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Claims 24 and 37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Groups II and III), there being no allowable generic or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 March 2, 2026, have been acknowledged. Claims 3, 5, 12-20, 25-34, 36, 38, and 42 were cancelled. Claims 1-2, 4, 6, 9, 11, and 41 were amended. Claims 43-49 are new. In light of the Applicant’s elected invention, claims 24 and 37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 1-2, 4, 6-11, 21-23, 35, 39-41, and 43-49 are pending and examined on the merits.
Priority
The applicant claims domestic priority from U.S. provisional application No. 63/018573, filed May 1, 2020. 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. Claims 1-2, 4, 6-11, 21-23, 35, 39-41, and 43-49 receive domestic benefit from U.S. provisional application No. 63/018573, filed May 1, 2020.
Response to Arguments
Applicant's arguments filed March 2, 2026, are acknowledged.
Applicant argues that the nucleotide sequence of adeno-associated virus serotype 2 was known to those of skill in the art at the time of the provisional application filing date, and cites to multiple prior art teaching AAV2 sequences. Thus, the sequence of the AAV2 VP1 capsid protein was known to those skilled in the art at the time of the filing date of the provisional application even though they were not designated by a specific sequence identifier such as SEQ ID NO: 1 (page 2, paragraph 3).
Applicant's arguments and the cited prior art have been fully considered and are considered persuasive.
Information Disclosure Statement
The information disclosure statement (IDS) filed on March 2, 2026, has been considered.
New 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 1-2, 4, 6-11, 21-23, 35, 39-41, and 43-49 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. This is a new rejection made in response to Applicant's amendments to the claims that is substantially similar to a previous rejection of record. Applicant’s traversal has been fully considered but is moot in response to the new rejection.
Claims 1-2, 4, 6, 9, 21, 44-45, and 47 recites the limitations "the variant minor capsid protein" (claims 1-2, 6, 9, 44-45, 47) and “the minor capsid protein(s)” (claims 4, 21, 48). There is insufficient antecedent basis for these limitations in the claims. Claims 1 and 44 refers to the at least one variant minor capsid protein VP1 or 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 or VP2, or both VP1 and VP2 variants.
Claims 2, 4, 6-11, 21-23, 35, 39-40, and 43 are also rejected because of their dependency on claim 1. Claims 45-49 are also rejected because of their dependency on claim 44.
Claim 8 recites the limitation "a variant minor capsid protein" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. Claim 1 refers to the at least one variant minor capsid protein VP1 or VP2, or both VP1 and VP2. Therefore, it is unclear whether a variant minor capsid protein is referring to the same at least one variant minor capsid protein, VP1, VP2, or both VP1 and VP2 variants of claim 1 or a different variant capsid protein.
The term “wherein the variant minor capsid protein is selectively mutated” in claims 1 and 44 is unclear which renders the claim indefinite. The term “selectively mutated” is not defined by the claim, the specification does not provide a definition for selectively mutated, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specifically, it is unclear how one is supposed to consider the selectively mutated language. It is unclear whether selectively mutated is meant to refer to the variant capsid as being selectively mutated while the other capsid proteins are not mutated. Alternatively, selectively mutated could mean that the variant minor capsid is selectively mutated only at the one or more amino acid residue sites to incorporate an unnatural amino acid. Therefore, the term is unclear.
Claims 2, 4, 6-11, 21-23, 35, 39-40, and 43 are also rejected because of their dependency on claim 1. Claims 45-49 are also rejected because of their dependency on claim 44.
Maintained Claim Rejections - 35 USC § 112
Claim 11 is 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. This rejection is repeated with regards to the rejection in the Non-final Office action mailed on November 3, 2025. Applicant’s traversal is addressed below.
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.
Response to Arguments
Applicant's arguments filed March 2, 2026, are acknowledged.
