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
Election/Restriction
Applicant’s election without traverse of species in the reply filed on 05/26/2026 is acknowledged.
Applicant elected:
Regarding claim 2 - Applicant elects a) and subsequently i)
Regarding claim 3 - Applicant elects i)
Regarding claim 5 - Applicant elects a)
Regarding claim 6 - Applicant elects polH and p10
Regarding claim 7 - Applicant elects a)
Regarding claims 8 -10 - due to the election of 7a) elections for these claims does not seem applicable.
Regarding claim 11 - Applicant elects a)
Regarding claim 12 - Applicant elects iii)
Regarding claim 14 - Applicant elects the filter having a nominal pore size of 30 - 70 nm
Regarding claim 15 - Applicant elects iii) from the at least one of option.
Claim 15 is being interpreted as A kit of parts comprising at least an insect cell as defined in claim 1 and the nucleic acid construct and iii) a nucleic acid construct comprising at least one expression cassette for expression of nucleotide sequence encoding parvoviral Rep proteins.
Claims 8-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/26/2026.
Claims 1-7, 11-15 are under consideration.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/28/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 6. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claims 1-3, 5, 7, 11, 12, 13, 15 are objected to because of the following informalities:
Claims 1-3, 5, 7, 11, 12, 13, 15: There is an inconsistency in how the claims are written with respect to lists, e.g. using either a) or i) as a starting point. Claim 1 has a preamble and then the use of i), ii), etc. Claim 2 has a preamble and then the use of a) and i). Claim 3 uses i). Claim 5 uses a). Claim 7 uses a). Claim 11 uses a). Claim 12 uses iii). Claim 13 uses a). And finally, claim 15 uses iii).
To overcome the objection, use the approach seen in claim 2 where the list starts with a) and then further sub-lists use i).
Claim 2: a) Change “comprises” to “comprising”. In i) Change “coding sequence” to “encoding sequence”.
Claim 3: i) Change “coding sequence” to “encoding sequence”.
Claim 12: iii) Change “expression cassette for expression of nucleotide sequence” to “expression cassette for the expression of a nucleotide sequence”.
Claim 15: iii) Change “expression cassette for expression of nucleotide sequence” to “expression cassette for the expression of a nucleotide sequence”.
Appropriate correction is required.
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 4, 5, 6, 12, 14 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.
See claims 4, 5, 6, 12, 14 as submitted 11/28/2023.
Claim 4: Claim 4 recites 90% amino acid sequence identity and 90% nucleotide sequence identity. However, without a reference sequence provided or the start/end positions of the alignment for 90%, it is unclear what is meant. Claim 4 also recites “with a corresponding common amino acid sequence”. However, “common” is a relative term and in this case, makes the claim indefinite (See MPEP 2173.05(b) Relative Terminology). Regarding the claim language, “that encode the common amino acid sequences have less than 90% nucleotide sequence identity” is unclear. It is unclear what the metes and bounds of “less than 90% nucleotide sequence identity” are.
Claims 5, 6, 12, 14 all recite “preferably” which is a relative term and makes the claim indefinite (See MPEP 2173.05(b) Relative Terminology).
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.
Claims 1-3, 5-7, 11-13, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Bakker et al. (Bakker)(EP3257937A1)(See PTO-892 Notice of References Cited) in view of Li et al (Li)(WO2019216932A1)(as cited in the IDS submitted 11/28/2023).
See claims 1-3, 5-7, 11-13, and 15 as submitted 11/28/2023.
Regarding claim 1 and 5, Bakker teaches the production of parvovirus vectors, especially to the production of recombinant adeno-associated viruses (rAAV) in insect cells, baculoviral expression vectors comprising a construct of the invention and a cell comprising such a baculoviral expression vector (Field of Invention, [0001]. Bakker also teaches “[i]n a preferred embodiment the nucleotide sequence of (iii) comprises an open reading frame comprising nucleotide sequences encoding the VP1, VP2 and VP3 capsid proteins. The capsid protein coding sequences may be present in various forms. e.g. separate coding sequences for each of the capsid proteins VP1, -2 and -3 may use, whereby each coding sequence is operably linked to expression control sequences for expression in an insect cell [0066]. Bakker further clarifies “[a]n expression control sequence is "operably linked" to a nucleotide sequence when the expression control sequence controls and regulates the transcription and/or the translation of the nucleotide sequence. Thus, an expression control sequence can include promoters, enhancers, internal ribosome entry sites (IRES), transcription terminators, a start codon in front of a protein-encoding gene, splicing signal for introns, and stop codons [0015].
Bakker also teaches different expression cassettes, albeit for different nucleotide sequences encoding different proteins. And the nucleotide sequences encode an mRNA which is then translated [0015, 0034].
