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 .
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
1. Claims 1, 3, 5, 7-10, 19, 20 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent Application Publication No. 20130072404 to Miller et al.
Miller et al. teaches determining phase transition characteristics of a macromolecule as demonstrated by teaching that “Variable concentration microdroplets could also be used to construct phase diagrams for physical and chemical phenomena such as chemical solubility, crystallization, and polymerization.” [0290].
Miller et al. teaches generating a stream of micro-droplets that include at least one constituent that can be a nucleic acid or protein which applicant discloses as being a macromolecule. [0037]
Miller et al. teaches varying the concentration of the macromolecule. (Abstract)
Miller et al. teaches measuring the concentration of the constituents of the macromolecule. [0029]-[0030].
While Miller et al. does not specifically teach measuring the phases of the macromolecule, as noted above, Miller et al. teaches that “Variable concentration microdroplets could also be used to construct phase diagrams for physical and chemical phenomena such as chemical solubility, crystallization, and polymerization.” which renders obvious the measurement of the phases of the macromolecule.” [0290]
Miller et al. provides examples of first and second components (constituents) of the micro-droplets in paragraph [0025] and teaches varying flow rates in a microfluidic device having multiple channels to vary the concentration of the micro-droplets. [0076]
Miller et al. further teaches the use of reporter molecules that can be a fluorescent dye that provides for optical measurement. [0030], [0280] The reporter molecules read on applicant’s further constituent that comprises an optical marker.
I.) Regarding applicant’s claim 1, as noted above Miller et al. teaches or renders obvious all the limitations of claim 1.
Therefore, Miller et al. renders claim 1 obvious.
II.) Regarding applicant’s clam 3, as noted above Miller et al. renders claim 1 obvious from which claim 3 depends.
Claim 3 recites that conditions in the micro-droplets are varied by varying the temperature of the micro-droplets, optionally wherein the temperature of the micro-droplets is varied by controlling the temperature of a channel in which the micro-droplets flow.
Miller et al teaches that the concentration profile of a solute is temperature dependent. [0108]-[0112].
Accordingly, it would have been obvious to one of ordinary skill in the art to vary the temperature of the micro-droplets for purposes of controlling the solubility of the solute in the solvent.
Therefore, Miller et al. renders claim 3 obvious.
III.) Regarding applicant’s clam 5, as noted above Miller et al. renders claim 1 obvious from which claim 5 depends.
Claim 5 recites that the stream of micro-droplets is a continuous stream, optionally wherein the measuring is performed continuously on the stream of micro-droplets.
Miller et al. teaches a microfluidic device that forms micro-droplets by injection. [0047], [0277]-[0278]. Miller et al. further teaches providing a continuous flow of a buffer to a microfluidic device which would provide a continuous stream of micro-droplets.
Therefore, Miller et al. renders claim 5 obvious.
IV.) Regarding applicant’s clam 7, as noted above Miller et al. renders claim 1 obvious from which claim 7 depends.
Claim 7 recites that the micro-droplets are collected and measuring is performed on the collected micro-droplets.
Miller et al. does note teach that the micro-droplets are collected and measuring is performed on the collected micro-droplets.
It would have been obvious to one of ordinary skill in the art that the micro-droplets can be measured at any time, including collecting and measuring the micro-droplets within a channel in a microfluidic device or after leaving the microfluidic device.
Therefore, Miller et al. renders claim 7 obvious.
V.) Regarding applicant’s clam 8, as noted above Miller et al. renders claim 1 obvious from which claim 8 depends.
Claim 8 recites that the stream of micro-droplets is generated by injecting a stream of a first fluid comprising the plurality of constituents into a stream of a second fluid, the second fluid being immiscible with the first fluid.
As noted above, Miller et al. teaches a microfluidic device that forms micro-droplets by injection
In Fig. 2 Miller et al. illustrates injecting a substrate and an enzyme into an oil phase.
Therefore, Miller et al. renders claim 8 obvious.
VI.) Regarding applicant’s clam 9, as noted above Miller et al. renders claim 1 obvious from which claim 9 depends.
