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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08/07/2026 has been entered.
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.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Schmidt et al (WO2019084015, hereinafter, “Schmidt”) in view of Tan et al (PLOS One, 2016, 10.1371/journal.pone.0165074, hereinafter, “Tan”), Boucas et al (J Gene Med, 2009, 10.1002/jgm.1392, hereinafter, “Boucas”), and Arsic et al (Mol Ther, 2003, 10.1016/S1525-0016(03)00034-0, hereinafter, “Arsic”).
Schmidt teaches AAV designed for receptor-targeted gene delivery (Abstract). Schmidt teaches the capsids of AAVs can be modified to be comprised of either components of a Tag-Catcher Pair, SpyTag or SpyCatcher (Figure 1B and Exemplary compositions and methods on page 30). Schmidt teaches this composition can be used can be used to target cancer cells by delivering a suicide gene (Exemplary compositions and methods on page 30).
Regarding claim 1, Schmidt teaches an AAV comprising a capsid modified to display SpyTag or SpyCatcher Figure 1B and Exemplary compositions and methods on page 30). Schmidt also teaches that the SpyTag can be inserted at position 588 of VP1 (Exemplary compositions and methods on page 30).
Schmidt does not explicitly the sequence SEQ ID NO: 1 relating to the SdyTag nor does Schmidt explicitly teach SEQ ID NO: 2 relating to the VP1 of AAV2. Schmidt also does not teach an AAV2 at a titer of greater than 1014.
However, Tan teaches the development of Tag-Catcher pairs related to SpyTag and SpyCatcher (Abstract). Tan teaches that SdyTag was constructed based on the native Cna protein B-type (CnaB) domain from a related fibronectin-binding protein in Streptococcus dysgalactiae (Abstract). Tan also teaches that SdyTag has the same function as SpyTag but binds to a different Catcher proteins that have high affinity to SdyTags (Abstract).
Regarding claim 1, SEQ ID NO: 1 is the SdyTag taught by Tan Catcher Construction/ Table S1- see alignment below).
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It would have been prima facie obvious to a person with ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Schmidt and Tan to engineer an AAV capsid polypeptide to contain the SdyTag sequence of SEQ ID NO: 1. One would have been motivated to do so for the advantage of tagging the viral capsid with a protein that is highly specific to a certain binding partner, as taught by Tan. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Schmidt and Tan do not explicitly the sequence SEQ ID NO: 2 relating to the VP1 of AAV2. Schmidt and Tan also do not teach an AAV2 at a titer of greater than 1014.
However, Boucas teaches that the most common site used for insertion into AAV2 capsids are amino acids 587 and 588 because they are located at the second highest capsid protrusion Aabstract). Boucas also teaches that insertion at amino acid residue 453 when residues 585 and 588 are mutated to alanine results in capsid mutants with higher receptor binding and transduction efficiency compared to insertion at residue 587 (Abstract). Finally, Boucas also clarifies that these amino acid residue numbers are in reference to VP1 numbering (introduction paragraph 2).
It would have been prima facie obvious to a person with ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Schmidt, Tan, and Boucas to insert the amino acid segment into position 453 or 588 of the capsid polypeptide of AAV2. Of note Schmidt teaches the insertion of SpyTag into position 588 of VP1 in AAV8. One would have been motivated to do so for the advantage of increased display of the inserted peptide due to high capsid protrusion and because of increased receptor binding and transduction efficiency. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Schmidt, Tan, and Boucas do not teach an AAV2 at a titer of greater than 1014.
However, Arsic teaches the use of AAV2 to deliver VEGF and angiopeitin-1 (Abstract). These vectors are prepared in a manner that results in high titer (Abstract). Specifically, Arsic teaches AAV2 “preparations used in this work for animal transduction had titers between 1 × 1013 and 1 × 1014 viral genome particles per ml” (Section: Material and Methods: Production, purification and characterization of rAAV vectors). Arsic teaches a standard, routine, and well-known protocol of generating AAV2 vector particles to achieve titers of 1014 by co-transfecting vector plasmid with the packaging/helper plasmid, pDG in 293 cells (Section: Material and Methods: Production, purification and characterization of rAAV vectors). Viral particles were then collected and concentrated using a CsCl gradient centrifugation (Section: Material and Methods: Production, purification and characterization of rAAV vectors).
