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 .
Election/Restrictions
Applicant’s election without traverse of Group I (Claims 1-11, 20-23, 35, and 39-42; drawn to a genetically modified AAV) in the reply filed on September 4, 2025, is acknowledged.
Claims 24 and 37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Groups II and III), there being no allowable generic or linking claim. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
DETAILED ACTION
The amended claims filed on September 4, 2025, have been acknowledged. Claims 12-19, 25-34, 36, and 38 were cancelled. Claims 1-2, 4-6, 9, 11, 20-24, and 37 were amended. In light of the Applicant’s elected invention, claims 24 and 37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-11, 20-23, 35, and 39-42 are pending and examined on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/018573, filed May 1, 2020, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. This provisional application does not provide information related to SEQ ID NO: 1. However, Application No. PCT/US2021030489, filed on May 3, 2021, did provide the above information. Therefore, claims 1-2, 5-11, 21-23, 35, and 39-42 receive domestic benefit from US provisional application 63/018573, filed May 1, 2020, while claims 3-4 and 20 receive domestic benefit from application No. PCT/US2021030489, filed on May 3, 2021.
Information Disclosure Statement
The information disclosure statements (IDS) filed on October 31, 2022, November 15, 2022, and October 2, 2025, have been considered.
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 1-11, 20-23, 35, and 39-40 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.
Claims 1-6, 9, and 20-21 recites the limitations "the variant minor capsid protein", “the AAV capsid protein”, “the capsid protein(s)”, “the mutated VP1“, and “the minor capsid protein”. There is insufficient antecedent basis for these limitations in the claims. Claim 1 refers to the at least one variant minor capsid protein VP1, VP2, or both VP1 and VP2. Therefore, it is unclear whether any of the recited limitations above are referring to the same at least one variant minor capsid protein, VP1, VP2, or both VP1 and VP2 variants.
Claims 2-11, 20-23, 35, and 39-40 are also rejected because of their dependency on claim 1.
The term “comparable” in claim 11 is a relative term which renders the claim indefinite. The term “comparable” 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. It is unclear what level of titer or infectivity would fall under comparable levels to a WT AAV. Furthermore, it is not clear what level of infectivity and titer is representative of AAV wild type as there are many production methods that have different activity levels.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3, 5-11, 20-23, 35, and 40 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by United States Patent No. 8889641 (Asokan), as evidenced by Genbank (AAC03780), Wang et al. (Annu. Rev. Biophys. Biomol. Struct. 35: 225–249. 2006), and United States Patent Application No. 2016029785 (Zhou).
Regarding claim 1, Asokan teaches a genetically modified AAV comprising a modified in the amino acid sequence in the three-fold axis loop 4 and virus capsids and viral vectors comprising the modified AAV capsid protein. The capsid subunits can be expressed independently to achieve modification in only one or two of the capsid subunits, such as VP1 alone, VP2 alone, or VP1 and VP2 (abstract and column 5, lines 24-34). This would result in a wild type VP3 capsid protein. Asokan teaches that the modification is incorporated into the region of amino acid 585 to 590 of the amino acid sequence of the AAV2 capsid protein or the corresponding positions of other AAV, including substitutions of those amino acids with naturally occurring or non-naturally occurring amino acids (column 17, line 13-column 21, line 16).
Regarding claim 5, Asokan teaches that one of the naturally occurring amino acid modifications can be a cysteine (column 17, line 13-column 21, line 16).
Regarding claim 6, Asokan teaches that the non-naturally occurring amino acid can be phenylalanine analogs (Table 3).
Regarding claims 6-8, Asokan teaches that the non-naturally occurring amino acid can be ones from Wang (column 13, lines 23-29). Wang evidences representative unnatural amino acid 25 that falls within a formula identified in claim 7 (Figure 5). Furthermore, Wang evidences representative unnatural amino acid 9 also known as p-benzoylphenylalanine (Figure 5 and page 238, column 1, paragraph 2). Therefore, the AAV capsid of Asokan could incorporate the non-natural amino acids of Wang to fall within the limitations of claims 6-8.
Regarding claims 9-10, the specification discloses that cysteine is a natural amino acid with bioconjugation handles and that VP1 and VP2 are present at 5 copies each per AAV capsid which equates to 5 or 10 handles per fully-assembled AAV capsid when VP1 (5), VP2 (5), or VP1 and VP2 (10) are modified to incorporate bioconjugation handles (paragraph 0010). As Asokan teaches that their modified AAV capsids can involve modification of just VP1, just VP2, or just VP1 and VP2 and that one modification of the VP1 or VP2 sequence can occur to incorporate a cysteine residue, this would lead to incorporation of 5 or 10 bioconjugation handles as a result of the single cysteine residue modification.
Regarding claim 11, Asokan teaches that the AAV2i mutants had comparable titers to that of parental (wild type) AAV2 vectors (Example 1).
Regarding claim 20, Asokan teaches that the AAV capsid protein can have the native AAV2 capsid protein or at least 90% sequence similar to the native sequence as identified by GenBank Accession No. AAC03780 (column 15, lines 13-18). GenBank (AAC03780) evidences that this sequence has 100% sequence identity to SEQ ID NO: 1 of the instant application. Asokan teaches that they mutated positions 585-590 (column 17, line 13-column 21, line 16).
