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 .
Election/Restrictions
Applicant’s election of the species of VIM-2 variant of SEQ ID NO: 115 in the reply filed on 13 May 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim 33 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 13 May 2026.
The elected species of a yeast cell where the antibiotic-inactivating enzyme is a VIM-2 variant having SEQ ID NO: 115 is free of the art, so search was expanded to the VIM-2 variant having SEQ ID NO: 46.
Claim Status
The amended claim set filed 13 May 2026 is acknowledged. Claims 1 and 23-42 are currently pending. Of those, claims 23-24, 26-27, and 31-33 are currently amended, and no claims are new. Claim 33 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 13 May 2026. Claims 2-22 are cancelled. Claims 1, 23-32, and 34-42 will be examined on the merits herein.
References to the Specification
The instant specification does not include paragraph numbers. To avoid ambiguity if future amendments to the specification change the page and line numbers where information is located, in this action references to the specification will use paragraph numbers from the Pre-Grant Publication US-20240368575-A1 (PTO-892).
Priority
The instant application claims priority to EP21306226.8 (filed 8 Sep 2021) and is a 371 of PCT/EP2022/075025 (filed 8 Sep 2022). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. What follows is the examiner’s claim-by-claim analysis of effective filing date for the claims currently under examination. If the applicant disagrees with this examiner’s determination of effective filing date for any claim, the applicant may identify text within the prior applications that provides support the claimed language.
The foreign priority document only includes SEQ ID NOs: 1-144. So, regarding claim 24(d), the foreign priority document does not contain SEQ ID NO: 122. Regarding claims 31-32, the foreign priority document does not contain SEQ ID NO: 115. Also for completeness, regarding withdrawn claim 33, foreign priority document does not contain SEQ ID NOs: 119-120 or functional variants thereof.
Regarding claim 30, the foreign priority document does not contain support for “enzymes inactivating chloramphenicol; enzymes inactivating fosfomycin; enzymes inactivating bacitracin; and enzymes inactivating a nitroimidazole”. The best support is found on pg. 9 par. 2, where the other types of antibiotic-inhibiting enzymes are disclosed.
Due to these issues, claim 1 and its dependent claims are not fully supported under 112 as required by MPEP 2152.01. Therefore, the effective filing date used for examining claims 1, 23-32, and 34-42 is 8 Sep 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 8 March 2024 was filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner. A signed copy of the statement is attached with this action.
Claim Objections
Claim 24 is objected to because of the following informalities: (1) The scientific name S. cerevisiae in (c) should be italicized in order to match convention in the field at the time of filing and the use of the term elsewhere in the claims.
(2) In (c), the text “the intron is” is duplicated. It is present both before the list of options and also is present within option (c). The unnecessary, duplicate text should be removed for clarity.
(3) The intron of the PRE3 gene is duplicated; it is recited in both part (a) and (e). The unnecessary, duplicate text should be removed for clarity.
(4) The intron of the EFB1 gene is duplicated; it is recited in both part (c) and (e). The unnecessary, duplicate text should be removed for clarity.
Appropriate correction is required.
Claim Interpretation
Regarding claim 29, the claim recites signal peptides that can be “a functional derivative thereof” (of specific sequences SEQ ID NOs: 5 or 7). The instant specification states “By “signal peptide”, “signal sequence” or “leader sequence” is meant a peptide sequence (e.g., 5, 10, 15, 20, 25 or 30 amino acids) present at the N-terminus of newly synthesized proteins that directs their entry to the secretory pathway.” [0143]. The broadest reasonable interpretation of the “functional derivative” limitation is that the sequence must signal as in the term’s definition (“directs their entry to the secretory pathway”), but that other forms of signaling are not required of the derivative sequence.
Claim Rejections - 35 USC § 112(b)
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 24 and 41 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.
Regarding claim 24, the claim recites “(d) the intron of SEQ ID NO:122”. Introns are nucleic acid sequences [instant specification 0045], but the submitted sequence is an amino acid sequence (see below). Therefore, the claim is indefinite because it is not apparent what sequence is actually claimed. If applicant responds to this rejection by submitting a new sequence listing, please be sure that the new CRF of the “Sequence Listing” in accordance with 37 CFR 1.821(e)(1)(i) or 1.821(e)(2)(i).
PNG
media_image1.png
188
478
media_image1.png
Greyscale
Regarding claim 41, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 41 recites the broad recitation “dysbiosis”, and the claim also recites “intestinal dysbiosis” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim Rejections - 35 USC § 112(a)
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, 23-32, and 34-42 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.
