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 without traverse of Group I (claims 209-238) in the reply filed on April 13, 2026 is acknowledged.
Applicant’s election without traverse of SEQ ID NO: 22 as the single gRNA targeting sequence, SEQ ID NO: 133 as the single CasX variant protein, SEQ ID NO: 168 as the single nuclear localization signal, SEQ ID NO: 2 as the single reference CasX protein, SEQ ID NO: 5 as the single reference gRNA, improved target nucleic acid sequence cleavage rate as the single improved characteristic, TTC as the single PAM sequence, SEQ ID NO: 22094 as the single PAM sequence, and AAV as the single vector comprising the sgRNA variant and CasX variant protein in the reply filed on April 13, 2026 is acknowledged.
Claims 213-215 in view of election of SEQ ID NO: 22, claims 227-231 in view of election of improved target nucleic acid sequence cleavage rate as the single improved characteristic, and claims 235-236 in view of selection of AAV as the single vector, withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on April 13, 2026.
Claims 239-246 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups II and III of invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on April 13, 2026.
Claims 209-212, 216-226, and 232-234, and 237-238 are pending and under examination.
Priority
Acknowledgment is made of applicant's claim for priority based on a US Provisional Application
No. 63/120,885 filed on 12/03/2020, and support for instant claims can be found in the following sections of the provisional application: instant claim 209 (claim 1), instant claim 210 (claim 2), instant claim 211 (claim 3), instant claim 212 (claim 7), instant claim 216 (claim 20), instant claims 217-218 (claim 35 and [00108]), instant claim 220 (Table 2, pg. 38), instant claim 221 ([00142]), instant claim 222 (claim 38, [00219]), instant claim 223 (claim 38), instant claim 224 (claims 44-46), instant claim 225 (claims 49-50), instant claim 226 (claim 51), instant claims 232-234 (claims 76-78), instant claim 237 (claim 81), instant claim 238 (claim 83).
Information Disclosure Statement
The information disclosure statement filed August 29, 2025 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered.
Applicant has cited US Patent Application Numbers 18/051,815, 18/466, 636, 18/667,609, and 18/869,765 under the section of Non Patent Literature Documents (Cite No. 156-159) and explicitly stated “Copy not attached”. However, a legible copy is required for each cited pending unpublished U.S. application, the application specification including the claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion (see MPEP Appendix R – Patent Rules, 1.98 “Content of information disclosure statement”)
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete. The Sequence Listing, in ASCII text file is designated SCRB_030_01WO_SeqList_ST25.txt, received on May 23, 2023, and is 9208287 B, while the Sequence Listing disclosed in the specification’s incorporation by reference statement is SCRB_030_01WO_SeqList_ST25.txt, created on December 1, 2021 and is 8.78MB. The names of the ASCII text file do match, but the size does not. Further, the size of the ASCII text file must be identified in bytes.
Required response - Applicant must:
• Provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The use of the term Zymoclean ([0683]), Gibson assembly ([0683]), Lipofectamine ([0708]), Miseq ([0747]), 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. Please review the specification for recited trademarks in additional paragraphs, as well as additional trademarks, and correction is required.
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 Objections
Claims 210, 217, and 221 are objected to because of the following informalities:
Claim 210, line 1, recites “the gRNA” but the claim from which it depends recites “the gRNA variant” in line 2. It is recommended to amend claim 210 to recite “the gRNA variant” for consistency.
In claim 217, line 3, the acronym “GATA1” indicates that it is defining the term “GATA1 erythroid-specific enhancer binding site”; however, in claim 217, line 4, the recitation of “GATA1 binding site” makes it unclear whether it is referring to the acronym or GATA1 transcriptional factor. It is recommended to amend claim 217 as follows: “an enhancer regulatory element selected from a GATA1 erythroid-specific enhancer (GATA1) binding site of the BCL11A gene and a sequence 5’ to the GATA1 binding site of the BCL11A gene” so that the acronym is defining the enhancer.
Claim 221, line 1, recites “wherein targeting sequence”. An article “the” is missing preceding the term “targeting sequence”.
Appropriate correction is required.
Claim Interpretation
Regarding claim 218, the recitation of “wherein the targeting sequence of the gRNA variant comprises a sequence having at least 90%.... identity to a sequence selected from…SEQ ID NO: 22” encompass nucleotide sequences that comprise at least 90% sequence identity to the full-length sequence of SEQ ID NO: 22 or at least 90% sequence identity to any portion of SEQ ID NO: 22. This claim limitation is anticipated by any two or more nucleotide sequences comprising at least 90% sequence identity to SEQ ID NO: 22.
Regarding claim 219, the recitation of “wherein the gRNA variant has a scaffold comprising a sequence…consisting of SEQ ID NO: 2238” encompass nucleotide sequences that comprise the full-length of SEQ ID NO: 2238 or any portion of SEQ ID NO: 2238. This claim limitation is anticipated by any nucleotide sequences comprising two or more nucleotides of SEQ ID NO: 2238.
Further, the recitation of “a sequence having at least about 70%...sequence identity thereto” encompasses nucleotide sequences that comprise at least about 70% sequence identity with the full-length of SEQ ID NO: 2238 or at least about 70% sequence identity with any portion of SEQ ID NO: 2238. This claim limitation is anticipated by two or more nucleotide sequences that share at least about 70% sequence identity to SEQ ID NO: 2238.
Regarding claims 222 and 223, the recitation of “wherein the CasX variant protein comprises a sequence of SEQ ID NO: 133” encompass amino acid sequences that comprise the full-length sequence of SEQ ID NO: 133 or any portion of SEQ ID NO: 133. This claim limitation is anticipated by any amino acid sequences comprising two or more amino acids of SEQ ID NO: 133.
Further, the recitation in claim 222 “a sequence having at least about 70%...sequence identity thereto” encompasses amino acid sequences that comprise at least about 70% identity with the full-length of SEQ ID NO: 133 or at least about 70% sequence identity with any portion of SEQ ID NO: 133. This claim limitation is anticipated by two or more amino acid sequences that share at least about 70% sequence identity to SEQ ID NO: 133.
In contrast, in claim 220 the recitation of “wherein the gRNA variant has a scaffold comprising the sequence of SEQ ID NO: 2238 encompass only sequences that comprise the full-length of SEQ ID NO: 2238. For example, if claims were amended to recite “wherein the CasX variant protein comprising the sequence of SEQ ID NO: 133, or the sequence having at least about 70%...sequence identity thereto”, the Examiner would interpret the claims to encompasss only sequences that comprise the full-length of the specified SEQ ID NO. or sequences having at least about 70% sequence identity with the full-length of the specific sequence, with or without additional amino acids at either or both ends.
In the interest of compact prosecution, the Examiner is interpreting claim 218 as “wherein the targeting sequence of the gRNA variant comprises the sequence having at least 90%...sequence identity to SEQ ID NO: 22”, claim 219 as “wherein the gNRA variant has a scaffold comprising the sequence of SEQ ID NO: 2238, or the sequence having at least about 70%...sequence identity thereto”, claim 222 and 223 as “wherein the CasX variant protein comprises the sequence of SEQ ID NO: 133, or the sequence having at least about 70%...sequence identity thereto”. This interpretation is supported by claim 220 and working examples disclosed in the specification ([0683]-[0754]). If Applicant agrees with the Examiner’s interpretation, appropriate amendment is recommended.
Improper Markush
Claims 219, 222, 223 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of claim 219, “a scaffold comprising a sequence selected from the group consisting of SEQ ID NOs: 2238-2285, 26794-26839, and 27219-27265, or a sequence having at least about 70%...sequence identity thereto” is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the recited scaffold sequences are distinct sequences with different modifications relative to SEQ ID NO: 5 ([0118]). The elected sequence SEQ ID NO: 2238 is referred to as guide 174 in the specification ([0119]). For example, “Guide 174 showed substantial improvement in the cleavage rate of the resulting RNP (~2.5-fold relative to 2, see FIG. 6), while guides 32 and 64 performed similar to or worse than guide 2.” ([0724]). The specification teaches that “different variants result in improvements of distinct characteristics” ([0725]). Thus, the scaffold sequences do not share a common use that flows from a substantial structural feature.
The Markush grouping of claim 222, “CasX variant protein comprises a sequence selected from the group consisting of SEQ ID NOS: 59, 72-99, 101-148, and 26908-27154, or a sequence having at least about 70%...sequence identity thereto” is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: each CasX variant has a different primary amino acid sequence (Tables 4 and 6). Table 4 is silent in the description of numerous CasX variants. The elected sequence SEQ ID NO: 133 is referred to as CasX variant 515 in the specification ([0028]). For example, “RNPs of 515.174 and 526.174 had competent fractions of 76% and 91%, respectively, as compared to 16% for 2.2 (FIG. 8, Table 13)” ([0728]). Further, Table 13 discloses CasX variant 491 displayed competent fractions of 5%, 11%, and 83% as compared to 2.2, depending on the guide sequence used. These data demonstrate that different CasX sequences result in different activities. Further, the specification teaches that the variants exhibit one or more improved characteristics relative to the reference CasX proteins of SEQ ID NOS: 1-3 ([0011]) or a naturally-occurring reference CasX protein ([0141]), where the improved characteristics may be different, such as different binding affinity for a protospacer adjacent motif ([0011]), improved folding of the variant, improved binding affinity to the gRNA, improved binding affinity to the target nucleic acid, improved ability to utilize a greater spectrum of PAM sequences in the editing and/or binding of target DNA, improved unwinding of the target DNA, increased editing activity, improved editing efficiency, etc. (p0149]). Thus, the different sequences result in different activities, and the CasX variants do not share a common use that flows from a substantial structural feature.
The Markush grouping in claim 223, “CasX variant protein comprises a sequence selected from the group consisting of SEQ ID NOS: 126, 133, 27043, 27046, and 27050” is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: as discussed above as applied to the Markush grouping of claim 222, SEQ ID NO: 133 referred to as variant 515, and SEQ ID NO: 126 referred to as variant 491, exhibit different activities and structures. Thus, the CasX variants in the recited Markush group do not share a common use that flows from a substantial structural feature.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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 209, 211-212, 219-226, 232-234, and 237-238 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 209 recites “wherein the gRNA variant comprises a targeting sequence complementary to a target nucleic acid sequence comprising a BCL11A” which renders the determination of the scope of the claim difficult. It is unclear what the target nucleic acid comprises. It is unclear whether the target nucleic acid comprises a BCL11A gene, a BCL11A protein, a region of non-coding sequences of a BCL11A gene, a BCL11A exon, a BCL11A intron, a promoter driving expression of a BCL11A protein, etc. In the interest of compact prosecution, claim 209 will be interpreted that that “a BCL11A” is referring to “a BCL11A gene”, as described in the specification ([0009], [0552]), and claim 211 that recites “wherein the BCL11 gene”. However, an appropriate amendment is required.
Claims 210, and 216-218 dependent of claim 209, remedy the indefiniteness therein with the recitation wherein the targeting sequence is complementary to a BCL11A intron, a BCL11A exon, a BCL11A intron-exon junction, a BCL11A regulatory element, and an intergenic region.
Those claims included in the statement of rejection but not otherwise discussed are rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 232 and 233 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 232 is drawn to a nucleic acid comprising a sequence encoding the CasX variant of claim 209. However, claim 232 fails to include all of the limitations of claim 209 from which it depends, including the requirement for CasX protein, as opposed to only a sequence encoding for it, and the gRNA variant.
Claim 233 is drawn to a nucleic acid comprising a sequence encoding the gRNA variant of claim 209. However, claim 233 fails to include all of the limitations of claim 209 from which it depends, including the requirement for CasX protein and gRNA variant itself, not only a sequence encoding for it.
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 209-212, 216-217, 219. 221-226, 232-234, and 237-238 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.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. Claim 209 is drawn to a system comprising a CasX variant protein and a guide ribonucleic acid (gRNA) variant. The breadth of the claims is drawn to possession of (1) a genus of any CasX variant protein that is capable of binding with a gRNA ([0094]), and (2) a genus of any gRNA variants comprising a targeting sequence complementary to a target nucleic acid sequence comprising a BCL11A gene, and a “protein-binding segment” also referred to as a “scaffold” ([0100]).
