DETAILED CORRESPONDENCE
Application Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicants’ amendment to the claims filed on 05/05/2026 in response to the Restriction Requirement mailed on 11/06/2025 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
3. Claims 231-252 are pending.
Election/Restrictions
4. Applicant's election with traverse of Group I, claims 231-235 and 240-241 in the reply filed on 05/05/2026 is acknowledged. The traversal is on the ground(s) that there would not be a serious burden on the Office to search and examine all of the pending claims of the application together as similar search parameters could be used to search the prior art for all groups. This is not found persuasive because as stated in the Restriction Requirement, the gRNA molecule of invention I can be used for entirely different purposes than the inventions of II, III and IV, and as such it would be serious search burden to examine all possible related art as encompassed by each individual groups. Furthermore, as it relates to the subcombinations of Inventions I and II, any claim(s) depending from or otherwise requiring all the limitations of the allowable subcombination will be examined for patentability.
The requirement is still deemed proper and is therefore made FINAL.
5. Applicant’s election without traverse of the species SEQ ID NO: 253 in the reply filed on 05/05/2026 is acknowledged.
6. Applicant's election with traverse of the species SEQ ID NO: 7811 in the reply filed on 05/05/2026 is acknowledged. The traversal is on the ground(s) that the Office has not demonstrated that a serious search and/or burden exists. This is not found persuasive because as stated in the Restriction Requirement, each sequence has a unique structure and function. As such, a search for each sequence would require a different field of search and examination of art pertinent to said species, and the search of one of the species is not likely to result in the finding of art pertinent to all of the other species.
The requirement is still deemed proper and is therefore made FINAL.
7. Claims 236-239 and 246-250 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 05/05/2026.
Claims 231-235 and 240-241 are pending and will be examined to the extent they read on the species SEQ ID NO: 253 and 7811.
Priority
8. Acknowledgement is made of this continuation of U.S. Non-provisional Application No. 16/066617, filed on 06/27/2018, which is a national stage entry of PCT/IB2016/058007, filed on 12/26/2016, which claims domestic priority to U.S. Provisional Application No. 62/347484 and 62/271968, filed on 06/08/2016 and 12/28/2015, respectively.
Information Disclosure Statement
9. The IDSs filed on 09/14/2023 and 05/06/2026 have been considered by the examiner and a copy of the Form PTO/SB/08 is attached to the office action.
Drawings
10. The Drawings filed on 10/13/2022 are acknowledged and accepted by the examiner.
Specification
11. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. 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. In the instant case, p. 43, 60, 379, 383, and 464 have embedded hyperlinks.
Claim Rejections – 35 USC § 103
12. 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.
13. Claim(s) 231-232, 234 and 240-241 is/are rejected under 35 U.S.C. 103 as being unpatentable over Friedland et al. (WO 2015/148860 A1, filing date 03/26/2014; cited on IDS filed on 09/14/2023) in view of Orkin et al. (US Patent Application Publication 2015/0132269 A1, filed on 11/13/2014; cited on IDS filed on 09/14/2023).
14. Claims 231-232 and 234 are drawn in relevant part to a gRNA molecule comprising a tracr and crRNA, wherein the crRNA comprises a targeting domain that is complementary with a target sequence of a human BCLa enhancer, wherein the targeting domain comprises SEQ ID NO: 253.
Claim 240 is drawn to a polynucleotide comprising a nucleic acid sequence that encodes the gRNA molecule of claim 231.
Claim 241 is drawn to a vector comprising the polynucleotide of claim 240.
15. With respect to claims 231-232 and 240, Friedland et al. teach a gRNA molecule comprising a tracr and crRNA, wherein the crRNA comprises a targeting domain that is complementary with a target sequence of a human BCL11a enhancer [see Abstract; p. 2-3; p. 8, lines 11-27; p. 498; p. 642, lines 8-17].
With respect to claim 234, Friedland et al. teach the gRNA molecule wherein one or more nucleic acid molecules of the gRNA molecule comprises a phoshorotioate at the 3’ end or 5’ end or 2’ methyl modification of one or more nucleic acid molecules [see p. 64].
With respect to claim 241, Friedland et al. teach a vector comprising the polynucleotide encoding the gRNA [see p. 611, lines 5-21].
However, Friedland et al. does not teach the gRNA of claims 231-232, 234, and 241 comprising or consisting of SEQ ID NO: 253.
