DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group II, claims 5-8, 18, 24, 25, 34, 35 in the reply filed on 6/25/2026 is acknowledged.
Claims 1-4, 9-12, 16, 20, 22 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/25/2026.
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.
Claim 8 is 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 8 recites the limitation "bacterial conjugation transfer genes" in line 2. There is insufficient antecedent basis for this limitation in the claim. For the purpose of compact prosecution, the claim(s) 8 is/are interpreted as dependent from claim 7 that recites “bacterial conjugation transfer genes”.
Claim Interpretation
Claim 6 depends from claim 5 that is directed to a bacterial expression vector comprising a gram-positive bacteria replication origin (SEQ ID No: 1-9, 311-319), a heterologous sequence and at least one open reading frame (ORF). Claim 5 further recites that the ORF encodes one or more of the listed Markush alternatives. Claim 6 recites that wherein the ORF of claim 5 encodes a sgRNA or Group II intron, the sgRNA or Group II intron targets the recited genes. Thus, the bacterial expression vector of claim 6 comprises a gram-positive bacteria replication origin (SEQ ID No: 1-9, 311-319), a heterologous sequence and at least one open reading frame (ORF), wherein if the ORF encodes a sgRNA or Group II intron then these must target the recited genes. However, Claim 6 does not require that the bacterial expression vector to necessarily encodes a sgRNA or a Group II intron.
Claim 34 depends from claim 24 that is directed to a method of genetically modifying a gram-positive human gut bacteria comprising a single active step of “transferring two or more distinct bacterial expression vector into a gram-positive human gut bacteria cell”. Claim 34 does not recite an active step but a product-by-process limitation wherein the product of gram-positive human gut bacteria cell used in the method of claim 24 is derived by the process of isolation from a sample obtained from a human. According to MPEP 2113, “Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps.” The process steps recited in claim 34 require the product of gram-positive human gut bacteria cell used in the method of claim 24 to have a structure that is of a gram-positive human gut bacteria cell which are derived from samples obtained from a human subject’s gut.
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.
Claim(s) 5, 6, 7, 18 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Heap et al (A modular system for Clostridium shuttle plasmids. Journal of Microbiological Methods 78 (2009) 79–85) as evidenced by FJ797645.1 (Genbank accession number for pMTL82151, published June 1, 2009; PTO-892) and FJ797647.1 (Genbank accession number for pMTL83151, published June 1, 2009; PTO-892).
Regarding claims 5 and 6, based on claim interpretation presented above, Heap discloses a bacterial expression plasmid (=claimed vector) comprising (a) a gram-positive bacteria replication origin such as pBP1, pCB102, pCD6, pIM13, (b) a heterologous nucleic acid sequence encoding an antibiotic resistance gene, and (c) at least one ORF encoding at least lacZ, a chemiluminescent gene (Figure 1A, Table 2, 2.2. Module and plasmid construction). The bacterial expression vectors disclosed by Heap that comprise pBP1, pCB102, pCD6, pIM13 replication origin are from gram-positive bacteria Clostridium botulinum, Clostridium butyricum, Clostridium difficile and Bacillus subtilis (page 82, col. 2, last para; page 83, col. 1, first para) and there sequences were made available to the public as Genbank accession numbers identified in the legend for Table 2.
FJ797645.1 is the Genbank accession number for pMTL82151 that comprises pBP1 replication origin and comprises sequences 100% identical to SEQ ID NO: 311 and 1 (sequence alignment in PTO-892). Of note, SEQ ID No: 311 comprises SEQ ID NO: 1.
FJ797647.1 is the Genbank accession number for pMTL83151 that comprises pCB102 replication origin and comprises sequences 100% identical to SEQ ID NO: 312 and 2 (sequence alignment in PTO-892). Of note, SEQ ID No: 312 comprises SEQ ID NO: 2.
Regarding claim 7, Heap discloses that their bacterial expression plasmid further comprises bacterial conjugation genes, traJ and oriT, and E.coli replication origin, colE1 (Figure 1A; page 81, col. 1, para 2; Table 1).
Regarding claim 18, Heap discloses an engineered gram-positive human gut bacterial cell comprising their plasmids, wherein the engineered gram-positive human gut bacterial cell is derived from Clostridiaceae (Table 3-5).
Therefore, Heap anticipates the claimed invention.
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.
Claim(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Heap as applied to claims 5, 7 above, and further in view of Elena et al (Expression of codon optimized genes in microbial systems: current industrial applications and perspectives. Front. Microbiol. 5:21. 2014).
The teachings of Heap and evidence from FJ797645.1, as discussed in the rejection of claims 5 and 7 are relied upon for the instant rejection.
Heap discloses the bacterial expression plasmid of claims 5 and 7 comprising bacterial conjugation transfer genes, gram-positive bacteria replication origin and heterologous nucleic acid encoding the selectable marker (Figure 1).