Claim 9 recites that relative concentrations of the plurality of constituents of the micro-droplets are varied by varying relative flow rates of respective streams of the plurality of constituents of the micro-droplets.
As noted above, Miller et al. teaches varying flow rates in a microfluidic device having multiple channels to vary the concentration of the micro-droplets. [0076]
Therefore, Miller et al. renders claim 9 obvious.
VII.) Regarding applicant’s clam 10, as noted above Miller et al. renders claim 1 obvious from which claim 10 depends.
Claim 10 recites that the first optical means illuminates the micro-droplets with illumination light and detects a response, optionally, wherein the relative concentrations of the constituents of the micro-droplets are determined based on the respective responses of the constituents to the illumination light, and optionally wherein each of the constituents whose relative concentrations are measured comprises a different fluorophore which emits light of a specific wavelength in response to the illumination light.
Miller et al. teaches optically measuring fluorescence which would measure concentrations of constituents of the micro-droplets. [0047]
Therefore, Miller et al. renders claim 10 obvious.
VIII.) Regarding applicant’s clam 19, as noted above Miller et al. renders claim 1 obvious from which claim 19 depends.
Claim 19 recites that the macromolecule comprises one or more of: a protein, and a nucleic acid.
As noted above, Miller et al. teaches generating a stream of micro-droplets that include at least one constituent that can be a nucleic acid or protein which applicant discloses as being a macromolecule. [0037]
Therefore, Miller et al. renders claim 19 obvious.
IX.) Regarding applicant’s clam 20, as noted above Miller et al. renders claim 1 obvious from which claim 20 depends.
Claim 20 recites that the plurality of constituents further comprise one or more of: a pH buffer, a phase separator, a salt solution and a therapeutic drug/drug candidate
As noted above, Miller et al. teaches generating a stream of micro-droplets that include at least one constituent that can be a nucleic acid or protein which applicant discloses as being a macromolecule. [0037]
Applicant discloses that therapeutic drug/drug candidates may be a small molecule or biologic, including but not limited to protein, nucleic acid, and others. (page 8, lines 6-7)
Therefore, Miller et al. renders claim 20 obvious.
X.) Regarding applicant’s clam 32, as noted above Miller et al. renders claim 1 obvious from which claim 32 depends.
Claim 32 recites that the one constituent comprising the macromolecule comprises one or more of: the macromolecule itself, a cell, a subcellular organelle, a cell lysate.
Miller et al. teaches that the target component is selected from the group consisting of nucleic acid, protein, enzyme, receptor, protein complex, protein-nucleic acid complex and cell. [0037]
Therefore, Miller et al. renders claim 32 obvious.
2. Claims 14, 17 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. as applied to claim 1 above, and further in view of Feng et al. (“Mapping Polymer Phase Diagram in Nanoliter Droplets,” Macromolecules 2011, 44, 686–689) (cited by applicant)
I.) Regarding applicant’s clam 14, as noted above Miller et al. renders claim 1 obvious from which claim 14 depends.
Claim 14 recites that the phases of the macromolecule present in the micro-droplets are measured by a second optical means, optionally wherein the second optical means obtains images of the micro- droplets and the phases of the macromolecule present in the micro-droplets are determined based on characteristics of the image indicative of particular phases, or optionally wherein the second optical means obtains a light-scattering profile of the micro-droplets and the phases of the macromolecule present in the micro-droplets are determined based on characteristics of the light scattering profile indicative of particular phases.
Miller et al. does not teach a second optical means for measuring the phases of the macromolecule present in the micro-droplets.
Miller et al. teaches constructing phase diagrams for physical and chemical phenomena such as chemical solubility, crystallization, and polymerization.
Feng et al. teaches phase changes in polymerization reactions can be detected by light scattering techniques (page 686, right-hand column second full paragraph).
It would have been obvious to one of ordinary skill in the art to modify Miller et al, to include a second optical means for detecting light scattering as taught by Feng et al. to detect/monitor light scattering associated with polymerization phase changes for monitor phase changes and developing phase change diagrams.
Therefore, Miller et al. in view of Feng et al. renders claim 14 obvious.
