Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of objections and rejections
1. Claims 1-3, 6-9, 12-16, 19, 23, 27-31 and 33 are pending. Claims 4, 5, 10, 11, 17, 18, 20-22, 24-26, 32 and 34-37 are cancelled. Claims 9, 19, 23, 27-31 and 33 are previously withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention. Accordingly, claims 1-3, 6-8 and 12-16 are examined on merits in the instant Office action.
2. The objection to claim 12 is withdrawn in light of claim amendments filed in the papers of July 10, 2026 and upon further consideration.
3. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
4. Rejection of Claims 1-3, 6-8 and 12-16 under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter is withdrawn in light of amendments to the claims filed in the papers of July 10, 2026 and upon further consideration.
5. Rejection of Claim(s) 1, 2, 3, 6, 7 and 8 under 35 U.S.C. 102(a)(1) as being anticipated by Ramesh et al. (Oligonucleotides 17:251-257, 2007) is withdrawn in light of amendments to the claims filed in the papers of July 10, 2026 and upon further consideration.
6. Rejection of Claims 1, 2, 3, 6, 7, 8 and 13-16 under 35 U.S.C. §103(a) as being unpatentable over Ramesh et al. (Oligonucleotides 17:251-257, 2007) in view of Heliwell et al. (Methods in Enzymology; 392: 24-35, 2005) and Jefferson et al., EMBO Journal, 6(13):3901–3907 (1987) is withdrawn in light of amendments to the claims filed in the papers of July 10, 2026 and upon further consideration.
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.
7. Claims 2, 3 and 6-8 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. This rejection has been necessitated due to claim amendments filed in the papers of July 10, 2026.
Amended claim 1 requires “sequences” from at least two different genes and requires those sequences to be concatenated within the stem region. Claims 2, 6, and 8 thereafter refer in the singular to “the sequence from the one or more orthotospoviruses.” It is unclear whether “the sequence” in each dependent claim refers to: (i) every sequence concatenated within the stem region; (ii) at least one of the concatenated sequences; (iii) one particular but unidentified concatenated sequence; or (iv) the concatenated sequence collectively. This ambiguity materially affects claim scope. For example, claim 8 may require that each individual gene-derived sequence be 100-200 nucleotides long, that only one unidentified sequence be 100-200 nucleotides long, or that the complete concatenated sequence be 100-200 nucleotides long. These are materially different constructions. Claim 3 depends from claim 2 and therefore incorporates the ambiguity of claim 2. Claim 7 depends from claim 6 and likewise incorporates the ambiguity of claim 6.
The rejection may be overcome by amending the claims to identify expressly whether the limitation applies to each concatenated sequence, at least one concatenated sequence, or the concatenated sequences collectively. For example, without suggesting that any particular amendment is necessarily supported, claim 2 could recite “wherein each of the sequences concatenated within the stem region is from a conserved region” or “wherein at least one of the sequences concatenated within the stem region is from a conserved region,” as intended.
This is a new ground of rejection necessitated by Applicant’s amendment of claim 1 to require multiple concatenated sequences.
Claim Rejections - 35 USC § 112
8. Claims 1-3, 6-8 and 12-16 remain rejected under 35 U.S.C. 112, 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(s), at the time the application was filed, had possession of the claimed invention for the reasons of record stated in the Office action mailed April 23, 2026.
The specification does not demonstrate that Applicant possessed the full scope of engineered RNA hairpins comprising sequences from at least two different orthotospovirus genes concatenated within the stem region.
A. LEGAL STANDARD: Under University of California v. Eli Lilly, 119 F.3d 1559, 1568 (Fed. Cir. 1997), written description requires “a precise definition, such as by structure, formula, [or] chemical name, of the claimed subject matter sufficient to distinguish it from other materials.” To adequately describe a genus, the specification must disclose a representative number of species with sufficient structural detail that one skilled in the art can “visualize or recognize the identity of the members of the genus.” Id. A description that relies on function or method of making without disclosing structure is typically insufficient, particularly when the claimed genus is large or diverse. See MPEP § 2163.
B. SCOPE OF CLAIMS: Amended claim 1 encompasses sequences from any two or more genes of any orthotospovirus. This creates a large genus: eight orthotospovirus species (claim 16) multiplied by approximately 5-7 genes per species, with sequence variants meeting 70% identity criteria. The claim further encompasses optional concatenation arrangements without specifying required order, orientation, or spacing. Dependent claims add modest limitations but do not substantially reduce the scope. Claim 12 narrows to SEQ ID NO: 1 for one concatenated sequence but leaves the second (or additional) gene sequence broadly defined.
C. SPECIFICATION’S STRUCTURAL DISCLOSURE: The specification describes a bioinformatic pipeline and provides Tables 1-2, Figures 1-2, and SEQ ID NOs: 1-10 identifying conserved regions across orthotospovirus species. However, upon careful review, the specification lacks adequate structural description of the claimed multi-gene concatenated constructs. The specification states that six constructs (A-F) were designed and transformed, but does not explicitly disclose which genes were selected for concatenation in each construct, the precise arrangement of concatenated sequences within the stem, whether sequence orientation matters, or whether spacing between genes is necessary.
The specification reports obtaining “transgenic resistance” but focuses on functional results rather than structural features defining the genus. See Examples 1-3; Tables 1-4. This functional approach is insufficient under University of California v. Eli Lilly. A POSA reading the specification would understand that TSWV hairpins can generate resistance but would not necessarily understand the structural features that distinguish effective multi-gene constructs from other possible arrangements of the same sequences.
D. APPLICANT’S ARGUMENTS: Applicant argues that the disclosure describes selecting conserved regions from orthotospovirus genomes, identifying candidate regions from multiple viral genes, and assembling multigenic hairpin constructs. Applicant further argues that the specification describes six unique constructs each including five genomic fragments from TSWV, one from each viral gene (response, page 9). These arguments are not found persuasive.
While the Office acknowledges that the specification describes selecting multiple conserved regions and mentions constructs A-F. However, the specification does not provide the structural detail necessary to demonstrate possession of the claimed genus. The statement that constructs include “five genomic fragments from TSWV, one from each viral gene” does not constitute adequate structural description of a multi-gene concatenated hairpin. Applicant does not identify which specific genes were selected for each construct, how they are arranged within the stem, or whether the order and arrangement are critical elements of the claimed invention. Under University of California v. Eli Lilly, naming a type of construct “without knowledge as to what that material consists of” is not adequate description. The specification must disclose the structure with sufficient precision that one skilled in the art can identify genus members. The specification’s description is more consistent with possession of TSWV-derived constructs than with possession of the full genus of orthotospovirus multi-gene concatenated hairpins spanning eight distinct species.
