DETAILED ACTION
Claims 18-27, 29-33, 35, 36, 39 and 41-55 are currently pending.
Claim 55 is free of the prior art; however, it is rejected under non-statutory double patenting.
Claim Rejections – 35 USC § 103
1. 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.
2. Claim(s) 18-27, 29-33, 35, 36, 39 and 41-54 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bikard et al (10,660,943; filed 2/7/14).
Bikard et al teach a pharmaceutical composition for killing targeted bacteria in a mixed bacterial population comprising: a pharmaceutically acceptable carrier and a packaged, recombinant phagemid that is packaged in a phage capsid, wherein the packaged phagemid comprises a clustered regularly interspaced short palindromic repeats (CRISPR) system, wherein the CRISPR system comprises DNA encoding: i) a type II CRISPR-associated enzyme; and ii) a targeting RNA that targets at least one bacterial chromosome at a target site; and wherein, upon contacting a bacterial population containing the at least one bacterial chromosome with the pharmaceutical composition, the phagemid is introduced into bacteria in the bacterial population, wherein subsequent to the introduction of the phagemid, the targeting RNA and the type II CRISPR-associated enzyme are expressed in the bacteria into which the phagemid is introduced, wherein the expressed type II CRISPR-associated enzyme cleaves the bacterial chromosome at the target site of the targeting RNA, and wherein the cleavage of the bacterial chromosome at the target site kills the bacteria. The type II CRISPR-associated enzyme is a Cas9 enzyme. The Cas9 enzyme may be a Streptococcus pyogenes Cas9. Methods of detecting the killing of bacteria using the pharmaceutical composition are taught. In the pharmaceutical composition the bacteria may be selected from the group consisting of Staphylococcus, Clostridium, Bacillus, Salmonella, Helicobacter pylori, Neisseria gonorrhoeae, Neisseria meningitidis, and Escherichia coli, including Staphylococcus aureus. Also taught is a pharmaceutical composition for killing targeted bacteria in a mixed bacterial population comprising: a pharmaceutically acceptable carrier and a packaged, recombinant phagemid that is packaged in a phage capsid, wherein the packaged phagemid comprises a clustered regularly interspaced short palindromic repeats (CRISPR) system, wherein the CRISPR system comprises DNA encoding: i) a type II CRISPR-associated enzyme; and ii) a targeting RNA that targets an antibiotic resistance gene on a plasmid at a target site within the plasmid; wherein, upon contacting a bacterial population containing the at least one antibiotic resistance gene on a plasmid with the pharmaceutical composition, the phagemid is introduced into bacteria in the bacterial population, wherein the targeting RNA and the type II CRISPR-associated enzyme are expressed in the bacteria into which the phagemid is introduced, wherein the expressed type II CRISPR-associated enzyme cleaves the antibiotic resistance gene on a plasmid at the target site within the plasmid, and wherein the cleavage of the bacterial plasmid at the target site kills the bacteria in the presence of the antibiotic. See claims 1-14 of Bikard et al.
Paragraph 10 of Birkard recites:
10) As is recognized in the art, a CRISPR site is a distinctive DNA locus (i.e., an array or cluster of DNA sequences) found in the genomes of many bacteria and archaea. It has been reported that CRISPR sequences can function as a type of “immune system” that help bacteria defend against phage infections (see, for example, Barrangou et al., “CRISPR Provides Acquired Resistance Against Viruses in Prokaryotes,” Science 315:1709-12 (March 2007); Deveau et al., J. Bacteriol. 190(4): 1390-1400 (February 2008); Horvath et al., J. Bacteriol. 190(4):1401-12 (February 2008)).
Claim Rejections – 35 USC § 102 or 103
3. 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.
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 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.
4. Claims 18-27, 29-33, 35, 36, 39 and 41-54 are rejected under 35 U.S.C. 103 as being unpatentable over Gomaa et al (Supplemental Material to “Programmable Removal of Bacterial Strains by Use of Genome-Targeting CRISPR-Cas Systems,” American Society for Microbiology 5(1):1-9 (January/February 2014): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3903277/#!po=4.68750 ), Zhang (US Patent Application Publication No. US 2014/0234972 A1; published on 21 August 2014), and Nakamura (Emerging Infectious Diseases 14(11):1784-1786. November 2008) as evidenced by Brouns et al (Science 321:960-964 (15 August 2008). http://science.sciencemag.org/content/321/5891/960 , Navarre et al (Genes & Development 21:1456-1471. 2007), and Stroebel et al (Microbiology 154:2533-2545. 2008); all references provided by Applicants.