Regarding genus (1), dependent claim 222 narrows the breadth of the claim to possession of a genus of CasX variant protein of elected sequence SEQ ID NO: 133, or a sequence having at least about 70%...80%...99% sequence identity thereto. SEQ ID NO: 133 consists of 978 amino acids and the claimed minimum sequence identity threshold allows variation up to 293 amino acids (30% of 978 is 293) while satisfying the requirement of at least 70% sequence identity to SEQ ID NO: 133. Therefore, the claimed genus (1) encompasses an enormous number of species comprising up to 293 amino acid substitutions, insertions, and deletions, while maintaining the required functional characteristics.
The specification discloses SEQ ID NO: 133, refers to as CasX variant 515, in complex with elected gRNA scaffold sequence SEQ ID NO: 2238 refers to as guide 174 demonstrated nearly two orders of magnitude higher than reference CasX 2.2 (Table 13) and that “the modifications made to the protein and guide have resulted in RNPs that are more stable, more likely to form active particles, and cut DNA much more efficiently on a per-particle basis as well” ([0728]). Thus, the specification discloses actual reduction to practice and complete structure of one specie, which is 100% sequence identity to SEQ ID NO: 133 that meets the disclosed correlation between function and structure requirement.
The specification further discloses “the CasX variant comprises at least one modification in the NTSB domain…in the TSL domain…in the helical I domain…in the helical II domain…in the RuvC DNA cleavage domain… in the OBD domain” ([0151]), and the CasX variant protein comprises at least one modification in at least 1 to at least each of 5 domains ([0152]). The specification also discloses CasX variants comprising combinations of amino acid substitutions and deletions relative to naturally occurring CasX protein, SEQ ID NO: 2 (Table 4).
The specification is silent on the description of SEQ ID NO: 133, for instance, how does the structure of each modification affect CasX variant protein’s function, binding to gRNA scaffold, to target nucleic acid, to protein folding, and etc. The mentioned disclosures do not constitute a representative number of species across the claimed genus, and there is no guidance regarding which substitutions, insertions, and/or deletions may be accumulated relative to SEQ ID NO: 133, or whether particular combinations would preserve the claimed function. Therefore, the specification does not provide sufficient disclosure of what the complete structure would be of any CasX variant protein comprising at least 70% sequence identity to SEQ ID NO: 133.
The state of the art teaches functions associated in each domain of the CasX protein, but the state of the art on generating CasX variant proteins is underdeveloped. For instance, Liu et al (CasX enzymes comprise a distinct family of RNA-guided genome editors; Nature, 2019, 566: 218-223) discloses a series of cryo-EM structures of CasX in different states to uncover targeting and cleavage mechanisms (pg. 220, col. 2, para. 1). Specifically, two domains are critical for DNA cleavage: the target-strand loading domain adjacent to the target strand DNA is located at the corresponding position of the Nuc domain of Cas12 and involved in DNA strand separation; and the non-target-strand binding domain moves towards and interacts with non-target strand DNA upon DNA binding (paragraph bridging pg. 220 and 221; pg. 222, col. 2, para. 1). Although specific domains involved in DNA targeting and cleavage is disclosed in prior art, predictability on generating CasX variant proteins remains unknown and Liu et al also discloses that “although CasX contains additional structural elements that appear analogous to those identified in other Cas proteins (including the helical I and helical II domains, and the REC1 and REC2 domains), these domains have highly distinct folds” (pg. 220, col. 2, para. 1). Therefore, one could not look to similar CRISPR systems to gauge the predictability of the invention.
Further, dependent claims of claims 210-212, 216-217, 219. 221-226, 232-234, and 237-238 are also rejected for depending from a rejected claim and failing to remedy the lack of written description therein. On the other hand, dependent claim 223 recites a CasX variant protein comprising 100% sequence identity to SEQ ID NO: 133 remedies the lack of written description therein as discussed above that the specification provides the complete structure of SEQ ID NO: 133 and actual reduction to practice this CasX variant protein with gRNA variant SEQ ID NO: 2238.
Regarding genus (2), dependent claim 220 narrows the breadth of the claim to possession of a genus of gRNA variants comprising scaffold sequence of elected sequence SEQ ID NO: 2238, or a sequence having at least about 70%...80%...99% sequence identity thereto. SEQ ID NO: 2238 consists of 89 nucleotides and the claimed minimum sequence identity threshold allows variation up to 27 nucleotides (30% of 89 is 27) while satisfying the requirement of at least 70% sequence identity to SEQ ID NO: 2238. Therefore, the claimed genus (2) encompasses an enormous number of species comprising up to 27 nucleotides substitutions, insertions, and deletions, while maintaining the required functional characteristics of able to bind to CasX protein ([0100]).
The specification discloses complete structure and actual reduction to practice of one specie comprising 100% sequence identity of SEQ ID NO: 2238 ([0728], [0738]).
The specification discloses gRNA variants comprise scaffolds relative to SEQ ID NO: 5, “a C18G substitution, a G55 insertion, a U1 deletion, and a modified extended stem loop in which the original 6 nt loop and 13 most-loop-proximal base pairs (32 nucleotides total) are replaced by a Uvsx hairpin (4 nt loop and 5 loop-proximal base pairs; 14 nucleotides total) and the loop-distal base of the extended stem was converted to a fully base-paired stem contiguous with the new Uvsx hairpin by deletion of the A99 and substitution of G64U.” ([0118]). Further, Table 3 teaches numerous gRNA variants comprising a variety of different modifications in the scaffold. However, no specific modification is detailed in the scaffold of SEQ ID NO: 2238. The specification is silent on the design and rationale for the design of SEQ ID NO: 2238. Thus, the mentioned disclosures do not constitute a representative number of species across the claimed genus, and there is no guidance regarding which substitutions, insertions, and/or deletions may be accumulated relative to SEQ ID NO: 2238, or whether particular combinations would preserve the claimed function. Therefore, the specification does not provide sufficient disclosure of what the complete structure would be of any gRNA variant comprising a scaffold of least 70% sequence identity to SEQ ID NO: 2238.
The state of the art, Liu et al teaches the gRNA scaffold “comprises three elements, a triple stem-loop that contacts the OBD domain, a “scaffold” stem that interacts with the helical II domain and a perpendicular stem-loop that projects away from the centre of mass of the structure” (pg. 221, col. 2, para. 2). Liu et al further teaches “alterations to the triplex or the scaffold stem diminished CasX activity in vivo, whereas truncated versions of the perpendicular stem-loop retained activity”. Thus, the state of the art teaches the triplex or scaffold stem is crucial for CasX activity whereas the perpendicular stem-loop can tolerate truncations. However, these teachings do not provide sufficient written description support on generating gRNA variants with substitutions, insertions, and/or deletions in the scaffold that is at least 70% sequence identity to SEQ ID NO: 2238. Further, one could not look to similar CRISPR systems to gauge the predictability of the invention as Liu et al teaches that structural modeling of CasX-sgRNA binary complex revealed that the gRNA accounts for about 26% of the mass which is a value greater than those observed in other type II or type V CRISPR-Cas effector complexes (pg. 221, col. 2, para. 2).
Further, dependent claims of claims 210-212, 216-217, 219. 221-226, 232-234, and 237-238 are also rejected for depending from a rejected claim and failing to remedy the lack of written description therein. On the other hand, dependent claim 220 recites a gRNA comprising a scaffold of 100% sequence identity to SEQ ID NO: 2238 remedies the lack of written description therein as discussed above that the specification provides the complete structure and actual reduction to practice of gRNA variant SEQ ID NO: 2238.
Based on the preponderance of the evidence, including the relevant teachings of the specification, the absence of working examples, and the state of prior art including the knowledge of CasX variant proteins and gRNA variant scaffold, one skilled in the art would conclude that Applicant was not in possession of the claimed genus (1) and (2).
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 209-212, 216-222, 224-226, and 232-234, and 237-238 are rejected under 35 U.S.C. 103 as being unpatentable over Oakes et al (US 2023/0081117 A1; Published Date: March 16, 2023; PCT Filed Date: Sept 09, 2020) in view of Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017).
Regarding claims 209, 219-220, 222, Oakes et al teach a system comprising a CasX variant protein of SEQ ID NO: 138 that is 99.7% identical to instant SEQ ID NO: 133 (see a portion of the alignment result reproduced below highlighting the residue mutation), and a gRNA variant comprising a scaffold sequence of SEQ ID NO: 2238 that is 100% identical to instant SEQ ID NO: 2238 (see sequence alignment below). Oakes et al refers the gRNA variant of SEQ ID NO: 2238 as “gNA variant guide 174” ([0147]).
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However, Oakes et al teach the gRNA variant comprises a targeting sequence complementary to a target nucleic acid sequence encoding a protein involved in antigen processing, antigen presentation, antigen recognition, and/or antigen response and/or its regulatory region ([0458]). Oakes et al does not teach the target nucleic acid sequence comprises a B-cell lymphoma/leukemia 11A (BCL11A) gene.
Boitano et al teach a system comprising a CRISPR Cas9 protein and a gRNA that comprising a targeting domain (i.e., targeting sequence) complementary to a target nucleic acid sequence comprising a BCL11A gene, specifically, the +58 enhance region of the BCL11A gene which is disposed 3’ to the GATA-1 binding site (pg. 188, lines 26-28; pg. 1, lines 19-30). Further, Boitano et al teach wherein the targeting sequence is SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see full sequence alignment reproduced below). Boitano et al also teach the system targets BCL11A gene in a cell to increase fetal hemoglobin expression and/or decrease expression of beta globin, especially beta globin that has a disease-causing mutation, so that the modified cell can be used to treat hemoglobinopathies including sickle cell disease and beta thalassemia (pg. 1, lines 19-23).
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Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the targeting sequence in the gRNA variant of Oakes et al to the targeting sequence complementary to a BCL11A gene taught by Boitano et al because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. The substituted component (targeting sequences) and its function (complementary to a specific genomic site and facilitate the gRNA-bound protein, e.g., CRISPR CasX or Cas9, to be located at the same genomic site for gene editing) were known in the art. One would have been motivated to have done so for the advantage of modulating expression of BCL11A as therapeutic target for hemoglobinopathies taught by Boitano et al. One would have had a reasonable expectation of success in doing so because Boitano et al teach a system also comprising a CRISPR Cas protein and a gRNA with targeting sequence complementary to a BCL11A gene.
Regarding claim 212, Oakes et al teach wherein the gRNA variant is a single molecule RNA ([0120]).
Regarding claim 221, Oakes et al teach wherein the targeting sequence is linked to the 3’ end of the scaffold of the gRNA variant ([0121]).
Regarding claim 224, Oakes et al teach wherein the CasX variant protein further comprises one or more nuclear localization signals (NLS), specifically the NLS of the SV40 virus large T-antigen having the amino acid sequence PKKKRKV, which is instant SEQ ID NO: 168 ([0354], [0355]).
Regarding claims 225 and 226, Oakes et al teach the CasX variant protein is capable of forming a ribonuclear protein complex with the gRNA variant ([0108]) and they exhibit an improved cleavage rate relative to the wild-type CasX2 of SEQ ID NO: 2, which is identical to instant reference CasX protein of SEQ ID NO: 2 ([0576], [0539]) (a portion of sequence alignment is reproduced below) and gRNA guide of SEQ ID NO: 5 that is identical to instant reference gRNA of SEQ ID NO: 5 (full sequence alignment is reproduced below). Further, as the CasX variant protein and the gRNA variant sequences of Oakes et al fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved cleavage rate of at least 1.1-fold required in instant claims as inherent properties.
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Regarding claims 232 and 233, Oakes et al teach nucleic acids comprising a sequence enoding the CasX variant protein and the gRNA variant ([0361])
Regarding claim 234, Oakes et al teach the sequence that encodes the CasX variant is codon optimized for expression in a eukaryotic cell ([0284]).
Regarding claims 237 and 238, Oakes et al teach an adeno-associated viral vector, including AAVl, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAVS, AAV9, AAV 10, AAV-Rh74 (Rhesus macaque-derived AAV), and AAVRhl0, comprising the CasX variant protein and the gRNA variant ([0399], [0400], [0402]).
Claim 223 is rejected under 35 U.S.C. 103 as being unpatentable over Oakes et al (US 2023/0081117 A1; Published Date: March 16, 2023; PCT Filed Date: Sept 09, 2020) in view of Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017) as applied to claim 222 above, and further in view of Doudna et al (US 2018/0346927 A1; Published Date: Dec 06, 2018).