Applicant argues that the term "comparable" is a standard term of art and known to one skilled in the art. Moreover, in the Figures and Examples of the specification, Applicants provide data comparing the activity of the genetically-modified AAV to wild- type AAV to make clear the meaning of the term "comparable" (page 3, paragraph 3-page 4, paragraph 2).
Applicant's arguments have been fully considered and are considered persuasive.
Although the term may be known and used in the art, how one defines the term will be different between groups. For example, some groups may define comparable as ±10% while others may define it as ±5%. Furthermore, the data cited in the specification is not a controlling definition for comparable. Furthermore, as identified in the rejection above, 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. This alone leads to considerable variability such that a genetically modified AAV may fall within the limitations of the claims compared to one method of producing wildtype AAV vectors but may not when compared to another method. Furthermore, the amendments to claim 11 fail to fix the issues associated with the term comparable. Therefore, Applicants arguments are considered unpersuasive and the rejection is maintained.
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, 11, 21-23, 35, 40, and 44-49 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) and Yin et al. (Molecular Therapy: Oncology 32: 1. 2024). This is a new rejection made in response to Applicant's amendments to the claims that is substantially similar to a previous rejection of record. Any aspect of Applicant’s traversal that is relevant to the rejection as newly written is addressed below.
Regarding claims 1 and 44, Asokan teaches a genetically modified AAV comprising a modification 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 (considered to fall under the selectively mutated limitation) (abstract and column 5, lines 24-34). This would result in a wild type VP3 capsid protein.
Asokan teaches that designation of all amino acid positions in the AAV capsid proteins in the description of the invention is with respect to VP1 capsid subunit numbering (native AAV2 VP1 capsid protein: GenBank Accession No. AAC0378) (column 5, lines 24-34). AAC0378 has 100% sequence identity to SEQ ID NO: 1 of the instant application. Therefore, the mutation site positioning is the same. 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 11, Asokan teaches that the AAV2i mutants had comparable titers to that of parental (wild type) AAV2 vectors (Example 1). Furthermore, Asokan teaches that the AAV2i8 which is modified at positions 585-590 shows similar transduction efficiency to the wild type AAV8 in muscle (Example 10 and Table 5). This is considered to fall within the limitation comparable infectivity of target cells and comparably infectivity titer.
Regarding claims 21-23, Asokan teaches that the non-naturally occurring amino acid can be ones from Wang et al. (Annu. Rev. Biophys. Biomol. Struct. 35: 225–249. 2006) (column 13, lines 23-29). Asokan teaches that the unnatural amino acids of Wang 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. Asokan identifies CDCRGDCFC as a tumor targeting peptide that can be used (column 22, line 35-column 25, line 61). Yin evidences that CDCRGDCFC is a cyclic RGD (column 2, paragraph 2).
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 their modified AAV vectors expressing a cancer cell antigen can be administered with nucleic acids encoding cytokines (column 39, lines 23-55). Asokan teaches that the pharmaceutical composition comprising the vector can include adjuvants (column 40, lines 3-13).
Regarding claim 46, 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 47, 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 claims 48-49, Asokan teaches that the virus capsid can be a targeted virus capsid comprising a targeting sequence (e.g., substituted or inserted in the viral capsid) that directs the virus capsid to interact with cell surface molecules present on a desired target tissue. Asokan identifies position 588 as being known to tolerate insertions. Asokan teaches that the exogenous targeting sequence may be any amino acid sequence encoding a peptide that alters the tropism of a virus capsid or virus vector comprising the modified AAV capsid protein. In particular embodiments, the targeting peptide or protein may be naturally occurring. Exemplary targeting sequences include ligands and other peptides that bind to cell Surface receptors and glycoproteins, such as RGD peptide sequences, bradykinin, hormones, peptide growth factors (e.g., epidermal growth factor, nerve growth factor, fibroblast growth factor, platelet-derived growth factor, insulin-like growth factors I and II, etc.), cytokines, melanocyte stimulating hormone (e.g., C. B or Y), neuropeptides and endorphins, and the like (column 22, line 35-column 23, line 64).