One of ordinary skill in the art at the time of filing, when viewing the specification in view of the art, would not have believed that the specification demonstrated possession of the yeast cells as broadly claimed that have the functional limitation of being able to prevent the production of the functional antibiotic-inactivating enzyme in a bacterial host cell. Instead, one of ordinary skill in the art would have recognized that the specification only demonstrates possession of introns that can be excised by the spliceosome of a yeast host cell and that are able to prevent the production of the functional antibiotic-inactivating enzyme in a bacterial host cell.
Claim 1 states “A yeast cell producing a functional antibiotic-inactivating enzyme, said yeast cell comprising an exogenous nucleic acid encoding the antibiotic-inactivating enzyme, wherein the exogenous nucleic acid comprises an intron able to prevent the production of the functional antibiotic-inactivating enzyme in a bacterial host cell.” (emphasis added). Dependent claims 25-32 and 34-42 do not limit the type of intron present in the cell, and dependent claim 24 includes derivatives defined based on still having the function of being “able to prevent the production of the functional antibiotic-inactivating enzyme in a bacterial host cell”.
The instant specification defines the term “intron” as “By “intron” is meant a non-coding sequence of a gene, or its primary transcript, that is removed from the primary transcript and is not present in the corresponding mature messenger RNA molecule.” [0069]. A review of the art reveals that the term “intron”, as defined in the specification and used in the art at the time of filing, includes several different types of introns. Introns, as broadly defined and used, are found in bacteria and archaea (not just eukaryotes) and can be self-spliced as well as being spliced by other proteins. Haugen et al. (2005; PTO-892) teaches “There are four major classes of introns: self-splicing group I and group II introns, tRNA and/or archaeal introns and spliceosomal introns in nuclear pre-mRNA. Group I introns are widely distributed in protists, bacteria and bacteriophages. Group II introns are found in fungal and land plant mitochondria, algal plastids, bacteria and Archaea. Group II and spliceosomal introns share a common splicing pathway and might be related to each other. The tRNA and/or archaeal introns are found in the nuclear tRNA of eukaryotes and in archaeal tRNA, rRNA and mRNA.” (Abstract).
In contrast to the breadth of introns claimed, the specification only contemplates certain types of introns. The specification states that yeast “have the ability to carry out splicing of introns, which is not the case for prokaryotic cells” [0045] and states that “The intron is any intron that can be excised by the spliceosome of a yeast host cell” [0070]. The examples use introns from either the PRE3 or EFB1 yeast genes [for example, Example 11]. However, these introns are both spliceosomal introns.
MPEP 2163 states: “The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by 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 inventor was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ( "[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. … A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.”
The spliceosomal introns contemplated in the examples and the broader text are not representative of other types of introns known to the art at the time of filing because the specification discloses that the splicing process and cell range of the intron are relevant properties that are used as part of the claimed invention, but the only a subset of those properties are contemplated in the specification. Therefore, one of ordinary skill in the art at the time of filing would recognize that the specification does not demonstrate support of the claimed invention by describing a representative number of species by reduction to practice or disclosure of relevant, identifying characteristics.
Also, there is no disclosed or art-known structure-function correlation that would allow one of ordinary skill in the art to determine what non-spliceosomal introns have the claimed function of “able to prevent the production of the functional antibiotic-inactivating enzyme in a bacterial host cell”. The specification does not discuss how to use self-splicing introns or introns from bacteria in the invention. The specification does not identify which introns are “able to prevent the production of the functional antibiotic-inactivating enzyme in a bacterial host cell”. Without such a disclosure, one of ordinary skill must individually test introns from these other groups. However, MPEP 2163 states that a research plan to identify which structures have the claimed function is not an adequate written description: “See Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406 (Holding that description of a gene’s function will not enable claims to the gene "because it is only an indication of what the gene does, rather than what it is."); see also Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991)). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that "[w]ithout such disclosure, the claimed methods cannot be said to have been described.").”
Therefore, one of ordinary skill in the art at the time of filing, when viewing the specification in view of the art, would not have believed that the specification demonstrated possession of the yeast cells as broadly claimed that have the functional limitation of being able to prevent the production of the functional antibiotic-inactivating enzyme in a bacterial host cell. Instead, one of ordinary skill in the art would have recognized that the specification only demonstrates possession of introns that can be excised by the spliceosome of a yeast host cell and that are able to prevent the production of the functional antibiotic-inactivating enzyme in a bacterial host cell.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1, 28, 30, 35, and 37-39 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Trotta (US-20070178456-A1; PTO-892).