Regarding claim 18, Gomaa teaches the use of a CRISPR-Cas system, i.e, an array, to selectively and quantitatively kill individual bacterial stains based on sequence information. See the Abstract:
…this approach could offer a novel means to quantitatively control the composition of environmental and industrial microbial consortia and may open new avenues for the development of “smart” antibiotics that circumvent multidrug resistance and differentiate between pathogenic and beneficial microorganisms.
See page 2, where Gomaa notes:
Finally, using genomic sequence information, we could selectively remove closely related bacterial strains whether in pure or mixed cultures. The extent of removal could even be modulated by mixing targeting and nontargeting plasmids. Our findings open the possibility of quantitatively controlling the composition of microbial consortia and selectively treating multidrug-resistant infections, particularly with ongoing advances in the delivery of nucleic acids to microorganisms.
Gomaa at page 6 further suggests:
In biotechnology, CRISPR-Cas systems could be used to selectively clear contaminating microorganisms or to quantitatively control the composition of microbial consortia in industrial processes or in environmental samples. In medicine, CRISPR-Cas systems could be used to control the composition of the gut flora or as ‘smart’ antibiotics that circumvent commonly transmitted modes of antibiotic resistance and distinguish between beneficial and pathogenic bacteria. For applications that require the removal of more than one strain, multiple spacers that target shared or unique sequences could be encoded in a single CRISPR array.
Gomaa discloses targeting essential genes, such as the essential ftsA gene involved in cell division. See Fig 2A and page 2, second column, last paragraph. Targeting a virulence factor in Salmonella enterica, such as the mviM gene is suggested. See page 4, second column, last paragraph. Gomaa at page 4 suggests:
One potential application of programmable removal with CRISPR-Cas systems is targeting pathogenic bacteria while sparing commensal bacteria. Toward this goal, we focused on E. coli K-12 (BW25113-T7), a derivative of commensal E. coli that naturally inhabits the human digestive tract, and on Salmonella enterica (SB300A#1, a derivative of LT2), a major food pathogen.
In order to demonstrate the process, at page 2 Gomaa teaches genome targeting with a type I-E CRISPR-Cas system in E. coli using inducible systems to express Cas:
…we used a previously developed system consisting of two plasmids (pCasA-E and pCas3) (see Fig. S1 in the supplemental material) that inducibly express all six cas genes. In addition, we generated a third plasmid, encoding an altered version of the endogenous CRISPR1 array in E. coli K-12 that accommodates the sequential insertion of engineered spacer sequences (pCRISPR) (see Fig. S1 and S2). pCRISPR plasmids encoding engineered, genome-targeting spacers were transformed into E. coli K-12 substrain BW25113 cells equipped with inducible expression of the T7 polymerase (BW25113-T7) and harboring the two cas-expressing plasmids (pCasA-E and pCas3) (see Fig. S1)...
Cas nucleases used by Gomaa in the experiments first shown under “Results” on page 2 were originally isolated from E. coli K12 W3110 (BW25113). See Gomaa at page 2, second column first paragraph under “Results” that refers to reference [26], Brouns. See the supplemental materials in Brouns, cited as evidence. As discussed in this section of Gomaa, the plasmids pCasA-E and pCas3 inducibly express all six cas genes. It was speculated that the casABCDE operon would be repressed by H-NS in E. coli K-12 under normal growth conditions. These cells were transformed with two plasmids encoding the Cas nuclease protein, plus a third plasmid (pCRISPR) engineered to encode the gene-targeting spacers. As Gomaa notes:
As part of the assay, we measured the transformation efficiency, a proxy for removal of strains in pure cultures, by dividing the number of viable transformants for each genome-targeting CRISPR plasmid by the number of viable transformants for the original pCRISPR plasmid. Lower ratios or transformation efficiencies indicate a greater extent of removal.
A first experiment uses an α-ftsA plasmid containing a spacer sequence complementary to the template strand of the essential fstA gene, demonstrated that the transformation efficiency was ~105-fold lower than that of the pCRISPR plasmid lacking the target sequences. See page 2, second column, last paragraph.
