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 claims 1-3, 8-11, 13-15, 17, and 18 (Group I) in the reply filed on 04/23/2025 is acknowledged.
Claims 19, 20, 22, 23, 24, 29, 30, 32, and 34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/23/2025.
Accordingly, claims 1-3, 8-11, 13-15, 17, and 18 are pending and under consideration.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The effective filing date of the instant application is 06/28/2019.
Information Disclosure Statement
Receipt of information disclosure statements on 12/28/2021, 08/17/2023, and 01/23/2024 is acknowledged. The signed and initialed PTO-1449‘s have been mailed with this action.
Claim Objections
Claims 1-3 and 13 are objected to because of the following informalities:
With regard to claims 1-3, which respectively recite “a guide RNA…which targets a sequence as shown in any of SEQ ID NOs: 29, 36 and 47 in a beta-globin gene,” “wherein the guide RNA comprises a polynucleotide sequence having at least 95% identity to any of SEQ ID NOS: 30-35, 37-42 and 48-53” or “wherein the guide RNA comprises a polynucleotide sequence of any of SEQ ID NOS: 30-35, 37-42 and 48-53” (bolded emphasis added), as currently structured, the claim language reads as if the targeted sequence and the guide RNA sequences must satisfy all of the claimed sequence limitations simultaneously. Given that a single targeted sequence or a single guide RNA sequence can only be individually defined by a single sequence, the examiner has interpreted these claim limitations to reflect selection between SEQ ID NOs: 29, 36 or 47 in instant claim 1, as well as selection between SEQ ID NOS: 30-35, 37-42 or 48-53 in instant claims 2 and 3 (bolded emphasis added). It would be remedial to update the claim language to recite SEQ ID NOs in the alternative, as set forth above.
Additionally, claims 2 and 3 incorporate a simple typographical error when reciting SEQ ID NOs. Rather than reciting “SEQ ID NOs,” the instant claims recite “SEQ ID NOS” (bolded emphasis added). It would be remedial to correct these typographical errors such that the claims recite “SEQ ID NOs” (bolded emphasis added).
With regard to claim 13, which recites “the donor nucleic acid is a single-strand DNA or double-strand DNA,” the field typically refers to nucleic acids such as DNA as being single-stranded or double-stranded as opposed to single-strand or double-strand, as is instantly claimed. It would be remedial to update the claim language to reflect “the donor nucleic acid is a single-stranded DNA or double-stranded DNA” (bolded emphasis added).
Appropriate correction is required.
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.
Claims 1-3 and 8 are rejected under 35 U.S.C. 101 because the claimed invention is directed to natural phenomena without significantly more. The claims recite a guide RNA (or nucleic acid encoding the same) targeting a beta-globin gene. The broadest reasonable interpretation of the claimed product is that it reads on a nucleic acid or fragment thereof found in nature. Accordingly, the claims recite natural phenomena.
This judicial exception is not integrated into a practical application.
[AltContent: textbox (SEQ ID NO: 29)]
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With regard to claims 1-3, independent claim 1 additionally recites that the guide RNA (or nucleic acid encoding the same) “targets a sequence as shown in any of SEQ ID NOs: 29, 36 [or] 47 in a beta-globin gene.” However, the sequences of each of these SEQ ID NOs are naturally occurring in the hemoglobin subunit beta gene, as shown in the alignments below, which map to GenBank accession number MK476172.1 (see cited documentation regarding GenBank MK476172.1).
[AltContent: textbox (SEQ ID NO: 36)]
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[AltContent: textbox (SEQ ID NO: 47)]
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Therefore, the limitation that the guide RNA (or nucleic acid encoding the same) targets SEQ ID NO: 29, 36, or 47 reads on natural phenomena and is still directed to the judicial exception without significantly more. While dependent claims 2 and 3 respectively limit the sequence of the guide RNA (or nucleic acid encoding the same) to comprise SEQ ID NOs: 30-35, 37-42 or 48-53 (or comprising at least 95% identity to the same), they still recite nucleic acid sequences, which are natural phenomena. The mere addition of SEQ ID NOs does not alter the broadest reasonable interpretation of the claimed product reading on a nucleic acid or fragment thereof found in nature. Therefore, claims 2 and 3 are also directed to the judicial exception without significantly more.