E. DEFICIENCY: LACK OF REPRESENTATIVE EXAMPLES: The specification provides detailed disclosure of constructs derived from TSWV BUT does not provide structural descriptions of representative multi-gene hairpins for other claimed orthotospoviruses (TCSV, GRSV, INSV, IYSV, MeSMV, CSNV, SVNV) and any other orthotospoviruses not claimed but encompassed by the breadth and scope of claims. While the specification mentions analysis of these species, analysis of sequences is not equivalent to structural description of constructs made from those sequences. Under University of California v. Eli Lilly, when a claimed genus is large and diverse, representative species must be structurally described. A person of ordinary skill (POSITA) could not visualize or recognize whether a multi-gene concatenated hairpin from, for example, GRSV would fall within the claimed genus or how it would be structured based on the specification’s disclosure. This is particularly problematic because each orthotospovirus species has distinct genetic organization and sequence characteristics. The specification’s focus on TSWV does not adequately establish possession of GRSV, INSV, or other orthotospoviruses.
F. DEFICIENCY: LACK OF STRUCTURAL DEFINITION OF CONCATENATION: The claim requires that sequences be “concatenated within the stem region,” but the specification does not define what this means structurally. The specification does not disclose whether concatenated sequences must be immediately adjacent or whether spacers are required, whether sequence orientation within the concatenation matters, whether the order of genes affects efficacy, or whether palindromic relationships between concatenated sequences are necessary. Without such disclosure, a POSA/POSITA cannot identify the boundaries of the claimed genus. The specification’s functional approach—reporting that constructs generate resistance—does not substitute for structural description. A POSA needs to understand the structural features that distinguish claimed constructs from alternative arrangements of the same sequences.
The specification adequately describes single-gene hairpins targeting conserved TSWV regions. However, it inadequately describes the full genus of multi-gene concatenated orthotospovirus hairpins. The specification fails to provide representative structural examples across multiple orthotospovirus species or precise structural definition of the concatenation requirement.
The Federal Circuit has clarified the application of the written description requirement to inventions in the field of biotechnology. did See University of California v. Eli Lilly and Co. , 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997). In summary, the court stated that a written description of an invention requires a precise definition, one that defines the structural features of the chemical genus that distinguishes it from other chemical structures. A definition by function does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. The court goes on to say, “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNAs, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus.” California v. Eli Lilly and Co See University of ., 119 F.3d 1559; 43 USPQ2d 1398, 1406 (Fed. Cir. 1997).
Thus, under Lilly and its progeny, the Specification does not show possession of a sufficient number of sequences falling within their potentially large genus to establish possession of their claimed genus. See Cf Enzo, 323 F.3d at 964 ("if the functional characteristic of... binding to [CD48] were coupled with a disclosed correlation between that function and a structure that is sufficiently known or disclosed," the written description requirement may be met). Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, ("definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is"); see also Kubin, 83 USPQ2d at 1416-17.
Also see in re Curtis (69 USPQ2d 1274 (Fed. Cir.2004), where the court held that there was sufficient evidence to indicate that one of ordinary skill in the art could not predict the operability of other species other that the single one disclosed in the specification. The court held that a disclosure naming a single species can support a claim to a genus that includes that species if a person of ordinary skill in the art, reading the initial disclosure, would “instantly recall” additional species of the genus already “stored” in the minds, but if other members of the genus would not “naturally occur” to a person of ordinary skill upon reading the disclosure, then unpredictability in performance of species other than specifically enumerated defeats claims to the genus
Therefore, given the lack of written description in the specification with regard to the structural and functional characteristics of the claimed compositions, it is not clear that Applicant was in possession of the claimed genus at the time this application was filed.
Accordingly, there is lack of adequate description to inform a skilled artisan that applicant was in possession of the claimed invention at the time of filing. See Written Description guidelines published in Federal Register/Vol.66, No. 4/Friday, January 5, 2001/Notices; p. 1099-1111.
Accordingly, claims 1-3, 6-8, and 12-16 are rejected under 35 U.S.C. § 112(a) for inadequate written description.
9. Claims 1-3, 6-8, and 12-16 remain rejected under 35 under first paragraph of 35 U.S.C. 112(a), because the specification, while being enabling for a DNA construct designed to express an RNA hairpin comprising sequence as set forth in SEQ ID NO: 1 (targets a conserved region of RdRp protein coding region of TSWV virus , wherein transgenic expression of said RNA hairpin construct in a tomato plant results in resistance to TSWV, does not reasonably provide enablement for (i) an RNA hairpin comprising one or more polynucleotide sequences having 70% identity to a sequence from any “target orthotospoviruses; (ii) any conserved regions, any conserved region including any regions of at least 25 nucleotides in which at least 85% of the nucleotide positions are conserved, any protein-encoding regions, any functional domains, any 100-200 nucleotide sequence length to any target sequence of any target virus; and (iii) any orthotospoviruse (except TSWV). 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 for the reasons of record stated in the Office action mailed April 23, 2026.
The specification does not enable a POSA to make and use hairpin constructs comprising concatenated sequences from two or more different genes across the full breadth of claimed orthotospoviruses without undue experimentation. A. LEGAL STANDARD: Under 35 U.S.C. § 112(a), the specification must enable one skilled in the art to make and use the invention. The Wands factors are applied: quantity of experimentation, guidance provided, working examples, nature of the invention, state of prior art, skill level, predictability of the art, and breadth of claims. In re Wands, 858 F.2d 731 (Fed. Cir. 1988). In unpredictable arts, the Federal Circuit requires disclosure commensurate with claim breadth. In re Wright, 999 F.2d 1557 (Fed. Cir. 1993).
B. UNPREDICTABILITY IN THE FIELD: The efficacy of RNA silencing constructs is highly sequence-dependent and unpredictable. Khvorova et al. (Cell, 115(2):209-216 (2003)) demonstrate that minor sequence variations significantly alter silencing efficiency, strand selection, and thermodynamic stability. Tenllado et al. (Journal of Virology, 75(4):1288-1297 (2001)) teach that “not all viral sequences are equally effective in inducing resistance” and that “empirical testing of individual viral fragments is required to determine efficacy.” See Tenllado et al., abstract and pages 12294-12296. This unpredictability is not peripheral but central to understanding whether a particular sequence combination will function as a silencing construct.
C. BREADTH OF CLAIMS VERSUS DISCLOSURE: Claims encompass multiple orthotospovirus species (eight listed), multiple genes within each species (5-7 per species), sequences meeting 70% identity criteria, and optional concatenation arrangements, implying that the breadth and scope of claims is very large. The specification provides working examples only for TSWV-derived constructs and does not provide examples or guidance for other orthotospovirus species. It does not demonstrate optimization of concatenation strategies or compare multi-gene to single-gene approaches.
D. APPLICANT’S ENABLEMENT ARGUMENT: Applicant argues that routine sequence alignment, sequence selection, cloning, and plant transformation are not undue experimentation and that the specification provides substantial guidance regarding how to identify useful orthotospovirus sequences (response, page 9). This is not persuasive.