Response to Arguments
Applicant's arguments filed March 2, 2026, are acknowledged.
Applicant argues only a single reference should be used in making a rejection under 35 U.S.C. 102. Extrinsic evidence may be used to explain but not expand the meaning of terms and phrases used in the reference relied upon as anticipatory of the claimed subject matter. In re Baxter TravenolLabs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991). The Examiner has cited not one, but three additional references in this rejection. Applicants submit that the three additional references are cited to expand the meaning of Asokan beyond the disclosure of the primary reference (page 5, paragraph 2- page 6, paragraph 1).
Applicant's arguments have been fully considered but they are not persuasive.
As an initial matter, the rejection has been changed in response to Applicant’s amendments to the claims and the Wang and Zhou references are no longer used as evidentiary references in the 102 rejection above. Regarding the GenBank Accession No. AAC03780 reference, Asokan specifically identifies that designation of all amino acid positions in the AAV capsid proteins in the description of the invention is with respect to VP1 capsid subunit numbering (native AAV2 VP1 capsid protein: GenBank Accession No. AAC0378) (column 5, lines 24-34). Thus, Asokan directly discusses GenBank Accession No. AAC03780 for numbering and using the GenBank Accession No. AAC03780 as evidence does not expand the meaning as all the reference provides is the sequence of AAC03780. Similarly, Asokan specifically identifies CDCRGDCFC as a tumor targeting peptide that can be incorporated into the AAV capsid and newly cited evidentiary art Yin provides evidence that CDCRGDCFC is a cyclic RGD peptide. Thus, Yin does not expand the meaning as it only identifies that CDCRGDCFC is a known cyclic RGD peptide.
Applicant argues there are significant differences between Applicants' claimed invention and the disclosure of Asokan. Asokan discloses AAV that modifies all three capsid proteins. Asokan does not disclose selective modification of AAV capsid proteins at an amino acid residue site to incorporate a natural amino acid or an unnatural amino acid (UAA) relative to the wildtype VP1 or VP2 minor capsid protein, wherein the mutation site is located at position 263, 454, 456, 587 or 588 of SEQ ID NO: 1.
Regarding claim 1, the Examiner states that Asokan discloses a genetically modified AAV 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.
But Asokan does not disclose how to selectively modify only the minor capsid proteins VP1 and/or VP2 without also modifying VP3. Asokan describes in detail the production of modified AAV2 with modifications of amino acid at positions 585-590 of the native AAV2 VP1 capsid protein, and in particular Asokan discloses a domain swapping approach to substitute a stretch of amnio acids from positions 585-590 (see
column 13, line 30 through column 14, line 18, in their Examples (see column 29, line 5 through column 31, line 23). There is no description of how to modify only the minor capsid proteins VP1 and/or VP2. Thus, in Asokan all three AAV2 capsid proteins VP1, VP2 and VP3 are modified. Asokan does not disclose that their hexapeptide substitution is limited to only minor capsid proteins VP1 or VP2. Thus, in Asokan all three AAV2 capsid proteins VP1, VP2 and VP3 are modified (page 6, paragraph 3-page 9, paragraph 1).
Applicant's arguments have been fully considered but they are not persuasive.