In the next experiment, these two plasmids (pCasA-E and pCas3) were introduced first into E. coli and Salmonella enterolitica, a major food pathogen. Both species are Gram-negative enterobacteria, and they share ~71% sequence homology. See page 4, second column, last paragraph. In both instances, these transformed cells were then transformed with the pCRISPR plasmids engineered with strain-specific target sequences. These experiments were done in pure cultures. See page 4 second column, last paragraph and demonstrate selective removal of E. coli or Salmonella enterolitica.
In a third experiment, two different strains of E. coli harboring the pCasA-E and pCas3 plasmids are cocultured and plated on agar. See page 4:
To begin exploring this possibility, we focused on two sub strains of E. coli. E. coli K-12 (BW25113-T7) and E. coli B [BL21(DE3)] (Fig. 4A). Because the genomes of these strains bear more than 99% sequence homology and almost all cellular processes are identical.
See pages 4-5:
We next proceeded from pure cultures to mixed cultures in order to evaluate the selective removal of target strains...These results demonstrate that CRISPR-Cas systems can be employed for the selective removal of bacterial strains in mixed cultures... We thus conclude that CRISPR-Cas systems can be reprogrammed to quantitatively modulate the composition of a mixed population.
Targeting the PAM-flanking sequence within the ogr gene selectively removed E. coli B [BL21(DE3)]. Targeting the PAM-flanking sequence within the fucP gene selectively removed E. coli K-12 (BW25113-T7). See page 5, first column. Under the Discussion at page 5, Gomaa teaches that sequence-specific removal of individual strains was extremely high (>99.999% for the α-ftsA plasmid). Gomaa at page 7 discloses that bacterial cells were plated on a surface. Such surfaces are further exemplified in Gomaa at Fig.5.
At page 6, Gomaa discloses that “bacteriophages have been widely used for heterologous protein expression, gene delivery, and the treatment of bacterial infections. Lysogenic bacteriophages or phagemids with broad host ranges would be particularly beneficial for the delivery of CRISPR-Cas-encoding constructs.”
Gomaa notes that an “array could even be reduced to a single repeat-spacer, paralleling the engineering of single-guide RNAs for use with Cas9.” See page 5, second column under Discussion. Gomaa cites reference [32], Jinek, as evidence that a dual-RNA-guided DNA endonuclease can be generated having both CrRNA and tracrRNA. Inclusion of tracrRNA in a CRISPR construct was known in the art.
The evidence provided on page 2, second column, last paragraph of Gomaa demonstrates that in the absence of the casABCDE operon the cells transformed with the α-ftsA plasmid yield similar transformation frequencies as those transformed with the parent pCRISPR plasmid lacking the target sequences. This indicates that the specific cell removal by an engineered pCRISPR plasmid nucleic acid expressing a targeting sequence depends upon the presence of an expressed casABCDE operon. See also page 3, column 2, last paragraph and Figure S6 in the Supplemental Materials for the Gomaa reference.
In the Supplemental Materials for Gomaa, the description of Figure S3A provides an example where the native CRISPR-Cas system is used to remove bacteria transformed with the α-ftsA plasmid. In Figure S3A it is shown that a functional endogenous Cas nuclease indeed can be used to remove bacteria transformed with a pCRISPR plasmid encoding engineered, genome-targeting spacers. The lowest transformation efficiency occurred when the native hns gene is deleted in the E. coli host cell. This supports the role that the hns gene plays in regulating the expression of the casABCDE operon. In fact, the H-NS system is present in Salmonella as well as the Enterobacteriaceae generally. See Navarre and Stoebel.