Regarding claims 2. a) i) and 3 i), Bakker teaches a single open reading frame encoding all three of the parvoviral (AAV) VP1, VP2, and VP3 capsid proteins, wherein the initiation codon for translation of the VP1 capsid protein is a suboptimal initiation codon that is not ATG…More preferred suboptimal initiation codons for the VP1 capsid protein may be selected from ACG, TTG, CTG and GTG, of which CTG and GTG are most preferred [0066].
Regarding claim 5 a), Bakker teaches wherein the first and second expression cassettes are present on a single nucleic acid construct, wherein the first and second expression cassettes are present in equimolar amount in the insect cell, and wherein the first promoter is equally strong as the second promoter (reference claim 1(b).
Regarding claim 6, Bakker teaches different baculoviral promoters such as polH and p10 (reference claim 6).
Regarding claim 12 iii), Bakker teaches “a first expression cassette comprising a nucleotide sequence encoding a parvoviral Rep protein which is operably linked to a first promoter that is capable of driving expression of the Rep protein in the insect cell” (reference claim 1. (ii)). Regarding claim 13, Bakker teaches reference claim 1, “A method for the production of a recombinant parvoviral virion, which method comprises the steps of…(b) culturing the cell defined in (a) under a condition conducive to the expression of the Rep and the capsid protein” and reference claim 2, “A method according to claim 1, wherein the method further comprises the step of recovering of the recombinant parvoviral virion”.
Regarding claim 15 iii), Bakker teaches “a kit comprising (a) a nucleic acid construct comprising the first and second expression cassette as defined above” [0091] where the first expression cassette is defined as a nucleotide sequence encoding a parvoviral Rep protein which is operably linked to a first promoter that is capable of driving expression of the Rep protein in the insect cell (as recited in reference claim 1 (ii)) and the second expression cassette is defined as a nucleotide sequence encoding a parvoviral capsid protein which is operably linked to a second promoter that is capable of driving expression of the capsid protein in the insect cell (as recited in reference claim 1 (iii)). Bakker also teaches “The kit may further comprise insect cells and a nucleic acid sequence encoding baculovirus helper functions for expression in the insect cell” [0093].
Bakker does not teach a first expression cassette construct where translation produces a parvoviral VP1 capsid protein and a second expression cassette construct where translation produces parvoviral VP 2 and VP3 capsid proteins.
Regarding claim 1, Li teaches “[i]n one embodiment the first nucleic acid sequence is only capable of expressing one of the three viral structural proteins [e.g., VP1, VP2, and VP3], the second nucleic acid sequence is capable of expressing only the other two viral structural proteins, but not the first” [00305]. Li also teaches insect cells [00301].
Regarding claim 7 a), Li teaches “An isolated AAV virion having at least two viral structural proteins from the group consisting of AAV capsid proteins, VP1, VP2, and VP3, wherein the two viral proteins are sufficient to form an AAV virion that encapsidates an AAV genome, and wherein at least one of the viral structural proteins present is from a different serotype than the other viral structural protein, and wherein the VP1 is only from one serotype, the VP2 is only from one serotype and the VP3 is only from one serotype” [00439].
Regarding claim 11 a), Li teaches several AAV serotypes such as AAV5.
One of ordinary skill in the art would have been motivated to combine the teachings of Bakker, particularly Bakker’s use of expression cassettes with that of Li for polyploid adeno-associated virus (AAV) capsid to make recombinant polyploid virions that are able to evade neutralizing antibodies. This is essential in clinical applications, since most people have been naturally exposed to AAVs. Also, one of ordinary skill in the art would have been motivated to combine the teachings of Bakker and Li to further improve the production of parvoviral vectors in insect cells on a large scale for a myriad of therapeutic uses (See MPEP 2143, Rationale A. Combining prior art elements according to known methods to yield predictable results and Rationale G. Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention).
One of ordinary skill in the art would have had a reasonable expectation of success for combining the teachings such as using different expression cassettes for parvoviral capsid protein expression (of same or different parvovirus types/serotypes), using suboptimal codons to regulate the ration of parvoviral capsid protein levels, employing late baculoviral promoters to improve yield and ultimately produce and recover a recombinant parvoviral virion at high titers from Bakker and Li. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of AAV vectors, gene therapy, immunology, and commonly used as evidenced by the applied prior art.
Therefore, the invention as a whole would have been prima facie obvious to one of
ordinary skill in the art before the effective filing date of the claimed invention.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Bakker in view of Li, as applied to claims 1-3, 5-7, 11-13, and 15, and further in view of Liu et al. (Liu)(See PTO-892 Notice of References Cited).
