than 21” (paragraph 0009). Therefore, a G/S rich peptide would be considered to be a flexible peptide segment.
The teachings of GenBank Accession No: AGA15926.1 as applied to claims 1,9 and 24 are described above.
GenBank Accession No: AGA15926.1 does not teach a substitution by a flexible peptide segment.
However, before the effective filing date, Feiner et al. teach rAAV’s provide outstanding options for customization and superior capabilities for gene therapy, and to access their full potential, facile genetic manipulation is pivotal, including capsid loop modifications (Abstract). Feiner et al. teach that flexible glycine-serine linkers of increasing sizes were introduced into the 587 loop region of the VP proteins of serotype 2 (Abstract and Intro, page 2). Feiner et al. teach glycine-serine linkers were chosen because of their flexibility and solubility, resulting in incremental changes correlating with length (Section 2.2, page 5). Feiner et al. teach production yields equal to that of rAAV wt showed compatibility with capsid assembly and regarding transduction, observed a significant impact of increasing insertion size with a non-linear decrease. The insertion of eight amino acids (GGSG)2 showed a significantly higher transduction compared to four amino acids (GGSG) (Section 3 Discussion, page 11).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to have modified the variant AAV VP1 capsid protein of GenBank Accession No. AGA15926.1 to include a substitution which is a flexible peptide segment in the recited amino acid positions according to the teachings of Feiner et al. with a reasonable expectation of success. There would be a reasonable expectation of success as Feiner et al. pertains to rAAV capsids and engineering and modification thereof for use in gene therapy and would amount to applying a known technique of capsid modification to a known product, ready for improvement to yield predictable results. One of ordinary skill in the art would have been motivated to modify the variant VP1 capsid protein of GenBank Accession No. AGA15926.1 to include a substitution which is a flexible peptide segment because Feiner et al. teach for rAAVs to access their full potential, facile genetic manipulation is pivotal, including capsid loop modifications and teach glycine-serine linkers of various sizes were chosen because of their flexibility and solubility and that production yields equal to that of rAAV wt showed compatibility with capsid assembly and regarding transduction, observed a significant impact of increasing insertion size with a non-linear decrease. The insertion of eight amino acids (GGSG)2 showed a significantly higher transduction compared to four amino acids (GGSG) (Section 3 Discussion, page 11).
Accordingly, the limitations of claim 11 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 25,28,46 and 82 are rejected under 35 U.S.C. 103 as being unpatentable over GenBank Accession No: AGA15926.1 as applied to claims 1,9 and 24 above, and further in view of During (US 20190085358, Published 21 Mar. 2019), previously cited.
The teachings of GenBank Accession No: AGA15926.1 as applied to claims 1,9 and 24 are described above.
GenBank Accession No: AGA15926.1 does not teach a plurality of multimers each comprising two or more AAV capsid proteins, or a variant AAV capsid and a heterologous nucleic acid, or a composition comprising the variant AAV capsid protein and a pharmaceutically acceptable carrier.
However, before the effective filing date, During teach rAAVRec2 and rAAVRec3 vectors have increased tropism to adipose and CNS tissue, respectively, and contain modifications of amino acid residues in the capsid VP1, VP2 and VP3 regions compared to those found in wild type AAV2 and AAV5 (paragraph 0004). During teach novel rAAV capsid proteins, as well as nucleic acids coding for the novel capsids are provided (paragraph 0005). During teaches the rAAV vectors contain modifications of amino acid residues in the capsid encoding VP1, VP2 and VP3 regions as compared to wild type AAV2 and AAV5, and display improved efficiency in transduction of a variety of cells, tissues and organs of interest. During also recites a nucleic acid molecule coding for: (i) one or more of the rAAVRec2 VP1, VP2 or VP3 sequences set forth in Fig. 1A; and/or (ii) one or more of the rAAVRec3 VP1, VP2 or VP3 sequences set forth in Fig. 1A (claim 1), with claim 2 reciting the nucleic acid comprises a recombinant adeno-associated virus (AAV) vector. Therefore, During recites an AAV capsid comprising a plurality of multimers, each comprising two or more AAV capsid proteins, as well as that the multimers differ with respect to the capsid protein isoforms (VP1, VP2, VP3).
During recites an AAV vector comprising one or more of the rAAVRec2 VP1, VP2 or VP3 sequences set forth in Fig. 1A; and/or one or more fAAVRec3 VP1, VP2 or VP3 sequences set forth in Fig. 1A; and a heterologous polynucleotide sequence, wherein the heterologous polynucleotide sequence is wild type TSC1, wild type TCS2 or wild type SMA gene (claim 8). The examiner is interpreting the heterologous polynucleotide sequence encoding the wild type TSC1, wild type TCS2 or wild type SMA gene as reading on a payload RNA agent of instant claim 46.
