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 .
Priority
This is a National Stage Entry under 35 U.S.C. 371 of International Patent Application
No. PCT/EP2021/074987, filed September 10, 2021. This application also claims priority to EP Provisional Application No. EP20195554.9, filed on September 10, 2020.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-13, and species (a) VP1 of AAV2 (SEQ ID NO: 2) (reading on claims 2 and 3) and (b) a RBD portion of the SARS-CoV-2 spike protein comprising the amino acid sequence of SEQ ID NO: 11 (reading on claim 9), in the reply filed on 1/26/2026 is acknowledged.
Claims 14 - 17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1/26/2026.
Specification
Objections to Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Examples include: https://robetta.bakerlab.org/, https://www.cgl.ucsf.edu/chimera, and https://www.rcsb.org/
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1– 13 are 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.
The term “about” in claims 1, 4, and 7 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 1 recites “about 75 - 400 amino acids”
Claim 4 recites “about 60 VPs”
Claim 7 recites “about 75 - 300 amino acids”
Regarding claims 1, 3 – 5, 9, and 11, the claim language ‘preferably’ renders the limitations because it is unclear if the claims specifically require such limitation(s) or not.
The dependent claims and do not add additional clarity and, therefore, are also indefinite.
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(s) 1 – 3, 5 – 8, 10, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Rybniker et al (J Virology, 2012, hereinafter, “Rybniker”) in view of Buning et al (Mol Ther Methods & Clinical Development, 2019, hereinafter, “Buning”) as evidenced by Denis et al, (Infect Immun, 1998, hereinafter, “Denis”).
Rybniker teaches the modification and engineering of AAV capsids to display antigens leading to antigen-specific immunogenicity (Abstract). Along with the use of AAV2 capsids as scaffolds for antigen presentation, Rybniker designed the payload of the AAV2 to overexpress transgenes to increase vaccine efficacy (Abstract). This combination leads to faster immune responses and an antibody pool with higher avidity than other vectors (Abstract).
Regarding claims 1 - 3, Rybniker teaches inserting the Ag85A gene lacking the mycobacterial leader peptide into VP2 (Page 13800 Col 1 ¶2). The VP1, VP2, and VP3, gene only differ in the N terminus composition, rendering the amino acid sequence after aa137 as identical to vp1 (Page 13800 Col 1 ¶2). Rybiker teaches that large insertions into VP2 are tolerated and produce infectious capsids that display antigens (Figure 1 and 2). Rybinker does not teach the specific insertion of the antigen into the variable region VIII or IV.
, Claim 1 recites the insertion of an amino acid into VR VIII or VR IV. Buning teaches the insertion of exogenous proteins into the VR VIII of VP2 the AAV2 capsid (Figure 2). VP1 and VP2 are encoded by the same gene and share 65 amino acids, known as the VP1/VP2 common region, and importantly VR VIII and VR IV are downstream of the VP1 unique region, thus making VR VIII and VR IV of VP1 and VP2 indistinguishable (Section: Capsid Modifications, ¶1, Figure 1). SEQ ID No: 2 of the instant application encodes for the VP1 of AAV2, and therefore also encodes for VP2.
With regards to claim 2 and 3, Buning teaches the insertion of amino acids into VR VIII at particular insertion sites, namely I-584, I585, I-587, and I-588, which results in the display of the exogenous protein on the AAV capsid (Tables 1 -4 and Page 253 Col 1 ¶2). Buning also teaches the insertion of amino acids into VR IV, particularly at I-453 (Tables 1 -4 and Page 253 Col 1 ¶2). Buning also teaches inserting exogenous proteins into I-585 and I-588 results in disruption of AAV2 binding to HSPG thereby reducing AAV attachment to cells (Page 253 Col 1 ¶2 and Page 256 Col 2 ¶2).
Regarding claim 5, Rybniker teaches the expression of Ag85 gene or the GFP gene inside an infectious modified capsid AAV where the transgenes are components of the ITR flanked genome (Figure 1, Page 13800 Col 1 ¶3).
