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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/11/2025 has been entered.
Claims 45-46,48, 65-66 and 68 are pending and are examined.
Specification
The disclosure remains objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See page 83,line 13, line 17. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
In the response filed 07/11/2025, Applicant has neither deleted the hyperlink nor argued against the objection.
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested:
RNA-BASED THERPEUTIC METHODS TO PROTECT PLANTS AND ANIMALS AGAINST PATHOGENIC BACTERIA.
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.
Claim 45-46,48, 65-66 and 68 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 45 is indefinite in the recitation of “15-30 base pairs” without referring to a specific nucleotide sequence or to a specific gene sequence(SEQ ID NO: ). Dependent claims do not obviate the rejection. Clarification is required to more clearly define the metes and bounds of the claims.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 45-46,48, 65-66 and 68 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are drawn to an invitro method that employs with a genus of siRNA having from 15 to 30 base pairs that inhibit specifically the expression of a genus of target bacterial genes in a genus of target Gram-negative bacterial cell, wherein the siRNA is not delivered into the target bacterial cell by transfection, extracellular vesicles, or nanoparticles, wherein the target bacterial cell is from a genus of plant or animal pathogenic bacteria. The claims also encompass the siRNA inhibits expression of a genus of bacterial antibiotic resistance genes including VIM-1, VIM-2,VIM-3, VIM-5, Case, OXA-28, OXA-14, OXA-19, OXA-145, PER-1, TEM-11 and GES-9.
The specification describes identification of double stranded RNA molecules that acts as siRNA precursor that can be processed into siRNA in planta by DCL proteins (page 15) and production of dsRNA and sRNA by invitro synthesis, in which the dsRNA were digested with RNase III to produce siRNA (Example 1 on page 79). Table 1 of the specification, on pages 56-64, provides SEQ ID NOs: of the dsRNAs for targeting specific genes in specific bacterial species. Example 1 of the specification also describes chimeric hairpins that produce artificial siRNAs targeting specific regions of specific genes and the SEQ ID NOs: of the first and second strands used to target the specific genes in specific bacterial species. The dsRNA sequences of SEQ ID NO:108-145 (first and second strands) concomitantly targeting specific genes in specific bacterial species. For example, SEQ ID NO: 108-109 targeting the DnaA, DnaN and GyrB genes of Pseudomonas aeruginosa ; SEQ ID NO: 110-111 targeting specifically the RpoC, SecE and SodB genes of P. aeruginosa; SEQ ID NO: 112-113 SEQ ID NO: 116-117 targeting specifically the FtsA, Can and Tsf genes of Shigella flexner; SEQ ID NO: 118-119 targeting the AccD, Der and Psd genes of Shigella Flexner; SEQ ID NO: 120-121 targeting the VirF, VirB and lcsA genes of Shigella flexner; etc. The dsRNA of SEQ ID NO: 1 is used to concomitantly target Hrp and Cfa6 genes of Pto DC3000. The working examples on pages 95-97 describes in-vitro synthesized siRNA directed against DnaA, DnaN, GyrB, RpoC, SecE or SodB were incubated with P.aeruginosa PAO strain, where the siRNA directed to inhibit GyrB,DnaN or SecE genes caused decreased growth of the bacterium. However, these iRNA or double stranded small RNAs do not represent the genus of siRNA having from 15 to 30 base pairs that can inhibit the expression of a genus of target antibiotic resistance bacterial genes in a genus of target Gram-negative animal/plant pathogenic bacterial cells. While the specification describes the large dsRNA sequences that are precursors for the siRNA, none of these sequences are recited in the rejected claims.
As stated in the last Office actions, the instant claims encompass an extremely large genus of siRNA having 15-30 base pairs that inhibits expression of an extremely large Gram-negative pathogenic bacterial target genes (including virulence genes, essential genes in a large number of animal and plant species. At page 21, “essential gene’ is defined “any bacterial gene that is essential for bacterial cell viability.......essential genes for bacteria is about 250- 500 in number;.........the essential genes encode proteins to maintain a central metabolism, replicate DNA, ensure proper cell division and/or elongation, translate genes into proteins, maintain a basic cellular structure, and mediate transport processes into an out of the cell. Similarly, a “virulence gene’ is defined as “ any bacterial gene that has been shown to play a critical role for at least one of the following: pathogenicity, disease development, colonization of a specific host tissues (e.g. vascular tissues) or host cell environment (e.g. the apoplast), modulation of plant hormone signaling and/or biosynthesis to facilitate multiplication and/or disease development, interference with conserved host regulatory processes to facilitate multiplication and/or disease development, etc.” Therefore, the claims encompass an extremely large genus of siRNAs having 15-30 bp that inhibit expression of an extremely large Gram-negative phytopathogenic bacterial genes in a large number of animal and plant species. The claims do not recite a specific sequence for the target gene or a specific sequence for the dsRNA that produces the siRNA.