While these techniques are routine, the application of those techniques to identify which specific two-gene combinations will generate effective silencing is not routine because the outcome is unpredictable without testing. Applicant’s statement that “a skilled artisan would not need to survey all viruses” is correct but does not address the core issue: whether a POSA could predict, based on the specification, which gene combinations from the same orthotospovirus species would yield optimal resistance.
The Applicant provides guidance on identifying conserved sequences but not on optimizing multi-gene concatenation strategies. To practice claim 1 across diverse orthotospovirus species and gene combinations, a POSA would need to construct and test multiple concatenation variants to identify which are effective. This is undue experimentation in an unpredictable field, particularly given the breadth of the claims.
E. WANDS FACTORS ANALYSIS: (i) Quantity of Experimentation: Substantial. To practice the full scope of claims, a POSA would construct and test multiple gene combinations from multiple species, optimizing concatenation arrangements. The specification does not reduce this burden; (ii) Guidance Provided: Moderate. The specification teaches sequence identification via bioinformatics but not optimization of multi-gene constructs or gene pair selection strategies; (iii) Working Examples: Limited to TSWV. No examples demonstrate multi-gene constructs for GRSV, INSV, IYSV, MeSMV, CSNV, or SVNV. No comparative data show whether concatenation is superior to single-gene or separate-construct approaches; (iv) Predictability: The art is unpredictable with respect to which gene combinations will generate effective silencing, as established by Khvorova et al. and Tenllado et al. as discussed above; and (v) Breadth: Claims are broad, encompassing multiple species and gene combinations, disproportionate to the working examples.
F. SPECIFIC ENABLEMENT GAPS: First, the specification does not enable extension of the multi-gene concatenation approach to orthotospoviruses beyond TSWV without substantial trial-and-error testing. Each orthotospovirus has distinct sequence characteristics and genetic organization. A POSA cannot predict whether techniques optimized for TSWV will translate to other species. Second, the specification does not enable identification of optimal gene pairs. It does not teach whether targeting RdRp + N gene is better than RdRp + Nsm, or whether the order of concatenation matters. Without such guidance, a POSA must test multiple combinations. Third, the specification does not provide data comparing concatenated multi-gene constructs to alternative approaches (single-gene hairpins, separate constructs). Without comparative data demonstrating superior results from concatenation, a POSA cannot predict whether this architectural choice is necessary or merely one option among many.
G. APPLICANT’S CLAIM NARROWING: Applicant argues that narrowing claims to orthotospoviruses and requiring multi-gene concatenation directly addresses the Examiner’s stated concern and narrowing directly addresses enablement (response, page 10). This is not persuasive.
Narrowing to orthotospoviruses is valuable and reduces (but does not eliminate) the scope. However, claims still encompass eight species and multiple genes per species. The specification remains limited to TSWV examples. For claims to be fully enabled after narrowing, the specification should either provide working examples and guidance for other orthotospoviruses or the claims should be further narrowed to TSWV or to specifically named species. The current scope remains broader than the disclosed examples, creating an enablement gap.
H. CONCLUSION ON ENABLEMENT: While the specification may enable hairpin constructs targeting single conserved regions of TSWV. However, it does not enable the full scope of multi-gene concatenated constructs across diverse orthotospoviruses without undue experimentation. To practice claims 1-3, 6-8, and 12-16 across their full scope would require substantial trial-and-error optimization of concatenation strategies and gene pair selection, which constitutes undue experimentation in this unpredictable field as discussed above.
Accordingly, claims 1-3, 6-8, and 12-16 remain rejected under 35 U.S.C. § 112(a) for lack of enabling disclosure.
Claim Rejections - 35 USC § 103
10A. Claims 1-3, 6-8 and 12-16 remain rejected under 35 U.S.C. §103(a) as being unpatentable over Huang et al. (US Patent NO. 8, 455, 716 B2, Issued June 4, 2013) and Kaye et al., Phytopathology, 101(1):147–153 (2011), and further in view of Ramesh et al., 17:251–257 (2007), Hamilton et al., Science, 286:950–952 (1999), and Jefferson et al., EMBO Journal, 6(13):3901–3907 (1987) for the reasons of record stated in the Office action mailed April 23, 2026.
Huang et al. teach that conserved regions (including coding sequences such as RdRP (RNA-dependent RNA polymerase) of various viral genomes, including tospoviruses (TSWV) may provide a broader spectrum of resistance against different variants within the species or closely related species. The reference further teaches using recombinant DNA constructs designed to express RNA hairpin structures comprising sequences targeted to said conserved regions provides resistance to wide range of viruses upon transformation of plants like tomato. The reference also teaches SEQ ID NO: 270 having 98% identity to instant SEQ ID NO: 1. See in particular, abstract, columns 9-12; example 3 at columns 33-34; Figure 11A and 11D.
Kaye et al. teach Tomato spotted wilt virus (TSWV) genes, including conserved coding regions of the nucleocapsid (N) gene), Nsm and RdRP (RNA-dependent RNA polymerase). Kaye et al. also teach that viral sequence fragments corresponding to Instant SEQ ID NO: 1 (RdRP). Kaye et al. further teach conservation among orthotospoviruses and the desirability of targeting conserved regions to achieve broad resistance. See in particular, pages 148-149, 151; Table 1 at page 148; Tables 2-3 at page 149; Table 4 at page 150; last paragraph at page 152.
The sequence homology between instant SEQ ID NO: 1 and GenBank Accession NO. FJ262087 citing Kaye et al. is shown as below:
FJ262087
LOCUS FJ262087 999 bp cRNA linear VRL 24-JUL-2016
DEFINITION Tomato spotted wilt virus isolate L34P7 RNA-dependent RNA
polymerase (RdRP) gene, partial cds.
ACCESSION FJ262087
VERSION FJ262087.1
KEYWORDS .
SOURCE Orthotospovirus tomatomaculae
ORGANISM Orthotospovirus tomatomaculae
Viruses; Riboviria; Orthornavirae; Negarnaviricota;
Polyploviricotina; Bunyaviricetes; Elliovirales; Tospoviridae;
Orthotospovirus.
REFERENCE 1 (bases 1 to 999)
AUTHORS Kaye,A.C., Moyer,J.W., Parks,E.J., Carbone,I. and Cubeta,M.A.
TITLE Population Genetic Analysis of Tomato spotted wilt virus on Peanut
in North Carolina and Virginia
JOURNAL Phytopathology 101 (1), 147-153 (2011)
PUBMED 20839960
REFERENCE 2 (bases 1 to 999)
AUTHORS Kaye,A.C.
