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 .
Claim Status
Claims 1-20 are pending.
Claims 1-20 are examined on the merits.
Claim Objections
Claim 9 is objected to because of the following informality: “wherein the a spacer sequence….” Has a grammar error. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 2, 4, and 8-13 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 1 is rejected as indefinite for the recitation “…. and/or the target site…”. The use of “and/or” renders the scope unclear because it suggested that the claim may require satisfaction of both the preceding BBX-gene sequence-identity limitations and the subsequent target-site sequence-identity limitations. However, it is not reasonably clear what embodiment should meet both set of limitations, or whether both are required versus only one.
Claims 4 is rejected as indefinite for the recitation “wherein the BBX gene: (a)….; (b)…..; (c); and/or (d)….”. The use of “and/or” between limitations (c) and (d). The “and/or” in limitation (d) renders the scope unclear and suggests that the BBX gene maybe required to satisfy limitations (a)-(c) and limitation (d), it is not reasonably clear what embodiment would satisfy the nucleotide-identity/region requirements of (a) and (b) and the polypeptide-identity requirement of (c) together with the additional requirement of (d) or whether (d) is optional, a person of ordinary skill in the art would not be reasonably apprised of the metes and bounds of the claim.
Claim 8 is rejected as indefinite for the recitation "...the endogenous BBX gene: (a)….; (b)…..; (c); and/or (d)….”. The use of “and/or” in the BBX gene definition renders it unclear for the same reason set forth above respect to claim 4.
Dependent claims 2, and 9-13 are included in this rejection because they do not include additional limitations to resolve the ambiguity.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Descriptions
Claim 12 is 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.
The Federal Circuit has clarified the application of the written description requirement. The court stated that a written description of an invention "requires a precise definition, such as by structure, formula, [or] chemical name, of the claimed subject matter sufficient to distinguish it from other materials". University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568; 43 USPQ2d 1398, 1406 (Fed. Cir. 1997). The court also concluded that "naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not description of that material". Id. Further, the court held that to adequately describe a claimed genus, Patent Owner must describe a representative number of the species of the claimed genus, and that one of skill in the art should be able to "visualize or recognize the identity of the members of the genus". Id.
Claim 12 regards an edited plant having the functional limitation of “attenuated Shade Avoidance Response compared to a control plant that is devoid of the edit”, while incorporating the broad structural scope of claim 8 (including BBX genes/regions defined by ≥80% identity).
“Shade avoidance response” refers (SAR) is a response to a decrease in the quality or quantity of available light in which a plant attempts to outcompete neighboring plants by growing toward resources (primarily light). Overcrowding of plants can lead to shade avoidance syndrome (SAS) where plants lack vigor and display decreased yield (instant invention, paragraph 0004).
The claim includes plants across a broad genus: any plant comprising an edit in an endogenous BBX gene meeting the ≥80% identity-defined scope of claim 8 (including the alternative nucleotide/protein/region definitions), wherein the edited plant exhibits the recited phenotype of attenuated shade avoidance response.
The specification only includes phenotype measurements for a limited subset of embodiments: a particular shade avoidance assay (example 3) and results for specific edited maize alleles generated using the disclosed guides (PWsp2100 (SEQ ID NO:86) or PWsp2101 (SEQ ID NO:87)) in the specifically disclosed maize BBX genes, with sheath height measurements reported for those particular alleles/genotype combinations under control and shade conditions (example 4, table 5-6, paragraph 0344-0351). Therefore, the specification does not reasonably convey possession that plants across the full scope of the ≥80% identity-defined BBX genus and the “or/and/or” permutations exhibit the claimed attenuated shade avoidance response.
This lack of possession is underscored by the fact that BBX proteins are zinc-finer transcription factors in which B-box domain integrity can be determinative. For example, mutation of conserved residues within a B-box can abolish BBX function, for example BBX24 is a key transcription factor promotes SAR in Arabidopsis, but mutant line bbx24-1 with mutation in BBX24 reduce SAR (Maite Saura-Sánchez, et. al., Plant Cell Physiol. 64(5): 474–485 (2023)) (page 476); BBX21 mutant line bbx21-1 also shows different phenotype (Dongqing Xu, et. al., Plant Physiology , March 2018, Vol. 176, pp. 2365–2375) (fig 2, page 2368). Such that sequence variation within an identity-defined genus, (such as ≥80% identity) can materially alter activity.
