Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 27, 2026, has been entered.
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Claims 27-28, 36, and 38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Groups II-IV (claim 36 and newly added claim 38)), there being no allowable generic or linking claim.
Applicant further elected the following species:
a. 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In light of the Applicant’s elected species, claims 20-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 March 27, 2026, have been acknowledged. Claims 1-15, 20-23, 25, 31, and 33 were cancelled. Claims 16-19, 32, and 36 were amended. Claims 37-38 are new. In light of the Applicant’s elected invention, claims 27-28, 36, and 38 (claim 38 is dependent on claim 36) are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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, 29-30, 32, 34-35, and 37 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, 29-30, 32, 34-35, and 37 find support in foreign application EP19185879.4.
Claim Rejections - 35 USC § 112
Claims 16-19, 24, 26, 29-30, 32, 34-35, and 37 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 “saturated or branched” in claim 16 is not clearly delineated as being a saturated or branched chemical chain or if it is meant to be read as a saturated or unsaturated C2-C40 hydrocarbon chain that is linear or branched. Similarly, it is not clear whether “optionally substituted” in claim 16 is meant to refer to the hydrocarbon chain or a chemical chain that is substituted. Applicant is recommended to use semicolons between the distinct spacer options to clearly delineate what is meant to be part of each spacer group and what is not.
Claims 17-19, 24, 26, 29-30, 32, 34-35, and 37 are also rejected because of their dependence on claim 16.
The term “one or several galactose” in claims 17 and 32 lacks clarity as it is unclear whether that is meant to represent a single galactose versus several galactose molecules or if it is meant to mean one or more of galactose, mannose, mannose-6-phosphate, N-acetylgalactosamine, or bridge GalNac. Claim 16 recites that the M is a monosaccharide or a polysaccharide moiety while claim 32 has been amended to recite that M is a polysaccharide. As currently written, claim 32 identifies one galactose as a possible M but this would fall outside of the required polysaccharide. As such, the lack of clarity needs to be fixed to address this issue. Applicant is recommended to recite similar language to what is used in claim 16 for the Spacer, e.g. selected from the group consisting of … and combinations thereof to make it clear if this is the intended meaning.
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, 29-30, 32, 34-35, and 37 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). This 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 16-19 and 31-32, Mevel teaches methods of chemically coupling ligands to the exterior surface of the capsid of AAV by reacting ligands 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 monosaccharide or polysaccharide 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 teaches that the that the obtained rAAVs retain infectivity, as illustrated in the examples, and more particularly in example 2.8 and Figures 3-4.
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). Furthermore, Francis teaches that their modified capsid is taken up by target cells after administration (paragraphs 0019 and 0066-0069).
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). Furthermore, Kothari teaches that they modified tyrosine (Iodogen method) and lysine (Modified Hunter-Bolton) residues through iodination and found that both modifications maintained infectivity and transduction capabilities with similar results (page 2, paragraph 5-page 3, paragraph 1 and Figures 3-4). 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)- (considered to fall within the spacer group as identified in claim 16), 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 claims 29 and 37, 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 claims 16, 35, and 37, Mevel teaches a reactant that can react with an NH2 to form a spacer and functional group that is identical to the spacer (polyethylene glycol) 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 and polysaccharides) 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) and (Id).
Response to Arguments
Applicant's arguments filed March 27, 2026, are acknowledged.
Applicant argues that one skilled in the art would not have had a reasonable expectation of success in reacting AAV with aryldiazonium so as to covalently bind a large ligand on the tyrosine residues in the AAV's capsid, because the results of such chemical modifications on the capsid integrity, the infectivity and the transduction efficacy of the AAV would have been totally unpredictable when considering the combined teachings of Mevel et al., Francis et al., and Kothari et al. The skilled artisan would not consider that chemical modifications of lysine residues is interchangeable with chemical modification of tyrosine residues in AAV capsid in view of the cited documents.