With regard to dependent claim 8, which additionally recites “the guide RNA is for Cpf1,” Zetsche et al., 2015 (cited in the IDS filed 12/28/2021) discloses that Cpf1 is a class 2 CRISPR effector that utilizes a single guide RNA (but not tracrRNA), naturally occurring in at least Acidominococcus and Lachnospiraceae (abstract). Therefore, while dependent claim 8 limits the guide RNA (or nucleic acid encoding the same) to functioning with Cpf1, the claimed guide RNA (or nucleic acid encoding the same) still recites nucleic acid sequences, which are natural phenomena. The additional limitation of the guide RNA (or nucleic acid encoding the same) functioning with naturally-occurring Cpf1 does not alter the broadest reasonable interpretation of the claimed product reading on a nucleic acid or fragment thereof found in nature. Therefore, claim 8 is also directed to the judicial exception without significantly more.
Viewed as a whole, the additional claim elements do not provide meaningful limitations to transform the judicial exception such that the claims amount to significantly more than the judicial exception itself.
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.
Claims 1-3 and 8 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by US 2018/0273609 A1 (hereinafter Porteus).
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With regard to claim 1, which recites “a guide RNA or a nucleic acid encoding the same, which targets a sequence as shown in any of SEQ ID NOs: 29, 36 [or] 47 in a beta-globin gene,” Porteus discloses materials and methods for treating hemoglobinopathies such as sickle cell anema and β-thalassemia via genome editing (abstract). Porteus specifically discloses gRNAs targeting the globin locus (paragraph [0066]), including the gRNA of SEQ ID NO: 148,893, which targets a sequence as shown in SEQ ID NO: 29. As shown in the alignment below, SEQ ID NO: 148,893 of Porteus (top line) targets the instantly claimed beta-globin gene region of SEQ ID NO: 29 (bottom line):
[AltContent: textbox (Porteus SEQ ID NO: 148,893)]
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Additionally, both SEQ ID NO: 148,893 of Porteus and instantly claimed SEQ ID NO: 29 align to the hemoglobin subunit beta gene (GenBank accession number MK476172.1 (see cited documentation regarding GenBank MK476172.1)). These alignments are shown below:
[AltContent: textbox (SEQ ID NO: 29)]
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Thus, the gRNA of SEQ ID NO: 148,893 of Porteus targets SEQ ID NO: 29 of a beta-globin gene, as instantly claimed.
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With regard to claims 2 and 3, which respectively recite “the guide RNA comprises a polynucleotide sequence having at least 95% identity to any of SEQ ID NO[s]: 30-35, 37-42 [or] 48-53” and “the guide RNA comprises a polynucleotide sequence of any of SEQ ID NO[s]: 30-35, 37-42 [or] 48-53,” SEQ ID NO: 148,893 of Porteus (top line) is identical to instantly claimed SEQ ID NO: 31 (bottom line), as shown in the alignment below:
It is noted that per MPEP § 2417, uracil found in RNA may be represented by “t” in DNA sequence listings. Thus, the gRNA of SEQ ID NO: 148,893 of Porteus is identical to instantly claimed SEQ ID NO: 31, satisfying all the limitations of instant claims 2 and 3.
With regard to claim 8, which recites “the guide RNA [of claim 1] is for Cpf1,” Porteus discloses that the gRNA corresponding to SEQ ID NO: 148,893 is intended to target the globin locus with a Cpf1 endonuclease (paragraph [0066]). Thus, the gRNA of SEQ ID NO: 148,893 of Porteus reads on the instantly claimed guide RNA for Cpf1.
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 9, 10, 14, 15, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2013/126794 A1 (hereinafter Bender) in view of US 2018/0273609 A1 (hereinafter Porteus).
With regard to claim 9, which recites “a composition comprising a CRISPR/Cas nuclease or a nucleic acid encoding the same; and the guide RNA or a nucleic acid encoding the same according to claim 1, wherein the CRISPR/Cas nuclease is associated with the guide RNA and is capable of cleaving the beta-globin gene,” the guide RNA or a nucleic acid encoding the same of to claim 1 is disclosed in Porteus and addressed above (see section Claim Rejections - 35 USC § 102). Porteus does not disclose a composition comprising a CRISPR/Cas nuclease and the gRNA of instant claim 1 (or a nucleic acid encoding the same).
