DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-10 are pending and examined on the merits.
Claim Objections
Claim 8 is objected to because of the following informalities:
The recitation “capable to consume the substrate” in the last line is grammatically incorrect. This objection can be overcome by amending claim 8 to recite “capable of consuming the substrate.”
Appropriate correction is required.
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.
Claims 1-10 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 1 is rendered indefinite by the recitation “the microorganism” in lines 7-8. Prior to the recitation, the claim refers to “at least one microorganism” in the sample in line 1. The term “at least one microorganism” includes the embodiment of multiple microorganisms. For that embodiment, it is unclear which one of the microorganisms is “the microorganism” of lines 7-8. It is unclear whether the fluorescent dye does not interact with only one, some, or all of the microorganisms, and it is unclear whether the fluorescent dye is not affected by the growth of only one, some, or all of the microorganisms. Since claim 1 is indefinite, then its dependent claims, claims 2-10, are rendered indefinite. Thus, claims 1-10 are rejected under 35 U.S.C. 112(b).
Claim 4 is indefinite because it is unclear whether the volume (from 1 pL to 100 nL) is the volume of each droplet or the volume of all droplets (i.e., the total volume of the droplets). For the purpose of applying prior art, claim 4 is interpreted as reciting “wherein the droplets obtained from step (i) each have a volume from 1 pL to 100 nL.”
Claim Interpretation
According to the specification, “…the expression ‘the fluorescent dye does not interact with the microorganism’ means that the structure, the properties and the amount of the fluorescent dye in a droplet are not altered by the microorganism or by any of its products (such as enzymes)” (page 4, lines 19-22). Therefore, that definition is applied to the limitation in lines 6-7 of claim 1 requiring that the fluorescent dye “does not interact with the microorganism.”
Notice Re: Prior Art Available Under Pre-AIA and AIA
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.
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.
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 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over Quiring (US 2019/0032105) in view of Stiefel (BMC Microbiology. 2015. 15:36. 9 pages) or Mason (FEMS Microbiology Letters. 1997. 153: 199-204), and further in view of Janiesch (Analytical Chemistry. 2015. 87: 2063-2067) and Courtois (Analytical Chemistry. 2009. 81: 3008-3016).
Quiring discloses methods for rapidly analyzing growth or number of one or more target microorganisms in a sample by partitioning the sample into a plurality of water-in-oil emulsion droplets; incubating the droplets for, or at least, 1 to 50 (e.g., 5 to 20) doubling times, and detecting the presence or absence of the target microorganisms in the droplets (paragraph [0159]).
With respect to the first step of Quiring, generally, the disclosed methods include encapsulating a sample in a plurality of water-in-oil emulsion droplets wherein the water-in-oil emulsion droplets further encapsulate a microbiological growth medium (paragraph [0160]). Furthermore, the water-in-oil emulsion droplets can contain one or more detection reagents (paragraph [0138]). The detection reagents can be intercalating dyes, wherein preferred intercalating dyes include fluorescent dyes (paragraph [0139]). Additionally, Quiring teaches that any suitable method and structure can be used to form the emulsion (paragraph [0172]). In exemplary embodiments, the droplet generator for generating the emulsions operates by microchannel flow focusing to generate an emulsion of monodisperse droplets (paragraph [0172]). Furthermore, suitable methods and structure for droplet generation include microfluidic droplet handling (paragraph [0172]). Therefore, Quiring teaches the embodiment of encapsulating a sample in a plurality of water-in-oil emulsion droplets using a microfluidic device. It would have been prima facie to combine these different embodiments (a microbiological growth medium in the water-in-oil emulsion droplets; an intercalating dye that is fluorescent dye in the water-in-oil emulsion droplets; using a microfluidic device to encapsulate the sample in a plurality of water-in-oil emulsion droplets) of Quiring to perform their method. Therefore, Quiring meets limitations of step (i) of instant claim 1 since Quiring renders obvious encapsulating a sample into a plurality of water-in-oil emulsion droplets using a microfluidic device, said water-in-oil emulsion droplets comprising a growth medium, a fluorescent dye, and a fraction of the sample.
