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
The text of those sections of Title 35, U.S. Code not included in this action can be found
in a prior Office action.
This application is in response to the papers filed on November 10, 2025. Pursuant to the amendment filed on November 10, 2025, claims 1, 15, 20, 28, 35, 108-110, 123, 126, 131-133, 164-210 are currently pending of which claims 1, 15, 20, 28, 35, 108-110, 123, 131-133, and 164 have been amended, claims 165-210 are newly added, and claims 2-5, 11, and 163 have been cancelled.
The Restriction Requirement set forth in the Office Action of December 6, 2024 was withdrawn between Groups I-V based on the amendments to the claims as stated in the Nonfinal Rejection; however, the Restriction Requirement was maintained for Groups VI-X, and specifically for pending claims 123, 126, and 132-133 despite the amendments to these claims. Furthermore, in view of the amendment filed on November 10, 2025, claims 198-207, which are dependent on claim 123, have been withdrawn since these claims are dependent upon withdrawn claims that are directed to a method of producing the recombinant AAV particle which were restricted to Group IX. The Restriction Requirement between Groups I-V and VI-X was previously made FINAL.
Therefore, claims 1, 15, 20, 28, 35, 108-110, 131, 164-197, and 208-210 are currently 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 the International Application No. PCT/US2020/034328, filed May 22, 2020. Applicant’s claim for the benefit of a prior-filed parent provisional application 62/852,791 filed on May 24, 2019 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is May 24, 2019.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on November 10, 2025 (two total), and March 6, 2025 were filed. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Furthermore, the Examiner was incorrect in their previous correspondence regarding the information disclosure statement filed March 6, 2025 missing the appropriate size fee assertion, and therefore has now been considered.
Response to Arguments
Withdrawn Objections/Rejections in response to Applicants’ arguments or amendments:
Specification
In view of the Amendment to the Specification dated November 10, 2025, wherein the embedded hyperlink and/or other form of browser-executable code have been removed, the objection to the Specification has been withdrawn accordingly.
Claim Objections
In view of the Amendment to the Claims dated November 10, 2025, wherein claim 109 has been amended, the objection to claim 109 has been withdrawn accordingly.
Claim Rejections - 35 USC § 112
In view of Applicants’ amendment to the claims dated November 10, 2025, wherein claims 1, 15, 20, 28, 35, 108-110, 123, 131-133, and 164 have been amended, and claims 2-5, 11, and 163 have been cancelled, the rejection to claims 1, 15, 28, 108-110, 131 and 164 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, are withdrawn, and the rejection to now cancelled claims 2-5, 11, and 163 have been rendered moot.
The rejection for claim 20 is maintained as listed below based on there being specific amino acid locations described in the claim, and there being no SEQ IDs provided therein to determine if such amino acid positions are accurate and defined in the art. Additionally, claim 35, remains rejected in relation to bullets (dd) and (ee) as explained below.
Claim Rejections - 35 USC § 103
In view of Applicants’ amendment to the claims dated November 10, 2025, wherein claims 1, 15, 20, 28, 35, 108-110, 123, 131-133, and 164 have been amended, and claims 2-5, 11, and 163 have been cancelled, the rejection to claims 1-5, 11, 15, 20, 28, 35, 108-110, 131 and 163-164 rejected under 35 U.S.C. 103 as being obvious over Kotin et al (US Publication No. 2017/0130245-A1, publication date May 11, 2017) as evidenced by NCBI Blast Sequence Alignments, are withdrawn.
The withdrawn rejections is in view of the extensive amendments to the claims in which claim 1 has been amended to specify “wherein the AAV capsid protein comprises at least an AAV VP3 amino acid sequence of an avian AAV (AAAV) capsid protein, a sea lion AAV capsid protein, or a squamate AAV capsid protein,” and “wherein the AAV capsid is modified to comprise at least a first member of a protein:protein binding pair ("first member").” The Kotin reference fails to explicitly teach a protein:protein binding pair.
Response to Applicants’ Arguments as they apply to rejection of claims under 35 USC § 103
Applicant’s arguments with respect to claims 1-5, 11, 15, 20, 28, 35, 108-110, 131 and 163-164 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Maintained Objections/Rejections in response to Applicants’ arguments or amendments:
Claim Rejections - 35 USC § 112
Claims 20 and 35 remain 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.