While Mevel et al. is concerned with chemically modified AAV to be used as gene vectors, the chemical modifications are performed on lysine or arginine residues in the viral capsid and not on tyrosine residue. Mevel et al. do not teach or suggest modification of a tyrosine residue. Furthermore, Mevel et al. teach that arginine and lysine residues are modified by reaction with thiocyanate reagent (-N=C=S). In contrast, tyrosine residues are modified by reaction with aryldiazonium reagent in the presently claimed invention. One cannot extrapolate the possible effects (e.g. on the capsid integrity, in terms of side reactions etc.) of an aryl diazonium reagent on the AAV capsid based on a teaching restricted to thiocyanate reagent as in Mevel et al.
In addition, arginine and lysine do not have the same chemical structure as tyrosine. Applicants further note that the biological functions of arginine/lysine and tyrosine residues in the AAV capsid are not the same. As such, the skilled artisan would not be able to predict the possible effects of tyrosine modification with aryldiazonium as presently claimed on the biological functions of the AAV (such as infectivity and transduction) from a teaching restricted to arginine and lysine modification as in the teachings of Mevel et al.
Francis et al. is not concerned with gene therapy or with the production of functional chemically-modified AAV that are able to both infect and transduce cells. In Francis et al., the viral vector is merely used as a vehicle/carrier and is devoid of any viral genome, including a viral genome comprising an exogenous gene. Indeed, Francis et al. teach carriers to deliver imaging agents or therapeutic agents to specifically cellular sites. Francis et al. do not aim at obtaining a chemically-modified viral particle containing a viral genome and retaining transduction efficacy, let alone a viral genome in which an exogenous nucleic acid sequence is introduced.
While Francis et al. may teach chemical modification of tyrosine residues in the capsid, the reference clearly teaches that tyrosine residues present in the interior surface of the capsid are to be chemically modified (see e.g. the claims and the description of Figure 2). The modification of the tyrosine in the interior surface of the capsid occurs after genome removal (see paragraph [0020]). Applicants further note that Francis et al. are totally silent with respect to AAV and while Francis et al. may refer to various virus families, including parvovirus, this is not a teaching that would direct one to the modification of AAV since many other viruses are included within the parvovirus family (see paragraph [0055]).
Of note, the preferred virus in the teachings of Francis et al. are Tobacco mosaic virus and MS2. All the examples provided in Francis et al. are performed on MS2 which is a bacteriophage. None of the examples is performed on AAV.
Applicants further submit that because Francis et al. do not aim to prepare gene vector since the viral genome is removed and because the teachings in the reference do not provide any data concerning AAV, the skilled artisan could have expected that the chemical modification of tyrosine in AAV capsid, as taught in the instant disclosure, would be deleterious to (i) the capsid integrity and (ii) the infection and transduction efficacy of the AAV. Thus, one skilled in the art would not have expected that an AAV vector modified at an exterior tyrosine residue would have been able to infect hepatic cell lines and induce an increased expression of the transgene evidenced by higher fluorescence intensity (Fig. 11) as compared to a similar non-chemically modified AAV vector.
Kothari et al. describe the radiochemical labeling (using iodine-124) of the capsid of an AAV encoding the CLN2 gene to enable in vivo tracking of the AAV. Kothari et al. use an iodination reaction which is dramatically different from aryl diazonium reaction of the Invention, In Kothari et al., the tyrosine residues is merely iodinated, meaning that "a iodine atom", a very tiny chemical moiety, is added on the tyrosine residue.
While the teachings of Kothari et al. may be interpreted as showing that iodination of a tyrosine residue on the surface of an AAV capsid maintains a certain degree of infectivity and transduction for the AAV, such a conclusion cannot be extrapolated to the introduction of any chemical group by any chemical reaction on tyrosine residues, let alone as shown in the instant application. Applicants note that while most radioiodinated capsids appeared to retain properties sufficient for infectivity, there was a significant decrease relative to a control group for both the Iodogen and Bolton-Hunter methods (see Kothari et al. at page 6). There, Kothari et al. show that the mere coupling of a tiny "iodine atom" on tyrosine residue results in a decrease of at least 30% of the infectivity of the AAV (see Figure 3). In view of such a result, a skilled artisan would not be motivated to covalently bind a larger group on tyrosine residues, let alone the chemical group of the present invention.