Regarding claim 223, Oakes et al teach a Cas variant of SEQ ID NO: 138 that is 99.7% identical to instant SEQ ID NO: 133 (see sequence alignment above as applied in claim 209). Additional teachings of Oakes et al are discussed above as applied to claim 209. Further, Oakes et al teach position 793 in CasX variant proteins is a permissive modification site in which substitutions or deletions are tolerated ([0249], [0255])). For instance, multiple alternative amino acid substitutions are possible at this position, including P793S, P793Q, and P793G ([0249], [0255]).
However, Oakes et al do not teach position 793 of SEQ ID NO: 138 comprises a proline residue.
Doudna et al teach a CasX protein comprising SEQ ID NO: 2 shares at least 93% sequence identity to instantly claimed CasX variant comprising SEQ ID NO: 133 (portions highlighting sequence mismatches and position 793 are reproduced below). Doudna et al further teach CasX proteins have critical structural domains, including RuvC-I, RuvC-II, RuvC-III, helical I, and helical II are located adjacent to each other (a portion of FIG. 3 is shown below), suggesting that residues in these domains are critical for CasX activity. Doudna et al also showed that proline at position 793 lies within the RuvC-II cleavage domain.
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Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified Oakes’ CasX variant protein comprising SEQ ID NO: 138 to restore or retain the proline residue at position 793 as taught by Doudna et al, because it would have merely amounted to applying a known technique to a known product ready for improvement to yield predictable results. Doudna et al teach wild-type CasX proteins detailing key amino acid residues in each domain responsible for the CasX protein’s activity, especially the proline at position 793 that is missing in CasX variant proteins of Oakes et al lies within the RuvCII domain. One of ordinary skill in the art would have applied the known molecular biology technique to incorporate or restore the deleted proline to obtain a CasX variant protein with a RuvCII cleavage domain comprising same sequence as the wild-type for its known activity. Further, this modification merely represents a finite number of predictable alternatives at a known permissive site, position 793, taught by Oakes et al. One would have had a reasonable expectation of success in doing so because Oakes et al already teach numerous CasX variant proteins sharing high sequence identity to instantly claimed SEQ ID NO: 133, a method of generating these CasX variant proteins, and Doudna et al teach the amino acid residues comprised in each critical domains of the CasX protein, especially proline at position 793 retains CasX activity.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8, 14, 15, 19, 23, and 25 of U.S. Patent No. 11,535,835 in view of Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). Although the claims at issue are not identical, they are not patentably distinct from each other because ‘835 teaches the instantly claimed CasX variant protein and gRNA variant scaffold sequences.
Regarding instant claims 209-211, 216-218, 222-223, 232-234, and 237-238, claims 1 and 19 of ‘835 recite a composition (i.e., system) comprising (i) a CasX variant protein comprising a sequence having at least 90% sequence identity to SEQ ID NO: 138, which is 99.7% identical to instantly claimed CasX variant protein of SEQ ID NO: 133 (the portion highlighting the difference between these two sequences is reproduced below), and (ii) a gRNA comprising a targeting sequence complementary to a rhodopsin gene target nucleic acid sequence. Accordingly, the full-length sequence of instantly claimed CasX variant protein comprising the sequence of SEQ ID NO: 133 is encompassed by the patented genus of CasX variant proteins.
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However, ‘835 does not teach wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
Boitano et al teach a system comprising a CRISPR Cas9 protein and a gRNA that comprising a targeting domain (i.e., targeting sequence) complementary to a target nucleic acid sequence comprising a BCL11A gene, specifically, the +58 enhance region of the BCL11A gene which is disposed 3’ to the GATA-1 binding site (pg. 188, lines 26-28; pg. 1, lines 19-30). Further, Boitano et al teach wherein the targeting sequence is SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see full sequence alignment reproduced below). Boitano et al also teach the system targets BCL11A gene in a cell to increase fetal hemoglobin expression and/or decrease expression of beta globin, especially beta globin that has a disease-causing mutation, so that the modified cell can be used to treat hemoglobinopathies including sickle cell disease and beta thalassemia (pg. 1, lines 19-23).
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Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the targeting sequence in the gRNA variant of ‘835 to the targeting sequence complementary to a BCL11A gene taught by Boitano et al because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. The substituted component (targeting sequences) and its function (complementary to a specific genomic site and facilitate the gRNA-bound protein, e.g., CRISPR CasX or Cas9, to be located at the same genomic site for gene editing) were known in the art. One would have been motivated to have done so for the advantage of modulating expression of BCL11A as therapeutic target for hemoglobinopathies taught by Boitano et al. One would have had a reasonable expectation of success in doing so because Boitano et al teach a system also comprising a CRISPR Cas protein and a gRNA with targeting sequence complementary to a BCL11A gene.
Regarding instant claim 212, ‘835 recites wherein the gRNA variant is a single-molecule RNA (claim 8).
Regarding instant claims 219-220, ‘835 teaches wherein the gRNA variant has a scaffold comprising a sequence of SEQ ID NO: 2238 that is identical to instant claimed SEQ ID NO: 2238 (see sequence alignment reproduced below) (claim 14).
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Regarding instant claim 221, ‘835 does not recite wherein the targeting sequence is linked to the 3’ end of the scaffold of the gRNA variant. The obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene is discussed above as applied to instant claim 209. Further, Boitano et al teach a targeting sequence of SEQ ID NO: 23 that is identical to instant targeting sequence of SEQ ID NO: 22 (claim 19), and this targeting sequence is disposed at the 3’ end (claim 20).
Regarding instant claim 224, ‘835 recites wherein the CasX variant protein comprises one or more nuclear localization signals (claim 15).
Regarding instant claims 225-226, the teachings of ‘835 regarding CasX variant protein of instant SEQ ID NO: 133 and gRNA variant of SEQ ID NO: 2238 are discussed above as applied to instant claims 209 and 219-220. ‘835 does not explicitly teach wherein instant CasX variant protein and gRNA variant are capable of forming a ribonuclear protein complex and exhibit an improved target nucleic acid sequence cleavage rate of at least about 1.1-fold relative to the reference CasX protein of SEQ ID NO: 2 (elected sequence) and gRNA sequence of SEQ ID NO: 5 (elected sequence). However, the claimed property is inherently possessed by the disclosed CasX variant protein and gRNA variant because identical protein and gRNA structures necessarily possess the same functional characteristics. Thus, any cleavage rate improvement relative to CasX protein of SEQ ID NO: 2 and gRNA sequence of SEQ ID NO: 5 exhibited by the claimed CasX variant protein and claimed gRNA variant would likewise be exhibited by the structurally identical protein and gRNA disclosed in ‘853, regardless of whether ‘853 expressly recognizes or discloses that property.
Regarding instant claims 232-233, and 237-238, ‘835 recites an AAV nucleic acid vector comprising sequences encoding the CasX variant protein and gRNA variant (claims 23 and 25). However, ‘835 does not specify the serotype of the AAV vector. Boitano et al teach nucleic acid vectors encoding the CasX and gRNA are delivered by a recombinant AAV vector selected from AAV4, AAV5, AAV6, AAV9, and AAV rh 10 (pg. 282, lines 15-24). Following the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene as taught by Boitano et al as discussed above as applied to instant claim 209, it would have also been obvious to choose a specific AAV vector serotype suggested by Boitano et al because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. One would have been motivated to have done so because Boitano et al has successfully demonstrated that the BCL11A gene can be targeted using CRISPR Cas protein and gRNA comprising instantly claimed targeting sequences via delivery into cells using these specific AAV serotypes.
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). Following the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene as taught by Boitano et al as discussed above as applied to instant claim 209, it would have also been obvious to modify the nucleic acid sequence encoding the CasX variant protein to be codon optimized for expression in a eukaryotic cell after delivery by an AAV vector as taught by Boitano et al because it would have merely amounted to use of known technique to improve similar products in the same way. The CRISPR Cas9 protein of Boitano et al is improved in the same way as the claimed invention, specifically by replacing at least one non-common codon or less common codon by a common codon (pg. 261, lines 31-34). Thus, one of ordinary skill in the art could have applied the same known “improvement” technique in the same way to the instantly claimed CasX variant protein to yield predictable results as demonstrated by Boitano et al that similar CRISPR Cas proteins can be codon optimized for expression in mammalian cells.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 25, and 27-28 of U.S. Patent No. 12,163,125 in view of Oakes et al (US 2023/0081117 A1; Published Date: March 16, 2023; PCT Filed Date: Sept 09, 2020) and Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). Although the claims at issue are not identical, they are not patentably distinct from each other because ‘125 teaches the instantly claimed CasX variant protein.
Regarding instant claim 209-211, 216-218, and 222-223, ‘125 recites a chimeric class 2, Type V CRISPR protein (i.e., CasX variant protein) comprising the sequence of SEQ ID NO: 416, or a sequence having at least 90% identity thereto (claims 25 and 28), which is 100% identical to instantly claimed CasX variant protein comprising the sequence of SEQ ID NO: 133 (see sequence alignment below).
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However, ‘125 does not recite a gRNA variant.
Oakes et al teach a system comprising a CasX variant protein of SEQ ID NO: 138 that is 99.7% identical to instant SEQ ID NO: 133 and a gRNA variant comprising a scaffold sequence of SEQ ID NO: 2238 that is 100% identical to instant SEQ ID NO: 2238 (see sequence alignment below). Oakes et al teach the CasX variant protein is capable of forming a ribonuclear protein complex with the gRNA variant ([0108]) and they exhibit an improved cleavage rate relative to the wild-type CasX2 of SEQ ID NO: 2, which is identical to instant reference CasX protein of SEQ ID NO: 2 ([0576], [0539]) and gRNA guide of SEQ ID NO: 5 that is identical to instant reference gRNA of SEQ ID NO: 5 (see sequence alignments provided above in 35 USC 103 rejection).
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Thus, it would have been obvious to one of ordinary skill in the art to have modified the CasX variant protein of ‘125 to comprise a gRNA variant as taught by Oakes et al because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. In this combination, each element merely performs the same function as it does separately (i.e., CasX variant protein and gRNA variant forms a ribonuclear protein complex, the gRNA variant comprising a targeting sequence then localize the CasX variant to a specific site to perform gene editing). One would have been motivated to have done so for the advantage of using the CasX variant protein in gene editing applications. One would have had a reasonable expectation of success in doing so because Oakes et al teach systems comprising both instantly claimed CasX variant proteins and gRNA variants.
However, ‘125 wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, the obviousness to modify the CasX variant protein of ‘125 to comprise a gRNA variant as taught by Oakes et al is discussed above as applied to instant claim 209. Further, Oakes et al teach wherein the gRNA variant is a single-molecule RNA (claim 24).
Regarding instant claims 219-220, the teachings of Oakes et al regarding a gRNA variant comprising a scaffold of instantly claimed SEQ ID NO: 2238, and the obviousness to modify the CasX variant protein of ‘125 to comprise a gRNA variant as taught by Oakes et al discussed above as applied to instant claim 209 equally applies here.
Regarding instant claim 221, the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene is discussed above as applied to instant claim 209. Further, Boitano et al teach a targeting sequence of SEQ ID NO: 23 that is identical to instant targeting sequence of SEQ ID NO: 22 (claim 19), and this targeting sequence is disposed at the 3’ end (claim 20).
Regarding instant claim 224, the obviousness to modify the CasX variant protein of ‘125 to comprise a gRNA variant as taught by Oakes et al is discussed above as applied to instant claim 209. Further, Oakes et al teach wherein the CasX variant protein further comprises one or more nuclear localization signal (NLS) (claim 36).
Regarding instant claims 225-226, ‘125 further recites wherein the CasX variant protein “exhibits improved characteristics compared to the reference protein of SEQ ID NO: 2 (claims 27-28), which is 100% identical to instantly recited reference CasX protein of SEQ ID NO: 2. Further, as the CasX variant protein of the patented claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, Boitano et al teach nucleic acid vectors encoding the CasX and gRNA are delivered by a recombinant AAV vector selected from AAV4, AAV5, AAV6, AAV9, and AAV rh 10 (pg. 282, lines 15-24). The obviousness to deliver the composition into the cell by AAV vectors as taught by Boitano et al is discussed above as applied to claims 232-233, and 237-238 in discussion regarding U.S. Patent No. 11,535,835.