With respect to the next step of incubating the droplets (paragraph [0159]), generally, the disclosed methods include incubating the plurality of water-in-oil emulsion droplets at a temperature permissive of microbiological growth, and for a period of time sufficient to allow the target microorganisms to go through 5 to 45 doubling times (paragraph [0160]). The incubation is further discussed in paragraphs [0183]-[0194]. The droplets can be incubated at a microbiological growth temperature for a selected number of doubling times, examples of which include, 2, 3, 4, 5,….or 5-15 times (paragraph [0185]). The doubling times fall within or overlap the claimed range of ‘at least two doubling times.’ Therefore, Quiring discloses step (ii) of instant claim 1 since Quiring teaches incubating the plurality of droplets at a temperature and for a period of time sufficient to allow at least one microorganism to grow for multiple doubling times that fall within or overlap the claimed range of ‘at least two doubling times.’
With respect to the next step of detecting the presence or absence of the target microorganisms in the droplets (paragraph [0159]), Quiring teaches that in some cases, detection can be detection of fluorescence of a fluorophore (paragraph [0197]). In some cases, the automated detection is performed by serially flowing the droplets through a detection region configured to detect transmission or emission (e.g., fluorescence) at one or more wavelengths (paragraph [0198]). For example, high throughput 3D particle counting can be used to detect a single-fluorescent droplet in a several milliliter pool of non-fluorescent droplets (paragraph [0198]). These teachings of Quiring meet limitations of step (iii) of instant claim 1 since they are directed to measuring the fluorescence in each individual droplet.
Additionally, Quiring teaches that after droplets are detected for the presence or absence of microorganisms, thus obtaining a number of positive droplets and a number of negative droplets, the data can be analyzed to determine a quantitative result, such as microbial load of a food matrix sample or the presence of a target microorganism in a clinical sample (paragraph [0201]). Therefore, Quiring teaches step (iv) of instant claim 1.
In sum, Quiring meets limitations of the claimed invention since Quiring renders obvious a method for detecting and/or quantifying at least one microorganism in a sample, the method comprising the following steps:
(i) encapsulating the sample into a plurality of water-in-oil emulsion droplets using a microfluidic device, said water-in-oil emulsion droplets comprising a growth medium, a fluorescent dye, and a fraction of the sample;
(ii) incubating the plurality of droplets at a temperature and for a period of time sufficient to allow at least one microorganism to grow for multiple doubling times that fall within or overlap the claimed range of ‘at least two doubling times’;
(iii) measuring the fluorescence in each individual droplet; and
(iv) detecting and/or quantifying at least one population of droplets comprising a microorganism, thereby determining the presence and/or the amount of at least one microorganism in the sample.
Quiring differs from the claimed invention in that Quiring does not expressly disclose:
(1) the fluorescent dye is non-exchangeable between the droplets and does not interact with the at least one microorganism (the Examiner’s interpretation of “the microorganism” in step (i) of instant claim 1), and the fluorescent dye is not affected by the growth of the at least one microorganism (the Examiner’s interpretation of “the microorganism” in step (i) of instant claim 1), as recited in step (i) of instant claim 1; and
(2) with respect to measuring the fluorescence in each individual droplet, droplets comprising no microorganism have a basal fluorescence intensity and droplets comprising a microorganism have a fluorescence intensity at least equal to 1.001 times the basal fluorescence intensity, as recited in step (iii) of instant claim 1.
Regarding the intercalating dyes, Quiring teaches that examples of the intercalating dyes include SYTO9 and acridine orange (paragraph [0139]). In discussing the intercalating dye, Quiring teaches an embodiment in which the cells do not need to be lysed to detect the target microorganism and monitor the growth of the target microorganism (paragraph [0139]).
Stiefel discloses bacterial viability tests are often performed with premixed, ready to use, dual staining kits, such as the BacLight™ Molecular Probes composed of two fluorophores SYTO9 and propidium iodide (PI) based on the detection of membrane integrity (page 2, left column, first full paragraph). Advantages of using such a kit are a rapid procedure, quantitative analyses, as well as a possibility to measure using various instruments such as flow cytometer, microplate reader, and microscope (page 2, left column, first full paragraph). The green-fluorescent nucleic acid strain SYTO9 enters live and dead bacterial cells (page 2, left column, second full paragraph). The fluorescent signal of SYTO9 is strongly enhanced when bound to nucleic acid and shows low intrinsic fluorescence signal when unbound (page 2, left column, second full paragraph).
