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 .
Priority
The instant application, filed 10/27/2023 is a 35 U.S.C. 371 national stage filing of PCT/US2022/026988, filed on 04/29/2022. Applicant's claim for the benefit of a prior-filed parent provisional application 63/182,738, filed on, filed on 04/30/2021, under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is 04/30/2021.
Claims
As of 06/26/2024, claims 1, 2, 4, 7, 10, 12, 14-18, 20-21, 23-25, 28, and 30-32 are pending. Claims 1, 2, 4, 7, 10, 12, 14, 16, 18, 20-21, 23-25, 28, and 30-31 are amended. Claims 3, 5-6, 8-9, 11, 13, 19, 22, 26-27, and 29 are cancelled. Therefore, claims 1, 2, 4, 7, 10, 12, 14-18, 20-21, 23-25, 28, and 30-32 are under examination in the instant application.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 4, 7, 10, 14-18, 20-21, 23-25, 28, and 30 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Venditti et al. (WO2020032986A1).
Regarding claim 1, Venditti et al. teaches a recombinant viral vector for integrating a transgene into a target integration site in the genome of a cell, comprising: a polynucleotide comprising a first nucleic acid sequence and a second nucleic acid sequence, wherein the first nucleic acid sequence comprises at least one exogenous gene sequence (MUT transgene reads on the claimed exogenous gene) and the second nucleic acid sequence is positioned 5' or 3' to the first nucleic acid sequence and promotes the production of two independent gene products upon integration into a target integration site, a third nucleic acid sequence positioned 5' to the polynucleotide and comprising a sequence that is homologous to a genomic sequence 5' of the target integration site, and a fourth nucleic acid sequence positioned 3' to the polynucleotide and comprising a sequence that is homologous to a genomic sequence 3' of the target integration site (paragraphs 0006-0008, 0011). Venditti et al. further discloses that the third nucleic acid sequence and fourth nucleic acid sequence are at least 1000 nucleotides (nt) in length and wherein the third nucleic acid sequence and fourth nucleic acid sequence are different lengths (Venditti et al. specifically teaches in paragraph 0015 that the third and/or fourth nucleic acids may be of significant length (e.g., at least 800 nucleotides in length). In some embodiments, the third nucleic acid is between 800-1,200 nucleotides. In some embodiments, the fourth nucleic acid is between 800-1,200 nucleotides). The range 800-1,200 nucleotides falls within the claimed at least 1000 nucleotides (nt) in length.
Regarding claim 4: Following discussion of claim 1, Venditti et al. further teaches in paragraph 0015 that the third nucleic acid may be of significant length (e.g., at least 800 nucleotides in length). In some embodiments, the third nucleic acid is between 800-1,200 nucleotides. The claimed at least 1000 nt in length of the third nucleic acid sequence falls within the range 800-1,200 nucleotides taught by Venditti et al.
Regarding claim 7: Following discussion of claim 1, Venditti et al. further teaches in paragraph 0015 that the fouth nucleic acid may be of significant length (e.g., at least 800 nucleotides in length). In some embodiments, the fouth nucleic acid is between 800-1,200 nucleotides. The claimed at least 1000 nt in length of the fouth nucleic acid sequence falls within the range 800-1,200 nucleotides taught by Venditti et al.
Regarding claim 10: Following discussion of claim 1, Venditti et al. further teaches in paragraph 0015 that the third and/or fourth nucleic acids may be of significant length (e.g., at least 800 nucleotides in length). In some embodiments, the third nucleic acid is between 800-1,200 nucleotides. In some embodiments, the fourth nucleic acid is between 800-1,200 nucleotides. This reads on both the third and fourth nucleic acid sequences are at least 1000 nt in length since the claimed at least 1000 nt in length of both the third and the fourth nucleic acid sequences falls within the range 800-1,200 nucleotides taught by Venditti et al.