TITLE Direct Submission
JOURNAL Submitted (28-SEP-2008) Plant Pathology, North Carolina State
University, 2510 Gardner Hall, Raleigh, NC 27695-7616, USA
FEATURES Location/Qualifiers
source 1..999
/organism="Orthotospovirus tomatomaculae"
/mol_type="viral cRNA"
/isolate="L34P7"
/host="Arachis hypogaea 'Perry'"
/db_xref="taxon:3052585"
/segment="L"
/geo_loc_name="USA: Lewiston-Woodville, NC"
/collection_date="17-Sep-2007"
gene <1..>999
/gene="RdRP"
CDS <1..>999
/gene="RdRP"
/codon_start=1
/product="RNA-dependent RNA polymerase"
/protein_id="ACO72768.1"
/translation="KTADSETETIKTIKNRLMTSLTFIEAFGNLSQQIKEIVDDDIRE
TMDEFLMNIRDNCLEGLENCKSVEEYDSYLDENGFNDTVELFENLLRTHDNFENEYSP
LFSEIVDKAKQYTRDLEGFKEILLMLKYSLINDASGFKSYRATGMHAVELMAKKHIEI
GEFNLLGMIQLIKACETCHNNDSILNLASLRNVLSRTYATFGRRIKLDHDLDLQNSLM
EKSYDFKTLVLPEIKLSELSKEILKENGFVISGENLKIDRSDEEFEGLASFNVLRLDE
EEMYEGLIKEMKIKRKKKGFLFPANTLLLSELIKFLIGGIKGTSFDIETLLRNSFRP
Query Match 100.0%; Score 167; Length 999;
Best Local Similarity 100.0%;
Matches 167; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AAAGCAAAACAGTATACTAGAGATTTAGAAGGTTTCAAAGAAATACTGCTCATGCTTAAA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 328 AAAGCAAAACAGTATACTAGAGATTTAGAAGGTTTCAAAGAAATACTGCTCATGCTTAAA 387
Qy 61 TATTCTCTGATAAATGATGCATCAGGATTTAAAAGCTATAGAGCCACTGGAATGCATGCT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 388 TATTCTCTGATAAATGATGCATCAGGATTTAAAAGCTATAGAGCCACTGGAATGCATGCT 447
Qy 121 GTTGAACTAATGGCAAAAAAGCACATAGAGATAGGGGAATTCAACTT 167
|||||||||||||||||||||||||||||||||||||||||||||||
Db 448 GTTGAACTAATGGCAAAAAAGCACATAGAGATAGGGGAATTCAACTT 494
Neither Huang et al. nor Kaye et al. teach designing RNA hairpin stem-loop constructs.
Ramesh et al. teach designing short hairpin RNA (shRNA) constructs comprising inverted repeat sequences forming a double-stranded stem and a single-stranded loop region. The reference explains that sequence complementarity within the stem confers silencing specificity and that stem-loop structures are effective for inducing RNA interference. Ramesh et al. teach that short hairpin RNA (shRNA) constructs targeting to specific conserved region of a viral genome gene(s) provides effective and broad resistance to multiple strains of a tomato virus in a transgenic tomato expressing said constructs. See in particular, Figures 1-3 at pages 253-254, Figure 4 at page 255.
Hamilton et al. teach that small antisense RNAs derived from double-stranded RNA mediate post-transcriptional gene silencing in plants The reference establishes the mechanistic basis for RNA silencing in plant systems and demonstrates that double-stranded RNA structure is processed into sequence-specific small RNAs responsible for target degradation. See in particular pages 950-951; Figs. 1-4.
Jefferson et al. teach the β-glucuronidase (GUS) gene as a widely used reporter and cloning element in plant molecular biology GUS fragments were routinely incorporated into plant expression vectors and were readily available as neutral sequence elements. See in particular, pages 3901–3903; Figures 1-4; materials and methods.
Given Huang et al. teach that conserved regions (including coding sequences such as RdRP (RNA-dependent RNA polymerase) of various viral genomes, including tospoviruses (TSWV) may provide a broader spectrum of resistance against different variants within the species or closely related species, it would have been obvious to a person of ordinary skill in the art prior to earliest filing date of the instantly claimed invention to incorporate the TSWV coding sequence taught by Kaye et al., including SEQ ID NO: 1, into a hairpin RNA construct design as taught by Ramesh et al. to generate double-stranded RNA targeting TSWV.
Given Kaya et al. identifies conserved coding regions which are suitable for resistance strategies as asserted by Huang et al., and Ramesh et al. teach that high sequence complementarity enhances silencing efficiency, and Hamilton et al. establish that double-stranded RNA in plants is processed into sequence-specific small RNAs that mediate gene silencing, it would have been obvious that the combination of Huang et al., Kaye et al., Ramesh et al. and Hamilton et al., teachings, therefore represents applying a known RNA silencing structure to a known viral sequence to achieve predictable antiviral silencing in plants.
Furthermore, selection of conserved regions of defined length, including fragments within 100–200 nucleotides, would have been a matter of routine optimization. Ramesh et al. demonstrate that effective silencing depends on sufficient complementary stem length, and selecting fragment sizes within known workable ranges represents ordinary skill experimentation.
It may be noted that the concatenation of sequences is a routine design variation, not an inventive step requiring creative insight. A POSA would view this as engineering optimization—deciding whether to target multiple genes in one construct versus separate constructs—a decision based on practical considerations well within the skill of the art. Ramesh et al., at pages 251-252, demonstrate constructs with stem and loop regions, and Applicant’s amended claim merely specifies that the stem contains sequences from two different genes rather than one. This is a predictable variation of known hairpin architecture.
Inclusion of a single-stranded linker between inverted repeats is expressly taught by Ramesh et al., and substitution of a GUS fragment as the linker would have been an obvious design choice. Jefferson et al. establish GUS as a ubiquitous cloning fragment in plant vectors, and Hamilton et al. demonstrate that silencing depends on the double-stranded stem region rather than the specific identity of unrelated spacer sequences. Substituting one known neutral spacer sequence for another constitutes predictable use of prior art elements according to their established functions.
Obviously, the motivation to combine arises from the recognized need to develop multiple virus resistance (including TSWV) as taught by Huang et al. and/or tospoviruses TSWV as taught by Kaye et al. (last paragraph of left column at page 152), and the well-established plant RNA silencing strategy using inverted repeat hairpin constructs (Ramesh et al., and Hamilton et al). The prior art provides a finite number of predictable options: known viral sequences, known hairpin architectures, and known spacer sequences. Applying the known hairpin RNA silencing approach to the known TSWV sequence would have yielded predictable results with a reasonable expectation of success in view of the established plant RNA silencing mechanism. The combination of references therefore represents the predictable use of prior art elements according to their established functions, consistent with the principles set forth in KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007).
Accordingly, claims 1-3, 6-8, and 12-16 remain rejected under 35 U.S.C. §103(a).