Claim 20 remains rejected for not providing SEQ IDs for the VP1 capsid protein of AAAV, VP1 capsid protein of a bearded dragon AAV, and the VP1 capsid protein of a sea lion AAV. The claim recites particular positions at which the different VP1 proteins have a first member of a protein:protein binding pair wherein specific amino acids are listed, yet there is no way to ascertain these locations are accurate and known in the art. For example, there are variants of these AAVs as seen in Table 2 of the instant Specification, and consequently there may be differences found at these amino acid positions. With this being said, SEQ IDs are required to clarify the positions claimed are true. Additionally, it is unclear if the coding region is for the entirety of the VP proteins (VP1-3), or rather just VP1. Lastly, the claim does not properly list positions with a particular amino acid and corresponding location (e.g., G123 [glycine, location 123]), but appears to only list the location, and not the amino acid found therein. This is corroborated with Fig 3B. describing G444 and K580 for AAAV, Fig 4B. and 5B describing N429, P430, T431, G432, S433, T434, R436, D437, and A565 for sea lion AAV, and Fig 6B describing G436 and T573 for bearded dragon AAV. Clarification is required.
Claim 35 is indefinite in view of the SEQ ID NOs provided, in particular the claim recites SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 53, 55, 57, 59, 61, 63, 65, 67, 69, and 71, and in steps: “(dd) an amino acid sequence of any AAV VP2 portions of the amino acid sequences set forth in any of (a)-(cc), and (ee) an amino acid sequence of any AAV VP3 portions of the amino acid sequences set forth in any one of (a)-(cc). However, without any specific locations described for the respective VP2 & VP3 protein within the claimed sequences, the limitations presented in (dd) and (ee) are considered indefinite.
New Grounds of Rejection:
Claim Rejections - 35 USC § 103
Claims 1, 108, 109, 110, 131, 164-166, 168-170,176, 182-197, and 208-210 are newly rejected under 35 U.S.C. 103 as being obvious over Li et al (US Publication No. 2018/0371496 A1, publication date December 27, 2018; of record IDS filed September 22, 2022(Cite No. A44)) in view of Bossis et al. (Journal of virology 77.12 (2003): 6799-6810;of record IDS filed September 22, 2022 (Cite No. C15)).
This is a new rejection necessitated by Applicants’ amendments to the claims in the response filed on November 10, 2025.
Claim 1 is directed to a recombinant adeno-associated virus (AAV) particle comprising: (i) an AAV capsid comprising an AAV capsid protein, wherein the AAV capsid protein comprises at least an AAV VP3 amino acid sequence of an avian AAV (AAAV) capsid protein, a sea lion AAV capsid protein, or a squamate AAV capsid protein, and (ii) packaged within the AAV capsid, a viral genome, wherein the AAV capsid is modified to comprise at least a first member of a protein:protein binding pair ("first member").
Li teaches a recombinant adeno-associated virus (AAV) particle comprising a capsid wherein the VP proteins are derived from different AAV serotypes, in particular wherein the VP3 is from a different AAV serotype (abstract); “In an alternative embodiment, a virion particle can be constructed wherein at least one viral protein from the group consisting of AAV capsid proteins, VP1, VP2 and VP3, is different from at least one of the other viral proteins, required to form the virion particle capable of encapsidating an AAV genome” (0015). Li describes the produced recombinant AAVs that comprise capsid proteins from different serotypes can have advantages such as improved transduction without eliminating tropism, and furthermore have the ability to escape the neutralization by neutralizing antibodies (NAbs) (0010).
In reference to the AAVs described, Li teaches the AAV serotypes include avian AAV (AAAV), and states the capsid proteins can be from AAAV (par 0081, 0149 0233; Table 1). Li states, “the AAV capsid proteins and virus capsids of this invention can be chimeric in that they can comprise all or a portion of a capsid subunit from another virus, optionally another parvovirus or AAV” (0150). In reference to the capsid comprising a protein:protein binding pair, Li teaches the virus capsid can be a targeted virus capsid comprising a targeting sequence (e.g., substituted or inserted in the viral capsid) that directs the virus capsid to interact with cell-surface molecules present on a desired target tissue(s) (0273-0278).
