Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim status
Claims 1-17 are pending and are examined in the office action.
Improper Incorporation by reference to a foreign patent
The incorporation of essential material in the specification by reference to an unpublished U.S. application, foreign application or patent, or to a publication is improper see amendment to specification first paragraph submitted on 09/14/2023. Applicant is required to amend the disclosure to include the material incorporated by reference, if the material is relied upon to overcome any objection, rejection, or other requirement imposed by the Office. The amendment must be accompanied by a statement executed by the applicant, or a practitioner representing the applicant, stating that the material being inserted is the material previously incorporated by reference and that the amendment contains no new matter. 37 CFR 1.57(g).
Specification
The disclosure is objected to because of the following informalities:
Spec, paragraph 0078-0081 states for example “Seq.1” or “SEQ.11” and Table 1 states for example “SEQ ID NO 1” which are incorrect sequence identifies, the correct sequence identifiers would be “SEQ ID NO:” or “Seq Id No.” (see MPEP § 2412.04 and 37 C.F.R. 1.831) Applicants are advised to use correct sequence identifier in each places sequence is stated in the disclosure.
Appropriate correction is required.
Claim Objections
Claims 4, 7-10, and 13 are objected to because of the following informalities:
Claim 4 line 2, applicant is suggested to add “wherein” prior to “the oil body”.
Claim 4 line 3, applicant is suggested to add “is” prior to “selected”.
Claim 7 line 2, applicant is suggested to change “the plant being” to “wherein the plant is”.
Claim 7-8 line 2, applicant is suggested to change “being” to “wherein the plant is”.
Claim 8 line 3, phrase “and preferably” is advised to unitalicized.
Claim 9-10, line 2, applicant is suggested to add “wherein” after “claim1,” and replace the term “being” with “is”.
Regarding claim 13, applicants are advised to include indentation for sub steps (i) and (ii) because where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i).
Regarding claim 14 line 6 and claim 17 line 2, claim recite the terms “heterozygotes” and “homozygotes”, applicant are advised to recite “homozygous” or “heterozygous” as an adjective describing the state of the gene in the recited plant.
Appropriate correction is required.
Claim Rejections - 35 USC § 112 - Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-17 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. All dependent claims are included in these rejections unless they include a limitation that overcomes the deficiencies of the parent claim.
Claims are drawn to a genetically engineered plant adapted for the production of recombinant proteins comprising an inactivated by knockout or RNA interference a gene involved in transcriptional or non-transcriptional gene silencing.
Regarding claim 1, claim recite the term “adapted” renders claim indefinite since it is not clear whether plant requires further step of adaptation other than comprising composition as in substeps (1) or (2). Furthermore, the claim does not further recite how to adapt the plant. For example, Flood et al. (Published: 2017, Journal: Current Opinion in Plant Biology, 36:88–94) teaches plant adapted for various natural environment, humans, or other organisms in different adaptive process (page 88, left last paragraph). Therefore, it is not clear in what process the plant has been adapted to other than the steps described in the RNA interference a gene involved in transcriptional or non-transcriptional gene silencing and inclusion of strong promoter for production of recombinant protein.
Regarding claim 8, the claim is directed to exemplary embodiments (recited as “preferably”) that fall within recited broad ranges. However, description of examples and preferences is properly set forth in the specification rather than in a single claim. A narrower range or preferred embodiment may also be set forth in another independent claim or in a dependent claim. If stated in a single claim, examples and preferences lead to confusion over the intended scope of the claim, because it is not clear whether the claimed narrower range is a limitation. See MPEP § 2173.05(c). A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. Note the explanation given by the Board of Patent Appeals and Interferences in Ex parte Wu, 10 USPQ2d 2031, 2033 (Bd. Pat. App. & Inter. 1989), where broad language is followed by "such as" and then narrow language. This can render a claim indefinite by raising a question or doubt as to whether the feature introduced by such language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Id. In the present instance, claim 8 recites relatively broader embodiments (of Nicotiana spp) followed by exemplary, narrower embodiments (limitations) (of Nicotiana benthaminana) further broader limitation of plant of deferent genus as Camelina sativa.
Regarding claims 12 and 13, claims recite the phrase “may be” renders claim indefinite since it has introduced ambiguity about the invention’s scope and what is required for infringement since it is not clear whether the claim requires the step of inserting to be carryout out after inactivating or not?
