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Application Status and Withdrawn Rejections
Applicant’s amendment filed May 19, 2026 amending claims 1, 19 and 21 is acknowledged. Claims 1-7, 12-16 and 19-22 are pending and under examination.
The amendment to claims 1, 19 and 21, changing the amino acid substitutions in the AAV3 variant species overcomes the §103 rejections and the nonstatutory double patenting (NSDP) rejections in the previous office action. All §103, and NSDP rejection in the previous office action are withdrawn. Applicant arguments directed to the withdrawn rejections have been fully considered, but are moot.
Any other rejection or objection not reiterated herein has been overcome by amendment. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Priority
As indicated in previous office actions, the first evidence of support of variant AAV3 particles with mutations at N588, A590, S384 or T717 and the claimed function is the provisional application 63/254984 (filed October 12, 2021). As such, the effective filing date for all claims is October 12, 2021.
Claim Rejections - 35 USC § 103 – Church in view of Genbank
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.
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 Rejections - 35 USC § 103 – Agbandje- McKenna in view of Church and Genbank
Claims 1-7, 12-15 and 19-22 are rejected under 35 U.S.C. 103 as being unpatentable over Agbandje- McKenna (US 20190345203 A1, published November 14, 2019; of record) in view of Church (US 20210230229 A1, published July 29, 2021, priority to at least May 8, 2019) and Genbank (3KIC_A, Chain A, Capsid protein V1, https://www.ncbi.nim.nih.gov/protein/3KIC_A/ [retrieved June 20, 2025], available at least as early as November 14, 2017; of record). This is a new rejection necessitated by amendment.
Regarding claim 1-2, 7 and 19-20, Agbandje-McKenna teaches variant AAVrh.10 viral particles engineered to escape host neutralizing antibodies but retain or improve transduction efficiency (Abstract). Agbandje-McKenna teaches variant AAVrh.10 viral particles comprising a VP1 capsid proteins with amino acid substitutions of N590S, A592Q and T719V (Fig 5A). Agbandje-McKenna teaches ADK8 antibodies recognizes AAVrh.10 particles having wild type VP1 capsid protein, but not viral particles having the N590S/A592Q VP1 capsid protein (Fig 5D). Agbandje-McKenna teaches AAVrh.10 particles with the N590S/A592Q VP1 capsid variant maintain transduction efficiencies compared to wild type AAVrh.10 particles (FIG. 11). Agbandje-McKenna teaches that both wildtype AAVrh.10 particles and wildtype AAV3 viral particles are recognized by the ADK8/9 antibodies (FIG 5B). Agbandje-McKenna teaches an amino acid alignment between the residues of VP1 loop VIII from AAVrh.10 and AAV3 (FIG 3C, 5B). Agbandje-McKenna teaches that AAVrh.10 and AAV3 VP1 have an asparagine (N) and alanine (A) at conserved positions in loop VIII (FIG. 5B).
Agbandje-McKenna does not teach AAV3 VP1 capsid variants or a full amino acid alignment between AAVrh.10 and AAV3. Agbandje-McKenna does not teach an amino acid substitution that is equivalent to S384A.
Church teaches viral capsid polypeptides with mutations that alters tissue tropisms (i.e., results in altered transduction efficiency relative to wild type viral capsid) (Abstract). Church teaches the sequence of the AAV2 capsid protein ([0059]) and the amino acid alteration S384A in the AAV2 capsid protein confers more efficient delivery to blood (Table 1) and liver (Table 7). Church teaches mutations that are equivalent positions in other homologous viruses can be made for improving virus infectivity including in AAV3 and AAV3B ([0063], [0077]). Church teaches that site-directed mutagenesis is known in the art and can be used to introduce the point mutations ([0064]).
Genbank teaches the amino acid sequence of VP1 from AAV3 (page3). Genbank teaches AAV3 VP1 has N and A residues at positions 588 and 590, respectively (page 3) and a sequence of NLQSSNTAP from position 583 to 591 (page 3). The sequence in Genbank is 100% identical to SEQ ID NO 26.
