The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This office action is in response to Applicants’ amendments/remarks received August 4, 2025.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
Claims 1-73, 80-86, 94 are canceled. Claims 87-92 are withdrawn. Claims 74-79, 93, 95-98, to a homing domain of an integrin receptor-binding domain, insertion position S454, a target tissue of integrin receptor, are under consideration.
Priority: This application is a 371 of PCT/US20/26485, filed April 2, 2020, which claims benefit of provisional applications 62/829608, filed April 4, 2019, 62/833516, filed April 12, 2019, 62/839368, filed April 26, 2019, 62/924107, filed October 21, 2019, and 62/963512, filed January 20, 2020.
Objections and Rejections
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 76-78, 93, 95-96 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.
Claim 76 recites wherein said heterologous protein is a homing domain. Claim 76 is dependent on claim 74, where claim 74 already recites that the heterologous protein is a homing domain. It is not clear how claim 76 further limits claim 74. Further correction is requested.
Claim 77 is included in this rejection because it is dependent on claim 76 and fail to cure its defects.
Claim 78 where wherein the peptide insertion comprises of consists of at least 4 contiguous or is 7 contiguous amino acids, in some instances, of the noted amino acid sequences. Claim 78 is dependent on claim 74, where claim 74 recites that the peptide insertion is at least 5 and up to 10. Therefore, the “at least 4” recited in claim 78 does not further limit claim 74. Further correction is requested.
Claim 93 is rejected under 35 U.S.C. 112(b) for the reasons similarly noted above for claim 78. Further correction is requested.
Claims 95-96 are included in this rejection because they are dependent on the above claim(s) and fail to cure its defects.
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.
Claims 74-78, 93, 95-96, 98 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Schaffer et al. (WO 2012145601; IDS 09.25.24). Schaffer et al. teach a peptide having a length of 5 to 11 amino acids, including 10 amino acids, inserted at amino acid 454 of AAV9 capsid protein (at least paragraphs 0078, 0080), where the insertion peptide is a peptide of from 5 to 11 amino acids, including 10 amino acids, where the insertion peptide is Formula IV: Y1Y2X1X2X3X4X5X6X7Y3Y4, where Y1-Y4, if present, are selected from Ala, Leu, Gly, Ser, and Thr, X1 is selected from amino acids including Arg, X2 is selected from amino acids including Gly, X3 is selected from amino acids including Asp, X4 is selected from amino acids including Lys, X5-X6 are selected from the noted amino acids, X7 if present is selected from the noted amino acids (at least paragraphs 0094-0096).
Therefore, Schaffer et al can be deemed to teach the AAV9 capsid protein comprising an insertion of a peptide of at least 5 and up to 10 contiguous amino acids of a peptide comprising an RGD motif, where the insertion peptide comprising an RGD motif and is a homing domain (instant claims 74-78, 93, 95-98).
Additionally, since the insertion peptide of Schaffer et al. has the same structural features recited in the instant claims and is further inserted at the same position 454 of a AAV9 capsid protein as recited in the claims, it would follow that the insertion peptide of Schaffer et al. inserted at position 454 of the AAV9 capsid protein comprises the recited properties and/or functionalities recited in the instant claims (instant claim 98).
Reply: In view of Applicants’ amendments/remarks, the previous rejection of instant claims 79, 97 as being anticipated by Schaffer et al. has been withdrawn.
However, instant claims 74-78, 93, 95-96, 98 remain rejected under 35 U.S.C. 102(a)(1) as being anticipated by Schaffer et al. for the reasons noted above.
Applicants assert that Schaffer et al. is directed to AAV2 variants having a peptide insertion into region VIII. Applicants assert that Schaffer et al. describe an AAV capsid “protein loop IV” or “GH loop” region as entirely the sequence from amino acids 411-650 based on AAV numbering. Applicants assert that further, no insertion sites other than the AAV2 587-588 site are enabled as taught by Schaffer et al.
Applicants’ remarks are not persuasive. It is known that disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). Furthermore, “[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). MPEP 2123.
In this instance and as noted above, Schaffer et al. still teach an insertion of a peptide of at least 5 and up to 10 contiguous amino acids of a peptide comprising an RGD motif, where the insertion peptide comprising an RGD motif and is a homing domain, at amino acid 454 of AAV9 capsid protein.
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.
Claims 74-79, 93, 95-98 are rejected under 35 U.S.C. 103 as being unpatentable over Lux et al. (WO 2008145400; IDS 09.25.24, previously cited) in view of DiMattia et al. (2012 Journal of Virology 86(12): 6947-6958; IDS 09.25.24, previously cited). Lux et al. disclose a capsid protein of a parvovirus comprising an amino acid insertion of one or more amino acids directly after position G453 of the AAV2 capsid protein or the corresponding amino acid of any other parvovirus, where the other parvovirus is an adeno-associated virus selected from among others AAV-9 (at least p. 97 claims 1-5), where the amino acid insertion has a length of about 4 to 30 amino acids, preferably about 5 to about 15 amino acids (at least p. 97, claim 7). Lux et al. disclose in an especially preferred embodiment, the inserted targeting sequence contains an RGD motif ACDCRGDCFCA (SEQ ID NO: 84), herein referred to as RGD-4C peptide; the RGD motif in general and especially the RGD-4C peptide mediate the binding to the integrins (p. 19 lines 18-23).