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 13, 15, and 18 of U.S. Patent No. 11,976,277 in view of Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). Although the claims at issue are not identical, they are not patentably distinct from each other because ‘277 teaches the instantly claimed CasX variant protein and gRNA variant scaffold sequences.
Regarding instant claim 209-211, 216-218, and 222-223, ‘277 recites a system comprising nucleic acids encoding for a CasX CRISPR nuclease (i.e., a CasX variant protein) comprising the sequence of SEQ ID NO: 189, or a sequence having at least 90% sequence identity thereto (claims 1, 8, and 18), which shares 99.7% sequence identity with instantly claimed SEQ ID NO: 133 (a portion of sequence alignment is reproduced below). Accordingly, the full-length sequence of instantly claimed CasX variant protein comprising the sequence of SEQ ID NO: 133 is encompassed by the patented genus of CasX variant proteins. ‘277 also recites the composition comprises a CRISPR guide RNA (i.e., gRNA variant) comprising a scaffold sequence of SEQ ID NO: 2238, which is 100% identical to instantly claimed gRNA variant of SEQ ID NO: 2238 (claim 13) (see sequence alignment below).
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However, ‘277 does not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, ‘277 recites wherein the gRNA variant is a single-molecule RNA (claim 11).
Regarding instant claims 219-220, ‘277 recites wherein the gRNA variant has a scaffold comprising a sequence of SEQ ID NO: 2238 that is identical to instant claimed SEQ ID NO: 2238 (see sequence alignment reproduced below) (claim 13).
Regarding instant claim 221, the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene is discussed above as applied to instant claim 209. Further, Boitano et al teach a targeting sequence of SEQ ID NO: 23 that is identical to instant targeting sequence of SEQ ID NO: 22 (claim 19), and this targeting sequence is disposed at the 3’ end (claim 20).
Regarding instant claim 224, Boitano et al teach wherein the Cas protein comprises one or more SV40 nuclear localization signal (NLS) (pg. 426, lines 9-11; Table 5). Thus, following the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene as discussed above as applied to instant claim 209, it would have been also obvious to have modified the CasX variant protein of ‘277 to comprise one or more NLS as taught by Boitano et al because it would have merely amounted to a simple combination of prior art elements according to known method to yields predictable results. Each element in the combination merely performs the same function as it does separately. One would have been motivated to have done so for the advantage of delivering CasX variant protein into the nucleus for site-specific genome editing localized by gRNAs designed with specific targeting sequences. One would have had a reasonable expectation of success in doing so because Boitano et al demonstrate Cas proteins comprising instantly claimed NLS are successfully delivered into the nucleus of eukaryotic cells for genome editing of BCL11A gene (Table 35).
Regarding instant claims 225-226, ‘277 further recites wherein the gRNA is capable of forming a RNP complex with the CasX variant protein (claim 15). As the CasX variant protein and the gRNA variant sequences of the patented claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, Boitano et al teach nucleic acid vectors encoding the CasX and gRNA are delivered by a recombinant AAV vector selected from AAV4, AAV5, AAV6, AAV9, and AAV rh 10 (pg. 282, lines 15-24). The obviousness to deliver the composition into the cell by specific AAV serotypes as taught by Boitano et al is discussed above as applied to claims 232-233, and 237-238 in discussion regarding U.S. Patent No. 11,535,835.
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 25 of U.S. Patent No. 11,560,555 in view of Oakes et al (US 2023/0081117 A1; Published Date: March 16, 2023; PCT Filed Date: Sept 09, 2020) and Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). Although the claims at issue are not identical, they are not patentably distinct from each other because ‘555 teaches the instantly claimed CasX variant protein.
Regarding instant claim 209-211, 216-218, and 222-223, ‘555 recites an engineered protein (i.e., CasX variant protein) comprising the sequence of SEQ ID NO: 3548, or a sequence having at least 70% sequence identity thereto (claim 25), which shares 99.7% sequence identity with instantly claimed SEQ ID NO: 133 (a portion of sequence alignment is reproduced below). Accordingly, the full-length sequence of instantly claimed CasX variant protein comprising the sequence of SEQ ID NO: 133 is encompassed by the patented genus of CasX variant proteins.
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However, ‘555 does not recite a gRNA variant.
The teachings of Oakes et al and the obviousness to modify the CasX variant protein to comprise a gRNA variant is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 12,163,125.
However, ‘555 does not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, the obviousness to modify the CasX variant protein of ‘555 to comprise a gRNA variant as taught by Oakes et al is discussed above as applied to instant claim 209. Further, Oakes et al teach wherein the gRNA variant is a single-molecule RNA (claim 24).
Regarding instant claims 219-220, the teachings of Oakes et al regarding a gRNA variant comprising a scaffold of instantly claimed SEQ ID NO: 2238, and the obviousness to modify the CasX variant protein of ‘555 to comprise a gRNA variant as taught by Oakes et al discussed above as applied to instant claim 209 equally applies here.
Regarding instant claim 221, the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene is discussed above as applied to instant claim 209. Further, Boitano et al teach a targeting sequence of SEQ ID NO: 23 that is identical to instant targeting sequence of SEQ ID NO: 22 (claim 19), and this targeting sequence is disposed at the 3’ end (claim 20).
Regarding instant claim 224, the obviousness to modify the CasX variant protein of ‘555 to comprise a gRNA variant as taught by Oakes et al is discussed above as applied to instant claim 209. Further, Oakes et al teach wherein the CasX variant protein further comprises one or more nuclear localization signal (NLS) (claim 36).
Regarding instant claims 225-226, as the CasX variant protein of the patented claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, Boitano et al teach nucleic acid vectors encoding the CasX and gRNA are delivered by a recombinant AAV vector selected from AAV4, AAV5, AAV6, AAV9, and AAV rh 10 (pg. 282, lines 15-24). The obviousness to deliver the composition into the cell by AAV vectors as taught by Boitano et al is discussed above as applied to claims 232-233, and 237-238 in discussion regarding U.S. Patent No. 11,535,835.
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 8, 13, 14, 18, 22, 24, and 25 of U.S. Patent No. 11,613,742 in view of and Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). Although the claims at issue are not identical, they are not patentably distinct from each other because ‘742 teaches the instantly claimed CasX variant protein and gRNA variant.
Regarding instant claim 209-211, 216-218, and 222-223, ‘742 recites a composition comprising nucleic acids encoding for a CasX CRISPR nuclease (i.e., a CasX variant protein) comprising the sequence of SEQ ID NO: 126, or a sequence having at least 90% sequence identity thereto (claims 1, 8, and 25), which shares 99.7% sequence identity with instantly claimed SEQ ID NO: 133 (a portion of sequence alignment is reproduced below). Accordingly, the full-length sequence of instantly claimed CasX variant protein comprising the sequence of SEQ ID NO: 133 is encompassed by the patented genus of CasX variant proteins. ‘742 further recite a gRNA comprising a targeting sequence complementary to a superoxide dismutase 1 gene (claim 18).
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However, ‘742 does not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, ‘742 recites wherein the gRNA variant is a single-molecule RNA (claim 8).
Regarding instant claims 219-220, ‘742 recites wherein the gRNA variant has a scaffold comprising a sequence of SEQ ID NO: 2238 that is identical to instant claimed SEQ ID NO: 2238 (see sequence alignment reproduced below) (claims 13, 18, and 25).
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Regarding instant claim 221, the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene is discussed above as applied to instant claim 209. Further, Boitano et al teach a targeting sequence of SEQ ID NO: 23 that is identical to instant targeting sequence of SEQ ID NO: 22 (claim 19), and this targeting sequence is disposed at the 3’ end (claim 20).
Regarding instant claim 224, ‘742 recite wherein the Cas protein comprises one or more SV40 nuclear localization signal (NLS) (claim 14). The obviousness to add a NLS to Cas protein as taught by Boitano et al is discussed above as applied to claim 224 in discussion regarding U.S. Patent No. 11,976,277.
Regarding instant claims 225-226, as the CasX variant protein and the gRNA variant sequences of the patented claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, ‘742 recites an AAV nucleic acid vector comprising sequences encoding the CasX variant protein and gRNA variant (claims 22 and 24). Boitano et al teach nucleic acid vectors encoding the CasX and gRNA are delivered by a recombinant AAV vector selected from AAV4, AAV5, AAV6, AAV9, and AAV rh 10 (pg. 282, lines 15-24). The obviousness to deliver the composition into the cell by specific AAV serotypes as taught by Boitano et al is discussed above as applied to claims 232-233, and 237-238 in discussion regarding U.S. Patent No. 11,535,835.
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 6, 7, 9, 10, 13, and 14 of U.S. Patent No. 12,551,560 in view of and Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). Although the claims at issue are not identical, they are not patentably distinct from each other because ‘560 teaches the instantly claimed CasX variant protein and gRNA variant.
Regarding instant claim 209-211, 216-218, and 222-223, ‘560 recites a composition comprising nucleic acids encoding for a CasX CRISPR nuclease (i.e., a CasX variant protein) comprising the sequence of SEQ ID NO: 138, or a sequence having at least 90% sequence identity thereto (claim 7), which shares 99.7% sequence identity with instantly claimed SEQ ID NO: 133 (a portion of sequence alignment is reproduced below). Accordingly, the full-length sequence of instantly claimed CasX variant protein comprising the sequence of SEQ ID NO: 133 is encompassed by the patented genus of CasX variant proteins. ‘560 further recite a gRNA comprising a targeting sequence complementary to a gene encoding a first protein involved in antigen processing (claims 1 and 6).
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However, ‘560 does not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, ‘560 recites wherein the gRNA variant is a guide RNA (claim 1). However, ‘560 does not explicitly recite the gRNA variant is a single-molecule RNA. Boitano et al teach the gRNA molecule consists of a single contiguous polynucleotide molecule (i.e., single-molecule RNA) (pg. 46, lines 21-22). The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Following this obviousness, it would have also been obvious to modify the gRNA variant of ‘560 to be a single-molecule RNA as taught by Boitano et al because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. One would have been motivated to have done so for the advantage of ensuring the gRNA scaffold and targeting sequences are expressed together as one single molecule and co-localized in the nucleus for targeted genome editing. One would have had a reasonable expectation of success in doing so because Boitano et al demonstrate successful genome editing of BCL11A gene using Cas protein and single-molecule gRNA.
Regarding instant claims 219-220, ‘560 recites wherein the gRNA variant has a scaffold comprising a sequence of SEQ ID NO: 2238 that is identical to instant claimed SEQ ID NO: 2238 (see sequence alignment reproduced below) (claim 1).
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Regarding instant claim 221, the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene is discussed above as applied to instant claim 209. Further, Boitano et al teach a targeting sequence of SEQ ID NO: 23 that is identical to instant targeting sequence of SEQ ID NO: 22 (claim 19), and this targeting sequence is disposed at the 3’ end (claim 20).
Regarding instant claim 224, ‘560 recite wherein the Cas protein comprises one or more SV40 nuclear localization signal (NLS) (claim 9). The obviousness to add a NLS to Cas protein as taught by Boitano et al is discussed above as applied to claim 224 in discussion regarding U.S. Patent No. 11,976,277.
Regarding instant claims 225-226, as the CasX variant protein and the gRNA variant sequences of the patented claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, ‘560 recites an AAV nucleic acid vector comprising sequences encoding the CasX variant protein and gRNA variant (claims 13 and 14). Boitano et al teach nucleic acid vectors encoding the CasX and gRNA are delivered by a recombinant AAV vector selected from AAV4, AAV5, AAV6, AAV9, and AAV rh 10 (pg. 282, lines 15-24). The obviousness to deliver the composition into the cell by specific AAV serotypes as taught by Boitano et al is discussed above as applied to claims 232-233, and 237-238 in discussion regarding U.S. Patent No. 11,535,835.
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 14, 15, 17, 18, and 23 of U.S. Patent No. 12,084,692 in view of Oakes et al (US 2023/0081117 A1; Published Date: March 16, 2023; PCT Filed Date: Sept 09, 2020), Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017), and Doudna et al (US 2018/0346927 A1; Published Date: Dec 06, 2018). Although the claims at issue are not identical, they are not patentably distinct from each other because ‘692 teaches the instantly claimed gRNA variant.