Orkin et al. teach methods for genome engineering and targeting of BCL11a enhancer region with TALEN effectors or CRISPR/Cas systems that target the targeting domain of SEQ ID NO: 253 [see Abstract, paragraphs 0012-0015; 0022; alignment attached as APPENDIX A].
Before the effective filing date of the claimed invention, it would have been obvious for one of ordinary skill in the art to combine the teachings of Friedland et al. and Orkin et al. according to the teachings of Orkin et al. to design a gRNA to target SEQ ID NO: 253 because Friedland et al. teach a gRNA molecule comprising a tracr and crRNA for targeting of a BCL11a enhancer sequence. Orkin et al. teach similar methods for genome engineering of BCL11a enhancer region wherein the targeting sequence is SEQ ID NO: 253 of the BCL11a enhancer region. One of ordinary skill in the art would have had a reasonable expectation of success and a reasonable level of predictability to combine the teachings of Friedland et al. and Orkin et al. because Orkin et al. acknowledges targeting regions of BCL11a that are useful for gene therapy and genome engineering. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
16. Claim 233 is rejected under 35 U.S.C. 103 as being unpatentable over Friedland et al. (WO 2015/148860 A1, filing date 03/26/2014; cited on IDS filed on 09/14/2023) in view of Orkin et al. (US Patent Application Publication 2015/0132269 A1, filed on 11/13/2014; cited on IDS filed on 09/14/2023) as applied to claims 231-232, 234 and 240-241 above, and further in view of Joung et al. (US Patent 9885033, filed 03/14/2014; examiner cited).
17. The relevant teachings of Friedland et al. and Orkin et al. as applied to claims 231-232, 234, and 240-241 are set forth above.
18. However, the combination of Friedland et al. and Orkin et al. does not explicitly teach SEQ ID NO : 7811.
Joung et al. teach methods for increasing the specificity of RNA-guided genome editing using CRISPR/Cas9 systems using synthetic gRNA wherein one or more nucleotides are modified having a target complementary region flanked at the 3’ end with uracil nucleotides sharing 100% sequence identity to SEQ ID NO: 7811 [see Abstract; column 2; alignment attached as APPENDIX B].
Before the effective filing date of the claimed invention, it would have been obvious for one of ordinary skill in the art to combine the teachings of Friedland et al., Orkin et al. and Joung et al. according to the teachings of Joung et al. because Friedland et al. and Orkin et al. teach gRNA for targeted genome engineering using CRISPR/Cas systems. Joung et al. teach synthetic gRNA systems that increase specificity of RNA-guided genome editing. One of ordinary skill in the art would have had a reasonable expectation of success and a reasonable level of predictability to combine the teachings of Friedland et al., Orkin et al. and Joung et al. because Joung et al. acknowledges that these synthetic gRNA systems increase the specification of CRISPR/Cas genome editing systems. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
19. Status of the claims:
Claims 231-252 are pending.
Claims 236-239 and 246-250 stand withdrawn pursuant to 37 CFR 1.142(b).
Claims 231-234 and 240-241 are rejected.
No claims are in condition for an allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PAUL J HOLLAND whose telephone number is (571)270-3537. The examiner can normally be reached Monday to Friday from 8AM to 5PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached at 571-272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PAUL J HOLLAND/Primary Examiner, Art Unit 1656
APPENDIX A
Orkin et al. with SEQ ID NO: 253
CC PN US2015132269-A1.
XX
CC PD 14-MAY-2015.
XX
CC PF 13-NOV-2014; 2014US-00540729.
XX
PR 13-NOV-2013; 2013US-0903823P.
PR 26-AUG-2014; 2014US-0042075P.
XX
CC PA (ORKI/) ORKIN S H.
CC PA (REIK/) REIK A.
CC PA (URNO/) URNOV F.
XX
CC PI Orkin SH, Reik A, Urnov F;
XX
DR WPI; 2015-30268U/34.
XX
CC PT New genetically modified cell comprising a genomic modification within
CC PT endogenous B-cell chronic lymphocytic leukemia/lymphoma-11A enhancer
CC PT sequence, made by a nuclease, useful e.g. to treat a patient having a
CC PT globinopathy e.g. thalassemia.
XX
CC PS Claim 7; SEQ ID NO 40; 111pp; English.