10B. Response to Applicant’s Arguments:
A. PRIOR ART TEACHINGS: Huang et al. teach that conserved regions of tospovirus genes, particularly RdRp, provide broader resistance against viral variants. See Huang et al., columns 9-12; Example 3. Kaye et al. identify specific conserved coding regions (RdRp, N gene, Nsm) across multiple orthotospovirus species and explicitly state at page 152 that targeting conserved regions overcomes resistance-breaking isolates. See Kaye et al., Tables 1-4; page 152. Ramesh et al. teach that hairpin RNA constructs targeting conserved viral regions generate effective antiviral resistance. See Ramesh et al., abstract; Figures 1-3. Hamilton et al. demonstrate that double-stranded RNA is processed into sequence-specific silencing compounds and that the stem region (not the loop) is critical for silencing. See Hamilton et al., pages 950-951. Jefferson et al. establish that GUS fragments are routine neutral spacer elements in plant vectors. See Jefferson et al., pages 3901-3903.
B. MOTIVATION TO COMBINE — EXPLICIT IN PRIOR ART: Applicant argues that the combination does not teach multi-gene concatenation and that motivation to combine is based on hindsight (response, pages 12-13). This argument is not persuasive.
Kaye et al., at page 152, explicitly recognize resistance-breaking isolates as a known problem and teach that targeting conserved regions provides a solution. A person of ordinary skill (POSA) reading Kaye et al. would understand that targeting a single region is vulnerable to escape mutations. The logical response—targeting multiple regions simultaneously—is not hindsight but rather a straightforward application of well-known principles in viral control and medicine. Multi-target therapeutic strategies have been recognized as superior to single-target strategies for decades.
Huang et al. further teach that conserved regions across different genes exist and are suitable targets. A POSA, motivated by Kaye’s explicit teaching regarding resistance-breaking and Huang’s identification of multiple conserved targets, would have been prompted to consider whether combining multiple targets within a single construct would enhance resistance. This motivation exists in the prior art and does not depend on hindsight review of Applicant’s results.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, POSA would have arrived at the instantly claimed invention with a reasonable expectation of success and without unexpected results by combining the cited art as discussed above in the rejection.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In the instant case, POSA would have arrived at the instantly claimed invention with a reasonable expectation of success and without unexpected results by combining the cited art as discussed above in the rejection.
C. OBVIOUSNESS OF MULTI-GENE CONCATENATION: Applicant argues that the combination does not teach or suggest amended claim 1 because the cited combination does not teach concatenated sequences from at least two different orthotospovirus genes (response, pages 12-13). This argument is not persuasive.
While no single reference explicitly teaches concatenating two different viral genes within one hairpin stem, the combination of references establishes clear motivation and a reasonable expectation of success. Ramesh et al. teach hairpin constructs with stem and loop regions. Hamilton et al. establish that the stem is the functional element, not the loop. A POSA reading these references would recognize that multiple viral sequences could be arranged within a single stem region rather than constructing separate hairpins. The advantage is straightforward: one construct targeting two genes reduces genetic load, simplifies transformation, and provides unified silencing from one promoter.
The concatenation of sequences is a routine design variation, not an inventive step requiring creative insight. A POSA would view this as engineering optimization—deciding whether to target multiple genes in one construct versus separate constructs—a decision based on practical considerations well within the skill of the art. Ramesh et al., at pages 251-252, demonstrate constructs with stem and loop regions, and Applicant’s amended claim merely specifies that the stem contains sequences from two different genes rather than one. This is a predictable variation of known hairpin architecture.
D. SUBSTITUTION OF GUS LINKER: Applicant argues that Jefferson does not teach GUS as a neutral linker in antiviral constructs and that the Office Action’s rationale that GUS could be used as a generic spacer is based on Applicant’s disclosure rather than on a teaching or suggestion in the prior art (response, pages 12-13). This argument is not persuasive.
Applicant’s argument mischaracterizes the prior art. Jefferson et al. explicitly teach that GUS fragments are “routinely incorporated into plant expression vectors” as “neutral, non-functional spacer or linker sequences.” See Jefferson et al., pages 3901-3903. Hamilton et al. demonstrate that silencing efficacy depends on the stem structure and sequence complementarity, not on the specific identity of non-functional loop/linker sequences. See Hamilton et al., Figures 1-4. Given these two teachings, a POSA would readily recognize that a GUS fragment—which is established as a neutral spacer element—could serve the loop/linker function in a hairpin construct. The substitution is not based on Applicant’s disclosure but on explicit teachings in the prior art establishing both that GUS is a suitable spacer and that the specific spacer identity does not affect silencing efficacy.
E. UNEXPECTED RESULTS: Applicant argues that the claimed constructs achieve unexpected results, including multi-generational resistance, protection against resistance-breaking strains, and high protection rates in fruit assays (Response, pages 12-13). The Office is not persuaded that these results are unexpected.
Huang et al. already teach that hairpin constructs targeting conserved tospovirus regions generate effective resistance. See Huang et al., Example 3. Ramesh et al. demonstrate that hairpin constructs against viral targets achieve antiviral resistance. See Ramesh et al., abstract and Figures 1-3. A POSA would expect that applying known RNAi methodology to conserved viral targets would yield effective resistance. The achievement of robust resistance is therefore predictable, not unexpected.
Regarding resistance-breaking strains, Kaye et al. explicitly recognize this problem and suggest targeting conserved regions as the solution. See Kaye et al., page 152. A POSA would expect that a construct targeting multiple conserved regions would provide protection against resistance-breaking isolates—this is the predictable result of implementing a known strategy to address a known problem. Applicant’s data demonstrate that the approach works, but prior art teaches that similar approaches (multi-target silencing of viral genes) should work. This does not establish unexpectedness.
F. LONG-FELT NEED: Applicant argues that orthotospoviruses represent a long-felt need and that no commercial virus-resistant tomato products existed prior to this invention (response, pages 12-13). This is not found persuasive.
While long-felt need may contribute to a nonobviousness analysis when accompanied by other evidence, it does not overcome clear prior art teaching and motivation to combine. Under KSR Int’l v. Teleflex, 550 U.S. 398 (2007), obviousness may be found when a POSA would have had reason to combine known elements with a reasonable expectation of success. Here, Huang, Kaye, Ramesh, Hamilton, and Jefferson provide explicit motivation and known solutions. The fact that no commercial product existed does not render the combination nonobvious when the prior art clearly teaches and motivates it. See MPEP § 2143.01(A) (long-felt need alone is weak secondary consideration). Applicant must demonstrate that the specific results achieved were unpredictable or significantly superior to prior art expectations—Applicant has not done so.
G. LEVEL OF ORDINARY SKILL: Applicant does not contest the Examiner’s definition of a POSA—a Ph.D.-level plant molecular biologist with experience in plant transformation and RNAi technologies. Such a person would be capable of reading Huang and Kaye’s identification of conserved tospovirus genes, understanding the motivation from Kaye to target multiple genes to prevent resistance-breaking, and applying Ramesh’s established hairpin methodology to those targets. This is well within the skill of the art.
H. CONCLUSION ON § 103: The combination of Huang, Kaye, Ramesh, Hamilton, and Jefferson establishes that a POSA would have had clear motivation to design an engineered RNA hairpin targeting at least two conserved orthotospovirus genes with a reasonable expectation of success. Each element of the claim is taught or suggested by the prior art. The narrowing amendments specify orthotospoviruses and multi-gene concatenation, but these represent predictable refinements within the scope of prior art teachings, not inventive features.
