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 .
DETAILED ACTION
Application status
Claims 1 and 31-45 are pending in this application.
Priority
The instant application is the 371 national stage entry of PCT/AU2021/051496, filed on 12/16/2021.
Acknowledgment is made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to a foreign patent application Australia, AU2020904689 filed on 12/16/2020.
Election
Applicant's election species: SEQ ID NOs: 60, 63-67, 70, 73, 74 and 78 corresponding to SEQ ID NOs: 4, 7-11, 14, 17, 18 and 22, respectively in the response filed on 04/28/2026, is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)).
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 06/14/2023 and 06/11/2025 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Objections to the Specification
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825; Applicants’ attention is directed to the final rulemaking notice published at 55 FR 18230 (May 1, 1990), and 1114 OG 29 (May 15, 1990). To be in compliance, Applicants should identify nucleotide sequences of at least 10 nucleotides and amino acid sequences of at least 4 amino acids in the specification by a proper sequence identifier, i.e., “SEQ ID NO:” (see MPEP 2422.01). If these sequences have not been listed in the computer readable form and paper copy of the sequence listing, applicant must provide an initial computer readable form (CRF) copy of the “Sequence Listing”, an initial paper copy of the “Sequence Listing”, as well as an amendment directing its entry into the specification, and a statement that the content of the paper and CRF copies are the same and, where applicable, include no new matter as required by 37 C.F.R. 1.821(e) or 1.821(f) or 1.821(g) or 1.821(b) or 1.825(d).
See particularly Figure 1; and Table 3 of the specification containing nucleic acid sequence/amino acid sequences, and therefore, those sequences should be represented by proper sequence identifier numbers.
If the noted sequences are not in a sequence listing as filed, Applicants must provide (1) an updated copy of the sequence listing containing the requisite sequences in computer readable form (CRF), (2) an amendment directing its entry into the specification, (3) a statement that no new matter has been added and (4) an amendment to the specification to identify each of the identified sequences by SEQ ID NO:, and (5) an incorporation by reference statement with the date of creation, sequence file name and size in bytes. – See also MPEP 2422.
Appropriate correction is required.
Claim Objections
Claims 1 and 38 are objected to because of the following informalities:
Claims 1 and 38 are objected to because the recitation of “SEQ ID Nos” which can be substantially improved with consistency. The Examiner suggests replacing the noted phrase with ---SEQ ID NOs---.
Appropriate correction is required.
Claim Rejections - 35 U.S.C. § 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.
Claims 1 and 31-45 are rejected under 35 U.S.C. § 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claims 1, 36 and 38 (31-35, 37 and 39-45 dependent therefrom) is confusing in the recitation of the phrase, “at lease or about”. The term “about” encompasses a range which includes values which are higher and lower than the recited reference value. The term “at least” implies that only values equal to or higher than the recited reference value are encompassed. Therefore, in the absence of a clear definition of what is encompassed by the term “about”, the term "at least about" is unclear and confusing since the term refers to values which are equal or higher than undefined values which are either higher or lower than the recited reference value. In essence, the term eliminates the relevance of the recited reference point because the reference value becomes variable and undefined. In the interest of advancing prosecution, the noted phrase is interpreted as “at least”.
Claims 1 and 32 recite “7 amino insertion”… and comprises the sequence set forth in any one of SEQ ID NOs: 58-85, which is unclear. It is noted by the Examiner that “7 amino insertion” contradicts the amino acid sequence disclosed in SEQ ID NOs: 58-85 because all of SEQ ID NOs: 58-85 disclose 9-amino acid sequences. In the interest of advancing prosecution, the Examiner has interpreted the noted phrase as “insertion of 9 amino acids”.
The following is a quotation 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.
Claims 1 and 31-45 are rejected under 35 U.S.C. § 112(a), written description, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims are directed to a genus of AAV capsid polypeptides, comprising a peptide modification relative to the AAV2 capsid polypeptide set forth in SEQ ID NO: 1, wherein: the peptide modification is in variable region 8 (VRVIII); the peptide modification comprises an insertion of 9 amino acids relative to the AAV2 capsid polypeptide set forth in SEQ ID NO: 1, and comprises the sequence set forth in any one of SEQ ID NOs:58-85; and the portion of the capsid polypeptide that is not the peptide modification comprises at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, or 96% sequence identity to positions 1-735, 138-735 or 203-735 of SEQ ID NO: 1. (see above claim interpretation under 112(b) rejection)
To satisfy the written description aspect of 35 U.S.C. § 112(a) for a claimed genus of [compositions or methods], it must be clear that: (1) the identifying characteristics of the claimed [compositions or methods] have been disclosed, e.g., structure, physical and/or chemical characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or a combination of these; and (2) a representative number of species within the genus must be disclosed.