All of the examples of bacteria provided in Gomaa have the capability to express the endogenous nucleic acid encoding a functional cas nuclease, except this expression is repressed by the H-NS system in such Gram negative enterobacteria as E. coli and Salmonella enterica. In order for an endogenous cas nuclease to be expressed and function in Gram negative enterobacteria, either more copies of the operon must be introduced via plasmids into the host cell, or the hns gene must be inactivated. The instant claims do not exclude host cells having an endogenous cas nuclease but lacking an H-NS system. The claims only require that the endogenous cas nuclease is “functional” and that any nucleic acid introduced into the host cell “does not encode said cas nuclease.” Gomaa meets this requirement even though the reference does not expressly suggest using such hns gene deleted cells having a functioning endogenous cas nuclease as the host cell within a mixed cell population. However, Zhang discloses at paragraph [261] that “because accumulated evidence indicates that CRISPR-mediated cleavage of the chromosome leads to cell death in many bacteria and archaea, it is possible to envision the use of endogenous CRISPR-Cas systems for editing purposes.” Paragraph [126] of Zhang further states that each of Type I, Type II and Type III CRISPR systems are known and used in the art. Given the teachings of Gomaa and Zhang it would have been obvious that any host cells having an endogenous casABCDE operon but lacking a functional hns gene would be eliminated from a mixed cell culture. Additionally, Zhang shows that many other CRISPR systems were known in the art and it would have been obvious to use any of these within the system taught by Gomaa, thus avoiding any specific issues regarding repression of cas expression.
In the specification of the ‘964 patent, examples 6 through 8 (columns 143-150) provide experimental data showing that the invention functions to remove Streptococcus thermophilus, a Gram-positive bacteria, in a mixture of other bacteria, including Lactobacillus lactis and E. coli. From an operational standpoint, the invention would be used in instances where different types of unmodified host cells present in a mixture will be subjected to treatment with the pCRISPR plasmid containing a strain-specific targeting sequence. The evidence suggests that the invention would not work to delete host enterobacteria that did not inactivate the hns gene or otherwise remove repression of the endogenous casABCDE operon.
Gomaa teaches at page 5 that sequence-specific removal of individual strains was extremely high (>99.999% for the α-ftsA plasmid).
Gomaa teaches plating of the mixed-culture of bacteria on a surface. See page 7 and Figure 5.
Gomaa teaches on page 4 and Figure 4 that E coli strains K-12 and B are 99% homologous, and sequence specific removal of an individual strain can be achieved by targeting the K-12 fucP gene or the B ogr gene. It would likely have been obvious that the two strains have 16s ribosomal RNA encoding DNA sequences that are 80% identical since “almost all cellular processes are identical.”
Gomaa states at page 4, second column that the system can target pathogenic bacteria while sparing commensal bacteria.
Nakamura discloses bacteria that are known in the art to be present in human fecal samples. Nakamura’s disclosure includes phylum Bacteroidetes and Firmicutes, and species of Bacteroides or Parabacteroides. Campylobacter jejuni was detected as a bacterial pathogen in a patient sample. See Figure and Table on p. 1785. Gomaa teaches at page 4 that a “potential application of programmable removal with CRISPR-Cas systems is targeting pathogenic bacteria while sparing commensal bacteria.” It would have been obvious to target known pathogenic bacteria for elimination while sparing beneficial or commensal Bacteroidetes bacteria. Claims 35 and 47-74 would have been obvious over the teachings of Gomaa, Zhang and Nakamura.
Gomaa teaches that lysogenic bacteriophages or phagemids can be used to deliver the CRISPR-encoding constructs. See page 6, first column, second full paragraph.
Gomaa notes that an “array could even be reduced to a single repeat-spacer, paralleling the engineering of single-guide RNAs for use with Cas9.” See page 5, second column under Discussion. [Gomaa cites reference 32 to Jinek as evidence that the dual-RNA-guided DNA endonuclease can be generated having both CrRNA and tracrRNA on a single guide RNA (gRNA)].
Gomaa teaches that smart antibiotics can be developed that circumvent multidrug resistance and differentiate between pathogenic and beneficial microorganisms. Treating multidrug resistant infections is envisioned. Including this CRISPER-Cas system in treatment would have been obvious. See Gomaa at page 2, second column, first full paragraph and page 6, first column, last paragraph.
Gomaa teaches that CRISPR-Cas systems can be used to control contaminating microorganisms or the composition of microbial consortia in industrial or environmental processes. Smart antibiotics are suggested for treating antibiotic resistance, distinguishing between beneficial and pathogenic bacteria. The system can be used to treat humans. See page 6, first column, second and third full paragraphs.
Gomaa teaches a mixed cell population comprising E. coli and Salmonella enterica. See page 4, second column.