Regarding claim 12 3rd to last line, the claim recite the phrase “the step of inserting” renders claim indefinite since there are two steps of inserting one for inserting nucleic acid RNA interference construct and one for inserting nucleic acid comprising a strong promoter linked coupled to a polynucleotide, it is not clear which step of inserting is performed before the step of inactivating as claim recite, therefore there is ambiguity about the invention’s scope and what is required for infringement.
Claim Rejections - 35 USC § 112 – written description rejection
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-17 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.
Analysis of Breadth of Claims
Genes involved in Transcriptional Gene Silencing (TGS) and/or Post Transcriptional Gene Silencing (PTGS) mechanism are large genus of genes (claims 1, 12 and 13).
The Dicer like (DCL), Argonaute (AGO), and RNA-dependent RNA polymerase (RDR) genes comprise any gene found in any plant (claim 2).
Target region of the TGS or PTGS genes comprise any target regions.
Protein from SARS-CoV-2 virus encompass any protein (claim 6).
What is Described in the Specification
Applicant does not describe any plant or a fusion protein as recited in the claims.
Difference Between What was Reduced to Practice and What is Claimed
Applicant has not described knockout or silencing of any genes involved in TGS or PTGS system (claims 1, 12 and 13).
Applicant has not described knockout or silencing of any Dicer like (DCL), Argonaute (AGO), and RNA-dependent RNA polymerase (RDR) genes (claim 2).
Applicant has not described target region of the TGS or PTGS genes that would cause RNA interference or knockout.
Applicant has not described any protein from the SARS-CoV-2 virus that would have use (claim 6).
Analysis
The purpose of the written description is to ensure that the inventor had possession at the time the invention was made, of the specific subject claimed. For a broad generic claim, the specification must provide adequate written description to identify the genus of the claim.
Applicant has not described knockout or silencing of any genes involved in TGS or PTGS system. Genes involved in TGS and PTSG system are large genus of molecules. See for example El-Sappah et al. (Published: 2021, Journal: Front. Plant Sci. 12:705249. doi: 10.3389/fpls.2021.705249) teaches various type of TGS and PTGS gene silencing mechanism exist for example RNA-Directed DNA Methylation, Paramutation etc. (pages 2-11) with various functions (pages 12-15) where there are large number of genes are involved in the mechanisms (see figure 2-9). Therefore, any gene involved TGS and PTSG system are large genus of molecules. Instead, applicant has not described knockout or silencing of any gene involved in TGS and PTGS gene silencing mechanism. Therefore, there is dearth of description of knockout or silencing of any gene involved in TGS and PTGS gene silencing mechanism.
Applicant has described not knockout or silenced of any Dicer like (DCL), Argonaute (AGO), and RNA-dependent RNA polymerase (RDR) genes. Su et al. (Published:2024, Journal: Epigenetics Insights, 17: e003, https://doi.org/10.48130/epi-0024-0005) teaches Dicer-like (DCL) and Argonaute (AGO) has very diverse structures and involved in various functions (page 2, right paragraph 1, see Fig. 1 below, page 7 right paragraph) across sample of 36 plant species which identified 113 DCLs and 334 AGOs across the species (page 2, right paragraph 1, see Fig. 1 below) with various conservation of different domains (page 3, left paragraph 1).
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Furthermore, Cao et al. (Published: 2016, Journal: Front. Plant Sci. 7:1614 doi: 10.3389/fpls.2016.01614) teaches 8 Dicer like (DCL), 27 Argonaute (AGO), and 16 RNA-dependent RNA polymerase (RDR) genes are found in Brassica napus (i.e. from Brassica genus) and are involved in RNA silencing (page 1 abstract). Cao et al. teaches Arabidopsis mutants of the genes as dcl4-2, ago9-1, rdr1-1, rdr6-11, and rdr6-15 which had modified function of increased susceptibility to S. sclerotiorum and dcl1-9 was more resistant. Therefore within a Brassica species there are diverse DCL, AGO and RDR proteins wherein the mutation of some DCL (i.e. DCL4) genes in Arabidopsis causes different function than the other (i.e. DCL1). Therefore, there is dearth of description that any genes when knocked out or inactivated using RNAi would have any effect on the production of any recombinant protein.
