DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group II (claims 23, 26-28, 30, 31, and 39) in the reply filed on April 15, 2026 is acknowledged. Claims 1, 3, 5, 7, and 44 are cancelled. Claims 49, 50, and 53-55 are new and are included into elected Group II of invention. Further, claims 32-36, 40, 42, and 43 are currently amended to fall under Group II of invention.
Applicant’s election without traverse of Species (SEQ ID NO: 2 and SEQ ID NO: 3) in the reply filed on April 15, 2026 is acknowledged. The elected species SEQ ID NO: 2 and SEQ ID NO:3 is free of prior art. Examiner has modified the provisional election of species requirement to search additional nonelected species. Upon searching the full scope of the Markush group, the genus of capsid proteins recited in claim 23 is determined to be allowable over the prior art. Thus, the provisional election of species has been withdrawn.
Accordingly, claims 23, 26-28, 30-36, 39-40, 42-43, 49-55 are under consideration.
Priority
Acknowledgment is made of applicant's claim for priority based on a US Provisional Application
No. 63/137,497 filed on 01/14/2021.
Claim Objections
The numbering of claims is not in accordance with 37 CFR 1.126 which requires the original numbering of the claims to be preserved throughout the prosecution. When claims are canceled, the remaining claims must not be renumbered. When new claims are presented, they must be numbered consecutively beginning with the number next following the highest numbered claims previously presented (whether entered or not).
Misnumbered claim 53 been renumbered 51.
Misnumbered claim 54 been renumbered 52.
Misnumbered claim 55 been renumbered 53.
Appropriate action is required to correct the numbering of the claims 51-53 and recitations of claims from which they depend on.
Claims 27, 28, 30, and 31 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim Rejections - 35 USC § 112
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 34-36 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 34 recites the limitation “the transduction-associated peptide” in line 3. There is insufficient antecedent basis for this limitation in the claim. There is no prior recitation of this limitation. Therefore, it is unclear which transduction-associated peptide claim 34 is referring to.
Claim 36 recites the limitation “the peptide” in line 3. There is insufficient antecedent basis for this limitation in the claim. It is noted that claim 34 recites “the transduction-associated peptide”, thus, it is unclear whether this limitation is related to “the peptide” in claim 36 or not.
Those claims included in the statement of rejection but not otherwise discussed are rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 26 is 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. 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 26 is directed to a nucleic acid encoding a recombinant AAV capsid protein of claim 23, which requires a recombinant AAV vector comprising a capsid protein. Claim 26 is drawn to nucleic acid and fails to include the capsid protein in claim 23. Thus, claim 26 fails to further limit the subject matter of the claim from which it depends and include all of the limitations of that claim.
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 43 and 50 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention and Breadth of the Claims
Claims 43 and 50 are directed to a method of treating a subject comprising administering an effective amount of a recombinant AAV vector comprising an amino acid sequence SEQ ID NO: 2, 4, 6, 8, 10, 12, or 14. The breadth of the claims is broad because it encompasses treatment of any disease or condition in any subject using the recited recombinant AAV vector, without any further limitations including disease indication, target tissue, route of administration, and therapeutic cargo.
Guidance of the Specification
The specification does not provide guidance commensurate with the breadth of the claims. The only disclosed example demonstrates transduction of T cells using a recombinant AAV vector of recited SEQ ID NOs carrying a nucleic acid cargo encoding for a green fluorescent protein (Example 3, FIG. 4). The specification does not provide any working example demonstrating treatment, prevention, or amelioration for any disease in any subject. Further, the specification does not disclose any data demonstrating in vivo or ex vivo delivery, therapeutic gene expression, efficacy, dosing parameters, of any successful disease modifications using the claimed recombinant AAV vectors. Accordingly, the specification provides guidance, at most, an example of fluorescent reporter transduction rather than an enabled embodiment of claimed method for treating any disease in a subject encompassed by the claims.
