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 .
This is a Final Office Action in response to amendment filed on 04/02/2026.
Claim Status
Claims 1, 4, 11, 12, 16, 18, 31, 52, 57, 59, 60, 64, 66, 68, 79-81, 83, 89 and 98 are pending. Claims 1, 4, 11, 12, 16, 18, 31, 52, 57, 59, 60, 66, 68, 79-81, 89 and 98 are currently amended. Claims 3 and 8 are currently canceled. Claims 1, 4, 11, 12, 16, 18, 31, 52, 57, 59, 60, 64, 66, 68, 79-81, 83, 89 and 98 are examined on the merits.
Response to Amendment
The objection of claims 1, 18, 52, 68, 89, and 98 are withdrawn in view of amendment to the claims.
The rejection of Claims 1, 3, 4, 8, 11, 12, 16, 18, 31, 52, 57, 59, 60, 64, 66, 68, and 98 rejected under 35 U.S.C. 112(b) are withdrawn in view of amendment to the claims.
The rejection of Claims 1, 3, 8, 11 and 12 rejected under 35 USC § 102(a)(1) is withdrawn in view of amendment to the claims. However, claims 1, 11, and 12 are now rejected under 35 U.S.C. §103 for the reasons set forth below.
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 1, 4, 11, 12, 16, 18, 31, 52, 57, 59, 60, 64, 66, 68, and 98 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
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.
The claims are broad in the following aspects:
Claims 1 and the dependent claims (claim 3, 4, 8, 11, 12, 16, 18, and 31), claims 52 and the dependent claims (claim57, 59, 60, 64, 66, and 68), claim 98, recite an “soybean plant endogenous BZR1 gene” or mutated BZR1 nucleic acids/polypeptides defined broadly by “at least 80% sequence identity” to various full-length and partial BZR1 sequences (SEQ ID NOs:69, 70, 72, 73, 75, 76, 78, and 79; SEQ ID NOs:71, 74, 77, and 80; SEQ ID NOs:81-84, 85-88, 89-92, 93-96, 99, 100, 103, 104, 107, 108, 110, and 111; SEQ ID NOs:97, 98, 101, 102, 105, 106, and/or 109)’
Claim 1 does not affirmatively required any particular functional activity beyond the plant “comprising at least one mutation in an endogenous BZR1 gene encoding a BZR1 polypeptide.” What it does require are structural/sequence limitations: the gene must meet at least one of the identity/region options in (a)—(d), e.g., endogenous BZR1 or region, which has ≥80% sequence identity. So, under BRI, claim reads on any soybean plant/part with any mutation anywhere in an endogenous BZR1 gene that fits the identity definitions, even if the mutation has no measurable effect on BZR1 phosphorylation, activity, or phenotype.
Brassinazole resistant 1 (BZR1) is a well-known plant specific transcription factor which functions directly in the BR signal pathway via BR gene expression regulation. A POSITA understands “a BZR1 polypeptide” to mean a protein that behaves like BZR1, it has the characteristic functional identity of BZR1-family transcription factors (regulatory activity in BR signaling, typically associated with phosphorylation/dephosphorylation states and specific regulatory regions such as a PEST region, nuclear localization, DNA-binding/regulatory function etc.) (p739) (Baoqiang Wang, Genome-wide identification, structural analysis, and expression profiles of the BZR gene family in tomato, Journal of Plant Biochemistry and Biotechnology, Volume 31, pages 739–750, 2022).
The claims, however, define the “BZR1” gene/polypeptide largely by broad sequence identity (as low as 80%) and even by partial “region” identity, which can encompass a wide variety of sequences for which BZR1-characteristic function /regulation is not assured.
The specification as filed, however, does not adequately describe (1) representative BZR1 species across the full 80% identity scope and /or (2) the common structural features that correlated with BZR1 activity/regulation such that a POSITA would understand the inventor possessed the full scope of “BZR1” variants encompassed by the claim. The specification only describes a very limited set of species within this broad genus. Example 1 describes an “editing strategy” in which only targets to PEST domain region of four specific soybean BZR1 genes: of Glyma·17g248900 (SEQ ID NO:69), Glyma·14G076900 (SEQ ID NO:72), Glyma·06G034000 (SEQ ID NO:75), and Glyma·04G033800 (SEQ ID NO:78). Example 2 and Table 1 provide specific edited alleles (alleles A-J), each defined by particular small deletions (e. g., 7-49 bp) round the PEST region in those same four BZR1 genes, with the resulting amino acid changes set forth in SEQ ID Nos: 117, 119, 121, 123, 125, 127, 129, 131, 133, and 135. The exemplified mutations are limited to a small number of in-frame and out-of-frame deletions in the PEST domain or nearby coding sequence of these exact soybean BZR1 genes. There is no example of a gene that is “only” about 80% identical to the reference sequences; all exemplified sequences are very close variants of the disclosed soybean BZR1 sequences.