In addition, BBX family members exhibit divergent expression patterns and functional divergence. For example, Wu (Zilin Wu, et. al., BMC Genomics (2023) 24:79) state that they call BBX genes “duplication events” only when the aligned region is on the longer sequence and the aligned portion has >80% similarity (page 3). In the species-specific syntenic (duplicated) pairs, they identify SsBBX8/SsBBX9 and SsBBX12/ssBBX13 as duplication-related pairs (page 9). Yet under low-nitrogen stress, they report that BBX shows “noticeably low or undiscovered” expression, while BBX8 is not in that low/undetected group and instead shows a different tissue trend (opposite leave vs stem bias) (page 13). Also, under low-nitrogen stress, BBX13 is singled out (with BBX1) as “significantly highly expressed int eh leaves” and shows a distinct time-course response pattern, while BBX12 is not single out that way, indicating different transcriptional regulation even within a syntenic pair (page 13). These evidences further supporting that phenotype cannot be assumed across the full breath of the identity-defined genus absent representatives.
Scope of Enablement
Claims 1- 4, 6, 8-13, 15, and 16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specifications, while being enabling for editing the corn BBX genes Zm00001d017147 (SEQ ID NO:72) and Zm00001d051018 (SEQ ID NO:69) with two CRISPR-Cas guide with spacer PWsp2100 (SEQ ID NO:86) or spacer PWsp2101 (SEQ ID NO:87) does not reasonably provide enablement for the full scope of the claimed gene editing system encompasses guide nucleic acids having spacer sequences that bind to a B-BOX gene broadly, including BBX/DBB family members (SEQ ID NO:71) having as little as 80% sequence identity.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
An “analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.” MPEP 2164.01. “A conclusion of lack of enablement means that. . . the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention [i.e. commensurate scope] without undue experimentation.” In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); MPEP 2164.01.
In In re Wands, 858 F.2d 731,8 USPQ2d 1400 (Fed. Cir. 1988), several factors implicated in determination of whether a disclosure satisfies the enablement requirement and whether any necessary experimentation is “undue” are identified. These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 858 F.2d 731,737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). No single factor is independently determinative of enablement; rather “[i]t is improper to conclude that a disclosure is not enabling based on an analysis of only one of the above factors while ignoring one or more of the others.” MPEP 2164.01. Likewise, all factors may not be relevant to the enablement analysis of any individual claim.
Claims 1, 4, 8, 15-16 and depend claims 2, 9-13 regard endogenous BBX genes/target sites defined by “at least 80% sequence identity” to recited nucleotide and amino acid sequences/regions. Claims 3 and the depend claim 6 regard “….the guide nucleic acid comprises a spacer sequence that binds to a B-BOX (BBX) gene”.
The claims encompass far more than the specific BBX genes and target sequence actually demonstrated in the specification. First, “a B-BOX (BBX) gene” is not limited to a particular BBX locus, BBX sequence, plant species, PAM context, genomic location, or editing outcome, and therefore reads on a broad range of BBX gene targets spanning diverse BBX family members and genomic contexts. Second, the recited “at least ≥80% sequence identity” thresholds of for (1) BBX genes itself and (2) BBX gene regions/target sites broaden the scope. ≥80% identity can cover a large number of distinct BBX-like sequences, not limited to the two maize BBX genes exemplified. The claims define not only whole genes/proteins, but also a “region” having ≥80% identity to listed sequences. Because the claim language does not meaningfully constrain region length or how the region relates to gRNA binding/PAM constrains, the scope includes numerous candidate target regions/sites that differ materially in their amenability to CRISPR targeting/editing. For CRISPR editing, small sequence differences can be outcome-determinative (guide binding/cleavage depends on the precise target sequence and PAM context), so the identity-based genus sweeps in many embodiments that may require different guide designs, different target choice and extensive validation to achieve editing.
Accordingly, the breadth created by defining BBX genes and a BBX/target regions by ≥80% identity is substantial and drives the enablement burden across a large universe of potential BBX targets and target sites. The specification provides, at most, limited and non-representative examples relative to the breadth of “a BBX gene”. The specification does not demonstrate that the inventor possesses and enables guide design and successful editing for BBX genes generally. Working disclosure is limited to a small number of specific BBX targets and specific guide spacers (e.g., Zm00001d017147 (SEQ ID NO:72) and Zm00001d051018 (SEQ ID NO:69) with two spacer PWsp2100 (SEQ ID NO:86) and spacer PWsp2101 (SEQ ID NO:87)). While those examples may enable editing for those particular disclosed sequences, they do not teach how to successfully practice the full genus encompassed by the ≥80% identity, including: BBX genes that meet ≥80% identity where guide complementarity is not assured, or where guide mismatches substantially reduce or abolish cleavage; and the large set of BBX/region embodiments within the identity-defined scope for which no guide design rules, validated targets, or success criteria are provide beyond the limited examples.