Claim 4 as submitted 11/28/2023.
See also the 35 U.S.C. 112(b) rejection above.
Bakker and Li teach claim 1 but do not specifically teach wherein the nucleotide sequence encoding the mRNA, translation of which in the cell produces only the parvoviral VP1 capsid protein, encodes a common amino acid sequence that has at least 90% amino acid sequence identity with a corresponding common amino acid sequence encoded in the nucleotide sequence encoding the mRNA, translation of which in the cell produces the parvoviral VP2 and VP3 capsid proteins, and wherein the parts in the nucleotide sequences that encode the common amino acid sequences have less than 90% nucleotide sequence identity.
Lu, however, teaches with respect to Parvoviridae, the virion is composed of two or three capsid proteins (VP1-VP3) which share an identical C-terminal sequence. The VP1 sequence comprises the entire VP2 sequence and an ~140 amino acid N-terminal extension called VP1 unique region (VP1u). The VP1u, especially the phospholipase A2 (PLA2) domain and the nuclear localization signal (NLS) located in the unique N terminus of VP1, is necessary for infectivity…The PLA2 domain is required for parvovirus infectivity…while the NLS plays an important role in the parvovirus replication cycle…In the early steps of infection, the NLS assists the translocation of viral genomes to the nucleus, whereas in the late steps of infection, the NLS is required for nuclear transport of viral capsid proteins. Liu also teaches Fig. 1 a. which shows an alignment of VP1 AAV, VP2 AAV and VP3 AAV amino acid sequences and the homology that is present, thus, in the absence of any reference sequence, satisfies the limitation of at least 90% amino acid sequence identity. With respect to the nucleotide sequence, the amino acid homology mentioned above and the generous limitation of less than 90% nucleotide sequence implies that the limitation would be met.
One of ordinary skill in the art would have been motivated to take into account the shared identical C-terminal sequence of the three capsid proteins as taught by Liu. and with alterations in initiation codons or the use of different serotypes (which may have distinct differences in amino acids) as taught by Bakker and Li, to further arrive at the limitation as discussed in the instant claim (See MPEP 2143 Rationale G. Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention).
One of ordinary skill in the art would have had a reasonable expectation of success for take into account the shared identical C-terminal sequence of the three capsid proteins as taught by Liu. and with alterations in initiation codons or the use of different serotypes as taught by Bakker and Li, to further arrive at the limitation as discussed in the instant claim. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of adeno-associated virology, gene therapeutics and/or immunity, and commonly used as evidenced by the applied prior art.
Therefore, the invention as a whole would have been prima facie obvious to one of
ordinary skill in the art before the effective filing date of the claimed invention.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Bakker in view of Li, as applied to claims 1-3, 5-7, 11-13, and 15, and further in view of Slack et al. (Slack)(WO2021041485A1)(See PTO-892 Notice of References Cited).
Claim 14 as submitted 11/28/2023.
Bakker and Li teach claim 13. Bakker and Li do not teach filtration over a filter having a nominal pore size of 30-70 nm.
Slack teaches methods and systems for use in the production of adeno-associated virus (AAV) particles, including recombinant adeno-associated virus (rAAV) particles. In certain embodiments, the production process and system use Spodoptera frugiperda insect cells (such as Sf9 or Sf21) as viral production cells. In certain embodiments, the production process and system use Baculoviral Expression Vectors (BEVs) in the production of AAV particles (Abstract). Slack also teaches both ultrafiltration with pore sizes typically between 0.001 and 0.1 mm [1-100nm] [0484] and nanofiltration with pore sizes typically less than 100 nm.
In this case, 30-70nm lies inside the range 1-100nm. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists (See MPEP 2144.05 I. Overlapping, Approaching, and Similar Ranges, Amounts, and Proportions).
One of ordinary skill in the art would have been motivated to use either ultrafiltration or nanofiltration for the recovery of the recombinant parvoviral virion to remove unwanted purities, particularly, in the case of nanofiltration, to remove aggregated clumps of viral particles or unwanted endogenous viral impurities like baculovirus (See MPEP 2143 Rationale A. Combining prior art elements according to known methods to yield predictable results).
One of ordinary skill in the art would have had a reasonable expectation of success for using ultrafiltration or nanofiltration as taught by Slack. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of AAV vectors, therapeutic gene delivery, and immunology, and commonly used as evidenced by the applied prior art.
Therefore, the invention as a whole would have been prima facie obvious to one of
ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Claire Cornelius whose telephone number is (571)272-0860. The examiner can normally be reached M-F, 0930-1700.
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/C.C./Examiner, Art Unit 1672
/M FRANCO G SALVOZA/Primary Examiner, Art Unit 1672
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