Furthermore, targeting any region of the DCL, AGO and RDR would not have any effect on the silencing leading to effect on the gene encoding recombinant protein production. For example Matsuo et al. (Published: 2017, Journal: Journal of Bioscience and Bioengineering 124 (2): 215-220 2017) teaches not all type of mutation in DCL gene in nicotiana would not affect the expression of fibroblast growth factor (aFGF) mRNA and protein levels in the ∆D2 and ∆D4 plants which required the double mutant ∆D2 ∆D4 or ∆D2 to have effective amount of aFGF increased compared to wildtype plant. Therefore, specific gene and target region would be required for the effective silencing leading to the effect on the production of recombinant protein compared to the wild type plants. Furthermore, Matsuo et al. teaches contribution of DCL3 to gene silencing under agroinfiltration appears to be very low wherein the expression level of NbDCL2 was approximately 20% higher in DD4 plants than that in wild-type plants (page 218, right paragraph 2). Furthermore, specific target sequence has been suggested to carryout effective knockout of the genes. Konstantakos et al. (Published: 2022, Journal: Nucleic Acids Research 50 (7): 3616–3637) teaches target sequence location is critical for effective alteration of gene expression or gene knockout. Konstantakos et al. teaches diminished activity of gRNAs targeting close to the C-terminus, since frameshift mutations close to the end of a protein are less likely to disrupt expression. Konstantakos et al. teaches gRNAs targeting non-coding regions, as well as 5 - or 3 -untranslated regions (UTRs), are ineffective, although target sites that disrupt splicing can be efficacious (page 3622, left paragraph 1). Konstantakos et al. teaches gRNA sequence is one of the most important determinants of cleavage efficiency (page3618, right paragraph 4, Table 1). Therefore, it would require specific target region to carryout effective knockout of the gene. Instead, applicant has not described any target region that would knockout any of the DCL, AGO or RDR genes. Therefore, there is dearth of description of carrying out knocking out on any of the gene involved in TGS and PTGS mechanism.
Applicant has not described any plant comprising protein from the SARS-CoV-2 virus that would have use. Gurkhali et al. (Published:2021, Journal: Bioinformatics and Biology Insights https://doi.org/10.1177/11779322211025876) teaches SARS-CoV-2 genome encodes different Non-structural and structural accessory proteins with various amino acid lengths (page 2, Figure 1, Table 1). Instead, applicant has not described any genetically engineered plant comprising the coding sequence of any protein of the SARS-CoV-2 virus.
Given the virtually large genes associated with TGS and PTGS and any of the DCL, AGO and RDRP or the Suppressor of Gene Silencing (SGS) genes, any target regions in the genes leading to knockout or silencing of the gene, the claims read on an extremely broad and highly diverse structures that needs to have specific function of generating genetically modified plants and the method of producing the that would require to have effect on the production of recombinant proteins. Thus, in view of the analysis presented above, a skilled artisan would appreciate that the claims are directed to extremely broad and highly diverge genus of sequence variants that are required to have the specific function of effect on the production of recombinant proteins.
Given the large size and structural diversity associated with the claimed genus, Applicant’s disclosure is not representative of the claimed genus as a whole. This point is particularly relevant because, as discussed above, the prior art speaks to the disconnection between the structure of the broadly claimed variants in any plants and the recited specific function.
"The test for sufficiency is whether the disclosure of the application relied upon reasonably conveys to one skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Ariad Pharm, Inc, v EH Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010). To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Lockwood v. Amer. Airlines, ina, 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). "An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations. Lockwood, 107 F.3d at 1572, 41 USPG2d at 1966". While the written description requirement does not demand either examples or an actual reduction, actual "possession" or reduction to practice outside of the specification is not enough. Ariad Pharm, Inc. v. Eli Lilly & Co., 598 F,3d 1336,1352 (Fed. Cir. 2010). Rather, it is the specification itself that must demonstrate possession. Id.
Thus, based on the analysis above, Applicant has not met either of the two elements of the written description requirement as set forth in the court's decision in Eli Lilly. As a result, it is not clear that Applicant was in possession of the claimed genus at the time this application was filed.
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Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Anticipated by Matsuo et al.
Claims 1-3, 8-10 and 12-14 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Matsuo et al. (Published: 2019, Journal: Planta 250:463–473).
Claims are drawn to a genetically engineered plant adapted for the production of recombinant proteins comprising an inactivated by knockout or RNA interference a gene involved in transcriptional or non-transcriptional gene silencing.