XX
CC The present invention relates to a novel genetically modified cell,
CC useful for treating a patient having globinopathy. The genetically
CC modified cell comprises a genomic modification made by a nuclease, where
CC the genomic modification is within an endogenous BCL11A enhancer
CC sequence, the nuclease is zinc finger nuclease (ZFN) or transcription
CC activator-like effector nuclease (TALEN), and the genomic modification is
CC one of insertions and/or deletions. The invention further relates to: (1)
CC a genetically modified differentiated cell descended from the stem cell;
CC (2) a DNA-binding protein comprising a zinc finger protein or a TALE-
CC effector protein (TALE); (3) a fusion protein comprising a zinc finger
CC protein (ZFP) or TALE protein and a wild-type or engineered cleavage
CC domain or cleavage half-domain; (4) a polynucleotide encoding the DNA-
CC binding protein; (5) an isolated hematopoietic stem cell comprising the
CC DNA-binding protein or its encoding polynucleotide; (6) a kit comprising
CC the DNA-binding protein; (7) a method for altering globin gene expression
CC in a cell, which involves introducing into the cell at least one
CC polynucleotide, under conditions so that the proteins are expressed and
CC expression of the globin gene is altered; (8) a method for producing the
CC genetically modified cell; (9) a kit for producing the genetically
CC modified cell; and (10) a method for treating a patient in need of an
CC increase in globin gene expression. The genetically modified cell of the
CC invention can be used for treating a patient in need of an increase in
CC globin gene expression, where the patient is known to have, is suspected
CC of having, or is at risk of developing a genetic disease, e.g.,
CC hemoglobinopathy (thalassemia (beta-thalassemia) or sickle cell disease
CC (sickle cell anemia)). The present sequence is a human BCL11A enhancer
CC region fragment sequence, used in the invention as a target for TALEN,
CC which is altered for increasing globin gene expression.
XX
SQ Sequence 21 BP; 6 A; 5 C; 2 G; 8 T; 0 U; 0 Other;
Query Match 100.0%; Score 20; Length 21;
Best Local Similarity 100.0%;
Matches 20; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CTAACAGTTGCTTTTATCAC 20
||||||||||||||||||||
Db 1 CTAACAGTTGCTTTTATCAC 20
APPENDIX B
Joung et al. with SEQ ID NO: 253
US-14-776-620A-15
(NOTE: this sequence has 2 duplicates in the database searched.
See complete list at the end of this report)
Sequence 15, US/14776620A
Patent No. 9885033
GENERAL INFORMATION
APPLICANT: THE GENERAL HOSPITAL CORPORATION
TITLE OF INVENTION: INCREASING SPECIFICITY FOR RNA-GUIDED GENOME EDITING
FILE REFERENCE: 40174-0009US1
CURRENT APPLICATION NUMBER: US/14/776,620A
CURRENT FILING DATE: 2015-09-14
PRIOR APPLICATION NUMBER: PCT/US2014/029304
PRIOR FILING DATE: 2014-03-14
PRIOR APPLICATION NUMBER: 61/921,007
PRIOR FILING DATE: 2013-12-26
PRIOR APPLICATION NUMBER: 61/838,178
PRIOR FILING DATE: 2013-06-21
PRIOR APPLICATION NUMBER: 61/838,148
PRIOR FILING DATE: 2013-06-21
PRIOR APPLICATION NUMBER: 61/799,647
PRIOR FILING DATE: 2013-03-15
NUMBER OF SEQ ID NOS: 115
SEQ ID NO 15
LENGTH: 80
TYPE: DNA
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Synthetic guide RNA oligonucleotide
FEATURE:
NAME/KEY: misc_feature
OTHER INFORMATION: Description of Combined DNA/RNA Molecule: Synthetic guide RNA
oligonucleotide
Query Match 100.0%; Score 80; Length 80;
Best Local Similarity 72.5%;
Matches 58; Conservative 22; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GTTTTAGAGCTAGAAATAGCAAGTTAAAATAAGGCTAGTCCGTTATCAACTTGAAAAAGT 60
|::::|||||:|||||:||||||::||||:|||||:||:|||::|:||||::|||||||:
Db 1 GUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGU 60
Qy 61 GGCACCGAGTCGGTGCTTTT 80
|||||||||||||:||::::
Db 61 GGCACCGAGTCGGUGCUUUU 80
Prosecution Insights