State of the Art
At the time of filling, the state of the art teaches immunological challenges are present in AAV gene therapies, which could compromise durability of transgene expression and long-term therapeutic benefits. Ertl et al (T Cell-Mediated Immune Responses to AAV and AAV Vectors; Frontiers in Immunology, 2021, 12: 1-11) teach induction of immune responses to AAV vectors present discrepancies in clinical trails for various disease treatments. For instance, “some trials for correction of ocular diseases reported stable transgene product expression for years without evidence for induction of T cell responses…others observed stimulation of adaptive immune responses combined in some cases with loss of therapeutic benefits” (pg. 5, col. 1, para. 1). Further, “some trails using AAV5 expressing the Padua variant of F.IX failed to observe any post-infusion transaminitis, which would be indicative of an anti-AAV immune response” (pg. 5, col. 1, para. 2), and “additional studies are needed to further determine the risk induction of T cells upon intramuscular injection of AAV vectors. It will be especially important to further elucidate the role of regulatory T cells in preventing immune-mediated destruction of AAV-transduced muscle cells” (pg. 5, col. 2, para. 3). Lastly, “it remains unclear how common T cells to AAV capsid or the encoded transgene product interfere with sustained therapeutic benefits” (pg. 6, col. 1, para. 4). Therefore, the discrepancies in clinical trial results render it unpredictable whether a particular AAV vector could successfully treat a given disease.
In addition, Belov et al (Opportunities and challenges for applying model-informed drug development approaches to gene therapies; CPT Pharmacometrics Syst. Pharmacol; 2021, 10:286–290) teach “immune tolerance to the AAV serotype and each transgene remains poorly understood” (pg. 288, col. 2, para. 3). Belov et al further teach “predicting transgene expression, protein and enzyme activity levels, and the potential for immune responses or other adverse events will be critical to help ensure [gene therapy] products remain within a therapeutic range acceptable for efficacy and safety…and predicting [these] features of AAVs continue to be a challenging topic” as these are topic with large knowledge gaps (pg. 289, col. 1, para. 1; Figure 2 shown below).
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The specification’s sole example is directed to transduction of claimed AAV vectors in T cells, which is a cell type that is closely tied to immune responses against AAV vectors leading to immune activation and clearance of transduced cells rather than stable therapeutic benefit as taught by
Ertl et al. Therefore, successful AAV vector transduction of T cells to express a fluorescent reporter would not reasonably enable predictable therapeutic efficacy across diseases in a subject. It would have been highly unpredictable that merely administering an effective amount of claimed AAV vector would treat a disease in a subject when Belov et al teach that transgene production, fate of transduced cell, and immune responses present a large knowledge gap to mechanistically and quantitatively elucidate the impact on downstream pathways that may influence the in vivo processing of AAV therapeutics (pg. 289, col. 1, para. 1).
Experimentation Required
In order to practice the claimed invention, an immense amount of experimentation would be required. For example, it would be necessary for one of ordinary skill in the art to determine whether the claimed recombinant AAV vectors treat any particular diseases, including identifying appropriate therapeutic cargos that would be packaged in the AAV vector, target tissue, delivery route, safety profile, and strategy to overcome immune responses challenges.
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, it is the conclusion that an unreasonable amount experimentation would be required to make and use the invention as claimed. Therefore, claims 43 and 50 are not considered to be enabled by the instant disclosure.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter:
Claims 23, 32, 33, 35, 40, 42, 49, and 51-53 recite recombinant AAV vectors comprising capsid proteins of amino acid sequences selected from the group consisting of SEQ ID NOs: 2, 4, 6, 8, 10, 12, and 14. The specific amino acid sequence modifications within residues 454-460 (Table 5) are free of prior art presently of record.
Tse et al (Structure-guided evolution of antigenically distinct adeno-associated virus variants for immune evasion; PNAS, 2017, 114(24): E4812–E4821) teach that surface-exposed capsid residues within region IV (456-AQNK-459) are suitable targets for saturation mutagenesis and AAV library generation for subsequent functional selection of antibody-evading AAV variants. Tse et al further disclosed selected variants CAM101-107, especially CAM106 comprising 456-SERR-459. Therefore, Tse et al demonstrate that these amino acid positions are known in the art for AAV capsid engineering to alter AAV properties. However, no prior art teaches or suggests the instant amino acid modifications spanning residues 454-460.
The closest art, Asokan et al (WO 2023/004407 A2; Published on Jan 26, 2023; Priority to 63/225,087 filed on July 23, 2021) teach recombinant AAV vectors comprising amino acid modifications also at positions 454-460, particularly the HAPRVEE mutations in instant SEQ ID NO: 2 obtained through mutagenesis and selection (bottom of pg. 55). However, Asokan et al claims priority to Provisional Application 63/225,087 filed in July 23, 2021 whereas the instant application has an effective filling date of January 14, 2021.
Claims 34-36 would be allowable if rewritten to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
Conclusion
Claims 23, 32, 33, 35, 40, 42, 49 are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to QIWEN SU-TOBON whose telephone number is (571)272-0331. The examiner can normally be reached Monday - Friday, 9:30am - 5:00pm.
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QIWEN SU-TOBON
Examiner
Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
Prosecution Insights