Li et al. does not teach the specific AAAV VP3 protein, but rather teaches the AAAV serotype with corresponding sequence, which encompasses the respective VP3 sequence, and moreover teaches capsid proteins from AAAV being combined with other capsid proteins to form a recombinant AAV. It is noted that Li references Bossis et al. as cloning AAAV particles.
Bossis teaches the cloning of AAAV wherein the VP3 sequence is mapped out and matched to AAV2, AAV4, and AAV5 as depicted in Fig. 4. Furthermore, in relation to sequence conservation Bossis states, “The N terminus of VP1 (aa 1 to 143), which is required for particle formation, is relatively conserved among AAAV, AAV2, AAV4, AAV5, and GPV. However, the start sites for VP2 and VP3 are found in a divergent region… most of the divergent regions among AAAV, AAV2, AAV4, AAV5, and GPV are located on the exterior of the virus, thus suggesting different uptake mechanisms and altered tissue tropism.” (p 6805, col 2). Bossis further describes, “Transduction efficiency of rAAAV was 10- to 300-fold higher in avian cells than in rAAV2, rAAV4, and rAAV5. In contrast, transduction of the mammalian cells in the panel by rAAAV was almost absent. This observation suggests that AAAV is using a different uptake or transduction mechanism compared with the primate AAVs.” (p 6807, col 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the VP3 of a recombinant AAV capsid with an avian VP3 protein, based on Li teaching the method of utilizing different AAV serotype capsid proteins that includes AAAV, with the specific AAAV VP3 taught by Bossis because it would have been obvious to combine prior art elements according to known methods to yield predictable results. In particular, Bossis teaches the full sequences of AAAV with VP3 mapped out, and further describing the AAAV as having improved transduction for avian cells in comparison to select AAV serotypes. Therefore, it would be obvious to select for AAAV VP3 in the recombinant AAV of Li that is comprised of different AAV capsid proteins, as there is an expectation that such vector would also have improved transduction in avian cells. Moreover, Li also teaches transduction efficiency can be improved when different AAV capsid proteins are be combined, and furthermore may also lead improvements in preventing neutralization by a host immune system.
Regarding claim 108, dependent on claim 1, Li teaches a packaging cell for producing the recombinant AAV particle, comprising a nucleic acid molecule comprising an AAV cap gene encoding the AAV capsid protein (0300-0302).
Regarding claims 109 and 110, dependent on claim 108, Li teaches the packaging cell of claim 108, comprising a nucleic acid molecule comprising a rep gene encoding one or more AAV Rep proteins, wherein said rep gene is operably linked to a promoter (0302, 0345). Furthermore, Bossis teaches the P5 and P19 promoters in AAV driving expression of the Rep proteins, particularly Rep78, Rep68, Rep52 and Rep40 (p 6799, col 1). The reference further describes the avian p19 and p40 promoters were identifiable based on homology to primate AAV serotypes (p 6805, col 1; Fig. 5).
Regarding claim 131, dependent on claim 1, Li teaches a pharmaceutical composition comprising (a) the recombinant AAV particle and (b) a pharmaceutically acceptable carrier or excipient (0213).
Regarding claim 164, dependent on claim 1, Li teaches wherein the AAV capsid protein further comprises a detectable label as seen in describing viral vectors can express epitopes and reporter polypeptides (0333, 0342). Furthermore, Li states the capsid proteins can have modified targeting sequences to chemically link molecules of interest to the AAV capsid protein, and also describes using poly-His tags (0274, 0222).
Regarding claim 165, dependent on claim 1, Li teaches wherein the AAV capsid protein comprises a non-chimeric AAV amino acid sequence based on teaching VP1 and VP2 are chimeric and only VP3 is non-chimeric or VP3 is chimeric and VP1 and VP2 are non-chimeric (0015).
Regarding claim 166, dependent on claim 1, the instant specification describes “VP1 comprises at its N-terminus sequence that it does not share with the VP2 or VP3, referred to as the VP1-unique region (VP1-u).” (par 0171). Li teaches wherein the AAV capsid protein comprises a VP1-unique region of a primate AAV capsid protein in teaching the VP1 can be from AAV across the serotypes listed in Table 1, which includes AAVs that infect primates (AAV1-AAV12).
Regarding claim 168, dependent on claim 1, Li teaches wherein the recombinant AAV particle infects a mammalian host cell (0330, 0376).