Regarding claim 1, Trotta teaches a “reporter gene-based assays described herein [that] may be conducted in an animalia or fungal cell genetically engineered to express a reporter gene… Examples of cells and cell types include, but are not limited to, … yeast cells,…” [0037]. “The reporter gene constructs utilized in the reporter gene-based assays described herein may comprise the coding region of a reporter gene and a tRNA intron that renders the mRNA coding the reporter gene out of frame. … In a specific embodiment, a reporter gene construct utilized in the reporter gene-based assays described herein comprises the coding region of a reporter gene and a tRNA intron within the open reading frame of the reporter gene” [0035] (i.e. wherein the exogenous nucleic acid comprises an intron able to prevent the production of the functional antibiotic-inactivating enzyme in a bacterial host cell). “Examples of reporter genes include, but are not limited to, … the gene encoding beta-lactamase,” [0036] (i.e. said yeast cell comprising an exogenous nucleic acid encoding the antibiotic-inactivating enzyme).
Regarding claim 28, Trotta teaches “The necessary transcriptional and translational signals can also be supplied by the reporter gene.” [0144]. As the gene sequence is providing the signal, there is a signal sequence.
Regarding claim 30, Trotta teaches the antibiotic- inactivating enzyme is selected from the group consisting of: enzymes inactivating a beta-lactam antibiotic [0036].
Regarding claim 31, Trotta teaches beta-lactamase sequences at [0131-0132]. Claim 31 is not included in this rejection because Trotta does not teach the elected species of beta-lactamase sequence; however, applicant is warned that Trotta may teach a non-elected species.
Regarding claim 35, “In a preferred embodiment, stable cell lines containing the constructs of interest are generated for high throughput screening.” [0152]. The process of creating the stable cell lines “allows cells to stably integrate the plasmid into their chromosomes” [0152].
Regarding claim 37, Trotta teaches the invention can be used with the yeast Saccharomyces cerevisiae [0189].
Regarding claim 38, Trotta teaches the yeast cell of claim 1. Trotta also teaches “The reporter gene-based assays may be conducted by contacting a compound or a member of a library of compounds with a cell genetically engineered to contain a reporter gene construct comprising a reporter gene and a tRNA intron within the open reading frame of the reporter gene, ... In a preferred embodiment, a negative control (e.g., phosphate buffered saline (“PBS”)) or another agent that is known to have no effect on the expression of the reporter gene) … are included in the cell-based assays described herein.” [0227]. So Trotta teaches a composition comprising the cell reporter and PBS. The preamble’s statement of “a pharmaceutical composition” is given its broadest reasonable interpretation as in MPEP 2111.02: “ a prior art structure which is capable of performing the intended use as recited in the preamble meets the claim. See, e.g., In re Schreiber, 128 F.3d 1473, 1477, 44 USPQ2d 1429, 1431 (Fed. Cir. 1997)”. The PBS composition in Trotta does not contain any ingredients that are toxic to a subject or otherwise incapable of being administered in a pharmaceutical setting, so it is capable of being administered as a pharmaceutical composition and meets the broadest reasonable interpretation of the claim.
Regarding claim 39, Trotta teaches assaying for reporter gene activity in a cell-based assay. “… beta-lactamase… are enzymes that can be analyzed in the presence of a substrate” [0231]. Therefore, Trotta teaches the parts of the yeast cell of claim 1 in combination with the substrate, an antibiotic which is sensitive to the enzyme produced by the yeast cell. The broadest reasonable interpretation for the intended use of “for separate, sequential or simultaneous administration” is met because these ingredients are capable of being administered because they do not contain any ingredients that are toxic to a subject or otherwise incapable of being administered in a pharmaceutical setting.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 1, 23, 28, 30-31, and 35-39 are rejected under 35 U.S.C. 103 as being unpatentable over Trotta (US-20070178456-A1; PTO-892).
The teachings of Trotta were discussed above and teach all limitations of claims 1, 28, 30, 35, and 37-39.
Trotta teaches cells that report on the activity of one or more components in the tRNA splicing pathway [Abstract] by measuring removal of “a tRNA intron” [0030] from a reporter gene. Trotta describes how the intron removal is based on interactions of the intron with multiple enzymes in the cell. Trotta is silent on the species that the tRNA intron in the reporter gene should be from.
Trotta does not teach wherein the intron is derived from an intron of a yeast gene, as in claim 23.