Regarding instant claim 209-211, 216-218, and 222-223, ‘692 recites a gRNA variant capable of binding to an engineered protein comprising a RuvC cleavage domain of SEQ ID NO: 2, and comprises a targeting sequence that is complementary to a target DNA sequence (claim 14).
However, ‘692 recites a RuvC cleavage domain that is also required in instantly claimed CasX variant protein, but ‘692 does not explicitly recite a CasX variant protein.
Doudna et al teach a CasX protein comprising SEQ ID NO: 2 shares at least 93% sequence identity to instantly claimed CasX variant comprising SEQ ID NO: 133 (a portion of the sequence alignment is reproduced below), and shares 100% sequence identity to SEQ ID NO: 2 of ‘692. Doudna et al further teach CasX proteins have critical structural domains, including RuvC-I, RuvC-II, RuvC-III, helical I, and helical II are located adjacent to each other (a portion of FIG. 3 is shown below), suggesting that residues in these domains are critical for CasX activity. Doudna et al also showed that proline at position 793 lies within the RuvC-II cleavage domain. Further, Doudna et al teach single-molecule RNAs (i.e., sgRNA) capable of forming ribonucleoprotein complexes with CasX proteins for genome editing (FIG. 27; [0152]).
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Thus, it would have been obvious to have modified the gRNA variant of ‘692 to include a CasX variant protein as taught by Doudna because it would have merely amounted to a simple substitution of prior art elements according to known method to yield predictable results. This modification is merely swapping similar CasX proteins that serve the same purpose. One would have been motivated to have done so for the advantage of using the composition for genome editing as demonstrated by Doudna. One would have had a reasonable expectation of success in doing so because Doudna teach a CasX protein of SEQ ID NO: 2 that is 100% identical to SEQ ID NO: 2 of ‘692, which the gRNA variant is capable of binding to its RuvC cleavage domain.
However, ‘692 does not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, ‘692 recites wherein the gRNA variant is a single guide RNA (claim 15).
Regarding instant claims 219-220, ‘692 recites wherein the gRNA variant has a scaffold comprising a sequence of SEQ ID NO: 2238 that is identical to instant claimed SEQ ID NO: 2238 (see sequence alignment reproduced below) (claims 17 and 18).
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Regarding instant claim 221, the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene is discussed above as applied to instant claim 209. Further, Boitano et al teach a targeting sequence of SEQ ID NO: 23 that is identical to instant targeting sequence of SEQ ID NO: 22 (claim 19), and this targeting sequence is disposed at the 3’ end (claim 20).
Regarding instant claim 223, the obviousness to substitute the CasX variant of ‘692 with the CasX variant protein of Doudna is discussed above as applied to claim 209. However, neither ‘692 or Doudna teach a CasX variant that shares 100% sequence identity to instantly claimed SEQ ID NO: 133.
Oakes et al teach a system comprising a CasX variant protein of SEQ ID NO: 138 that is 99.7% identical to instant SEQ ID NO: 133 (see a portion of the alignment result reproduced below highlighting the residue mutation), and a gRNA variant comprising a scaffold sequence of SEQ ID NO: 2238 that is 100% identical to instant SEQ ID NO: 2238. However, Oakes et al do not teach position 793 of SEQ ID NO: 138 comprises a proline residue.
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Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified Oakes’ CasX variant protein comprising SEQ ID NO: 138 to restore or retain the proline residue at position 793 as taught by Doudna et al, because it would have merely amounted to applying a known technique to a known product ready for improvement to yield predictable results. Doudna et al teach wild-type CasX proteins detailing key amino acid residues in each domain responsible for the CasX protein’s activity, especially the proline at position 793 that is missing in CasX variant proteins of Oakes et al lies within the RuvCII domain. One of ordinary skill in the art would have applied the known molecular biology technique to incorporate or restore the deleted proline to obtain a CasX variant protein with a RuvCII cleavage domain comprising same sequence as the wild-type for its known activity. Further, this modification merely represents a finite number of predictable alternatives at a known permissive site, position 793, taught by Oakes et al. One would have had a reasonable expectation of success in doing so because Oakes et al already teach numerous CasX variant proteins sharing high sequence identity to instantly claimed SEQ ID NO: 133, a method of generating these CasX variant proteins, and Doudna et al teach the amino acid residues comprised in each critical domains of the CasX protein, especially proline at position 793 retains CasX activity.
Regarding instant claim 224, Boitano et al teach wherein the Cas protein comprises one or more SV40 nuclear localization signal (NLS) (pg. 426, lines 9-11; Table 5). The obviousness to add a NLS to Cas protein as taught by Boitano et al is discussed above as applied to claim 224 in discussion regarding U.S. Patent No. 11,976,277.
Regarding instant claims 225-226, as the CasX variant protein and the gRNA variant sequences of the patented claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, Boitano et al teach nucleic acid vectors encoding the CasX and gRNA are delivered by a recombinant AAV vector selected from AAV4, AAV5, AAV6, AAV9, and AAV rh 10 (pg. 282, lines 15-24). The obviousness to deliver the composition into the cell by specific AAV serotypes as taught by Boitano et al is discussed above as applied to claims 232-233, and 237-238 in discussion regarding U.S. Patent No. 11,535,835.
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 171, 176, 177, 180, 182, 184, and 185 of copending Application No. 17/829,206 in view of Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). This is a provisional nonstatutory double patenting rejection.
Regarding instant claim 209-211, 216-218, and 222-223, ‘206 recites a composition comprising a CasX CRISPR nuclease (i.e., a CasX variant protein) comprising the sequence of SEQ ID NO: 138, or a sequence having at least 95% sequence identity thereto (claim 171), which shares 99.7% sequence identity with instantly claimed SEQ ID NO: 133 (a portion of sequence alignment is reproduced below). Accordingly, the full-length sequence of instantly claimed CasX variant protein comprising the sequence of SEQ ID NO: 133 is encompassed by the patented genus of CasX variant proteins. ‘206 further recite a gRNA comprising a targeting sequence complementary to a huntingtin gene (claim 171).
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However, ‘560 does not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, ‘560 recites wherein the gRNA variant is a guide RNA (claim 1). However, ‘560 does not explicitly recite the gRNA variant is a single-molecule RNA. Boitano et al teach the gRNA molecule consists of a single contiguous polynucleotide molecule (i.e., single-molecule RNA) (pg. 46, lines 21-22). The obviousness to modify the gRNA variant to be single-molecule RNA is discussed above as applied to claim 212 in discussion regarding U.S. Patent No. 12,551,560.
Regarding instant claims 219-220, ‘206 recites wherein the gRNA variant has a scaffold comprising a sequence of SEQ ID NO: 2238 that is identical to instant claimed SEQ ID NO: 2238 (see sequence alignment reproduced below) (claims 176 and 182).
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Regarding instant claim 221, the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene is discussed above as applied to instant claim 209. Further, Boitano et al teach a targeting sequence of SEQ ID NO: 23 that is identical to instant targeting sequence of SEQ ID NO: 22 (claim 19), and this targeting sequence is disposed at the 3’ end (claim 20).
Regarding instant claim 224, ‘206 recite wherein the Cas protein comprises one or more SV40 nuclear localization signal (NLS) (claim 177). The obviousness to add a NLS to Cas protein as taught by Boitano et al is discussed above as applied to claim 224 in discussion regarding U.S. Patent No. 11,976,277.
Regarding instant claims 225-226, as the CasX variant protein and the gRNA variant sequences of the copending claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, ‘206 recites an AAV nucleic acid vector comprising sequences encoding the CasX variant protein and gRNA variant (claims 184 and 185). Boitano et al teach nucleic acid vectors encoding the CasX and gRNA are delivered by a recombinant AAV vector selected from AAV4, AAV5, AAV6, AAV9, and AAV rh 10 (pg. 282, lines 15-24). The obviousness to deliver the composition into the cell by specific AAV serotypes as taught by Boitano et al is discussed above as applied to claims 232-233, and 237-238 in discussion regarding U.S. Patent No. 11,535,835.
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 215, 222, 226, 227, and 228 of copending Application No. 17/791,130 in view of Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). This is a provisional nonstatutory double patenting rejection.
Regarding instant claim 209-211, 216-218, and 222-223, ‘130 recites a system comprising a CasX CRISPR nuclease (i.e., a CasX variant protein) comprising the sequence of SEQ ID NO: 138, or a sequence having at least 90% sequence identity thereto (claim 222), which shares 99.7% sequence identity with instantly claimed SEQ ID NO: 133 (a portion of sequence alignment is reproduced below). Accordingly, the full-length sequence of instantly claimed CasX variant protein comprising the sequence of SEQ ID NO: 133 is encompassed by the patented genus of CasX variant proteins. ‘130 also recites a CasX variant protein comprising the sequence of SEQ ID NO: 145 which is 100% identical to instantly claimed SEQ ID NO: 133 (see sequence alignment below). ‘130 further recite a gRNA comprising a targeting sequence complementary to a PCSK9 target nucleic acid sequence (claim 215).
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However, ‘130 does not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, ‘130 recites wherein the gRNA variant is a single-molecule RNA (claim 226).
Regarding instant claims 219-220, ‘206 recites wherein the gRNA variant has a scaffold comprising a sequence of SEQ ID NO: 2238 that is identical to instant claimed SEQ ID NO: 2238 (see sequence alignment reproduced below) (claim 227).
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Regarding instant claim 221, the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene is discussed above as applied to instant claim 209. Further, Boitano et al teach a targeting sequence of SEQ ID NO: 23 that is identical to instant targeting sequence of SEQ ID NO: 22 (claim 19), and this targeting sequence is disposed at the 3’ end (claim 20).
Regarding instant claim 224, Boitano et al teach wherein the Cas protein comprises one or more SV40 nuclear localization signal (NLS) (pg. 426, lines 9-11; Table 5). The obviousness to add a NLS to Cas protein as taught by Boitano et al is discussed above as applied to claim 224 in discussion regarding U.S. Patent No. 11,976,277.
Regarding instant claims 225-226, as the CasX variant protein and the gRNA variant sequences of the copending claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, ‘130 recites an AAV nucleic acid vector comprising sequences encoding the CasX variant protein and gRNA variant (claims 215 and 229). Boitano et al teach nucleic acid vectors encoding the Cas9 and gRNA are delivered by a recombinant AAV vector selected from AAV4, AAV5, AAV6, AAV9, and AAV rh 10 (pg. 282, lines 15-24). The obviousness to deliver the composition into the cell by specific AAV serotypes as taught by Boitano et al is discussed above as applied to claims 232-233, and 237-238 in discussion regarding U.S. Patent No. 11,535,835.
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11, 41, 47, 79, 81, and 84 of copending Application No. 17/932,798 in view of Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). This is a provisional nonstatutory double patenting rejection.
Regarding instant claim 209-211, 216-218, and 222-223, ‘798 recites a system comprising nucleic acids encoding for a CasX CRISPR nuclease (i.e., a CasX variant protein) comprising the sequence of SEQ ID NO: 138, or a sequence having at least 90% sequence identity thereto (claim 1), which shares 99.7% sequence identity with instantly claimed SEQ ID NO: 133 (a portion of sequence alignment is reproduced below). Accordingly, the full-length sequence of instantly claimed CasX variant protein comprising the sequence of SEQ ID NO: 133 is encompassed by the patented genus of CasX variant proteins. ‘130 further recite a guide nucleic acid (i.e., gRNA) comprising a targeting sequence complementary to a chromosome 9 open reading frame 72 gene (claim 1).
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However, ‘798 does not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, ‘798 recites wherein the gRNA variant is a single-molecule RNA (claim 11).
Regarding instant claims 219-220, ‘798 recites wherein the gRNA variant has a scaffold comprising a sequence of SEQ ID NO: 2238 that is identical to instant claimed SEQ ID NO: 2238 (see sequence alignment reproduced below) (claim 227).
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Regarding instant claim 221, the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene is discussed above as applied to instant claim 209. Further, Boitano et al teach a targeting sequence of SEQ ID NO: 23 that is identical to instant targeting sequence of SEQ ID NO: 22 (claim 19), and this targeting sequence is disposed at the 3’ end (claim 20).
