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 .
Status of Claims
Claims 17-24 are pending.
Priority
Claims 17-24 are a DIV of 17/541,141 filed on December 2, 2021 of PAT 11674154 which has priority to PRO 63/251,822 filed on October 4, 2021 and PRO 63/121,221 filed on December 3, 2020.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on July 25, 2023, Was filed before the mailing of the First Office Action on November 15, 2025. The Non-Patent literature is in compliance with the provisions of 37 CFR 1.97 and are being considered by the examiner.
Drawings
The drawings are objected to because:
Fig. 1A – is not legible.
Fig. 1B – characters and lines are blurry.
Fig. 2A – is not legible.
Fig. 3A – characters and lines are blurry.
Fig. 3B – characters and lines are blurry.
Fig. 3C – description on y-axis not legible.
Fig. 4C – characters and lines blurry.
Fig. 8A – characters and lines are blurry.
Fig. 8B – characters and lines are blurry.
Fig. 8C – first graph characters and lines are blurry.
Fig. 9 – characters and lines are blurry.
Fig. 10A – characters and lines are blurry.
Fig. 10B – characters and lines are blurry.
Fig. 11 – characters not legible.
Fig. 12 – characters and lines are blurry.
Fig. 13B – characters and lines are blurry.
Fig. 14A – is not legible.
Fig. 15B – characters and lines are blurry.
Fig. 28C – characters and lines are blurry.
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 Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 17-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 17 uses the generic term “sgRNA” as it relates to a recombinant gene editing complex that contains a sgRNA where the sgRNA has been separated into a first and second rAAV particle. The same generic scope of “sgRNA” is present in each of the dependent claims, i.e. 19, 21-24
The specification provides antecedent basis for “sgRNA” for a recombinant gene editing complex that contains a sgRNA [pg. 2 line 13].
Applicant’s specification provides that “for purpose of genome editing, the CRISPR system can be modified to combine tracrRNA and crRNA into a single guide RNA (sgRNA) or just (gRNA)” [pg. 28 Line 28]. The specification further states that “…”sgRNA” refer to a polynucleotide sequence that is complementary to a target sequence in a cell and associates with a Cas nuclease, thereby directing the Cas nuclease to the target sequence” [Id.]. It further states that the Cas protein and sgRNA can be expressed from the same vector or expressed from separate vectors [pg. 29 line 3-4]. However, the specification does not provide any Cas systems that utilize sgRNA and yet are protospacer adjacent motif (PAM)-independent. While the specification does reference gene editing tools that include other TALEN, Zinc-finger, Meganuclease, as well as other Cas systems that utilize crRNA. The specification is silent as to what, if any, Cas systems that utilize a sgRNA and are capable of editing without the presence of a PAM. To date, there are no known Cas systems that utilize a sgRNA without requiring a PAM.
Additionally, Su et al., discussing CRISPR based editing, discloses that sgRNA is specifically used with Cas9 nucleases and that DNA targeting by Cas9 requires a PAM [Introduction ¶ 3, CRISPR/Cas9-based gene targeting using synthetic guide RNAs enables robust cell biological analyses, Mol Biol Cell, 2018]. Su et al. further discloses that while there are Cas systems that use tracrRNA and crRNA individually, Cas systems using a sgRNA require a PAM. A person of ordinary skill in the art would not understand how to practice the claimed invention as described in claim 17 without the use of a PAM given that Cas systems that utilize sgRNA require the presence of a PAM.
Given the generic scope of “sgRNA” as it relates to a recombinant gene editing complex that contains a sgRNA where the sgRNA has been separated into a first and second rAAV particle and the absence of teaching of what Cas systems could be utilized without the presence of a PAM, the Artisan would not understand Applicant to be in possession of the generic scope of “sgRNA” as it relates to what is claimed in claim 17.