Regarding claim 1-2, 7, 19 and 20, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have created an AAV3 variant particle comprising a VP1 capsid protein having SEQ ID NO 26 and comprising N588S, A590Q, S384A and T717V substitutions. It would have amounted to using the amino acid substitution techniques for improving an AAV vector of Agbandje-McKenna and Church to improve the known wild type AAV3 VP1 capsid protein by known means to yield predictable results. Genbank's AAV3 VP1 protein (i.e., SEQ ID NO 26) is a base product upon which the claimed VP1 variant capsid protein can be seen as an improvement. Agbandje-McKenna teaches the AAV3 particles react against neutralizing antibodies and therefore would be recognized as an AAV that could be improved. The AAVrh.10 and AAV2 variants of Agbandje-McKenna and Church, respectively, are comparable devices to the claimed AAV3 variant because Agbandje-McKenna teaches that the VP1 capsid protein of AAVrh.10 and AAV3 have regions of homology, especially in exposed loops that are known to bind to neutralizing antibodies and Church teaches the variants in AAV2 can be incorporated into the analogous residues in AAV3. The skilled artisan would have recognized that AAV3 VP1 could be improved by making the analogous amino acid substitutions because it is evident from the alignments between AAVrh.10 and AAV2 with AAV3 that there is considerable homology in the regions that were modified by Agbandje-McKenna and Church (see OA Appendix). From the provided alignment using the sequences in Agbandje-McKenna, Church and Genbank, the following residues between AAVrh.10, AAV2 and AAV3 are homologous.
AAV3
AAV2
AAVrh.10
N588
N587
N590
S384
S384
S387
A590
Q589
A592
T717
T716
T719
Thus, the N590S, A592Q and T719V substitutions in Agbandje-McKenna’s AAVrh.10 is analogous to the claimed N588S, A590Q and T717V substitutions in AAV3B, and the S384A substitution in Church’s AAV2 is analogous to the claims S384A mutation in AAV3B. The skilled artisan would have predicted that at least the N588S and A590Q substitutions in AAV3 VP1 would have rendered the AAV3 particle less reactive to the ADK8 antibody than AAV3 particles with wild type VP1 (i.e., SEQ ID NO 26) because Agbandje-McKenna teaches that such mutations in the conserved region of AAVrh.10 render AAVrh.10 less reactive to ADK8 antibodies. Likewise, it would have been entirely predictable that the S384A substitution in AAV3 VP1 would render it more infective because Church teaches the analogous substitutions can be made in AAV3 for the same purpose. Finally, the skilled artisan would have predicted that the T717V substitution could be made in the AAV2 based on the conserved protein structure between AAVrh.10 and AAV3 in C-terminal region of the proteins. The skilled artisan would have been motivated to make the substitution combinations in AAV3 in order to improve the function of AAV3 particles for gene delivery as taught in Agbandje-McKenna and Church.
Regarding claims 3-4, Agbandje-McKenna teaches that ADK8/9 is a neutralizing antibody of AAV8 ([0098], FIG. 4).
Regarding claim 5-6, Agbandje-McKenna teaches that the reactivity of the AAVrh.10 variant particle having the N590S/A592Q VP1 capsid protein has 100% reduction in reactivity to the ADK8 neutralizing antibody (FIG. 5D). The skilled artisan would have predicted that an AAV3 variant particle comprising the analogous N588S/A590Q VP1 capsid protein substitutions would likewise have a near complete reduction in reactivity to the ADK8 antibody because of the conserved amino acid sequence between AAVrh.10 VP1 and AAV3 VP1 in the loop VIII region.
Regarding claims 12-13, Agbandje-McKenna teaches that the modified AAV vectors can be used for delivering therapeutic genes of interest, including those that code for therapeutic antibodies and growth factors ([0017]).
Regarding claims 14, Agbandje-McKenna teaches the variant AAV particles in a composition with a pharmaceutically acceptable carrier ([0020]).
Regarding claim 15, Agbandje-McKenna teaches methods for delivering a transgene encoding a gene of interest by administering the variant AAV particles in a pharmaceutical composition to a subject ([0020]). Agbandje-McKenna teaches that therapeutic genes of interest include those that code for therapeutic antibodies and growth factors ([0017]).
Regarding claim 21, Agbandje-McKenna teaches vectors encoding the variant VP1 capsid proteins that are used to form the variant AAV particles ([0022]).
Regarding claims 22, Agbandje-McKenna teaches the vector encoding the variant VP1 in a kit that also includes vectors encoding AAV helper genes provided in a separate container ([0023]).