Regarding claim 169, dependent on claim 1, the rejection above to claim 1 makes obvious that a capsid protein can be derived from avian AAV to be combined with capsid proteins from other AAV serotypes, and therefore makes obvious this claim. The reference teaches the VP1/2 region may be from the same serotype, e.g. AAAV, while the VP3 is of a different serotype (par 0015, Table 1).
Regarding claim 170, dependent on claim 164, the claim recites SEQ ID Nos: 44 and 45 which encode c-myc and B1 tags, respectively. The Li reference teaches using a B1 antibody specific to the AAV capsid proteins of AAV2 and AAV8, and therefore is expected to teach SEQ ID No: 45 (680, 861). The reference list several AAV vectors in Table 1, and the AAV2 accession listed, NC_001401, depicts the B1 sequence located on VP1-3 as seen in the alignment provided starting on page 3 (provided with this Office Action, under the name “GenBankAAV2_ NC001401_B1seqeunce(SEQIDNO45)”). Altogether, it would be obvious to use a B1 tag as listed in SEQ ID No:45 as this is sequence is conserved across the VP proteins of AAV2 and AAV8.
Regarding claim 176, dependent on claim 1, Li teaches wherein the recombinant AAV particle further comprises a reference AAV capsid protein such that the AAV capsid is a mosaic AAV capsid (“One approach for generating rAAV with mixed or mosaic capsid shells has been to add AAV helper plasmids encoding the capsid proteins (VP1, VP2, and VP3) from a mixture of AAV serotypes.” (0011)).
Regarding claim 182, the rejection to claim 1 is applied herein in which Li teaches wherein the AAV capsid comprises: (a) a chimeric AAV VP1 capsid protein comprising:
Regarding claim 183, Li teaches wherein the viral genome comprises an AAV Inverted Terminal Repeat (ITR) sequence (0107, 0302).
Regarding claim 184, dependent on claim 183, Li teaches wherein the AAV ITR sequence is a primate animal AAV ITR sequence by describing the sequences can be from “serotypes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 or any other AAV now known or later discovered (0108).
Regarding claim 185, dependent on claim 183, Li teaches wherein the viral genome further comprises a polynucleotide of interest operably linked to one or more AAV ITR sequence (0106, 0343).
Regarding claim 186, dependent on claim 185, Li teaches wherein the polynucleotide of interest is a reporter gene (“Heterologous nucleic acid sequences encoding polypeptides include those encoding reporter polypeptides” (0333)).
Regarding claim 187, dependent on claim 186, Li teaches wherein the reporter gene encodes a reporter protein that comprises Green Fluorescent Protein (GFP), luciferase, β-galactosidase, alkaline phosphatase, luciferase, or chloramphenicol acetyltransferase gene (0333).
Regarding claim 188, dependent on claim 185, Li teaches wherein the polynucleotide of interest encodes a therapeutic protein (“therapeutic polypeptide”; 0350-0353).
Regarding claim 189, dependent on claim 109, Li teaches wherein the rep gene and the cap gene are from two different AAV (“In a further experiment, two helper plasmids are again used with different AAV serotypes as the source for the Rep and Cap genes.” (0733)).
Regarding claim 190, dependent on claim 110, Bossis teaches the p5, p19 and CMV promoters (p 6805, col 2).
Regarding claims 191-194, all dependent on claim 109, Li teaches using Rep proteins and related sequences required for AAV replication (0082, 0302-0303). Li does not specify as to the particular Rep proteins, but rather states they are known in the art (0082). In reference to rep proteins being primate AAV Rep proteins (claim 193) or rather non-primate AAV Rep proteins (claim 194), Li teaches using Rep proteins and/or sequences from different viral or non-viral vectors. Bossis teaches the AAV Rep proteins: Rep78, Rep68, Rep52 and Rep40, and teaches the Rep sequences of non-primate AAVs, e.g. AAAV, and primate AAVs, e.g. AAV2, AAV5, and AAV5 (p 6799, col 1; Fig. 4).
Regarding claim 195, dependent on claim 109, the rejection to claims 183-185 describe the AAV ITRs, and the rejection to claims 191-194 teach the Rep proteins of the AAV vector. Furthermore, Li teaches Bossis teaches the ITRs serve as origin of replication, and contain cis-acting elements required for
rescue, integration, excision from cloning vectors, and packaging (p 6799, col 1). Therefore, it is expected the included Rep proteins would interact with the employed ITR sequences as it is required for replication.
