DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of claims
Claims 1, 2 and 4-21 as amended on 5/06/2025 are pending.
Claims 17-21 were withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/11/2024.
Claims 1, 2 and 4-16 as amended on 5/06/2025 are under examination in the instant office action.
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.
Claims 1, 2, 6-11, 15 and 16 as amended are rejected under 35 U.S.C. 103 as being unpatentable over US 2013/0143312 (Wheeler et al), WO 2016/102927 (Williams et al), Pit et al (“High-throughput sorting of drops in microfluidic chips using electric capacitance”. Biomicrofluidics 9, 044116 (2015), pages 1-12) and Turan et al (“Evaluation of Factors that may Cause False Positive Growth Signals in Blood Cultures-As the Word 'Factors' will Include Both Microbial and Patients as well as Others”. Int Clin Med Microbiol 2018, 3, 137, pages 1-4).
US 2013/0143312 (Wheeler et al) teaches a method for determining an interaction between a medicament and a biological cell in a digital microfluidic device (DMF); wherein the method comprises steps (par. 0014-0017):
providing an array of first microdroplets containing cells (par. 0014, lines 1-4) derived from a biological sample (0118);
providing an array of second microdroplets containing medicaments or chemical, biochemical and biological reagents (par.0014, lines 5-8) at one or more predetermined concentrations;
merging or mixing the array of first microdroplets and the array of second microdroplets to form an array of merged microdroplets (par. 0015);
incubating the merged/mixed microdroplets and monitoring/analyzing the characteristics of the merged microdroplets (par. 0017) using an optical detection system (0054; 0081) to detect an interaction between cell and medicament/reagent.
In the cited method of US 2013/0143312 (Wheeler et al) the step of providing an array of microdroplets comprises the use of emulsifying surfactant, pluronic F68, (see par. 0061-0062) that facilitates formation of aqueous microdroplets with cells and reagents (0061-0062). In the cited method the microdroplets are manipulated by actuating electrodes (0014, lines 4; par. 0023, 0026); wherein term “actuating electrodes” is considered to be a generic term for the claim-recited “electrowetting electrodes” within the broadest meaning of the claims. The cells are analyzed for viability (0058, 0064) and proliferation (0064-0065). The cell-containing microdroplets contain at least one and more or at least about 10 viable cells (par. 0068).
But the cited method of US 2013/0143312 (Wheeler et al) does not comprise step of discarding empty microdroplets after sorting microdroplets into cell-containing microdroplets.
However, steps of sorting cell-containing microdroplets and discarding empty microdroplets in the methods for determining interaction between medicament (antibiotics) and cells have been practiced in the prior art as evidenced by WO 2016/102927 (Williams et al), for example: see page 6 and page 29.
The cited reference by Pit teaches the use of electrowetting techniques in microfluidics for separation of empty microdroplets without biological contents (see abstract, see page 4, par. 3, last line).
Furthermore, the cited reference by Turan teaches that false positive antibiotic results are common when there is no microbial cells observed or no microbial growth in the culture systems (see page 3, col. 2, par. 3) and that the false positive results cause misinterpretation errors, additional examinations, inappropriate antibiotic uses (page 1, col.1, last 3 lines).
Therefore, it would have been obvious to one having ordinary skill in the art at the time the claimed invention was filed to modify the method of US 2013/0143312 (Wheeler et al) for determining an interaction between medicaments and biological cells in microdroplets in a digital microfluidic device (DMF) by adding steps of sorting and discarding empty microdroplets without cells for the reasonably expected benefits in eliminating microdroplets without target cells, thus, avoiding detection of false effects resulting from using empty microdroplets without cells.
Thus, the claimed invention as a whole was clearly prima facie obvious, especially in the absence of evidence to the contrary.
The claimed subject matter fails to patentably distinguish over the state art as represented be the cited references. Therefore, the claims are properly rejected under 35 USC § 103.