Regarding Applicant’s argument that Asokan does not disclose how to selectively modify only the minor capsid proteins VP1 and/or VP2 without also modifying VP3, MPEP 2152.02(b) states that the prior art provisions of AIA 35 U.S.C. 102(a)(1) and (a)(2) require only that the claimed invention is "described" in a prior art document (patent, published patent application, or printed publication). There are two basic requirements that must be met by a prior art document in order to describe a claimed invention such that it is anticipated under AIA 35 U.S.C. 102. First, "each and every element of the claimed invention" must be disclosed either explicitly or inherently, and the elements must be "arranged or combined in the same way as in the claim." See In re Gleave, 560 F.3d 1331, 1334, 90 USPQ2d 1235, 1237-38 (Fed. Cir. 2009), citing Eli Lilly & Co. v. Zenith Goldline Pharms., Inc., 471 F.3d 1369, 1375, 81 USPQ2d 1324,1328 (Fed. Cir. 2006); Net MoneyIN, Inc. v. VeriSign, Inc., 545 F.3d 1359, 1370, 88 USPQ2d 1751, 1759 (Fed. Cir. 2008); In re Bond, 910 F.2d 831, 832-33, 15 USPQ2d 1566, 1567 (Fed. Cir. 1990). Second, a person of ordinary skill in the art must have been enabled to make the invention without undue experimentation. See Gleave, 560 F.3d at 1334, 90 USPQ2d at 1238 (citing Impax Labs., Inc. v. Aventis Pharms. Inc., 545 F.3d 1312, 1314, 88 USPQ2d 1381, 1383 (Fed. Cir. 2008), and In re LeGrice, 301 F.2d 929, 940-44, 133 USPQ 365, 372 (CCPA 1962)). Thus, in order for a prior art document to describe a claimed invention such that it is anticipated under AIA 35 U.S.C. 102(a)(1) or (a)(2), it must disclose all elements of the claimed invention arranged as they are in the claim, and also provide sufficient guidance to enable a person skilled in the art to make the claimed invention. There is, however, no requirement that a prior art document meet the "how to use" requirement of 35 U.S.C. 112(a) in order to qualify as prior art. See Gleave, 560 F.3d at 1334, 90 USPQ2d at 1237-38; see also In re Schoenwald, 964 F.2d 1122, 1124, 22 USPQ2d 1671, 1673 (Fed. Cir. 1992) (holding that a claimed compound was anticipated even though the prior art reference did not disclose a use for the compound); Schering Corp. v. Geneva Pharms., Inc., 339 F.3d 1373, 1380-81, 67 USPQ2d 1664, 1670 (Fed. Cir. 2003) (pointing out that actually reducing the invention to practice is not necessary in order for a prior art reference to anticipate); Impax Labs, 468 F.3d at 1382 (stating that "proof of efficacy is not required for a prior art reference to be enabling for purposes of anticipation"). Furthermore, compliance with the "how to make" requirement is judged from the viewpoint of a person of ordinary skill in the art, and thus does not require that the prior art document explicitly disclose information within the knowledge of such a person. See In re Donohue, 766 F.2d 531, 533, 226 USPQ 619, 621 (Fed. Cir. 1985).
As identified in Asokan, Asokan teaches a genetically modified AAV comprising a modification 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 (considered to fall under the selectively mutated limitation) (abstract and column 5, lines 24-34). This would result in a wild type VP3 capsid protein.
Asokan teaches that designation of all amino acid positions in the AAV capsid proteins in the description of the invention is with respect to VP1 capsid subunit numbering (native AAV2 VP1 capsid protein: GenBank Accession No. AAC0378) (column 5, lines 24-34). AAC0378 has 100% sequence identity to SEQ ID NO: 1 of the instant application. Therefore, the mutation site positioning is the same. 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).
Therefore, Asokan fulfills the first requirement for a 102 rejection.
Regarding the second element, although Asokan does not identify a specific method of expressing VP1 alone, VP2 alone or VP1 and VP2, methods of accomplishing this were already well known within the art. In order to complete the art of record and rebut Applicant’s arguments, Warrington et al. (Journal of Virology 78: 6595–6609. 2004) evidences that it was already known how one can express the VP1 and/or VP2 without expressing VP3 by altering the start codons associated with each one (whole document). Therefore, there would be no undue experimentation associated with expressing the capsid subunits independently to achieve modification in only one or two of the capsid subunits.
Therefore, Asokan fulfills the second requirement for a 102 rejection.
