DETAILED ACTION
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. Applicant’s Request for Continued Examination, Amendment and Arguments/Remarks received on 07 July 2025 have been entered. Claims 1, 3, 16, 22, 24, 28-30, 45-46, 58, 62, 76, 78-79, 82-85, and 87-92 were previously pending in the application. Claim 3 has been cancelled, and new claims 93-96 have been added by Applicant. Claims 1, 16, 22, 24, 28-30, 45-46, 58, 62, 76, 78-79, 82-85, and 87-96 are currently pending in the application. Claims 1, 16, 22, 28, 29, 30, 45, 62, and 88 are independent claims.
The election of Group I, drawn to a modified adeno-associated virus (AAV) capsid protein comprising an amino acid substitution at one or more positions corresponding to amino acids S194, G474, N564, and/or N573; a modified adeno-associated virus (AAV) capsid protein comprising: a G at the position corresponding to amino acid 194, an R at the position corresponding to amino acid 474, an R at the position corresponding to amino acid 564, and/or an R at the position corresponding to amino acid 573; a method of producing an AAV capsid protein; and a recombinant adeno-associated viral (rAAV) particle, remains in effect in the instant application.
Claims 1, 16, 22, 24, 28-30, 45-46, 58, 62, 76, 78-79, 82-85, and 87-96 are currently pending and under examination in the instant application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application claims priority to U.S. Provisional Application No. 62/967,416, filed 29 January 2020. Thus, the earliest possible priority for the instant application is 29 January 2020.
Information Disclosure Statement
The information disclosure statement filed 07 July 2025 has been considered by the Examiner. Examiner notes the filing of IDS Size Fee assertions for the IDS filed 07 July 2025, as required under 37 CFR 1.98, along with payment of the appropriate Size Fee with the IDS filed 07 July 2025, as required under 37 CFR 1.17(v)(1).
Claim Objections
Amended claim 45 is newly objected to because of the following informalities: amended independent claim 45 recites, “a (rAAV) particle comprising”, which appears to be an unintended carry-over from the prior version of the claim in that the parenthesis should have been deleted when the term “adeno-associated virus” was deleted. Appropriate correction is required.
Applicant is advised that should claim 45 be found allowable, claim 92 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 112(b)
The rejection of amended claim 90 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for reciting “a recombinant cell comprising the nucleic acid of claim 89”, is withdrawn in view of Applicant’s amendments to claim 90 such that claim 90 now recites the nucleic acid of claim 88.
Claim Rejections - 35 USC § 112(d)
Previously presented claims 76 is newly rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 76 recites, “the modified capsid protein of claim 16, wherein the modified capsid protein is a modified capsid protein pf AAV5”, which does not add any additional limitations to the modified AAV5 capsid protein claimed in claim 16.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)- Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 16, 45-46, 76, 78-79, 82-85, and 88-92 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
a modified AAV5 capsid protein for transducing ocular cells comprising:
a G at the position corresponding to amino acid 194, wherein the modified AAV5 capsid protein comprises the amino acid sequence set forth in SEQ ID NO: 3;
an R at the position corresponding to amino acid 564, wherein the modified AAV5 capsid protein comprises the amino acid sequence set forth in SEQ ID NO: 7; or
an R at the position corresponding to amino acid 573, wherein the modified AAV5 capsid protein comprises the amino acid sequence set forth in SEQ ID NO: 9;
wherein numbering of the position is based on the amnio acid sequence of the wild-type AAV5 VP1 as set forth in SEQ ID NO: 1;
does not reasonably provide enablement for:
a modified AAV5 capsid protein comprising:
a G at the position corresponding to amino acid 194;
an R at the position corresponding to amino acid 564; and/or
an R at the position corresponding to amino acid 573;
wherein the modified AAV5 capsid protein comprises any amino acid at any other position relative to the wild-type AAV5 VP1 as set forth in SEQ ID NO: 1; and
wherein numbering of the position is based on the amino acid sequence of the wild-type AAV5 VP1 as set forth in SEQ ID NO: 1.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The rejection comprises two (2) separate issues: 1) the absence of an enabling disclosure for a modified AAV5 capsid protein with tropism to cells other than ocular cells; and 2) the absence of an enabling disclosure for a modified AAV5 capsid protein with mutations other than 194G, 564R, or 573R relative to the wildtype AAV5 of instant SEQ ID NO: 1. These issues were identified by the Office after analysis of the disclosure provided by the specification. The Office has analyzed the specification in direct accordance to the factors outlined in In re Wands, namely 1) the nature of the invention, 2) the state of the prior art, 3) the predictability of the art, 4) the amount of direction or guidance present, and 5) the presence or absence of working examples, and presented detailed scientific reasons supported by publications from the prior art for the finding of a lack of enablement for the scope of the instant methods. The Wands analysis and supporting specific evidence are presented below for each of the identified issues.
