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
Applicant's amendments and remarks filed on August 20, 2025 are acknowledged. Claims 1-37 and 42 have been canceled. Claims 38-40, 44, 45, and 47 were amended. Claims 38-41 and 43-60 are pending and are examined on the merits herein.
Withdrawn Objections
In view of Applicant’s amendments and response, the objections to claims 10, 14, and 39 are withdrawn.
In view of Applicant’s amendments and response, the objections to the specification are withdrawn. It is noted that Applicant’s remarks indicate to amend paragraph [0114] of the specification on page 31 (reproduced below):
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. However, it appears that Applicant may have intended to indicate to amend paragraph [0115] of the specification instead of paragraph [0114] because paragraph [0115] of the specification corresponds to the paragraph that Applicant indicates in the remarks (see below).
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Therefore, the instruction should have been to amend paragraph [0115]. In the interest of compact prosecution, the amendment has been entered with the correction noted here.
Withdrawn Rejections
In view of Applicant’s amendments and response, the 35 U.S.C 112(a) enablement rejection is withdrawn.
Drawings
The drawings were received on July 6, 2021.
The drawings are objected to because 37 CFR 1.84 (u)(1) states “View numbers
must be preceded by the abbreviation "FIG."”. In the current case, the view number for Figure 1 is preceded by the word "Figure" instead of the abbreviation "FIG.".
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.
Claim Objections
Claims 38 and 50 are objected to because of the following informalities:
Claims 38 and 50 have periods within each claim at the bullet points (part “a.” and part “b.”). See MPEP 608.01(m).
Appropriate correction is required.
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.
Claims 38-41 and 43-60 are 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.
The term “substantially” in claims 38 and 50 is a relative term which renders the claims indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification discloses in paragraph [0024] that adjectives such as “substantially” is understood to mean that the condition or characteristic is defined to within tolerances that are acceptable for operation of the embodiment for an application for which it is intended. However, it is still unclear what is meant by the term “substantially”. Therefore, the phrase “substantially at the same time” has been rendered indefinite by the use of the term “substantially” because one of skill cannot know what is or is not considered substantially at the same time because the term “substantially” is an undefined relative term.
Claims 39-41, 43-49, and 51-60 are indefinite because the claims depend from a rejected claim (claims 38 and 50) without addressing the issue in claims 38 and 50.
Response to Arguments
Applicant's arguments filed August 20, 2025 have been fully considered but they are not persuasive.
Applicant’s remarks indicate that claim 38 was amended to delete the term “substantially”; however, the term “substantially” is still recited in the claim. Therefore, the Examiner is maintaining the 35 U.S.C. 112(b) rejection in reference to the use of the relative term “substantially” for the reasons of record.
Claim Rejections - 35 USC § 103
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.
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 38, 39, 40, 46-52, and 57-60 are rejected under 35 U.S.C. 103 as being unpatentable over Caorsi et al. (Pediatric Rheumatology 2014), Caorsi et al. (Pediatric Rheumatology 2015), Zhang et al. (US 20140179770), and Hashem et al. (Blood 2017).
Regarding claims 38, 39, 40, 46, 48, 49, 50, 51, 52, 57, 59, and 60, Caorsi et al. (Pediatric Rheumatology 2014) teaches that mutations of ADA2 have been recently reported as causative of an inflammatory condition characterized by polyarteritis, cerebral stroke and immunodeficiency; the response to immunosuppressors and biologic drugs is not univocal [page 1, left column, first paragraph]. Further, analysis of CERC1 gene revealed the T360A homozygous mutation [page 1, right column].
Regarding claims 47 and 58, the structure in the prior art is indistinguishable from the structure in this claim, and absent evidence to the contrary, the recited limitations are a function that is an inherent property of the structure. See MPEP 2112.
Caorsi et al. (Pediatric Rheumatology 2015) teaches that molecular analysis of CERC1 gene identified homozygosis or compound heterozygosis for deleterious mutations (G47R, G47A, P251L, R312X, E328D, T360A) in all patients (page 1, left column, fifth paragraph].
Thus each Caorsi et al. reference taught that the T360A was deleterious, thereby providing motivation to pursue methods of repairing the mutation. However, these references did not teach the instantly claimed guide RNA sequences or CRISPR technology.