Claims 17, 18, and 23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 23 recites a split adenine base editor system where the protospacer and mutation are located on the N-terminal fragment. However, Claims 17 and 18 are drawn to generic split ABE system that is not limited to the protospacer and mutation being limited to the N-terminal and includes configurations in which the protospacer and mutation may be located on the C-terminal fragment. Claims 17 and 18 are also rejected given that these claims encompass variations that does not include protospacer and mutations located on the N-terminal ABE.
The specification provides antecedent basis for the protospacer and mutation being located on the N-terminal ABE fragment [pg. 4 line 15].
Applicant’s specification states “in some embodiments, the N-terminal ABE construct comprises protospacer having the AVCR1-R206H mutation” [pg. 4 line 15]. Fig. 11, as well as Example 4, also show this. However, Wright et al., discussing split Cas9 designs, discloses that Cas9 can be divided into N-terminal (alpha-helical/REC lobe) and C-terminal (nuclease) fragments, but that neither fragment alone is functional [Design and functional validation of split-Cas9, Rational design of a split-Cas9 enzyme complex, PNAS Biochemistry, 2023]. Wright et al. further teaches that the N-terminal fragment, which contains the REC lobe which is essential for gRNA binding and target recognition, differs from the C-terminal fragment which does not contain the mechanisms for recognition and is incapable of binding or direct cleavage [Id]. Because of this, the protospacer and any targeting mutation is required to reside on the N-terminal fragment given that placement on the C-terminal fragment would yield an inactive complex [Id.]. Because of this, a person of ordinary skill would not reasonable understand how to position the protospacer and targeting mutation on the C-terminal fragment of the ABE.
Given this, and the absence of teachings of alternative protospacer and targeting mutation locations, an Artisan would not understand Applicant to be in possession of the generic scope of a split Cas9 complex made up of a N-terminal portion and a C-terminal portion.
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 20 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.
Claim 20 recites the limitation "the recombinant gene editing protein " in Line 1 and 2. There is insufficient antecedent basis for this limitation in the claim. To clarify, claim 17 references “a first recombinant gene editing protein” in part (ii) and “a second recombinant gene editing protein” in part (iii).
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.
Claims 17-24 are rejected under 35 U.S.C. §103 as being unpatentable over Kim et al. [Concurrent progress of reprogramming and gene correction to overcome therapeutic limitation of mutant ALK2-iPSC, Nature Experimental & Molecular Medicine, 2016], in view of Liu et al. [WO 2020 236982 A1, 2020], in view of Gaudelli et al. [Programmable base editing of A-T to G-C in genomic DNA without DNA cleavage, Nature, 2017].
For claim 17, Kim et al. discloses a recombinant gene editing complex: comprising (i) a single guide RNA (sgRNA) that specifically hybridizes to a target nucleic acid sequence of an ACVR1 gene [Abstract, Reprogramming factors and gene editing tools ¶ 1].
Kim et al. does not teach a first rAAV particle encoding a first recombinant gene editing protein or fragment thereof; and a second rAAV particle encoding a second recombinant gene editing protein or fragment thereof. However, Liu et al. discloses a dual-vector rAAV system where two recombinant adeno-associated viral particles each contain a portion of a gene editing construct [¶ 0004]. Specifically, the first rAAV particle encodes one recombinant gene editing protein component, and the second rAAV particle encodes the complementary recombinant component necessary to reconstitute the complete gene editing complex in the target cell [Id]. Based on this, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Kim et al. that disclosed a gene editing complex consisting of Cas9 that targeted a gene construct within the ACVR1 gene with the additional teachings of Liu et al. that discloses the use of a dual vector rAAV system. Given this, there is a reasonable expectation of success that a person skilled in the art would have recognized that employing a dual-vector rAAV approach of Liu et al. would enable efficient in vivo delivery of the Cas9 editing system disclosed in Kim et al. given that both references address compatible gene editing systems, and rAAV dual-vector strategies were known to reconstitute full-length editing proteins in target cells.
For claim 18 where the first recombinant editing complex is a Cas9-based adenine base editor N-terminus portion and the second recombinant editing complex is a Cas9-based adenine base editor C-terminus, Liu et al. discloses adenine base editor where the adenine base editor is divided into an N-terminus and C-terminus halves.
