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 .
Claims 56-71, of record 3/17/2025, are pending and subject to prosecution.
Priority
The instant application is a DIV of 16/909283 (US patent 12134767, filed 6/23/2020), which is a DIV of 15/550943 (US patent 10738305, filed 8/14/2017), which is a national stage entry of PCT/IB16/00276 (filed 2/23/2016), which claims benefit of provisional application 62/119754 (filed 2/23/2015).
According to 35 U.S.C. 121, a patent issuing on an application with respect to which a requirement for restriction under this section has been made, or on an application filed as a result of such a requirement, shall not be used as a reference either in the Patent and Trademark Office or in the courts against a divisional application or against the original application or any patent issued on either of them, if the divisional application is filed before the issuance of the patent on the other application It is noted that the instant application is considered. See MPEP 804. It is noted that no restriction requirement was set forth in the ‘283 application. In the ‘983 application, the applicant elected group II, claims 32-45 and 55, drawn to a method of increasing the level of fetal hemoglobin in a human cell by genome editing using DNA endonuclease to effect a double strand break at one or more loci within the β-globin region of human chromosome 11, causing deletions or insertions of chromosomal DNA at the one or more loci that results in increased expression of γ-globin, thereby increasing the level of fetal hemoglobin in the cell. Both the ‘283 application and the instant application claim subject matter encompassed by the elected invention of the ‘983 application (namely, use of a DNA endonuclease to edit a double strand break in the β-globin region of human chromosome 11 at one locus or more in order to increase γ-globin expression). The ‘283 application and the instant application are therefore considered not to have been filed as the result of the 5/3/2019 restriction requirement in the ‘943 application, and the 121 shield is not available for the pending claims of the instant application.
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.
Claim 64 is 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.
Claim 64 recites the limitations “the 5’ DSB locus” and “the 3’ DSB locus” in lines 3-4. There is insufficient antecedent basis for this limitation in the claim. Parent claim 58 recites a DSB at one or more loci within the δβ-globin region of human chromosome 11, and it is unclear exactly what loci are required to be targeted by ZFNs in claim 64.
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.
(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 56-57 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Musunuru et al. (WO 2015006498 A2).
Regarding claims 56-57: Musunuru et al. teach CRISPR/Cas systems for treating or preventing blood disorders (See Abstract). The HBB gene can be targeted for treating sickle cell disease (See ¶0110, 0156, and 0160). Cas can be delivered to or expressed in a cell along with one or two ribonucleic acids, at least one of which comprises tracrRNA and at least one of which comprises crRNA (See ¶0260-0262). The possibility for the tracrRNA and crRNA to be located within a single ribonucleic acid reads on “sgRNA”. Musunuru et al. teach a gRNA comprising a sequence identical to instant SEQ ID NO 40 (See SEQ ID NO 868, fig. 5, and alignment below).
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The teachings of Musunuru et al. therefore anticipate the claimed invention.
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 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.
Claims 56-71 are rejected under 35 U.S.C. 103 as being unpatentable over Musunuru et al. (WO 2015006498 A2) in view of Takeuchi et al. (US 20150166969 A1).
The teachings of Musunuru et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claims 58-63, 65-67, and 69-70: Following the discussion of claims 56-57, Musunuru et al. teach methods for HBB gene editing using CRISPR/Cas systems (See ¶0004, 0058, and 0110). HBB can be altered to treat abnormal phenotypes (See ¶0155). Alteration can result in knockout of the target for treating a disorder associated with expression of the target polynucleotide (See ¶0183-0184). The target sequences can be cleaved such that a double strand break results and can comprise at least a portion of HBB (See ¶0227 and 0362). The cell can be a pluripotent cell or hematopoietic stem cell (which reads on “an isolated progenitor cell”, “hematopoietic progenitor cell”, and “capable of giving rise to cells of the erythroid lineage”) (See ¶0028 and 0414). Cas can be introduced into the cell as a Cas9-encoding nucleic acid, such as mRNA (which reads on “one or more RNAs”) (See ¶0260). Musunuru et al. do not expressly teach targeting of the β-globin locus in order to increase γ-globin expression.