Furthermore, interpreted as being directed to polypeptides having at least 80% identity to the amino acid sequence, 80% identical protein might come from a much higher or much lower DNA identity, depending on which codons differ and how many substitutions occur. On the other hand, 80% identity in DNA may result in protein sequence having 40% (when the non-wobble nucleotides of each of the 60% of codons are mutated. For example, for a 300-nt ORF, 80% identity allows for 60 nucleotide mutations, that could result in 60 out of the 100 codons mutated, and the encoded amino acid only 40% identical); not to mention frameshifts by indels. A protein or polypeptide claims with 80% identity does not cover any specific percentage identity at the nucleotide level unless explicitly recited. The two scopes do not automatically overlap. Much lower polypeptides identity such as (40% identity) can be end up with even more proteins with different functions. Under the broadest reasonable interpretation, the recited sequence identity threshold (e. g., as low as 40% amino acid identity) defines an extremely broad genus of polypeptides. At this level of identity, the claimed mutant would reasonably be understood by a POSITA to encompass distant paralogs, unrelated prescription factors, proteins with different domain architectures, such variants would fifer in key functional motifs (e.g., DNA-binding domain, phosphorylation sties, PEST regions) and may not retain brassinosteroid-related activity. Because the literal claim scope extends to a wide universe of polypeptides sharing only limited primary sequence similarity and potentially performing entirely different biological functions.
Even “At least 80% sequence identity” of polypeptide to BZR1 is very broad. For example, in rice, both BZR1 and BES1 (bri1-ems-suppressor 1) are belong to BZR family, their protein sequence similarity is 88%, and their N-terminal domain similarity is 97%, but they do not have the same function (Wang p740). In Arabidopsis thaliana, all the eight BZR1/BES1 family members have an N-terminal bHLH DNA binding motif that is potentially responsible for DNA binding as transcriptional factors, whereas the functions of those BZR1 homologs have diverged. BZR1 represses the expression of BR-biosynthetic genes through binding to BR-response elements (BRRE, CGTGC/TG), while BES1 is demonstrated to activate gene expression via binding to the E box motif (CANNTG) (Zuo p12) (Chunliu Zuo et. al., Evolutionary analysis and functional characterization of BZR1 gene family in celery revealed their conserved roles in brassinosteroid signaling, BMC Genomics (2022) 23:568).
On the other hand, the applicant does not describe or exemplify BZR1 genes from other soybean cultivars or other species that are ~80% identical to SEQ ID Nos: 69, 70, 72, 73, 75, 76, 78, or 79; does not provide any sequence-to-function correlation or teaching that would allow a POSITA to recognize which of the vast number of BZR1-like sequences that share≥80% identity to these SEQ ID NOs would behave like the disclosed soybean BZR1 alleles in terms of phosphorylation, stability, or yield traits; does not provide representative examples distributed across the full scope of the claimed genus defined by the 80% identity thresholds in (a)-(d).
In addition, the state of the art indicates that BZR1-like transcription factors in soybean are highly conserved and functionally sensitive to specific amino acid change, particularly with the PEST domain, and therefore do not support a broad genus of “at least 80% identity” variants and having the same functional properties as the exemplified alleles (Song p3-4) (Li Song et. al., GmBZL3 acts as a major BR signaling regulator through crosstalk with multiple pathways in Glycine max, BMC Plant Biology, Volume 19, article number 86, 2019).
Also, each plant species typically contains multiple BZR1 genes, total of 20, 11, 9 and 7 BZR1 genes were identified in ginseng, lettuce, celery and grape, respectively (Zuo, p2). Zuo mentions 9 celeries BZR1s have different tissue-specific expression profiling and extensive involve in the developmental processes with both function redundancy and divergence in celery, Zuo also mentions, thousands of nonfunctional duplicates existing in the plant genome (p10-11).
Song preformed ChIP-seq and showed that BmBZL3 directly binds thousands of genomic sites and regulates hundreds of genes involved in hormone signaling (auxin, GA, JA, ethylene), disease resistance, stress responses, cell expansion, and other development pathway. Thus BZR1-like proteins act as genome-wide transcriptional hubs shoes activities are tightly regulated by BR levels, phosphorylation status, and specific domain motifs. Song further shows that natural variation in GmBZL3 coding sequence is extremely limited: in a panel of 106 soybean genotypes, only two synonymous SNPs(no amino acid changes) and a rare frameshift deletion (introducing a premature stop and disrupting the PEST region) are detected, again indicating very little tolerated amino-acid diversity in functional alleles (p5-6).
One of ordinary skill in the art would not reasonably conclude that any polypeptide or nucleic acid having “at least 80% sequence identity” to the listed BZR1 sequences would necessarily retain the same BR-signaling, phosphorylation, or yield trait phenotypes as the narrow subset of alleles actually exemplified in the specification. Rather, the art shows that BZR1-like proteins are highly sensitive to particular amino-acid changes in defined regulatory domains, and that functional outcomes cannot be predicted solely from abroad percent-identity threshold.
From the specification, alleles summarized in (Table 1: Alleles A-J) all introduce relatively simple deletions within the short PEST-encoding region, yet the phenotypic data (in tables 2-6) show a wide spectrum of outcomes: some in -frame deletions in the PEST region are associated with increased pods or seeds per plant, whereas other, closely related deletions result in little change or even apparent reductions in yield-associated traits. Thus, even when the modifications are confined to a small, conserved PEST segment of highly homologous BZR1 genes, the functional consequences are heterogeneous and not predictable from sequence identity alone. This variability in outcome from “simple” PEST deletions is fully consistent with, and further reinforces, the conclusion that broad “≥80% identity” ranges ae not adequately supported by the limited set of specific alleles actually exemplified.