Regarding claim 14: Following discussion of claim 1, Venditti et al. further teaches in paragraph 0009 and claims 21, 37, and 55 that the viral vector is an AAV vector.
Regarding claim 15: Following discussion of claim 14, Venditti et al. further teaches that the viral vector is AAV8, AAV9, AAV-DJ, or AAV-LK03 (paragraph 0009, claims 5 and 56 of Venditti et al.).
Regarding claim 16: Following discussion of claim 1, Venditti et al. further teaches that a composition comprising the recombinant viral vector (claims 3 and 54 of Venditti et al.). Venditti et al. further teaches in paragraphs 0128-0129 that PBS is used in preparing the virus for dosing. PBS actually reads on a pharmaceutically acceptable excipients.
Regarding claim 17: Following discussion of claim 16, Venditti et al. further teaches a method of integrating a transgene into the genome of one or more cells in a tissue in a subject, said method comprising administering to a subject in which cells in the tissue fail to express a functional protein encoded by a gene product, a composition comprising the recombinant viral vector, wherein the target integration site is in the genome of the one or more cells (claims 1 and 3 of Venditti et al.).
Regarding claim 18: Following discussion of claim 16, Venditti et al. further teaches that the one or more cells are liver, muscle, or CNS cells (claims 12 and 29, paragraphs 0012 and paragraph 0174, Example 18, Targets).
Regarding claims 20-21: Following discussion of claim 17, Venditti et al. further teaches that the composition is administered during a postnatal period wherein the composition is administered before 28 days postnatal (paragraphs 0047 and 0157).
Regarding claim 23: Following discussion of claim 17, Venditti et al. further teaches that the transgene is UGT1A1, or Factor IX (paragraphs 0023, 0044-0045, 0141, and 0144-0145).
Regarding claim 24: Following discussion of claim 17, Venditti et al. further teaches that the integration efficiency is improved relative to a reference composition (paragraph 0042, Fig. 24 and paragraph 0079).
Regarding claim 25: Following discussion of claim 17, Venditti et al. further teaches that the composition is administered at a dosage of at least 5E13 viral genomes per kilogram (vg/kg) (paragraph 0047, 0157, and 0169).
Regarding claim 28: Following discussion of claim 17, Venditti et al. further teaches that the subject is an animal (paragraph 0147 teaches integrating Factor IX transgene at different doses into mice).
Regarding claim 30: Following discussion of claim 28, Venditti et al. further teaches that the subject has or is suspected to have Crigler-Najjar syndrome, hemophilia (paragraphs 0023, 0044, 0141).
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.
Claim(s) 1 and 2 are rejected under 35 U.S.C. 103 as being unpatentable over Venditti et al. (WO2020032986A1), in view of Pati et al. (WO1999060108A2).
Regarding claim 1, the teachings of Venditti et al. are set forth in detail above.
Regarding claim 2: Following discussion of claim 1 above, Venditti et al. fails to teach that the exogenous gene sequence is between 500 nt and 2500 nt in length, or the exogenous gene sequence is between 1000 nt and 2000 nt in length.
However, Pati et al. discloses a gene sequence between 500 nt and 2500 nt (Pati et al. specifically teaches on page 21, lines 23-25 that targeting polynucleotides are generally at least about 500-2000 nucleotides long, which falls within the claimed range of 500-2500 nt). Pati et al. further teaches that as the length of a targeting polynucleotide increases beyond about 20,000 to 50,000 to 400,000 nucleotides, the efficiency or transferring an intact targeting polynucleotide into the cell decreases (page 21, lines 25-27). It is believed that the addition of recombinases permits efficient gene targeting with targeting polynucleotides having short (i e , about 100 to 2000 nucleotide long) segments of homology (page 22, lines 7-10).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have modified the exogenous gene sequence in the first nucleic acid sequence of the polynucleotide of the recombinant viral vector with a polynucleotide target gene sequence of 500-2000 nucleotides in length with a reasonable expectation of success. One would have been motivated to have done so to provide the benefit of using exogenous gene sequence of a certain length that is stable for homologous recombination and allows for efficient gene targeting and recombination of whole proteins.