As a first issue (1), the specification does not provide an enabling disclosure for a modified AAV5 capsid protein with tropism to any cells other than ocular cells. The broadest independent claim, claim 16, recites a modified AAV5 capsid protein comprising:
a G at the position corresponding to amino acid 194;
an R at the position corresponding to amino acid 564; and/or
an R at the position corresponding to amino acid 573;
wherein numbering of the position is based on the amino acid sequence of the wild-type AAV5 VP1 as set forth in SEQ ID NO: 1. Claims 45-46, 76, 78-79, 82-85, and 88-92 depend on or encompass independent claim 16.
The specification discloses in Example 3 that the claimed G474R, N564R, and N573R variants were delivered intravitreally or subretinally to evaluate tropism, wherein the three variants transduced the ONL of the retina and RPE cells similarly to WT AAV5, and also acquired novel tropism for corneal epithelial cells [0198, Figure 4]. Example 4 of the specification discloses that the S194G variant demonstrates increased potency in transducing outer retinal cells/photoreceptors following subretinal injection, whereas the S2G, S2P, S194P, S2G/S194G, and S2P/S194P resulted in reduced levels of transgene expression in photoreceptors [0199-0202, Table 4, Figure 6]. The specification only teaches administration to and transduction of ocular cells.
The art at the time of filing teaches that different AAV serotypes have been shown to exhibit distinct tropism for various tissues and organs, and that novel AAV serotypes can be designed and optimized to target specific tissues and organs [Srivastava 2016, Current Opinion in Virology, 21, 75-80, column 4 ¶ 4, column 7 ¶ 1]. Srivastava also teaches that wildtype AAV5 specifically requires both binding to α2-3 N-linked SIAs and the platelet-derived growth factor receptor (PDGFR) to gain entry into cells, whereas other serotypes requires different cell surface interactions [column 3 ¶ 2- column 4 ¶ 1]. Additionally, Asokan teaches many mutations which alter the tissue tropism of AAV particles [Asokan & Pulicherla (WO2012109570A1), published 16 August 2012, cited in a prior action, page 2 lines 14-27, page 15 lines 7-29, page 20 lines 34, Table 8, Figure 1]. Church also teaches mutations which alter the tissue tropism of AAV particles, to either improve or reduce tropism to a particle tissue or cell type [Church et al. (US20210230229A1), published 29 July 2021, filed 8 May 2019 with priority to the U.S. provisional application 62/671,949 filed 15 May 2018, cited in a prior action, 0006-0011, 0038-0041].
Neither the specification nor the art at the time of filing teaches that a variant AAV5 can transduce any cell type from any organism. Thus, in view of the numerous tropisms resulting from AAV capsid variation, the ability of a single point to mutation to alter tropism (e.g., as taught in the instant specification for each of G474R, N564R, and N573R), the ability of a single point mutation to offset a change in tropism derived from a tropism-altering mutation (e.g., as taught in the instant specification such that S194G efficiently transduces photoreceptors but that the double mutant S2G/S194G lacks photoreceptor transduction), and the breadth of the claims, the skilled artisan would have considered using the claimed AAV5 variants for transducing cells other than ocular cells as highly unpredictable. As such it would have required undue experimentation to practice the scope of applicant’s invention as claimed.
As a second issue (2), the specification does not provide an enabling disclosure for a modified AAV5 capsid protein with mutations other than 194G, 564R, or 573R. The broadest independent claim, claim 16, recites a modified AAV5 capsid protein comprising:
a G at the position corresponding to amino acid 194;
an R at the position corresponding to amino acid 564; and/or
an R at the position corresponding to amino acid 573;
wherein numbering of the position is based on the amino acid sequence of the wild-type AAV5 VP1 as set forth in SEQ ID NO: 1. Claims 45-46, 76, 78-79, 82-85, and 88-92 depend on or encompass independent claim 16.
The specification discloses in Example 3 that the claimed G474R, N564R, and N573R variants were delivered intravitreally or subretinally to evaluate tropism, wherein the three variants transduced the ONL of the retina and RPE cells similarly to WT AAV5, and also acquired novel tropism for corneal epithelial cells [0198, Figure 4]. Example 4 of the specification discloses S194G variants demonstrated increased potency in transducing outer retinal cells/photoreceptors following subretinal injection, whereas the S2G, S2P, S194P, S2G/S194G, and S2P/S194P resulted in reduced levels of transgene expression in photoreceptors [0199-0202, Table 4, Figure 6]. The specification only teaches administration of each of these variants individually, wherein the claimed mutation is the only alteration to an otherwise WT AAV5 capsid protein according to instant SEQ ID NO: 1 or wherein any additional mutations abolish the increased transduction observed for the claims mutations (e.g., S2G/S194G).