Regarding claims 1-3, Matsuo et al. discloses a genetically engineered knockout plant of N. benthamiana for the knocked out gene RNA-dependent RNA polymerase 6 (RDR6) (i.e. ΔRDR6 plants) wherein the ΔRDR6 plants accumulated larger amounts of green fluorescent protein (GFP) (see snippets of figure 5 below) and GFP mRNA than the wild-type (WT) plants and small RNA sequencing analysis revealed that levels of small interfering RNA against the GFP gene were greatly reduced in the ΔRDR6 plants, as compared to that of the WT plants, therefore the ΔRDR6 plants can express larger amounts of recombinant proteins than WT plants. Matsuo et al. discloses RDR6 is involved in gene silencing (page 470, left paragraph 2).
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The plant comprise a construct pBE2113:GFP and the GFP was transiently expressed under control of the 35S promoter of the cauliflower mosaic virus (CaMV) (i.e. strong promoter) in the ΔRDR6 and WT plants. Wherein the GFP protein is recombinant protein and the inactivated RDR6 is involved in gene silencing.
Regarding claim 8, Matsuo et al. discloses the genetically engineered plant sis from N. benthamiana.
Regarding claim 9, Figure 3 and 4 discloses vegetative organs as leaves of the genetically engineered plant.
Regarding claim 10, the strong promoter 35S CaMV is a viral promoter.
Regarding claims 12-13, Matsuo et al. discloses the knockout was created by the method of CRISPR-Cas9 with sgRNA targeting the RDR6 gene (Figure 1) (page 463, abstract). Matsuo et al. discloses the Cas9-sgRNA expression vector used for inactivation of the N. benthaminana RDR6 gene (page 466, Figure 1). Matsuo et al. discloses the method produce the recombinant GFP protein in the genetically engineered plant.
Regarding claim 14, Matsuo et al. discloses flower of the ΔRDR66 plants (page 468, Figure 3). Collecting seeds of the genetically engineered plant would have been within scope of the skilled in the art. The plant would have either homozygous or heterozygous to the RDR6 gene.
Therefore Matsuo et al. anticipates the claims.
Anticipated by Matsuo et al.’17
Claims 1-2, 5, 8-10 and 12-14 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Matsuo et al.’17 (Published: 2017, Journal: Journal of Bioscience and Bioengineering 124 (2): 215-220 2017).
Claims are drawn to a genetically engineered plant adapted for the production of recombinant proteins comprising an inactivated by knockout or RNA interference a gene involved in transcriptional or non-transcriptional gene silencing. The claims are drawn wherein the recombinant protein is selected among the coding sequence of a protein selected among antibodies, growth factors and antigens.
Regarding claims 1-2, Matsuo et al.’17. discloses RNA interference technology to develop DCL2- and DCL4-repressed transgenic N. benthamiana plants (∆D2, ∆D4, and ∆D2∆D4 plants) which lowers levels of NbDCL2 and/or NbDCL4 mRNAs than wild-type plants wherein the plants accumulated larger amounts of green fluorescent protein (GFP) and human acidic fibroblast growth factor (aFGF) wild-type plants and so would be useful for recombinant protein production (page 215, Abstract).
Matsuo et al.’17 discloses DLC’ are involved in involved in transcriptional gene silencing (page 215, left paragraph 2).
Matsuo et al.’17 discloses the gene was in the plant from Matsuo et al.’2016 wherein Matsuo et al.’17 shows the evidence the gene was under cauliflower mosaic virus 35S promoter (i.e. strong promoter) (page 352, left paragraph 1).
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Regarding claim 5, the RNA interference of DCL genes in the repressed plant accumulated large amount of recombinant protein of human acidic fibroblast growth factor (aFGF) (see Figure 5).
Regarding claim 8, Matsuo et al.’17 discloses the genetically engineered plant sis from N. benthamiana.
Regarding claim 9, Figure 3 and 4 discloses vegetative organs as leaves of the genetically engineered plant.
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Regarding claim 10, the strong promoter 35S CaMV is a viral promoter.
Regarding claims 12-13, Matsuo et al.’17 discloses inactivation DCL’s were carried out by inserting in the plant RNA interference construct targeting RNA molecule of DCL (page 216, Figure 1).
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Regarding claim 14, Matsuo et al.’17 discloses flower of the ΔRDR66 plants (page 217, Figure 3). Collecting seeds of the genetically engineered plant would have been within scope of the skilled in the art. The plant would have either homozygous or heterozygous to the RDR6 gene.
Therefore Matsuo et al.’17 anticipates the claim.
