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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/7/2025 has been entered.
Application Status
This action is written in response to applicant’s correspondence received 10/7/2025. Claims 1-5, 8, 10, 12-14, 16-17, 19-23, 25-28, and 30 are currently pending. Claims 19-23, 25-28, and 30 are withdrawn from prosecution as being drawn to non-elected subject matter. Accordingly, claims 1-5, 8, 10, 12-14, 16-17 are examined herein. Applicant cancelled claim 7 and incorporated its limitations into independent claim 1.
The restriction requirement mailed 06/12/2024 is still deemed proper. Applicant's elected Group I, claims 1-8, 10, 12-14, and 16-17 and Species of Group A, a retroviral integrase: human immunodeficiency virus (HIV) Integrase; Species of Group B, a Cas protein: Cas9; Species of Group C, a HIV integrase sequence: SEQ ID NO: 1; Species of Group D, a Cas9 sequence: SEQ ID NO: 42; Species of Group E, a NLS sequence: SEQ ID NO: 51; Species of Group F, a fusion protein: SEQ ID NO: 57; and Species of Group G, a nucleic acid sequence: SEQ ID NO: 155 without traverse in the reply filed 09/20/2024.
Claims 19-23, 25-28, and 30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09/20/2024.
SEQ ID NOs: 2-40 in claim 8; SEQ ID NOs: 41 and 43-46 in claim 10; SEQ ID NOs: 58-98 and SEQ ID NOs: 156-196 in claim 17 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 9/20/24.
With regard to the election of species for Group E – NLS sequences, the Office is extending the search of NLS sequences to non-elected species of SEQ ID NOs: 47-50 and 52-56.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Drawings
The drawings received on 10/7/2025 are acceptable. The petition for color drawings was approved 1/15/2026.
Claim Rejections - 35 USC § 103 – new rejection necessitated by amendment
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.
Claims 1-5,8, 10, 12-14, and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Sheikh (US20180080051A1; published 03/22/2018), in view of Bridier-Nahmias (US20180022781A1; published 01/25/2018), and Baker et al. (Scientific Reports 6: 25529, pages 1-10, 2016). This rejection has been modified as necessitated by Applicant’s amendment to incorporate the limitation of claim 7 into claim 1.
Sheikh’s disclosure is directed to engineered proteins such as Cas9, Cpf1, TALE and Zinc finger proteins attached with a viral integrases, recombinase, or transposase in order to deliver a DNA sequence of interest (or gene of interest) to a targeted site in a genome of a cell or organism (see abstract).
Regarding claim 1, Sheikh teaches a fusion protein comprising a retroviral integrase (IN), a CRISPR-associated (Cas) protein, and further teach that Cas integrase fusion protein may be designed with a nuclear localization signal (NLS) (see abstract; Table 1; paras 0002-0015; 0137-0138; and Examples 6 and 9).
However, Sheikh does not specifically teach that the NLS is a retrotransposon NLS.
Bridier-Nahmias’s disclosure is directed to polypeptide for engineering integrase chimeric proteins and their use in gene therapy (see abstract). Bridier-Nahmias teaches Ty1 retrotransposon and fusion integrases comprising a CRISPR/Cas nuclease (see paras 0003-0005, 0033-0035, and 0065).
Regarding claim 1, Bridier-Nahmias teaches a retrotransposon NLS that is Ty1 NLS (see paras 0005, 0033-0035 and 0098).
Baker’s disclosure is directed to nuclear transport of Cas9 by Ty1 (see abstract).
Regarding claim 1, Baker teaches that the Ty1 NLS is effective in nuclear transport of Cas9 (entire document).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Sheikh’s fusion protein comprising a retroviral IN, a CRISPR-Cas protein, and an NLS with the Ty1 NLS described by Bridier-Nahmias and by Baker because it would have amounted to a simple substitution of known NLSs to obtain predictable results. One would have had a reasonable expectation of success because Sheikh and Bridier-Nahmias teach fusion polypeptides comprising integrases for genome editing and because Baker teaches the advantages of using Ty1 NLS with Cas9. Thus, the claimed invention as a whole is prima facie obvious.
Regarding claim 2, Sheikh teaches that the retroviral IN is human immunodeficiency virus (HIV) IN and Mouse mammary tumor virus (MMTV) IN (see paras 0002-0005, 0015, and 0131-0134).
Regarding claim 3, Sheikh teaches retroviral IN fragments comprises the IN N-terminal domain (NTD) and the IN catalytic core domain (CCD) (see paras 0134).