II.) Regarding applicant’s clam 17, as noted above Miller et al. renders claim 1 obvious from which claim 17 depends.
Claim 17 recites that the varied relative concentrations of the plurality of constituents of the micro-droplets are varied based on the measured relative concentrations of the plurality of constituents of, and the measured phases of the macromolecule present in, the micro-droplets, optionally wherein the relative concentrations of the constituents of the micro-droplets are systematically varied so as to generate micro-droplets having conditions at which, or substantially close to which, the macromolecule transitions from a first phase to a second phase.
Miller et al. does not teach varying relative concentrations of the constituents of the micro-droplets based on the measured relative concentrations of the constituents of, and the phases of the macromolecule present in, the micro-droplets, optionally wherein the relative concentrations of the constituents of the micro-droplets are systematically varied so as to generate micro-droplets having conditions at which, or substantially close to which, the macromolecule transitions from a first phase to a second phase.
As noted above, Miller et al. teaches varying the constituents of the micro-droplets, measuring the concentration of the constituents.
In addition, as noted above, Miller et al. in view of Feng et al. teaches measuring the phases of the micro-droplets.
It would have been obvious to one of ordinary skill in the art to modify Miller et al. in view of Feng et al to vary the constituents of the micro-droplets base on the measured concentration of the constituents and the phases for purposes of determining how phase change relates to concentrations of the constituents.
Therefore, Miller et al. in view of Feng et al. renders claim 17 obvious.
III.) Regarding applicant’s clam 33, as noted above Miller et al. renders claim 1 obvious from which claim 33 depends.
Claim 33 recites that phase transition characteristics of two or more macromolecules are measured simultaneously, at least one constituent comprising a further macromolecule.
Miller et al. does not teach measuring the phase transition characteristics of two or more macromolecules are simultaneously, at least one constituent comprising a further macromolecule.
As noted above, Miller et al. in view of Feng et al. teaches measuring the phases of the micro-droplets.
It would have been obvious to one of ordinary skill in the art to modify Miller et al. in view of Feng et al to measure the phase transition characteristics of multiple macromolecule in separate light-scattering areas in a microfluidic device since duplication has no patentably significance unless a new and unexpected result is produced.
Therefore, Miller et al. in view of Feng et al. renders claim 33 obvious.
3. Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Miller et al.
I.) Claim 21 recites a method of screening therapeutic drug candidates, the method comprising the steps of the method of claim 1, wherein at least one constituent of the micro-droplets, other than the macromolecule, comprises a drug candidate.
As noted above, Miller et al. teaches generating a stream of micro-droplets that include at least one constituent that can be a nucleic acid or protein which applicant discloses as being a macromolecule. [0037]
Applicant discloses that therapeutic drug/drug candidates may be a small molecule or biologic, including but not limited to protein, nucleic acid, and others. (page 8, lines 6-7)
Therefore, Miller et al. renders claim 21 obvious.
4. Claims 22-24, 27 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Miller et al, in view of Feng et al.
Regarding applicant’s claim 22, claim 22 recites an apparatus for measuring phase transition characteristics of a macromolecule, the apparatus comprising:
a microfluidics system configured to generate a stream of micro-droplets, each micro- droplet comprising a plurality of constituents, of which one constituent comprises the macromolecule, vary a relative concentration in the microdroplets of the constituent comprising the macromolecule and vary a relative concentration in the microdroplets of at least one further constituent, wherein the constituent comprising the macromolecule and the at least one further constituent each comprise a respective optical marker;
a first optical system configured to measure the relative concentration in the microdroplets of the constituent comprising the macromolecule and the relative concentration in the microdroplets of at least one further constituent for each of the micro-droplets in the stream of micro-droplets generated by the microfluidics system, based on the respective optical markers; and
a second optical system configured to measure phases of the macromolecule present in each of the micro-droplets in the stream of micro-droplets generated by the microfluidics system, so as to obtain data points relating to the phases of the macromolecule in at least a two-dimensional chemical-space; and
a control processor configured to control the microfluidics system to vary the relative concentrations in the microdroplets of the constituent comprising the macromolecule and at least one further constituent, so as to obtain data points relating to the phases of the macromolecule in at least a two-dimensional chemical-space, at or substantially close to a phase boundary at which the macromolecule transitions from a first phase to a second phase.