Takeuchi et al. teach methods for treating hemoglobinopathies (See Abstract). Modifications can be made to a human β-globin locus and/or to a γ-globin gene promoter (which reads on “the γ-globin regulatory region of human chromosome 11”) to achieve increased expression of a γ-globin gene (See Abstract and ¶0072). Expression of γ-globin genes in the fetus is normally replaced by expression of δ- and γ-globin genes in the adult (See ¶0007 and 0106). Elevated γ-globin gene expression and a corresponding increase in HbF protein production can be used to achieve therapeutic efficacy for hemoglobinopathies such as sickle cell disease (See ¶0109 and 0122).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Musunuru et al. to comprise editing of a γ-globin promoter in a β-globin locus to effect γ-globin expression, as taught by Takeuchi et al. One would be motivated to make this modification because Takeuchi et al. indicate that HbF can be used in place of HBS (sickled HbB) in hemoglobin (See ¶0010). There would be a reasonable expectation of success in doing so because Takeuchi et al. teach that γ-globin editing can be done using CRISPR (See Abstract and ¶0022) and because Musunuru et al. teach that multiplex editing can be performed for simultaneously altering multiple target sequences in a cell (See ¶0291-0292 and 0295).
Regarding claim 64: Following the discussion of claims 58-63, 65-67, and 69-70, Musunuru et al. teach genome editing using a Cas endonuclease and do not teach a zinc finger nuclease.
Takeuchi et al. teach that targeted gene modification can be achieved using ZFNs, TALENs, homing endonucleases, or Cas9 in combination with an RNA guide strand (See ¶0089).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to further modify the method of Musunuru et al., modified by Takeuchi et al., to substitute ZFNs (which would read on “a first pair of ZFNs that target a segment of the 5′ DSB locus” and “a second pair of ZFNs that target a segment of the 3′ DSB locus”) for Cas for targeting one or more loci. Substitution of one known element for another known element is considered to be prima facie obvious, absent a showing that the substitution yields more than predictable results. See MPEP 2143(I)(B). Takeuchi et al. teach that both ZFNs and Cas9 function as targeted gene editing nucleases (See ¶0089), and one of ordinary skill could readily apply ZFNs to the method rendered obvious by Musunuru et al., modified by Takeuchi et al.
Regarding claim 68: Following the discussion of claims 58-63, 65-67, and 69-70, Musunuru et al. teach that the edited cell can be a pluripotent stem cell (See ¶0028 and 0414) but do not expressly teach an iPSC.
Takeuchi et al. teach that iPSCs can be edited by CRISPR to ameliorate hemoglobinopathies in mature erythroid cells (See ¶0029-0030 and 0119).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to further modify the method of Musunuru et al., modified by Takeuchi et al., to edit iPSCs. Combining prior art elements according to known methods to yield predictable results is considered to be prima facie obvious. See MPEP 2143(I)(A). Editing in iPSCs could be performed in the same manner as with PSCs, to similar results.
Regarding claim 71: Following the discussion of claims 58-63, 65-67, and 69-70, Musunuru et al. teach that Cas9 can be introduced into a cell in the form of a nucleic acid encoded by a vector (See ¶0260) but do not expressly teach Cas9 and gRNAs encoded by a single vector.
Takeuchi et al. teach that a polynucleotide encoding one or more Cas9 endonuclease and one or more RNA guide strands can be operably linked to a promoter sequence within a viral vector (which reads on “a single vector”) (See ¶0032).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to further modify the method of Musunuru et al., modified by Takeuchi et al., to edit iPSCs. Combining prior art elements according to known methods to yield predictable results is considered to be prima facie obvious. See MPEP 2143(I)(A). Encoding Cas9 and gRNAs in a single vector would be predictably expected to result in expression within cells, and such a modification could be readily made by one of ordinary skill.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 56-63 and 65-57 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-8, and 13-14 of U.S. Patent No. 12129471. Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons.