As such, Applicant’s arguments are considered unpersuasive.
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 1-2 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 Feiner et al. (Int. J. Mol. Sci. 20: 1-19. 2019). This is a new rejection made in response to Applicant's amendments to the claims.
The teachings of Asokan are as discussed above.
Asokan is silent regarding the method of expressing the capsid subunits independently to achieve modification in only VP2.
However, Feiner teaches genetically modified AAV vectors wherein β-Lactamase was inserted into the VP2 capsid subunit at position 587. Feiner teaches that they used an adapted plasmid system for the production of mosaic rAAVs exclusively bearing VP2 loop modifications (abstract, page 2, paragraph 4-page 3, paragraph 1). 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. Plasmid CMV_Kozak_VP2 (pZMB0315) solely expressed VP2 (Figure 4a, lane 4) was detected with an expected increase in chemiluminescence. 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). 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, disclosed by paragraph 0010 of the instant specification (page 12, paragraphs 4-5). Therefore, VP1 and VP3 would have wild type capsid proteins. As can be seen in Figure 6, the TNLQRGNRQAAT corresponds to positions 581-592 in SEQ ID NO: 1 of the instant application and also identified as corresponding to positions 581-592 in Feiner. Therefore, Feiner is modifying position 587 in correspondence with position 587 of SEQ ID NO: 1 of the instant application.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the method of Feiner to generate VP2 modified AAV capsids to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use the method of Feiner with a reasonable expectation of success because Asokan and Feiner are interested in modifying VP2 alone without modifying VP1 or VP3 to generate an AAV vector comprising the modified capsid and both are interested in modifying VP2 in the 587 loop region (Asokan wants to modify positions 585-590 and Feiner wants to modify position 587). Furthermore, Feiner successfully reduces to ractice that their method can modify VP2 alone by preventing translation of VP3 by removing the VP3 start codon and incorporating a Kozak sequence upstream of the VP2 start codon. Therefore, it would have been obvious that this method could be used to generate modified VP2 alone as it has already been shown to work. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1, 4, 6-10, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent No. 8889641 (Asokan) and Feiner et al. (Int. J. Mol. Sci. 20: 1-19. 2019) as applied to claim 1 above, and further in view of Katrekar et al. (Scientific Reports 8: 1-8. 2018), as evidenced by Wang et al. (Annu. Rev. Biophys. Biomol. Struct. 35: 225–249. 2006). This is a new rejection made in response to Applicant's amendments to the claims.
Regarding claim 4, the teachings of Asokan and Feiner are as discussed above. Asokan, as stated supra, 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)
The combined teachings of Asokan and Feiner do not teach wherein a stop codon is incorporated in the capsid protein.
However, Katrekar teaches that stop codons (specifically TAG) 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 TAG 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 Asokan and Feiner by incorporating a TAG 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 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, including substitutions of those amino acids with non-naturally occurring amino acids. Furthermore, Katrekar teaches that modification at position 587 to incorporate a TAG stop codon and a UAA led to a 5-15 fold increase in the viral titer. Therefore, it would have been obvious to modify position 587 to incorporate a TAG stop codon and a UAA as Asokan already identifies that this position can be modified with an unnatural amino acid and Katrekar teaches that modifying this position increased the viral titer. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 6, Katrekar teaches that the TAG stop codon can be incorporated into AAV vectors at position 589 (the specification discloses that TAG is a suppressor stop codon (paragraphs 0016 and 0091)) and Asokan teaches that the non-naturally occurring amino acid can be phenylalanine analogs (Table 3).
Regarding claims 7-8, 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 7-8.