Claim(s) 1 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Venditti et al. (WO2020032986A1), in view of Li et al. (Li et al., “Optimization of Genome Engineering Approaches with the CRISPR/Cas9 System”. PLOS One. 2014. Pages 1-10).
Regarding claim 1, the teachings of Venditti et al. are set forth in detail above.
Regarding claim 12: Following discussion of claim 1 above, Venditti et al. teaches in paragraph 0015 that the third and/or fourth nucleic acids may be of significant length (e.g., at least 800 nucleotides in length). In some embodiments, the third nucleic acid is between 800-1,200 nucleotides. In some embodiments, the fourth nucleic acid is between 800-1,200 nucleotides. This reads on the third nucleic acid sequence is 1000 nt in length (the claimed 1000nt length actually falls within the range of 800-1,200 nucleotides that is taught by Venditti et al.) Venditti et al. further teaches in claims 14 and 15 that the third and fourth nucleic acid sequences are homology arms that direct integration of the polynucleotide cassette immediately 3' of the start codon of the endogenous albumin gene or immediately 5' of the stop codon of the endogenous albumin gene. Venditti et al. further teaches in paragraph 0048 that the viral vector remains effective with mismatched homology arms.
However, Venditti et al. fails to specifically teach that the fourth nucleic acid sequence is 1600 nt in length.
However, Li et al. teaches that increasing homology arm size can compensate for increased insert size. For example, at the Mef2c locus, 2135 bp fragment was introduced with 19.6% efficiency with 1 kb and 4 kb homology arms. Therefore, we recommend use of homology arms of this length for larger DNA insertions (page 10, column 1, paragraph 2).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the
effective filing date of the claimed invention to have modified the length of the fourth nucleic acid sequence in the viral vector of Venditti et al. to be 1600nt with a reasonable expectation of success. One would have been motivated to have optimized the length of the fourth nucleic acid sequence to allow for increased insert size since Li et al. establishes that increasing homology arm size would have required only routine experimentation.
Claim(s) 31 is rejected under 35 U.S.C. 103 as being unpatentable over Burleigh et al. (US20210015869A1) in view of Barzel et al. (US20170088856A1), and Li et al. (Li et al., “Optimization of Genome Engineering Approaches with the CRISPR/Cas9 System”. PLOS One. 2014. Pages 1-10).
Regarding claim 31, Burleigh et al. discloses a method of determining homology arm lengths for a polynucleotide cassette by specifically teaching in paragraph 0531 that the overall length of a template polynucleotide could be limited by parameters such as plasmid size or viral packaging limits. Burleigh et al. also teaches in paragraph 0556 that the template polynucleotide may comprise a payload, a 5′ homology arm, a 3′ homology arm. Burleigh et al. teaches in paragraph 0531 that the homology arm overall length could be limited by parameters such as plasmid size or viral packaging limits. This reads on (a) determining the length of a polynucleotide cassette. Burleigh et al. further teaches in paragraph 0529 the nuclease target site(s) contained in the double-stranded template polynucleotide are for the same nuclease(s) used to cleave the endogenous target into which the cleaved template polynucleotide is integrated via homology-independent methods. Burleigh et al. further discloses the length of the cassette in paragraph 0529 (the double-stranded template polynucleotide includes sequences (e.g., coding sequences, also referred to as transgene) greater than 1 kb in length).
However, Burleigh et al. fails to specifically teach (b) if the lengths of step (a) is less than 2.7 kilobases (kb), then the length of the 3' homology arm sequence is 1 kb or less and the length of the 5' homology arm sequence is 2.7kb - the length of the 3' homology arm, and (c) if the length of step (a) is greater than 2.7kb, then the 5' and 3' homology arms are each [4.7kb - the length of step (a)]/2 nucleotides in length.