During teach pharmaceutical compositions containing rAAVRec2 or rAAVRec3 vectors, and which compositions may contain a pharmaceutically acceptable carrier (paragraphs 0010, 0047). During teach such compositions can be formulated by conventional methods and can be administered to the subject at a suitable dose, and can determine a dosage range to effectively treat a patient having a particular disease or disorder (paragraph 0048).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to have incorporated the AAV VP1 capsid protein of GenBank Accession No. AGA15926.1 with a plurality of multimers each comprising two or more AAV capsid proteins, and wherein the variant AAV capsid comprise two or more multimers that differ with respect to the capsid protein isoforms as taught by During, with a reasonable expectation of success. There would be a reasonable expectation of success, as this would have amounted to combining known prior art elements, ready for improvement. One of ordinary skill in the art would have been motivated to do so because During teach rAAVRec2 and rAAVRec3 vectors have increased tropism to adipose and CNS tissue, respectively, and contain modifications of amino acid residues in the capsid VP1, VP2 and VP3 regions and display improved efficiency in transduction of a variety of cells, tissues and organs of interest, and recite a combination of one or more rAAVRec2 VP1, VP2 or VP3 sequences and/or one or more rAAVRec3 VP1, VP2 or VP3 sequences.
Accordingly, the limitations of claims 25 and 28 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to have incorporated the AAV VP1 capsid protein of GenBank Accession No. AGA15926.1 with a heterologous nucleic acid comprising a polynucleotide encoding a payload RNA agent, and to have incorporated the AAV VP1 capsid protein of GenBank Accession No. AGA15926.1 with a pharmaceutically acceptable carrier to form a composition based on the teachings of During with a reasonable expectation of success. There would be a reasonable expectation of success, as both GenBank Accession No. AGA15926.1 and During pertain to variant AAV capsid proteins. One of ordinary skill in the art would be motived to incorporate the VP1 capsid protein of GenBank Accession No. AGA15926.1 with a heterologous nucleic acid comprising a polynucleotide encoding a payload RNA agent, in order to deliver the heterologous polynucleotide sequence to a mammal, and would be motivated to provide the VP1 capsid protein of GenBank Accession No. AGA15926.1 with a pharmaceutically acceptable carrier in order to provide a composition for treatment of a patient having a particular disease or disorder according to During.
Accordingly, the limitations of claims 46 and 82 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over GenBank Accession No: AGA15926.1 and During as applied to claims 25,28,46 and 82 above, and further in view of Feiner et al. (Int. J. Mol. Sci. 14 Nov 2019, 20, 5702), cited above.
The teachings of GenBank Accession No: AGA15926.1 and During as applied to claims 25,28,46 and 82 are described above.
GenBank Accession No: AGA15926.1 and During do not teach wherein two or more AAV capsid proteins are connected by a linker.
However, before the effective filing date, Feiner et al. teach rAAV’s provide outstanding options for customization and superior capabilities for gene therapy, and to access their full potential, facile genetic manipulation is pivotal, including capsid loop modifications (Abstract). Feiner et al. teach that flexible glycine-serine linkers of increasing sizes were introduced into the 587 loop region of the VP proteins of serotype 2 (Abstract and Intro, page 2). Feiner et al. teach glycine-serine linkers were chosen because of their flexibility and solubility, resulting in incremental changes correlating with length (Section 2.2, page 5). Feiner et al. teach production yields equal to that of rAAV wt showed compatibility with capsid assembly and regarding transduction, observed a significant impact of increasing insertion size with a non-linear decrease. The insertion of eight amino acids (GGSG)2 showed a significantly higher transduction compared to four amino acids (GGSG) (Section 3 Discussion, page 11).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to further modify the AAV VP1 capsid protein of GenBank Accession No. AGA15926.1 and a plurality of AAV capsid protein multimers as taught by During, with the peptide linker of Feiner et al. with a reasonable expectation of success. There would be a reasonable expectation of success as GenBank Accession No. AGA15926.1, During and Feiner et al. all pertain to rAAV capsids. This would amount to applying a known technique of rAAV capsid modification to a known product, ready for improvement to yield predictable results. One of ordinary skill in the art would have been motivated to provide a linker to connect two of the two or more AAV capsid proteins of each of the multimers of the VP1 capsid protein of GenBank Accession No. AGA15926.1 and the one or more rAAVRec2 VP1, VP2 or VP3 sequences and/or one or more rAAVRec3 VP1, VP2 or VP3 sequences, because
Feiner et al. teach for rAAVs to access their full potential, facile genetic manipulation is pivotal, including capsid loop modifications and teach glycine-serine linkers of various sizes were chosen because of their flexibility and solubility and that production yields equal to that of rAAV wt showed compatibility with capsid assembly and regarding transduction, observed a significant impact of increasing insertion size with a non-linear decrease. The insertion of eight amino acids (GGSG)2 showed a significantly higher transduction compared to four amino acids (GGSG) (Section 3 Discussion, page 11).
Accordingly, the limitations of claim 26 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Conclusion
Claims 1,9,11,24-26,28,46 and 82 are rejected.
Claim 3-8 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHANIE L SULLIVAN whose telephone number is (703)756-4671. The examiner can normally be reached Monday-Friday, 7:30-3:30 EST.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636