One of ordinary skill in the art at the time of filing would consider it prima facie obvious to modify the β-lactamase-expressing S. cerevisiae cell reporter of Trotta by using the tRNA intron from the same species as the cell (S. cerevisiae), thereby arriving at the claimed invention, because the introns and intron-removing proteins in a species evolved to work together and Trotta does not teach that one should mix introns from one species into a different host cell. This choice would be beneficial because it reduces the time and cost of experimentation by reducing the number of experimental variables; one does not have to test whether another species’ tRNA intron is capable of being removed by the yeast intron-removal machinery because it is already known that the yeast cell can remove its own intron. See MPEP 2144(II): “The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art … that some advantage or expected beneficial result would have been produced by their combination.” This modification could be performed with a reasonable expectation of success because Trotta teaches the molecular biology techniques to combine the disclosed elements into a gene expression construct.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that the simple substitution of one known element for another to obtain predictable results is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results". In the instant case, the prior art (Trotta) teaches a product that only differs from the claimed invention by the substitution of a single component (i.e. substitution of a specific tRNA intron’s host species in place of a generic one); the substituted element (i.e. the yeast tRNA intron) was already known and already shown to function as a tRNA intron, therefore no change in the function of the substituted element occurred; and one of ordinary skill in the art would be capable of substituting one intron for another with a reasonable expectation of success (i.e. the substitution of the element would lead to predictable results). Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Claims 1, 23, 28, 30-31, and 35-39 are rejected under 35 U.S.C. 103 as being unpatentable over Trotta (US-20070178456-A1; PTO-892) in view of Cartwright et al. (1994; hereafter Cartwright; PTO-892) as evidenced by Patrick (2014; hereafter AddGene; PTO-892).
The teachings of Trotta were discussed above and teach all limitations of claims 1, 23, 28, 30, 35, and 37-39.
Regarding claim 36, Trotta teaches that the reporter gene constructs can be either a stable cell line expression vector with a genomic integration site or “an episomal mammalian expression vector” [0148].
Trotta does not teach wherein the signal peptide is a signal peptide of a protein naturally found in yeast; the prepro-leader sequence of the a-factor mating pheromone of Saccharomyces cerevisiae comprising SEQ ID NO:5 or a functional derivative thereof; or the leader sequence of the K1 killer toxin of Kluyveromyces lactis comprising SEQ ID NO:7 or a functional derivative thereof, as in claim 29. Trotta does not teach wherein the exogenous nucleic acid is integrated in a yeast episomal plasmid, as in claim 36.
Regarding claims 28-29, Cartwright teaches a Saccharomyces cerevisiae expressing a β-lactamase fused to S and P, two fragments of the K1 killer preprotoxin (Abstract) (i.e. a signal peptide of a protein naturally found in yeast). The use of this signal sequence “results in efficient secretion” in single and multi-copy vectors with multiple different promoters and varying nutritional conditions (Abstract).
Regarding claim 36, AddGene defines that the term “episomal plasmid” refers to plasmids with “A fragment from the 2 micron circle (a natural yeast plasmid) [that] allows for 50+ copies to stably propagate per cell.” (pg. 2 par. 6). Cartwright teaches expressing the β-lactamase reporter from a plasmid comprising a 2 micron fragment (Figure 1 on pg. 499), so Cartwright teaches an episomal plasmid.
One of ordinary skill in the art at the time of filing would consider it prima facie obvious to modify the β-lactamase-expressing S. cerevisiae cell reporter of Trotta by using the translation and secretion signals of Cartwright and/or by using the episomal plasmid of Cartwright, thereby arriving at the claimed invention, because there is a benefit to using a gene expression system that is already validated to work in the yeast species to express the desired gene would reduce the time and cost of producing the desired cell line. See MPEP 2144(II): “The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art … that some advantage or expected beneficial result would have been produced by their combination.” This modification could be performed with a reasonable expectation of success because both Trotta and Cartwright teach the molecular biology techniques to combine known elements into a gene expression construct and because Trotta teaches that other types of episomal plasmids can be used with the invention.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that the use of known techniques to improve similar devices, methods or products in the same way is obvious because enhancing a particular class of devices, methods, or products has been made part of the ordinary capabilities of one skilled in the art based upon the teaching of such improvement in other situations. In the instant case, Trotta teaches a “base” product that is a S. cerevisiae yeast expressing a β-lactamase reporter gene with an intron in the open reading frame, and Cartwright teaches a comparable S. cerevisiae yeast expressing a β-lactamase reporter gene wherein the use of the K1 killer preprotoxin signal sequence and the use of an episomal plasmid is taught as advantageous for efficient secretion of the reporter gene in multiple different conditions. Thus, one of ordinary skill in the art could have applied the known technique of Cartwright to the base molecular biology method to make the product taught by Trotta to yield predictable results (i.e. the same advantages). Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Claims 1, 23, 28, 30, 35, and 37-39 are rejected under 35 U.S.C. 103 as being unpatentable over Trotta (US-20070178456-A1; PTO-892) in view of De Gunzberg et al. (WO-2019081614-A1; hereafter De Gunzberg; PTO-892).
