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 .
Application Status
The Amendments and Remarks filed 20 November 2025 in response to the Office Action 27 August 2025 are acknowledged and have been entered. Claim 1 is amended. Claims 2-9, 12-13, 15-23, 26-32, 35, 38-44, 47-74, 77 are cancelled. Claims 1, 10-11, 14, 24-25, 33-34, 36-37, 45-46 and 75-76, 78-88 are pending. Claims 46 and 85-86 are withdrawn as being drawn to a nonelected invention Claims 1, 10, 11, 14, 24-25, 33-34, 36-37, 45, 75-76, 78-84, and 87-88 are under examination on the merits.
Any objection or rejection not reiterated herein has been withdrawn in view of applicant’s claim amendments.
Priority
The instant application is a 371 PCT of application US2018/039878 filed 06/27/2018 which claims priority to application 62/525,708 filed 06/27/2017.
Information Disclosure Statement
The information disclosure statement filed 10/1/2004 has been considered.
Claim Rejections - 35 USC § 103
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.
Claims 1, 10-11, 14, 24-25, 33, 37, 75-76, 78-84, and 87-88 are rejected under 35 U.S.C. 103 as being unpatentable over Ried (Ried et al. (2002); J. Viral. 76(9):4559-4566) in view of Arnold (Arnold et al. Molecular Therapy Vol. 14, No. 1, July 2006, cited on the Information Disclosure Statement filed 11/20/2025), Boucas (Boucas et al. J Gene Med 2009; 11: 1103–1113, cited on the Information Disclosure Statement filed 11/20/2025), Mali (US 2020/0340012 A1; provisionally filed 4/4/2017), and Veggiani (Veggiani et al. Trends Biotechnol. 2014 October ; 32(10): 506–512).
Regarding claims 1, 11, 14, 24-25, and 33 Ried teaches a versatile recombinant adeno-associated virus (rAAV) vector targeting system which would allow one to redirect rAAV binding to specific cell surface receptors by simple coupling of different ligands to its capsid [abstract]. Ried teaches the insertion of an immunoglobulin G (IgG) binding domain of protein A, Z34C, into the adeno-associated virus type 2 (AAV2) capsid protein at amino acid position 587 (i.e., heterologous amino acid sequence comprising a first member of a protein:protein binding pair) [abstract; Fig. 1]. Ried teaches that the rAAV2-Z34C vectors can be coupled to antibodies against CD29 (β1-integrin), CD117 (c-kit receptor), and CXCR4 (i.e., targeting ligand, antibody) specifically and allowed the vectors to transduce distinct human hematopoietic cell lines, thereby retargeting the rAAV vectors to specific cell surface receptors. [abstract].
Although Reid teaches insertion of Z34C in to the AAV2 capsid at amino acid position 587, Reid do not teach that this position is an exposed variable loop. Ried do not teach that the immunoglobulin G (IgG) binding domain of protein A, Z34C is a peptide tag and that the viral capsid protein further comprises a second cognate member of the protein:protein binding pair, wherein the first member and the second cognate member are bound by an isopeptide bond.
Arnold teaches the development of multiple targeted AAV vectors utilizing a single capsid modification via straightforward avidin–biotin ligand coupling [abstract]. Arnold teaches that there are sites within the AAV2 capsid gene known to permit the addition of exogenous sequences, of which two are within the VP1/VP2 unique region and three are located within the VP3 region of the AAV2 Cap ORF [pg. 98, col. 2, para 2]. Arnold teaches the selection of sites in serotype 1, 3, 4, and 5 Cap ORFs based on structural similarity to the surface-exposed loop region of the AAV2 capsid protein defined by amino acids 584–590 [pg. 98, col. 2, para 2]. Thereby Arnold teaches that amino acid 587 of AAV2 capsid is in the surface-exposed loop.
Boucas teaches that most reported targeting approaches are based on insertion of small peptide ligands within the cap open reading frame (ORF) [pg. 1104, col. 1, para 2]. Boucas teaches that this ORF codes for three structural proteins [(VP1 (90 kDa), VP2 (72 kDa) and VP3 (60 kDa)] that share most of their amino acid sequence and that build up the capsid in a 1 : 1 : 10 ratio [pg. 1104, col. 1, para 2]. Boucas teaches that preferred sites for peptide insertion in AAV serotype 2 capsids are amino acid positions 587 and 588 (according to VP1 numbering), which are located in a region common to all three capsid proteins [pg. 1104, col. 1, para 2].
Mali teaches an AAV capsid engineered to comprise SpyTag or a KTag [0019] in order to selectively deliver Cas9 to cells that express KTag or SpyTag, respectively, on its surface [230-231]. Mali teaches that SpyTag or KTag is incorporated at amino acid residue R447, S578, N587 or S662 of VP1 [0021]. Mali teaches that when a SpyTag is incorporated onto the capsid pseudotyping can be achieved through click chemistry which involves the conjugation of a KTag to the moiety to be pseudotyped [0229]. Thereby Mali teaches the ability to use the SpyTag/ KTag protein:protein binding pairs in order to change viral tropism.