Regarding instant claim 224, ‘798 recite wherein the Cas protein comprises one or more SV40 nuclear localization signal (NLS) (claim 41). The obviousness to add a NLS to Cas protein as taught by Boitano et al is discussed above as applied to claim 224 in discussion regarding U.S. Patent No. 11,976,277.
Regarding instant claims 225-226, as the CasX variant protein and the gRNA variant sequences of the copending claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, ‘798 recites an AAV nucleic acid vector comprising sequences encoding the CasX variant protein and gRNA variant (claims 79 and 81). ‘798 also recites wherein the AAV vector is the instantly recited serotypes (claim 84).
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 88, 94-97, 116, 119-120, and 124 of copending Application No. 18/608,127 in view of Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). This is a provisional nonstatutory double patenting rejection.
Regarding instant claim 209-211, 216-218, and 222-223, ‘127 recites a composition comprising a CasX CRISPR nuclease (i.e., a CasX variant protein) comprising the sequence of SEQ ID NO: 2373, or a sequence having at least 70% sequence identity thereto (claim 222), which shares 99.9% sequence identity with instantly claimed SEQ ID NO: 133 (a portion of sequence alignment is reproduced below). Accordingly, the full-length sequence of instantly claimed CasX variant protein comprising the sequence of SEQ ID NO: 133 is encompassed by the patented genus of CasX variant proteins. ‘127 further recite a gRNA comprising a targeting sequence complementary to a target nucleic acid of a cell to be modified (claim 116).
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However, ‘127 does not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, the obviousness to modify the gRNA variant to be single-molecule RNA is discussed above as applied to claim 212 in discussion regarding U.S. Patent No. 12,551,560.
Regarding instant claims 219-220, ‘127 recites wherein the gRNA variant has a scaffold comprising a sequence of SEQ ID NO: 2238 that is identical to instant claimed SEQ ID NO: 2238 (see sequence alignment reproduced below) (claims 96, 120, and 124).
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Regarding instant claim 221, the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene is discussed above as applied to instant claim 209. Further, Boitano et al teach a targeting sequence of SEQ ID NO: 23 that is identical to instant targeting sequence of SEQ ID NO: 22 (claim 19), and this targeting sequence is disposed at the 3’ end (claim 20).
Regarding instant claim 224, ‘127 recite wherein the Cas protein comprises one or more SV40 nuclear localization signal (NLS) (claim 94). The obviousness to add a NLS to Cas protein as taught by Boitano et al is discussed above as applied to claim 224 in discussion regarding U.S. Patent No. 11,976,277.
Regarding instant claims 225-226, as the CasX variant protein and the gRNA variant sequences of the copending claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, ‘127 recites instantly recited AAV serotype vectors comprising nucleic acid that comprises sequences encoding the CasX variant protein and gRNA variant (claims 88, 97, and 116).
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 176, 206, 209-210, and 222 of copending Application No. 18/266,076 in view of Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). This is a provisional nonstatutory double patenting rejection.
Regarding instant claim 209-211, 216-218, and 222-223, ‘076 recites a polynucleotide comprising sequences encoding a CasX CRISPR nuclease (i.e., a CasX variant protein) comprising the sequence of SEQ ID NO: 145, or a sequence having at least 90% sequence identity thereto (claim 176, 206, 208), which shares 100% sequence identity with instantly claimed SEQ ID NO: 133 (a portion of sequence alignment is reproduced below). ‘076 further recite a polynucleotide encoding a gRNA comprising a targeting sequence complementary to a target nucleic acid of a gene in a cell (claim 210).
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However, ‘076 does not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, the obviousness to modify the gRNA variant to be single-molecule RNA is discussed above as applied to claim 212 in discussion regarding U.S. Patent No. 12,551,560.
Regarding instant claims 219-220, ‘076 recites wherein the gRNA variant has a scaffold comprising a sequence of SEQ ID NO: 2238 that is identical to instant claimed SEQ ID NO: 2238 (see sequence alignment reproduced below) (claims 209).
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Regarding instant claim 221, the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene is discussed above as applied to instant claim 209. Further, Boitano et al teach a targeting sequence of SEQ ID NO: 23 that is identical to instant targeting sequence of SEQ ID NO: 22 (claim 19), and this targeting sequence is disposed at the 3’ end (claim 20).
Regarding instant claim 224, Boitano et al teach wherein the Cas protein comprises one or more SV40 nuclear localization signal (NLS) (pg. 426, lines 9-11; Table 5). The obviousness to add a NLS to Cas protein as taught by Boitano et al is discussed above as applied to claim 224 in discussion regarding U.S. Patent No. 11,976,277.
Regarding instant claims 225-226, as the CasX variant protein and the gRNA variant sequences of the copending claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, ‘076 recites instantly recited AAV serotype vectors comprising nucleic acid that comprises sequences encoding the CasX variant protein and gRNA variant (claims 176 and 222).
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 26, 21, 42, 87, and 96 of copending Application No. 18/869,765 in view of Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). This is a provisional nonstatutory double patenting rejection.
Regarding instant claim 209-211, 216-218, and 222-223, ‘765 recites an engineered CasX protein comprising the sequence of SEQ ID NO: 49699 which shares 100% sequence identity with instantly claimed SEQ ID NO: 133 (a portion of sequence alignment is reproduced below) (claim 42). ‘076 further recite an engineered ribonucleic acid scaffold (i.e., gRNA variant) comprising a targeting sequence complementary to a target nucleic acid sequence (claim 26).
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However, ‘765 does not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, the obviousness to modify the gRNA variant to be single-molecule RNA is discussed above as applied to claim 212 in discussion regarding U.S. Patent No. 12,551,560.
Regarding instant claims 219-220, ‘076 recites wherein the gRNA variant has a scaffold comprising a sequence of SEQ ID NO: 17 that is identical to instant claimed SEQ ID NO: 2238 (see sequence alignment reproduced below) (claims 209).
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Regarding instant claim 221, ‘765 recite wherein the targeting sequence is linked at the 3’end of the gRNA scaffold (claim 26).
Regarding instant claim 224, Boitano et al teach wherein the Cas protein comprises one or more SV40 nuclear localization signal (NLS) (pg. 426, lines 9-11; Table 5). The obviousness to add a NLS to Cas protein as taught by Boitano et al is discussed above as applied to claim 224 in discussion regarding U.S. Patent No. 11,976,277.
Regarding instant claims 225-226, as the CasX variant protein and the gRNA variant sequences of the copending claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, ‘765 recites instantly recited AAV serotype vectors comprising nucleic acid that comprises sequences encoding the CasX variant protein and gRNA variant (claims 96 and 87).
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 21, and 41 of copending Application No. 18/872,584 in view of Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). This is a provisional nonstatutory double patenting rejection.
Regarding instant claim 209-211, 216-218, and 222-223, ‘584 recites a recombinant adeno-associated virus comprising a polynucleotide that encodes a CasX protein comprising the sequence of SEQ ID NO: 197, or a sequence having at least 90% sequence identity thereto (claim 2), which shares 100% sequence identity with instantly claimed SEQ ID NO: 133 (a portion of sequence alignment is reproduced below). ‘076 further recite a polynucleotide encoding a gRNA comprising a targeting sequence complementary to a target nucleic acid of a cell (claim 1).
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However, ‘584 does not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, the obviousness to modify the gRNA variant to be single-molecule RNA is discussed above as applied to claim 212 in discussion regarding U.S. Patent No. 12,551,560.
Regarding instant claims 219-220, ‘584 recites wherein the gRNA variant has a scaffold comprising a sequence of SEQ ID NO: 2238 that is identical to instant claimed SEQ ID NO: 2238 (see sequence alignment reproduced below) (claims 21).
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Regarding instant claim 221, the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene is discussed above as applied to instant claim 209. Further, Boitano et al teach a targeting sequence of SEQ ID NO: 23 that is identical to instant targeting sequence of SEQ ID NO: 22 (claim 19), and this targeting sequence is disposed at the 3’ end (claim 20).
Regarding instant claim 224, Boitano et al teach wherein the Cas protein comprises one or more SV40 nuclear localization signal (NLS) (pg. 426, lines 9-11; Table 5). The obviousness to add a NLS to Cas protein as taught by Boitano et al is discussed above as applied to claim 224 in discussion regarding U.S. Patent No. 11,976,277.
Regarding instant claims 225-226, as the CasX variant protein and the gRNA variant sequences of the copending claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, ‘076 recites instantly recited AAV serotype vectors comprising nucleic acid that comprises sequences encoding the CasX variant protein and gRNA variant (claims 1 and 41).
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13, 25, 39, and 41 of copending Application No. 18/568,029 in view of Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). This is a provisional nonstatutory double patenting rejection.
Regarding instant claim 209-211, 216-218, and 222-223, ‘029 recites a glycoprotein comprising sequences encoding a CasX protein comprising the sequence of SEQ ID NO: 668, or a sequence having at least 90% sequence identity thereto (claim 39), which shares 99.9% sequence identity with instantly claimed SEQ ID NO: 133 (a portion of sequence alignment is reproduced below). ‘029 further recite the glycoprotein comprises a gRNA (claim 39).
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However, ‘029 does not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, the obviousness to modify the gRNA variant to be single-molecule RNA is discussed above as applied to claim 212 in discussion regarding U.S. Patent No. 12,551,560.
Regarding instant claims 219-220, ‘076 recites wherein the gRNA variant has a scaffold comprising a sequence of SEQ ID NO: 945 that is identical to instant claimed SEQ ID NO: 2238 (see sequence alignment reproduced below) (claims 39).
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Regarding instant claim 221, ‘029 recites wherein the targeting sequence is linked to the 3’end of the gRNA scaffold (claim 41).
Regarding instant claim 224, Boitano et al teach wherein the Cas protein comprises one or more SV40 nuclear localization signal (NLS) (pg. 426, lines 9-11; Table 5). The obviousness to add a NLS to Cas protein as taught by Boitano et al is discussed above as applied to claim 224 in discussion regarding U.S. Patent No. 11,976,277.
Regarding instant claims 225-226, as the CasX variant protein and the gRNA variant sequences of the copending claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, ‘076 recites AAV vectors comprising nucleic acid that comprises sequences encoding the CasX variant protein and gRNA variant (claim 13). The obviousness to deliver the composition into the cell by instantly recited AAV serotypes as taught by Boitano et al is discussed above as applied to claims 232-233, and 237-238 in discussion regarding U.S. Patent No. 11,535,835.
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 41, 43, 48-50, and 73 of copending Application No. 19/343,806 in view of Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). This is a provisional nonstatutory double patenting rejection.
Regarding instant claim 209-211, 216-218, and 222-223, ‘806 recites a system comprising a chimeric engineered CasX protein (i.e., a CasX variant protein) comprising the sequence of SEQ ID NO: 5, or a sequence having at least 90% sequence identity thereto (claim 43), which shares 100% sequence identity with instantly claimed SEQ ID NO: 133 (a portion of sequence alignment is reproduced below). ‘806 further recite a gRNA comprising a targeting sequence complementary to a lipoprotein(a) gene (claim 1).
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However, ‘806 does not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, the obviousness to modify the gRNA variant to be single-molecule RNA is discussed above as applied to claim 212 in discussion regarding U.S. Patent No. 12,551,560.
Regarding instant claims 219-220, ‘806 recites wherein the gRNA variant has a scaffold comprising a sequence of SEQ ID NO: 464 that is identical to instant claimed SEQ ID NO: 2238 (see sequence alignment reproduced below) (claims 1).
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Regarding instant claim 221, the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene is discussed above as applied to instant claim 209. Further, Boitano et al teach a targeting sequence of SEQ ID NO: 23 that is identical to instant targeting sequence of SEQ ID NO: 22 (claim 19), and this targeting sequence is disposed at the 3’ end (claim 20).
Regarding instant claim 224, ‘806 recite wherein the Cas protein comprises one or more SV40 nuclear localization signal (NLS) (claims 48 and 49). The obviousness to add a NLS to Cas protein as taught by Boitano et al is discussed above as applied to claim 224 in discussion regarding U.S. Patent No. 11,976,277.