Thus, the number and diversity of examples are not commensurate with the claim breadth.
Even assuming a POSITA understands general CRISPR methods, success across the full identity-defined genus is unpredictable without extensive screening, because, the claims require a guide spacer that binds a target site within an endogenous BBX gene and (in claim8) achieves site-specific cleavage/editing at that target site. The specification does not provide sufficient guidance for a person of ordinary skill to practice the invention across the full scope without undue experimentation. In particular, the disclosure does not provide a roadmap for selecting among BBX gene family members to target; identifying suitable target sites that satisfy PAM constrains and yield effective binding/cleavage in the relevant genomic context; ensuring specificity to a chosen BBX locus where related sequences may exist; and confirming successful editing across different BBX genes and plant system. Consequently, practicing the claimed system for “a BBX gene” would require extensive iterative spacer design, screening, and validation, amounting to undue experimentation.
For many embodiments within the ≥80% identity scope, achieving binding/cleavage is not a routine, predictable extension of the examples, because guide-target performance depends strongly on exact target sequence, PAM presence, mismatch position/tolerance, and biological context. Also, the specification does not provide enabling guidance for the full scope on how to select target sites across the broad set of ≥80% identity BBX genes/regions such that a spacer will reliably bind and CRISPR-Cas will reliably cleave and generate and edit, without undue trail-and-error (e. g., iterative design/testing of many guide per candidate BBX gene/region).
As a result, to practice the invention across the entire claimed genus, a POSITA would need to undertake an extensive experimental program: identify candidate BBX genes/regions within the ≥80% scope, locate workable PAM-adjacent target sites, design and test numerous guide, evaluate editing efficiency and specificity, and repeat across many sequence variants.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 3, 6 and 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mullineaux (WO2022129856A1, filed 2021-11-18, published 2022-06-23).
Claim 3 recites a gene editing system comprising a CRISPR-Cas effector protein in association with a guide nucleic acid, wherein the guide nucleic acid comprises a spacer sequence that binds to a B-BOX (BBX) gene.
Mullineaux discloses a gene editing system comprising a CRISPR-Cas effector protein complexed with a guide nucleic acid (gRNA) , wherein the gRNA includes a spacer sequence complementary to and binding a target site in an Arabidopsis B-BOX (BBX) gene (BBX32) (claim 9 and 11, and page 29), thereby anticipating the claimed CRISPR-Cas/guide system in which the spacer binds a BBX gene.
Claim 6 recites the gene editing system of claim 3, further comprising a tracr nucleic acid that associates with the guide nucleic acid and a CRISPR-Cas effector protein, optionally wherein the tracr nucleic acid and the guide nucleic acid are covalently linked.
Mullineaux discloses tracrRNA, CRISPR-Cas effector protein and sgRNA concepts directly (page 29). Accordingly claim 6 is anticipated with Mullineaux.
Claim 14 recites a method of generating variation in a plant BBX transcription factor, comprising contacting an endogenous BBX gene within a plant cell with a CRISPR-Cas editing system, wherein the system is targeted to a region of the gene that encodes the transcription factor.
Mullineaux discloses a gene editing system(claim 9, 11, 12-14, 16, 18, 22, and page 29) to modify Arabidopsis BBX32 gene (a B-BOX transcription factor) through plant cell ( plant cell is plant part as claim 16 in Mullineaux). Accordingly claim 14 is anticipated with Mullineaux.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 2, 4, 5, 7, 8-11, 13, 15-17 and 20 are rejected under 35 U.S.C. §103 as being unpatentable over Mullineaux (WO2022129856A1, 2022) as applied claim 3 and 14, in view of Li (Li, Wenlan et al. Functional & integrative genomics 17.6, pp: 653-666, 2017).
Claims 3 and 14 as the teaching of Mullineaux is discussed above.
Claims 4, 5 and 7 are interpreted as depend of claim 3.