However, Barzel et al. discloses the 5′ homology arm and the 3′ homology arm lengths. Barzel et al. specifically teaches in paragraphs 0007 and 0014 that the length of the 5′ and 3′ arms are 1.3 and 1.4-kb (2.7kb-1.4kb=1.3kb is 2.7- the length of the 3' homology arm as claimed), respectively. Barzel et al. further teaches in paragraphs 0048 and 0053 a polynucleotide cassette and the length of the recombinant cassette is less than or more than 2.7kb (he flanking recombination sequences can be of any length, e.g. 10 nucleotides or more, 50 nucleotides or more, 100 nucleotides or more, 250 nucleotides or more, 500 nucleotides or more, 1000 nucleotides (1 kb) or more, 5000 nucleotides (5 kb) or more, 10000 nucleotides (10 kb) or more etc.)
Although Barzel et al. does not specifically teach that if the length of polynucleotide cassette without the homology arms is greater than 2.7kb, then the 5' and 3' homology arms are each [4.7kb - the length of step (a)]/2 nucleotides in length, Li et al. actually provides motivation to use greater homology arm lengths for larger insertions. Li et al. specifically teaches that increasing homology arm size can compensate for increased insert size. For example, at the Mef2c locus, 2135 bp fragment was introduced with 19.6% efficiency with 1 kb and 4 kb homology arms. Therefore, we recommend use of homology arms of this length for larger DNA insertions (page 10, column 1, paragraph 2).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the
effective filing date of the claimed invention to have modified the method of determining homology arm lengths for a polynucleotide cassette such that if the length of polynucleotide cassette without the homology arms is greater than 2.7kb, then the 5' and 3' homology arms are each [4.7kb - the length of step (a)]/2 nucleotides in length with a reasonable expectation of success. One would have been motivated to have optimized the length of the 5' and 3' homology arms to allow for increased insert size since Li et al. establishes that increasing homology arm size would have required only routine experimentation.
Claim(s) 32 is rejected under 35 U.S.C. 103 as being unpatentable over Venditti et al. (WO2020032986A1) in view of Burleigh et al. (US20210015869A1), Barzel et al. (US20170088856A1), and Li et al. (Li et al., “Optimization of Genome Engineering Approaches with the CRISPR/Cas9 System”. PLOS One. 2014. Pages 1-10).
Regarding claim 32: Following discussion of claim 31 above, Venditti et al. discloses a recombinant viral vector for integrating a transgene into a target integration site in the genome of a cell, comprising: a polynucleotide comprising a first nucleic acid sequence and a second nucleic acid sequence, wherein the first nucleic acid sequence comprises at least one exogenous gene sequence (MUT transgene reads on the claimed exogenous gene) and the second nucleic acid sequence is positioned 5' or 3' to the first nucleic acid sequence and promotes the production of two independent gene products upon integration into a target integration site, a third nucleic acid sequence positioned 5' to the polynucleotide and comprising a sequence that is homologous to a genomic sequence 5' of the target integration site, and a fourth nucleic acid sequence positioned 3' to the polynucleotide and comprising a sequence that is homologous to a genomic sequence 3' of the target integration site (paragraphs 0006-0008, 0011). Venditti et al. further teaches in claims 14 and 15 that the third and fourth nucleic acid sequences are homology arms that direct integration of the polynucleotide cassette immediately 3' of the start codon of the endogenous albumin gene or immediately 5' of the stop codon of the endogenous albumin gene. Venditti et al. further teaches in paragraph 0048 that the viral vector remains effective with mismatched homology arms.
However, Venditti et al. fails to teach determining the length of each of the third nucleic acid sequence and fourth nucleic acid sequence of the polynucleotide.