Lux et al. disclose that AAV and other parvoviruses are suitable backbones for vaccination purposes and/or retargeting approaches in the gene therapy context, but an additional insertion site with equal or improved properties is needed (at least p. 6 lines 11-15). Lux et al. disclose that it has now been surprisingly found that the position after amino acid G453 of AAV2 is especially suitable for such insertions (at least p. 6 lines 21-22) and that accordingly, the major objection of the present invention is a structural protein of AAV which comprises an amino acid insertion of one or more amino acids located directly adjacent to amino acid G453 in the sequence of AAV2 or to the corresponding amino acid of an AAV-2 variant or of any other parvovirus (at least p. 6 lines 24-29), where a “parvovirus” means a member of the family of Parvoviridae and preferred parvoviruses are members of the genus Parvovirus, such as AAV-9 (p. 10 lines 1-10). Lux et al. disclose alignment of AAV2 with other parvovirus amino acid sequences (at least p. 8) and disclose that in addition to AAV2, in a preferred embodiment, the parvovirus is AAV-9 (at least p. 15 lines 15-17). Lux et al. do not explicitly teach the amino acid sequence of AAV9 capsid protein.
DiMattia et al. disclose the AAV9 capsid protein is most similar to AAV2 and AAV8 (at least p. 6950-6953). DiMattia et al. disclose the sequence alignment of AAV2 capsid protein and AAV9 capsid protein where position G453 of the AAV2 capsid protein corresponds to position S454 of the AAV9 capsid protein (at least p. 6954, Fig. 5). DiMattia et al. disclose the AAV9 capsid exhibits the surface topology conserved in all AAVs (at least p. 6947). DiMattia et al. disclose that AAV9 is a human AAV serotype that greatly enhanced transduction efficiency in various tissue relative to other serotypes (p. 6947); furthermore, while preexisting antibodies to AAVs have been shown to be detrimental to AAV gene delivery, the prevalence of antibodies to AAV9 is lower in humans than those of other serotypes, for example, AAV1 and AAV2 (at least p. 6947-6948).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to arrive at the claimed rAAV9 capsid protein comprising a peptide insertion of at least 5 and up to 10 contiguous amino acids, where the peptide insertion occurs directly after position S454 of the rAAV9 capsid protein and the peptide insertion comprises an RGD motif and is a homing domain (instant claims 74-75, 95-97). The motivation to do so is given by the prior art, which disclose inserting a peptide sequence having a RGD motif between 5-11 amino acids in length at noted positions in AAV capsid proteins, including at positions S454 of AAV9 capsid protein. One of ordinary skill would have a reasonable expectation of success because the sequences of the AAV capsid proteins are known in the prior art and the positions for peptide insertion are also identified in the prior art.
Regarding instant claims 76-78, 93, 98, Lux et al. disclose the amino acid insertion contains an RGD motif, wherein the amino acid insertion is ACDCRGDCFCA (at least p. 99 claim 17). Therefore, Lux et al. can be deemed to disclose a peptide insertion of at least 5 or 7 contiguous amino acids and no more than 11 contiguous amino acids of a peptide comprising an RGD motif. While the insertion peptide of Lux et al. can contain one additional amino acid residues, it is noted that the recitation of “comprising” and “having” in the claim(s) is open-ended and does not exclude additional, unrecited elements. MPEP 2111.03. Therefore, the insertion peptide ACDCRGDCFCA of Lux et al. can still be deemed to be at least 5 and up to 10 contiguous amino acids within the AAV9 capsid protein. Additionally, since the insertion peptide of Lux et al. has the same structural features recited in the instant claims and is further inserted at the same position 454 of a AAV9 capsid protein as recited in the claims, it would follow that the insertion peptide of Lux et al. inserted at position 454 of the AAV9 capsid protein comprises the recited properties and/or functionalities recited in the instant claims.
Regarding instant claim 79, as noted above, Lux et al. disclose a peptide having a length of 11 amino acids inserted at amino acid 454 of AAV9 capsid protein, wherein the amino acid insertion is ACDCRGDCFCA (at least p. 99 claim 17, at least p. 97 claims 1-5, 7). Therefore, Lux et al can be deemed to disclose the AAV9 capsid protein comprising an insertion of a peptide of at least 5 contiguous amino acids from CRGDC (SEQ ID NO: 155).
Reply: Applicants’ amendments/remarks have been considered but they are not persuasive.