Regarding claims 56, 58-59, and 62: Patented claim 1 recites a method of gene editing, the method comprising introducing Cas9 endonuclease, a first guide RNA (gRNA), and a second gRNA into a human cell to effect a pair of double-strand breaks (DSBs) within the δβ-globin region of human chromosome 11, wherein the first gRNA comprises a spacer sequence that hybridizes to the same target sequence of the δβ-globin region of human chromosome 11 as a nucleic acid having the nucleic acid sequence of any one of SEQ ID NO: 1-117 and 129-137, the second gRNA comprises a spacer sequence that hybridizes to the same target sequence of the δβ-globin region of human chromosome 11 as a nucleic acid having the nucleic acid sequence of any one of SEQ ID NO: 1-117 and 129-137, and wherein the first gRNA hybridizes to a different target sequence than the second gRNA. Patented claim 13 recites the method of patented claim 1, wherein: (a) the first gRNA comprises a spacer sequence that is complementary to SEQ ID NO: 4 and the second gRNA comprises a spacer sequence that is complementary to SEQ ID NO: 19; or (b) the first gRNA comprises a spacer sequence that is complementary to SEQ ID NO: 4 and the second gRNA comprises a spacer sequence that is complementary to SEQ ID NO: 20; or (c) the first gRNA comprises a spacer sequence that is complementary to SEQ ID NO: 83 and the second gRNA comprises a spacer sequence that is complementary to SEQ ID NO: 43; or (d) the first gRNA comprises a spacer sequence that is complementary to SEQ ID NO: 83 and the second gRNA comprises a spacer sequence that is complementary to SEQ ID NO: 15; or (e) the first gRNA comprises a spacer sequence that is complementary to SEQ ID NO: 83 and the second gRNA comprises a spacer sequence that is complementary to SEQ ID NO: 43. Patented claim 14 recites the method of patented claim 1, wherein the first gRNA and/or the second gRNA comprises a spacer sequence that hybridizes to the same target sequence of the δβ-globin region of human chromosome 11 as a nucleic acid having the nucleic acid sequence of any one of SEQ ID NOs: 4, 5, 6, 15, 19, and 20. The patented claims anticipate the instant claims.
Regarding claims 57 and 63: Following the discussion of claims 56, 58-59, and 62, patented claim 5 recites the method of patented claim 1, wherein the first gRNA and/or the second gRNA are single-molecule gRNAs. The patented claims anticipate the instant claims.
Regarding claim 60: Following the discussion of claims 56, 58-59, and 62, patented claim 2 recites the method of patented claim 1, wherein the method comprises introducing into the cell one or more polynucleotides encoding the Cas9 endonuclease. The patented claims anticipate the instant claim.
Regarding claim 61: Following the discussion of claims 56, 58-59, and 62, patented claim 3 recites the method of patented claim 1, wherein the method comprises introducing into the cell one or more RNAs encoding the Cas9 endonuclease. The patented claims anticipate the instant claim.
Regarding claims 65-67: Following the discussion of claims 56, 58-59, and 62, patented claim 6 recites the method of patented claim 1, wherein the human cell is an isolated progenitor cell. Patented claim 7 recites the method of patented claim 6, wherein the isolated progenitor cell is a hematopoietic progenitor cell. Patented claim 8 recites the method of patented claim 7, wherein the hematopoietic progenitor cell is capable of giving rise to cells of the erythroid lineage. The patented claims anticipate the instant claims.
Claims 56-63 and 65-66 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, 7, 10-11, and 72-74 of co-pending Application No. 18769239 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons.