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Agbandje- McKenna (US 20190345203 A1, published November 14, 2019; of record), Church (US 20210230229 A1, published July 29, 2021, priority to at least May 8, 2019) and Genbank (3KIC_A, Chain A, Capsid protein V1, https://www.ncbi.nim.nih.gov/protein/3KIC_A/ [retrieved June 20, 2025], available at least as early as November 14, 2017; of record), as applied to claims 1-7, 12-15 and 19-22 above, and further in view of Brown (Brown et al., Human Gene Therapy (2020), 31: 1114-1123; published July 10, 2020; of record). This is a new rejection necessitated by amendment.
The teachings of Agbandje-McKenna, Church and Genbank are recited above and applied as for claims 1-7, 12-15 and 19-22. Agbandje-McKenna also teaches that AAVrh.10 has been used for gene delivery to treat hemophilia ([0003]).
Agbandje-McKenna, Church and Genbank do not teach what diseases AAV3 can be used to treat.
Brown teaches AAV3 is a candidate for treating hemophilia via gene therapy (Title). Brown teaches the hFIX transgene inserted into an AAV3 vector and packaged into an AAV3 capsid yields therapeutic levels of the transgene in hemophilia Band in humanized-mice (Abstract).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used the AAV3 particle comprising the N588S/A590Q/S384A/T717V VP1 capsid protein rendered obvious above in a method to treat hemophilia. It would have amounted to using the obvious AAV3 particle to treat a known disease for which AAV3 particles are known to be effective. The skilled artisan would have predicted that the AAV3 particle comprising the N588S/A590Q/S384A/T717V VP1 capsid protein could be used to treat hemophilia because Agbandje-McKenna teaches that the analogous AAVrh.10 particle variant with N590S/A592Q VP1 can be used to treat hemophilia and Church teaches the S384A variant allows increased infectivity for delivery to blood cells.
Claim Rejections - 35 USC § 103 – Agbandje- McKenna in view of Lochrie, Church and Genbank
Claims 1-7, 12-15 and 19-22 are rejected under 35 U.S.C. 103 as being unpatentable over Agbandje- McKenna (US 20190345203 A1, published November 14, 2019; of record) in view of Lochrie (Lochrie et al., Journal of Virology (2006), 80: 821-834), Church (US 20210230229 A1, published July 29, 2021, priority to at least May 8, 2019) and Genbank (3KIC_A, Chain A, Capsid protein V1, https://www.ncbi.nim.nih.gov/protein/3KIC_A/ [retrieved June 20, 2025], available at least as early as November 14, 2017; of record). This is a new rejection necessitated by amendment.
Regarding claim 1-2, 7, 19-22, Agbandje-McKenna teaches variant AAVrh.10 viral particles engineered to escape host neutralizing antibodies by retaining or improving transduction efficiency (Abstract). Agbandje-McKenna teaches variant AAVrh.10 viral particles comprising a VP1 capsid proteins with amino acid substitutions of N590S and A592Q (Fig 5A). Agbandje-McKenna teaches ADK8 antibodies recognizes AAVrh.10 particles having wild type VP1 capsid protein, but not viral particles having the N590S/A592Q VP1 capsid protein (Fig 5D). Agbandje-McKenna teaches AAVrh.10 particles with the N590S/A592Q VP1 capsid variant maintain transduction efficiencies compared to wild type AAVrh.10 particles (FIG. 11). Agbandje-McKenna teaches that both wildtype AAVrh.10 particles and wildtype AAV3 viral particles are recognized by the ADK8/9 antibodies (FIG 5B). Agbandje-McKenna teaches an amino acid alignment between the residues of VP1 loop VIII from AAVrh.10 and AAV3 (FIG 3C, 5B). Agbandje-McKenna teaches that AAVrh.10 and AAV3 VP1 have an asparagine (N) and alanine (A) at conserved positions in loop VIII (FIG. 5B). Agbandje-McKenna teaches that any amino acid can be substituted at the N590 position ([0050]).
Agbandje-McKenna does not teach AAV3 VP1 capsid variants or a full amino acid alignment between AAVrh.10 and AAV3.