Mason discloses that acridine orange (AO) is a fluorescent compound extensively used for the detection and enumeration of microorganisms (page 199, left column, first paragraph). Photo emissions from the dye are dependent on the manner of its interaction with nucleic acids (page 199, left column, first paragraph). Rapidly growing organisms will have a high RNA content, in contrast to inactive bacteria which contain mostly DNA (page 199, right column, first paragraph). Thus, cell-associated AO fluorescence from active (rapidly growing) organisms is predominant at 640 nm and that of inactive organisms predominant at 530 nm (page 199, right column, first paragraph). In the study of Mason, samples of cultures of E. coli were stained with AO (page 200, left column, last paragraph and right column, first full paragraph). Mason found that the number of bacteria exhibiting acridine orange associated fluorescence at 550 nm corresponded to counts of colony forming units (abstract).
Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to select SYTO9 or acridine orange as the intercalating dye in the method rendered obvious by Quiring. It would have been prima facie obvious to do this because SYTO9 and acridine orange are taught by Quiring as suitable intercalating dyes serving as detection agents for inclusion in their water-in-oil emulsion droplets (paragraph [0139]). Additionally, one of ordinary skill in the art would have been motivated to select SYTO9 or acridine orange as the intercalating dye because Stiefel and Mason teach STYO9 and acridine orange, respectively, as being intercalating dyes that are fluorescent dyes, thus being suitable for performing the embodiment of Quiring in which fluorescence of the droplets is measured for detection and quantification of microorganisms. Based on the teachings of Stiefel and Mason, SYTO9 and acridine orange are each directed to a fluorescent dye that “does not interact with microorganism” (see ‘Claim Interpretation’ section above) and is not affected by the growth of the microorganism, thereby meeting limitations of the fluorescent dye set forth in step (i) in instant claim 1. In particular, SYTO9 and acridine orange bind with nucleic acid of the microorganism. In binding with the nucleic acid, then the structure, properties, and the amount of each of SYTO9 and acridine orange are not altered by the microorganism or by any of its products. Furthermore, based on the teachings of Stiefel and Mason, the binding of each of SYTO9 and acridine orange with the nucleic acid results in an increase of fluorescence. When performing the method rendered obvious by Quiring in view of Stiefel or Mason, since there is a measurable increase in fluorescence for nucleic acid binding only when a microorganism is present in a water-in-oil emulsion droplet, then it is obvious that droplets comprising no microorganism have a basal fluorescence intensity and droplets comprising a microorganism have a fluorescence intensity at least equal to 1.001 times the basal fluorescence intensity. Therefore, step (iii) of instant claim 1 is rendered obvious.
Regarding the claimed limitation of ‘the fluorescence dye is non-exchangeable between the droplets’:
Quiring teaches that their water-in-oil chemistries include droplets with skins and dual-phase surfactant droplets (paragraph [0059]). The dual-phase surfactant droplets contain an oil and an oil-phase surfactant as the non-aqueous phase, and water and an aqueous-phase surfactant as the aqueous phase (paragraph [0059]). Each of the two types of water-in-oil droplets (droplets with skins; dual-phase surfactant droplets) can comprise fluorinated oil in the non-aqueous phase (paragraphs [0069] and [0097]).
Janiesch discusses water-in-emulsion droplets created in droplet-based microfluidic devices, and fluorescence measurement applied to them (abstract). Emulsion droplets do not always provide entirely sealed microcompartments, and the release of dyes or fluorescently labeled proteins to the oil phase is frequently observed (page 2063, right column; abstract). In order to minimize the transport due to diffusion and to reduce the solubility of biomolecules and fluorophores in the oil phase to a minimum, fluorinated oil became the prominent choice in droplet-based microfluidics (page 2063, right column). Janiesch investigated the retention of 12 commonly used water-soluble dyes in droplets having six different aqueous phase conditions (abstract). The tested surfactants were dissolved in fluorinated oil, and the hydrophilicity of the fluorophores with a hydrolyzed active group was analyzed (page 2064, left column, last paragraph). Through their study, Janiesch demonstrated that with the right choice of fluorophores and optimized surfactant physicochemical properties, the partitioning to the oil phase can be minimized or avoided (page 2064, left column, first full paragraph). Janiesch found that the hydrophilicity level of the dye is a key factor influencing the retention within the droplets (page 2066, left column, last paragraph). They demonstrated that highly hydrophilic dyes showed stable retention within the droplets, independent of buffer/medium type (page 2066, left column, last paragraph). In the case of less hydrophilic dyes, stable retention can be achieved by optimization of the surfactant physical properties, such as geometry, molecular weight, and concentration (page 2066, left column, last paragraph).