Scope of Enablement
Claim 1, 3, 4, 8, 11, 12, 16, 18, 31, 52, 57, 59, 60, 64, 66, 68, and 98 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 a soybean plant (or part) comprising one of the specifically described edited alleles A-J (SEQ ID NO: 116-135) does not reasonably provide enablement for the full scope of the claimed inventions. 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 and the dependent claims (claim 3, 4, 8, 11, 12, 16, 18, and 31), claims 52 and the dependent claims (claim57, 59, 60, 64, 66, and 68), claim 98, recite an “soybean plant endogenous BZR1 gene” or mutated BZR1 nucleic acids/polypeptides defined broadly by “at least 80% sequence identity” to various full-length and partial BZR1 sequences (SEQ ID NOs:69, 70, 72, 73, 75, 76, 78, and 79; SEQ ID NOs:71, 74, 77, and 80; SEQ ID NOs:81-84, 85-88, 89-92, 93-96, 99, 100, 103, 104, 107, 108, 110, and 111; SEQ ID NOs:97, 98, 101, 102, 105, 106, and/or 109)
“≥80%” identity of polypeptides or polynucleotides sequence makes the claim broad because it captures many divergent BZR1-line sequence whose PEST-domain regulation and response to editing are not taught; adding limitations that pin the claim to the four disclosed loci and the specific target region/edits/guides can narrow the scope to what the spec actually enables.
The breath of the genera has been discussed above.
In contrast, the specification provides only a limited number of working examples (examples 1-3 paragraph 0333-0337) in soybean (Glycine max), describes an editing strategy focused on the PEST domain of certain soybean BZR1 genes to decrease phosphorylation and thereby increase BZR1 Activity and potentially improve yield traits, and provides a finite set of edited alleles (e. g., specific deletions/frameshifts) and observed phenotype measurements in limited experiments (paragraph 0333-0337).
However, the claims extend far beyond that disclosure. The claims cover any mutation in the defined endogenous BZR1 genes/regions (claim 1), including mutations outside the PEST domain (claim 1, 8, 11, and 12). The claims include broad identity-based variants (≥80 nucleotide/ amino acid identity; 90% for mutated sequences), which encompass numerous non-exemplified alleles and potentially multiple BZR1-like loci. The claims cover a broad genome-editing method and guide RNAs across a large space of potential targets (claim 52, and 98) without teaching sufficient guidance to practice eth entire scope.
BZR1-like transcription factors in soybean are highly conserved and functionally sensitive to specific amino acid change, particularly with the PEST domain, and therefore do not support a broad genus of “at least 80% identity” variants and having the same functional properties as the exemplified alleles (Song). (see alignment for detail conserved domain and binding site).
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Multiple amino acid sequence alignment of the GmBZL in Soybean and Arabidopsis. The marked features are the N-terminal DNA binding domain (blue underline), putative 14–3-3 binding site (blue letters and box), putative sites of phosphorylation by GSK-3 kinase (red star), and the PEST domain (green letter and over line). The conserved amino acid (proline) between Arabidopsis and soybean in the PEST region is indicated by a red box, and was mutated to the amino acid leucine for the validation of conserved functional
Song characterized four soybean BZR1-like proteins, and showed that these genes arose by ancient segmental duplication events and are under strong purifying selection (Ka/Ks 0.05-0.15), consistent with tight functional and structural constraints on the encoded polypeptides. Song further showed that BmBZL3 (SEQ ID NO:75 in instant claims) contains the same conserved functional domains as Arabidopsis BZR1/BES1, including an N-terminal DNA-binding domain, a 14-3-3 binding site, multiple BIN2/GSK3 phosphorylation sites, and a C-terminal PEST domain that contains a highly conserved proline residue. In functional studies, overexpression of wild-type GmBZL3 in the Arabidopsis bri1-5 BR-insensitive mutant did not rescue the dwarf for BR-insensitive phenotypes, where as a single Pro to Leu substitution in the PEST motif converted BmBZL3 into a dominant gain of function allele, which did partially rescue plant height and BR responsiveness in bri1-5. Song reports that the wild type GmBZL3 transgene is expressed at even higher RNA levels than GmBZL3P219L, yet only the PEST mutated version alters the phenotype, demonstrating that the precise identity of residues within the PEST domain, rather than overall sequence similarity or expression level, determines function (p4-5).
Although for the claims focus on a “PEST” domain, the prior art as we discussed before, does not support that the PEST domain is a simple, universally interchangeable target where any edit predictably produces the asserted biochemical/phenotypic outcomes. The effect of a given nucleotide change (or indel) on phosphorylation, stability, protein activity, and downstream agronomic traits depends on precise sequence context, including which residue correspond to phosphorylation motifs, the spacing of those motifs, local secondary structure.
Thus, while the specification may teach how to generate certain exemplified edits, it does not teach how to practice the full breath of the claims as drafted (especially those lacking an explicit function) without substantial additional research and screening.
The state of art reflects that predicting the phenotypic and biochemical consequences of arbitrary edits in BZR1 is unpredictable, particularly for complex and agronomic traits. Practicing the claims across their full breath would require, designing and generating large numbers of different substitution/insertions/deletions across BZR1 loci and regions that meet the identity definitions,
For the claim encompasses any mutation in the region encoding the PEST domain, or further encompasses disruption of phosphorylation sites, the specification does not provide sufficient direction to identify which specific sites are phosphorylation sites in each claimed endogenous BZR1 gene nor ow particular nucleotide edits will disrupt them while retaining operability. For the claims lack function (e. g., claim 1, 3, 4, 8, 11, 12, 52, 57,, 59, 60, 98), because the claims do not require any functional outcome, they encompass a vast number of PEST-region edits that are non-operable for the stated purpose, and the specification does not teach how to select operable edits from inoperable ones without undue experimentation.