However, Burleigh et al. discloses a method of determining homology arm lengths for a polynucleotide cassette by specifically teaching in paragraph 0531 that the overall length of a template polynucleotide could be limited by parameters such as plasmid size or viral packaging limits. Burleigh et al. also teaches in paragraph 0556 that the template polynucleotide may comprise a payload, a 5′ homology arm, a 3′ homology arm. Burleigh et al. teaches in paragraph 0531 that the homology arm overall length could be limited by parameters such as plasmid size or viral packaging limits. This reads on (a) determining the length of a polynucleotide cassette. Burleigh et al. further teaches in paragraph 0529 the nuclease target site(s) contained in the double-stranded template polynucleotide are for the same nuclease(s) used to cleave the endogenous target into which the cleaved template polynucleotide is integrated via homology-independent methods. Burleigh et al. further discloses the length of the cassette in paragraph 0529 (the double-stranded template polynucleotide includes sequences (e.g., coding sequences, also referred to as transgene) greater than 1 kb in length).
However, Burleigh et al. fails to specifically teach (b) if the lengths of step (a) is less than 2.7 kilobases (kb), then the length of the 3' homology arm sequence is 1 kb or less and the length of the 5' homology arm sequence is 2.7kb - the length of the 3' homology arm, and (c) if the length of step (a) is greater than 2.7kb, then the 5' and 3' homology arms are each [4.7kb - the length of step (a)]/2 nucleotides in length.
However, Barzel et al. discloses the 5′ homology arm and the 3′ homology arm lengths. Barzel et al. specifically teaches in paragraphs 0007 and 0014 that the length of the 5′ and 3′ arms are 1.3 and 1.4-kb (2.7kb-1.4kb=1.3kb is 2.7- the length of the 3' homology arm as claimed), respectively. Barzel et al. further teaches in paragraphs 0048 and 0053 a polynucleotide cassette and the length of the recombinant cassette is less than or more than 2.7kb (he flanking recombination sequences can be of any length, e.g. 10 nucleotides or more, 50 nucleotides or more, 100 nucleotides or more, 250 nucleotides or more, 500 nucleotides or more, 1000 nucleotides (1 kb) or more, 5000 nucleotides (5 kb) or more, 10000 nucleotides (10 kb) or more etc.)
Although Barzel et al. does not specifically teach that if the length of polynucleotide cassette without the homology arms is greater than 2.7kb, then the 5' and 3' homology arms are each [4.7kb - the length of step (a)]/2 nucleotides in length, Li et al. actually provides motivation to use greater homology arm lengths for larger insertions. Li et al. specifically teaches that increasing homology arm size can compensate for increased insert size. For example, at the Mef2c locus, 2135 bp fragment was introduced with 19.6% efficiency with 1 kb and 4 kb homology arms. Therefore, we recommend use of homology arms of this length for larger DNA insertions (page 10, column 1, paragraph 2).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the
effective filing date of the claimed invention to have modified the method of determining homology arm lengths for a polynucleotide cassette such that if the length of polynucleotide cassette without the homology arms is greater than 2.7kb, then the 5' and 3' homology arms are each [4.7kb - the length of step (a)]/2 nucleotides in length with a reasonable expectation of success. One would have been motivated to have optimized the length of the 5' and 3' homology arms to allow for increased insert size since Li et al. establishes that increasing homology arm size would have required only routine experimentation.
Furthermore, it would have been prima facie obvious to one of the ordinary skills in the art before the
effective filing date of the claimed invention to have used the method of determining homology arm lengths for a polynucleotide cassette of Burleigh et al. in view of Barzel et al. and Li et al. to determine the length of each of the third nucleic acid sequence and fourth nucleic acid sequence of the polynucleotide in the recombinant viral vector of Venditti et al. with a reasonable expectation of success. One would have been motivated to have done so to provide the benefit of using homology arms of a certain length that is suitable for homologous recombination and allows for efficient gene insertions and additional improvements in editing activity.
Conclusion
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Hanan Isam Abuzeineh
/H.I.A./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633