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 .
Request for Reconsideration
Applicant's reply filed 4/24/2026 has been entered. The claims were not amended. Claims 1-20 remain pending, of which claims 1-17 are being considered on their merits. Claims 18-20 remain withdrawn from consideration. References not included with this Office action can be found in a prior action. Any rejections of record not particularly addressed below are withdrawn in light of the claim amendments and/or applicant’s comments.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-5 and 7-17 are rejected under 35 U.S.C. 103 as being unpatentable over Arab et al. (US 2018/0172675; provided in the IDS dated 3/24/2021) in view of Arab et al. (US 2016/0271576, and hereafter referred to as “Arab 2016”) and Blainey et al. (WO 2016/149661).
Arab teaches a method of analyzing a sample comprising microorganisms, the method comprising the steps of: (a) contacting a sample containing microbes (e.g. a plurality of microbes or at least two species of microbes) with at least one reporter forming a sample mixture, wherein optical emissions of the reporter indicate microbial cell viability; (b) dividing the sample mixture into at least two portions, wherein a first portion is treated with an antimicrobial drug forming a test portion and the second portion is a control portion; (c) partitioning the test portion and the control portion into two-dimensional arrays of small volume partitions (i.e. droplets), wherein some of the small volume partitions have one microbe or one natural microbe aggregate per small volume partitions; (d) incubating the small volume partitions for a period of time at a specified temperature or series of temperatures; (e) monitoring optical emissions of the small volume partitions during the incubation time; (f) constructing an optical emission waveform for each small volume partitions based on the optical emissions of the small volume partitions over time resulting in a small volume partitions waveform; (g) identifying the microbes in the sample using the small volume partitions waveforms; and (h) determining susceptibility of the microbes in the sample to the antimicrobial drug by comparing waveforms for small volume partitions of the treated portion to waveforms of the small volume partitions of the control portion, wherein differences in the small volume partitions waveforms between the small volume partitions of the treated portion to small volume partitions of the control portion indicates susceptibility to the antimicrobial (e.g. antibiotic) (claims 1 and 2), reading in-part on 1, 3, 7-11, and 17. Arab teaches partitioning the control and test samples ([0027]), reading in-part on the partitioning step of claim 1.
In a separate embodiment, Arab teaches a method of analyzing a sample comprising microorganisms, 1) generating droplets comprising microorganisms, culture broth, and resazurin, 2) measuring the fluorescence of the resazurin to detect the presence or absence of the microorganism (¶0055-0061), reading on claims 2 and 4.
Arab teaches that the droplets are formed by dispersing aqueous liquid surround by an immiscible carrier fluid such as fluorocarbon oil, wherein said fluorocarbon oil is advantageous as it is able to dissolve gases and is biologically inert (¶0057), reading on claim 5.
Arab teaches generating partitions such as droplets by microfluidics (¶0029), reading in-part on claims 13-16.
Regarding claim 1, Arab does not teach wherein: the first and second devices comprises a first chip defining a microfluidic network that includes: one or more inlet ports; a test volume; and one or more flow paths extending between the inlet port(s) and the test volume; and generating the first droplets is performed in the microfluidic network of the first chip at least by: disposing the first liquid within a first one of the inlet port(s); and directing the first liquid along the flow path(s) such that, for each of the flow path(s), at least a portion of the first liquid flows from the first inlet port, through at least one droplet-generating region in which a minimum cross- sectional area of the flow path increases along the flow path, and to the test volume; and capturing the first set of data comprises analyzing the first droplets that are disposed in the test volume. Regarding claim 1, Arab does not teach the partitioning step comprising a second device therein, the second device comprising a plurality of microfluidic networks that each include: one or more inlet ports; a test volume; and one or more flow paths extending between at least one of the inlet port(s) and the test volume.
Regarding claim 14, Arab does not teach wherein for at least one of the microfluidic network(s): for at least one of the flow path(s), in at least one of the droplet-generating region(s) the flow path includes a constricting section, a constant section, and an expanding section such that liquid flowing from the first inlet port to the test volume is permitted to exit the constricting section into the constant section and flow to the expanding section; wherein: the depth of the constant section is at least 50% larger than the depth of the constricting section and is substantially the same along at least 90% of a length of the constant section; and the depth of the expanding section increases moving away from the constant section. Regarding claim 5, Arab does not teach a single embodiment wherein the first/second liquids comprise a non-aqueous liquid. Regarding claim 15, Arab does not teach wherein for the first microfluidic chip: the microfluidic network comprises: one or more outlet ports; and one or more outlet channels in fluid communication between the test volume and the outlet port(s); and generating the first droplets is performed such that at least some of the first droplets flow from the test volume, through the outlet channel(s), and into the outlet port(s). Regarding claim 16, Arab does not teach comprising removing at least some of the first droplets from the outlet port(s).
