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 with traverse of Group I (Claims 16-24, 26, 29-32, and 34-35; drawn to an AAV vector) in the reply filed on March 10, 2025, is acknowledged.
Claims 27-28, and 36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Groups II-IV (newly added claim 36)), there being no allowable generic or linking claim.
Applicant further elected the following species:
a. A monosaccharide (a ligand) as the functional moiety
b. N-acetylgalactosamine (GalNac) as the monosaccharide moiety
In light of the Applicant’s elected species, claims 20-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
DETAILED ACTION
The amended claims filed on September 22, 2025, have been acknowledged. Claims 1-15, 25, and 33 were cancelled. Claims 16, 26-27, 29-32, and 34-36 were amended. In light of the Applicant’s elected invention and species, claims 20-23, 27-28, and 36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 16-19, 24, 26, 29-32, and 34-35 are pending and examined on the merits.
Priority
The applicant claims foreign priority from EP19185879.4 filed on July 11, 2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55, received January 10, 2022. Claims 16-19, 24, 26, 29-32, and 34-35 find support in foreign application EP19185879.4.
Specification
The substitute specification filed September 22, 2025, has been entered.
Withdrawn Claim Rejections - 35 USC § 102
The prior rejection of claims 16-18 and 24 under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by United States Patent Application No. 20110104051 (Francis) is withdrawn in light of Applicant’s amendments to claim 16 to recite a specific structure for the chemically modified tyrosine and wherein the AAV comprises an exogenous nucleic acid and is capable of infecting and transducing cells.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 16, 29, and 31 under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 20110104051 (Francis) is withdrawn in light of Applicant’s amendments to claim 16 to recite a specific structure for the chemically modified tyrosine and wherein the AAV comprises an exogenous nucleic acid and is capable of infecting and transducing cells.
The prior rejection of claims 16, 18-19, 29, and 32 under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 20110104051 (Francis), as applied to claims 16, 18, and 29 above and in further view of World Intellectual Property Organization Application No. 2017212019 (Mevel; cited in IDS), and Medina et al. (Biomaterials 32: 4118-4129. 2011) is withdrawn in light of Applicant’s amendments to claim 16 to recite a specific structure for the chemically modified tyrosine and wherein the AAV comprises an exogenous nucleic acid and is capable of infecting and transducing cells.
The prior rejection of claims 16, 18-19, 25-26, 29, and 32-33 under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 20110104051 (Francis), as applied to claims 16, 18, and 29 above and in further view of World Intellectual Property Organization Application No. 2017212019 (Mevel), Medina et al. (Biomaterials 32: 4118-4129. 2011), and Dai et al. (Cancer Gene Therapy 19: 77–83. 2012) is withdrawn in light of Applicant’s amendments to claim 16 to recite a specific structure for the chemically modified tyrosine.
The prior rejection of claims 16 and 29-30 under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 20110104051 (Francis), as applied to claims 16 and 29 above and in further view of Boutureira et al. (Chem Rev 115: 2174-2195. 2015; cited in IDS) is withdrawn in light of Applicant’s amendments to claim 16 to recite wherein the AAV comprises an exogenous nucleic acid and is capable of infecting and transducing cells.
The prior rejection of claims 16, 29, and 35 under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 20110104051 (Francis) and Boutureira et al. (Chem Rev 115: 2174-2195. 2015), as applied to claims 16 and 29 above and in further view of World Intellectual Property Organization Application No. 2017212019 (Mevel) and Medina et al. (Biomaterials 32: 4118-4129. 2011) is withdrawn in light of Applicant’s amendments to claim 16 to recite wherein the AAV comprises an exogenous nucleic acid and is capable of infecting and transducing cells.
New 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 16-19, 24, 26, 29-32, and 34-35 are rejected under 35 U.S.C. 103 as being unpatentable over World Intellectual Property Organization Application No. 2017212019 (Mevel; cited in IDS), United States Patent Application No. 20110104051 (Francis), and Kothari et al. (Scientific Reports 7: 1-10. 2017).
Regarding claims 16-19 and 31-32, Mevel teaches methods of chemically coupling ligands to the exterior surface of the capsid of AAV by reacting ligands (such as monosaccharides) to reactive moieties of amino acids located at the surface of the AAV particles. Mevel teaches AAV vector particles wherein the capsid is modified by chemically coupling N-acetylgalactosamine (NAcGal) to improve delivery of an exogenous gene to targeted hepatocyte cells through selective transduction of hepatocytes (page 1, lines 3-24, page 5, lines 22-30, page 14, lines 5-16, and page 28, line 12-page 30, line 29 and Figure 1). Mevel teaches that their AAV vectors can be used to treat cancer (page 33, lines 1-7). Mevel is focused on modifying primary amine groups, such as from lysine (claim 1 and page 11, lines 11-25).