Claims 15-17 are interpreted as depend of claim 14.
Claim 1 is drawn to a guide nucleic acid that binds to a target site within an endogenous B-BOX (BBX) gene encoding a BBX transcription factor, where the BBX gene and/or the target site is defied by sequence identity (at least 80% identity) to the nucleotide sequences of any one of SEQ ID NOs: 69 and 70; or a polypeptide sequence of SEQ ID NO:71.
Mullineaux teaches that B-BOX DOMAIN CONTAINING PROTEIN32 (BBX32) is a negative regulator of photosynthetic capacity (page 2, line 20-35), abolishing the expression of at least one nucleic acid sequence encoding a B-Box Domain containing protein 32 (BBX32) polypeptide reducing or abolishing the activity of a BBX32 polypeptide in the plant (page 19, lime 19-36, page 20, line 1-8).
Mullineaux teaches a CRISPR/Cas gene editing system to mutate a BBX gene (claims 11, 21), Mullineaux teaches designing and using a guide nucleic acid in association with a CRISPR-Cas effector to bind and target a specific site within the endogenous light related BBX gene for site-specific cleavage/editing (page 29). Mullineaux further teaches “plants comprise one or more mutations in BBX32” (claim 21 and 22), with “one or more mutations are introduced into a least one plant cell and the plant is regenerated from the at least one mutated plant cell “(page 34, line 5-24).
Mullineaux does not teach the recited BBX genes, and their sequence-based identification. Mullineaux does not teach mutating the B-BOX domain in related DBB/BBX genes.
Li teaches ZmDBB4 gene as GRM2M2G019335 (Chr4: 137141449-137142700 (-)). The instant application identifies DBB4/BBX10 as Zm00001d051018 (Zm00001d051018 Chr4: 137141449-137142700 (-)) (paragraph 0344), with SEQ ID NO: 69, 70, and 71 as genomic sequence, cDNA sequence and polypeptide sequence. Therefore, Li teaches the same gene as claimed DBB4/BBX10 (alignment below).
Claim 2 is drawn to the guide nucleic acid of claim 1 .
Claim 5 is drawn to the gene editing system of claim 3, wherein the guide nucleic acid comprises a spacer having SEQ ID NO:86 or SEQ ID NO:87.
SEQ ID NO:86 matching a segment within the cDNA of ZmDBB4 (GRMZM2G019335) (below).
Claim 4 is drawn to the gene editing system of claim 3, wherein the BBX gene and/or the target site is defined by sequence identity to the nucleotide sequences of any one of SEQ ID NOs:69 and 70; or a polypeptide sequence of SEQ ID NO:71. Li teaches BBX gene SEQ ID NO:71 as mention before.
Claim 7 is drawn to the gene editing system of claim 3, wherein BBX gene is a BBX10 (DBB4) /DBB6 gene. Li teaches BBX gene SEQ ID NO:71.
Claim 8 is drawn to a method for editing a plant cell genome by introducing a CRISPR-Cas system (effector protein and guide nucleic acid) to cleave an endogenous BBX gene at a specific site. Wherein the BBX gene and/or the target site is defied to the nucleotide sequences of any one of SEQ ID NOs:69 and 70; or a polypeptide sequence of SEQ ID NO:71. Mullineaux teaches applying the CRISPR editing system to BBX genes, and Li teaches BBX gene SEQ ID NO:71 as mentioned before.
Claims 9, 10, 11, and 13 are drawn to a method depend on claim 8, wherein a spacer sequence comprises a nucleotide sequence of SEQ ID NO:86 or SEQ ID NO:87 (claim 9), wherein the edit results in a mutation in the B-BOX domain of the BBX transcription factor (claim 10), wherein the edit is located in a region of a B-BOX domain encoded by the endogenous BBX gene (claim 13), the method further comprising regenerating a plant from the plant cell comprising the edit in the endogenous BBX gene to produce a plant comprising the edit in its endogenous BBX gene (claim 11).
Mullineaux teaches “In certain embodiments, one or more mutations are introduced into a least one plant cell and the plant is regenerated from the at least one mutated plant cell” (page 35, line 4-5). Mullineaux further teaches that B-BOX DOMAIN CONTAINING PROTEIN32 (BBX32) is a negative regulator of photosynthetic capacity (page 2, line 20-35), abolishing the expression of at least one nucleic acid sequence encoding a B-Box Domain containing protein 32 (BBX32) polypeptide reducing or abolishing the activity of a BBX32 polypeptide in the plant (page 19, lime 19-36, page 20, line 1-8). Mullineaux teaches “plants comprise one or more mutations in BBX32” (claim 21 and 22).