It is also important to note that KSR forecloses the argument that a specific teaching, suggestion or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, -- USPQ2d --, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396).
It may be noted that obviousness does not require an absolute certainty of success but merely a reasonable expectation thereof, so long as the motivation or suggestion to combine the teaching of the cited references is known or disclosed in the prior art and is obvious to one skilled in the art and this is sufficient to establish a prima facie case of obviousness. In this case, it would have been obvious and within the scope of an ordinary skill in the art to have arrived at the instantly claimed invention with a reasonable expectation of success and without any surprising results by combining the teachings of the cited art as discussed above.
Thus, the claimed invention as a whole is prima facie obvious over the combined teachings of the prior art.
11. Claims 1, 2, 6-8, 15, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Huang et al. (U.S. Patent No. 8,455,716 B2, Issued June 4, 2013) in view of Wang et al. (Int. J. Mol. Sci. 2016, 17, 705; doi:10.3390/ijms17050705), and further in view of Kaye et al. (Phytopathology 101(1):147-153, 2011).
This rejection is necessitated by Applicant’s amendment of independent claim 1 filed in the papers of July 10, 2026 to add the requirement that sequences from at least two different orthotospovirus genes are concatenated within the stem region.
Huang et al. teach recombinant nucleic-acid constructs for producing double-stranded RNA in plants to confer resistance to multiple plant viruses. The reference further teaches that RNA-mediated gene suppression may be obtained using an inverted-repeat transgene cassette that generates siRNAs from the double-stranded region of the transcript. See in particular Huang, Abstract; col. 9, line 50 through col. 10, line 38; col. 11, lines 1-67; FIGS. 2A-2D and 4A-4B.
Huang et al. further teach targeting tospoviruses, including Tomato spotted wilt virus (“TSWV”), Groundnut bud necrosis virus (“GBNV”), and Capsicum chlorosis virus (“CaCV”). See Huang, col. 10, lines 39-67; col. 11, lines 1-35; FIGs. 2D, 6, and 11A-11B; Tables 3 and 5.
Huang et al. further teach that sequences targeting the coat or nucleocapsid protein, RNA-dependent RNA polymerase, movement protein NsM, and glycoprotein genes of tospoviruses may be used for RNA-mediated suppression. See Huang, col. 10, line 55 through col. 11, line 21; Table 5. Table 5 of Huang et al identifies tospovirus target sequences directed to the L-segment RdRp gene, the M-segment glycoprotein and NsM genes, and the S-segment nucleocapsid gene. See Huang, Table 5, SEQ ID NOs: 43, 47, 51, 55, 59, 63, and 67.
Huang et al. also teach artificial dsRNA fusion constructs comprising concatenated virus-derived segments arranged in an antisense-loop-sense orientation for dsRNA expression. See Huang, col. 20, lines 1-48; FIGS. 4A-4B; Example 3, col. 33, line 55 through col. 34, line 67; SEQ ID NOs: 452-454. In particular, Huang et al. teach SEQ ID NO: 453 comprising a 160-bp TSWV coat-protein segment, a 296-bp TSWV coat-protein segment, a 231-bp PepMV coat-protein segment, and a 232-bp CaCV/GBNV coat-protein segment in an artificial dsRNA fusion construct. See Huang, Example 3, col. 34, lines 1-30; FIGS. 4B and 15; SEQ ID NO: 453.
Huang et al. therefore teach engineered inverted-repeat RNA-silencing constructs, orthotospovirus-derived target sequences, target sequences from multiple distinct orthotospovirus genes, and concatenation of multiple viral target fragments in an artificial dsRNA fusion construct.
Huang does not expressly teach that sequences selected from at least two different genes of an orthotospovirus are concatenated together within the stem region of the same RNA hairpin.
Wang et al. teach an engineered hairpin RNA construct targeting four different genes of Rice black-streaked dwarf virus, namely the S1, S2, S6, and S10 genes. These genes encode an RNA-dependent RNA polymerase, a putative core protein, an RNA-silencing suppressor, and an outer capsid protein, respectively. See Wang, Abstract; page 2, right column, first full paragraph; section 2.1; FIG. 1A.
Wang et al. also teach that fragments from the four different viral genes were joined to form a chimeric fusion sequence in a single hairpin RNA construct. See Wang, section 2.1; FIG. 1A; section 4.2.
Wang et al. further teach that siRNAs corresponding to all four viral gene sequences were detected in resistant transgenic plants, demonstrating that the entire chimeric fusion sequence was efficiently processed into siRNAs. See Wang, Abstract; section 2.4; FIG. 4; Discussion, first and second paragraphs.
Wang et al. conclude that a long hairpin RNA targeting multiple viral genes may be used to produce stable and durable viral resistance in plants. See Wang, Abstract; Discussion, final paragraph.
Wang et al. therefore teach the feature not expressly taught by Huang: concatenating sequences from multiple different viral genes into the same engineered hairpin RNA.
Wang et al do not teach that the multiple gene sequences are derived from an orthotospovirus.
Kaye et al. teach nucleotide sequencing and population analysis of selected regions of three different TSWV genes: the nucleocapsid gene, the movement-protein gene, and the RNA-dependent RNA polymerase gene. See Kaye, Abstract; page 148, left column through right column; Table 1.
Kay et al. identify the corresponding TSWV genomic loci, primer sequences, amplification products, and deposited sequence information for the N, NSm, and RdRp regions. See Kaye, pages 148-149; Tables 1-3.
Kaye therefore establishes that nucleotide sequences from multiple distinct genes of the same orthotospovirus were known and available to a person of ordinary skill in the art.
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify Huang et al’s TSWV-targeting inverted-repeat construct according to the multigene hairpin arrangement taught by Wang by concatenating target sequences from at least two different TSWV genes within the stem-forming portion of the construct.
Huang et al. identify several different TSWV genes as suitable RNA-silencing targets and teaches artificial fusion constructs containing concatenated viral fragments. Wang teaches that fragments from multiple different viral genes may be concatenated in one hairpin and processed into siRNAs corresponding to each component fragment. Kaye et al. provides known sequence information for three different TSWV genes suitable for selection in making the modified construct.
A person of ordinary skill seeking to improve the breadth and durability of Huang et al.’s TSWV resistance would have had reason to apply Wang et al.’s multigene hairpin design. Wang et al. teach that simultaneous targeting of four viral genes produces strong resistance and that the entire multigene fusion is processed into siRNAs.
Targeting at least two different TSWV genes would provide more than one independently complementary viral target and would reduce reliance on silencing a single viral gene or genomic region. This would further Huang et al.’s stated objective of obtaining effective and durable resistance against plant viruses.