Applicants assert that the examiner has not met the burden of a prima facie case of obviousness because the examiner has not provided evidence that one skilled in the art would choose to modify AAV9 by inserting a homing peptide in the VR-IV region of the capsid. Applicants assert that Lux et al. is directed to AAV2 capsid proteins having amino acid insertions, primarily for vaccination purposes. Applicants assert that as pointed out by the examiner, Lux et al. do not provide a sequence for AAV9 capsid protein. Applicants assert that Lux et al. provide an advantage of disclosure with respect to AAV2 serotypes, but Lux et al. make no inferences that AAV9 would be interchangeable with AAV2.
Applicants’ remarks are not persuasive. MPEP 2123 notes that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). Furthermore, “[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
In this instance, Lux et al. disclose that AAV and other parvoviruses are suitable backbones for vaccination purposes and/or retargeting approaches in the gene therapy context, but an additional insertion site with equal or improved properties is needed (at least p. 6 lines 11-15). Lux et al. disclose that it has now been surprisingly found that the position after amino acid G453 of AAV2 is especially suitable for such insertions (at least p. 6 lines 21-22) and that accordingly, the major objection of the present invention is a structural protein of AAV which comprises an amino acid insertion of one or more amino acids located directly adjacent to amino acid G453 in the sequence of AAV2 or to the corresponding amino acid of an AAV-2 variant or of any other parvovirus (at least p. 6 lines 24-29), where a “parvovirus” means a member of the family of Parvoviridae and preferred parvoviruses are members of the genus Parvovirus, such as AAV-9 (p. 10 lines 1-10).
Therefore, Lux et al. expressly disclose and identify AAV-9 capsid protein as an alternative to AAV-2 capsid protein for insertion of a peptide at the position corresponding to amino acid G453 in the sequence of AAV2.
Therefore, Applicants’ remarks that Lux et al. make no inferences that AAV9 would be interchangeable with AAV2 are not persuasive.
As noted in the 103 rejection, the deficiency of Lux et al. to not explicitly teach the amino acid sequence of AAV9 capsid is remedied by DiMattia et al., which disclose the sequence alignment of AAV2 capsid protein and AAV9 capsid protein where position G453 of the AAV2 capsid protein corresponds to position S454 of the AAV9 capsid protein (at least p. 6954, Fig. 5).
Therefore, it would have been obvious to arrive at a rAAV9 capsid protein comprising a peptide insertion where the peptide insertion occurs directly after position S454 of the rAAV9 capsid protein.
Applicants assert that DiMattia et al. do not cure the deficiencies of Lux et al. but rather teaches away. Applicants assert that DiMattia et al. focus on the differences between AAV9 and AAV2 or AAV8. Applicants assert that DiMattia et al. confirm that there are topological differences between AAV9 and AAV2 at VR-IV. Applicants assert that a person of ordinary skill reading DiMattia et al. would understand that topological differences between the VR-IV region of AAV2 and the VR-IV region of AAV9 introduces uncertainties about whether insertions into AAV2 can be used to predict the effect of insertions into AAV9.
Applicants’ remarks are not persuasive. DiMattia et al. actually disclose that the AAV9 capsid exhibits the surface topology conserved in all AAVs (at least p. 6947). DiMattia et al. disclose that AAV9 is a human AAV serotype that greatly enhanced transduction efficiency in various tissue relative to other serotypes (p. 6947); furthermore, while preexisting antibodies to AAVs have been shown to be detrimental to AAV gene delivery, the prevalence of antibodies to AAV9 is lower in humans than those of other serotypes, for example, AAV1 and AAV2 (at least p. 6947-6948). Therefore, DiMattia et al. disclose the advantages of AAV9 over AAV2 in gene therapy. While DiMattia et al. note that the variable regions, including the VR-IV region, may differ by amino acid residues among the parvoviruses, DiMattia et al. disclose that it is these regions, including VR-IV, that are the probably determinants of AAV9’s superior transduction of cardiac and skeletal muscle and liver and pancreatic tissue compared to AAV1, AAV2, and AAV8 (at least p. 6954-6955).
Therefore, DiMattia et al. disclose the advantages of AAV9 over AAV2 for gene therapy.
In this instance, since Lux et al. have identified an amino acid insertion site 453 in the sequence of AAV2 capsid protein or the corresponding amino acid of any other parvovirus (at least p. 97 claims 1-2), where the parvovirus is AAV-9 (p. 97 claim 5).
Therefore, one of ordinary skill would have a reasonable expectation of success that a peptide insertion can be incorporated into an AAV-9 capsid protein at a position corresponding to insertion site 453, which is position S454 in the AAV9 capsid protein because the sequences of the AAV capsid proteins are known in the prior art and the positions for peptide insertion are also identified in the prior art.
For at least these reasons, the 103 rejection is maintained.
No claim is allowed.
THIS ACTION IS MADE FINAL. 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 Marsha Tsay whose telephone number is (571)272-2938. The examiner can normally be reached M-F.
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/Marsha Tsay/Primary Examiner, Art Unit 1656
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