Accordingly, the specification does not enable the full scope of the claims. Even when limited to edits in the PEST-domain-encoded region, successful mutations are not predictable from sequence conservation alone and require mutation-by-mutation design, regeneration, and empirical testing to confirm that the edit “works” (e. g., disrupts phosphorylation without rendering the BZR1 protein nonfunctional or the plant nonviable). Because the claims encompass broad classes of substitutions, insertions, and deletions across multiple endogenous BZR1 gene/regions defined primarily by sequence identity, and the specification provides only limited examples and insufficient guidance for selecting operable nucleotide positions and edit types across that breath, practicing the full scope would require undue experimentation. Therefore, the claims are rejected under 35 U.S.C. 112(a) for lacking of enablement.
Response to Applicant’s Remarks: 35 USC § 112(a), Written Description
Applicant argues that the § 112(a) written description rejection is overcome by amendment of the independent claims to add narrower structural limitations. Specifically, claim 1 now requires a base deletion in the BZR1 gene region encoding the PEST domain that disrupts phosphorylation sites, while claim 52 and 98 are limited to an endogenous soybean BZR1 gene with further defined target-site sequences.
Applicant further contends that the specification supports the claimed 80% sequence identity scope through disclosed Allele I and Allele J examples, and that the amended claims now recite sufficient structural and functional features to demonstrate possession of the invention. Applicant cites Enzo Biochem V. Gen-probe and requests withdrawal of the written description rejection.
Applicant’s arguments have been considered but are not persuasive. Although Applicant amended claim 1 to recite a base deletion in the region encoding the PEST domain that disrupts phosphorylation sites, and amended claims 52 and 98 to recite an endogenous soybean BZR1 gene, the claims still rely on broad sequence-identity language, including sequences having at least 80% identity to numerous BZR1 nucleotide and amino acid sequences.
The amendment does not cure the original 112(a) issue because the specification does not identify common structural features, conserved residues, phosphorylation motifs, or PEST-domain boundaries that would correlated the full 80% identity genus with the claimed BZR1 function or regulatory effect. A sequence having 80% identity may differ at many positions, including positions within the PEST domain or phosphorylation sites. The specification does not show that all such variants would retain the relevant BZR1 structure, contain corresponding phosphorylation sites, or be predictably disrupted by a base deletion.
Applicant’s reliance on Allele I and Allele J is insufficient. The disclosure of two alleles, even if they share less than 80% identity with each other, does not demonstrate possession of the full genus of ZAR1 genes, target regions, guide-binding sites, and edited variants. The specification also does not identify common structural features that distinguish operable variants across the full 80% identity scope.
Further, claims 52 and 98 remain broad because the target site and guide nucleic acid are defined by 80% identity to numerous sequences. The specification does not adequately teach which divergent target sites within that scope would be recognized and successfully edited. Thus, substantial case-by-case testing would still be required
Accordingly, the rejection of claims 1, 4, 11, 12, 16, 18, 31, 52, 57, 59, 60, 64, 66, 68, and 98 is maintained.
Response to Applicant’s Remarks: 35 USC § 112(a), Enablement
(1) Applicant’s main amended to narrow scope, especially:
Claim 1 now requires a base deletion in the PEST deletion in the PEST-domain-encoding region disruption phosphorylation sites.
Claim 52 defines the target-site region in an endogenous soybean BZR1 gene.
Claim 98 similarly narrows the guide target site.
(2) Working examples now match the amended claims, so Applicant argues the specification enables the full scope as amended.
(3) CRISPR editing methods were well known in the art, so a POSITA could practice the claims without undue experimentation.
(4) Applicant cites Wands and MPEP sections, asserting the disclosure provides sufficient guidance and examples.
Applicant’s arguments regarding enablement have also been considered but are not persuasive.
Applicant argues that amendment of claims 1, 52, and 98 cures the enablement issue. However, the amendments do not remove the core breadth problem because the claims still encompass BZR1 genes, target regions, and guide-binding sequences defined by at least 80% sequence identity to numerous recites sequences. Such scope extends well beyond the specific soybean loci and edited sequences actually exemplified.
Applicant argues the working examples enable the amended claims. However, the examples remain limited to particular disclosed soybean BZR1 loci, particular guide RNAs, and particular edits within specific PEST-domain regions. The specification does not demonstrate that the same editing strategy will function across the full universe of sequences sharing only 80% identity, where sequence divergence may alter PAM availability, guide binding efficiency, chromatin accessibility, exon structure, or editing outcomes.
Applicant further argues that claim 1 is narrowed to a base deletion disrupting phosphorylation sites in the PEST domain. However, the specification does not teach how to identify, across the full claimed 80% identity range, which divergent BZR1 variants retain corresponding PEST domains or phosphorylation motifs, or which deletions would disrupt such sites while preserving viable BZR1 function and producing the claimed phenotype.
Applicant’s reliance on general CRISPR knowledge is unpersuasive. While CRISPR systems were known, routine knowledge of gene editing does not supply missing guidance regarding which specific target sites among numerous 80%-identity variants are operable, nor which guide nucleic acids within the scope of claim 98 will effectively bind and generate the claimed mutations.
Thus, substantial sequence-by-sequence screening and empirical redesign would still be required to determine operable genes, claims therefore target sites, guides, and edits throughout the full claimed scope. The claims therefore remain broader than the enabling disclosure.
Accordingly, the rejection of claims 1, 4, 11, 12, 16, 18, 31, 52, 57, 59, 60, 64, 66, 68, and 98 is maintained.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The rejection under 35 U.S.C. 103 is modified to address Applicant’s claim amendments.
Claim 1, 4, 11, 12, 16, 18, and 31 are rejected under 35 U.S.C. §103 as being unpatentable over Song (Li Song et. al., BMC Plant Biology (2019) 19:86, pp1-15).