Mevel does not teach modifying tyrosine residues.
However, Francis teaches that viral capsids, such as parvoviruses (AAV viruses are a species of parvovirus; paragraphs 0053-0055), could be chemically modified at interior or exterior tyrosine residues using polymers and carbohydrates to attach therapeutic agents, such as diagnostic imaging compounds labeled with 18F, such as 2-18F-2-deoxy-D-glucose (paragraphs 0006, 0053-0078, Figures 2-3, and claims 1, 3-6, and 15-17).
Kothari teaches that they modified tyrosine residues on the AAV capsid with iodine-124 to track the spatial and temporal distribution of the actual gene transfer vector independent of the transgene. Kothari teaches that Adeno-associated virus serotype rh.10 was reproducibly labeled with I-124 and its distribution in the mouse brain was observed. When compared to free I-124, which was cleared from the brain within about two hours, the labeled virus was observable up to eight days after administration. The radiolabeling approaches described herein have the potential for wide application in gene therapy trials, and in particular in vivo observation of radioactivity from I-124 should be useful as a surrogate marker for vector distribution to the CNS in the first week after administration (page 2, paragraph 2 and page 6, paragraph 5). Figure 3 of Kothari shows that tyrosine modified AAVs were able to infect and transduce cells.
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 capsid modification of the AAV vector of Mevel to covalently couple NAcGal to an exterior tyrosine, as identified by Francis and Kothari, instead of lysine 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 Mevel has successfully reduced to practice that NAcGal can be chemically coupled to an exterior amino acid residue of an AAV capsid and that this modification improves delivery of an exogenous gene to targeted hepatocyte cells and can be used to treat cancer. Furthermore, Francis and Kothari identify tyrosine residues as reasonable amino acids for chemical modification to attach compounds. Kothari has successfully reduced to practice that chemical compounds can be coupled to tyrosine residues on AAV vectors and maintain infectivity and transduction capabilities. Furthermore, although Mevel focuses on modifying primary amine groups of lysine residues, Kothari teaches that lysine residues have also been targeted for chemical modification, that lysine residues occur with nearly the same frequency as tyrosine residues on the AAV2 capsid, and contemplates the interchangeability of chemically modifying lysine or tyrosine residues (page 6, paragraph 2). As such, it would have been obvious that one can modify tyrosine residues with carbohydrates instead of lysine residues for selective targeting of hepatocytes. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
The combined teachings of Mevel, Francis, and Kothari do not teach the specific structure of formula (Ic).
However, Francis embodies tyrosine modifications of tyrosine residues in the capsid interior of MS2 bacteriophage in Figure 3. As stated supra, although Francis embodies the tyrosine modification on MS2 bacteriophage capsids, Francis contemplates that parvoviruses (AAV viruses are a species of parvovirus; paragraphs 0053-0055) are also suitable viral capsids for modification. Therefore, although Francis embodies it only with MS2 bacteriophage capsids, it would be well understood that this tyrosine modification could be incorporated in the capsid of other viral capsids, such as parvoviruses.
The structure from Figure 3 of Francis shown below teaches a tyrosine modification comprising a structure that is close to what is found in formula (Ic) comprising a substituted aryl group, an X2 of NH-C(=O)- that is meta to the phenyl group, a spacer group of C2-NH-C(=O)-, and a functional moiety of FAM (a fluorescein derivative) which would instead be the N-acetylgalactosamine (NAcGal) of Mevel.
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Francis Figure 3
Francis does not teach a structure that falls under formula (Ic) as the aryl group comprises a substituted substituent (NO2).
However, Boutureira teaches that tyrosine residues can be modified by reaction with diazonium salts (the same reaction as used by Francis (paragraph 21)) to generate an aryl ring with no substituted substituents and with an X2 of CONH2 (the same X2 of Francis if there was no additional spacer group in Figure 3) (scheme 3). As such, it would have been obvious that a non-substituted aryl ring could have also been used as the aryl ring for modifying tyrosine residues instead of the substituted aryl ring of Francis, as Boutureira shows that this represents another possible option for diazonium salt reactions with exposed tyrosine residues. As a result, one of ordinary skill in the art would only have to replace the p-nitroaniline linker of Francis with an aryldiazonium linker as used by Boutureira. Therefore, as Boutureira also teaches that aryldiazonium linkers can be used to modify tyrosine residues, it would have been obvious that an aryldiazonium linker could have been used instead of the p-nitroaniline linker of Francis.