It would have been prima facie obvious to a person with ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Schmidt, Tan, Boucas, and Arsic to insert SEQ ID NO: 1 into position 588 of VP1 of an AAV2. One would have been motivated to do so for the advantage of increased display of the inserted peptide due to high capsid protrusion and because of increased receptor binding and transduction efficiency. As taught by Boucas, AAV2 are common serotypes used in biotechnological research. One would have been motivated to do so for the advantage of using a readily-engineered AAV2 subtype to enable further modification of the engineered capsid by cellular proteases. Furthermore, as taught by Arsic, one of ordinary skill in the art would be motivated to increase viral titers to 1014 because achieving high titers increases the number of cells infected. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention, especially in the absence of evidence to the contrary.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Schmidt, Tan, Boucas, and Arsic as applied to claim 1 above, and further in view of Lee et al (Curr Opin Biomed Eng, 2018, 10.1016/j.cobme.2018.09.004, hereinafter, “Lee”).
As discussed above, claim 1 was rendered prima facie obvious by the teachings of Schmidt, Tan, Boucas, and Arsic. These references do not teach that the capsid polypeptide comprises protease cleavage site.
However, Lee teaches design strategies for AAV capsid engineering (abstract). Specifically, Lee teaches that the AAV2 capsid has been successfully engineered to contain nonviral motifs (page 60- insertion of nonviral parts into AAV capsid) and that an AAV2-based product was the first FDA-approved gene therapy of a hereditary disease (page 59- AAV as a gene therapy vector). Lee also teaches that small peptides flanked by protease cleavage sequences have been inserted into the AAV2 capsid and that the protease cleavage sites enable the peptide to be cleaved off of the capsid by extracellular proteases. For example, the peptide can prevent the AAV vector from transducing cells until the peptide is cleaved off by extracellular proteases, enabling fine tuning of transduction (page 60- insertion of nonviral parts into AAV capsid).
It would have been prima facie obvious to a person with ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Schmidt, Tan, Boucas, and Arsic and Lee to modify the capsid of AAV2 and to include a protease cleavage site in the engineered capsid polyprotein. One would have been motivated to do so for the advantage of using a readily-engineered AAV2 subtype that has previously received FDA-approval and to enable further modification of the engineered capsid by cellular proteases. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Claims 9 – 11, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Schmidt in view of Tan and Kang et al (PNAS, 2009, 10.1073/pnas.0906826106, hereinafter, “Kang”).
As discussed above and previously, SEQ ID NO: 1 is the SdyTag taught by Tan (Catcher Construction/ Table S1). Tan also teaches that SdyTag has the same function as SpyTag but binds to a different Catcher protein (abstract). Schmidt teaches engineering AAV capsids using SpyTag/ SpyCatcher (Figure 1B and Exemplary compositions and methods on page 30) and multiplexed gene delivery using multiple AAVs with engineered capsids (pages 30-31, exemplary compositions and methods).
These references fail to teach the newly added limitation of an a second AAV comprising the sequence set forth in SEQ ID NO: 10.
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Regarding claims 9 and 15, Tan also teaches polypeptide tag-catcher pairs that covalently ligate upon binding. Specifically, SpyTag which binds to SpyCatcher and SdyTag which binds to SdyCatcher (abstract and introduction paragraph 2). Tan teaches that conjugating polypeptides (i.e. SpyCatcher and SdyCatcher) can be engineered to have two binding motifs (Figures 4C and 4D). Additionally, Tan teaches the binding motif SdyCatcher comprises SEQ ID NO: 10 with a single conservative substitution of valine to isoleucine (Table S1, “wild type short” SdyCatcher sequence- see alignment below). In the sequence listing, applicant notes that X in SEQ ID NO: 10 can be V, as it is in the SdyCatcher sequence taught by Tan.