Regarding claims 56, 58-59, and 62: Co-pending claim 1 recites a method of increasing the level of fetal hemoglobin (HbF) in a human cell by genome editing, the method comprising introducing Cas9 endonuclease, a first guide RNA (gRNA), and a second gRNA into a human cell to effect a pair of double-strand breaks (DSBs) within the δβ-globin region of human chromosome 11, wherein the first gRNA comprises a spacer sequence that hybridizes to the same target sequence of the δβ-globin region of human chromosome 11 as a nucleic acid having the nucleic acid sequence of any one of SEQ ID NO: 1-117 and 129-137, the second gRNA comprises a spacer sequence that hybridizes to the same target sequence of the δβ-globin region of human chromosome 11 as a nucleic acid having the nucleic acid sequence of any one of SEQ ID NO: 1-117 and 129-137, wherein the first gRNA hybridizes to a different target sequence than the second gRNA, wherein the editing results in increased expression of γ-globin, thereby increasing the level of HbF in the cell. Co-pending claim 72 recites the method of co-pending claim 1, wherein: (a) the first gRNA comprises a spacer sequence that is complementary to SEQ ID NO: 4 and the second gRNA comprises a spacer sequence that is complementary to SEQ ID NO: 19; or (b) the first gRNA comprises a spacer sequence that is complementary to SEQ ID NO: 4 and the second gRNA comprises a spacer sequence that is complementary to SEQ ID NO: 20; or (c) the first gRNA comprises a spacer sequence that is complementary to SEQ ID NO: 83 and the second gRNA comprises a spacer sequence that is complementary to SEQ ID NO: 43; or (d) the first gRNA comprises a spacer sequence that is complementary to SEQ ID NO: 83 and the second gRNA comprises a spacer sequence that is complementary to SEQ ID NO: 15; or (e) the first gRNA comprises a spacer sequence that is complementary to SEQ ID NO: 4 and the second gRNA comprises a spacer sequence that is complementary to SEQ ID NO: 15. Co-pending claim 73 recites the method of co-pending claim 1, wherein the first gRNA and/or the second gRNA comprises a spacer sequence that hybridizes to the same target sequence of the δβ-globin region of human chromosome 11 as a nucleic acid having the nucleic acid sequence of any one of SEQ ID NOs: 4, 5, 6, 15, 19, and 20. Co-pending claim 74 recites a method of ameliorating a β-hemoglobinopathy in human patient comprising administering to such patient a human cell, wherein the human cell has been modified by introducing into the cell Cas9 endonuclease, a first guide RNA (gRNA), and a second gRNA to effect a pair of double-strand breaks (DSBs) within the δβ-globin region of human chromosome 11, wherein the first gRNA comprises a spacer sequence that hybridizes to the same target sequence of the δβ-globin region of human chromosome 11 as a nucleic acid having the nucleic acid sequence of any one of SEQ ID NO: 1-117 and 129-137, the second gRNA comprises a spacer sequence that hybridizes to the same target sequence of the δβ-globin region of human chromosome 11 as a nucleic acid having the nucleic acid sequence of any one of SEQ ID NO: 1-117 and 129-137, wherein the first gRNA hybridizes to a different target sequence than the second gRNA, wherein the editing results in increased expression of HbF in the cell. The co-pending claims anticipate the instant claims.
Regarding claims 57 and 63: Following the discussion of claims 56, 58-59, and 62, co-pending claim 7 recites the method of co-pending claim 1, wherein both guide RNAs are single-molecule guide RNAs. The co-pending claims anticipate the instant claims.
Regarding claim 60: Following the discussion of claims 56, 58-59, and 62, co-pending claim 3 recites the method of co-pending claim 1, wherein the method comprises introducing into the cell one or more polynucleotides encoding the Cas9 endonuclease. The co-pending claims anticipate the instant claim.
Regarding claim 61: Following the discussion of claims 56, 58-59, and 62, co-pending claim 4 recites the method of co-pending claim 1, wherein the method comprises introducing into the cell one or more RNAs encoding the Cas9 endonuclease. The co-pending claims anticipate the instant claim.
Regarding claims 65-66: Following the discussion of claims 56, 58-59, and 62, co-pending claim 10 recites the method of co-pending claim 1, wherein the human cell is an isolated progenitor cell. Co-pending claim 11 recites the method of co-pending claim 10, wherein the isolated progenitor cell is a hematopoietic progenitor cell. The co-pending claims anticipate the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/JENNIFER S SPENCE/Examiner, Art Unit 1633