Thus, Applicants dispute the argument that Kothari et al. have "successfully reduced to practice that chemical compounds can be coupled to tyrosine residues on AAV vectors and maintain infectivity and transduction efficacy" (page 8 of the Office Action). On the contrary, Kothari et al. illustrate that covalent coupling on tyrosine residues can have a significant impact on both infectivity and transduction. Additionally, the teachings of Kothari et al., which are limited to iodination of tyrosine (e.g. introduction of an iodine atom) does not enable one skilled in the art to predict the possible impact of a larger group on tyrosine residues, let alone as shown in the present invention. Thus, the teachings of Kothari et al. do not remedy the defects in the combined teachings of Mevel et al. and Francis et al.
Of note, Boutureira et al. do not provide any particular teaching to perform chemical modifications in AAV that would permit the AAV to maintain capsid integrity and transduction efficacy. Indeed, Boutureira et al. is silent about chemical modification of AAV capsid (page 8, paragraph 3-page 13, paragraph 2).
Applicant's arguments have been fully considered but they are not persuasive.
As an initial matter, regarding Applicant’s statement that because Francis et al. do not aim to prepare gene vector since the viral genome is removed and because the teachings in the reference do not provide any data concerning AAV, the skilled artisan could have expected that the chemical modification of tyrosine in AAV capsid, as taught in the instant disclosure, would be deleterious to (i) the capsid integrity and (ii) the infection and transduction efficacy of the AAV, this is entirely speculative and not based on any evidence. Arguments of counsel cannot take the place of factually supported objective evidence in the record. See In re Schulze, 346 F.2d 500, 602, 145 USPQ 716, 718 (CCPA 1965), In re Huang, 100 F.3d 135, 139-40, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Thus, Attorney statements regarding the chemical modification of tyrosine in AAV capsid would be deleterious to (i) the capsid integrity and (ii) the infection and transduction efficacy of the AAV are not evidence without a supporting declaration. There is nothing within Applicant’s arguments nor any of the cited prior art that shows that this would be the case.
In order to complete the art of record and rebut Applicant’s arguments, Kanaan et al. (Molecular Therapy: Nucleic Acids 8:184-197. 2017) evidences that mutating tyrosine residues on AAV2, AAV5, and AAV8 improved the efficacy of infection and transduction and Kothari, as stated in the rejection above, identified that chemical modification of tyrosine residues of AAV10 maintained their ability to infect and transduce cells. Furthermore, Mevel identifies that their AAVs with chemically modified lysine and/or arginine residues retain infectivity and transduction capabilities, as illustrated in the examples, and more particularly in example 2.8 and Figures 3-4, and Francis identifies that their modified capsid is taken up by target cells after administration (paragraphs 0019 and 0066-0069). Therefore, although the prior art does not specifically identify the chemical modification as claimed and even if one were to take Applicant’s arguments at face value, the preponderance of the evidence suggest that the modified AAVs would retain their infectivity and transduction capabilities.
Furthermore, as stated in the rejection above, Mevel is focused on chemically coupling ligands to the exterior surface of the capsid of AAV, such as monosaccharide or polysaccharide N-acetylgalactosamine (NAcGal), to improve delivery of an exogenous gene to targeted hepatocyte cells through selective transduction of hepatocytes. Mevel focuses on chemically modifying lysine and arginine residues. The Adeno-Associated Virus (AAV) claimed in claim 1 (product) differs from that disclosed in Mevel in that the modified amino acid residues are different (lysine/arginine in Mevel vs tyrosine residues in the instant application). However, Francis discloses 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, the effect of which is to couple a required ligand at the surface of the virus capsid to improve functionality, the same as that of Mevel.