Anticipated by Moloney et al.
Claims 15-17 are rejected under 35 U.S.C. 102 (a) (1) and/or (a)(2) as being anticipated by Moloney et al. (US Patent No.: US 7,091,401 B2, Date of Patent: Aug. 15, 2006).
Claims are drawn to a fusion protein comprising a recombinant protein and an oil-body protein.
Regarding claim 15-17, Moloney et al. discloses a oleosin-epidermal growth factor (EGF) (a hEGF from human, see example 1) fusion construct (Figure 1) and transgenic (Oleosin-pro-EGF) Arabidopsis seeds producing oleosin-epidermal growth factor fusion protein (Col. 12, lines 57-67). Claims 21 and 23 recites the recombinant EGF oil body fusion protein wherein the oil body protein is an is an oleosin, caleosin or steroleosin.
Since the method of claims 15-17 only describes the fusion protein was produced in the genetically engineered plant of claim 15 and by method of claim 16-17 that recites the method involves inactivating different genes (i.e. genes involved in TGS or PTGS mechanism) the composition and function of the fusion protein would have been different from the Oleosin-EGF fusion protein from transgenic Arabidopsis plants.
The claim is interpreted as “product by process claim” wherein [E]ven though product by process claim is limited by and defined by the process, determination of patentability is based on the product itself. If the product in the product by process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process."
Therefore Moloney et al. anticipate the claim.
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 factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Obvious over Matsuo et al.’17 and further in view of Ward et al.
Claims 1 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Matsuo et al.’17, and further in view of Ward et al. (Published: 2020, Journal: medRxiv https://doi.org/10.1101/2020.11.04.20226282doi, posted November 6, 2020. , pages 1-58) and as evidenced by Matsuo et al.’2016 (Published: 2016, Journal: Journal of Bioscience and Bioengineering 122 (3):351-356).
Claims are drawn to a genetically engineered plant adapted for the production of recombinant proteins of the SARS-CoV-2 virus comprising an inactivated by knockout or RNA interference a gene involved in transcriptional or non-transcriptional gene silencing.
Regarding claim 1, Matsuo et al.’17 teaches RNA interference technology to develop DCL2- and DCL4-repressed transgenic N. benthamiana plants (∆D2, ∆D4, and ∆D2∆D4 plants) which lowers levels of NbDCL2 and/or NbDCL4 mRNAs than wild-type plants wherein the plants accumulated larger amounts of green fluorescent protein (GFP) and human acidic fibroblast growth factor (aFGF) wild-type plants and so would be useful for recombinant protein production (page 215, Abstract).
Matsuo et al.’17 teaches DLC’ are involved in involved in transcriptional gene silencing (page 215, left paragraph 2).
Matsuo et al.’17 teaches the gene was in the plant from Matsuo et al.’2016, wherein Matsuo et al.’2016 shows the evidence the gene was under cauliflower mosaic virus 35S promoter (i.e. strong promoter) (page 352, left paragraph 1).
Regarding claim 6, Ward et al. teaches full-length S glycoprotein of SARS-CoV-2, strain hCoV-19/USA/CA2/2020, corresponding in sequence to nucleotides 21563 to 25384 from EPI_ISL_406036 in GISAID database (https://www.gisaid.org/) was expressed in Nicotiana benthamiana plants (page 8, paragraph 2).
Ward et al. teaches CoVLP, a virus-like particle (VLP) vaccine that is produced by transient transfection of Nicotiana benthamiana plants wherein the recombinant platform has been used to produce hemagglutinin (HA)-bearing VLP vaccines for avian (monovalent) and seasonal (quadrivalent) influenza that induce balanced humoral and T cell responses (page 7 and 8, last and first paragraph). Ward et al. teaches upon administration of the formulation containing protein the antibody and cellular responses were highest in subjects (page 3, first paragraph) and the vaccine is crucial for ending the SARS-CoV-2 disease (page 3, last paragraph).
Therefore it would have been obvious to a skilled in the art before the effective date of filing as known work in one field of endeavor for increasing expression of human acidic fibroblast growth factor (aFGF) in Arabidopsis plant by silencing Dicer-like (DCL) genes encoding Dicer-like proteins as taught by Matsuo et al.’17 and it may prompt variations of it for use in expression of S glycoprotein of SARS-CoV-2 based on the high demand of effective SARS-CoV-2 vaccine to end the disease wherein the variations are predictable to have effect to the SARS-CoV-2 virus to one of ordinary skill in the art.