For claim 19 where the recombinant gene editing complex has a protospacer adjacent motif, Liu et al. discloses a protospacer adjacent motif with a Cas9 editing complex [¶ 0073].
For claim 20 where the recombinant gene editing protein is a protein of the CRISPR-Cas9 system, Liu et al. discloses CRISPR-Cas9 as the gene editing complex [¶ 0074].
For claim 21 where the recombinant gene editing complex of claim 17 uses rAAV particles from AAV9, Liu et al. discloses that the AAV9 particles were used [¶ 00505].
For claim 22 where the recombinant gene editing complex of claim 18 for the N-terminus and C-terminus ABE constructs are divided by using a trans-splicing intein, Liu et al. teaches the use of trans-splicing inteins to cytosine base editors and adenine base editors to be divided into halves that are each smaller than the AAV packaging size [¶ 00498].
Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Kim et al. that discloses a gene editing complex, e.g. CRISPR-Cas9 system, that uses a sgRNA targeting a specific area in the ACVR1 gene with the teachings of Liu et al. that discloses the use of a dual-vector rAAV delivery system based off of the Cas9 system that includes adenine base editors for the N-terminus and C-terminus portions where the Cas9 system contains a protospacer adjacent motif, and the N-terminus and C-terminus adenine based editor is divided by a trans-splicing intein. Because of this, there is reasonable expectation of success that a person of ordinary skill in the art would combine Kim et al. with the additional teachings of Liu et al. allowing a dual-vector Cas9 gene editing complex that contains an adenine base editor that has been divided into a N-terminus and C-terminus adenine base editor for packaging purposes that is capable of targeting the ACVR1 gene.
For claim 23 where the N-terminus adenine base editor contains a protospacer have the ACVR1-R206H mutation, Gaudelli et al. discloses adenine base editors that enable conversion of A-T to G-C base pairs at target genomic loci using a Cas9 nickase to an evolved adenine deaminase that is guided by a protospacer and an sgRNA that can hybridize a target sequence [Abstract, Fig. 1] showing that adenine base editor systems can correct pathogenic single-base substitutions in human disease. Additionally, Kim et al. discloses correction of the ACVR1 (also known as ALK2) R206H mutation in patient derived iPSCs using Cas9 mediated homology directed repair.
For claim 24 where the recombinant gene editing complex of claim 22 with the C-terminus construct integrated into an AAV9 capsid protein, Liu et al. discloses delivering a split Cas9 protein or split nucleobase editor into a cell where both the C-terminus and/or N-terminus are integrated into an AAV capsid protein [¶ 00444]. Liu et al. further discloses the AAV9 cytosine and adenine base editors in heart, muscle, and liver given that AAV9 has a strong tropism toward muscle tissue.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Kim et al. and Liu et al. with the additional teachings of Gaudelli et al. where it was shown that adenine base editors are capable of correcting pathogenic single-base substitutions. Therefore, there is a reasonable expectation of success that a person of ordinary skill would combine the teachings of Kim et al. and Liu et al. with the further teachings of Gaudelli et al. in order to construct a gene editing tool that consists of a dual-vector capable of delivering a divided adenine base editor where the N-terminus portion contains a protospacer with a ACVR1-R206H mutation where the complex is integrated into a AAV9 capsid protein given that AAV9 is known for its strong tropism towards skeletal muscle.
The Supreme court has acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable varition..103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions…
…the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) emphasis added.
In KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court reaffirmed "the conclusion that when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273,282 (1976)). The Supreme Court also emphasized a flexible approach to the obviousness question, stating that the analysis under 35 U.S.C. § 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418; see also id. at 421 ("A person of ordinary skill is... a person of ordinary creativity, not an automaton.").
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN DAVID MOORE whose telephone number is (703)756-1887. The examiner can normally be reached M-F 8-5.
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/JOHN DAVID MOORE/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638