Arab 2016 teaches methods and devices for forming droplets (Abstract). Arab teaches a microchannel emulsification device for generating droplets (e.g. a device defining a microfluidic network) comprising one or more inlet ports/channels establishing a flow path and wherein the width of the flow path increases distally from the inlet channel (Fig. 1A, 1B and ¶0057-0058), reading on claims1, 12 and 13. Arab teaches a microchannel emulsification device wherein the depth of the flow path increases distally and step-wise from the inlet channel (Fig. 2, and ¶0058) and wherein the depth of section FSH1 is at least 50% greater than the depth of the height of the inlet channel CH (¶0087 and Fig. 9), reading on the flow path comprising a constricting, constant, and expanding section and the depth increasing distally from the inlet channel and constant section being the same for at least 90% of its length of claim 14. Arab 2016 teaches a droplet collection chamber fluidly connected to the microchannel emulsification device (e.g. a chamber fluidly connect to the droplet generating section by outlet channels and outlet ports) (¶0081 and Fig. 8), reading on claims 15 and 16. Arab 2016 teaches a separate imaging chamber for imaging the droplets (¶0104), reading in-part on claim 16. Arab 2016 teaches that the nozzles can be advantageously configured to generate droplets of differing diameters (¶0082), reading on claims 12-16. Arab 2016 teaches detecting fluorescently labeled droplets (¶0077), reading on claims 12-16. Arab 2016 envisions loading the droplets with cells (¶0106), reading on claims 12-16.
Blainey teaches microfluidic devices that allow for scalable on-chip screening of combinatorial libraries and methods of use thereof (Abstract). Blainey teaches screening for antibiotic and adjuvant pairs, and generating a first and second set of droplets comprising the antibiotic and adjuvant respectively ([0006)), reading on the partitioning step and the test reagent of the first droplets being different from that of the second droplets of claim 1. Blaney teaches a microfluidic device comprising at least one droplet input 215 (See Figure 3), at least one flow channel 205, and an array of microwells 215 (e.g. networks) ([0029]), reading on the partitioning step and the second device of claim 1. Blainey teaches optically barcoding the droplets with a reporter system to allow for simultaneous optical phenotyping and molecular species identification ([0053]), reading on claim 1. Blainey teaches connecting a first microfluidic device directly to a second microfluidic device ([0029] and [0044]), reading on claim 1. Blainey teaches loading P. aeruginosa expressing GFP (i.e. a visual reporter) into droplets and imaged via fluorescent microscopy (Fig. 9 and [0016]), reading on claim 1. Blainey teaches that the method would be advantageous to screen multiple libraries of chemically distinct molecular species ([0043]), reading on claim 1.
Regarding claims 1 and 13-16, it would have been obvious to a person of ordinary skill in the art before the invention was filed to substitute the generic droplet generator of Arab for the microchannel (microfluidic) droplet generator of Arab 2016. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Arab and Arab 2016 are directed towards droplet generator devices, because Arab expressly considers utilizing a microfluidic device for droplet generation, and because both Arab and Arab 2016 teach loading the droplets with cells. The skilled artisan would have been motivated to do so because Arab 2016 teaches that the microchannel emulsification/droplet generator is advantageous for generating droplets of differing diameters.
Regarding the first and second devices of claim 1, it would have been obvious to a person of ordinary skill in the art before the invention was filed to further add the microfluidic device of Blainey and partitioning step of Blainey to the methods of Arab. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Arab and Blainey are directed towards droplet generator devices, because Arab expressly considers utilizing a microfluidic device for droplet generation, because both Arab and Blainey teach loading the droplets with cells, and because Blainey expressly considers operatively connecting two microfluidic devices to each other. The skilled artisan would have been motivated to do so because Blainey teaches that the method would be advantageous to screen multiple libraries of chemically distinct molecular species, and would therefore predictably improve upon the methods of Arab by screening for multiple potential antimicrobial compounds in the method of Arab.
