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 of Group III, a zeta globin gene, an alpha-globin gene cluster on chromosome 16, a nucleic acid {DNA or mRNA} encoding the Cas endonuclease and a nucleic acid encoding a guide RNA, and a RREB1 binding site in the reply filed on 2025 November 06 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). The search and examination has been extended to the species of an alpha-globin gene and a AAVS1 genomic safe harbor.
Application Status
The Amendments and Remarks filed 07 July 2026 are acknowledged and have been entered. Claim 19 is amended. Claims 1-24 are pending. Claims 1-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 18-24 are pending and being examined on the merits.
Any rejection or objection not reiterated herein has been overcome by applicants claim amendments and/or applicants arguments.
Priority
This application is a 371 PCT of US20/44562 filed 7/31/2020 which claims priority to application 62/881,726 filed 08/01/2019.
Drawings
The drawings are objected to because Figure 10 list the number 721 that is not defined by the specification. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Response to Arguments
Applicant's arguments filed 07 July 2026 have been fully considered but they are not persuasive. It is noted that applicants submitted amendments to the drawings for Figure 10 and deleted one instance of “721”; however, Figure 10 still contains another item labeled as 721 that is not defined by the specification.
Specification
The disclosure is objected to because of the following informalities: Paragraphs 0101-0102 explain the compositions for gene replacement as labeled in Figure 10. Paragraph 102 discloses that the Cas endonuclease is identified as 707. Figure 10 does not contain any item labeled as 707; however, it does contain an item labeled as 721 which is not defined by the specification.
Appropriate correction is required.
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 18-22 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Boitano (US 2019/0010495 A1) in view of Waye (Waye et al. Clin Invest Med; Vol 24, no 2, April 2001, cited on the Information disclosure statement). This rejection is modified to clarify the motivation and reasonable expectation of success in view of Applicant’s arguments, does not constitute a new ground of rejection, and continues to rely on the same references, findings, and combination set forth in the prior Office Action.
Regarding claim 18, Boitano teaches genome editing systems, reagents and methods for the treatment of hemoglobinopathies [abstract]. Boitano teaches that a genetic defect in alpha globin or beta globin is corrected, e.g., by homologous recombination, using the Cas9 molecules and gRNA molecules, e.g., CRISPR systems, described herein [0527]. Boitano teaches that a gene encoding a wild type (e.g., non-mutated) copy of alpha globin or beta globin (i.e. a globin gene) is inserted into the genome of the cell, e.g., at a safe harbor site, e.g., at an AAVS1 safe harbor site, by homologous recombination using a CRISPR system (i.e., gene editing system) and methods described herein. The recitation of “a composition for treatment of alpha thalassemia in a fetus or a patient no older than one year of age, or a cell thereof” is an intended use statement. “Where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation" MPEP 2111.02II.
Regarding claims 21 and 24, Boitano teaches that the Cas9 molecules can be delivered as mRNA or protein [0680].
Regarding claim 22, the recitation of “when introduced into a fetus, a patient no older than one year of age, or into cells obtained therefrom, introduce a change into a sequence within a globin gene within genomic material of the fetus, patient, cells, or progeny thereof, wherein the change activates or derepresses the globin gene” is a functional limitation and does not distinguish the composition from the prior art teachings of Boitano as discussed above in claim 18.
Regarding claim 19-20, Boitano teaches that the first gRNA molecule and Cas9 molecule are present in a ribonuclear protein complex (RNP) [0023, 106-107]. Boitano teaches compositions that include one or more gRNAs where each of said gRNA molecules is in a RNP with a Cas9 molecule [0131]. Boitano teaches that the alpha gene is inserted into genome of the cell as an AAVs1 safe harbor site. Boitano does not teach where the RNP bind to a locus within an alpha-globin gene cluster in chromosome 16 of the genomic material, and introduce the alpha-globin gene into the locus within the alpha-globin gene cluster.