Li teaches the two B-BOX domains in DBB4 gene (GRMZM2G019335), and teaches the important function of B-Box domain (page 653, introduction).
Claims 15-17 are drawn to the method of claim 14, wherein the endogenous BBX gene is SEQ ID NOs:69 or 70, and/or encodes an amino acid SEQ ID NO:71 (claim 15), wherein the targeted region is SEQ ID NOs:75-78 or 79-82 and/or encodes an amino acid sequence SEQ ID NOs:83-85 (claim16), and wherein the variation is generated in a region of the BBX transcription factor comprising a B-BOX domain (claim 17).
The sequence-identity limitations recited in claims 15 and 16 correspond to the BBX gene/target-site sequence-identity limitations of claim1, and the B-BOX domain variation recited in claim 17 corresponds to the spacer/B-BOX domain related limitation addressed above (e.g., claim 10 and 13). Accordingly, claims 15-17 do not recite additional limitations.
A POSITA would have been motivated by Mullineaux to mutate a light-regulated endogenous BBX/DBB gene to validate and alter gene function using CRISPR spacer-guided target/editing (including routine design of a complementary guide once the target gene/region is known), and would have applied that approach to ZmDBB because Li reports that ZmDBB genes are implicated in plant development and show significant expression changes under light/dark and phytohormone treatments - including involvement in light and hormone signaling pathways (Li, page 653, 655 and 657), thereby, providing a reasonable expectation of success in designing guides to target the BBX/DBB sequences identified by Li, and obtaining edited plants for functional assessment.
A POSITA would have been further motivated to apply Mullineaux’s CRISPR-Cas spacer-sequence/target-region guided targeting and site-specific editing approach to the endogenous maize BBX/DBB genes identified by Li, including targeting regions within a BBX (B-BOX) domain of the encoded BBX transcription factor. Once a specific endogenous BBX gene and target region are identified, selection and design of an appropriate guide RNA spacer complementary to that target region would have been a routine and recitable step, performed in accordance with well-established CRISPR design principles, such as sequence complementarity, PAM compatibility, and avoidance of off-target effects. Under these routine design considerations, spacer sequences corresponding to disclosed target regions, including a spacer targeting the sequence of SEQ ID NO;86, would have been selected as a matter of ordinary skill.
A skilled artisan would therefore have reasonably expected that introducing a site-specific edit into the endogenous BBX gene in a plant cell and regenerate a plant comprising the edit, would successfully enable assessment of BBX/DBB gene function, including roles in light signaling/ photosynthesis.
The claimed invention in claims 1, 2, 4, 5, 7, 8-11, 13, 15-17 and 20 as a whole is prima facie obvious over the combined teachings of the prior arts above.
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Claims 12, 18, and 19 are rejected under 35 U.S.C. §103 as being unpatentable over WO2022129856A1 (Mullineaux 2022) as applied on claim 14, in view of Li (2017) as applied on claims 8, and further in view of Crocco (Carlos D. Crocco et. al., Nature communications 6:6202, pp1-10, 2015).
Claim 8 as the teachings of Mullineaux and Li is discussed above.
Claim 14 as the teachings of Mullineaux is discussed above.
Claim 12 is interpreted as dependent of claim 8.
Claim 18 is interpreted as dependent of claim 14.
Claim 12 depends from claim 8 and is drawn to the plant comprising the edit in its endogenous BBX gene has an attenuated Shade Avoidance Response.
18 and 19 drawn to the method of producing edit plant and subsequent regenerating a plant from the edited cell, selfing the plant to obtain E1 progeny, and selecting progeny with reduced shade avoidance response relative to a control plant (claim 18), further comprising selfing the selected progeny to produce E2, and selecting progeny with reduced SAR relative to a control (claim 19).