Lochrie teaches that AAV2 vectors are sensitive to antibody-mediated neutralization (page 821, ¶4). Lochrie teaches that of humans can have neutralizing antibodies to AAV1, 2, 3, 4, 5, 6, and 8 (page 822, ¶2). Lochrie teaches neutralizing epitopes on AAV2 capsids and regions of the external surface of the AAV2 capsid that influence neutralization (page 822, ¶6). Lochrie teaches the N587 residue is in a “spike” region of capsid structure (Fig 1D, 1G). Lochrie teaches AAV2 VP1 protein having an N587A substitution had higher transducing activity than wildtype (page 825, ¶8; Table 1). Lochrie teaches that the N587A mutant was more resistant to neutralization by all three anti-sera tested (page 828, ¶4; Table 3).
Church teaches the sequence of the AAV2 capsid protein ([0059]). Church teaches amino acid alterations N587 in the AAV2 capsid protein can be altered to confer more efficient delivery to various tissues (Tables 1-2, 7-12). Church teaches mutations that are equivalent positions in other homologous viruses can be made for improving virus infectivity including in AAV3 and AAV3B ([0063], [0077]). Church teaches that site-directed mutagenesis is known in the art and can be used to introduce the point mutations ([0064]).
Genbank teaches the amino acid sequence of VP1 from AAV3 (page3). Genbank teaches AAV3 VP1 has residues of N588 and A590 (page 3). The sequence in Genbank is 100% identical to SEQ ID NO 26.
Regarding claim 1-2, 7 and 19-20, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have created an AAV3 variant particle comprising a VP1 capsid protein having N588A and A590Q substitutions. It would have amounted to using the amino acid substitution techniques for improving an AAV vector of Agbandje-McKenna and Lochrie to improve the known wild type AAV3 VP1 capsid protein by known means to yield predictable results. Genbank's AAV3 VP1 protein is a base product upon which the claimed VP1 variant capsid protein can be seen as an improvement. Agbandje-McKenna teaches the AAV3 particles react against neutralizing antibodies and therefore would be recognized as an AAV that could be improved. The AAVrh.10 and AAV2 variants of Agbandje-McKenna and Lochrie, respectively, are comparable devices to the claimed AAV3 variant because Agbandje-McKenna teaches that the VP1 capsid protein of AAVrh.10 and AAV3 have regions of homology, especially in exposed loops that are known to bind to neutralizing antibodies and Church teaches the variants in AAV2 can be incorporated into the analogous residues in AAV3. The skilled artisan would have recognized that AAV3 VP1 could be improved by making the analogous amino acid substitutions because it is evident from the alignments between AAVrh.10 and AAV2 with AAV3 that there is considerable homology in the regions that were modified by Agbandje-McKenna and Lochrie (see OA Appendix). From the provided alignment using the sequences in Agbandje-McKenna, Church and Genbank, the skilled artisan would conclude the following residues between AAVrh.10, AAV2 and AAV3 are homologous.
AAV3
AAV2
AAVrh.10
N588
N587
N590
S384
S384
S387
A590
Q589
A592
T717
T716
T719
Thus, the A592Q substitution in Agbandje-McKenna’s AAVrh.10 is analogous to the claimed A590Q substitution in AAV3B, and the N587A substitution in Lochrie’s AAV2 is analogous to the claimed N588A mutation in AAV3B. The skilled artisan would have predicted that the N588A and A590Q substitutions in AAV3 VP1 would have rendered the AAV3 particle less reactive to the ADK8 antibody than AAV3 particles with wild type VP1 (i.e., SEQ ID NO 26) because Agbandje-McKenna and Lochrie teaches that the analogous mutations in the conserved region of AAVrh.10 and AAV2 render the AAVs less reactive to neutralizing antibodies. The skilled artisan would have been motivated to make the substitution combinations in AAV3 in order to improve the function of AAV3 particles for gene delivery as taught in Agbandje-McKenna, Lochrie and Church.
Regarding claims 3-4, Agbandje-McKenna teaches that ADK8/9 is a neutralizing antibody of AAV8 ([0098], FIG. 4). Lochrie teaches the neutralizing antibodies are against AAV1, 2, 3, 4, 5, 6, and 8 (page 822, ¶2).
Regarding claim 5-6, Agbandje-McKenna teaches that the reactivity of the AAVrh.10 variant particle having the N590S/ A592Q VP1 capsid protein has 100% reduction in reactivity to the ADK8 neutralizing antibody (FIG. 5D). Lochrie teaches AAV2 mutants with the N587A substitution have increased neutralization resistance by 3-5 fold. The skilled artisan would have predicted that an AAV3 variant particle having the analogous N588A/A590Q VP1 capsid protein substitutions would likewise have a near complete reduction in reactivity to the ADK8 and other neutralizing antibodies because of the conserved amino acid sequence between AAVrh.10 VP1, AAV2, and AAV3 VP1 in the loop VIII region.
