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 .
Claim Status
Claims 1-38 are presented and examine on the merits.
Priority
The applicant’s application is a U.S. National Stage application of PCT International Patent Application Serial No. PCT/IB2021/000550, filed August 11, 2021, which itself claims the benefit of Provisional Application 63064047, filed August 11, 2020 is acknowledged. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Objections
Claims 4-9, 11, 13, 16-17, 19-38 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim 3. See MPEP § 608.01(n). Accordingly, the claims 4-9, 11, 13, 16-17, 19-38 not been further treated on the merits.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 2 is rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception(s) (i.e., a law of nature, a natural product, and/or an abstract idea) without significantly more.
The claim recites a composition comprising a first nucleic acid encoding a Cas9 polypeptide and a second nucleic acid encoding a nucleic acid repair protein, wherein the Cas9 polypeptide and nucleic acid repair protein are from different organisms. The claimed nucleic acids encoding Cas9 and the repair protein are not markedly different than the naturally occurring counterpart. The mere recitation that the nucleic acid sequences are “from different organisms” does not confer eligibility, as naturally occurring nucleic acids from different organisms may be combined without the hand of man (mix of different bacteria).
The judicial exception is not integrated into a practical application because no elements in addition to the judicial exception are recited in the claim. Specifically, the claim lacks limitations describing non-natural modifications to the nucleic acid sequences.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1-3, 10, 14, 18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cheng et al. (“Cheng”, WO 2020/041172 A1).
Regarding claim 1-2, 14, 18, Cheng teaches methods comprising delivering to a cell a programmable nuclease-based gene editing system that comprises a programmable nuclease linked to a DNA repair domain, wherein the programmable nuclease cleaves a target nucleic acid sequence, and the DNA repair domain is selected from the group consisting of: RPAl; RPA2; FANCM; BRCAl; RAD54L; PALB2; XRCC3; FENl; RECQ5; FANCB; USPl; FANCF; and FANCG (e.g., paragraph 3rd, page 4). Cheng teaches a programmable nuclease comprises an RNA-guided nuclease, such as Cas9 nuclease or Cas9 nickase. A method further comprises delivering to the cell a gRNA or a nucleic acid encoding a gRNA that specifically binds to a target nucleic acid sequence (e.g., paragraph 4th, page 4). Cheng teaches gRNA, an RNA-guided nuclease, a DNA repair protein, and/or a donor nucleic acid are encoded on independent vectors or on the same vector (e.g., paragraph 4th, page 3).
Regarding claims 3, 10, Cheng teaches DNA repair domain comprises an enzymatic activity selected from the group consisting of ligase activity, polymerase activity, topoisomerase activity, helicase activity, and nuclease activity. In some embodiments, a DNA repair domain comprises a ligase, a polymerase, a topoisomerase, a helicase, or a nuclease. DNA repair domain may comprise a protein selected from the group consisting of: Replication Protein Al (RPAl); Replication Protein A2 (RPA2); Fanconi Anemia Complementation Group M (FANCM); RAD51 Recombinase (RAD51); RAD52 Homolog, DNA Repair Protein (RAD52); RAD51 Paralog C (RAD51C); RAD18 E3 Ubiquitin Protein Ligase (RAD18); RB Binding Protein 8, Nuclease (RBBP8/CTIP); Tumor Protein P53 Binding Protein 1 (TP53BP1); BRCAl DNA Repair Associated (BRCAl); RAD54-like (RAD54L); Partner and Localizer of BRCA2 (PALB2); X-Ray Repair Cross Complementing 3 (XRCC3); MREll Homolog, Double Strand Break Repair Nuclease (MREl lA); Flap Structure-Specific Nuclease 1 (FENl); RecQ Like Helicase 5 (RECQ5); FA Complementation Group B (FANCB); Ubiquitin Specific Peptidase 1 (USPl); FA Complementation Group F (FANCF); and FA Complementation Group G (FANCG) (e.g., paragraph 2nd, page 3).
Claims 1-2, 10, 14, 18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jayavaradhan et al. (“Jayavaradhan”, Nature Commun. 2019).
Regarding claim 1-2, 14, 18, Jayavaradhan teaches genome editing/correction of DNA double-strand breaks (DSBs) induced by CRISPR Cas9 by homology-dependent repair (HDR) is limited by the competing error-prone nonhomologous end-joining (NHEJ) DNA repair pathway. fused a dominant-negative mutant of 53BP1 (DNA repair protein), DN1S, to Cas9 nucleases, and the resulting Cas9-DN1S fusion proteins significantly block NHEJ events specifically, at Cas9 cut sites and improve HDR frequency; HDR frequency reached 86% in K562 cells. Cas9-DN1S protein maintains this effect in different human cell types, including leukocyte adhesion deficiency (LAD) patient-derived immortalized B lymphocytes, where nearly 70% of alleles were repaired by HDR and 7% by NHE (e.g., abstract; Figs. 2-3). Jayavaradhan teaches the generation and testing of Cas9-DN fusion constructs (e.g., paragraph 5th, column 2, page 9 [Methods]).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Cheng et al. (“Cheng”, WO 2020/041172 A1) in view of Mao et al. (“Mao”, Science, 2011).
The teachings of Cheng are discussed above.
Cheng does not teach repair protein SIRT6, as required by claim 12. However, this is cured by Mao.
Mao teaches that mammalian cells subjected to oxidative stress SIRT6 is recruited to the sites of DNA double-strand breaks (DSBs) and stimulates DSB repair, through both nonhomologous end joining and homologous recombination (e.g., abstract; Fig. 1B).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to use the DNA repair protein SIRT6 taught by Mao and integrate in the composition – a RNA-guided nuclease, a DNA repair protein, and/or a donor nucleic acid are encoded on independent vectors or on the same vector taught by Cheng, for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of obtaining a composition: a RNA-guided nuclease, a SIRT6 DNA repair protein, and gRNA encoded on independent vectors or on the same vector as a DNA repair method.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do so in order to develop a method for DNA repair using an RNA-guided nuclease, a SIRT6 DNA repair protein, and gRNA.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Cheng et al. (“Cheng”, WO 2020/041172 A1) in view of Yoshiba et al. (“Yoshiba”, Oncology Letters, 2019).
The teachings of Cheng are discussed above.
Cheng does not teach first and second nucleic acid are on the same vector and are separated by an internal ribosome entry site (IRES), as required by claim 15. However, this is cured by Yoshiba.
Yoshiba teaches therapeutic strategies that specifically target E6, which is constitutively expressed in tumors and is not present in normal tissues, may be highly effective and safe. CRISPR-CRISPR associated protein 9 (Cas9) (e.g., abstract). Yoshiba teaches the construction of the plasmid vector Cas9-expression (pCMV-Cas9-HA-IRES-bsr) (e.g., paragraph 4th, column 1, page 2198).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to use the Cas9-expression vector (pCMV-Cas9-HA-IRES-bsr) taught by Yoshiba and replace the “bsr” by a DNA repair protein taught by Cheng, for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of obtaining a vector for the coexpression of CRISPR Cas9 and a DNA repair protein mediated by IRES.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do so in order to develop a method for DNA repair using a vector that coexpresses CRISPR Cas9 and a DNA repair protein.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JULIO GOMEZ RODRIGUEZ whose telephone number is (571)270-0991. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm.
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/JULIO WASHINGTON GOMEZ RODRIGUEZ/Examiner, Art Unit 1637
/J. E. ANGELL, Ph.D./Primary Examiner, Art Unit 1637