Regarding claim 5, it would have been obvious to a person of ordinary skill in the art before the invention was filed to add the fluorocarbon oil (e.g. non-aqueous liquid) of Arab to the microbial detection and droplet formation methods of Arab. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because Arab expressly considers the combination. The skilled artisan would have been motivated to do so because that fluorocarbon oil is advantageous as it is able to dissolve gases and is biologically inert.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Arab, Arab 2016, and Blainey as applied to claims 1 and 5 above, and further in view of Agresti et al. (US 9,017,948).
The teachings of Arab, Arab 2016, and Blainey are relied upon as set forth above.
Regarding claim 6, Arab, Arab 2016, and Blainey do not teach a non-aqueous liquid having a specific gravity greater than or equal to 1.2.
Agresti teaches methods of making droplets comprising a cell or DNA (Abstract). Agresti teaches that the droplets comprise a one liquid suspended in a second liquid, such as a hydrophilic liquid suspended in a hydrophobic liquid (Col. 7, line 61 through Col. 8, line 14). Agresti teaches FC3283, FC40, and Krytox as exemplary species of fluorocarbon oil for the hydrophobic liquid, having a specific gravity of about 1.4-2 (Col. 8, lines 13-33), reading on claim 6.
Regarding claim 6, it would have been obvious to a person of ordinary skill in the art before the invention was filed to select a fluorocarbon oil having a specific gravity of about 1.4-2 as taught by Agresti for use in the methods of Arab. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Agresti and Arab are directed towards methods of making droplets comprising cells, and both Agresti and Arab are directed towards fluorocarbon oil as a species of liquid immiscible in water (e.g. hydrophobic). The skilled artisan would have been motivated to do so because the simple substitution of a specific fluorocarbon oil as taught by Agresti for the generic fluorocarbon oil of Arab would predictably yield an operable fluorocarbon oil for making droplets in the methods of Arab. See M.P.E.P. § 2143(I)(B).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Response to Arguments
Applicant's arguments on pages 7-12 of the reply have been fully considered, but not found persuasive of error for the reasons given below.
On pages 7-9 of the reply, Applicant alleges that argument on pages 7-8 of the reply that Blainey is deficient by teaching a microwell-array platform and alleging that Blainey does not describe the droplets as aliquots of a second sample portion. This is not found persuasive of error because one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, Applicant appears to allege that Blainey is deficient by not teaching every element of claim 1. However, Blainey is not applied alone in any 35 U.S.C. § 102 rejection, but is applied as a secondary reference with Arab and Arab 2016 under 35 U.S.C. § 103 and the claimed invention becomes obvious when the references are considered together as a whole rather than each alone. None of Applicant’s arguments address the specific rationale to combine Blainey and Arab 2016 with Arab as set forth above.
On page 10 of the reply, Applicant traverses Blainey with respect to the claimed “networks”. This is not found persuasive because no controlling (re)definition of “networks” was found in the specification, and so Blainey’s interconnected microwells meets the broadest reasonable interpretation of the claimed “networks”. See M.P.E.P. § 2111.
Applicant’s arguments on pages 10-11 of the reply are not found persuasive, because Blainey teaches screening for antibiotic and adjuvant pairs, and generating a first and second set of droplets comprising the antibiotic and adjuvant respectively ([0006)), reading on the partitioning step and the test reagent of the first droplets being different from that of the second droplets of claim 1. The adjuvant of the second droplets is not present in the first droplets, thus reading on the broadest reasonable interpretation of “for at least one of the aliquots, introducing a test reagent into at least some of the second droplets, wherein the test reagent is a reagent that is not introduced into the first droplets” of claim 1.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, a specific rationale to combine the teachings of Arab 2016 and Blainey is set forth above and none of Applicant’s arguments address what the combination of reference would (or would not) reasonably suggest to a person of ordinary skill in the art.
On pages 11-12 of the reply, Applicants rely on arguments traversing the above rejection of claim 1 over Arab in view of Arab 2016 and Blainey to traverse the rejection of claim 6 further in view of Agresti. Therefore, the response set forth above to arguments also applies to this rejection.
Conclusion
No claims are allowed. No claims are free of the art.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN C BARRON whose telephone number is (571)270-5111. The examiner can normally be reached 7:30am-3:30pm EDT/EST (M-F).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached at 571-272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Sean C. Barron/Primary Examiner, Art Unit 1653
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