As noted above, Miller et al. teaches determining phase transition characteristics of a macromolecule as demonstrated by teaching that “Variable concentration microdroplets could also be used to construct phase diagrams for physical and chemical phenomena such as chemical solubility, crystallization, and polymerization.” [0290].
As further noted above, Miller et al. teaches generating a stream of micro-droplets that include at least one constituent that can be a nucleic acid or protein which applicant discloses as being a macromolecule. [0037]
Miller et al. further teaches varying the concentration of the macromolecule. (Abstract)
Miller et al. further teaches measuring the concentration of the constituents of the macromolecule. [0029]-[0030].
While Miller et al. does not specifically teach measuring the phases of the macromolecule, as noted above, Miller et al. teaches that “Variable concentration microdroplets could also be used to construct phase diagrams for physical and chemical phenomena such as chemical solubility, crystallization, and polymerization.” which renders obvious the measurement of the phases of the macromolecule.
Miller et al. provides examples of first and second components (constituents) of the micro-droplets in paragraph [0025] and teaches varying flow rates in a microfluidic device having multiple channels to vary the concentration of the micro-droplets. [0076]
Miller et al. further teaches the use of reporter molecules that can be a fluorescent dye that provides for optical measurement. [0030], [0280] The reporter molecules read on applicant’s “further constituent.”
As noted above, Feng et al. teaches phase changes in polymerization reactions can be detected by light scattering techniques (page 686, right-hand column second full paragraph).
It would have been obvious to one of ordinary skill in the art to modify Miller et al, to include a second optical means for detecting light scattering as taught by Feng et al. to detect/monitor light scattering associated with polymerization phase changes for monitor phase changes and developing phase change diagrams.
Miller et al. teaches a “a high-speed data-acquisition and control system.” [0057]
Miller et al. further teach controlling and varying the flow rates. [0243]
It would have been obvious to one of ordinary skill in the art to modify the control in Miller et al. using processor to vary the relative concentrations in the microdroplets of the constituent comprising the macromolecule and at least one further constituent, so as to obtain data points relating to any of the phases of the macromolecule including at or substantially close to a phase boundary at which the macromolecule transitions from a first phase to a second phase.
Therefore, Miller et al. in view of Feng et al. renders claim 22 obvious.
II.) Regarding applicant’s claim 23, as noted above, Miller et al. in view of Feng et al. renders claim 22 obvious from which claim 23 depends.
Claim 23 recites a plurality of inlets configured to input streams of respective constituents of the at least two constituents; a first channel through which a stream of a first fluid is configured to flow, the first fluid comprising the plurality of constituents from the at least two inlets; and a second channel through which a stream of a second fluid is configured to flow, the second fluid being immiscible with the first fluid; wherein the first channel comprises a nozzle opening into the second channel and configured to inject the stream of the first fluid into the stream of the second fluid and generate micro-droplets of the first fluid within the second fluid.
As noted above, Miller et al. teaches a microfluidic device that forms micro-droplets by injection
As further noted above, in Fig. 2 Miller et al. illustrates injecting a substrate and an enzyme into an oil phase.
The substrate and enzyme would necessarily be provided in separate inlets and injected together from a common channel to for individual micro-droplets.
The oil phase (an immiscible fluid) would necessarily be provided in a separate inlet/channel.
Therefore, Miller et al. in view of Feng et al. renders claim 23 obvious.
III.) Regarding applicant’s claim 24, as noted above, Miller et al. in view of Feng et al. renders claim 22 obvious from which claim 24 depends.
Claim 24 recites a plurality of pumps corresponding to the plurality of inlets, the plurality of pumps being configured to vary relative flow rates of streams of the respective constituents so as to vary the relative concentrations of the plurality of constituents of the generated micro-droplets or substantially close to which, the macromolecule transitions from a first phase to a second phase.
As noted above, Miller et al. teaches a microfluidic device that forms micro-droplets by injection and teaches pumps to control flow rates. [0076]
As further noted above, in Fig. 2 Miller et al. illustrates injecting a substrate and an enzyme into an oil phase.