Claim 1 recites a soybean plant or part thereof comprising at least one mutation in an endogenous BRASSINAZOLE-RESISTANT 1 (BZRI) gene encoding a BZR1 polypeptide, wherein the endogenous BZR1 gene: (c) encodes a polypeptide comprising a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 77, wherein the at least one mutation comprises a base deletion in the region of the endogenous BZR1 gene that encodes the PEST domain of the BZR1 polypeptide, and wherein the at least one mutation disrupts phosphorylation sites in the PEST domain.
Song teaches GmBZL3 (sequence shows in fig 1) and GmBZL3 is SEQ ID NO:77 in instant claims, Song further teaches GmBZL1, 2, 4 are also showed to be SEQ ID 71, 74, 80 respectively (see alignment below). Song further teaches that soybean BZR1-line/BZL proteins contain a PEST domain with multiple phosphorylation-related residues, and that phosphorylation state in this region is tired to BZR/BZL activity and BR-related phenotypes (page 3, right column). Song also teaches naturally occurring soybean allelic variation, including a nucleic acid deletion in soybean lines PI594599 and PI603154 causing a frameshift and premature stop codon (page 9, left column), and further teaches a PEST-region mutation, P129L, associated with altered localization, phosphorylation-related behavior, and bzr1-1D-like phenotypes (page 4, paragraph 2). Thus, song teaches the soybean BZR1 gene/protein context, the functional importance of the PEST-domain region, and that alteration of this region affects BZR1 activity.
Song does not explicitly teach a soybean plant having an endogenous BZR1 base deletion specifically in the region encoding the PEST domain that disrupts phosphorylation sites as now recited.
However, Song teaches base deletion can completely change the conserved PEST sequence in GmBZL3 (page 9, paragraph 1). it would have been obvious to a person of ordinary skill in the art at the time of the invention to introduce a base deletion into the PEST-domain-encoding region of the endogenous soybean BZR1 gene in view of Song’s teachings. A POSITA would have understood that disrupting one or more phosphorylation-associated residues or motifs within the PEST domain was a predictable way to reduce inhibitory phosphorylation and thereby alter BZR1 activity. A POSITA also would have found it obvious to make the change in the endogenous soybean locus, rather than only in a heterologous us or transgenic context, in order to obtain a stably inherited soybean trait-associated allele in the native genomic setting.
In view of Song’s teachings regarding the soybean BZR1 PEST domain and phosphorylation-linked regulation, a POSITA would have had a reasonable expectation of success that introducing a base deletion in that region would disrupt phosphorylation sites in the PEST domain and alter BZR1 activity. Therefore, claim 1 is obvious over Song.
Claim 4 recites the soybean plant or part thereof of claim 1, wherein at least one mutation results in a mutated BZR1 polypeptide having increased activity or constitutive activity.
For the same reason set forth with respect to claim 1, Song teaches that a PEST-region mutation such as GmBZL3P219L can produce bzr1-1D-like phenotypes indicative of enhanced or constitutive BZR1-related activity (page 4, paragraph 2). Claim 4 is obvious over Song.
Claim 11 recites the soybean plant or part thereof of claim 1, wherein the base deletion is an in-frame deletion.
For the same reason set forth with respect to claim 1, once it would have been obvious to introduce a base deletion in the PEST-domain-encoding region of endogenous soybean BZR1 to disrupt phosphorylation-associated sequence features, it would have been obvious to select the deletion size such that the deletion is in-frame, because in-frame deletions represent a routine and predictable design choice when modifying a protein regulatory region while preserving the remaining overall reading frame and much of the protein structure. A POSITA would have recognized that an in-frame deletion is a conventional option for altering specific residues or motifs, such as phosphorylation-associated residues, while retaining a largely intact BZR1 Polypeptide. Therefore, claim 11 is obvious over Song.
Claim 12 recites the soybean plant or part thereof of claim 1, wherein the base deletion is an out-of-frame deletion.
For the same reason set forth with respect to claim 1, it would have been obvious to introduce a base deletion in the PEST-domain-encoding region of endogenous soybean BZR1. It would have been obvious to select the deletion such that is out-of-frame. Therefore, claim 11 is obvious over Song.
Claim 16 recites the soybean plant or part thereof of claim 1, wherein the plant or part thereof comprising the at least one mutation exhibits a phenotype of improved yield traits, as compared to a plant that is devoid of the at least one mutation.
Song teaches BZR1 family regulators positively control growth response, and Song expressly links brassinosteroids to developmental outputs including seed development/seed filling, yield-relevant process (page 1, Abstract), (for examples, overexpressed GmBZL2 P216L mutant increase the seed number per silique), supporting that enhancing BR signaling output could impact yield-related traits (page 2, left column, paragraph 3).
For the same reason set forth with respect to claim 1, claim 16 is obvious over Song.
Claim 18 recites the soybean plant or part thereof of claim 1, wherein the at least one mutation results in a mutated BZR1 gene having at least 90% sequence identity to a nucleotide sequence of SEQ ID NO:116, 118, 120, 122, 124, 126, 128, 130, 132, or 134 and/or a mutated BZR polypeptide having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:117, 119, 121, 123, 125, 127, 129, 131, 133, or 135.
For the same reason set forth with respect to claim 1, Song teaches natural soybean alleles exist with small deletions in the BZR1-faimily gene with a 1-bp deletion causing a frameshift and premature stop; and completely changes PEST sequence (page 9, paragraph 1).