Obvious over Matsuo et al.’17 and further in view of Cao et al. and Zheng et al.
Claims 1 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Matsuo et al.’17 and further in view of Cao et al. (Published: 2016, Front. Plant Sci. 7:1614. doi: 10.3389/fpls.2016.01614), and further in view of Zheng et al. (Published: 2020, Journal: Plant Biotechnology Journal 18: 644–654 doi: 10.1111/pbi.13228).
Claims are drawn to a genetically engineered plant from Brassica genus adapted for the production of recombinant proteins comprising an inactivated by knockout or RNA interference a gene involved in transcriptional or non-transcriptional gene silencing.
Regarding claim 1, Matsuo et al.’17 teaches RNA interference technology to develop DCL2- and DCL4-repressed transgenic N. benthamiana plants (∆D2, ∆D4, and ∆D2∆D4 plants) which lowers levels of NbDCL2 and/or NbDCL4 mRNAs than wild-type plants wherein the plants accumulated larger amounts of green fluorescent protein (GFP) and human acidic fibroblast growth factor (aFGF) wild-type plants and so would be useful for recombinant protein production (page 215, Abstract).
Matsuo et al.’17 teaches DLC’ are involved in involved in transcriptional gene silencing (page 215, left paragraph 2).
Matsuo et al.’17 teaches the gene was in the plant from Matsuo et al.’2016, wherein Matsuo et al.’2016 shows the evidence the gene was under cauliflower mosaic virus 35S promoter (i.e. strong promoter) (page 352, left paragraph 1).
Regarding claim 7, Matsuo et al.’17 does not teach the plant is from Brassica genus.
Cao et al. teaches 8 Dicer like (DCL), 27 Argonaute (AGO), and 16 RNA-dependent RNA polymerase (RDR) genes are found in Brassica napus (i.e. from Brassica genus) and are involved in RNA silencing (page 1 abstract). Cao et al. teaches Arabidopsis mutants of the genes as dcl4-2, ago9-1, rdr1-1, rdr6-11, and rdr6-15 which had modified function of increased susceptibility to S. sclerotiorum and dcl1-9 was more resistant.
Knocking out a Brassica gene using a CRISPR/Cas9 system was known in the art. Zheng et al. teaches knockout of all four BnaMAX1 alleles resulted in modified phenotypes with higher yield compared to wildtype (page 644, Summary).
Therefore it would have been obvious from teaching, suggestion and motivation of Matsuo et al. to knockout RDR6 gene leading to increased production of recombinant protein produced by a gene under strong promoter and utilize the knockout in the Brassica plant with RDR genes taught by Cao et al. by the efficient targeted knockout technique as taught by Zheng et al. in the Brassica plant that would lead to the invention of a Brassica plant with knocked out RDR6 gene involved in gene silencing and someone skilled in the art would use a strong promoter as taught by Matsuo et al. along with a gene to screen for the increased expression leading to the invention of the recited Brassica plant.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
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Claim 1-5, 9, 12-13 and 15-17 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2,3, 5, 6-8 of copending Application No. 18714592 (reference application, hereafter cited as ‘592). Although the claims at issue are not identical, they are not patentably distinct from each other because.
Regarding claims 1, 12 and 13, copending application ‘592 claims 1, 2 and 5 recite method of producing genetically engineered plant expressing a recombinant protein wherein the plant comprise inactivated gene involved in TGS and PTGS, and wherein the recombinant protein and oil body protein are fused.
The method would produce the plant recited in claim 1.
Regarding claims 2 and 3, Applicant teaches RDR family protein is involved in TGS mechanism (page 8, paragraph 0024). Furthermore, Matsuo et al. shows the evidence that RDR6 is involved in gene silencing (page 470, left paragraph 2).
Regarding claim 4, Copending application ‘592 claim 6 and 7 recite the pol body protein is oleosin.
Regarding claim 5, copending application ‘592 claim 8 recite the recombinant protein is growth factors.
Regarding claim 9, copending application ‘592 claim 3 recite leaves (i.e. vegetative organs) of the engineered plant.
Regarding claims 15-17, copending application ‘592 claim 1 recite the recombinant protein and oil body protein are fused.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 6 and 8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2 and 5 of copending Application No. ‘592 in view of Ward et al.