The substrate and enzyme would necessarily be provided in separate inlets and injected together from a common channel to for individual micro-droplets.
The oil phase (an immiscible fluid) would necessarily be provided in a separate inlet/channel.
Separate pumps would be necessary to cause the substrate/enzyme and oil phase to flow.
Therefore, Miller et al. in view of Feng et al. renders claim 24 obvious.
IV.) Regarding applicant’s claim 27, as noted above, Miller et al. in view of Feng et al. renders claim 22 obvious from which claim 27 depends.
Claim 27 recites that the first optical system comprises: a light source configured to illuminate the micro-droplets with illumination light; and a detector configured to detect the response of the micro-droplets to the illumination light, optionally wherein the light source comprises a plurality of light emitting parts each configured to emit light of a different wavelength, optionally wherein the detector comprises a plurality of light detection parts each configured to detect light of a different wavelength.
Miller et al. teaches that “the response of the system may be measured by quantifying an optical signal. The optical signal may be emitted by the product of the reaction between the components of the system. Preferably, the optical signal is fluorescent signal.” [0026]
Therefore, Miller et al. in view of Feng et al. renders claim 27 obvious.
V.) Regarding applicant’s claim 30, as noted above, Miller et al. in view of Feng et al. renders claim 22 obvious from which claim 30 depends.
Claim 30 recites that the second optical system comprises an imaging element configured to obtain images of the micro-droplets, optionally wherein the second optical system comprises: a light source configured to illuminate the micro-droplets; and a detector configured to obtain a light-scattering profile of light from the light source scattered by the micro-droplets.
As noted above, Feng et al. teaches phase changes in polymerization reactions can be detected by light scattering techniques (page 686, right-hand column second full paragraph).
As further noted, it would have been obvious to one of ordinary skill in the art to modify Miller et al, to include a second optical means for detecting light scattering as taught by Feng et al. to detect/monitor light scattering associated with macromolecule phase changes in the micro-droplets.
Therefore, Miller et al. in view of Feng et al. renders claim 30 obvious.
Response to Arguments
Applicant's arguments filed 12/08/2025 have been fully considered but they are not persuasive.
Applicant argues that claim 1 has been amended to make clearer the multidimensional nature of the invention by specifying that microdroplets are generated with varying conditions, by varying the concentrations of at least two constituents of interest, namely the constituent comprising the macromolecule and at least one further constituent (e.g. a phase separator and/or drug).
However, claim 1 recites that the further constituent comprises an optical marker.
As noted above, Miller et al. teaches reporter molecules that can be a dye, or a fluorescent dye which reads on the “optical marker” recited in claim 1. Varying the concentration of the reporter molecule in Miller et al. to enhance the detection of the dye would have been obvious to one of ordinary skill in the art for detection purposes.
Applicant notes that Miller et al. describes a multiple component system, e.g. at paragraph [0023]. However, applicant argues that the relative concentration in the microdroplet is only varied for one solute. The relative concentration in the microdroplet of the second component is not varied.
As noted above, Miller et al.’s reporter molecules reads on applicant’s claimed “further constituent” and it would have been obvious to vary the concentration of the reporter molecules in Miller et al. for detection purposes.
It is noted that Miller et al also teaches that the second component can be an enzyme or one of many target molecules. [0025]
Applicant argues that although Feng et al. relates to measuring phase transition characteristics of a macromolecule, the type of phase separation behavior that Feng et al. is concerned with is very different to the type of phase separation behavior that the invention is concerned with. In particular, Feng et al. is concerned with measuring how phase behavior of a polymer depends on temperature and polymer concentration.
As noted above, Feng et al. has been relied upon as teaching that phase changes can be detected by light scattering techniques, which teaching is applicable to other particles and not limited to polymers.
Conclusion
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 MICHAEL S. GZYBOWSKI whose telephone number is (571)270-3487. The examiner can normally be reached M-F 8:30-5:00.
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/M.S.G./Examiner, Art Unit 1798
/CHARLES CAPOZZI/Supervisory Patent Examiner, Art Unit 1798