The state of the prior art teach the importance of the description of the silencing sequences for targeting specific genes in specific bacterial species that infects specific plant or animal species. The teachings of Good et al, Caswell et al , Gong et al, and Borges et al have been discussed in the last office actions and reiterated in this office action. The art, however, does not teach a representative species of siRNAs having 15-30 in length for inhibiting the expression of a genus of target genes in a genus of pathogenic Gram-negative bacterial species that infects in a genus of animal and plant species. No single small RNA that is siRNA having 15-30 in length for inhibiting the expression of the specific bacterial antibiotic resistance target genes has been described by a complete structure, let alone the genus of pathogenic Gram-negative bacterial species that infects in a genus of animal and plant species. A substantial variation in structures and in function are expected among the genus of siRNA of 15-30 nucleotides in length that inhibit the expression of target genes including virulence genes, essential bacterial genes, or the genus of antibiotic resistance genes in a genus pathogenic Gram-negative bacterial species that infects animal and plant species. In addition, the specification fails to describe a structure common to the members of the genus siRNAs having both the structural and functional properties as recited in the claims, that would allow one of skill in the art to determine the identity of the members of the genus claimed. Therefore, the specification has not met either of the two elements of the written description.
MPEP 2163 and related case laws state that the written description requirement may be satisfied through sufficient description of a representative number of species by disclosing relevant and identifying characteristics such as structural or other physical and/or chemical properties, by disclosing functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the invention as claimed. See E/i Lilly,119 F.3d at 1568, 43 USPQ2d at 1406.
Since the specification fails to sufficiently describe the siRNAs as broadly claimed, methods that employ said siRNAs are similarly not described. Therefore, the specification fails to sufficiently describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize that Applicant was in possession of the invention as broadly claimed at the time of filing.
Response to Applicant’s Arguments
At the outset, the MPEP 2111 states the following:
During patent examination, the pending claims must be "given their broadest reasonable interpretation consistent with the specification." The Federal Circuit’s en banc decision in Phillips v. AWH Corp., 415 F.3d 1303, 1316, 75 USPQ2d 1321, 1329 (Fed. Cir. 2005) expressly recognized that the USPTO employs the "broadest reasonable interpretation standard:
The Patent and Trademark Office ("PTO") determines the scope of claims in patent applications not solely on the basis of the claim language, but upon giving claims their broadest reasonable construction "in light of the specification as it would be interpreted by one of ordinary skill in the art." In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1364[, 70 USPQ2d 1827, 1830] (Fed. Cir. 2004). Indeed, the rules of the PTO require that application claims must "conform to the invention as set forth in the remainder of the specification and the terms and phrases used in the claims must find clear support or antecedent basis in the description so that the meaning of the terms in the claims may be ascertainable by reference to the description." 37 CFR 1.75(d)(1).
Applicant’s arguments filed 07/11/2025 have been considered but are not deemed to be persuasive for the following reasons: 1) with respect to the arguments on pages 6-7 of the response, it is noted that Applicant’s discovery of specific dsRNAs that produce specific siRNA sequences that inhibit specifically the expression of target bacterial genes do not provide written description for any siRNA with 15-30 bp that inhibits expression of any bacterial genes including any essential bacterial gene, or any virulence genes, any antibiotic resistance in any Gram-negative bacterial species that infects any animal or plant species. This description is NOT a unique description because the functional characteristics is not coupled with a known structure. According to the MPEP 2163 and related case laws state “….one must define a compound by "whatever characteristics sufficiently distinguish it"). Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991). 2) With respect to the arguments that the term small RNAs are well known and that one of ordinary skill in the art can easily visualize siRNA having 15-30 nucleotides and can design small RNAs specific to targeting a given bacterial gene, it is noted that since neither the target genes nor the small RNAs are identified by structure (sequence) and function in the claims, one of ordinary skill in the would not visualize the identity of a siRNA having 15-30 nucleotides that inhibits expression of any virulence gene, any essential bacterial gene, or any antibiotic resistance gene in any pathogenic Gram-negative bacterial species of any animal or plant species.