Regarding claim 4, Sheikh teaches that the Cas protein can be Cas9 or Cpf1 (see abstract and paras 0273-0274).
Regarding claim 5, Sheikh teaches that the Cas protein is catalytically deficient (dCas) (see paras 0002, 0009-0013; and 0110-0117).
Regarding claim 8, Sheikh teaches the sequence of SEQ ID NO: 58 encoding a fusion protein named ABBIE1 comprising 99.4% sequence identity (which is greater than the required at least 70%) to Applicant’s elected SEQ ID NO: 1 (see OA.Appendix for sequence alignment from Office Action mailed 12/31/2024 for SEQ ID NO: 1-99-4 percent; Table 1; and para 0211). Sheikh further teaches SEQ ID NO: 80 encoding a retroviral IN having 100% sequence identity to Applicant’s elected SEQ ID NO: 1. (see OA.Appendix from Office Action mailed 12/31/2024 for sequence alignment for SEQ ID NO: 1-100 percent; and Table 1).
Regarding claim 10, Sheikh teaches the sequence of SEQ ID NO: 52 encoding a Cas protein comprising 100% sequence identity (which is greater than the required at least 70%) to Applicant’s elected SEQ ID NO: 42 (see OA.Appendix from Office Action mailed 12/31/2024 for sequence alignment; para 0009 and Table 1).
Regarding claim 12, Sheikh teaches the amino acid sequence of SEQ ID NO: 58 encoding a fusion protein with an NLS comprising 81.8% sequence identity to Applicant’s SEQ ID NO: 47 (encoding 1xSV40 NLS), 100% sequence identity to Applicant’s SEQ ID NO: 49 (encoding 3xFLAG NLS), and 75.1% sequence identity to Applicant’s SEQ ID NO: 52 (see OA.Appendices for sequence alignments for SEQ ID NOs: 47, 49, and 52 from Office Action mailed 12/31/2024).
Regarding claim 13, Sheikh teaches the amino acid sequence of SEQ ID NO: 58 encoding a fusion protein with an NLS comprising 100% sequence identity to SEQ ID NO: 49 (encoding 3xFLAG NLS) (see OA.Appendix for sequence alignment from Office Action mailed 12/31/2024).
Regarding claims 12-13, Bridier-Nahmias teaches that the sequence of SEQ ID NO: 12 encoding a Ty1 sequence comprising 100% sequence identity (which is greater than the required at least 70%) to Applicant’s elected SEQ ID NO: 51 (see alignment below. Qy is SEQ ID NO: 51 and DB is SEQ ID NO: 12).
(Applicant SEQ ID NO: 51)
Qy 1 NSKKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRIH 39
|||||||||||||||||||||||||||||||||||||||
Db 17 NSKKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRIH 55
(Bridier-Nahmias SEQ ID NO: 12)
Regarding claim 14, Sheikh teaches a fusion protein encoded by the SEQ ID NO: 58 having 96.3% (which is greater than the required 70%) sequence identity to Applicant’s elected SEQ ID NO: 57 (see OA.Appendix for sequence alignment from Office Action mailed 12/31/2024).
Regarding claims 16-17, Sheikh teaches the nucleic acid molecule having the sequence of SEQ ID NO: 57 encoding a fusion protein comprising 90% sequence identity (which is greater than the required at least 70%) to Applicant’s SEQ ID NO: 155 (see OA.Appendix for sequence alignment from Office Action mailed 12/31/2024).
Therefore the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments
Applicant’s arguments filed 10/7/2025 have been fully considered but they are not persuasive. Applicant argues that using Ty1 would not have been obvious based on Sheikh and Bridier-Nahmias. The Office has issued a new rejection in view of Applicant’s amendments to claim 1, therefore, the arguments of the previous rejection are moot.
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 1-4, 8, 10, 12-14, and 16-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 32-39, 41-46, and 49-50 of copending Application No. 17/366,419, in view of Sheikh (US20180080051A1; published 03/22/2018). This rejection has been modified in view of Applicant’s amendment to cancel claim 7.
Claims 32-39, 41-47, and 49-50 of the ‘419 encompass a fusion protein comprising a Cas editing protein and a Ty1 NLS and a nucleic acid molecule encoding the fusion protein. Claims 32-39, 41-47, and 49-50 of the ‘419 further encompass a fusion protein having the Ty1 NLS comprise the SEQ ID NO: 51 and a fusion protein having a Cas9 protein encoded by SEQ ID NOs: 41, 43, or 45.