Regarding claims 12-13, Agbandje-McKenna teaches that the modified AAV vectors can be used for delivering therapeutic genes of interest, including those that code for therapeutic antibodies and growth factors ([0017]). Lochrie teaches AAV vectors are used as gene therapy vectors (page 821, ¶3).
Regarding claims 14, Agbandje-McKenna teaches the variant AAV particles in a composition with a pharmaceutically acceptable carrier ([0020]).
Regarding claim 15, Agbandje-McKenna teaches methods for delivering a transgene encoding a gene of interest by administering the variant AAV particles in a pharmaceutical composition to a subject ([0020]). Agbandje-McKenna teaches that therapeutic genes of interest include those that code for therapeutic antibodies and growth factors ([0017]).
Regarding claim 17, Agbandje-McKenna teaches vectors encoding the variant VP1 capsid proteins that are used to form the variant AAV particles ([0022]).
Regarding claims 21-22, Agbandje-McKenna teaches a kit comprising the vector encoding the variant VP1 in a kit that also includes vectors encoding AAV helper genes provided in a separate container ([0023]).
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Agbandje- McKenna (US 20190345203 A1, published November 14, 2019; of record), Lochrie (Lochrie et al., Journal of Virology (2006), 80: 821-834), Church (US 20210230229 A1, published July 29, 2021, priority to at least May 8, 2019) and Genbank (3KIC_A, Chain A, Capsid protein V1, https://www.ncbi.nim.nih.gov/protein/3KIC_A/ [retrieved June 20, 2025], available at least as early as November 14, 2017; of record), as applied to claims 1-7, 12-15 and 19-25 above, and further in view of Brown (Brown et al., Human Gene Therapy (2020), 31: 1114-1123; published July 10, 2020; of record). This is a new rejection necessitated by amendment.
The teachings of Agbandje-McKenna, Lochrie, Church and Genbank are recited above and applied as for claims 1-7, 12-15 and 19-25. Agbandje-McKenna also teaches that AAVrh.10 has been used for gene delivery to treat hemophilia ([0003]).
Agbandje-McKenna, Church, Lochrie and Genbank do not teach what diseases AAV3 can be used to treat.
Brown teaches AAV3 is a candidate for treating hemophilia via gene therapy (Title). Brown teaches the hFIX transgene inserted into an AAV3 vector and packaged into an AAV3 capsid yields therapeutic levels of the transgene in hemophilia Band in humanized-mice (Abstract).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used the AAV3 particle comprising the N588A/A590Q VP1 capsid protein rendered obvious above in a method to treat hemophilia. It would have amounted to using the obvious AAV3 particle to treat a known disease for which AAV3 particles are known to be effective. The skilled artisan would have predicted that the AAV3 particle comprising the N588A/A590Q VP1 capsid protein could be used to treat hemophilia because Agbandje-McKenna teaches that the analogous AAVrh.10 particle variant with N590S/A592Q VP1 can be used to treat hemophilia.
Response to Arguments - §103
Applicant’s arguments with respect to the obviousness rejections (Remarks, page 8) 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.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-7, 12-16 and 19-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of U.S. Patent No. 10723768 in view of Agbandje- McKenna (US 20190345203 A1, published November 14, 2019; of record), Lochrie (Lochrie et al., Journal of Virology (2006), 80: 821-834), Genbank (3KIC_A, Chain A, Capsid protein V1, https://www.ncbi.nim.nih.gov/protein/3KIC_A/ [retrieved June 20, 2025], available at least as early as November 14, 2017; of record) and Church (US 20210230229 A1, published July 29, 2021, priority to at least May 8, 2019). This is an updated rejection, necessitated by amendment.