Regarding claims 9-10, the specification discloses that in one ernbodirnent of the present invention the nmtated amino acid residue(s) of the modified AA Vis functionalized or conjugated with a chemical or protein entity (also referred to herein as a bioconjugation handle or group) (paragraph 0023). Furthermore, the specification discloses 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 handles per fully-assembled AAV capsid when VP2 (5) is modified to incorporate bioconjugation handles (paragraph 0010). As the combined teachings of Asokan, Feiner, and Katrekar teaches that their modified AAV capsids can involve modification of just VP2 and that one modification of the VP2 sequence can occur to incorporate a non-naturally occurring amino acid, such as the ones from Wang et al. (Annu. Rev. Biophys. Biomol. Struct. 35: 225–249. 2006) (column 13, lines 23-29) and that the unnatural amino acids of Wang can be can be incorporated into the AAV capsid subunit to chemically link molecules of interest (i.e. bioconjugation handles) to the AAV capsid protein including RGD for targeted delivery to cancer cells, this would lead to incorporation of 5 bioconjugation handles as a result of the unnatural amino acid modification and chemical linkage of molecules of interest at a single amino acid residue, such as position 589.
Regarding claim 41, the teachings of Asokan and Feiner are as discussed above. Feiner, as stated supra, 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).
The combined teachings of Asokan and Feiner do not wherein the host cell comprises a coding sequence encoding an engineered aminoacyl-tRNA synthetase.
However, Katrekar teaches that stop codons (specifically TAG) 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.
Therefore, it would have been obvious to transfect the host cells with a sequence encoding an engineered aminoacyl-tRNA synthetase in order to incorporate the unnatural amino acid at the amber stop codon at position 587.
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). This rejection is repeated with regards to the rejection in the Non-final Office action mailed on November 3, 2025. Applicant’s traversal has been addressed above.
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 43 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent No. 8889641 (Asokan), Feiner et al. (Int. J. Mol. Sci. 20: 1-19. 2019), Katrekar et al. (Scientific Reports 8: 1-8. 2018) as applied to claims 1 and 4 above, and further in view of United States Patent No. 9012224 (Bowles) and Wang et al. (Annu. Rev. Biophys. Biomol. Struct. 35: 225–249. 2006). This is a new rejection made in response to Applicant's amendments to the claims.
The teachings of Asokan, Feiner, and Katrekar are as discussed above.
The combined teachings of Asokan, Feiner, and Katrekar do not teach wherein a stop codon is incorporated in the capsid protein at position 454.
However, Bowles teaches chimeric virus vectors comprising a chimeric AAV capsid comprising one or more selective amino acid insertions and/or substitutions selected from the group consisting of substituting position 454 with a glycine, alanine, valine, lysine, isoleucine, proline, serine, threonine or asparagine into the capsid subunit(s) (column 14, line 61-column 17, line 44). Bowles teaches that modification at position 454 improved muscle transduction for AAV2 (Figure 6 and column 36, lines 4-8).
Wang teaches that photocaged serine can be site-specifically incorporated into proteins. The side chain hydroxy or thiol groups of these amino acids are blocked by nitrobenzyl groups, which can be photochemically removed either in vivo or in vitro upon irradiation with 330 nm light (page 238, column 2, paragraph 2-page 239, column 1, paragraph 1).
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 Asokan, Feiner, and Katrekar by incorporating a TAG stop codon at position 454 and then incorporating a photocaged serine UAA at that position using a tRNA/aminoacyl-tRNA synthetase 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 Bowles identifies position 454 as one suitable for modification that is capable of altering tissue specific transduction efficiency and that one of those modifications can be a serine. Furthermore, Wang teaches that photocaged serine can be incorporated into a protein allowing for photochemical modification of the serine to open the side chain hydroxy upon irradiation with 330 nm light. This alteration would allow for the modified AAV capsid to be modified, as needed, to alter tissue specific transduction, thus increasing flexibility of the modified AAV. Katrekar already teaches that incorporating a TAG stop codon can be used to introduce an unnatural amino acid at position 587. It would have been obvious that the same method could be used to introduce the photocaged serine at position 454. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Conclusion
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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/KEENAN A BATES/Examiner, Art Unit 1631
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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