Veggiani teach that an ideal interaction between proteins would be covalent, specific, require addition of only a peptide tag to the protein of interest, and form under a wide range of conditions [abstract]. Veggiani teach that a direct isopeptide bond formation between the irreversible peptide-peptide interaction of SpyTag and KTag or SpyCatcher and SpyTag can be used to direct affibodies or antibodies to the surfaces of cells [pg. 4, para 2; pg. 5, para 1; Fig. 2, 3, 4; abstract]
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to try to genetically fuse the SpyTag of Mali to the AAV2 capsid of Ried, instead of Z34C, at amino acid position 587, which is within an exposed variable loop, and conjugate the CD29, CD117, and CXCR4 antibodies to SpyCatcher or KTag which are capable forming an irreversible isopeptide bond with a SpyTag. One of ordinary skill would be motivated to make the modification given the teachings of Arnold and Boucas that the preferred sites for peptide insertion in AAV serotype 2 capsids are amino acid positions in the exposed variable loop. One of ordinary skill would also be motivated to make the modification to SpyCatcher or KTag since the substitution and rearrangement of parts will achieve the same result of retargeting the AAV vector of Reid to a tissue or cell type of interest and the use of the peptide tags would create an ideal covalent interaction that is irreversible as taught by Veggiani. The combination of prior art elements according to known methods to yield predictable results supports can support a conclusion of obviousness. See MPEP 2143(I). One of ordinary skill in the art would have a reasonable expectation of success since both Ried, Arnold Boucas, and Mali all teach genetically altering AAV2 surface proteins to display proteins of interest for the purpose of retargeting AAV2 virus particles to specified cells.
Regarding claim 10, Ried teaches that a AAV2-Z34C mutant that additionally contains a
deletion of 9 aa [pg. 4561, col. 2, para 1-2].
Regarding claim 37 and 81, Ried teaches the production of AAV2 particles that contained GFP as a transgene [pg. 4561, col. 1, para 3; pg. 4563, col. 1, para 1] and the delivery of the GFP transgene to targeted cells [pg. 4563, col.1, para 2].
Regarding claim 75, Ried teaches that the natural tropism of the AAV2-Z34C mutants was reduced [pg. 4562, col. 1, para 2]. Therefore, it would be obvious that the recombinant viral capsid protein as taught and suggested as discussed above would also have reduced natural tropism.
Regarding claim 76, Ried teaches the retargeting (redirection) of mutant rAAVGFP587Z34C [pg. 4563, col. 1, para 2]. Therefore, it would be obvious that the recombinant viral capsid protein as taught and suggested as discussed above would also have redirected tropism.
Regarding claims 78-80, Ried do not teach that the targeting ligand specifically binds the cell surface molecules claimed or bind molecules repressed on a neuronal or muscle cell. Ried teaches that that rAAV vectors can be targeted to specific cell surface receptors by use of a universal targeting approach [pg. 4565, col. 1, para 4]. Therefore, it would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention that the rAAV vectors as taught and suggested as discussed above could be designed to target any cell, including a neuronal or muscle cell, or bind any cell surface marker based on which cell surface receptor the immunoglobulin binding domains of the capsid protein is targeting.
Regarding claim 82, Ried teaches the transduction of human hematopoietic cells [abstract].
Regarding claims 83-84, the teachings of Reid are discussed above as applied to claims 78-79 and 81-82.
Regarding claim 87, Ried teaches the production of AAV2-based vectors with a recombinant capsid [pg. 4560, col. 2, para 3].
Regarding claim 88, Ried teaches a AAV cap gene encoding the rAAV capsid protein [Fig. 1].
Claims 34 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Ried (Ried et al. (2002); J. Viral. 76(9):4559-4566) in view of Arnold (Arnold et al. Molecular Therapy Vol. 14, No. 1, July 2006, cited on the Information Disclosure Statement filed 11/20/2025), Boucas (Boucas et al. J Gene Med 2009; 11: 1103–1113, cited on the Information Disclosure Statement filed 11/20/2025), Mali (US 2020/0340012 A1; provisionally filed 4/4/2017) and Veggiani (Veggiani et al. Trends Biotechnol. 2014 October ; 32(10): 506–512) as applied to claims 1 and 33, and further in view of Choi (Choi et al. Curr Gene Ther. 2005 June ; 5(3): 299–310.).
The teachings of Ried, Arnold, Boucas, Mali, and Veggiani are discussed above as applied to claims 1 and 33 and similarly apply to claim 34 and 36.
Ried, Arnold, Boucas, Mali, and Veggiani do not teach a recombinant viral capsid protein comprising the recombinant viral capsid protein and the reference viral capsid protein lacking any member of the specific protein:protein binding pair at a ratio between 1: 1 and 1: 15.