Heap does not teach codon optimization of these sequences.
However, codon optimization to improve gene expression from bacterial plasmids was well known.
Elena teaches that codon optimization significantly improves gene expression and has been used to increase gene expression in variety of bacterial species, such as from Clostridiaceae (Abstract; Introduction, para 1; Table 1; page 4, col. 1, para 1). Elena also teach methods used for codon-optimization such as “one amino acid-one codon” and “codon randomization” and codon optimized sequences are offered by commercial vendors at no additional cost (Section Gene Design, para 1, 2, 3).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to codon optimize the nucleic acid sequences in Heap’s plasmid. An ordinary artisan would be motivated to codon optimize the nucleic acid sequences in Heap’s plasmid because it would allow for improved gene expression. An ordinary artisan would reasonably expect to codon optimize nucleic acid sequences in Heap’s plasmid using methods taught by Elena or from a commercial vendor.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Claim(s) 24, 25, 34, 35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Heap et al (A modular system for Clostridium shuttle plasmids. Journal of Microbiological Methods 78 (2009) 79–85) in view of Gama et al (Co-resident plasmids travel together. Plasmid 93 (2017) 24–29) as evidenced by FJ797645.1 (Genbank accession number for pMTL82151, published June 1, 2009; PTO-892) and FJ797647.1 (Genbank accession number for pMTL83151, published June 1, 2009; PTO-892).
Regarding claim 24 and 25, Heap teaches several bacterial expression plasmids that comprise (a) a gram-positive bacteria replication origin such as pBP1, pCB102, pCD6, pIM13, (b) a heterologous nucleic acid sequence encoding an antibiotic resistance gene, and (c) at least one ORF encoding at least lacZ, a chemiluminescent gene (Figure 1A, Table 2, 2.2. Module and plasmid construction) and further comprise bacterial conjugation genes, traJ and oriT, and E.coli replication origin, colE1 (Figure 1A; page 81, col. 1, para 2; Table 1).
The bacterial expression vectors disclosed by Heap that comprise pBP1, pCB102, pCD6, pIM13 replication origin are from gram-positive bacteria Clostridium botulinum, Clostridium butyricum, Clostridium difficile and Bacillus subtilis (page 82, col. 2, last para; page 83, col. 1, first para) and there sequences were made available to the public as Genbank accession numbers identified in the legend for Table 2.
FJ797645.1 is the Genbank accession number for pMTL82151 that comprises pBP1 replication origin and comprises sequences 100% identical to SEQ ID NO: 311 and 1 (sequence alignment in PTO-892). Of note, SEQ ID No: 311 comprises SEQ ID NO: 1.
FJ797647.1 is the Genbank accession number for pMTL83151 that comprises pCB102 replication origin and comprises sequences 100% identical to SEQ ID NO: 312 and 2 (sequence alignment in PTO-892). Of note, SEQ ID No: 312 comprises SEQ ID NO: 2.
Heap teaches a method of using their plasmids to genetically modify gram-positive human gut bacteria cell by transferring the plasmid into the gram-positive human gut bacteria cell by conjugation, wherein the gram-positive human gut bacteria cell are Clostridum species, such as C. botulinum, C. difficile, that have the structure of gram-positive human gut bacteria cell that are isolated from human gut samples, such as recited in claim 34 (see claim interpretation above; 2.1. Bacterial strains, growth and plasmid transfer; Table 3-5).
Heap does not explicitly teach delivery of two distinct plasmid simultaneously via conjugation, as recited in claim 24. However, Heap teaches that since they teach modular plasmids with different replication origin, “two modular plasmids can be maintained in an E. Coli host simultaneously” (page 83, col. 1, para 3).
Gama teaches bacterial cell frequently harbor multiple distinct plasmids and during conjugation, a host comprising two plasmids co-transfers both plasmids to a donor if the plasmid with the lower conjugation rate is transferred (page 25, col. 1, para 2; Figure 1B).
Therefore, based on Gama’s teachings, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention that a host comprising two distinct modular plasmids of Heap when used in Heap’s method would transfer the two distinct plasmid simultaneously via conjugation when the plasmid with the lower conjugation rate is transferred. An ordinary artisan would be motivated to transfer two distinct plasmids of Heap to a gram-positive human gut bacterial cell of Heap in order to transfer two distinct transgenes to the bacterial cell. An ordinary artisan would reasonably expect to transfer two distinct plasmids of Heap to a gram-positive human gut bacterial cell of Heap based on teachings from Gama. Furthermore, such a method would produce the cell of claim 35.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Conclusion
No claim is allowed.
Relevant prior art: Guo et al (Depletion of microbiome-derived molecules in the host using Clostridium genetics. Science, 366, 2019) teach CRISPR-based genetic modification of Clostridium species bacteria wherein the plasmid encode sgRNA.
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/MATASHA DHAR/Examiner, Art Unit 1632
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