The Federal Circuit court stated that a written description of an invention "requires a precise definition, such as by structure, formula [or} chemical name, of the claimed subject matter sufficient to distinguish it from other material". University of California v. Eli Lilly and Co., 43 USPQ2d 1398 (Fed. Cir. 1997). The court also stated "naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of is not a description of that material". Id.
The University of Rochester v. G.D. Searle & Co., Inc.(, U.S. District Court, Western District of New York, Decision and Order No. 00-CV-6161L,) decided 05 March 2003, at page 8, bottom paragraph, that method claims are properly subjected to a written description requirement if the starting material which requires that method is itself inadequately described. The court specifically stated, "(T)he claimed method depends upon finding a compound that selectively inhibits PGHS-2 activity. Without such a compound, it is impossible to practice the claimed method of treatment. It means little to “invent” a method if one does not have possession of a substance that is essential to practicing that method. Without that substance, the claimed invention is more theoretical than real;……… and there is no meaningful possession of the method."
3) With regard to Applicant’s reliance on Hybritech, Inc V. Monoclonal antibodies, Inc that states “the information that is well known in the art need not be described in the detail in the specification”, it is noted that the MPEP 2163 section II(3)(a) that cites the case law continues that statement with the following “[h]owever, sufficient information must be provided to show the inventor had possession of the invention as claimed”. Because neither the specification nor the prior art provides the core structure required for the function of inhibiting specifically the expression of any pathogenic bacterial gene as required by the claimed method, one of ordinary in the art would not know that Applicant is in possession of the invention as broadly claimed. Further, while Applicant is not required to repeat what is known in the prior art, it is Applicant’s own specification that has to provide the written description of the claimed invention. See, the First Paragraph Statutory requirement under 35 U.S.C. 112(a) where it clearly states “the specification shall contain a written description of the invention…”
4) Applicant’s arguments on pages 11-13 and 15 of the response are basically in support of “make and/or use” (enablement involves assessment of whether one of skill in the art could make and use the invention without undue experimentation) issues but the instant rejection is a written description rejection rather than an enablement rejection. Applicant should note that the written description requirement is separate and distinct from enablement requirement. See the MPEP 2161 II “…….[a] disclosure could be enabling without describing the invention (e.g., a specification describing a method of making and using a paint composition made of functionally defined ingredients within broad ranges would be enabling for formulations falling within the description but would not describe any specific formulation). Examiner agrees with Applicant that the science of RNA interference and gene silencing via double stranded RNA and techniques of controlling gene expression via RNA interference are well established in the art and as evidenced by the teachings of each of Good et al, Caswell et al , Gong et al, Huang et al , Borges et al cited by the Examiner, and Andrew Fire and Craig Mello cited by the Applicant in the response. However, each one of these reference teaches siRNAs and miRNAs as regulators controlling gene expression in bacteria as well as dsRNA and small RNAs, the mechanisms of gene inhibition, and the complementarity between the specific siRNA/miRNA sequence and the specific bacterial gene sequence they silence. However, neither the prior art references nor the instant specification provides a core structure/sequence/domain required for the function of inhibiting specifically the expression of any Gram-negative pathogenic bacterial gene that infects any animal or plant species. There is no known correlation between the structure and function of the siRNA as recited in the claims. See the MPEP 2163. II(A)3(a).