Regarding claim 7, Buning teaches insertion into multiple points of the VP2 (Table 3; Position: I-520 and I-584).
Regarding claim 10, Denis evidences that AG85 has a binding domain for fibronectin (Page 1527, Col 2 ¶1).
Regarding claim 13, Rybniker teaches the use of AAV2 capsids with antigens included in the VP2 for vaccination (Abstract).
Rybniker and Buning are considered to be analogous to the claim invention because they both aim to display exogenous proteins on the AAV2 capsid. Rybniker and Buning teach that the exogenous proteins can be displayed by insertion into the VP 1, 2, and 3 genes. Rybinker teaches the insertion of a large antigen, that is about 290 amino acids in size as a N-terminal fusion to VP2, teaching that large antigen displays in the AAV2 capsid are possible and still result in an infectious virus (Rybinker, Page 13800 Col 1 ¶2; see also Denis, Page 1527, Col 2 ¶1). Buning teaches that exogenous proteins can be inserted in to the VR VIII region and that inserting at specific points, such as between I-587 and I-588, leads to disruption of HSPG binding allowing the viral particle to remain in a non-cell bound conformation for longer (Page 253 Col 1 ¶2 and Page 256 Col 2 ¶2).
Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to utilize the art-recognized method to insert the large antigen as taught by Rybniker with the specific insertion sites taught by Buning because doing so would advantageously allow one to not only display a large antigen but to also disrupt HSPG binding without affecting viral activity. One of ordinary skill in the art would have had a reasonable expectation of success in inserting a different large antigen into VR VIII at sites between I-585 and I-588 given that this method is well known, has been successfully demonstrated, and commonly used in 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 4 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Rybniker and Buning as applied to claims 1 – 3, 5 – 8, 10, and 13 above, and further in view of Warrington et al. (J Virologyy, 2004, hereinafter, “Warrington”) and Buning et al. (EP3461836A1, hereinafter, “Buning ‘836”).
As discussed above, claims 1 – 3, 5 – 8, 10, and 13 were rendered prima facie obvious by the teachings of Rybniker and Buning. The references fail to teach the specific ratio of VPs or composition of the capsid or the use of the AAV2 with a pharmaceutically acceptable excipient.
However, Warrington teaches insertion of large peptides into the N-terminus at VP2 of AAV (Abstract). Warrington teaches the insertion peptides from 8 kDa to 30 kDa into VP1, 2, and 3 of AAV and uses specific combinations of the VPs to produce AAV or AAVLP (Abstract, Table 2). These large insertions resulted in the successful infection and monitoring of AAVs (Abstract).
Buning ‘836 teaches modifying the capsid of AAV to include exogenous proteins with multiple insertions in the capsid.
Regarding claim 4, Warrington teaches that an AAV or AAVLP can be made from VP3 alone (Table 2).
Regarding claim 12, Buning ‘836 teaches the use of a modified AAV2 with the use of excipients (¶0100).
Rybniker, Buning, Warrington, and Buning ‘836 are considered to be analogous to the claim invention because they aim to display exogenous proteins on the AAV2 capsid. Warrington and Buning ‘836 teach that the exogenous proteins can be displayed by insertion into the VP 1, 2, and 3 genes. Warrington teaches that the AAV and AAVLP can be made by a number of different VP1, VP2, and VP3 combinations (Table 2). Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to utilize the art-recognized method to insert the large antigen as taught by Rybniker with the specific insertion sites taught by Buning in the ratio and combinations taught by Warrington and Buning ‘836 because doing so would advantageously allow one to display a large antigen while maintaining AAV activity. One of ordinary skill in the art would have reasonable expectation of success in inserting a different large antigen into the AAV capsid at different VP ratios, along with an excipient, given that this method is well known, has been successfully demonstrated, and commonly used in 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 6, 8, and 9 is rejected under 35 U.S.C. 103 as being unpatentable over Rybniker and Buning as applied to claims 1 – 3, 5 – 8, 10, and 13 above, and further in view of Lu et al. (Cell Research, August 2020, hereinafter, “Lu”) in further view of Oostvogels (US Application US20220211838A1, hereinafter “Oostvogels”).