The Court of Appeals for the Federal Circuit has recently held that a “written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as be structure, formula [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials.” University of California v. Eli Lilly and Co., 1997 U.S. App. LEXIS 18221, at *23, quoting Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) (bracketed material in original). To fully describe a genus of genetic material, which is a chemical compound, applicants must (1) fully describe at least one species of the claimed genus sufficient to represent said genus whereby a skilled artisan, in view of the prior art, could predict the structure of other species encompassed by the claimed genus and (2) identify the common characteristics of the claimed molecules, e.g., structure, physical and/or chemical characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or a combination of these (paraphrased from Enzo Biochemical Inc. v. Gen-Probe Inc. (CAFC (2002) 63 USPQ2d 1609).
The specification discloses only a single representative species of AAV capsid polypeptide set forth in SEQ ID NO: 1 as a backbone, to which residues 587-595 are replaced with the peptide sequences set forth in SEQ ID NOs: 58-85. However, this single disclosed species fails to provide adequate written description for AAV capsid polypeptides, which encompasses those comprising a peptide modification relative to the AAV2 capsid polypeptide set forth in SEQ ID NO: 1, wherein: the peptide modification comprises an insertion of 9 amino acids set forth in any one of SEQ ID NOs:58-85 into the VRVIII of SEQ ID NO: 1, and comprises a genus of any portion of the capsid polypeptide, that is not the peptide modification, comprising at least 80% sequence identity to positions 1-735, 138-735 or 203-735 of SEQ ID NO: 1, which includes substituting as many as 147 amino acid residues (111 amino acid residues for claim 38) with any one of 20 different amino acid residues (italicized for added emphasis).
In this case, the specification fails to describe any identification of structural characteristics or properties of the genus of any portions of capsid polypeptides, (no other capsid backbones are described for these particular insertions other than SEQ ID NO: 1), that is not the peptide modification, having at least 80% or 85% sequence identity to SEQ ID NO: 1 such that one can readily envision structural characteristics and/or properties of such genus, which encompasses making 111-147 amino acid substitutions with any combinations of 20 different amino acid residues, while maintaining the functional characteristics of being an AAV capsid polypeptide. An adequate description of the claimed genus is even more important in the instant case because the field of AAV capsid engineering is notoriously unpredictable, and even a single amino acid substitution or small insertions can abolish capsid assembly, packaging efficiency, stability, tropism or immunogenicity (see page 4, center column, 2nd para of Ogden et al. (Comprehensive AAV capsid fitness landscape reveals a viral gene and enables machine-guided design, Science 366 (6468), 1139-1143, 2019). It is noted by the Examiner that none of the dependent claims remedy the deficiencies noted above regarding the written description requirement.
Taken together, the genus of claimed “AAV capsid polypeptides” encompasses widely variant species, having widely variant structures. While M.P.E.P. section 2163 acknowledges that a single species can describe a genus, it also acknowledges that for a genus that encompasses widely variant species, disclosure of a single species within the genus fails to adequately describe all members of the genus. Please refer to the M.P.E.P. section 2163.05 [R-7.2022] under I, B for more details with respect to sufficient number of representative species that should be disclosed to describe a widely variant genus.
Given the lack of additional representative species of a genus of “AAV capsid polypeptides” as encompassed by the claims, Applicants have failed to sufficiently describe the claimed invention, in such full, clear, concise, and exact terms that a skilled artisan would recognize Applicants were in possession of the claimed invention.
Applicant is referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112(a) published in the Official Gazette and also available at www.uspto.gov.
Claim Rejections - 35 USC § 103
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1 and 31-45 are rejected under 35 U.S.C. 103 as being unpatentable over Muller et al. (Random peptide libraries displayed on adeno-associated virus to select for targeted gene therapy vectors, Nature Biotechnology, volume 21, pages1040–1046 (2003)) in view of Asokan et al. (US Patent No. 11059862 published on 12/27/2018), and KSR International Co. v. Teleflex Inc., 550 U.S.--, 82 USPQ2d 1385 (2007).