5) With regard to Applicant’s arguments on the paragraph bridging pages 15-16 that multiple of examples and bacterial genes are provided in the specification that show Applicant is in possession of the invention as claimed, it is noted that the specification describes specific dsRNA or chimeric hairpin constructs designed to produce specific siRNAs to specifically inhibit the expression of specific target genes in specific bacterial species. Table 1 of the specification shows dsRNA sequences identified by SEQ ID NO: that are used to target different bacterial genes in specific bacterial species. For example, SEQ ID NO: 1-13 represent CFA6/HRPL dsRNA to concomitantly target HrpL, Cfa6, and/or Hrcc bacterial genes of Pto DC3000. Example 1, on pages 71-72 of the specification, shows an IR-CFA6/HRPL chimeric hairpin to produce artificial siRNA targeting a 250 bp region of Cfa6 nucleotide sequence and a 250 b region of HrpL nucleotide sequence expressed under the control of a promoter in transgenic Arabidopsis plants. However, the specification does not describe the identity/structure of the siRNAs as required by the claimed method. In addition, the specification shows no structural relationship between the sequences of the dsRNA that are used to generate the chimeric hairpin constructs and a single siRNA having 15 to 30 bp that inhibits expression of a targeted bacterial gene. No siRNA sequences produced from the dsRNA constructs described in the specification are disclosed in the specification. Therefore, the fact that bacterial genes including virulence, antibiotic resistance and essential genes are known in the art and the dsRNA that produces the siRNA can be designed does not put Applicant in possession of the genus of siRNA having the properties recited in the claims.
With respect to Applicant’s arguments regarding the functional language In Re Rasmussen ( 650 F.2d 1212, 1214, 211 USPQ 323, 326-27 (CCPA 1981) on pages 19-20 , it is noted that in In re Rasmussen the written description issue is to changes in claim scope rather than to the original claim. Unlike in Rasmussen where the description of a single method of adheringly applying one layer to another was found sufficient to support a generic claim to "adheringly applying" because one skilled in the art reading the specification would understand that it is unimportant how the layers are adhered, so long as they are adhered, the instant method claims require a genus of siRNA that specifically inhibits the expression of any bacteria virulence gene, any essential bacterial gene, or any antibiotic resistance gene of any animal and plant pathogenic gram-negative bacterial species. At page 21, “essential gene” is defined “any bacterial gene that is essential for bacterial cell viability…….essential genes for bacteria is about 250-500 in number”; a “virulence gene” is defined as “ any bacterial gene that has been shown to play a critical role for at least one of the following: pathogenicity, disease development, colonization of a specific host tissues (e.g. vascular tissues) or host cell environment (e.g. the apoplast), suppression of PTI and ET1 response, modulation of plant hormone signaling and/or biosynthesis to facilitate multiplication and/or disease development, interference with conserved host regulatory processes to facilitate multiplication and/or disease development, etc.” Since rejected claims do not recite a specific sequence for the specifically targeted bacterial gene, one would not envision the sequence of effective siRNA.
With respect to Capon support arguments on pages 21-22, it is noted that the claim drawn to a chimeric gene encoding an scFv of an antibody and a gene encoding another protein is more specific and narrower than the instant claims drawn to an invitro method that employs with a genus of siRNA having 15-30 bp that inhibits specifically the expression of any pathogenic bacterial gene in any Gram-negative bacterial species including a large genus of phytopathogenic bacteria. At page 21, “essential gene” is defined “any bacterial gene that is essential for bacterial cell viability…….essential genes for bacteria is about 250-500 in number”; a “virulence gene” is defined as “ any bacterial gene that has been shown to play a critical role for at least one of the following: pathogenicity, disease development, colonization of a specific host tissues (e.g. vascular tissues) or host cell environment (e.g. the apoplast), modulation of plant hormone signaling and/or biosynthesis to facilitate multiplication and/or disease development, interference with conserved host regulatory processes to facilitate multiplication and/or disease development, etc. In addition, every patent application is examined based on the facts that are presented in the application and the policy and the procedures of the office at the time the application is filed. The MPEP 2163 (I) states “[c]ompliance with the written description requirement is a question of fact which must be resolved on a case-by-case basis. Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116 (Fed. Cir. 1991).
Applicant should note that while each of In Re Rasmussen ( 650 F.2d 1212, 1214, 211 USPQ 323, 326-27 (CCPA 1981) 8 F and Capon v. Esshar, 418 F.3d 11349 (Fed. Cir. 2005) are cited in the MPEP 2163 (Written Description Requirement), they are not cited as controlling precedent like Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997); Fiers v. Revel, 984 F.2d 1164 (Fed. Cir. 1993); Amgen, Inc. v. Chugai Pharmaceutical Co., 927 F.2d 1200 (Fed. Cir. 1991); and Enzo Biochem, Inc. v. Gen-Probe, Inc., 296 F.3d 1316 (Fed. Cir. 2002).