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 capsid tyrosine chemical modification of the AAV vector to have a structure that falls within formula (Ic), as identified by Francis and Boutureira, 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 Francis and Boutureira successfully reduce to practice structures that have been used to modify tyrosine residues that, when their teachings are combined, would fall within formula (1c) and Francis successfully reduces to practice that a similar structure to formula (Ic) has been used for chemically modifying a tyrosine residue of a viral capsid to attach a functional moiety. Mevel has successfully reduced to practice that NAcGal can be chemically coupled to an exterior amino acid residue of an AAV capsid and that this modification improves delivery of an exogenous gene to targeted hepatocyte cells and can be used to treat cancer. As such, it would have been obvious that the combined structure of Francis and Boutureira with a GalNAc functional moiety, as used by Mevel, can be chemically coupled to a tyrosine residue of an AAV vector. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 24, Mevel teaches that the Recombinant Adeno-Associated Virus (rAAV) vector can be in a particle pharmaceutical composition with a pharmaceutically acceptable excipient (page 31, lines 5-31).
Regarding claim 26, Mevel teaches that the rAAV can encode therapeutic nucleic acids (i.e. a heterologous polypeptide to an AAV) (page 6, line 24-page 7, line 9 and claim 19).
Regarding claim 29, Boutureira teaches that as part of using an aryldiazonium linker, the X2 group would be positioned in the para position, as shown by scheme 3.
Regarding claims 30, Francis, as stated supra, teaches that they used the structure from Figure 3 comprising an X2 of NH-C(=O)-
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Francis Figure 3
Regarding claim 34, the teachings of Mevel, Francis, and Kothari are as discussed above.
Mevel teaches that at least one primary amino group contained in the capsid protein can be chemically coupled and that lysine and arginine are amino groups that can be targeted for chemical coupling (claim 1 and page 11, lines 11-25). Furthermore, Mevel teaches that the obtained Recombinant Adeno Associated Virus (rAAV) vector particle may be further reacted for modifying the capsid proteins in a second coupling step, in particular by chemical coupling with unreacted amino groups from the first coupling step (page 27, lines 20-23). Francis teaches that the exterior surface of the capsid can be modified with PEG chains to shield the capsid from an immune response (paragraph 0009). As shown in Figure 3, PEGylation of lysine residues would modify up to 360 of the available lysine residues on the exterior surface (paragraph 0021). Francis teaches that another potential target for chemical modification on the exterior surface is arginine (paragraphs 0053-0060). Mevel teaches that PEGyllated primary amines has been previously shown to protect AAV vectors against antibody neutralization (page 28, lines 13-27).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the capsid through chemical modification of arginine and lysine residues of the tyrosine modified AAV vector of the combined teachings of Mevel, Francis, and Kothari 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 Mevel and Francis identify PEGylation as an important chemical modification for protection against the innate immune response by protecting the vector from antibody neutralization. Mevel specifically identifies that PEGyllated primary amines has been previously shown to protect AAV vectors against antibody neutralization. Additionally, Mevel and Francis identify lysine and arginine as amino group containing residues that are suitable for chemical modification of their primary amino groups and Francis specifically identifies that lysine and arginine residues are suitable for chemical modification to prevent the capsid from eliciting an immune response (paragraphs 0053-0060). Therefore, it would have been obvious that one of ordinary skill in the art could further chemically modify the tyrosine chemically modified AAV vector at lysine and arginine residues by PEGylation of these residues to protect the AAV vectors against antibody neutralization.
Regarding claim 35, Mevel teaches a reactant that can react with an NH2 to form a spacer and functional group that is identical to the spacer and functional group of instant claim 35 (Example 1 and Scheme 4). Mevel teaches methods of chemically coupling ligands to the exterior surface of the capsid of AAV by reacting ligands (such as monosaccharides) to reactive moieties of amino acids located at the surface of the AAV particles (page 1, lines 3-24, page 5, lines 22-30, page 14, lines 5-16, and page 28, line 12-page 30, line 28 and Figure 1). Therefore, the replacement of the FAM functional moiety of the chemically modified tyrosine of the combined teachings of Mevel, Francis, and Boutureira would result in a structure of Formula (II),
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.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Doug Schultz can be reached at (571) 272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KEENAN A BATES/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631