Regarding claim 196, dependent on claim 195, the rejection to claims 183-185 describe the AAV ITRs are from either the same or different AAVs, and therefore make obvious the instant claim.
Regarding claim 208, dependent on claim 1, Li teaches wherein the AAV capsid protein further comprises a point mutation (“Further, the viral capsid or genomic elements can contain other modifications, including insertions, deletions and/or substitutions.” (0111)).
Regarding claim 209, dependent on claim 208, Li teaches wherein the point mutation reduces the natural tropism of the AAV particle as seen in describing an example wherein the capsid proteins were modified, and reduced tropism was observed for the liver (0214, 0274). Li also states, “Capsid mutation may change AAV tropism and transduction efficiency.” (0692).
Regarding claim 210, the rejection to claim 186 and 187 describe the AAV vectors as including reporters, e.g. GFP, luciferase, and the rejection to claim 210 describes the capsid proteins as containing point mutations. Therefore, it would be obvious to modify the AAV capsid protein in a way for the detectable label to function such as by including functional mutations, and moreover it would be obvious to do so based on the reporter sequences being used in the AAV vectors all of which is taught by Li.
Claims 1, 15 are newly rejected under 35 U.S.C. 103 as being obvious over Li et al (US Publication No. 2018/0371496 A1, publication date December 27, 2018; of record IDS filed September 22, 2022(Cite No. A44)) in view of Bossis et al. (Journal of virology 77.12 (2003): 6799-6810;of record IDS filed September 22, 2022 (Cite No. C15)), as applied to claim 1, and in further view of Penzes et al. (Journal of General Virology 96.9 (2015): 2769-2779; of record IDS filed September 22, 2022 (Cite No. C120)).
This is a new rejection necessitated by Applicants’ amendments to the claims in the response filed on November 10, 2025.
Regarding claim 1, the disclosure of Li in view of Bossis is applied as in the 103 rejections above, the content of which is incorporated above, in its entirety.
Regarding claim 15, dependent on claim 1, Li does not teach wherein the squamate AAV capsid protein is a bearded dragon AAV capsid protein, but rather teaches the avian AAAV capsid protein that is combined with other AAV capsids. Bossis teaches an AAAV capsid protein, not a bearded dragon AAV capsid.
Penzes teaches the complete genome analysis of the first lizard parvovirus (BDPV), obtained from four bearded dragons (Pogona vitticeps) wherein the complete genome sequence including the ITRs is identified as GenBank accession number “KP733794”. A sequence alignment is provided in Fig. 1 with other lizard viruses, organization of the BDPV genome is depicted in Fig. 3, and the phylogeny of Dependoparvovirus is depicted in Fig. 4.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the VP3 of a recombinant AAV capsid with a bearded dragon VP3 protein, based on Li teaching the method of utilizing different AAV serotype capsid proteins, and furthermore Penzes teaching the bearded dragon VP3 because it would have been obvious to combine prior art elements according to known methods to yield predictable results. In particular, Penzes teaches the full sequences of BDPV with the VP3 mapped out, and furthermore Li teaching recombinant AAV comprised of different AAV capsid proteins may have improved transduction efficiency for select target cells when different AAV capsid proteins are be combined, and furthermore may also lead improvements in preventing neutralization by a host immune system. Altogether, the combination of capsid proteins that comprises the bearded dragon VP3 taught by Penzes is expected to yield a predictable outcomes of a recombinant AAV capable of transduction of select cell types.
Claims 1, 20, 28, 167, 171-175, 178 and 179 are newly rejected under 35 U.S.C. 103 as being obvious over Li et al (US Publication No. 2018/0371496 A1, publication date December 27, 2018; of record IDS filed September 22, 2022(Cite No. A44)) in view of Bossis et al. (Journal of virology 77.12 (2003): 6799-6810;of record IDS filed September 22, 2022 (Cite No. C15)), as applied to claim 1, and in further view of Byrne et al. (US Publication No. 2020/0407751 A1)).
This is a new rejection necessitated by Applicants’ amendments to the claims in the response filed on November 10, 2025.
Regarding claim 1, the disclosure of Li in view of Bossis is applied as in the 103 rejections above, the content of which is incorporated above, in its entirety.