For all the reasons discussed above and in the last Office actions, the written description rejection is maintained for the claimed invention drawn to a method that employs with a genus of siRNA having 15-30 bp that inhibits specifically the expression of any bacterial gene in any Gram-negative bacterial species including a large genus of phytopathogenic and animal pathogenic bacteria.
The amendment to claims 45 and 48 to recite ”wherein the small RNA is NOT delivered into the target bacterial cell by transfection, extracellular vesicles or nanoparticles”, does not help the written description of the genus of siRNA as recited in the claims.
Applicant may amend the claims to recite specific sequences (SEQ ID NO: ) for the double stranded RNA (dsRNA) that produce said siRNA, to obviate the rejection.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 45-46 and 65-66 are rejected under 35 U.S.C. 103 as being unpatentable over each of Gong et al (BMB Report, Korean Society for Biochemistry and Molecular Biology (2014) 203-208; Applicant’s IDS) Yanagihara et al (Journal of Antimicrobial Chemotherapy (2006) 57:122-126; Applicant’s IDS) in view of Van De Craen et al (WO 2006/046148 A2) and each of Sardelic et al (Letters: Emerging Infectious Disease (2003)9(8):1022) and Hocquet et al (Antimicrobial Agents and Chemotherapy (2010)54(8):3512-1515) .
The claims are drawn to an in vitro method for inhibiting the expression of at least one gene in a target Gram-negative bacterial cell, said method comprising the step of contacting said target Gram-negative bacterium with extracellularly siRNA having from 15 to 30 base pairs and having sequence homology to the target bacterial gene inhibiting specifically the expression of the target Gram- negative bacterial gene; wherein the siRNA is not delivered into the target cell by transfection, extracellular vesicles or nanoparticle; wherein the bacterial cell is from a phytopathogenic bacterium or animal pathogenic bacterium ; said method wherein said siRNAs are in a composition comprising extracellular free small RNA or apoplastic fluid containing said siRNA.
Gong et al teach an in-vitro siRNA-mediated gene silencing of MexB in Pseudomonas aeruginosa strain PAO1, a Gram-negative pathogenic bacteria , in which siRNA having 21 base pairs introduced into the strain was effective in reducing expression of the MexB and affecting antimicrobial sensitivity, as well disrupting the expression and function of the MexA-MexB-OprM efflux which may be a useful in decreasing drug resistance in the bacterium Pseudomonas aeruginosa (pages 205-206). Therefore, Gong et al teach inhibiting specifically expression of at least one antibiotic resistance gene using siRNA.
At page 203,first column, Gong et al cite Yanagihara et al, who teach an in vitro method of inhibiting the pathogenicity of the bacterial species Staphylococcus aureus using siRNA having 21-22 bp, and show that the siRNA significantly inhibited the expression both the coagulase mRNA expression and the protein after addition of siRNA to the bacteria; Yanagihara et al also teach 21bp duplexes siRNAs shown on Table1 designed against S. aureus coagulase and was shown that the siRNA inhibit the expression of coagulase mRNA and production after culturing S. aureus with the siRNA (pages 123-124 and Fig. 1). Therefore, Yanagihara et al teach a delivery of the siRNA that is not via transfection, extracellular vesicles or nanoparticle. At the paragraph bridging pages 122 and 123, Yanagihara et al state “recognition of double stranded RNA leads to the production of small interfering RNAs (siRNAs) of 21 to 22 nucleotides that associate with a multiprotein complex known as the RNA-induced silencing complex. This ultimately targets homologous mRNAs for degradation based on complementary base pairing. Therapeutic advantages of siRNAs are expected for the treatment of viral infection, dominant disorders, cancer and neurological disorders. However, there have not been any reports on the efficacy of siRNA against Bacteria. Therefore, Yanagihara et al provide the motivation to target bacterial genes siRNA to reduce bacterial infection in human. Yanagihara et al suggest further studies to confirm the siRNA inhibitory potential with other bacterial strains (page 125, right column).