The instant claims are drawn to an AAV capsid polypeptide, comprising a peptide modification relative to the AAV2 capsid polypeptide set forth in SEQ ID NO: 1, wherein: the peptide modification is in variable region 8 (VRVIII); the peptide modification comprises an insertion of 9 amino acids relative to the AAV2 capsid polypeptide set forth in SEQ ID NO: 1, and comprises the sequence set forth in any one of SEQ ID NOs:58-85; and the portion of the capsid polypeptide that is not the peptide modification comprises at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, or 96% sequence identity to positions 1-735, 138-735 or 203-735 of SEQ ID NO: 1. (see above claim interpretation under 112(b) rejection)
Muller et al. teach the foundational AAV2 random peptide display library platform, wherein random 7-amino acid peptides (9-mer with two amino acids added at each end due to two SfiI restriction sites, see Figure 1 (b) on page 1041) are inserted into the AAV2 capsid at the VRVIII site, immediately following R588, which abolish heparin (R588 is known to bind heparan sulfate proteoglycans (HSPGs) in the relevant field of art) while preserving capsid assembly and packaging, and the library is screened to isolate variants with altered tropism (see RESULTS on page 1041). It is noted by the Examiner that this identical library-construction strategy is used in the instant specification for producing peptides (9-mer) of SEQ ID NOs: 58-85, which were inserted at the Sfil-engineered N587 site of AAV2 set forth in SEQ ID NO: 1 which is essentially an identical backbone. Muller et al. further teach packaging the modified capsids into recombinant AAV vectors, providing nucleic acids (plasmids) encoding the variant capsid genes, and using host cells, i.e. HEK293 cells, for vector production (see Figure 2 on page 1042, and related discussions).
Muller et al. do not teach the peptide sequences of SEQ ID NOs: 58-85; and one or more amino acid substitutions at positions 585, 586 and/or 589, which are optionally R585G, G586Q and/or Q589A.
Asoka et al. teach AAV2 capsid polypeptide comprising R585Q, G586Q, R588T, Q589A substitutions, which alters tropism for CNS, i.e. neuronal and glial cell expression (see claims 7 & 8; and Figure 11).
It would have been obvious to a person of ordinary skill in the art (POSITA) prior to the effective filing date of the instant application to make and use AAV capsid polypeptides with analogous 9-mer peptides set forth in SEQ ID NOs: 58-85 with introduction of known substitutions R585Q, G586Q, R588T, Q589A substitutions in AAV2 in order to alter tropism for CNS/neuronal/glial expression as taught by Muller et al. and Asokan et al. because Muller et al. teach the foundational methods of generating random 9-mer peptides to be inserted at Sfil sites located within VRVIII of AAV2, packaging the resulting capsids into recombinant AAV vectors, expressing them from nucleic acid constructs and producing them in host cells. A POSITA would have been motivated to make and use such AAV capsid polypeptides in order to enhance tropism for CNS/neuronal/glial expression as taught by Asokan et al.
Even though prior art does not teach the exact peptide sequences of SEQ ID NOs: 58-85, a POSITA would have arrived at these exact 9-mer sequences with routine experimentation. It is noted by the Examiner that the specific peptide sequences set forth in SEQ ID NOs: 58-85 are NOT structurally or functionally inventive, as they are simply expected products of a known, optimization technique applied to a known starting capsid AAV2 and known cloning/production strategy as taught by Muller et al. which is identically used/followed in the instant case. See KSR International Co. v. Teleflex Inc., 550 U.S.--, 82 USPQ2d 1385 (2007). Also see MPEP 2144.05.
A POSITA would have had a reasonable expectation of success to make and use such AAV capsid polypeptides because all of the required biochemical reagents and techniques were readily available and rampantly used as evidenced by Muller et al. and Asokan et al. prior to the filing of the instant application.
For the reasons provided herein, the invention as claimed is prima facie obvious over the combined teachings of the prior art.
Conclusion
Claims 1 and 31-45 are rejected for the reasons as stated above. Applicants must respond to the objections/rejections in this Office action to be fully responsive in prosecution.
The instant Office action is non-final.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAE W LEE whose telephone number is (571)272-9949. The examiner can normally be reached on M-F between 9:00-6:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath 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.
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/JAE W LEE/
Examiner, Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656
Prosecution Insights