Song does not teach the specific SEQ ID NOs:116, 118, 120, 122, 124, 126, 128, 130, 132, 134 and SEQ ID NOs:117, 119, 121, 123, 125, 127, 129, 131, 133, 135, nor the requirement that the mutated gene/polypeptides has “≥90% identity” to those particular sequences.
In view of Song’s teaching that small deletions/frameshifts in a soybean BZR1 family gene exist and alter the protein, a POSITA would have been motivated to generate soybean plants having a mutated BZR1 gene/polypeptide with at least 90% sequence identity to the listed SEQ ID NOs. In soybean, naturally occurring allelic variation among cultivars and closely related BZR1 sequences is expected, therefore implementing Song’s taught mutation in BZR1 coding sequences that remain highly homologous (≥90% identity) would have been a predictable, routine approach to obtain the same activity-shifted BZR1 while preserving core BZR1 structure and function. Accordingly, a POSITA would reasonably expect that BZR1 variants retaining ≥90% identity to the disclosed sequences, still carrying the taught mutation, would function as mutated BZR1 genes/polypeptides as recited in claim 18.
Claim 31 recites a soybean plant regenerated from the plant part of claim 1 and comprising the mutation in the endogenous BZR1 gene, wherein the plant exhibits a phenotype of improved yield traits, compared to a plant that is devoid of the at least one mutation.
For the same reason set forth with respect to claim 1 and 16, claim 31 is obvious over Song.
Claim 52, 57, 59, 60, 64, 66, 68, 79, 80, 81, 83, 89, and 98 are rejected under 35 U.S.C. §103 as being unpatentable over Song (2019), in view of Lu (Qing Shi Mimmie Lu et. al., BMC Biotechnology, Volume 22, article number 7, 2022).
Claim 52 recites method for producing a soybean plant/part a mutation in an endogenous BZR1 by contacting a target site in the BZR1 gene with a nuclease (cleavage + nucleic acid binding domain) that binds to a target site in BZR1; BZR1 defined by identity to the SEQID NOs; target site in particular regions (SEQ ID NOs:81-84, 85-88, 89-92, 93-96, 99, 100, 103, 104, 107, 108, 110, 111 /97, 98, 101, 102, 105, 106, 109).
Song teaches that BZR1 activity is regulated by phosphorylation, and specifically describes that BIN2 phosphorylates BZR1 and that BZR1 contains a phosphorylated PEST domain that includes conserved phosphorylation sites (page 3, right column). Song teaches that alterations in /around PEST region are functionally meaningful, describing a P219L mutation and stating that this mutation affects nuclear localization, protein stability, and phosphorylation / dephosphorylation (page 4, left and right column). Song teaches yield-relevant phenotypes tied to BZR1 variants, reporting that BmBZL2 (P216L)/GmBZL3(P219L) behave like bzr1-1D, and that overexpression of these variants increased seed number (and plant height) in the reported system (page 2, left column, paragraph 3).
Song does not teach a soybean genome editing method that “contacts a target site” with a nuclease system to create mutations in an endogenous soybean BZR1 gene.
Lu teaches a CRISPR/Cas genome editing system for inducing heritable mutations in soybean via stable transformation, and explicitly states the system “can be employed to edit other genes for soybean trait improvement”(page1, abstract). Lu teaches that in engineered CRISPR/Cas9, Cas9 is guided to a specific genomic locus by a single guide RNA (sgRNA) containing a 20-nt target sequence adjacent to a PAM (page 2, left column). Lu teaches design/selection of guide sequences and routine specificity checking using CRISPR design tools and BLAST against soybean genomic resources (page 3, right column).
Given Song’s teaching that BZR1 phosphorylation (including within the PEST domain) controls BZR1 function and that BZR1 variants are associated with increased seed number, one of ordinary skill would have been motivated to introduce targeted mutations into the endogenous soybean BZR1 genes to alter phosphorylation/activation state, and would have reasonably expected success using Lu’s established soybean CRISPR/Cas9 system which is expressly presented as usable to edit other soybean genes for trait improvement.
Accordingly, claim 52 would have been obvious over Song and Lu.
Claim 57 recites the method of claim 52, wherein the mutation is a base substitution. Claim 59 recites the method of claim 52, wherein the mutation is a base deletion or a base insertion of one or more base pairs. Claim 60 recites the method of claim 59, wherein the base deletion er is an in-frame deletion or an out-of-frame deletion, and wherein the base insertion is an in-frame insertion or an out-of-frame insertion.
Lu teaches that CRISPR/Cas editing in soybean yields mutations including deletions/insertions, and further reports that substitutions can also occur among observed outcomes (page 5, left column, paragraph 2; page 7, left column, paragraph 1).
Lu teaches that soybean edits are short deletions (one to several nucleotides), longer deletions (~60 nucleotides), insertions (commonly 1 nt insertion), which in target coding regions, resulting frameshifting or amino acid altering (in-frame) (page 10, left and right column; page 11, fig 7).
Thus claim 57, 59 and 60 is obvious over Song and Lu.
Claim 64 recites the method of claim 52, wherein the mutation in the endogenous BZR1 gene produces a BZR1 polypeptide having reduced phosphorylation.
Song teaches that BZR1 is phosphorylated by BIN2, and that BZR1 contains a phosphorylated PEST domain with conserved phosphorylation sites(page 2, left column, paragraph 1; and page 3, left and right column). Song further teaches that changes in this region (e. g., P219L) are associated with altered phosphorylation /dephosphorylation behavior (page 10, left and right column).
Song does not teaches how to generate endogenous BZR1 gene produces a BZR1 polypeptide having reduced phosphorylation.