Patented claim 1 recites a modified adeno associated virus (AAV) capsid protein comprising a non-tyrosine amino acid at one or more positions that correspond to Tyr252, Tyr272, Tyr275, Tyr281, Tyr444, Tyr500, Tyr508, Tyr612, Tyr704, Tyr720, Tyr730, or Tyr673 in a wild-type AAV2 capsid protein. Patented claim 3 recites wherein the capsid protein is of a serotype selected from the group consisting of an AAV serotype 3 (AAV3). Patented claims 5-6 recite A recombinant adeno-associated viral (rAAV) particle that comprises the modified AAV capsid protein according to claim 1 that is serotype of AAV3. Patented claim 7 recites the rAAV particle according to claim 5, further comprising at least a first nucleic acid segment that encodes a therapeutic agent operably linked to a promoter capable of expressing said segment in a host cell. Patented claim 12 recites wherein the therapeutic agent is selected from the group consisting of a polypeptide, a peptide, an antibody, an antigen binding fragment. Patented claim 13 recites A composition comprising the rAAV particle according to claim 5. Patented claim 14 recites A method for administering a therapeutic or a diagnostic agent to a mammal in need thereof, the method comprising: providing to at least a first cell, tissue or organ of the mammal the composition according to claim 13, wherein the transduction efficiency of the rAAV particle comprised in the composition is higher than that of a particle comprising a corresponding, unmodified, wild-type capsid protein. Patented claim 15 recites wherein the rAAV particle is AAV3. Patented claim 16 recites wherein the transduction efficiency of the rAAV particle comprising the modified capsid protein is at least 4-fold higher than that of a rAAV particle comprising the corresponding, unmodified capsid protein. Patented claim 28 recites wherein the mammal has cancer, diabetes, autoimmune disease, kidney disease, cardiovascular disease, pancreatic disease, intestinal disease, liver disease, pulmonary disease, an a-1 antitrypsin deficiency, ischemia, stroke, or any combination thereof. Patented claim 29 recites A method of treating or ameliorating one or more symptoms of a disease, a disorder, a dysfunction, an injury, or trauma in a mammal, comprising administering to the mammal an effective amount of the recombinant adeno-associated viral (rAAV) particle according to claim 5; wherein the particle comprises a nucleic acid segment that encodes a therapeutic peptide, polypeptide, or RNA, operably linked to at least one promoter that expresses the nucleic acid segment in one or more cells of the selected population.
The patented claims do not recite substitutions at positions N588, A590, S384 or T717. The patented claims do not recite the modulated reactivity to neutralizing antibodies (claims 3-6). The patented claims do not recite vectors or kits comprising the vectors (claims 21-22).
The teachings of Agbandje-McKenna are recited above in paragraphs 28 and 33-39 and are incorporated here. The teachings of Lochrie are recited above in paragraph 29 and incorporated here. The teachings of Genbank are recited above in paragraph 31 and are incorporated here. The teachings of Church are recited above in paragraph 30 and are incorporated here.
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have further modified the patented rAAV3 particle comprising the Y[Wingdings font/0xE0]P substitutions in the capsid protein by incorporating N588A, A590Q, S384A and T717V mutations in rAAV3 that are analogous to the VP1 N587A substitution taught in Lochrie, the VP1 A592Q and T719V substitutions taught in Agbandje-McKenna, and the S384A substitution taught in Church. It would have amounted to using the amino acid substitution improvement technique of an AAV vector taught in Agbandje-McKenna to the related patented AAV3 VP1 capsid protein by known means to yield predictable results. The patented rAAV3 comprising a YIP-modified capsid protein is a base product upon which the claimed VP1 variant capsid protein can be seen as an improvement. Agbandje-McKenna teaches AAV3 particles react against neutralizing antibodies and therefore the patented AAV3 particles would be recognized as a device that could be improved. The AAVrh.10 and AAV2 variants are comparable devices to the claimed AAV3 variant because Agbandje-McKenna and Church teaches that the VP1 capsid protein of AAVrh.10, AAV2 and AAV3 have regions of homology, especially in exposed loops that are known to bind to neutralizing antibodies. The skilled artisan would have recognized that the patented AAV3 capsid protein could be improved by making the homologous amino acid substitutions because Agbandje-McKenna and Church teaches that there is considerable homology in the loop area between AAVrh.10, AAV2 and AAV3. Although none of Agbandje-McKenna, Lochrie, Church or the patented claims provide residue numbers for AAV3, it is clear from the Genbank sequence, that the sequence in FIG 5B of Agbandje-McKenna is residues 583 to 591 of AAV3 VP1. From this alignment and comparison to Genbank sequence the N590, A592, T719 residues of AAVrh.10 align with the N588, A590, T717 residues in AAV3. As such, the skilled artisan would conclude that N590 and N588 are conserved, A592 and A590, S384 and S384 are conserved and T719 and T717 are conserved. The skilled artisan would have predicted that the N588S/A, A590Q, S384A and T717V substitutions in the patented AAV3 capsid protein would render the AAV3 particle less-reactive to the ADK8 antibody than AAV3 particles with wild type VP1 (i.e., SEQ ID NOs 24 and 26) because Agbandje-McKenna and Lochrie teach that such mutations in the conserved region of AAVrh.10 and AAV3 VP1 render the respective AAV particles less reactive to antibodies, including ADK8 antibodies. The skilled artisan would have been motivated to make the additional N588A/S, A590Q, S384A and T717V substitutions in the patented rAAV3 in order to reduce the patented rAAV3 particles antibody-reactivity so as to make them more useful for therapeutic gene deliver.