The teachings of Trotta were discussed above and teach all limitations of claims 1, 23, 28, 30, 35, and 37-39.
Regarding claims 31-32, Trotta teaches “A large number of b-lactamases have been isolated and characterized, all of which would be suitable for use in accordance with the present invention … As would be readily apparent to those skilled in the field, this and other comparable sequences for peptides having b-lactamase activity would be equally suitable for use in accordance with the present invention” [0131-0132].
Trotta does not teach wherein the antibiotic-inactivating enzyme is a VIM-2 variant is SEQ ID NO: 46, as in the elected species from claims 31-32.
De Gunzberg teaches an isolated β-lactamase polypeptide that is a VIM-2 variant and a nucleic acid encoding the polypeptide [Title, Abstract]. The VIM-2 variant has “ improved properties such as improved protease stability, stability in intestinal medium, improved activity against one or more antibiotics, improved specific activity and/or improved production in a host cell.” [Abstract]. De Gunzberg teaches that the VIM-2 variant polypeptide can be SEQ ID NO: 6, which has the mutations VIM-2 V10A Q34R E130D [pg. 4 para. 5, pg. 5 par. 4]. This sequence is identical to instant SEQ ID NO: 46 (see alignment below).
Alignment 1: Alignment of instant SEQ ID NO: 46 with De Gunzberg SEQ ID NO: 6.
PNG
media_image2.png
410
642
media_image2.png
Greyscale
One of ordinary skill in the art at the time of filing would consider it prima facie obvious to improve the β-lactamase-expressing S. cerevisiae cell reporter of Trotta by using the β-lactamase gene with improved stability, activity, and production from De Gunzberg, thereby arriving at the claimed invention, because these properties would make the reporter gene able to be detected when there is lower protein expression level. Therefore the combination would be desirable because it would improve the reporter cell’s sensitivity. See MPEP 2144(II): “The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art … that some advantage or expected beneficial result would have been produced by their combination.” This modification can be performed with a reasonable expectation of success because Trotta teaches the molecular biology techniques to make the construct and teaches that all β-lactamases can be used, and because De Gunzberg teaches the sequence for the improved β-lactamase variant.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that the simple substitution of one known element for another to obtain predictable results is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results". In the instant case, the prior art (Trotta) teaches a product that only differs from the claimed invention by the substitution of a single component (i.e. substitution of the β-lactamase protein sequence used); the substituted element (i.e. the SEQ ID NO: 46 β-lactamase variant) was already known and already shown to function as a β-lactamase, therefore no change in the function of the substituted element occurred; and one of ordinary skill in the art would be capable of substituting one gene for another with a reasonable expectation of success (i.e. the substitution of the element would lead to predictable results). Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Leonard et al. (1989; PTO-892) teaches human volunteers who were administered the antibiotic ceftriaxone. “in the feces of the four other volunteers, β-lactamase activity was high during ceftriaxone administration, but no ceftriaxone was detected. In these volunteers, ceftriaxone administration was not followed by any significant change in counts of anaerobes or Candida species. This appeared to be due to the intraintestinal hydrolysis of ceftriaxone by resident β-lactamase-producing anaerobes. In gnotobiotic mice associated with a human fecal flora containing no β-lactamase-producing anaerobes, it was possible to prevent the deleterious effects of ceftriaxone on intestinal microbial composition and on colonization resistance (against a strain of Candida albicans and one of ceftriaxone-resistant Enterobacter cloacae) by feeding the animals with an association of four β-lactamase producing anaerobic strains” (Abstract). Leonard et al. also contemplates administering β-lactamase producing anaerobes to humans, but warns that such administration has the potential to allow disease by ampicillin sensitive strains of bacteria (pg. 279 col. 2 par. 1-2).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMELIA N DICKENS whose telephone number is (571)272-0381. The examiner can normally be reached M-F 8:30-4:30 (EDT/EST).
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, Samira Jean-Louis can be reached at (571) 270-3503. 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.
/AMELIA NICOLE DICKENS/Examiner, Art Unit 1645
Prosecution Insights