Regarding claim 20, dependent on claim 1, the rejection to claim 20 under 35 USC 112(b) above describes indefinite issues with determining the positions recited for the listed VP proteins, and therefore the insertion of a first member at those sites. However, despite this lack of clarity, Li describes the viral capsid or genomic elements can contain other modifications, including insertions, deletions and/or substitutions; and furthermore such modification between amino acids 575-600 of VP1 (0111, 0219).
Li in view of Bossis do not teach the insertion in relation to a first binding pair.
Byrne teaches an AAV wherein the capsid surface comprises one or more peptide tags that form a bond with a binding-partner, in which the peptide tag is a polypeptide that can form a bond with a binding-partner. Byrne further describes the suitable tags include SpyTag and its binding-partner SpyCatcher, SnoopTag and its binding-partner SnoopCatcher, and SpyTag002 and its binding-partner, SpyCatcher002 (0016-0018). The tag is engineered to be expressed on the surface of the AAV by mutating the genetic sequence encoding AAV polypeptides having extracellular domains to include such tags such as capsid proteins (0019, 0044). Byrne describes the purpose as “By expressing this peptide tag on the surface of the AAV virion and expressing a binding-partner on either another AAV or another protein, the inventive AAV vector can link (such as, for example, covalently link) capsids to each other and/or to proteins, creating a larger infectious unit. This highly flexible, expandable and modular system for delivery of genes and proteins into cells greatly expands the capabilities of AAV for gene and protein delivery” (0005).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the recombinant AAV taught by Li in view of Bossis to include a tag (first member of a protein:protein binding pair) in order to improve outcomes related to AAV delivery as described by Byrne. In particular, it would be obvious to further modify the AAV taught by Li in view of Bossis that contains a modified AAAV VP protein to contain a tag that is expected to interact with a binding-partner, and furthermore, such insertions would be obvious in view of Li describing the capsids can modified in such ways, and in view of Bossis teaching the full sequence of AAAV.
Regarding claim 28, dependent on claim 1, Byrne teaches the first member is selected from the group consisting of SpyTag and SpyTag002 (0016-0018).
Regarding claim 167, dependent on claim 1, Byrne teaches wherein the protein:protein binding pair directs the tropism of the AAV particle (“By linking together AAV capsids to form conjugates, the present invention can double (or more than double) the carrying capacity of AAV vectors, enabling delivery of large genes and multiple genes through obligate AAV coinfection. Furthermore, by tethering proteins to the outside of the AAV capsid, the present invention harnesses the tropism and infectivity of the virus while delivering biologically active proteins,” (0006)).
Regarding claim 171, dependent on claim 28, that is directed to wherein the first member comprises SpyTag comprising an amino acid sequence set forth as SEQ ID NO: 42, Byrne teaches the SpyTag sequence as part of other constructs wherein the provided sequences are listed in nucleic acid format. The instant SEQ ID NO: 42,‘AHIVMVDAYKPTK’, is expected to be encompassed in these sequences when translated. Moreover, GenBank lists this identical sequence as “Chain D, SpyTag” with a reference date of 2014 (provided with this Office Action, under the name “NCBI_SEQID42_SpyTag”). Altogether, the amino acid sequence of SpyTag as listed in SEQ ID No:42 was known at the time of filing of the claimed invention.
Regarding claims 172-173, dependent on claim 1, Byrne teaches using SpyTag/SnoopTag linkers to connect AAVs on the exterior surface via VP proteins. Byrne teaches AAVs can have various tags or linkers, in some case up to three linkers (Fig 1B), and in other cases more than three to form multimeric conjugate units (Fig. 1D) (0008, 0011).In reference to claim 173, Byrne teaches the first and second linker can be identical or not identical (0026-0029; Figure 1B,D).
Regarding claim 174, dependent on claim 172, Byrne teaches the linkers can be various sequences such as GSGGSGGSG as seen in SEQ ID NO: 5 and 6, or the TG_GLS linker as seen in SEQ ID NO: 1 and 2; and in view of using both a first and second linker, Byrne teaches the linkers 10 a.a. in length. Moreover, the reference describes using stiff linkers, long flexible linkers, and shorter linkers for SpyTag/SnoopTag/SpyTag002, and for VP2 (par 0028).