Zhang et al. teaches delivery, engineering, optimization and therapeutic applications of systems, methods, and compositions used for the control of gene expression involving sequence targeting, such as genome perturbation or gene-editing, that relate to Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and components thereof [0005]. Zhang et al. also teaches that DNA double-strand break repair promotes gene editing. A repair template in the form of a plasmid or single-stranded oligodeoxynucleotides can be supplied to leverage the homology-directed repair pathway which allows high fidelity and precise editing [0115]. Zhang et al. provided guidance with regard to identifying PAM sites for various endonucleases such as Cas9 (see e.g. Example 3 at [0697]-[0699]) as well as construction of sgRNAs (see [0902]-[0906] and [0911]-[0913]. Paragraph [0844] teaches an adenovirus/AAV vector system comprising a Cas9 and the guide RNA along with an adenovirus/AAV vector system comprising the homology repair template. Zhang et al. also teaches that the CRISPR enzyme and/or any of the RNAs (i.e. a guide RNA) can be delivered using various viral vectors either as a single dose or multiple doses [0210]. A dosage may further contain a pharmaceutically acceptable carrier [0211].
Hashem et al. teaches that deficiency of adenosine deaminase 2 (DADA2) is caused by biallelic deleterious mutations in CECR1. DADA2 results in variable autoinflammation and vasculopathy, immunodeficiency and bone marrow failure. Hematopoietic stem cell transplantation (HSCT) represents a potential definitive treatment. Hashem et al. also teaches that varying grades of acute graft-versus-host disease was observed in several patients who received HSCT for DADA2 [abstract].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have scanned the genome for PAM sites in the vicinity of the mutation, and to have designed guide RNAs adjacent to those sites in order to correct the T360A mutation in hematopoietic stem cells of the patient of Caorsi et al. Although Hashem et al. taught that DADA2 can be treated by providing HSCs that express normal ADA2, there may be problems with immune rejection of the transplanted cells. Therefore, one of skill would be motivated to develop a treatment that uses corrected versions of a patient’s own stem cells rather than cells from donors because a patient’s own stem cells would be expected to be less immunogenic and thus less likely to cause graft-versus-host disease. Further, it would have been obvious to have arrived at the instantly claimed gRNAs and the instantly claimed method in the course of basic research to determine if correction of the T360A mutation could be achieved in sufficient frequency to restore meaningful function.
Claims 41 and 53 are rejected under 35 U.S.C. 103 as being unpatentable over Caorsi et al. (Pediatric Rheumatology 2014), Caorsi et al. (Pediatric Rheumatology 2015), Zhang et al. (US 2014/0179770), and Hashem et al. (Blood 2017) as applied to claims 38, 39, 40, 46-52, and 57-60 above, and further in view of Hequet (Journal of Blood Medicine 2015).
Regarding claims 41 and 53, the teachings of Caorsi et al. (Pediatric Rheumatology 2014), Caorsi et al. (Pediatric Rheumatology 2015), Zhang et al., and Hashem et al. are discussed above.
However, Caorsi et al., Zhang et al., and Hashem et al. do not teach obtaining the cell from the subject by mobilization and/or by apheresis or by bone marrow aspiration.
Hequet teaches that hematopoietic stem and progenitor cell transplantation is a referent treatment for severe hematological diseases [page 55, second sentence of introduction]. The current protocol recommended for bone marrow harvesting consists in aspirating bone marrow from the posterior iliac crest in a donor [page 56, left column, second full paragraph]. Hequet also teaches that peripheral blood hematopoietic stem and progenitor cell can be harvested by mobilization and apheresis techniques [page 58, second column through page 63, left column].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to obtain the cell of the method of Caorsi et al., Zhang et al., and Hashem et al. by mobilization, mobilization/apheresis, apheresis, or bone marrow aspiration because these methods are well known and widely used to obtain HSPCs. One of ordinary skill in the art has a reasonable expectation of success at using any of these techniques because the art as evidenced by Hequet teaches that these techniques are commonly used to obtain HSPCs.
Claims 43, 44, 54, and 55 are rejected under 35 U.S.C. 103 as being unpatentable over Caorsi et al. (Pediatric Rheumatology 2014), Caorsi et al. (Pediatric Rheumatology 2015), Zhang et al. (US 2014/0179770), and Hashem et al. (Blood 2017) as applied to claims 38, 39, 40, 46-52, and 57-60 above, and further in view of Zielske et al. (Molecular Therapy 2004).
Regarding claims 43, 44, 54, and 55, the teachings of Caorsi et al. (Pediatric Rheumatology 2014), Caorsi et al. (Pediatric Rheumatology 2015), Zhang et al., and Hashem et al. are discussed above.
However, Caorsi et al., Zhang et al., and Hashem et al. do not teach culture expanding the cell or cell culture with cytokine.
Zielske et al. teaches that cytokines and chemokines can have profound effects on cell physiology and gene transfer efficiency. Further, advances in ex vivo transduction of hematopoietic stem cells has been closely coupled to the discovery of cytokines and the understanding of their effects on maintaining cell viability, maintaining stem cell pluripotency, inducing proliferation, and causing differentiation [page 211, left column, first full paragraph]. Zielske et al. also teaches that hematopoietic stem cells treated with cytokines (G-CSF, GM-CSF, stem cell factor, Flt-3L) will cause mobilization of the stem cells for collection for therapeutic use [page 211, left column, last paragraph bridging to right column].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to culture the cells of Caorsi et al., Zhang et al., and Hashem et al. with a cytokine for mobilization of the stem cells for therapeutic use as taught by Zielske et al.