The proposed combination would have involved the application of a known technique to a known composition ready for improvement. Huang provides an orthotospovirus-targeting inverted-repeat dsRNA construct. Wang et al. provide the known technique of concatenating fragments from multiple different viral genes in one hairpin. Kaye et al. provide known sequences from multiple TSWV genes.
Applying Wang et al.’s technique to Huang et al.’s TSWV construct would have predictably produced a hairpin comprising concatenated sequences from at least two different TSWV genes. Each fragment would continue to perform its established function as a sequence-specific RNA-silencing target.
There would have been a reasonable expectation of success because Huang et al. demonstrate that sequences from multiple TSWV genes are suitable RNA-silencing targets, and Wang et al. demonstrate that multiple different viral gene fragments concatenated in one hairpin are expressed and processed into corresponding siRNAs.
The claimed sequence-identity threshold would have been met by using actual TSWV sequences identified by Huang et al. or Kaye et al. A viral fragment selected directly from a TSWV gene is 100% identical to its source sequence and therefore has at least 70% identity to that sequence.
Huang et al. further teach selecting tospovirus targets from protein-encoding regions, including RdRp, NsM, glycoprotein, and nucleocapsid genes. Wang et al. likewise targets genes encoding proteins involved in replication, viral structure, silencing suppression, and encapsidation. See Huang et al., Table 5; Wang et al., Abstract and section 2.1.
Huang et al. expressly teaches a 160-bp TSWV target fragment in its artificial dsRNA fusion construct. See Huang et al., Example 3, col. 34, lines 1-30; FIGs. 4B and 15. Selection of that fragment or another fragment of comparable length would satisfy the recited range of 100-200 nucleotides.
Huang et al. and Kaye et al. each expressly teach TSWV, which is one of the alternatives recited in claims 15 and 16.
The proposed modification represents the predictable use of prior-art elements according to their established functions. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 416-421 (2007). Under KSR, when a known technique has been used to improve one composition and a person of ordinary skill would recognize that the technique would improve a similar composition in the same way, use of the technique is obvious unless its application is beyond ordinary skill. Id. at 417. Here, Wang et al.’s multigene-hairpin technique was known to produce siRNAs corresponding to multiple viral genes. Huang et al.’s TSWV inverted-repeat construct was a closely analogous antiviral RNA-silencing composition. Applying Wang et al.’s technique to Huang et al.’s construct using the known TSWV sequences of Kaye would have been within ordinary molecular-biological skill and would have yielded the predictable result of simultaneous RNA silencing directed to multiple TSWV genes.
Accordingly, the combined teachings of Huang et al., Wang et al., and Kaye et al. render claims 1, 2, 6-8, 15, and 16 prima facie obvious over Huang et al. (U.S. Patent No. 8,455,716 B2, Issued June 4, 2013) in view of Wang et al. (Int. J. Mol. Sci. 2016, 17, 705; doi:10.3390/ijms17050705), and further in view of Kaye et al. (Phytopathology 101(1):147-153, 2011).
12. Claims 1, 2 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over Huang et al. (U.S. Patent No. 8,455,716 B2, Issued June 4, 2013) in view of Wang et al. (Int. J. Mol. Sci. 2016, 17, 705; doi:10.3390/ijms17050705) and Kaye et al. (Phytopathology 101(1):147-153, 2011), as applied to claims 1 and 2 above, and further in view of Ramesh et al. (Oligonucleotides 17:251-257, 2007).
This rejection is necessitated by Applicant’s amendment of independent claim 1 filed in the papers of July 10, 2026 to add the requirement that sequences from at least two different orthotospovirus genes are concatenated within the stem region.
Huang et al. teachings are taught supra.
Wang et al. teachings are taught supra.
Ramesh et al. teachings are taught supra.
Huang in view of Wang et al. and Kaye et al. renders obvious the engineered multigene orthotospovirus hairpin and the selection of conserved orthotospovirus target regions, as discussed above.
The combination of Huang in view of Wang et al. and Kaye et al. teachings do not expressly define the conserved region as including at least 25 nucleotides in which at least 85% of the nucleotide positions are conserved.
Ramesh teaches the design of hairpin RNA constructs directed to conserved viral sequences in the AC1 and AC4 regions of Tomato leaf curl virus for obtaining resistance to the virus. See Ramesh, Abstract; pages 251-252; FIGs. 1-3 at pages 253-254. Ramesh teaches selecting viral target sequences based on sequence conservation and complementarity to the viral gene, thereby permitting the resulting siRNAs to recognize the corresponding viral targets. See Ramesh, pages 251-253; FIGs. 1 and 2.
The sequence comparison and alignment of record for the conserved Ramesh et al. target region establish a contiguous region of at least 25 nucleotides in which at least 85% of the nucleotide positions are conserved.
It would have been obvious to apply the conserved-target selection taught by Ramesh et al. when selecting the individual TSWV gene fragments for the hairpin rendered obvious by Huang et al., Wang et al., and Kaye et al.
A person of ordinary skill would have had reason to select a region meeting the recited conservation level in order to maintain sequence complementarity across viral isolates and thereby increase the likelihood that hairpin-derived siRNAs would recognize the corresponding viral sequences.
Selection of a region containing at least 25 nucleotides with at least 85% conserved positions would have represented routine application of the known conserved-region selection principle to the known TSWV gene sequences.
Accordingly, the combined teachings of Huang et al., Wang et al., Kaye et al., and Ramesh et al. render claim 3 prima facie obvious.
13. Claims 1 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Huang et al. (U.S. Patent No. 8,455,716 B2, Issued June 4, 2013) in view of Wang et al. (Int. J. Mol. Sci. 2016, 17, 705; doi:10.3390/ijms17050705) and Kaye et al. (Phytopathology 101(1):147-153, 2011), as applied to claim 1 above.
This rejection is necessitated by Applicant’s amendment of independent claim 1 filed in the papers of July 10, 2026 to add the requirement that sequences from at least two different orthotospovirus genes are concatenated within the stem region.
Huang in view of Wang et al. and Kaye et al. renders obvious an engineered RNA hairpin comprising concatenated sequences from at least two different TSWV genes, as discussed above.
The combined teachings further establish the particular TSWV RdRp sequence recited in claim 12.
Huang et al teach tospovirus RdRp sequences as RNA-silencing targets. See Huang, col. 10, line 55 through col. 11, line 21; Table 5, SEQ ID NOs: 43 and 47; FIG. 11A.
Huang et al. further teach TSWV sequence SEQ ID NO: 270, which the sequence comparison made of record establishes as having approximately 98% identity to instant SEQ ID NO: 1.
Kaye et al. teach a partial TSWV RdRp coding sequence deposited as GenBank Accession No. FJ262087. See Kaye, pages 148-149; Table 1; associated GenBank sequence record FJ262087.
The sequence comparison made of record establishes that instant SEQ ID NO: 1 corresponds identically to nucleotides 328-494 of FJ262087, with 167 of 167 nucleotide positions matching as discussed in item 10A above.