However, Bender discloses compositions and methods for the treatment of hemoglobinopathies such as thalassemias and sickle cell disease, including one or more endonucleases (such as CRISPR endonucleases) to modify or correct an adult human beta-globin locus (abstract). These compositions are disclosed to comprise at least one CRISPR endonuclease in combination with one or more RNA guides (paragraph [0020]). Thus, the disclosed composition of Bender reads on the instantly claimed “complex comprising a CRISPR/Cas nuclease and [a] guide RNA,” while Porteus discloses a gRNA that reads on the gRNA of instant claim 1.
Bender additionally discloses SEQ ID NO: 14-a 606 base pair region of the human beta-globin gene that contains the majority of mutations leading to severe thalassemia as well as the mutation causing sickle cell disease (paragraph [0042]). As shown in the alignment below, SEQ ID NO: 14 of Bender comprises instant SEQ ID NO: 29 (as in instant claim 1), meaning the gRNA of Porteus (SEQ ID NO: 148,893) that targets instant SEQ ID NO: 29 also targets SEQ ID NO: 14 of Bender.
With regard to claim 10, which recites “the CRISPR/Cas nuclease is a Cpf1 nuclease,” Porteus discloses that the gRNA corresponding to SEQ ID NO: 148,893 is intended to target the globin locus with a Cpf1 endonuclease (paragraph [0066]), which reads on the instantly claimed Cpf1 nuclease.
Given that Porteus discloses the gRNA of instant claim 1 (see section Claim Rejections - 35 USC § 102) for use with Cpf1 and that Bender discloses a composition to modify or correct an adult human beta-globin locus comprising at least one CRISPR endonuclease in combination with one or more RNA guides, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to assemble the composition of Bender with Cpf1 and its associated gRNA (as disclosed in Porteus) to predictably target the human beta-globin gene using Cpf1, as directed by its associated gRNA (i.e. SEQ ID NO: 148,893 of Porteus). One would have been motivated to make such a modification in order to receive the expected benefit of targeting a region of the human beta-globin gene (that contains the majority of mutations leading to severe thalassemia as well as the mutation causing sickle cell disease) for further editing or modification with a CRISPR nuclease such as Cpf1.
With regard to claim 14, which recites “an isolated mammalian cell comprising the composition of claim 9,” Porteus discloses increasing the level of fetal hemoglobin by genome editing (paragraph [0023]) in an isolated human cell, such as a hematopoietic progenitor cell or an induced pluripotent stem cell (paragraph [0030]). While Porteus does not, on its own, disclose the composition of claim 9, Bender in view of Porteus does disclose the composition of claim 9, as set forth above.
With regard to claim 15, which recites “the isolated mammalian cell of claim 14, which is a stem cell, wherein the stem cell is a hematopoietic stem/progenitor cell (HSPC),” Porteus discloses increasing the level of fetal hemoglobin by genome editing (paragraph [0023]) in an isolated human cell, such as a hematopoietic progenitor cell or an induced pluripotent stem cell (paragraph [0030]).
With regard to claim 17, which recites “the isolated mammalian cell of claim 14, which is obtained from a subject having beta-thalassemia or sickle cell disease,” Porteus discloses increasing the level of fetal hemoglobin by genome editing (paragraph [0023]) in an isolated human cell, such as cells derived from a patient with sickle cell disease or beta-thalassemia (paragraphs [0030] and [0037]).
Given that Bender, in view of Porteus, discloses the composition of claim 9 (as set forth above) and that Porteus additionally discloses increasing the level of fetal hemoglobin by genome editing in an isolated human cell such as a hematopoietic progenitor cell or a cell derived from a patient with sickle cell disease or beta-thalassemia, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to edit an isolated human cell such as a hematopoietic progenitor cell or a cell derived from a patient with sickle cell disease or beta-thalassemia (as disclosed in Porteus) by providing the composition of claim 9 (as set forth above) to predictably target the human beta-globin gene in these cells. One would have been motivated to make such a modification in order to receive the expected benefit of targeting a region of the human beta-globin gene (that contains the majority of mutations leading to severe thalassemia as well as the mutation causing sickle cell disease) in an isolated human cell such as a hematopoietic progenitor cell or a cell derived from a patient with sickle cell disease or beta-thalassemia for further editing or modification with a CRISPR nuclease such as Cpf1.
Claims 11 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2013/126794 A1 (hereinafter Bender) and US 2018/0273609 A1 (hereinafter Porteus) as applied to claims 9 and 14 above, and further in view of US 2019/0010495 A1 (hereinafter Boitano).