As discussed above, claims 1 – 3, 5 – 8, 10, and 13 were rendered prima facie obvious by the teachings of Rybniker and Buning. The references fail to teach the insertion of a portion of the SARS-CoV-2 spike protein into the AAV2 capsid.
However, regarding claims 6 and 8, Lu teaches the use of the SARS-CoV-2 spike protein in a VLP to induce immune responses within subjects (Figure 1).
Regarding claim 9, Lu includes using the RBD domain alone to stimulate an immune response (Figure 1). Oostvogels uses the mRNA RBD of the SARS-CoV-2 spike protein in combination with lipid nanoparticles as a vaccine to stimulate an immune response (¶0003, ¶0207 -¶0209), teaching the exact sequence as SEQ ID No: 9 (reproduced below, “Qy” is the instant application, “Db” is Oostvogels).
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Rybniker, Buning, Lu, and Oostvogels are considered to be analogous to the claim invention because they aim to use a portion of immunogenic protein to induce an immune response. Lu teaches that the spike protein of SARS-CoV-2 displayed on a VLP can stimulate an immune response. Lu also teaches that the RBD domain of the spike protein can stimulate an immune response. However, Lu does not explicitly teach displaying the RBD domain on the VLP, nor does Lu teach the exact sequence of SEQ ID No: 11. Oostvogels does teach the exact sequence of SEQ ID No:9 and teaches this portion can be used to stimulate an immune response.
Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to utilize the art-recognized method of inserting an RBD domain, as taught by Lu, into the VP2 of AAV2 large antigen, as taught by Rybniker and Buning with the exact RBD sequence taught by Oostvogels. Lu teaches that the spike protein can be displayed in a VLP and that the RBD is enough to stimulate an immune response while Rybniker and Buning teach a large antigen can be inserted into the VP2 portion of the AAV2 capsid because combining the two methods would advantageously allow one to display a RBD of SARS-CoV-2 while directing AAV activity. One of ordinary skill in the art would have reasonable expectation of success in inserting a RBD of SARS-CoV-2 into the AAV capsid given that this method is well known, has been successfully demonstrated, and commonly used in 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.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Rybniker and Buning as applied to claims 1 – 3, 5 – 8, 10, and 13 above, and further in view of Eichhoff et al (Molecular Therapy Methods & Clinical Development, 2019, hereinafter, “Eichhoff”).
As discussed above, claims 1 – 3, 5 – 8, 10, and 13 were rendered prima facie obvious by the teachings of Rybniker and Buning. The references fail to teach the protein inserted into the capsid is a single-domain antibody.
However, , Eichhoff teaches the inclusion of a single domain antibody inserting into I-453 to I-459 of VP1 capsid protein of AAV2 (Section: Results, ¶1).
Rybniker, Buning, and Eichhoff are considered to be analogous to the claim invention because they aim to use AAV capsid modifications. Eichoff teaches the insertion of a single-domain antibody into the capsid of AAV2. Rybniker and Buning teach that AAV and AAVLP with an insertion of an antigen in VP2 can induce an immune response. Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to utilize the art-recognized method of inserting a single domain antibody, as taught by Eichhoff, into the VP2 of AAV2, as taught by Rybniker and Buning because doing so would advantageously allow targeting of specific cell types using a modified AAV2. One of ordinary skill in the art would have reasonable expectation of success in inserting a single domain antibody into the AAV capsid given that this method is well known, has been successfully demonstrated, and commonly used in 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.
Conclusion
NO CLAIMS ARE ALLOWED
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Danyal H Alam whose telephone number is (571)272-1102. The examiner can normally be reached M - F 9am - 5pm.
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/DANYAL HASSAN ALAM/ Examiner, Art Unit 1672
/THOMAS J. VISONE/ Supervisory Patent Examiner, Art Unit 1672