It would have been obvious to select this known TSWV RdRp sequence as one of the concatenated gene-derived fragments in the multigene hairpin rendered obvious by Huang et al., Wang et al., and Kaye et al.
Huang et al. expressly identifies RdRp as a suitable tospovirus RNA-silencing target. Kaye et al. supplies the particular TSWV RdRp nucleotide sequence. Wang et al. teach incorporating fragments from different viral genes into a single chimeric hairpin.
A person of ordinary skill would therefore have had reason to use the known RdRp sequence corresponding to instant SEQ ID NO: 1 as one component of the multigene TSWV hairpin in order to target an essential viral replication gene together with at least one other viral gene.
There would have been a reasonable expectation of success because Huang et al. teach successful processing of tospovirus RdRp-directed RNA-silencing sequences, and Wang et al. demonstrate that each gene-derived component of a multigene hairpin may be processed into corresponding siRNAs.
Accordingly, the combined teachings of Huang et al., Wang et al., and Kaye et al. render claim 12 prima facie obvious.
14. Claims 1 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Huang et al. (U.S. Patent No. 8,455,716 B2, Issued June 4, 2013) in view of Wang et al. (Int. J. Mol. Sci. 2016, 17, 705; doi:10.3390/ijms17050705) and Kaye et al. (Phytopathology 101(1):147-153, 2011), as applied to claim 1 above, and further in view of Helliwell et al. (Methods in Enzymology 392:24-35, 2005).
This rejection is necessitated by Applicant’s amendment of independent claim 1 filed in the papers of July 10, 2026 to add the requirement that sequences from at least two different orthotospovirus genes are concatenated within the stem region.
Huang et al. in view of Wang et al. and Kaye et al. renders obvious the engineered multigene orthotospovirus hairpin, as discussed above.
The combination of Huang et al. in view of Wang et al. and Kaye et al. do not necessarily require that the loop comprise a single-stranded linker sequence not derived from the targeted orthotospovirus.
Helliwell et al. teach plant hairpin RNA constructs comprising an inverted repeat of a target-gene fragment separated by a spacer. Helliwell et al explain that the spacer permits construction of the inverted repeat and forms the intervening portion of the expressed hairpin RNA. See in particular, page 25, first and second full paragraphs; FIG. 1 at page 26.
Helliwell et al. further teach intron-containing hairpin constructs in which the complementary target sequences are separated by a heterologous intron spacer. See in particular, pages 25-31; FIGs. 1-4; Table I at page 31.
The intron or spacer sequences taught by Helliwell are not derived from the viral target sequences being silenced.
It would have been obvious to include Helliwell et al.’s heterologous spacer between the complementary arms of the multigene TSWV hairpin rendered obvious by Huang et al., Wang et al., and Kaye et al.
Helliwell et al. teach the spacer-containing architecture as a standard and effective arrangement for expression of self-complementary hairpin RNA in plants. The spacer would perform its known function of separating the inverted-repeat arms and forming the loop region of the hairpin.
The modification would have been the use of a known hairpin component according to its established function and would have yielded the predictable formation and processing of the hairpin RNA.
Accordingly, the combined teachings of Huang et al., Wang et al., Kaye et al., and Helliwell et al. render claim 13 prima facie obvious over Huang et al. (U.S. Patent No. 8,455,716 B2, Issued June 4, 2013) in view of Wang et al. (Int. J. Mol. Sci. 2016, 17, 705; doi:10.3390/ijms17050705) and Kaye et al. (Phytopathology 101(1):147-153, 2011), as applied to claim 1 above, and further in view of Helliwell et al. (Methods in Enzymology 392:24-35, 2005).
15. Claims 1, 13 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Huang et al. (U.S. Patent No. 8,455,716 B2, Issued June 4, 2013) in view of Wang et al. (Int. J. Mol. Sci. 2016, 17, 705; doi:10.3390/ijms17050705), Kaye et al. (Phytopathology 101(1):147-153, 2011), and Helliwell et al. (Methods in Enzymology 392:24-35, 2005), as applied to claims 1 and 13 above, and further in view of Jefferson et al. (EMBO Journal 6(13):3901-3907; 1987).
This rejection is necessitated by Applicant’s amendment of independent claim 1 filed in the papers of July 10, 2026 to add the requirement that sequences from at least two different orthotospovirus genes are concatenated within the stem region.
Huang in view of Wang et al., Kaye et al., and Helliwell et al. render obvious an engineered multigene TSWV hairpin comprising a heterologous single-stranded linker or spacer, as discussed above.
The combination of Huang in view of Wang et al., Kaye et al., and Helliwell et al. do not expressly teach that the linker sequence is a fragment of the E. coli glucuronidase gene.
Jefferson et al. teach the E. coli β-glucuronidase or GUS gene as a heterologous nucleic-acid sequence suitable for incorporation into plant expression constructs. See in particular, Abstract; page 3901, right column through page 3902, left column; FIG. 1; Materials and Methods at pages 3905-3906.
Jefferson et al. teach construction of GUS gene fusions under plant promoters and successful introduction and expression of GUS-containing constructs in transformed plant cells. See in particular, pages 3901-3904; FIGs. 1-4.
Jefferson et al. therefore establishes that GUS-derived sequences were well-characterized, readily available, compatible with plant transformation vectors, and capable of being incorporated as heterologous sequence elements in plant nucleic-acid constructs.
It would have been obvious to use a fragment of the known GUS sequence taught by Jefferson et al. as the heterologous linker or spacer in the hairpin construct rendered obvious by Huang et al., Wang et al., Kaye et al., and Helliwell et al.
Helliwell et al. teach that a heterologous spacer may separate the inverted-repeat arms of a plant hairpin construct. Jefferson et al teach GUS as a known heterologous sequence routinely incorporated into plant expression constructs. A person of ordinary skill selecting a heterologous nonviral spacer would therefore have considered an available GUS fragment to be one of a finite number of familiar plant-vector sequence elements suitable for that position.
The proposed substitution would not alter the established function of the linker. The GUS fragment would function as an intervening heterologous sequence separating the complementary viral arms and forming the loop portion of the expressed hairpin.
Where the linker’s function is to provide physical separation rather than sequence-specific silencing, substituting one known plant-vector-compatible heterologous sequence for another would have produced the predictable result of a hairpin having a nonviral loop sequence.
The modification therefore represents the substitution of one known element for another to obtain predictable results and the use of known prior-art elements according to their established functions. See KSR, 550 U.S. at 416-421.
Accordingly, the combined teachings of Huang et al., Wang et al., Kaye et al., Helliwell et al., and Jefferson et al. render claim 14 prima facie obvious.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Conclusion
16. Claims 1-3, 6-8 and 12-16 remain rejected.
Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Vinod Kumar whose telephone number is (571) 272-4445. The examiner can normally be reached on 8.30 a.m. to 5.00 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amjad A. Abraham can be reached on (571) 270-7058 The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/VINOD KUMAR/Primary Examiner, Art Unit 1663
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