Each of Congo et al and Yanagihara et al do not teach target bacterial cell from a plant pathogenic bacterium, or the specific antibiotic resistance genes of VIM-1, VIM-2,VIM-3, VIM-5, Case, OXA-28, OXA-14, OXA-19, OXA-145, PER-1, TEM-11 or GES9 of claim 66.
Van De Craen et al teach a method that employs siRNAs of about 21 bp that inhibits a target gene in a plant pathogenic pest , said siRNAs produced from dsRNAs having from 50 to 2000 bp (pages 1-9) and can comprises multiple dsRNA fragments to target multiple genes simultaneously; said target gene include an essential gene, a pathogenicity gene (pages 7-8); said method wherein the plant pathogenic pests include bacterial pathogens (page 26, lines 1-9 and page 27, lines 33-35) including , Agrobacterium ssp, Clavibacter ssp Pseudomonas spp (pages 27-28); wherein the pest cell or pest species may be contacted with the dsRNA (page 7, lines 13-14) preventing pest infestation of a cell or an organism by contacting said pest species with said dsRNA or dsRNA construct whereby the dsRNA is taken up by the pest species, wherein said dsRNA is in a liquid composition that can be sprayed on to the surface to be treated; and by applying an effective amount of the dsRNA for treating or preventing pest infestation; (page 38, lines 6-8 and 18-26), and when the bacterial cells come in contact with the liquid composition comprising the dsRNA, the applied dsRNA comes in contact the extracellularly of the treated substrate. Van De Craen et al also teach a method of developing transgenic plants having resistant against pests as result of expressing exogenous dsRNA construct f or RNAi mediated pest gene silencing (pages 31 and 34).
Sardelic et al teach that the Carbapenem-resistant Pseudomonas aeruginosa isolates and other Gram-negative bacteria carrying VIM-type genes including VIM-1, VIM-2, VIM-3, VIM-4,VIM-5 and VIM-6 are known (see the whole document).
Hocquet et al teach identification of the extended -spectrum (ESBLSs), extended spectrum metallo-beta-lactamases (MBLs), and extended-spectrum Oxacillinases (ES-OXAs) in clinical Pseudomonas aeruginosa that is leading to become resistant to any of the antibiotics used to treat Gram-negative nosocomial infections (see Table 1). At the last full paragraph on page 3514, Hocquet et al suggest the need for a simple and reliable routine test that can detect ESBLs, MBLs, and ES-OXAs produced by said bacterial strains to rapidly control and prevent the spread of multidrug-resistant strains carrying emerging resistance mechanisms.
Therefore, it would have been obvious to one or ordinary skill in the art before the effective filing date of the claimed invention to use the in-vitro method of controlling Gram-negative pathogenic bacterial genes via siRNA having from 15 to 30 bp produced from dsRNA that inhibits expression of pathogenicity genes, including antibiotic resistance genes in human cells as taught by each of Congo et al and Yanagihara et al, or in plant cells as by Van De Craen et al, and to modify that method by incorporating the specific antibiotic resistance genes of ESBLs, MBLs, and ES-OXAs taught by each of Sardelic et al and Hocquet et al, given the effectiveness of the siRNA in inhibiting the expression of target genes in Gram-negative pathogenic bacteria as taught each of Gong et al, Yanagihara et al and Van De Craen et al, given that the problem of infestation and damage caused by Gram-negative pathogenic bacterial species in crop production as taught by Van De Craen et al. One of skill in the art would have been motivated to use siRNA-mediated methods to inhibit the expression of target antibiotic bacterial target genes in the Gram-negative bacterial species, given the emerging and increasing resistance to antibiotics which has become a threat to the public health globally, and given that Pseudomonas aeruginosa is the leading antibiotic resistant bacterium, and plays a role in the establishment of nosocomial infectious worldwide as taught by Hocquet et al, and given the prevalence of antibiotic resistance genes of ESBLs, MBLs, and ES-OXAs in Pseudomonas aeruginosa species and the need to identify and control them in hospitals for therapeutic purposes as taught by each of Sardelic et al and Hocquet et al. One would also have been motivated to look into various methods of siRNA delivery other than transfection, extracellular vesicles or nanoparticles, depending on the characteristics of the siRNA molecules, given the siRNA delivery limitations including and the large polar RNA is unable to cross the cell membrane and the rapid digestion by extracellular RNAase.
Therefore, for all the reasons above and in the last office action, the claimed invention as whole is a prima facie obvious.