The copending claims do not teach that the fusion protein comprises a retroviral integrase, or fragment thereof (claim 1), the IN is from HIV and MMTV (claim 2), the retroviral IN fragment comprises the IN NTD and the CCD (claim 3), the Cas protein is catalytically deficient (dCas) (claim 5), the retroviral IN comprises a sequence at least 70% identical to one of SEQ ID NO: 1 (claim 8), a fusion protein comprising a sequence at least 70% identical to SEQ ID NO: 57 (claim 14), and a nucleic acid molecule encoding the fusion protein of claim 1 (claim 16) comprising a sequence at least 70% identical to SEQ ID NO: 155 (claim 17).
However, the teachings of Sheikh are discussed above. In particular, the teachings of Sheikh regarding the fusion protein comprising a retroviral integrase, Sheikh’s SEQ ID NO: 58 encoding a fusion protein named ABBIE1 comprising 99.4% sequence identity (which is greater than the required at least 70%) to Applicant’s elected SEQ ID NO: 1, the fusion protein comprising dCas and comprising the sequence of SEQ ID NO: 42, the sequence of SEQ ID NO: 52 encoding a Cas protein comprising 100% sequence identity, and the nucleic acid molecule having the sequence of SEQ ID NO: 57 encoding a fusion protein comprising 90% sequence identity (which is greater than the required at least 70%) to Applicant’s SEQ ID NO: 155.
It would have been obvious to one of ordinary skill in the art to have modified the fusion protein of the copending claims to include the retroviral integrase as taught by Sheikh and further to include a dCas9 because it would have amounted to a simple combination of prior art elements according to known methods to yield predictable results. One would have had a reasonable expectation of success because the copending claims and Sheikh are directed to fusion proteins comprising Cas9 and NLS and nucleic acid molecules encoding the fusion molecules.
This is a provisional nonstatutory double patenting rejection.
Claims 1-5, 8, 10, 12-13, and 16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of copending Application No. 18/556536 (reference application). This rejection has been modified in view of Applicant’s amendment to cancel claim 7.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims and conflicting claims are drawn to a fusion protein comprising a retroviral integrase or a fragment thereof, a CRISPR-associated (Cas) protein, and a nuclear localization signal (NLS) or a nucleic acid molecule comprising one or more nucleic acid sequences encoding a retroviral integrase (IN) or a fragment thereof, a CRISPR-associated (Cas) protein, and a retrotransposon nuclear localization signal (NLS) (instant claims 1 and 16). Copending claims 1-13 of the ‘536 application encompass the retroviral IN being selected from the group consisting of human immunodeficiency virus (HIV) IN, Rous sarcoma virus (RSV) IN, Mouse mammary tumor virus (MMTV) IN, Moloney murine leukemia virus (MoLV) IN, bovine leukemia virus (BLV) IN, Human T-lymphotropic virus (HTLV) IN, avian sarcoma leukosis virus (ASLV) IN, feline leukemia virus (FLV) IN, xenotropic murine leukemia virus-related virus (XMLV) IN, simian immunodeficiency virus (SIV) IN, feline immunodeficiency virus (FIV) IN, equine infectious anemia virus (EIAV) IN, Prototype foamy virus (PFV) IN, simian foamy virus (SFV) IN, human foamy virus (HFV) IN, walleye dermal sarcoma virus (WDSV) IN, and bovine immunodeficiency virus (BIV) IN (instant claim 2), the IN comprises the NTD and CCD and comprises a sequence at least 70% identical to SEQ ID NOs: 1-40 (instant claims 3 and 8), the Cas protein is selected from Cas9 or Cpf1 (instant claim 4) and comprises a sequence at least 70% identical to one of SEQ ID NOs: 41-46 (instant claim 10), and the Cas9 protein being dCas9 (instant claim 5). Copending claims 1-13 of the ‘536 application further encompass that the NLS is a Ty1 NLS (instant claim 1) and comprising a sequence at least 70% identical to one of SEQ ID NO: 51 (instant claims 12-13).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 10/7/2025 have been fully considered but they are not persuasive. Applicant requests that the rejection be held in abeyance until allowable subject matter is identified. However, such a response is not a proper reply to the outstanding rejection of record.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KHALEDA B HASAN whose telephone number is (571)272-0239. The examiner can normally be reached IFP, Monday - Friday 7:30am-5pm.
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/KHALEDA B HASAN/Examiner, Art Unit 1636
/BRIAN WHITEMAN/Primary Examiner, Art Unit 1636
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