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 03 August 2022 are acknowledged and have been entered. Claim 3 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 Claims 1-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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.
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.
Information Disclosure Statement
The information disclosure statements filed 11/03/2023 and 11/06/2025 have been considered.
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.
Specification
The use of the terms Taqman and Synthego, to name a few, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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 19 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 19 recites “a first Cas9 ribonucleoprotein (RNP) that includes a first guide RNA (gRNA) and a second Cas9 RNP” (which is also recited throughout the specification). A Cas9 RNP comprises of a Cas9 protein and a gRNA. It is unclear how a Cas9 RNP can include a second Cas9 RNP. It is unclear if the first Cas9 is made up of two gRNA and two Cas9 proteins, if the first Cas9 RNP comprises a second gRNA vs. a second Cas9 RNP, or if there are two Cas9-gRNA (RNP) complexes. Paragraph 0103 in the specification teaches this complex as that shown in Figure 10. The first Cas9 RNP is labeled as 701, the first gRNA is labeled as 315; however, there is no label for a 2nd Cas9 RNP nor is a 2nd Cas9 RNP depicted in Figure 10. Figure 10 list does list 721 twice; however, this label is not defined in the specification as objected above.
Claim Rejections - 35 USC § 102
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 18, 20-22 and 24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Boitano (US 2019/0010495 A1).
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 claim 20, Boitano teaches that the alpha gene is inserted into genome of the cell as an AAVs1 safe harbor site.
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.
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 Wang (Wang et al. Clin Invest Med; Vol 24, no 2, April 2001, cited on the Information disclosure statement).
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.
Wang 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]. Wang teaches that the alpha-globin gene cluster is on chromosome 16 [pg. 103, col. 1, para 2; col. 2, para 2-3]. Wang 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]. 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 deliver the alpha-globin gene to the alpha-globin gene cluster in chromosome 16 to fetuses in utero. 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.
Claims 18, 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over Boitano (US 2019/0010495 A1) in view of Gregory (Gregory et al. Blood (2020) 136 (Supplement 1): 3–4) and Chen (The Journal Of Biological Chemistry VOL. 285, NO. 14, pp. 10189–10197, April 2, 2010, cited on the Information Disclosure Statement).
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.
Boitano does not teach where the globin gene is the zeta gene.
Gregory teaches that the embryonic zeta globin gene, which is expressed early in gestation prior to alpha globin, may compensate for the lack of alpha globin and that induction of zeta globin after it has naturally been silenced may become a new therapy for patients with alpha thalassemia major and may play a role in survival to birth in alpha thalassemia patients [see Introduction and Conclusion].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the alpha globin gene of Boitano for the zeta globin gene for treatment of the hemoglobinopathy of alpha thalassemia. One of ordinary skill would be motivated to make the modification since Gregory teaches that zeta globin gene may compensate for the lack of alpha globin and plays a role in the spontaneous survival to birth in a subset of alpha thalassemia patients.
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 23, 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].
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 and Gregory where the reagents introduce a mutation in a RREB1 binding site. 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.
Conclusion
No claims allowed.
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.
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, Jennifer Dunston can be reached at 571-272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637