The combined disclosures of Bender and Porteus are described above and applied as before. However, these disclosures do not teach the donor nucleic acid comprising a transgene encoding a wildtype beta-globin polypeptide (or an isolated mammalian cell comprising the same) of instant claims 11 and 18.
With regard to claims 11 and 14, which respectively recite “the composition of claim 9 further compris[es] a donor nucleic acid, wherein the donor nucleic acid comprises a transgene encoding a wildtype beta-globin polypeptide,” and “the isolated mammalian cell of claim 14 further compris[es] a transgene encoding a wildtype beta-globin protein,” Boitano discloses genome editing systems, reagents and methods for the treatment of hemoglobinopathies (abstract) such as sickle cell disease and beta thalassemia (paragraph [0004]), specifically in which a genetic defect in beta globin is corrected by using CRISPR systems to mediate insertion of a gene encoding a wild type copy of beta globin via homologous recombination (paragraphs [0527] and [0528]). The gene inserted via homologous recombination and encoding a wild type copy of beta globin is considered to read on the instantly claimed donor nucleic acid comprising a transgene encoding a wildtype beta-globin polypeptide.
Given that Boitano discloses correction of a genetic defect in beta globin by inserting a donor nucleic acid comprising a wild type copy of the beta globin sequence via CRISPR-induced homologous recombination and that Bender and Porteus collectively disclose the composition of instant claim 9 and the isolated mammalian cell of instant claim 14 (as set forth above), both comprising a CRISPR nuclease and associated gRNA targeting the beta-globin locus, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to add the donor nucleic acid of Boitano to the composition or isolated mammalian cell comprising a CRISPR nuclease and associated gRNA targeting the beta-globin locus to predictably rescue beta globin function by inserting the wildtype beta-globin sequence at the user-specified locus as driven by CRISPR-induced homologous recombination. One would have been motivated to make such a modification in order to receive the expected benefit of rescuing beta globin function by inserting a donor nucleic acid comprising a wild type copy of the beta globin sequence via CRISPR-induced homologous recombination.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2013/126794 A1 (hereinafter Bender), US 2018/0273609 A1 (hereinafter Porteus), and US 2019/0010495 A1 (hereinafter Boitano) as applied to claim 11 above, and further in view of Devkota, 2018.
The combined disclosures of Bender, Porteus, and Boitano are described above and applied as before. However, these disclosures do not explicitly teach the single-stranded or double-stranded donor nucleic acid of instant claim 13.
With regard to claim 13, which recites “the donor nucleic acid [of the composition of claim 11] is a single-strand[ed] DNA or double-strand[ed] DNA,” Devkota, 2018 teaches that while the efficiency of homology directed repair (which reads on the homologous recombination induced by CRISPR addressed above) may be impacted by the choice of donor DNA (i.e. double-stranded or single-stranded), both double-stranded and single-stranded donor DNA have been documented to function in CRISPR-mediated homology directed repair (or homologous recombination) (page 440, column 1, paragraph 2).
Given that Bender, Porteus, and Boitano collectively disclose the composition of instant claim 11 (as set forth above) comprising a CRISPR nuclease, associated gRNA targeting the beta-globin locus, and a donor polynucleotide comprising a transgene encoding a wildtype beta-globin polypeptide and that Devkota, 2018 discloses the efficacy of both single- and double-stranded donor DNA molecules in CRISPR-mediated homology directed repair (or homologous recombination), it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to utilize a single- or double-stranded donor DNA molecule (as in Devkota, 2018) comprising a transgene encoding a wildtype beta-globin polypeptide (as in Boitano) in the composition comprising a CRISPR nuclease and associated gRNA targeting the beta-globin locus (as in Bender and Porteus) to predictably rescue beta globin function by inserting the wildtype beta-globin sequence at the user-specified locus as driven by CRISPR-induced homologous recombination. One would have been motivated to make such a modification in order to receive the expected benefit of rescuing beta globin function by inserting a donor DNA molecule (either single-stranded or double-stranded) comprising a wild type copy of the beta globin sequence via CRISPR-induced homologous recombination.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sarah E Allen whose telephone number is (571)272-0408. The examiner can normally be reached M-Th 8-5, F 8-12.
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/SARAH E ALLEN/ Examiner, Art Unit 1637
/J. E. ANGELL, Ph.D./ Primary Examiner, Art Unit 1637