Regarding instant claims 225-226, as the CasX variant protein and the gRNA variant sequences of the copending claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, ‘806 recites AAV vectors comprising nucleic acid that comprises sequences encoding the CasX variant protein and gRNA variant (claims 50 and 73). The obviousness to deliver the composition into the cell by instantly recited AAV serotypes as taught by Boitano et al is discussed above as applied to claims 232-233, and 237-238 in discussion regarding U.S. Patent No. 11,535,835.
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 169, 175-177, and 183-184 of copending Application No. 17/641,426 in view of Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). This is a provisional nonstatutory double patenting rejection.
Regarding instant claim 209-211, 216-218, and 222-223, ‘426 recites a composition comprising a CasX variant protein comprising the sequence of SEQ ID NO: 126, or a sequence having at least 90% sequence identity thereto (claim 169), which shares 99.7% sequence identity with instantly claimed SEQ ID NO: 133 (a portion of sequence alignment is reproduced below). Accordingly, the full-length sequence of instantly claimed CasX variant protein comprising the sequence of SEQ ID NO: 133 is encompassed by the patented genus of CasX variant proteins. ‘076 further recite a gRNA comprising a targeting sequence complementary to a superoxide dismutase 1 gene (claim 169).
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However, ‘426 does not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, the obviousness to modify the gRNA variant to be single-molecule RNA is discussed above as applied to claim 212 in discussion regarding U.S. Patent No. 12,551,560.
Regarding instant claims 219-220, ‘426 recites wherein the gRNA variant has a scaffold comprising a sequence of SEQ ID NO: 2238 that is identical to instant claimed SEQ ID NO: 2238 (see sequence alignment reproduced below) (claims 209).
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Regarding instant claim 221, the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene is discussed above as applied to instant claim 209. Further, Boitano et al teach a targeting sequence of SEQ ID NO: 23 that is identical to instant targeting sequence of SEQ ID NO: 22 (claim 19), and this targeting sequence is disposed at the 3’ end (claim 20).
Regarding instant claim 224, ‘426 recite wherein the Cas protein comprises one or more SV40 nuclear localization signal (NLS) (claim 176). The obviousness to add a NLS to Cas protein as taught by Boitano et al is discussed above as applied to claim 224 in discussion regarding U.S. Patent No. 11,976,277.
Regarding instant claims 225-226, as the CasX variant protein and the gRNA variant sequences of the copending claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, ‘426 recites AAV vectors comprising nucleic acid that comprises sequences encoding the CasX variant protein and gRNA variant (claims 183-184). The obviousness to deliver the composition into the cell by instantly recited AAV serotypes as taught by Boitano et al is discussed above as applied to claims 232-233, and 237-238 in discussion regarding U.S. Patent No. 11,535,835.
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 169, 176-177, 179, 182, and 186-187 of copending Application No. 18/168,426 in view of Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). This is a provisional nonstatutory double patenting rejection.
Regarding instant claim 209-211, 216-218, and 222-223, ‘426 recites a method of treating a superoxide dismutase 1-related disease using a composition that comprises a CasX variant protein comprising the sequence of SEQ ID NO: 126, or a sequence having at least 90% sequence identity thereto (claim 169), which shares 99.7% sequence identity with instantly claimed SEQ ID NO: 133 (a portion of sequence alignment is reproduced below). Accordingly, the full-length sequence of instantly claimed CasX variant protein comprising the sequence of SEQ ID NO: 133 is encompassed by the patented genus of CasX variant proteins. ‘426 further recite the composition comprises a gNA (i.e., gRNA) that comprises a targeting sequence complementary to a SOD1 gene (claim 169).
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However, ‘426 does not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, ‘426 recites wherein the gRNA variant is a single-molecule RNA (claim 177).
Regarding instant claims 219-220, ‘076 recites wherein the gRNA variant has a scaffold comprising a sequence of SEQ ID NO: 2238 that is identical to instant claimed SEQ ID NO: 2238 (see sequence alignment reproduced below) (claims 39).
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Regarding instant claim 221, the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene is discussed above as applied to instant claim 209. Further, Boitano et al teach a targeting sequence of SEQ ID NO: 23 that is identical to instant targeting sequence of SEQ ID NO: 22 (claim 19), and this targeting sequence is disposed at the 3’ end (claim 20).
Regarding instant claim 224, ‘426 recites wherein the Cas protein comprises one or more SV40 nuclear localization signal (NLS) (claim 182). The obviousness to add a NLS to Cas protein as taught by Boitano et al is discussed above as applied to claim 224 in discussion regarding U.S. Patent No. 11,976,277.
Regarding instant claims 225-226, as the CasX variant protein and the gRNA variant sequences of the copending claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, ‘426 recites AAV vectors comprising nucleic acid that comprises sequences encoding the CasX variant protein and gRNA variant (claim 186-187). The obviousness to deliver the composition into the cell by instantly recited AAV serotypes as taught by Boitano et al is discussed above as applied to claims 232-233, and 237-238 in discussion regarding U.S. Patent No. 11,535,835.
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 40, 41, and 44 of copending Application No. 18/778,393 in view of Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). This is a provisional nonstatutory double patenting rejection.
Regarding instant claim 209-211, 216-218, and 222-223, ‘393 recites a gene editing pair comprising an engineered protein (i.e., a CasX variant protein) comprising the sequence of SEQ ID NO: 270, or a sequence having at least 70% sequence identity thereto (claim 44), which shares 99.7% sequence identity with instantly claimed SEQ ID NO: 133 (a portion of sequence alignment is reproduced below). Accordingly, the full-length sequence of instantly claimed CasX variant protein comprising the sequence of SEQ ID NO: 133 is encompassed by the patented genus of CasX variant proteins. ‘393 further recite a gRNA (claim 1).
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However, ‘393 not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, the obviousness to modify the gRNA variant to be single-molecule RNA is discussed above as applied to claim 212 in discussion regarding U.S. Patent No. 12,551,560.
Regarding instant claims 219-220, ‘393 recites wherein the gRNA variant has a scaffold comprising a sequence of SEQ ID NO: 2238 that is identical to instant claimed SEQ ID NO: 2238 (see sequence alignment reproduced below) (claims 46).
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Regarding instant claim 221, the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene is discussed above as applied to instant claim 209. Further, Boitano et al teach a targeting sequence of SEQ ID NO: 23 that is identical to instant targeting sequence of SEQ ID NO: 22 (claim 19), and this targeting sequence is disposed at the 3’ end (claim 20).
Regarding instant claim 224, Boitano et al teach wherein the Cas protein comprises one or more SV40 nuclear localization signal (NLS) (pg. 426, lines 9-11; Table 5). The obviousness to add a NLS to Cas protein as taught by Boitano et al is discussed above as applied to claim 224 in discussion regarding U.S. Patent No. 11,976,277.
Regarding instant claims 225-226, as the CasX variant protein and the gRNA variant sequences of the copending claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, Boitano et al teach nucleic acid vectors encoding the Cas9 and gRNA are delivered by a recombinant AAV vector selected from AAV4, AAV5, AAV6, AAV9, and AAV rh 10 (pg. 282, lines 15-24). The obviousness to deliver the composition into the cell by instantly recited AAV serotypes as taught by Boitano et al is discussed above as applied to claims 232-233, and 237-238 in discussion regarding U.S. Patent No. 11,535,835.
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 31, 39-42, and 47 of copending Application No. 19/532,260 in view of Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). This is a provisional nonstatutory double patenting rejection.
Regarding instant claim 209-211, 216-218, and 222-223, ‘260 recites a gene repressor system (i.e., composition) comprising a catalytically-dead CRISPR protein (i.e., a CasX variant protein) comprising the sequence of SEQ ID NO: 59353, or a sequence having at least 70 % sequence identity thereto (claim 39), which shares 99.5% sequence identity with instantly claimed SEQ ID NO: 133 (a portion of sequence alignment is reproduced below). Accordingly, the full-length sequence of instantly claimed CasX variant protein comprising the sequence of SEQ ID NO: 133 is encompassed by the patented genus of CasX variant proteins. ‘260 further recite the system comprises a gRNA that comprises a targeting sequence complementary to a target nucleic acid sequence of a gene targeted for repression (claim 31).
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However, ‘260 does not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, the obviousness to modify the gRNA variant to be single-molecule RNA is discussed above as applied to claim 212 in discussion regarding U.S. Patent No. 12,551,560.
Regarding instant claims 219-220, ‘260 recites wherein the gRNA variant has a scaffold comprising a sequence of SEQ ID NO: 2238 that is identical to instant claimed SEQ ID NO: 2238 (see sequence alignment reproduced below) (claims 39).
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Regarding instant claim 221, the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene is discussed above as applied to instant claim 209. Further, Boitano et al teach a targeting sequence of SEQ ID NO: 23 that is identical to instant targeting sequence of SEQ ID NO: 22 (claim 19), and this targeting sequence is disposed at the 3’ end (claim 20).
Regarding instant claim 224, ‘260 recites wherein the Cas protein comprises one or more SV40 nuclear localization signal (NLS) (claims 40 and 41).
Regarding instant claims 225-226, as the CasX variant protein and the gRNA variant sequences of the copending claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, ‘426 recites AAV vectors comprising nucleic acid that comprises sequences encoding the CasX variant protein and gRNA variant (claim 47). The obviousness to deliver the composition into the cell by instantly recited AAV serotypes as taught by Boitano et al is discussed above as applied to claims 232-233, and 237-238 in discussion regarding U.S. Patent No. 11,535,835.
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 68, 82, 85, 128, 131-132, and 135 of copending Application No. 18/872,544 in view of Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). This is a provisional nonstatutory double patenting rejection.
Regarding instant claim 209-211, 216-218, and 222-223, ‘544 recites a system comprising a CasX protein comprising the sequence of SEQ ID NO: 5, or a sequence having at least 90% sequence identity thereto (claim 130), which shares 100% sequence identity with instantly claimed SEQ ID NO: 133 (a portion of sequence alignment is reproduced below). ‘426 further recite the system comprises a gRNA that comprises a targeting sequence complementary to a PCSK9 gene (claim 1).
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However, ‘544 does not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, The obviousness to modify the gRNA variant to be single-molecule RNA is discussed above as applied to claim 212 in discussion regarding U.S. Patent No. 12,551,560.
Regarding instant claims 219-220, ‘544 recites wherein the gRNA variant has a scaffold comprising a sequence of SEQ ID NO: 466, or a sequence having at least 90% sequence identity thereto (see sequence alignment reproduced below) (claim 2). Accordingly, the full-length sequence of instantly claimed gRNA variant scaffold comprising the sequence of SEQ ID NO: 2238 is encompassed by the genus of gRNA variant scaffold recited by ‘544.
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Regarding instant claim 221, the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene is discussed above as applied to instant claim 209. Further, Boitano et al teach a targeting sequence of SEQ ID NO: 23 that is identical to instant targeting sequence of SEQ ID NO: 22 (claim 19), and this targeting sequence is disposed at the 3’ end (claim 20).
Regarding instant claim 224, ‘544 recites wherein the Cas protein comprises one or more SV40 nuclear localization signal (NLS) (claim 131).
Regarding instant claims 225-226, as the CasX variant protein and the gRNA variant sequences of the copending claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, ‘544 recites AAV vectors comprising nucleic acid that comprises sequences encoding the CasX variant protein and gRNA variant (claim 68, 82, 85, 132 and 135). The obviousness to deliver the composition into the cell by instantly recited AAV serotypes as taught by Boitano et al is discussed above as applied to claims 232-233, and 237-238 in discussion regarding U.S. Patent No. 11,535,835.
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 37, 44, 48-49, 54, and 56 of copending Application No. 19/343,818 in view of Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). This is a provisional nonstatutory double patenting rejection.
Regarding instant claim 209-211, 216-218, and 222-223, ‘818 recites an mRNA encoding a CasX variant protein comprising the sequence of SEQ ID NO: 2405, or a sequence having at least 90% sequence identity thereto (claim 44), which shares 99.6% sequence identity with instantly claimed SEQ ID NO: 133 (a portion of sequence alignment is reproduced below). Accordingly, the full-length sequence of instantly claimed CasX variant protein comprising the sequence of SEQ ID NO: 133 is encompassed by the patented genus of CasX variant proteins. ‘818 further recite an mRNA encoding a gRNA that comprises a targeting sequence complementary to a target nucleic acid sequence of a gene in a cell (claim 54).