Regarding claims 21-23, Asokan teaches that the unnatural amino acids of Wnag can be can be incorporated into the AAV capsid subunit to chemically link molecules of interest to the AAV capsid protein including RGD for targeted delivery to cancer cells (column 22, line 35-column 23, line 7). Zhou evidences that cyclic RGD is a known type of RGD for targeting tumor cell surface proteins (paragraph 0039).
Regarding claim 35, Asokan teaches that their modified AAV vectors expressing a cancer cell antigen can be administered with nucleic acids encoding cytokines (column 39, lines 23-55).
Regarding claim 40, Asokan teaches that the pharmaceutical composition comprising the vector can include adjuvants (column 40, lines 3-13).
Claims 1-3, 5, 9, 11, and 41 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Feiner et al. (Int. J. Mol. Sci. 20: 1-19. 2019), as evidenced by United States Patent No. 8889641 (Asokan), Genbank (AAC03780), and GenBank (AY425988).
Regarding claim 1, Feiner teaches genetically modified AAV vectors wherein β-Lactamase was inserted into the VP2 capsid subunit at position 587 (abstract, page 2, paragraph 4-page 3, paragraph 1). Feiner teaches that although the lactamases pose a steric hindrance to the interaction with the cell, the wild-type capsid proteins can still engage with HSPG. Furthermore, Feiner teches that there are ~5 β-lactamases on the modified AAV which would account for β-lactamases only being incorporated in the VP2 subunit, discloses by paragraph 0010 of the instant specification (page 12, paragraphs 4-5). Therefore, VP1 and VP3 would have wild type capsid proteins.
Regarding claim 2, Feiner teaches that they removed the VP3 start codon and incorporated a Kozak sequence upstream of the VP2 start codon to prevent VP3 translation and only generate modified VP2 capsid proteins (page 7, paragraph 4-page 9, paragraph 3 and Figure 4).
Regarding claim 3, Feiner teaches that the wild type sequence used for modification is based on the AAV2 wild type sequence (Figure 3). As stated supra, the vector produced by Feiner results in incorporation of wild type VP1 and VP3 capsid proteins. Asokan evidences that the native AAV2 capsid protein is represented by GenBank Accession No. AAC03780 (column 15, lines 13-18). GenBank (AAC03780) evidences that this sequence has 100% sequence identity to SEQ ID NO: 1 of the instant application. Therefore, the VP1 capsid protein of the AAV vector would have a sequence 100% identical to SEQ ID NO: 1.
Regarding claims 5 and 9, Feiner Supplementary Table S3 teaches that the β-lactamase used for insertion is β-lactamase 14FM which is based on the β-lactamase of GenBank ID: AY425988 with 14 mutations. GenBank (AY425988) evidences that the β-lactamase insertion of Feiner would have three cysteine residues. The specification discloses that cysteine is a natural amino acid with bioconjugation handles (paragraph 0010).
Regarding claim 11, Feiner teaches that rAAV_VP2_587_bla has a comparable titer (Table 2).
Regarding claim 41, Feiner teaches that they eliminated the VP2 start codon in one plasmid (Rep_VP13 plasmid (pZMB0600) and eliminated the start codon for VP3 in a separate plasmid (pZMB0577_pSB1C3_001_CMV_Kozak_VP2 _453_587wtbla) as part of a four plasmid system in cells (page 7, paragraph 4-page 9, paragraph 3 and Figure 4).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent No. 8889641 (Asokan) as applied to claim 1 above, and further in view of United States Patent Application No. 2016029785 (Zhou).
Regarding claim 39, the teachings of Asokan are as discussed above.
Asokan does not teach wherein the genetically modified AAV vector is part of a kit.
However, Zhou teaches that their genetically modified AAV vector can be incorporated in a kit (claims 1 and 19 and paragraph 0086).
As Zhou teaches that genetically modified AAV vectors can be incorporated into a kit, it would have been obvious that the genetically modified AAV of Asokan could also be incorporated into a kit. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1-4 and 41-42 are rejected under 35 U.S.C. 103 as being unpatentable over Feiner et al. (Int. J. Mol. Sci. 20: 1-19. 2019) as applied to claims 1-3 and 41 above, and further in view of Katrekar et al. (Scientific Reports 8: 1-8. 2018).
The teachings of Feiner are as discussed above.
Feiner not teach wherein a stop codon is incorporated in the capsid protein.
However, Katrekar teaches that stop codons can be incorporated into AAV vectors at position 589 for incorporation of UAA amino acids using a vector encoding a tRNA/aminoacyl-RNA synthetase in transfected cells. Katrekar teaches that incorporation of a stop codon and UAA at position 589 lead to a 5-15 fold increase in viral titer (page 2, paragraph 2-page 3, paragraph 2 and page 5, paragraph 6)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the AAV vector of Feiner by incorporating a stop codon at position 587 and then incorporating a UAA at that position using a tRNA/aminoacyl-tRNA synthetase, as identified by Katrekar, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because modification at position 587 to incorporate a UAA led to a 5-15 fold increase in the viral titer. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEENAN A BATES whose telephone number is (571)270-0727. The examiner can normally be reached M-F 7:30-5:00.
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/KEENAN A BATES/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
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