Kang teaches the methods to resolve a high-resolution structure of SpaA isopeptide-forming pilin-related protein from Streptococcus pyogenes (Figure 1). Kang also teaches the sequence of this protein (“Gram-positive pilus structure and assembly came with the structural analysis of the major pilin Spy0128 from Streptococcus pyogenes”). Regarding amended claim 9, Kang teaches a sequence with 99% sequence identity to SEQ ID NO: 10, including that Xaa at in SEQ ID NO: 10 can be D (reproduced below, Query is SEQ ID NO: 10; Sbjct is Kang).
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It would have been prima facie obvious to a person with ordinary skill in the art before the effective filing date of the claimed invention modify the known template sequence taught by Kang and mutate the 44th position to V, as taught by Tan, because doing so would generate a SdyCatcher that has strong affinity to SdyTag. One would have been motivated to do so for the for the advantage of tagging the viral capsid with a protein that is highly specific to a certain binding partner without interference of similar tagged capsids or cells with SpyTag allowing for multiplexed cell population targeting. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claims 10 and 11, Tan teaches that SdyTag (i.e. SEQ ID NO: 1) binding to SdyCatcher creates a covalent ligation (Table 1). Schmidt teaches that covalent attachments to AAV capsids allow for complex mixtures of viral particles with different transgenes to target the same cell (page 4 lines 1-9).
Tan teaches that SdyTag (i.e. SEQ ID NO: 1) binding to SdyCatcher creates a covalent ligation (Table 1). Schmidt teaches that covalent attachments to AAV capsids allow for complex mixtures of viral particles with different transgenes to target the same cell (page 4 lines 1-9).
It would have been prima facie obvious to a person with ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Tan, Schmidt, and Kang to generate a composition of two distinct AAVs with one comprising a capsid polypeptide comprising SEQ ID NO: 1 and the other SEQ ID NO:10. One would have been motivated to do so for the advantage of delivering multiple genes to the target cell, as taught by Schmidt, and for the advantage of tagging the viral capsid with a protein that is highly specific to a certain binding partner, as taught by Tan. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
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, 5, and 9 – 11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 and 22 of copending Application No. 18277933 as evidenced by Buning.
Claim 1 of the instant application and claims 1 and 3 of copending application ‘933 are drawn to a SdyTag inserted into the capsid polypeptide of AAV. However, claim 1 of copending application ‘933 specifies that the AAV comprises VP1, VP2, and VP3 polypeptides and that the heterologous amino acid sequence (i.e. SdyTag) is inserted into VP3. Buning evidences that VP1, VP2, and VP3 are the AAV capsid proteins (introduction paragraph 3). Buning also evidences that VP3 is a common region shared amongst all three AAV capsid proteins (introduction paragraph 4 and Figure 1). Thus, an AAV comprising VP1, VP2, and VP3 polypeptides (i.e. copending application ‘933 claim 1) is not distinct from an AAV comprising a capsid polypeptide (i.e. instant claim 1). Finally, claim 3 of copending application ‘933 is drawn to the heterologous amino acid sequence inserted into VP3 being SEQ ID NO: 1. SEQ ID NO: 1 of the instant application (as required by claim 1) is identical to SEQ ID NO: 1 of copending application ‘933 (see alignment below). Thus, claim 1 of the instant application is not patentably distinct from claims 1 and 3 of copending application ‘933.
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Amendments to claim 1 include the further limitation of SEQ ID NO: 1 being inserted at position 588, the AAV is an AAV2, and with a titer greater than 1014.
The amendments still do not address the overlap between the instant application and ‘933:
The AAV being AAV2 (claim 2 of instant application and claim 2 of copending application ‘933)
The heterologous amino acid sequence inserted into the AAV capsid comprising SEQ ID NO: 1 (claim 3 of instant application and claim 3 of copending application ‘933)
The SEQ ID NO: 1 polypeptide being inserted within 3 amino acid residues of position 588 of SEQ ID NO: 2 (claim 4 of instant application and claim 4 of copending application ‘933; 100% identity between SEQ ID NO: 2 of both applications- see alignment below)
At position 588 is still within three amino acid residues of position 588
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The AAV2 titer being greater than 1014 (claim 7 of ‘933 recites an AAV titer greater than 1011)
Regarding claim 5 the AAV capsid polypeptide comprising a protease cleavage site (claim 5 of instant application and claim 5 of copending application ‘933).