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However, ‘818 does not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, The obviousness to modify the gRNA variant to be single-molecule RNA is discussed above as applied to claim 212 in discussion regarding U.S. Patent No. 12,551,560.
Regarding instant claims 219-220, ‘076 recites wherein the gRNA variant has a scaffold comprising a sequence of SEQ ID NO: 1746, or a sequence having at least 90% sequence identity thereto (see sequence alignment reproduced below) (claim 56). Accordingly, the full-length sequence of instantly claimed gRNA variant scaffold comprising the sequence of SEQ ID NO: 2238 is encompassed by the genus of gRNA variant scaffold recited by ‘818.
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Regarding instant claim 221, the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene is discussed above as applied to instant claim 209. Further, Boitano et al teach a targeting sequence of SEQ ID NO: 23 that is identical to instant targeting sequence of SEQ ID NO: 22 (claim 19), and this targeting sequence is disposed at the 3’ end (claim 20).
Regarding instant claim 224, ‘818 recites wherein the Cas protein comprises one or more SV40 nuclear localization signal (NLS) (claims 48-49).
Regarding instant claims 225-226, as the CasX variant protein and the gRNA variant sequences of the copending claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, ‘426 recites nucleic acid that comprises sequences encoding the CasX variant protein and gRNA variant (claims 44 and 54). The obviousness to deliver the composition into the cell by instantly recited AAV serotypes as taught by Boitano et al is discussed above as applied to claims 232-233, and 237-238 in discussion regarding U.S. Patent No. 11,535,835.
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 194 and 198 of copending Application No. 18/039,858 in view of Oakes et al (US 2023/0081117 A1; Published Date: March 16, 2023; PCT Filed Date: Sept 09, 2020) and Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). This is a provisional nonstatutory double patenting rejection.
Regarding instant claim 209-211, 216-218, and 222-223, ‘858 recites a gene editing pair comprising an engineered CasX protein an comprising the sequence of SEQ ID NO: 93 which shares 99.9% sequence identity with instantly claimed SEQ ID NO: 133 (a portion of sequence alignment is reproduced below) (claim 194). ‘858 further recite a gRNA (claim 76).
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However, ‘858 does not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, The obviousness to modify the gRNA variant to be single-molecule RNA is discussed above as applied to claim 212 in discussion regarding U.S. Patent No. 12,551,560.
Regarding instant claims 219-220, the teachings of Oakes et al regarding a gRNA variant comprising a scaffold of instantly claimed SEQ ID NO: 2238, and the obviousness to modify the CasX variant protein of ‘858 to comprise a gRNA variant as taught by Oakes et al discussed above as applied to instant claim 209 equally applies here.
Regarding instant claim 221, the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene is discussed above as applied to instant claim 209. Further, Boitano et al teach a targeting sequence of SEQ ID NO: 23 that is identical to instant targeting sequence of SEQ ID NO: 22 (claim 19), and this targeting sequence is disposed at the 3’ end (claim 20).
Regarding instant claim 224, Boitano et al teach wherein the Cas protein comprises one or more SV40 nuclear localization signal (NLS) (pg. 426, lines 9-11; Table 5). The obviousness to add a NLS to Cas protein as taught by Boitano et al is discussed above as applied to claim 224 in discussion regarding U.S. Patent No. 11,976,277.
Regarding instant claims 225-226, as the CasX variant protein sequence of the copending claims and Oakes gRNA variant fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, ‘Boitano et al teach nucleic acid vectors encoding the CasX and gRNA are delivered by a recombinant AAV vector selected from AAV4, AAV5, AAV6, AAV9, and AAV rh 10 (pg. 282, lines 15-24). The obviousness to deliver the composition into the cell by instantly recited AAV serotypes as taught by Boitano et al is discussed above as applied to claims 232-233, and 237-238 in discussion regarding U.S. Patent No. 11,535,835.
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 29, 35, 42-44, and 58-59 of copending Application No. 18/663,845in view of Oakes et al (US 2023/0081117 A1; Published Date: March 16, 2023; PCT Filed Date: Sept 09, 2020) and Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). This is a provisional nonstatutory double patenting rejection.
Regarding instant claim 209-211, 216-218, and 222-223, ‘845 recites a method of editing a target nucleic acid in a cell comprising using nucleic acid encoding a gene editing pair (claim 29). ‘845 further recited wherein the gene editing pair comprises a Class 2, Type V CRISPR protein (i.e., a CasX variant protein) comprising the sequence of SEQ ID NO: 416, or a sequence having at least 70% sequence identity thereto (claim 35), which shares 100% sequence identity with instantly claimed SEQ ID NO: 133 (a portion of sequence alignment is reproduced below). ‘845 further recite a gRNA (claim 29).
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However, ‘845 does not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, The obviousness to modify the gRNA variant to be single-molecule RNA is discussed above as applied to claim 212 in discussion regarding U.S. Patent No. 12,551,560.
Regarding instant claims 219-220, the teachings of Oakes et al regarding a gRNA variant comprising a scaffold of instantly claimed SEQ ID NO: 2238, and the obviousness to modify the CasX variant protein of ‘845 to comprise a gRNA variant as taught by Oakes et al discussed above as applied to instant claim 209 equally applies here.
Regarding instant claim 221, ‘845 recite wherein the targeting sequence is linked at the 3’end of the gRNA (claim 42).
Regarding instant claim 224, Boitano et al teach wherein the Cas protein comprises one or more SV40 nuclear localization signal (NLS) (pg. 426, lines 9-11; Table 5). The obviousness to add a NLS to Cas protein as taught by Boitano et al is discussed above as applied to claim 224 in discussion regarding U.S. Patent No. 11,976,277.
Regarding instant claims 225-226, as the CasX variant protein sequence of the copending claims and Oakes gRNA variant fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, ‘’845 recites instantly claimed AAV serotype vectors comprising nucleic acid encoding the CasX protein and gRNA (claims 29, and 58-59).
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18, and 21-23 of copending Application No. 18/909,093 in view of Oakes et al (US 2023/0081117 A1; Published Date: March 16, 2023; PCT Filed Date: Sept 09, 2020) and Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017). This is a provisional nonstatutory double patenting rejection.
Regarding instant claim 209-211, 216-218, and 222-223, ‘093 recites a system (i.e., composition) comprising an engineered protein (i.e., a CasX variant protein) comprising the sequence of SEQ ID NO: 336, or a sequence having at least 95% sequence identity thereto (claim 8), which shares 99.7% sequence identity with instantly claimed SEQ ID NO: 133 (a portion of sequence alignment is reproduced below). Accordingly, the full-length sequence of instantly claimed CasX variant protein comprising the sequence of SEQ ID NO: 133 is encompassed by the patented genus of CasX variant proteins. ‘093 further recite the system comprises a gRNA (claim 18).
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However, ‘093 does not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, The obviousness to modify the gRNA variant to be single-molecule RNA is discussed above as applied to claim 212 in discussion regarding U.S. Patent No. 12,551,560.
Regarding instant claims 219-220, the teachings of Oakes et al regarding a gRNA variant comprising a scaffold of instantly claimed SEQ ID NO: 2238, and the obviousness to modify the CasX variant protein of ‘093 to comprise a gRNA variant as taught by Oakes et al discussed above as applied to instant claim 209 equally applies here.
Regarding instant claim 221, the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene is discussed above as applied to instant claim 209. Further, Boitano et al teach a targeting sequence of SEQ ID NO: 23 that is identical to instant targeting sequence of SEQ ID NO: 22 (claim 19), and this targeting sequence is disposed at the 3’ end (claim 20).
Regarding instant claim 224, Boitano et al teach wherein the Cas protein comprises one or more SV40 nuclear localization signal (NLS) (pg. 426, lines 9-11; Table 5). The obviousness to add a NLS to Cas protein as taught by Boitano et al is discussed above as applied to claim 224 in discussion regarding U.S. Patent No. 11,976,277.
Regarding instant claims 225-226, as the CasX variant protein sequence of the copending claims and Oakes gRNA variant fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, ‘093 recites instantly claimed AAV serotype vectors comprising nucleic acid encoding the CasX protein and gRNA (claims 22-23).
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Claims 209-212, 216-226, and 232-234, and 237-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 45, 53, 59, and 79 of copending Application No. 18/693,062 in view of Oakes et al (US 2023/0081117 A1; Published Date: March 16, 2023; PCT Filed Date: Sept 09, 2020), Boitano et al (WO 2017/115268 A1; Published Date: July 06, 2017), and Doudna et al (US 2018/0346927 A1; Published Date: Dec 06, 2018). This is a provisional nonstatutory double patenting rejection.
Regarding instant claim 209-211, 216-218, and 222, ‘062 recites a gene repressor system (i.e., composition) comprising a CRISPR Type V protein and a gRNA comprising a targeting sequence that is complementary to a target nucleic acid sequence of a gene targeted for repression (claim 1).
However, ‘062 does not explicitly recite a CasX variant protein.
The teachings of Doudna et al regarding a CasX protein that shares at least 93% sequence identity to instantly claimed SEQ ID NO: 133 are discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 12,084,692. Further, the obviousness to substitute the CRISPR protein of ‘062 with the CasX protein of Doudna equally applies here.
However, ‘062 does not recite wherein the gRNA variant comprises a targeting sequence complementary to a B-cell lymphoma/leukemia 11A (BCL11A) gene target nucleic acid sequence.
The teachings of Boitano et al and the obviousness to modify the targeting sequence of the gRNA variant to be complementary to the GATA1 binding site of the BCL11A gene is discussed above as applied to claim 209 in discussion regarding U.S. Patent No. 11,535,835. Further, Boitano et al teach wherein the targeting sequence if SEQ ID NO: 23, which is identical to instant SEQ ID NO: 22 (see sequence alignment above).
Regarding instant claim 212, the obviousness to modify the gRNA variant to be single-molecule RNA is discussed above as applied to claim 212 in discussion regarding U.S. Patent No. 12,551,560.
Regarding instant claims 219-220, ‘062 recites wherein the gRNA variant has a scaffold comprising a sequence of SEQ ID NO: 2238 that is identical to instant claimed SEQ ID NO: 2238 (see sequence alignment reproduced below) (claim 59).
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Regarding instant claim 221, the obviousness to modify the instant targeting sequence to a sequence complementary to the BCL11A gene is discussed above as applied to instant claim 209. Further, Boitano et al teach a targeting sequence of SEQ ID NO: 23 that is identical to instant targeting sequence of SEQ ID NO: 22 (claim 19), and this targeting sequence is disposed at the 3’ end (claim 20).
Regarding instant claim 223, the obviousness to substitute the CasX variant of ‘062 with the CasX variant protein of Doudna is discussed above as applied to claim 209. Further, the obviousness to restore the proline residue at position 793 of Oakes’ CasX variant protein as taught by Doudna is discussed above as applied to claim 223 in discussion regarding U.S. Patent No. 12,084,692.
Regarding instant claim 224, ‘062 recite wherein the Cas protein comprises one or more SV40 nuclear localization signal (NLS) (claims 45 and 53). The obviousness to add a NLS to Cas protein as taught by Boitano et al is discussed above as applied to claim 224 in discussion regarding U.S. Patent No. 11,976,277.
Regarding instant claims 225-226, as the CasX variant protein and the gRNA variant sequences of the copending claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics recited in the instant claims as inherent properties.
Regarding instant claims 232-233, and 237-238, ‘062 recite nucleic acids encoding the gRNA variant (claim 79). Boitano et al teach nucleic acid vectors encoding the CasX and gRNA are delivered by a recombinant AAV vector selected from AAV4, AAV5, AAV6, AAV9, and AAV rh 10 (pg. 282, lines 15-24). The obviousness to deliver the composition into the cell by specific AAV serotypes as taught by Boitano et al is discussed above as applied to claims 232-233, and 237-238 in discussion regarding U.S. Patent No. 11,535,835.
Regarding instant claim 234, Boitano et al teach the Cas protein is codon optimized for expression in a eukaryotic cell (pg. 261, lines 31-34). The obviousness to codon optimizes the Cas protein as taught by Boitano et al is discussed above as applied to claim 234 in discussion regarding U.S. Patent No. 11,535,835.
Conclusion
No claims are allowable.
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/QIWEN SU-TOBON/
Examiner
Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
Prosecution Insights