While tyrosine and lysine/arginine residues are structurally distinct, one of ordinary skill in the art would be well aware that there a differences between tyrosine residues and lysine/arginine residues and that the specific reagents used for modifying these residues would be different. Kothari identifies that lysine residues have also been targeted for chemical modification; lysine residues occur with nearly the same frequency as tyrosine residues on the AAV2 capsid; and Kothari contemplates the interchangeability of chemically modifying lysine or tyrosine residues (page 6, paragraph 2). Furthermore, Kothari identifies that they modified tyrosine (Iodogen method) and lysine (Modified Hunter-Bolton) residues through iodination and found that both modifications maintained infectivity and transduction capabilities (page 2, paragraph 5-page 3, paragraph 1 and Figures 3-4). Although Kothari does not teach the specific modification used in the claimed AAV vector, Kothari has successfully reduced to practice that chemical modification of tyrosine and lysine residues with iodine led to similar results.
Additionally, one skilled in the art would understand that different methods would need to be used for modifying tyrosine residues compared to lysine/arginine residues, as highlighted by the different methods for iodination used by Kothari and the different methods used by Mevel and Francis to modify the lysine or tyrosine residues, respectively. As Mevel already discusses the possibility of modifying AAV capsid residues to improve targeting to cells of interest, Francis already identifies that tyrosine residues of viral capsids can be modified, and Kothari successfully reduces to practice that tyrosine and lysine can be chemically modified with similar results, it would be obvious to one of ordinary skill to modify tyrosine residues and to select the corresponding reaction reagents based on the specific modification methods disclosed in Francis and the intended modification ligands of Mevel. Indeed, Boutureira identifies 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).
Based on the prior art it is known that: (1) chemical modification of Lysine/Arginine residues of AAV capsids with monosaccharides/polysaccharides can improve delivery of an exogenous gene to targeted hepatocyte cells through selective transduction of hepatocytes (Mevel); (2) chemical modification of tyrosine residues of viral capsids to improve functionality was known (Francis); (3) lysine residues occur with nearly the same frequency as tyrosine residues on the AAV2 capsid, the prior art contemplated the interchangeability of chemically modifying lysine or tyrosine residues, and successfully reduced to practice that chemical modification of tyrosine and lysine residues led to similar results (Kothari).
Thus, one of ordinary skill in the art would identify tyrosine residues as a viable option for modifying AAV capsids using the known methods of Francis and Boutureira. Furthermore, Kothari identified that chemical modification of tyrosine or lysine residues of AAV10 maintained their ability to infect and transduce cells. Mevel identifies that their AAVs with chemically modified lysine and/or arginine residues retain infectivity and transduction capabilities, as illustrated in the examples, and more particularly in example 2.8 and Figures 3-4. Francis identifies that their modified capsid is taken up by target cells after administration (paragraphs 0019 and 0066-0069). Therefore, although the prior art does not specifically identify the chemical modification as claimed, the preponderance of the evidence supports that the resulting AAV vectors with chemically modified tyrosine residues as outlined in the claims would maintain the capabilities of viral infectivity and transduction.
Therefore, Applicant’s arguments are considered unconvincing.
Finally, contrary to the Examiner's assertion (see page 8 of the Office Action), Applicants submit that a skilled artisan would not consider chemical modification on tyrosine and chemical modification on lysine as interchangeable. While tyrosine and lysine residues may occur in the same frequency in the AAV capsids, such a statement does not support interchangeability. As explained above, lysine residues do not have the same chemical structure as tyrosine (page 13, paragraph 1).
Applicant's arguments have been fully considered but they are not persuasive.
As stated in the rejection above, Kothari directly identifies that they performed iodination of tyrosine (Iodogen) and lysine (Modified Hunter’s Bolton) residues of AAV10 with similar results (Figure 3). Kothari directly contemplates looking at chemical modifications of tyrosine and lysine residues and their roles in infectivity. Therefore, based on the findings of Kothari, there is a reasonable expectation that chemical modification of tyrosine residues would exhibit similar results as similar chemical modifications of lysine residues.
Therefore, Applicant’s arguments are considered unconvincing.
Conclusion
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/KEENAN A BATES/Examiner, Art Unit 1631
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