Gomaa discloses targeting virulence or essential genes. See page 4, second column. The sequence specific removal of an individual strain can be achieved by targeting the E. coli K-12 fucP gene or the E. coli K-12 B ogr gene. Also, at page 2, second column, last paragraph, the ftsA gene in E. coli is targeted, as it is involved in cell division. See Figure 2A.
Nakamura teaches that Bacteroidetes is the most frequently detected bacterial species comprising the normal flora of the human intestine. See page 1784, second column, second full paragraph. Gomaa teaches at page 4 that a “potential application of programmable removal with CRISPR-Cas systems is targeting pathogenic bacteria while sparing commensal bacteria.” It would have been obvious to target known pathogenic bacteria for elimination while sparing beneficial or commensal Bacteroidetes bacteria.
Gomaa teaches at page 4 a mixed population comprising different E. coli strains for specific targeting. At page 2, second column, Gomaa states:
Finally, using genomic sequence information, we could selectively remove closely related bacterial strains whether in pure or mixed cultures. The extent of removal could even be modulated by mixing targeting and nontargeting plasmids. Our findings open the possibility of quantitatively controlling the composition of microbial consortia and selectively treating multidrug-resistant infections, particularly with ongoing advances in the delivery of nucleic acids to microorganisms.
Nakamura provides information regarding the normal flora of the human intestine. See the Figure on page 1784. Nakamura also notes that Campylobacter is a known pathogen in this mixed culture. Targeted removal of pathogenic microorganisms in a mixed culture of several types of bacteria would have been obvious given the teachings of Gomaa, Zhang and Nakamura, resulting in a bacterial population encompassed by the instant claims.
Gomaa teaches at page 4 a mixed population comprising different E. coli strains for specific targeting. At page 2, second column, Gomaa states:
Finally, using genomic sequence information, we could selectively remove closely related bacterial strains whether in pure or mixed cultures. The extent of removal could even be modulated by mixing targeting and nontargeting plasmids. Our findings open the possibility of quantitatively controlling the composition of microbial consortia and selectively treating multidrug-resistant infections, particularly with ongoing advances in the delivery of nucleic acids to microorganisms.
Nakamura provides information regarding the normal flora of the human intestine. See the Figure on page 1784. Nakamura also notes that Campylobacter is a known pathogen in this mixed culture. Targeted removal of pathogenic microorganisms in a mixed culture of several types of bacteria would have been obvious given the teachings of Gomaa, Zhang and Nakamura, resulting in a bacterial population encompassed by the instant claims. Gomaa teaches at page 5 that sequence-specific removal of individual strains was extremely high (>99.999% for the α-ftsA plasmid).
Gomaa teaches plating of the mixed-culture of bacteria on a surface. See page 7 and Figure 5.
Gomaa teaches on page 4 and Figure 4 that E coli strains K-12 and B are 99% homologous, and sequence specific removal of an individual strain can be achieved by targeting the K-12 fucP gene or the B ogr gene. It would likely have been obvious that the two strains have 16s ribosomal RNA encoding DNA sequences that are 80% identical since “almost all cellular processes are identical.”
Gomaa states at page 4, second column that the system can target pathogenic bacteria while sparing commensal bacteria.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made that the methods of the prior art could be used to produce a bacterial population comprising a mixed population of first and second species.
Double Patenting
5. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321I or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
6. Claims 18-27, 29-33, 35, 36, 39 and 41-55 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 11,844,760.
The instant claims were not restricted from the allowed claims in this parent application so a double patenting rejection is applicable.
The patented claims recite a method to produce a modified bacterial population with a similar method. The process to modify the mixed population of bacteria in the co-pending claims is substantially the same method used in the instant process claims. Although the patented claims transfer the conjugate plasmid form cells of the first bacterial subpopulation to the target host cells while the instant method recites transferring the second bacterial subpopulation to the target host cells, the steps are the same and it would have been obvious that either could be done to produce the modified mixed population of bacteria. Accordingly, the claimed methods are similar methods would create populations with reduced target populations and be essentially the same. Accordingly, the scope of the patented claims and instant claims is not patentably distinct.