Lu teaches routine, targeted creation of indels/substitutions in soybean coding regions via CRISPR/Cas9.
Thus, a POSITA is motivated to modifying the BZR1 region implicated by Song using Lu’s method to generate endogenous BZR1 gene produces a BZR1 polypeptide having reduced phosphorylation. Accordingly, Claim 64 is obvious over Song and Lu.
Claim 66 recites the method of claim 52, wherein the soybean plant that is produced exhibits an improved yield trait as compared to a control plant that is devoid of the mutation, as compared to a soybean plant that is devoid of the mutation.
Song teaches that BZR1-type variants linked to increased reproductive output, such as increased seed number in the reported system (abstract). Combining with Lu’s soybean editing method, a POSITA would be motivated to make BZR1 mutants in soybean expecting improvements in yield components (more seeds, pods, biomass, etc.). Accordingly, claim 66 is obvious over Song and Lu.
Claim 68 recites the method of claim 52, wherein the mutation results in a mutated BZR1 gene having at least 90% sequence identity to a nucleotide sequence of SEQ ID NO:116, 118, 120, 122, 124, 126, 128, 130, 132, or 134 and/or a mutated BZR polypeptide having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:117, 119, 121, 123, 125, 127, 129, 131, 133, or 135.
Song teaches the functional importance of specific PEST/phosphorylation related alterations in soybean BZR1-type proteins.
Song does not teach producing soybean plants having a mutation that results in a mutated BZR1 gene or BZR1 polypeptides with ≥90% sequence identity to the specific edited sequence recited in claim 68, nor does Song disclose generating those specific edited alleles by genome editing.
Lu teaches that CRISPR/Cas9 in soybean produces a range of allele sequences, including deletion s extending to dozens of nucleotides, and that such edits can be inherited.
Accordingly, the recited “mutated BZR1 gene/polypeptide≥90% identity” to a set of edited sequences would have been obvious as it encompasses the expected spectrum of closely related edited alleles produced when applying Lu’s soybean CRISPR mutagenesis to the Song motivated BZR1 target region.
Claim 81 recites a modified BRASSINAZOLE-RESISTANT 1 (BZR1) polypeptide comprising a sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:117, 119, 121, 123, 125, 127, 129, 131, 133, or 135.
Song teaches soybean BZR1 family protein GmBZL3 (SEQ ID NO:77 in instant case) containing a PEST domain, identifying a conserved proline in the PEST region that affects protein localization and phosphorylation status, and describing a P219L PEST region mutation that produces bzr1-1D-like BR-response phenotypes when expressed in Arabidopsis (fig 1, figs2-3; page 4, right column and left column).
Song does not teach using soybean CRISPR methods to generate endogenous edited alleles, nor does it explicitly disclose the applicants’ SEQ ID NOs as written.
Lu teaches a stable, heritable CRISPR-Cas9 workflow in soybean (Agrobacterium transformation using “half-seed” explants), producing indels with high efficiencies and transmission to progeny (abstract/results, construct description and mutation outcomes)
In view of Song’s identification of the PEST region and conserved residue affecting phosphorylation/localization and BR signaling, a POSITA would have been motivated to use Lu’s established soybean CRISPR system to generate high-identity BZR1 variants(e. g., sing-amino acid substitutions or small in-frame indels) in the endogenous soybean BRZR homologs with reasonable expectation of success, thereby meeting the broad ≥90%identity scope of claim 81. Accordingly claim 81 is obvious in view of Song and Lu.
Claim 79 recites a nucleic acid encoding the BRASSINAZOLE- RESISTANT 1 (BZR1) polypeptide of claim 81, wherein the nucleic acid comprises a mutation, further wherein the mutation is an in-frame base deletion or out-of-frame base deletion.
Song teaches BZR1-family proteins with a PEST domain and putative phosphorylation sites by GSK-3 kinase (sequence/feature mapping in fig.1) and that mutation in the PEST motif (P219L) alters BR response phenotypes (abstract).
Song does not teach specific in-frame base deletions in soybean BZR1 genes or their nucleic acids.
Lu teaches CRISPR -Cas9 editing in soybean routinely yields insertions/deletions at targeted loci, including coding-region indels that can be in-frame depending on size(e.g., multiples of 3), and such edits can be inherited (Fig 7).
It would have been obvious to introduce a small in-frame indels in the PEST /phosphorylation-relevant region of soybean BZR1 homologs (Song) using a routine soybean CRISPR platform to generate nucleic acids encoding modified BZR1 proteins withing the scope of claim 79. Accordingly claim 79 is obvious in view of Song and Lu.
Claim 80 recites a nucleic acid of claim 79, wherein the nucleic acid comprises a mutated BZR1 gene having at least 90% sequence identity to a nucleotide sequence of SEQ ID NO:116, 118, 120, 122, 124, 126, 128, 130, 132, or 134. Song teaches the type and location of functionally relevant sequence features (PEST region; phosphorylation-related features) for soybean BZR1 family proteins.
Song does not teach the applicants’ specific mutant nucleotide sequences enumerated as SEQ ID NOs:116, 118, 120, 122, 124, 126, 128, 130, 132 or 134.
Lu teaches generating of multiple independent alleles via CRISPR in soybean, with variable indel lengths and types, producing edited alleles that remain highly similar to the wild-type locus outside the edit site (thus typically satisfying high “90% identity” thresholds), and inheritable edits (Abstract, fig 7).