Response to Applicant’s Arguments
Applicant’s arguments on pages 24-28 are summarized as follows: 1) Applicants argue that Gong et al do not teach contacting the target bacterial with extracellular small RNA, wherein the small RNA is not delivered by transfection, extracellular vesicles or nanoparticles.2) Applicants argue Yanagihara reference works with Gram-positive bacterial rather than Gram-negative bacteria required by the claimed invention. Applicant also argues that Yanaghira et al suggested siRNA delivery method other than extracellular contact due to the extra-cellular barrier to the entry of siRNA into the bacterial cells for better transfection efficiency. 3) Applicants argues that Applicants were first to show that target genes in Gram-negative bacteria can be silenced by contacting with extracellular small RNA. Applicant also argues that this discovery is unexpected and is answer to long-felt need. Applicant therefore, requests withdrawal of the rejection.
These arguments have been considered but are not deemed persuasive because of the following reasons: 1) Cong et al was relied upon because it teaches an in-vitro siRNA-mediated gene silencing in Pseudomonas aeruginosa strain PAO1, a Gram-negative pathogenic bacteria , in which siRNA having 21 base pairs introduced into the strain was effective in reducing expression of the MexB gene and affecting antimicrobial sensitivity, as well disrupting the expression and function of the MexA-MexB-OprM efflux which may be a useful in decreasing drug resistance in the bacterium Pseudomonas aeruginosa. 2) Yanagihara etal, cited by Cong et al , was relied upon because it shows that 21 bp duplexes siRNAs designed against S. aureus coagulase successfully inhibited the expression of coagulase mRNA and production after culturing the S. aureus with the siRNA. Therefore, Yanagihara et al teach a delivery of the siRNA that is not via transfection, extracellular vesicles or nanoparticle. Since this rejection is an obvious rejection and not one of anticipation, Yanagihara et al need not teach a Gram-negative bacteria. Cong et al who cited Yanagihara et al teach a Gram-negative bacteria. Further, since Yanagihara has successfully showed siRNA inhibition of a target gene in Gram-positive bacteria that has an additional extracellular barrier, one of skill in the art would have been motivated to incorporate the co-culturing step of the siRNA with the Gram-negative bacteria of Congo et al, with a reasonable expectation of success. One would have been motivated to target the antibiotic resistance genes listed in claim 66, given the prevalence of antibiotic resistance genes of ESBLs, MBLs, and ES-OXAs in Pseudomonas aeruginosa and the need to identify and control them in hospitals for therapeutic purposes as taught by each of Sardelic et al and Hocquet et al. 4) Regarding the arguments of long-felt need and failure by others, it is noted that while the need to protect plants and animals against Gram-negative pathogenic bacterial via siRNA -based therapeutic methods existed in the art, others were able to develop both in-vitro and in-vivo small RNA -based therapeutic methods to protect plants and animals against Gram-negative bacteria by targeting bacterial genes including antibiotic resistance genes before Applicant's invention as evidenced by Congo et al taken with Yanagihara et al.
In KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. ___, 82 USPQ2d 1385 (2007), the Supreme Court particularly emphasized “the need for caution in granting a patent based on the combination of elements found in the prior art.” It states “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.”Id. at ___, 82 USPQ2d at 1395. The Supreme Court further stated that:
“When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability. For the same reason, if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill. Id. at ___, 82 USPQ2d at 1396. The court also states “[t]he obviousness analysis cannot be confined by . . . overemphasis on the importance of published articles and the explicit content of issued patents. . . . . In many fields it may be that there is little discussion of obvious techniques or combinations, and it often may be the case that market demand, rather than scientific literature, will drive design trends.” KSR , 550 U.S. at ___, 82 USPQ2d at 1396.
Therefore, for all the reasons above and in the last office action, the claimed invention as whole is a prima facie obvious.
Remarks
No claim is allowed.
Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MEDINA AHMED IBRAHIM whose telephone number is (571)272-0797. The examiner can normally be reached Monday-Friday, 9:00 - 6:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, SHUBO ZHOU can be reached at 5712720724. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
MEDINA AHMED. IBRAHIM
Primary Examiner
Art Unit 1662
/MEDINA A IBRAHIM/ Primary Examiner, Art Unit 1662