Waye teaches that alpha-thalassemia is caused by alpha-globin gene mutations that result in deficient or absent alpha-globin chain production where common mutations are deletions, involving only 1 alpha-globin gene, both alpha-globin genes in tandem, or the entire ζ-α-globin gene cluster [pg. 104, col. 2, para 3]. Waye teaches that the alpha-globin gene cluster is on chromosome 16 [pg. 103, col. 1, para 2; col. 2, para 2-3]. Waye teaches that a subset of fetuses that have inherited deletion of 2 alpha-globin genes on 1 chromosome 16 plus a non-deletional alpha 2-globin gene mutation on the other chromosome 16 have very severe anemia and hypoxia in utero [pg. 106, col. 1, para 2]. Thereby Waye identifies the alpha-globin gene cluster on chromosome 16 as the locus responsible for alpha-thalassemia and explains that severe fetal disease results from defects at that locus.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to design the guide RNA of Boitano to target the alpha-globin gene cluster on chromosome 16, as identified by Waye so that the CRISPR-Cas system could introduce the donor alpha-globin sequence into the disease-causing locus through the homologous recombination techniques taught by Boitano. Doing so would have predictably corrected the known genetic effect underlying alpha-thalassemia. One of ordinary skill would be motivated to make the modification to provide increased expression of alpha-globin gene to fetuses with severe anemia and hypoxia in utero due to having alpha-thalassemia since Waye provides the biological target and disease motivation, while Boitano provides the editing technology. A person of ordinary skill seeking to adapt Boitano’s CRISPR therapy to alpha-thalassemia would have recognized the chromosome 16 alpha-globin cluster as the logical genomic target because it is the known disease-causing locus.
Claims 18, 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over Boitano (US 2019/0010495 A1) in view of Chen (The Journal Of Biological Chemistry VOL. 285, NO. 14, pp. 10189–10197, April 2, 2010, cited on the Information Disclosure Statement). This rejection is modified to remove Gregory but does not constitute a new ground of rejection, and continues to rely on the same references, findings, and combination set forth in the prior Office Action as Chen independently provides the teachings previously attributed in part to Gregory.
Regarding claim 18 and 23, Boitano teaches genome editing systems, reagents and methods for the treatment of hemoglobinopathies [abstract]. Boitano teaches that a genetic defect in alpha globin or beta globin is corrected, e.g., by homologous recombination, using the Cas9 molecules and gRNA molecules, e.g., CRISPR systems, described herein [0527]. Boitano teaches that a gene encoding a wild type (e.g., non-mutated) copy of alpha globin or beta globin (i.e. a globin gene) is inserted into the genome of the cell, e.g., at a safe harbor site, e.g., at an AAVS1 safe harbor site, by homologous recombination using a CRISPR system (i.e., gene editing system) and methods described herein. The recitation of “a composition for treatment of alpha thalassemia in a fetus or a patient no older than one year of age, or a cell thereof” is an intended use statement. “Where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation" MPEP 2111.02II.
Boitano does not teach where the globin gene is the zeta gene. Boitano do not teach wherein the gene editing reagents introduce a mutation into a RREB1 binding site.
Chen teaches that the RREB1 is a repressor involved in the developmental silencing of the human zeta-globin gene and that identification of RREB1 as a possible switch factor for the zeta-globin gene expression provides a new research target for the treatment of certain forms of severe alpha-thalassemia. Chen teaches that mutation of the putative RREB1 binding site (mCC) resulted in a 2-fold higher zeta globin promoter activity [pg. 10191, col. 2, para 3; Fig. 1b], Chen also teaches that the zeta and alpha globin mRNA levels increased in RREB1 depleted cells [pg. 10195, col. 1, para 3]. Therefore, Chen teaches that RRBE1 represses zeta and alpha globulin expression and that disrupting the RREB1 binding site increases their expression.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the gene editing reagents as taught and suggested by Boitano where the reagents introduce a mutation in a RREB1 binding site as taught by Chen. Chen teaches that RREB1 is a transcriptional repressor involved in the development of the human zeta-globin gene and that identification of RREB1 as a switch factor for zeta-globin expression provides a therapeutic target for treatment of certain forms of severe alpha-thalassemia. Chen further teaches that the mutation of RREB1 binding sites increases zeta-globin promoter activity and that depletion of RRREB1 increases both zeta and alpha globin mRNA levels. Therefore, one of ordinary skill would be motivated to make the modification for the advantage of increasing zeta and alpha globin mRNA levels in patients and fetuses with alpha thalassemia. One of ordinary skill would also be motivated to adapt Boitano’s CRISPR editing platform to target the zeta-globin regulatory mechanism taught by Chen to treat alpha-thalassemia, with a reasonable expectation of success since Chen discloses a direct relationship between zeta-globin expression and alpha thalassemia treatment and because Chen teaches that reactivation of zeta-globin represents a therapeutic strategy for severe alpha-thalassemia while Boitano provides a known and predictable genome-editing platform for modifying globin genes.