Claims 45 and 56 are rejected under 35 U.S.C. 103 as being unpatentable over Caorsi et al. (Pediatric Rheumatology 2014), Caorsi et al. (Pediatric Rheumatology 2015), Zhang et al. (US 2014/0179770), and Hashem et al. (Blood 2017) as applied to claims 38, 39, 40, 46-52, and 57-60 above, and further in view of Shi et al. (Molecules 2018).
Regarding claims 45 and 56, the teachings of Caorsi et al. (Pediatric Rheumatology 2014), Caorsi et al. (Pediatric Rheumatology 2015), Zhang et al., and Hashem et al. are discussed above.
However, Caorsi et al. and Hashem et al. do not teach electroporation of cells. Zhang et al. teaches that a variety of delivery systems can be introduced to introduce Cas9 and guide RNA into the host cell including electroporation; however, Zhang et al. does not explicitly disclose the benefit of electroporation.
Shi et al. teaches that due to its feasible control and efficiency in cell transfection and desirable delivery for a huge variety of cargos from small molecules to larger proteins/antibodies, electroporation has been deemed one of the most promising methods and widely utilized for intracellular delivery [page 3, second full paragraph]. Further, Shi et al. teaches that electroporation, as a common membrane-disrupted intracellular cargo molecule delivery method, has been reported to be utilized for delivering the CRISPR/Cas9 gene editing materials and thus play a profound role in gene editing. Miniaturized electroporation can potentially further spur the development of genome editing by improving the delivery efficiency of novel gene editing molecular agents into difficult-to-transfect cell types such as immune cells and stem cells [page 12 last paragraph bridging to page 13].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Caorsi et al., Zhang et al., and Hashem et al. by subjecting the cells to electroporation due to its efficiency in cell transfection as taught by Shi et al.
Response to Arguments
Applicant’s arguments filed August 20, 2025 have been fully considered but they are not persuasive.
Applicant asserts that narrowing the scope of claim 38 and the possible sequences of the claimed guide such that the guide portion of the RNA molecule used for correction has 17-20 of the nucleotides set forth in SEQ ID NOS: 2626, 2601, 2615, 2598, or 2613 overcomes the 35 U.S.C. 103 rejections. Applicant further asserts that none of the cited references disclose the SEQ ID NOS. set forth in claim 38 or provide indicia or suggestions that would lead a person of ordinary skill in the art to such sequences. Although the applied references do not explicitly teach the instantly claimed SEQ ID NOS., it would have been obvious to have scanned the genome for PAM sites in the vicinity of the T360A mutation and to have designed guide RNAs adjacent to those sites in order to correct the T360A mutation in hematopoietic stem cells. Further, it would have been obvious to have arrived at the instantly claimed gRNAs and the instantly claimed method in the course of basic research to determine if correction of the T360A mutation could be achieved in sufficient frequency to restore meaningful function.
Applicant asserts that the identification of T360A as a potential site for editing does not render the instantly claimed gRNAs obvious and a comprehensive set of guide RNAs that could edit ADA2 at T360 would still consist of hundreds, and perhaps thousands, of permutations of gRNAs. Applicant further asserts that each of such gRNAs would then need to be prepared and tested experimentally to determine which guides will edit ADA2 at T360A and there is nothing in the references that would provide direction amongst the potential gRNA candidates to arrive at the claimed sequences. Finally, undue experimentation would be required to identify the sequences set forth in claim 38 and thus the claim is not obvious.
These arguments are not found persuasive. At the time of the claimed invention, Hashem et al. taught that although there may be problems with immune rejection of the transplanted cells, DADA2 can be treated by providing HSCs that express normal ADA2. Therefore, one of skill would be motivated to develop a treatment that uses corrected versions of a patient’s own stem cells rather than cells from donors. One of ordinary skill in the art would have had a reasonable expectation of success designing a gRNA adjacent to a PAM site because the sequence of the target is known and thus the target site comprises a finite number of solutions which are predictably designed based on their proximity to a PAM site. Therefore, even if a comprehensive set of guide RNAs that could edit ADA2 at T360 consists of hundreds, and perhaps thousands, of permutations of gRNAs as Applicant asserts, this is a finite number of guide RNAs.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 CHRISTINA TRAN whose telephone number is (571)270-0550. The examiner can normally be reached M-F 7:30 - 5:00pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached on (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637