Regarding claims 1, copending application ‘592 claims 1, 2 and 5 recite method of producing genetically engineered plant expressing a recombinant protein wherein the plant comprise inactivated gene involved in TGS and PTGS, and wherein the recombinant protein and oil body protein are fused.
Regarding claim 6 and 8, Ward et al. teaches full-length S glycoprotein of SARS-CoV-2, strain hCoV-19/USA/CA2/2020, corresponding in sequence to nucleotides 21563 to 25384 from EPI_ISL_406036 in GISAID database (https://www.gisaid.org/) was expressed in Nicotiana benthamiana plants (page 8, paragraph 2).
Ward et al. teaches CoVLP, a virus-like particle (VLP) vaccine that is produced by transient transfection of Nicotiana benthamiana plants wherein the recombinant platform has been used to produce hemagglutinin (HA)-bearing VLP vaccines for avian (monovalent) and seasonal (quadrivalent) influenza that induce balanced humoral and T cell responses (page 7 and 8, last and first paragraph). Ward et al. teaches upon administration of the formulation containing protein the antibody and cellular responses were highest in subjects (page 3, first paragraph) and the vaccine is crucial for ending the SARS-CoV-2 disease (page 3, last paragraph).
Therefore it would have been obvious to a skilled in the art before the effective date of filing as known work in one field of endeavor for increased production of recombinant protein fused to oil body in Nicotiana benthamiana plants by silencing genes involved in PTGS or TGS system as by teaching suggestions and motivation of copending application ‘592 and it may prompt variations of it for use in expression of S glycoprotein of SARS-CoV-2 based on the high demand of effective SARS-CoV-2 vaccine to end the disease wherein the variations are predictable to have effect to the SARS-CoV-2 virus to one of ordinary skill in the art.
Claims 1, 7, 10-11 and 14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2 and 5 of copending Application No. ‘592 and further in view of Cao et al., and further in view of Zheng et al.
Regarding claims 1, copending application ‘592 claims 1, 2 and 5 recite method of producing genetically engineered plant expressing a recombinant protein wherein the plant comprise inactivated gene involved in TGS and PTGS, and wherein the recombinant protein and oil body protein are fused.
Regarding claim 7, copending application ‘592 does not teach the plant is from Brassica genus.
Cao et al. teaches 8 Dicer like (DCL), 27 Argonaute (AGO), and 16 RNA-dependent RNA polymerase (RDR) genes are found in Brassica napus (i.e. from Brassica genus) and are involved in RNA silencing (page 1 abstract). Cao et al. teaches Arabidopsis mutants of the genes as dcl4-2, ago9-1, rdr1-1, rdr6-11, and rdr6-15 which had modified function of increased susceptibility to S. sclerotiorum and dcl1-9 was more resistant.
Knocking out a Brassica gene using a CRISPR/Cas9 system was known in the art. Zheng et al. teaches knockout of all four BnaMAX1 alleles resulted in modified phenotypes with higher yield compared to wildtype (page 644, Summary). Zheng et al. teaches a strong promoter 35S promoter operatively linked to BnaMAX1 gene from Brassica (page 650, left last paragraph).
Therefore it would have been obvious from teaching from copending application ‘592 to silence and inactive gene involved in PTGS or TGS system leading to increased production of recombinant protein produced by a gene and utilize the knockout in the Brassica plant with gene involved in TGS or PTGS systems taught by Cao et al. by the efficient targeted knockout technique as taught by Zheng et al. in the Brassica plant that would lead to the invention of a Brassica plant with knocked out gene involvedin PTGS or TGS system and someone skilled in the art would use a strong promoter as taught by Zheng et al. along with a gene to screen for the increased expression leading to the invention of the recited Brassica plant.
Regarding claim 10, Zheng et al. teaches a strong promoter 35S promoter operatively linked to BnaMAX1 gene from Brassica (page 650, left last paragraph).
Regarding claim 11, someone skilled in the art would attach strong promoter for the production of recombinant protein fused to oil body of copending application ‘592, leading to the invention of the nucleic acid.
Regarding claim 14, Zheng et al. teaches collecting T0 seeds of Brassica napus and growing seeds in MS medium to produce seedlings and selecting identifying positive T2 rapeseed plants by PCR (page 651, right paragraph 1).
This is a provisional nonstatutory double patenting rejection.
Summary
No claim is allowed.
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/SANTOSH SHARMA/Examiner, Art Unit 1663
/DAVID H KRUSE/Primary Examiner, Art Unit 1663