Regarding claim 175, dependent on claim 1, Byrne teaches wherein the first member, e.g. SpyTag, is operably linked to a variable region of the AAV capsid protein based on the SpyCatcher being attached to a VP2 or VP3 regions (0019).
Regarding claim 178, Byrne teaches wherein the AAV capsid protein further comprises a second cognate member of the protein:protein binding pair ("second cognate member"), wherein the first member and the second cognate member are bound by a covalent isopeptide bond (“an AAV comprising an exterior surface, which surface comprises one or more peptide tags that form a covalent bond with a binding-partner, wherein the AAV is a live virus. Linker peptides (tags) SpyTag and SnoopTag, and the specific binding-partner, SnoopCatcher, were engineered into surface exposed regions of the AAV capsid (0051-0052)).
Regarding claim 179, dependent on claim 178, Byrne teaches (i) the first member comprises SpyTag and the second cognate member comprises SpyCatcher; (iv) the first member comprises SnoopTag and the second cognate member comprises SnoopCatcher; (vi) the first member comprises SpyTag002 and the second cognate member comprises SpyCatcher002 (0018).
Claims 1, 178, 180-181 are rejected under 35 U.S.C. 103 as being obvious over Li et al (US Publication No. 2018/0371496 A1, publication date December 27, 2018; of record IDS filed September 22, 2022(Cite No. A44)) in view of Bossis et al. (Journal of virology 77.12 (2003): 6799-6810;of record IDS filed September 22, 2022 (Cite No. C15)), as applied to claim 1, and in further view of Byrne et al. (US Publication No. 2020/0407751 A1), and as applied to claim 178, and in further view of Alam et al. (ChemBioChem 18.22 (2017): 2217-2221).
This is a new rejection necessitated by Applicants’ amendments to the claims in the response filed on November 10, 2025.
Regarding claim 1 and 178, the disclosure of Li in view of Bossis and Byrne are applied as in the 103 rejections above, the content of which is incorporated above, in its entirety.
Regarding claims 180 and 181, Li in view of Bossis and Byrne teach the second cognate member can have attachments such as Cas9 for gene editing (Byrne 0009), and moreover, Li teaches the AAV can be used in delivery of monoclonal antibodies and antibody fragments thereof (Li 0332).
Li in view of Bossis and Byrne do not teach wherein the second cognate member is fused to a targeting ligand (claim 180), and wherein the targeting ligand is an antibody, or a portion thereof (claim 181).
Alam teaches using the SpyTag/SpyCatcher systems for the design of recombinant antibodies by combining the variable and constant regions together with such system, stating “This strategy will create optimized recombinant antibody devices at reduced costs and with shortened development times.” (abstract; Fig. 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have attached an antibody to the second cognate member, e.g. Spycatcher, based on Alam teaching that antibodies can be attached to the SpyTag:SpyCatcher system, and therefore there is an expectation that antibodies can be attached with this system on the claimed AAVs with a reasonable expectation of success, moreover there is a reason to do so based on Li teaching that antibodies can be attached to the AAV for delivery.
Claim Rejections - 35 USC § 112
Claims 176, 177, 182 and 197 are newly 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.
Claims 176, 177, and 197 are indefinite in the usage of “reference AAV capsid protein” and “reference capsid protein” as the scope of using “reference” is not clear. In particular, “reference” is described in the Specification on page 77, wherein it is described it is used in the context of testing the effects of a test viral particle. However, the claims are directed to a composition, and not a method of use, and therefore it is unclear how this limitation changes the scope of the structure for the claimed composition as there are no specific detail on what is considered a “reference” versus a “test” capsid protein.
Claim 182 is indefinite as it is unclear if (a), (b), (c) are in the alternative or rather all comprised in the AAV capsid. In particular, it is unclear how in (a) the chimeric VP1 contains VP1/2 and VP3 sequences, and furthermore, it is how these sequences are included in view of (b) and (c) that also includes VP2 and VP3 sequences respectively, but are not chimeric. For these reasons the claim scope is indefinite, and clarification is required.
Conclusion
Claims 1, 15, 20, 28, 35, 108-110, 131, 164-197, and 208-210 are rejected. No claims are 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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/MICHAEL ANGELO RIGA/ Examiner, Art Unit 1634
/TERESA E KNIGHT/ Primary Examiner, Art Unit 1634