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 .
DETAILED ACTION
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed on October 30, 2025. Claims 17-18 and 22 are currently amended. Claims 2-3 are canceled. Claims 1 and 35 are independent claims.
Therefore, claims 1 and 4-43 are currently under examination.
Priority
The present application filed May 09, 2022 is a CON of PCT/US2020/060586, filed November 13, 2020, which claims the benefit under 35 U.S.C. 119(e) of prior -filed U.S. provisional application 62/936,248, filed November 15, 2019. 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.
Applicants’ claim for the benefit of the November 15, 2029 provisional date has been reconsidered. Upon further review U.S. Provisional Application No. 62/936,248, the Examiner finds that the provisional application provides adequate written description support under 35 U.S.C 112(a) for the subject matter of claims 1,4-14, 16-18, and 20-43.
However, applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date, for claims 15 and 19, under 35 U.S.C. 112 as follows:
The later-filed application must be an application for a patent for an invention that is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later -filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for claims 15 and dependent claim 19. Specifically, the transgenes FIX (Pauda Variant) and LDLR are not supported by the earlier specification filed November 15, 2019. Should the applicant disagree, the applicant is encouraged to point out with particularity by page and line number where such support might exist in each intervening document. In order to properly claim priority, the support for each of the claim limitations must exist in each of the intervening documents. Thus, the earliest possible priority for claims 15 and 19 is November 13, 2020.
Withdrawn- Specification Objection
In view of the concurrent submission of a substitute specification, removing hyperlinks the objections to the specification have been withdrawn.
Withdrawn- Claim Objections
In view of Applicants’ amendment to claims 18 and 22, the objection to improper form is moot and has been withdrawn.
Withdrawn Claim Rejection- 35 USC§ 102
The rejection of claims 1, 4-14, 16-18, and 20-43 under 35 U.S.C. 102(a)(1) as being anticipated by Cromer et al. (bioRxiv, October 28, 2020, pp. 1-48, see IDS filed 05/13/2025, Cite No. 1), as evidenced by Belato et al. (Genome Biol Evol. 2020 Oct 1;12(10):1719-1733) is withdrawn.
Maintained Claim Rejections - 35 USC § 102
Claims 15 and 19 remain rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cromer et al. (bioRxiv, October 28, 2020, pp. 1-48, see IDS filed 05/13/2025, Cite No. 1), as evidenced by Belato et al. (Genome Biol Evol. 2020 Oct 1;12(10):1719-1733).
Regarding claims 1 and 15, Cromer discloses a CRISPR-Cas9/sgRNA/AAV6 mediated gene editing therapeutic method utilizing hybridization of guide RNA sequences which specifically targets HBA1 in HSPCs (Abstract; pg. 20, para. 3). Cromer discloses β-thalassemia major is caused by homozygous (or compound heterozygous) loss-of-function mutations throughout the β-globin (HBB) gene. The method comprises gene replacement in HSPCs to correct deleterious HBB mutations by mediating site-specific gene replacement of the endogenous HBA1 gene with a full-length HBB transgene and demonstrated efficacy by transplantation, or reintroduction, into the immunodeficient NSG mouse subject (pg. 1-3, Abstract). The gene editing method is disclosed to alternatively cleave either HBA1 or HBA2 by selectively targeting the claimed discriminated target sites, such as the specified 5’UTRs or 3’UTRs (pg. 4, para. 2). Cromer discloses the method of targeting just one of the two HBA paralogs, in the presence of a donor template comprising a transgene, enables the transgene to integrate into the genome at the site of cleavage by homology directed recombination (pg. 5-6, bridging para.). This is disclosed to allow for replacement of the endogenous HBA1 or HBA2 gene with the HBB transgene, normalizing the β-globin: α-globin imbalance in β-thalassemia-derived HSPCs and rescued functional adult hemoglobin tetramers in RBCs, with high efficiency and while reducing deleterious rearrangements that arise when both loci are cut simultaneously (pg. 6-7 bridging para.; pg. 9, Section: Gene replacement with HBB transgene in β-thalassemia-derived HSPCs corrects α-globin:β-globin imbalance; pg. 10, Section: Discussion).
Subject Matter Free of the Prior Art
Claims 1, 4-14, 16-18, and 20-43 contain allowable subject matter. The closest prior art found includes Amendola et al. (WO 2019/138082 A1, see IDS), which discloses targeted integration of transgenes into globin genes in hematopoietic stem and progenitor cells, as well as prior art including Mettananda et al. (Nat Commun. 2017 Sep 4;8(1):424., see IDS), Bak et al. (Elife. 2017 Sep 28:6:e27873.), and Hendel et al. (Nat Biotechnol. 2015 Sep;33(9):985-989. Epub 2015 Jun 29.). These describe CRISPR/Cas9 editing if HSPCs, Cas9 ribonucleoprotein delivery, AVV6 donor mediated homologous recombination, and chemically modified guide RNAs. While these references demonstrate that CRISPR editing of HSPCs and insertion of therapeutic genes at globin loci were known, the prior art does not teach or suggest selectively targeting only one of the two highly homologous alpha-globin paralogs, HBA1 or HBA2, while leaving the other intact. The closest prior art, the disclosure of Amendola, discloses editing of globin genes generally or editing of “at least one” alpha-globin gene, but does not teach or suggest guide RNAs capable of discriminating between HBA1 and HBA2 selectively to cleave one, while integrating a transgene, as the other remains intact.
The present claims further require guide RNA sequences corresponding to SEQ ID NO:2 and SEQ ID NO:5, wherein SEQ ID NO:2 specifically cleaves HBA2 and SEQ ID NO: 5 specifically cleaved HB1, thereby enabling selective targeting of a single alpha-globin paralog by alternatively cleaving either HBA1 or HBA2 and by selectively targeting the claimed discriminated target sites, such as the specified 5’UTRs or 3’UTRs. Although sequence searches identified prior art sequences with 100% identity to SEQ ID NO: 2 and SEQ ID NO: 5, the prior art did not disclose or suggest selectively employing these sequences in the claimed gene-editing context. The inventive concept of using these sequences to selectively target individual HBA paralogs in human hematopoietic stem and progenitor ells was not found in the prior art. The identified references do not teach or suggest the use of these sequences in the specific manner recited in the claims, nor do they provide a teaching or motivation that would lead one of ordinary skill in the art to apply the identified sequences in the claimed context to achieve the claimed result.
Conclusion
Claims 15 and 19 remain rejected. Claims 1, 4-14, 16-18, and 20-43 allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOEL D LEVIN whose telephone number is (571)270-0616. The examiner can normally be reached Fulltime Teleworker.
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/J.D.L./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633