As applied to claim 2: in the cited method of US 2013/0143312 (Wheeler et al) the second microdroplets contain various or a plurality of different concentrations for each medicament/reagent (0067).
As applied to claim 6: the cited method of US 2013/0143312 (Wheeler et al) comprises the use of emulsifying surfactant, pluronic F68, (see par. 0061-0062) that facilitates formation of aqueous microdroplets with cells and reagents (0061-0062). In the cited method the microdroplets are manipulated by actuating electrodes (0014, lines 4; par. 0023, 0026); wherein term “actuating electrodes” is considered to be a generic term for the claim-recited “electrowetting electrodes” within the broadest meaning of the claims.
As applied to claim 7: in the cited method of US 2013/0143312 (Wheeler et al) the assay(s) are performed on several sub-samples of one or more cells from one or more microdroplets (figure 5) including before merging/mixing or prior to actuating the microdroplets (0034). In the cited method assay(s) are also performed on sub-samples or sub-cultures upon “splitting” microdroplets into smaller droplets (0076).
As applied to claim 8: in the cited method of US 2013/0143312 (Wheeler et al) the assays performed include lysis of cells (0035), thus, the cells were analyzed by “destructive lysis assay” within the broadest meaning of the claims.
As applied to claim 9: in the cited method of US 2013/0143312 (Wheeler et al) the assay(s) involving lysis of cells (0035) are performed prior manipulating/merging/mixing or prior to actuating the microdroplets (0035).
As applied to claims 10-11: in the cited method of US 2013/0143312 (Wheeler et al) the computer programmer is used for selected cell assays (par. 0026, last 3 lines); thus, the cells are analyzed “utilizing a classification algorithm” within the broadest meaning of the claims. The cell features are analyzed by proliferation assays (0065; 0089) or for “cell proliferation behavior” within the broadest meaning of the claims.
As applied to claim 15: in the cited method of US 2013/0143312 (Wheeler et al) the first and/or second microdroplets comprise a growth media (0116-0117).
As applied to claim 16: the cited method of US 2013/0143312 (Wheeler et al) comprises the step of splitting microdroplets with cells into a single-cell microdroplet (0073, last 2 lines); thus, forming “a clonal colony” within the broadest reasonable meaning of the claims and in view of the lack of definitions in the as-filed specification.
The claimed subject matter fails to patentably distinguish over the state art as represented be the cited references. Therefore, the claims are properly rejected under 35 USC § 103.
Claims 1, 2, 4-11, 15 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over US 2013/0143312 (Wheeler et al), WO 2016/102927 (Williams et al), Pit et al (“High-throughput sorting of drops in microfluidic chips using electric capacitance”. Biomicrofluidics 9, 044116 (2015), pages 1-12) and Turan et al (“Evaluation of Factors that may Cause False Positive Growth Signals in Blood Cultures-As the Word 'Factors' will Include Both Microbial and Patients as well as Others”. Int Clin Med Microbiol 2018, 3, 137, pages 1-4) as applied to claims 1, 2, 6-11, 15 and 16 above, and further in view of Lam et al (“Culturing aerobic and anaerobic bacteria and mammalian cells with a microfluidic differential oxygenator”. Anal. Chem. 2009, 81, pages 5918-5924).
The references US 2013/0143312 (Wheeler et al), WO 2016/102927 (Williams et al), Pit et al and Turan et al as above.
In the method of the cited US 2013/0143312 (Wheeler et al) for determining an interaction between a medicament and a biological cell in a digital microfluidic device (DMF) the microdroplets are exposed to aerobic conditions that are optimal culturing conditions for the biological cells that are analyzed in DMF of the cited US 2013/0143312 (Wheeler et al).
Thus, the cited US 2013/0143312 (Wheeler et al) is silent about incorporation of parts with anaerobic conditions into microfluidic devices.
However, the prior art teaches culturing aerobic and anaerobic bacteria and mammalian cells in microfluidic device having sections for aerobic and for anaerobic conditions. For example: see abstract of Lam et al.