Mullineaux teaches modifying an endogenous BBX transcription factor gene in a plant using targeted genome editing (e. g., CRISPR/Cas with a guide nucleic acid) to generate mutations in the endogenous BBX gene and to obtain plants having the resulting increasing photosynthesis and improving yield genotype (claim 24). Mullineaux further teaches a workflow of regeneration, comprising: (1) producing an edited BBX gene in a plant part (cell); (2) regenerating a plant from the edited plant part (cell); (3) advancing to progeny generations (T1) via selfing/propagation; (4) phenotyping/screening and selecting progeny exhibiting the desired phenotype relative to a control (page 35-37); (5) and advancing edited /regenerated plants through successive progeny generations (e. g., T2 and later generations) by repeated selfing, coupled with phenotyping/assaying and selecting progeny having the desired phenotype (page 35). “T1/T2” (Mullineaux) is alternative conventional label of “E1/E2” for instant claims.
Mullineaux does not explicitly teach the particular maize BBX/DBB gene sequence set recited in claim12 (e. g., the specific SEQ ID NO selections and/or the “≥80% identity” framing as applied to the particular claimed maize BBX gene region/polypeptide).
Li teaches the identification/characterization of maize BBX/DBB genes, provides maize DBB/BBX genes sequence and structural (such as double B-box, without CCT domain)(fig 4, page 658), and points out BBX/DBB genes (DBB4/DBB6) “play an essential role in the light signaling pathway”(page 663), Li also teaches in BBX family “similar gene structures may share the similar gene functions”(page 663).
Crocco teaches that BBX24 in Arabidopsis sharing the same structure as maize DBB4/6 (two B-Box)(page 2), and participating in light-response/photomorphogenesis networks (including shade avoidance response) (abstract). Crocco further teaches mutating BBX24 results “shade-response defect”(abstract).
A person of ordinary skill in the art would have been motivated to apply Mullineaux’s CRISPR-based editing approach for endogenous BBX genes to the specific maize BBX/DBB family members identified/characterized by Li, because Li provides concrete maize BBX/DBB targets within the same gene family addressed by Mullineaux. Further, Crocco and the BBX family domain-structure framework (Sreeramaiah N. Gangappa et al., Trends in Plant Science, July 2014, Vol. 19, No. 7) support that BBX genes sharing the relevant conserved domain architecture are credible regulators of light/shade response outputs, mutate BBX gene causes avoid SAR. Accordingly, the skilled artisan would have been motivated to apply Mullineaux’s CRISPR-Cas spacer-guided targeting/editing approach to Li’s identified maize DBB/BBX genes, then regenerate a plant and self across generations (E1/E2) with assaying /selection for reduced shade avoidance, in order to generate targeted edits and assess BBX/DBB function in light signaling/photosynthesis-related pathways, with a reasonable expectation of success, because Li links ZmDBB genes to light-responsive regulation/expression and Crocco supports BBX involvement in shade/light-regulated development.
The claimed invention in claims 12, 18 and 19 as a whole is prima facie obvious over the combined teachings of the prior arts above.
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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 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 15, 24, 67, 89, 111, and 114 of copending Application No. US18593162 (reference application). Although the instant claims and the reference claims are not identical, they are not patentably distinct from each other because they do not add any non-obvious structural or procedural limitation beyond what is already claimed for editing the same endogenous BBX gene/target site.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Instant claims 8-17 recite introducing a targeted nuclease system (explicitly CRISPR-Cas) to cleave/edit the same endogenous BBX garget site defined by the same sequence identity limitations, thereby generating an edit/mutation, which is an obvious species/implementation of the reference’s claimed targeted nuclease editing of the same BBX loci (reference claim 67), including B-Box domain embodiments (reference claim 15) and reduced SAR embodiments (reference claims 24/89/114).
Instant claims 11, 18, and 19 add routine downstream steps (regenerating plants, selfing, assaying/sleeting progeny) that would have been obvious and conventional once the reference already claims producing plants having the BBX mutation and reduced SAR phenotype (reference claims 67, 89, 114). These steps do not render the claimed subject matter patentably distinct.
Instant claims 1-7 and 20 recite guides/CRISPR systems and transformed plants/constructs directed to binding /targeting the same BBX loci defined by the same sequence identity limitations. Such claims are obvious variants for practicing the reference’s claimed mutated plants and traits (reference claims 1, 24, 67, 89, 114), and therefore are not patentably distinct.
Accordingly, the claims 1-20 of application 18644352 are not patentably distinct from the claims of the reference application and a provisional obviousness-type double patenting rejection is appropriate.
Conclusion
No claims are allowed.
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/YANXIN SHEN/ Examiner, Art Unit 1663
/WEIHUA FAN/ Primary Examiner, Art Unit 1663