Courtois discloses water-in-oil microdroplets in microfluidics having great potential for quantitative high-throughput biological screening (abstract). However, this depends upon contents of the droplets not leaking out into the oil phase (abstract). Courtois thus studied the retention of derivatives of fluorescein, a fluorophore used to monitor reaction progress in biochemical assays, in microdroplet emulsions in a microfluidic chip (page 3009, right column, first paragraph). Courtois found that the addition of bovine serum albumin (BSA) to the aqueous phase of the droplets increased the retention of the fluorophore (page 3012, right column, last paragraph).
Before the effective filing date of the claimed invention, it would have been prima facie obvious to the person of ordinary skill in the art to use fluorinated oil as the non-aqueous phase of the water-in-oil emulsion droplets when performing the method rendered obvious by Quiring in view of Stiefel or Mason, since it is taught for both types of water-in-oil emulsion droplets in Quiring. Moreover, one of ordinary skill in the art would have been motivated to do this because it would have minimized the transport of SYTO9 or acridine orange to the oil phase based on Janiesch (page 2063, right column). Additionally, it would have been obvious to the person of ordinary skill in the art to apply the techniques of Janiesch and Courtois, specifically selecting a surfactant for inclusion in the fluorinated oil as taught by Janiesch and including BSA in the aqueous phase, to the preparation of the water-in-oil emulsion droplets when performing the method rendered obvious by Quiring in view of Stiefel or Mason. One of ordinary skill in the art would have been motivated to do this in order to reduce or prevent the transport of SYTO9 or acridine orange to the oil phase. In doing so, then it is obvious that the SYTO9 or acridine orange is non-exchange between the droplets of the method rendered obvious by the references. There would have been a reasonable expectation of preventing SYTO9 or acridine orange from being exchanged between droplets because the issue of dye retention is addressed with different strategies and it is unlikely that SYTO9 or acridine orange diffuses from the aqueous phase of a droplet to the oil phase (which is reduced or prevented by the techniques of Janiesch and Courtois) and then the extra step of diffusing into the aqueous phase of another droplet.
Therefore, Quiring in view of Stiefel or Mason and further in view of Janiesch and Courtois renders obvious instant claims 1 and 9 (BSA is directed to the claimed ‘compound that prevents or limits the transfer of the fluorescent dye between the droplets’).
Regarding instant claim 2, Quiring teaches that the target microorganism(s) can be or include bacteria, yeasts, or molds (paragraph [0144]). Yeast and molds are fungi. Therefore, instant claim 2 (bacteria, yeast, fungi) is rendered obvious.
Regarding instant claim 3, the growth media of the aqueous phase of the water-in-oil droplets of Quiring generally contain a nitrogen source, a carbon source, and various essential elements (paragraph [0119]). For a growth medium that comprises essential elements thar are not salts, then the growth medium is directed to having a salt concentration of 0 g/L, meeting a limitation of instant claim 3. Also, Quiring teaches that salts compatible with microbial growth and/or detection may be present in the aqueous phase (paragraph [0115]). Exemplary salts include NaCl (paragraph [0116]). In some cases, the concentration of sodium salt (e.g., NaCl), can be about, more than about, or less than about 10 mM (paragraph [0116]). A concentration of 10 mM NaCl converts to about 0.5844 g/L, based on the well known molecular weight of NaCl. See that calculation below. About 0.5844 g/L falls within the claimed salt concentration of ‘from 0 to 10 g/L.’ Additionally, Quiring teaches that the growth medium contains various essential elements (paragraph [0119]), and essential elements include sodium (paragraph [0121]). Based on these teachings, it would have been obvious to include a salt such as NaCl in the concentrations disclosed by Quiring (e.g., about 0.5844 g/L) in the microbiological growth medium included in the water-in-oil emulsion droplets for the invention rendered obvious by Quiring in view of Stiefel or Mason and further in view of Janiesch and Courtois. Thus, instant claim 3 is rendered obvious.
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Regarding instant claim 4, Quiring teaches that the average volume of droplets may be about 100 µL to 10 nL, 200 µL to 5 nL, about 0.5 nL, about 1 nL, about 2 nL, about 3 nL, or about 5 nL (paragraph [0173]). The two ranges overlap the claimed droplet volume range, and the volumes of about 0.5 nL, about 1 nL, about 3 nL, and about 5 nL fall within the claimed range. Therefore, instant claim 4 is rendered obvious.