Regarding claims 21-22, it also would have been obvious to one skilled in the art to provide a vector encoding the obvious variant of the AAV capsid protein in a kit with helper genes because Agbandje-McKenna teaches when the capsid-encoding vectors are provided with AAV helper genes, they can be used to produce the rAAV particles for gene delivery.
Claims 1-7, 12-16 and 19-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of U.S. Patent No. 10934327 in view of Agbandje- McKenna (US 20190345203 A1, published November 14, 2019; of record), Lochrie (Lochrie et al., Journal of Virology (2006), 80: 821-834), Genbank (3KIC_A, Chain A, Capsid protein V1, https://www.ncbi.nim.nih.gov/protein/3KIC_A/ [retrieved June 20, 2025], available at least as early as November 14, 2017; of record) and Church (US 20210230229 A1, published July 29, 2021, priority to at least May 8, 2019). This is an updated rejection, necessitated by amendment.
Patented claim 1 recites an rAAV3 vector (i.e., particle) comprising a modified capsid protein that comprises: a non-serine amino acid residue at S663 of the wild-type AAV3 capsid protein as set forth in SEQ ID NO:3, and a non-threonine amino acid residue at T492 of the wild-type AAV3 capsid protein as set forth in SEQ ID NO:3. Patented claim 4 recites wherein the transduction efficiency of the vector is about 2- to about SO-fold higher in a selected mammalian host cell than that of a virion that comprises a corresponding, unmodified, rAAV3 vector (i.e., SEQ ID NO 24 or 26 of the examined claims). Patented claims 8, 13 and 15 recite wherein the vector further comprises a nucleic acid segment that encodes a therapeutic agent operably linked to a promoter capable of expressing the nucleic acid segment in a suitable host cell comprising the vector, wherein the nucleic acid segment encodes a polypeptide or a cytokine. Patented claim 16 recites A composition comprising the rAAV3 vector in accordance with claim 1. Patented claim 18 recites A method for treating, or ameliorating at least one or more symptoms of liver cancer in a mammal, the method comprising, administering to a mammal in need thereof the rAAV3 vector in accordance with claim 8, in an amount and for a time sufficient to diagnose, prevent, treat or ameliorate the one or more symptoms of the liver cancer in the mammal.
The patented claims do not recite substitutions at positions N588, A590, S384 or T717. The patented claims do not recite the modulated reactivity to neutralizing antibodies (claims 3-6). The patented claims do not recite vectors or kits comprising the vectors (claims 21-22).
The teachings of Agbandje-McKenna are recited above in paragraphs 28 and 33-39 and are incorporated here. The teachings of Lochrie are recited above in paragraph 29 and incorporated here. The teachings of Genbank are recited above in paragraph 31 and are incorporated here. The teachings of Church are recited above in paragraph 30 and are incorporated here.
The obviousness of having included additional N588A/S, A590Q, S384A and T717V substitutions in the capsid protein of the patented rAVV3 particle are recited above in paragraph 51. Regarding claims 21-22, the obviousness of having provide a vector encoding the obvious variant of the AAV capsid protein in a kit with helper genes is recited above in paragraph 52.
Response to Arguments - NSDP
Applicant requests reconsideration of the NSDP rejections in view of the claim amendments (Remarks, pages 8-9. The rejections have been reconsidered and are updated to reflect the claim amendments.
Conclusion
No claims are allowable.
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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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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