Therefore, it would have been obvious to one having ordinary skill in the art at the time the claimed invention was filed to modify the method of US 2013/0143312 (Wheeler et al) for determining an interaction between medicaments and biological cells in a digital microfluidic device (DMF) by providing different oxygenation culture conditions including aerobic and anaerobic conditions depending of optimal culture conditions for the biological cells under analysis as taught/suggested by Lam. One of skill in the art would have a reasonable expectation of success in doing so because microfluidic devices with sections for anaerobic and anaerobic culture conditions have been known and used in the prior art.
Thus, the claimed invention as a whole was clearly prima facie obvious, especially in the absence of evidence to the contrary.
The claimed subject matter fails to patentably distinguish over the state art as represented be the cited references. Therefore, the claims are properly rejected under 35 USC § 103.
Claims 1, 2 and 4-16 are rejected under 35 U.S.C. 103 as being unpatentable over US 2013/0143312 (Wheeler et al), WO 2016/102927 (Williams et al), Pit et al (“High-throughput sorting of drops in microfluidic chips using electric capacitance”. Biomicrofluidics 9, 044116 (2015), pages 1-12), Turan et al (“Evaluation of Factors that may Cause False Positive Growth Signals in Blood Cultures-As the Word 'Factors' will Include Both Microbial and Patients as well as Others”. Int Clin Med Microbiol 2018, 3, 137, pages 1-4) and Lam et al (“Culturing aerobic and anaerobic bacteria and mammalian cells with a microfluidic differential oxygenator”. Anal. Chem. 2009, 81, pages 5918-5924) as applied to claims 1, 2, 4-11, 15 and 16 above, and further in view of Lyu et la. (IDS reference; Sensors & Actuators: B. Chemical. 2018, 270, pages 396-404).
The cited documents US 2013/0143312 (Wheeler et al), WO 2016/102927 (Williams et al), Pit et al., Turan et al. and Lam et al as above.
In the method of the cited US 2013/0143312 (Wheeler et al) for determining an interaction between a medicament and a biological cell in a digital microfluidic device (DMF) the merged microdroplets containing cells and medicaments/reagents are analyzed for cell viability and cell proliferation.
But the cited documents US 2013/0143312 (Wheeler et al) is silent about determining minimum inhibitory concentration (MIC) of antibiotics.
However, the prior art teaches determining minimum inhibitory concentration (MIC) of antibiotics in merged droplets of microfluidic devices; for example: see abstract of the cited reference by Lyu.
Therefore, it would have been obvious to one having ordinary skill in the art at the time the claimed invention was filed to modify the method of US 2013/0143312 (Wheeler et al) for determining an interaction between medicaments and biological cells in a digital microfluidic device (DMF) as intended for determining MIC of antibiotics with as reasonable expectation of success in doing so because microfluidic devices with microdroplets have been used for analyzing various cell assays including determining minimum inhibitory concentration (MIC) of antibiotics.
Thus, the claimed invention as a whole was clearly prima facie obvious, especially in the absence of evidence to the contrary.
The claimed subject matter fails to patentably distinguish over the state art as represented be the cited references. Therefore, the claims are properly rejected under 35 USC § 103.
Response to Arguments
Applicant's arguments filed on 5/06/2025 have been fully considered but they are not all found persuasive.
The rejection of claims under 35 U.S.C. 102 (a) (1) as being anticipated by US 2013/0143312 (Wheeler et al) has been withdrawn because the cited method does not comprise step of sorting microdroplets into cell-containing microdroplets and empty microdroplets and discarding empty microdroplets.
With regard to the claim rejection under 35 USC § 103 Applicant’s arguments were considered but are moot in view of new grounds of rejection necessitated by amendment.
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 VERA AFREMOVA whose telephone number is (571)272-0914. The examiner can normally be reached Monday-Friday: 8.30am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (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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Vera Afremova
August 13, 2025
/VERA AFREMOVA/ Primary Examiner, Art Unit 1653
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