7. Claims 18-27, 29-33, 35, 36, 39 and 41-55 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 10,463,049.
Although the claims at issue are not identical, they are not patentably distinct from each other because the process to modify the mixed population of bacteria in the patent claims is substantially the same method used in the instant process claims. Although the patented claims use an ‘engineered nucleic acid’ and do not specifically recite the use of a ‘plasmid’, the scope of the claims is such that the plasmid and oriT would be encompassed by the claims. Accordingly, the claimed bacterial population produced by the similar methods would create populations with reduced target populations and be essentially the same. Accordingly, the scope of the patented claims and instant claims is not patentably distinct.
8. Claims 18-27, 29-33, 35, 36, 39 and 41-55 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 10,524,477. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are drawn to methods of modifying a mixed population of bacteria with first and second bacterial populations which also involve transferring conjugative plasmids of cells from a bacterial subpopulation to target host cell which produces crRNA in target host cells under control of an inducible promoter in the host cells.
Accordingly, the scope of the patented claims and instant claims is not patentably distinct.
9. Claims 18-27, 29-33, 35, 36, 39 and 41-55 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-53 of U.S. Patent No. 11,517,582.
Although the claims at issue are not identical, they are not patentably distinct from each other because each are drawn to a method of modifying a mixed population of bacteria. The process to modify the mixed population of bacteria in the co-pending claims is substantially the same. The patented method describes ‘contacting the first population of cells with the engineered nucleic acid, e.g., which includes a plasmid or mobile genetic element. Although the patented claims use an ‘engineered nucleic acid’ and do not specifically recite the use of a ‘plasmid’, the scope of the claims is such that the plasmid and oriT would be encompassed by the claims. Accordingly, the claimed bacterial population produced by the similar methods would create populations with reduced target populations and be essentially the same. Accordingly, the scope of the patented claims and instant claims is not patentably distinct.
10. Claims 18-27, 29-33, 35, 36, 39 and 41-55 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of U.S. Patent No. 11,642,363.
Although the claims at issue are not identical, they are not patentably distinct from each other because the process to modify the mixed population of bacteria in the co-pending claims is substantially the same method used in the instant process claims. Although the patented claims use an ‘engineered nucleic acid’ and do not specifically recite the use of a ‘plasmid’, the scope of the claims is such that the plasmid and oriT would be encompassed by the claims. Accordingly, the claimed bacterial population produced by the similar methods would create populations with reduced target populations and be essentially the same. Accordingly, the scope of the patented claims and instant claims is not patentably distinct.
11. Claims 18-27, 29-33, 35, 36, 39 and 41-55 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of U.S. Patent No. 12,514,867.
Patent Claim 1 recites:
A method of modifying a mixed population of bacteria, wherein the mixed population of bacteria comprises cells of a first bacterial species of Bacillus subtilis, host cells of a second bacterial species, and a third bacterial species Lactobacillus lactis, and wherein the second bacterial species is a different species than the first bacterial species, the method comprising: (a) contacting the mixed population of bacteria with a plurality of vectors comprising a first nucleic acid sequence encoding a Cas nuclease and a second nucleic acid sequence for producing a host modifying crRNA (HM-crRNA), and (b) expressing the Cas nuclease and the HM-crRNA in the host cells, wherein the HM-crRNA is operable with the Cas nuclease in the host cells, wherein the second nucleic acid sequence and the Cas nuclease are comprised by a HM-CRISPR/Cas system and wherein the HM-crRNA comprises a nucleic acid sequence that is capable of hybridizing to a target sequence in the host cells to guide the Cas nuclease to cut the target sequence in the host cells of the second bacterial species; whereby the host cells of the second bacterial species are killed or growth of the host cells is reduced, thereby reducing the proportion of the host cells of the second bacterial species and altering the relative ratio of the first and second bacterial species in the mixed population of bacteria; and wherein the host cells of the second bacterial species are killed by at least 1000-fold or growth of the host cells of the second bacterial species is reduced by at least 1000-fold, and wherein the first bacterial species is not killed or growth of first bacterial species is not reduced.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are drawn to a method of modifying a mixed population of bacteria like the patented claims. The process to modify the mixed population of bacteria in the co-pending claims is substantially the same method used in the product-by-process claims. Although the instant claims do not specifically recite the Genus/species of the bacterium, they allow for any genus/species. Accordingly, the claimed bacterial population produced by the similar methods would create populations with reduced target populations and be essentially the same.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Status of Claims:
No claims are allowed.
The claims should be amended to recite that the crRNA is (HM-crRNA) as recited in the parent application.
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