Given Song’s mapping of the functional region to target and Lu’s demonstration that soybean CRISPR routinely generated a range of small indel alleles, it would have been obvious to obtain mutant BZR1 nucleic acids having ≥90% identity to the corresponding wild-type type sequence while carrying indels in the targeted region, as required by claim 80. Accordingly claim 80 is obvious in view of Song and Lu.
Claim 83 recites a soybean or part thereof comprising the nucleic acid of claim 79.
Song teaches soybean BZR1-family gene/protein context and functionally relevant PEST-region features affecting phosphorylation/localization and BR signaling.
Song does not teach soybean plants comprising CRISPR-generated nucleic acids encoding in-frame indel variants in the PEST region.
Lu teaches recovery of transformed soybean plants and progeny containing CRISPR-induced mutations at targeted loci through stable transformation and regeneration.
It would have been obvious to produce soybean plants/parts comprising the modified nucleic acids of claim 79 by applying Lu’s soybean CRISPR transformation /regeneration methods to implement Song’s teaching of targeting the PEST/Phosphorylation-related region.
Accordingly claim 83 is obvious in view of Song and Lu.
Claim 89 recites a plant genome or plant genomic DNA comprising a nucleotide sequence encoding the modified BRASSINAZOLE-RESISTANT 1 (BZR1) polypeptide of claim 81, wherein the nucleotide sequence is NO:116, 118, 120, 122, 124, 126, 128, 130, 132, or 134.
Song teaches soybean BZR1 family proteins and the PEST/phosphorylation feature mapping (fig 1) supporting the motivation to target this region to alter BR signaling.
Song does not teach the applicants’ specific genomic sequences SEQ ID NOs:116, 118, 120, 122, 124, 126, 128, 130, 132, or 134.
Lu teaches CRISPR edits introduced at endogenous loci become part of the plant genome, and edited loci can be transmitted to progeny (Abstract).
It would have been obvious that implementing Song-motivated edits using Lu’s soybean CRISPR system yields soybean genomic DNA comprising edited BZR1 loci encoding modified BZR1 proteins as broadly claimed. Accordingly claim 89 is obvious in view of Song and Lu.
Claim 98 recites a guide nucleic acid that binds to a target site within an endogenous gene encoding a BRASSINAZOLE-RESISTANT 1 (BZR1), with the various ≥80% identity recitations.
Song teaches identification of soybean BZR1 family proteins and specific functional regions/feature (PEST region, phosphorylation-related sites) suitable for targeted modification.
Song does not teach any guide nucleic acids, CRISPR targeting rules, or guide designs for soybean BZR1 loci.
Lu teaches construction and use of sgRNA/guide RNAs to target specific soybean genomic loci for CRISPR editing using stable transformation and regeneration, including the standard guide/PAM targeting framework and successful recovery of edited plants.
A POSITA would have been motivated to design guide nucleic acids targeting the Song-identified BZR1 regions/features to obtain CRISPR -induced edits, with a reasonable expectation of success. Accordingly claim 83 is obvious in view of Song and Lu.
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Response to Applicant’s Remarks:
Applicant’s Main 103 Arguments:
(1) Claims 4, 16, 18, and 31:
Song does not teach a soybean plant with a mutation in an endogenous soybean BZR1 gene.
Song uses a transgenic Arabidopsis plant expressing mutated GmBZL3, not edited soybean plants.
Song does not teach improved yield traits in soybean.
Therefore, song allegedly does not teach or suggest all claim elements.
(2) Claims 52, 57, 59, 60, 64, 66, 68, 79-81, 83, 89, and 98:
Lu only edits PDS genes, not BZR1 ,
Lu mentions low mutation efficiency in soybean, so no reasonable expectation of success.
Song and Lu allegedly do not teach the claimed modified BZR1 polypeptides or guide nucleic acids.
Therefore, the combination is said to be nonobvious.
Applicant’s arguments have been considered but are not persuasive.
With respect to claim 4, 16, 18, and 31, Applicant’s assertion that Song does not disclose an endogenous mutated soybean BZR1 gene or improved yield traits is not persuasive. Song expressly disclose an endogenous mutated soybean BZR1 gene or improved yield traits (page 9, left column; page 4, paragraph 2; page 2, left column, paragraph 3), Song teaches the PEST domain of soybean BZR1-family proteins contains phosphorylation sites that regulate activity and BR-related phenotypes, and that alterations in this region affect functional output (page 3, right column; page 4, paragraph 2). A POSITA would have been motivated to introduce mutations in the endogenous soybean BZR1 PEST region to disrupt phosphorylation as a predictable way to modulate activity, with a reasonable expectation of success. Further, Song links BAR1/BR signaling to growth and reproductive development, making generation, regeneration, and selection of soybean plants exhibiting yield-related traits an obvious extension. The recited ≥90% identity limitations represent routine sequence variation of such mutants.
With respect to claims 52, 57, 59, 60, 64, 66, 68, 79-81, 83, 89 and 98, Applicant’s arguments over Song in view of Lu are unpersuasive. Song provides the motivation to target the BZR1 PEST/phosphorylation region (page 5, left column; page 10, right column paragraph 1; page 11, right column, Conclusion), while Lu teaches a general and effective CRISPR/Case system for targeted genome editing in soybean, including guide design, indel formation, and recovery of edited plants. A POSITA would have been motivated to apply Lu’s routine soybean editing system to the Song-identified BZR1 target with a reasonable expectation of success accordingly, the rejections are maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to YANXIN SHEN whose telephone number is (571)272-7538. The examiner can normally be reached Monday-Friday.
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/YANXIN SHEN/Examiner, Art Unit 1663
/WEIHUA FAN/Primary Examiner, Art Unit 1663
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