Choi teaches the engineering of adeno-associated virus (AAV) capsid, in order to increase efficiency in targeting specific cell types that are nonpermissive to wild type (wt) viruses and to improve efficacy in infecting only the cell type of interest [abstract]. Choi teaches the generation of capsid mutants, or hybrid serotypes, by various methods and strategies [abstract]. Choi teaches the generation of mosaic capsid by packaging a mixture of capsid proteins from two different serotypes by using different ratios of input plasmids encoding different serotype capsid sequences [see section 2.3].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to generate a recombinant viral capsid as taught and suggested by Ried, Arnold, Boucas, Mali, and Veggiani, where the recombinant viral capsid protein and the reference viral capsid protein has a ratio between 1: 1 by using a 1:1 ratio of plasmid encoding the recombinant viral capsid protein to plasmid encoding the reference viral capsid protein as taught by Choi. The combination of prior art elements according to known methods to yield predictable results supports can support a conclusion of obviousness. See MPEP 2143(I). One of ordinary skill in the art would have a reasonable expectation of success since both Ried, Arnold, Boucas, Mali and Choi teach engineering of adeno-associated virus (AAV) capsid, in order to increase efficiency in targeting specific cell types.
Claim 45 is rejected under 35 U.S.C. 103 as being unpatentable over Ried (Ried et al. (2002); J. Viral. 76(9):4559-4566) in view of Arnold (Arnold et al. Molecular Therapy Vol. 14, No. 1, July 2006, cited on the Information Disclosure Statement filed 11/20/2025), Boucas (Boucas et al. J Gene Med 2009; 11: 1103–1113, cited on the Information Disclosure Statement filed 11/20/2025), Mali (US 2020/0340012 A1; provisionally filed 4/4/2017) and Veggiani (Veggiani et al. Trends Biotechnol. 2014 October ; 32(10): 506–512) as applied to claims 1, 33, and 37, and further in view of Wang (US 8,273,344 B2, 9/25/2012).
The teachings of Ried, Arnold, Boucas, Mali, and Veggiani are discussed above as applied to claims 1, 33, and 37 and similarly apply to claim 45.
Ried, Arnold, Boucas, Mali, and Veggiani do not teach a recombinant viral particle comprising a pharmaceutically acceptable carrier.
Wang teaches pharmaceutical application of the recombinant adeno-associated virus comprising a nucleotide of interest [col. 1, lines 8-18]. Wang teaches a pharmaceutical composition comprising the rAAV and a pharmaceutically acceptable carrier or excipient [col. 3, lines 42-45].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to include a pharmaceutically acceptable carrier as taught by Wang with the recombinant viral particle comprising a nucleotide of interest encapsulated by the recombinant viral capsid as taught and suggested by Ried, Arnold, Boucas, Mali, and Veggiani for the advantage of using it in a pharmaceutical application. The combination of prior art elements according to known methods to yield predictable results supports can support a conclusion of obviousness. See MPEP 2143(I). One of ordinary skill in the art would have a reasonable expectation of success since both Ried, Mali, and Wang teach delivery of virus particles.
Response to Arguments
Applicant’s arguments, see pgs. 11-21, filed 05 February 2025, with respect to the rejection of claims 1, 10-11, 14, 24-25, 33-34, 36-37, 45, 75-84 and 87-88 under 35 U.S.C. § 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn in view of the amendment to the claims to require “a first member of a protein:protein binding pair inserted into an exposed variable loop of the viral capsid protein.” However, upon further consideration, a new ground(s) of rejection is made in view of Arnold and Boucas.
Applicants argue that (a) Veggiani and Mali teach away from inserting a first member of an isopeptide bond-forming protein:protein binding pair ("first member") into an exposed variable loop of an AAV capsid protein. Accordingly, (b) in view of Ried, Mali, and Veggiani, there would be no reasonable expectation of successfully producing a retargeted AAV vector with transduction efficiency that maintains or exceeds that of a wild-type counterpart by inserting a first member into an exposed variable loop of the AA V capsid protein.
All of applicants’ arguments have been considered and are not found persuasive. The rejection was based on a modification of Reid with the teachings of Mali and Veggiani. Reid has successfully inserted a first member of a protein-protein pain into an exposed variable loop without structure disruption and function. Although Veggiani teaches that SpyTag fusions may interfere with folding or protein interactions, Veggiani proceeds this by teaching that SpyTag must be cloned onto the protein of interest case by case [pg. 6, para 3]. Mali teaches AAV2 particles have SpyTags and SpyTags with linker peptides with and without the HSPG binding peptide, but fails to identify which bar in Fig. 15 corresponds to which particle configuration. Furthermore, while the data presented in Figure 15 of Mali shows where some particles exhibit significantly reduced transduction, there is one particle that is able to transduce cells. Therefore, Mali shows that with the correct SpyTag/linker/binding peptide configuration of AAV particles are still able to transduce cells. Therefore, when considering the totality of the teaching from Reid, Mali, Veggiani, Arnold, and Boucas, a skilled artisan would be motivated to, with a reasonable expectation of success, try to insert a first member into an exposed variable loop and maintain or exceed transduction efficiency of an AAV vector, especially for the retargeting strategies.
Conclusion
No claims 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIFFANY N GROOMS whose telephone number is (571)272-3771. The examiner can normally be reached M-F 830-530.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached on 571-272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637