Regarding instant claim 5, Quiring teaches that the samples for partitioning into water-in-oil droplets can include any sample known or suspected of containing a target microorganism (paragraph [0144]). The samples can be food, environmental samples taken from surfaces, and clinical samples (paragraph [0144]). Therefore, instant claim 5 (environmental sample, food sample, clinical sample, sample taken from a surface) is rendered obvious.
Regarding instant claim 6, Quiring teaches that any microorganism can be identified using their methods (paragraph [0145]). Example target microorganism(s) include various species, “or a combination thereof” (paragraphs [0145]-[0146]). Also, the sample can be assayed for total microbial load, total bacterial load, total coliforms, yeasts, molds, or a combination thereof (paragraph [0199]). Alternatively, specific microorganisms are identified and, optionally, quantified (paragraph [0199]). Given these teachings then Quiring renders obvious a mixed population of two or more distinct microorganisms in the water-in-oil emulsion droplets, and detecting and/or quantifying each distinct microorganism. Thus, instant claim 6 is rendered obvious.
Regarding instant claim 7, Quiring teaches that in some aspects the aqueous phase of the water-in-oil emulsion droplets can contain an antimicrobial (paragraph [0124]). The antimicrobial can be included to assess antimicrobial susceptibility of a target microorganism, or class of target microorganism (paragraph [0124]). Therefore, instant claim 7 is rendered obvious.
Regarding instant claim 8, Quiring teaches that the aqueous phase of their water-in-oil droplets can include detection reagents such as fluorogenic or colorimetric substrates (paragraph [0114]). In some embodiments, the detection reagent is a product of a reaction between a fluorogenic or colorimetric substrate and an enzyme produced by the target microorganism (paragraph [0141]). For example, a digestion of a fluorogenic or colorimetric substrate can be detected by detecting droplets that exhibit characteristic absorbance or fluorescence (paragraph [0197]). It would have been obvious to the person of ordinary skill in the art to further include a colorimetric substrate in the aqueous phase of the water-in-oil droplets when performing the method rendered obvious by Quiring in view of Stiefel or Mason and further in view of Janiesch and Courtois, in order to detect and/or quantitate the target microorganisms by multiple means, thereby ensuring successful detection and quantitation of different target microorganisms. Therefore, instant claim 8 is rendered obvious.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Quiring in view of Stiefel or Mason and further in view of Janiesch and Courtois as applied to claims 1-9 above, and further in view of Bernath (Analytical Biochemistry. 2004. 325: 151-157).
As discussed above, Quiring in view of Stiefel or Mason and further in view of Janiesch and Courtois renders obvious claims 1-9. The references differ from claim 10 in that they do not expressly disclose a step (v) of sorting the droplets depending on their fluorescence intensity.
Bernath discloses using fluorescence activated cell sorting (FACS) for analyzing water-in-oil emulsions by re-emulsifying water-in-oil emulsions to give water-in-oil-in water (w/o/w) emulsions (abstract). As shown in Figure 1, the fluorescent product is in the internal aqueous phase. Droplets containing fluorescent markers can be isolated by FACs, in which the resulting w/o/w emulsion can be sorted by FACS while the content of the aqueous droplets of the primary w/o emulsion remains intact (abstract). FACS has the ability to analyze and sort up to 40,000 events per second, giving this technology a wide potential in the area of high-throughput screening (abstract; page 151, first paragraph).
Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to perform FACS on the water-in-oil emulsion droplets for performing the detection and quantitation of the target microorganisms when performing the method rendered obvious by Quiring in view of Stiefel or Mason and further in view of Janiesch and Courtois, by re-emulsifying the water-in-oil emulsion droplets to give water-in-oil-water emulsions for sorting by FACS according to Bernath. One of ordinary skill in the art would have been motivated to do this in order to obtain high-throughput screening of the water-in-oil emulsion droplets, thereby more efficiently performing the detection and quantitation of the target microorganisms in a sample when performing the method rendered obvious by Quiring in view of Stiefel or Mason and further in view of Janiesch and Courtois. There would have been a reasonable expectation of detecting and/or quantifying target microorganisms by applying FACS as taught by Bernath since Bernath successfully applied FACS to water-in-oil emulsion droplets in which the content of the aqueous droplets of the primary w/o emulsion remains intact. Therefore, instant claim 10 is rendered obvious.
Conclusion
No claims are allowed.
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Sef
/SUSAN E. FERNANDEZ/ Examiner, Art Unit 1651
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