The art at the time of filing teaches that different AAV serotypes have been shown to exhibit distinct tropism for various tissues and organs, and that novel AAV serotypes can be designed and optimized to target specific tissues and organs [Srivastava, column 4 ¶ 4, column 7 ¶ 1]. Srivastava also teaches that wildtype AAV5 specifically requires both binding to α2-3 N-linked SIAs and the platelet-derived growth factor receptor (PDGFR) to gain entry into cells, whereas other serotypes requires different cell surface interactions [column 3 ¶ 2- column 4 ¶ 1]. Additionally, Asokan teaches many mutations which alter the tissue tropism of AAV particles [page 2 lines 14-27, page 15 lines 7-29, page 20 lines 34, Table 8, Figure 1]. Church also teaches mutations which alter the tissue tropism of AAV particles, to either improve or reduce tropism to a particle tissue or cell type [0006-0011, 0038-0041]. Church further teaches that most mutations are deleterious [0038].
Neither the specification nor the art at the time of filing teaches that any variant of AAV5 can transduce any cell type from any organism, that any AAV5 variant can specifically have improved transduction of ocular cells, nor that any additional variations/mutations in addition to the claimed mutations will maintain or improve transduction of any cell type. Thus, in view of the numerous tropisms resulting from AAV capsid variation, the ability of a single point mutation to alter tropism (e.g., as taught in the instant specification for each of G474R, N564R, and N573R), the ability of a single point mutation to offset a change in tropism derived from a tropism-altering mutation (e.g., as taught in the instant specification such that S194G efficiently transduces photoreceptors but that the double mutant S2G/S194G lacks photoreceptor transduction), the teachings that most mutations are deleterious to transduction, and the breadth of the claims, the skilled artisan would have considered a modified AAV5 capsid protein comprising the claimed variants in combination with each other or any other modifications (e.g., wherein the AAV5 capsid protein is only 80% identical to the instant SEQ ID NO: 1) as highly unpredictable. As such it would have required undue experimentation to practice the scope of applicant’s invention as claimed.
Claim Rejections - 35 USC § 103
The rejection of amended, previously presented, original, and cancelled claims 1, 3, 16, 22, 24, 28-30, 45-46, 58, 62, 76, 84-85, and 87-92 under 35 U.S.C. 103 as being unpatentable over Asokan & Pulicherla (WO2012109570A1), published 16 August 2012, in view of Stagg et al. 2022, Chem. Rev., Vol. 122, 14018-14054, is withdrawn in view of Applicant’s claims which recite AAV5 capsid proteins with specific individual mutations which exhibit improved and/or novel transduction efficiency not taught by the prior art.
The rejection of amended, previously presented, original, and cancelled claims 1, 3, 16, 22, 24, 28-30, 45-46, 58, 76, 78-79, 82-85, and 87-92 under 35 U.S.C. 103 as being unpatentable over Church et al. (US20210230229A1), published 29 July 2021, filed 8 May 2019 with priority to the U.S. provisional application 62/671,949 filed 15 May 2018, in view of Stagg et al. 2022, Chem. Rev., Vol. 122, 14018-14054, Tseng et al. 2015, J. Virol., Vol. 80(2), 821-834, Alberts et al. 2002, Molecular Biology of the Cell, 4th Edition, New York: Garland Science, retrieved from the Internet: <https://www.ncbi.nlm.nih.gov/books/NBK26830/>, and Jin et al. 2017, Human Gene Therapy Methods, Vol. 28(5), 255-267, is withdrawn in view of Applicant’s claims which recite AAV5 capsid proteins with specific individual mutations which exhibit improved and/or novel transduction efficiency not taught by the prior art.
Allowable Claims
Claims 1, 22, 24, 28-30, 58, 62, 87, and 93-96 are considered free of the art of record and considered allowable. The closest prior art is considered to be 1) Asokan & Pulicherla (WO2012109570A1), published 16 August 2012, in view of Stagg et al. 2022, Chem. Rev., Vol. 122, 14018-14054; and 2) Church et al. (US20210230229A1), published 29 July 2021, filed 8 May 2019 with priority to the U.S. provisional application 62/671,949 filed 15 May 2018, in view of Stagg et al. 2022, Chem. Rev., Vol. 122, 14018-14054, Tseng et al. 2015, J. Virol., Vol. 80(2), 821-834, Alberts et al. 2002, Molecular Biology of the Cell, 4th Edition, New York: Garland Science, retrieved from the Internet: < https://www.ncbi.nlm.nih.gov/books/NBK26830/>, and Jin et al. 2017, Human Gene Therapy Methods, Vol. 28(5), 255-267; as described in the prior 103 rejections. However, the specifically recited sequences of SEQ ID NOs: 3, 5, 7 and 9 are not taught by the prior art and have functional properties which are not reasonably expected based on the prior art, such that SEQ ID NO: 3 has demonstrated increased potency in transducing photoreceptors and SEQ ID NOs: 5, 7, and 9 have acquired tropism for corneal endothelial cells.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dr. KATIE L PENNINGTON whose telephone number is (703)756-4622. The examiner can normally be reached M-Th 8:30 am - 5:30 pm, Friday 8:30 am - 12:30 pm CT.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634