Regarding claims 21 and 24, Boitano teaches that the Cas9 molecules can be delivered as mRNA or protein [0680].
Regarding claim 22, the recitation of “when introduced into a fetus, a patient no older than one year of age, or into cells obtained therefrom, introduce a change into a sequence within a globin gene within genomic material of the fetus, patient, cells, or progeny thereof, wherein the change activates or derepresses the globin gene” is a functional limitation and does not distinguish the composition from the prior art teachings of Boitano as discussed above in claim 18.
Response to Arguments
Applicant’s arguments, see pages 11-13, filed 07 July 2026, with respect to the rejection under 35 U.S.C. § 102 have been fully considered and are persuasive. The rejection of claims 18, 20-22 and 24 under 35 U.S.C. 102(a)(1)has been withdrawn.
Applicant's arguments filed 07 July 2026, with respect to the rejection under 35 U.S.C. § 103 have been fully considered but they are not persuasive.
Applicant argues that Boitano is directed to the treatment of b-hemoglobinopathies that therefore does not teach or suggest composition for treating alpha-thalassemia. Applicant further argues that Waye merely describes alpha-thalassemia and the location of the alpha-globin gene cluster and does not teach CRISPR-mediated genome editing, guide RNAs, donor templates, or fetal gene therapy. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The rejection does not rely upon Waye for teaching genome-editing technology. Rather, Boitano is relied upon for teaching CRISPR-Cas-genome editing compositions comprising Cas9, guide RNAs, donor nucleic acids, and methods for correcting globin gene defects though homologous recombination and insertion of functional globin gene into a genomic locus. Boitano therefore provides the claims genome-editing platform. Waye is relied upon for the well-established biological relationship between alpha-thalassemia and the alpha-globin gene cluster. The combination merely applies the known genome-editing platform to Boitano to the known disease locus identified by Waye. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant argues that Boitano’s therapeutic rationale is directed to increasing fetal hemoglobin (Hbf) for b-hemoglobinopathies and would not motivate the treatment of alpha-thalassemia. While Boitano does include embodiments directed to increasing Hbf for b-hemoglobinopathies, the rejection relies upon Boitano’s broader disclosure of CRISPR-mediated correnction of globin gene defects through the insertion of a functional globin gene into a genomic locus. The fact that one embodiment of Boitano is directed to Hbf induction does not negate its broader teaching that CRISPR genome editing may be employed to correct globin gene defects. A reference must be considered for all that it fairly teaches, not merely its preferred embodiments.
Applicant additionally argues that there would not have been a reasonable expectation of success because Boitano does not address alpha-globin deficiency. The proposed modification does not require altering the underlying CRISPR editing technology disclosed by Boitano. Rather, it requires selecting a different genomic target based upon Waye’s teaching of the genetic basis of alpha-thalassemia. Once the disease-causing locus was known, selecting that locus as the target for the known CRISPR editing platform would have represented the predictable use of prior art elements according to their established functions. Absolute predictability is not required; rather, only a reasonable expectation of success is necessary.
Applicant further argues that Boitano teaches editing adult-derived human CD34+ cells and contains no disclosure of fetal therapy, in utero therapy, or treatment of infants. While Boitan’s examples utilize adult-derived human CD34+ cells, the rejection does not rely on those examples to teach fetal administration. The claims are directed to a composition, not a method requiring a particular mode of administration. The recitation that the composition if “for treatment of alpha-thalassemia in a fetus or a patient no older than one year of age, or into cells obtained therefrom” merely identified the intended patient population for the use of the composition and does not structurally distinguish the claimed composition for the prior art genome-editing compositions. Moreover, Waye traches that alpha-thalassemia is manifested during fetal development because alpha-globin genes are expressed early in gestation, thereby providing motivation to employ the known genome-editing compositions at an earlier stage of the disease.
Applicant argues that Gregory does not qualify as prior art under 35 U.S.C. § 102(a)(1). Upon further consideration, the reliance on Gregory has been withdrawn. The rejection is maintained because the teachings previously relied upon from Gregory regarding the therapeutic significance of zeta-globin are independently taught by Chen, which was discussed and relied upon in the previous office action. The maintained rejection is a refinement of the existing rejection that relies on the same teachings that rendered the claims obvious. Therefore Applicants arguments directed to Gregory are moot.
Conclusion
No claims allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIFFANY N GROOMS whose telephone number is (571)272-3771. The examiner can normally be reached M-F 830-530.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637
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