The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 16, 2026 has been entered.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
Claims 1-73, 75-77, 80-86, 94 are canceled. Claims 87-92 are withdrawn. Claims 74, 78-79, 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 78, 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 78, in some instances, recites wherein the peptide insertion comprises or consists of at least 4 contiguous or is 7 contiguous amino acids, 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.
Claims 95-96 are included in this rejection because they are dependent on the above claim(s) and fail to cure its defects.
Reply: In view of Applicants’ amendments/remarks, claim 78 and its dependent claims remain rejected under 35 U.S.C. 112(b) for the reasons noted.
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.
Claims 74, 78, 93, 95-96, 98 are rejected under 35 U.S.C. 103 as being unpatentable over Schaffer et al. (WO 2012145601; IDS 09.25.24, previously cited) in view of Lowell et al. (Overview: studying integrins in vivo. 2012 Methods Mol Biol. 757: 369-97). Schaffer et al. disclose adeno-associated virus (AAV) virions with altered capsid protein, wherein the AAV virions exhibit greater infectivity of retinal cells (at least abstract, p. 2). Schaffer et al. disclose 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. fairly disclose a recombinant AAV9 capsid protein comprising a peptide insertion 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 is a homing domain. Schaffer et al. do not explicitly teach a RGD motif also targets muscle.
Lowell et al. disclose that integrins are αβ heterodimeric, transmembrane proteins that recognize the RGD motif (at least p. 369-370). Lowell et al. disclose integrins are critical in ocular and CNS development and hemostasis; within the eye, the tissue consists of assemblies of fibrinogen, collagen, and laminin (at least p. 379-380). Lowell et al. disclose an RGD-binding integrin plays a critical role in maintenance of retinal pigment epithelial cells in the eye (at least p. 380-381). Lowell et al. also disclose that a number of RGD, collagen, and laminin-binding integrins serve critical roles in muscle structures (at least p. 386-388).
MPEP 2144 notes that it is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006).
Therefore, 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 in view of the teachings of Schaffer et al. (instant claims 74, 78, 93, 95-96, 98). The motivation to do so is given by Schaffer et al., which disclose AAV capsid proteins, including AAV9, can be altered with a peptide insertion for greater infectivity, including a peptide of 5-10 amino acids comprising an RGD motif. One of ordinary skill would have a reasonable expectation of success because Schaffer et al. disclose the insertion site (position 454) for AAV9 capsid protein and the amino acids for the peptide of 5-10 amino acids to include the RGD motif, which is recognized by retinal tissue.
The instant specification discloses that instant SEQ ID NO: 118 is the amino acid sequence of AAV9 capsid protein. Since Schaffer et al. disclose insertion of a peptide at the same position recited 454 of AAV9 capsid protein, Schaffer et al. can be deemed to disclose the amino acid sequence of AAV9 capsid protein (instant claims 1, 95-96), and thereby instant SEQ ID NO: 118.
Regarding instant claim 98, since Schaffer et al. disclose a rAAV9 capsid protein comprising an insertion peptide that is structurally the same as the claimed rAAV9 capsid protein and also comprising the RGD motif, it would follow that the rAAV9 capsid protein comprising an insertion peptide 5-10 amino acids comprising an RGD motif of Schaffer et al. targets a cell comprising an integrin receptor.
Reply: In view of Applicants’ amendments/remarks, the previous 102(a)(1) rejection as being anticipated by Schaffer et al. has been withdrawn. However, Schaffer et al. is maintained as a 103 reference in view of newly cited Lowell et al. for the reasons noted above.
Regarding Applicants’ remarks that Schaffer et al. do not teach a muscle homing domain, the remarks are not persuasive.
MPEP 2144 notes that it is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006).
In this instance, the fact that Applicants incorporate a peptide of 5-10 amino acids having a RGD motif that is a “muscle homing” domain in a AAV9 capsid protein does not alter the conclusion that its use in the prior art (to increase infectivity of retinal cells or target retinal cells) would have been prima facie obvious from the purpose disclosed in the references.
In this instance, Schaffer et al. still disclose 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, which is structurally the same as the claimed rAAV9 capsid protein and insertion peptide.
Applicants assert that formula IV (the peptide insertion sequence) is far broader than what the office explains. Applicants assert that the consensus sequence describes over 16 million or more possible peptides.
Applicants’ remarks are not persuasive. While Schaffer et al. disclose a formula for the peptide insertion of 5-10 amino acids, Schaffer et al. still provide guidance on which specific amino acid residues are selected for arriving at the peptide insertion of 5-10 amino acids. Schaffer et al. has disclosed that the peptide insertion in the AAV capsid protein alters the AAV capsid protein so that it exhibits greater infectivity of retinal cells (at least abstract, p. 2). It is disclosed that peptides/proteins having the RGD motif are recognized by integrins which are present in the retinal tissue (Lowell et al.). Therefore, the prior art recognize that at a minimum the RGD motif is present in the peptide/protein for binding to integrin. As noted above, Schaffer et al. disclose that 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. disclose a finite number of amino acids to choose from to arrive at the RGD motif for the peptide of 5-10 amino acids that is inserted into the AAV9 capsid protein. Therefore, Applicants’ remarks that the consensus sequence describes over 16 million or more possible peptides are not found persuasive.
Regarding Applicants’ remarks that Schaffer et al. is not enabled for the claimed invention, the remarks are not persuasive. MPEP 2121 notes that when the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to rebut the presumption of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980).
In this instance, one of ordinary skill would have a reasonable expectation of success because Schaffer et al. disclose the insertion site (position 454) for AAV9 capsid protein and the amino acids for the peptide of 5-10 amino acids to include the RGD motif, which is recognized by retinal tissue.
For at least these reasons, the 103 rejection is maintained.
Claims 74, 78-79, 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, 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 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. The reasons for maintaining the 103 rejection are the same as previously noted and are incorporated herein.
Applicants previously asserted 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 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.
Regarding Applicants’ remarks that Lux et al. provide several negative indications associated with the G453 insertion and one of skill in the art would be dissuaded by these teachings to combine the G453 with AAV9, the remarks are not persuasive. Lux et al. expressly disclose that the mutants including a single peptide comprising RGD at G453 of AAV2, compared to wild-type, assembled capsids and packaged efficiently viral genomes and had considerably high transducing titers of at least 107 transducing particles per mL (at least p. 74). Lux et al. further disclose that both wild-type and an A2 mutant did not show any binding to integrin (αvβ3); however, the mutants including a single peptide comprising RGD at G453 of AAV2 showed clearly detectable binding of αvβ3 (at least p. 76).
Further, as already noted, Lux et al. disclose that it has 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).
Therefore, Applicants’ remarks that Lux et al. provide several negative indications associated with the G453 insertion and that one of skill in the art would be dissuaded by these teachings to combine the G453 with AAV9 are not found persuasive.
As previously noted, 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.
Regarding Applicants’ remarks that DiMattia et al. provide no reason to alter AAV9, the remarks are not persuasive. DiMattia et al. is cited with Lux et al., which disclose there is interest in altering AAV capsid proteins, including AAV9, where 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).
For at least these reasons, the 103 rejection is maintained.
No claim is allowed.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath N. Rao can be reached on 571-272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Marsha Tsay/Primary Examiner, Art Unit 1656
Prosecution Insights