Regarding, claims 9 – 11 of the instant application and claim 22 of copending application ‘933 are drawn to a composition of two genetically distinct AAVs wherein the first AAV comprises SEQ ID NO: 1 inserted into the capsid polypeptide. However, claim 22 of copending application ‘933 specifies that the AAV comprises VP1, VP2, and VP3 polypeptides and that the heterologous amino acid sequence (i.e. SdyTag) is inserted into VP3. For the same reasons detailed above, Buning evidences that insertion into VP1, VP2, and VP3 is not patentably distinct from insertion into an AAV capsid polypeptide. Furthermore, SEQ ID NO: 10 of the instant application and SEQ ID NO: 60 of ‘933 are 100% identical (reproduced below, Sequence 1 is SEQ ID NO: 10 of the instant application, Sequence2 is SED IS NO:60 of ‘933). Regarding claims 10 and 11 ‘933 also includes a second AAV if covalently attached to the first [¶0014]
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Thus, claims 9 – 11 of the instant application is not patentably distinct from claim 22 of copending application ‘933.
Response to Arguments
Applicant requests clarification for the apparent withdrawal of the 35 U.S.C. § 102(a)(1) rejection by Tan et al with regards to claim 15
The rejection of claim 15 under 35 U.S.C. § 102(a)(1) over Tan et al. was withdrawn in view of Applicant’s amendment to the claims in the Response filed on 09/16/2025, which added additional limitations that were not disclosed by Tan et al. In view of Applicant’s amendment, a new ground of rejection for claim 15 under 35 U.S.C. § 102(a)(1) using Kang et al. was set forth in the final Office action, mailed 04/20/2026.
2) Applicant states that Tan, Schmidt, Boucas, Lee and Arsic do not teach a titer of 1014
The arguments are not persuasive. Increasing titers to a level of 1014 is a matter of routine optimization that can vary based on starting production conditions and concentrating methods. Arsic teaches a standard, known protocol of generating AAV2 vector particles to achieve titers of 1014 by co-transfecting vector plasmid with the packaging/helper plasmid in 293 cells followed by the concentration of the viral particles using a CsCl gradient centrifugation. Arsic teaches known methods of producing high titer AAV2. Therefore, a high titer preparation of AAV2 comprised of proteins in its capsid is not surprising or unexpected. To further rebut Applicant’s argument, Korbelin et al (US20190153034A1, hereinafter, “Korbelin”) evidences that high titers of AAV comprised of exogenous proteins are known in the art. Korbelin evidences the insertion of peptides into the capsid of AAV2 for targeted transfer into the brain and spinal cord (Abstract, ¶0023,0024). Korbelin evidences that the modified capsid AAV2 is administered at titers of 1014 (¶0066). Therefore, it would have been prima facie obvious to one of ordinary skill in the art to optimize the start conditions and/or concentration methods to arrive at a titer of 1014.
3)Applicant has amended claim 15 to recite that the Xaa at position 44 of SEQ ID NO: 10 is valine. Applicant states Schmidt, Tan, and Kang do not teach a SEQ ID NO: 10, wherein the Xaa at position 44 of SEQ ID NO: 10 is valine
As discussed above, Kang teaches a known base template for the generation of a tag-catcher pair. Kang teaches a sequence that has a 2 amino acid difference from the SdyTag taught by Tan and only a single amino acid difference from SEQ ID NO: 10. Tan teaches that SdyTag has the same function as SpyTag but binds to a different Catcher protein (SdyCatcher). By mutating the 44th position of the sequence taught by Kang to a V, one of ordinary skill in the art would have a reasonable expectation of success in increasing the proteins binding affinity to SdyCatcher. This would allow one of ordinary skill to use both the SpyTag and SdyTag system in the same population of cells as the it lowers the chance of cross talk and allows for multiplexed cell population targeting. Therefore,it would have been prima facie obvious to one of ordinary skill in the art to modify the wild type known template sequence taught by Kang to arrive at SEQ ID NO:10 because doing so would result in a known method of conjugating proteins.
Conclusion
NO CLAIMS ARE ALLOWED
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/DANYAL HASSAN ALAM/Examiner, Art Unit 1672
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672
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