DETAILED ACTION
Response to Arguments
Rejections under 35 USC 103
Applicant's arguments filed 02/27/2026 have been fully considered.
The arguments directed to the combination of Li and Gentalen (see pgs. 2-3 of the Remarks) are found to be unpersuasive because the combination is proper and renders the claimed invention obvious. Li is directed to a microfluidic gas assisted ionization structure and method. Li teaches most limitations of claim 1, however Li fails to teach explicitly wherein the fluid channel comprises a separation channel configured to perform isoelectric focusing or electrophoretic separation of a sample comprising a mixture of analytes in the fluid channel. Rather, Li discusses an example of an electrophoretic separation system 2 upstream of the microfluidic chip (Li, [0027], Fig. 1). Gentalen is directed to devices and methods for characterization of analyte mixtures, and includes a microfluidic device with an electrospray ionization orifice (Gentalen, [0057]) and having a fluid channel that comprises a separation channel configured to perform an electrophoretic separation of a sample comprising a mixture of analytes int eh fluid channel (Gentalen, [0045], Fig. 1). Gentalen and Li are analogous art (both directed to electrospray ionization utilizing microfluidic chips) and it would be obvious to combine the features of Gentalen with Li because Gentalen provides motivation to include a fluid channel that performs electrophoretic separation, namely that such a configuration allows the channel to be used to separate and/or enrich an analyte and/or a portion of an analyte, (Gentalen, [0045]). Although Li’s example of electrophoretic separation is shown as occurring prior to the microfluidic chip, Li mentions that the optional separation system may comprise any number of systems known in the art for separating molecules, and does not teach against any integration of the electrophoretic separation. Gentalen demonstrates an example of electrophoretic separation known in the art. Consequently, one of ordinary skill would look to Gentalen as a possible way of involving electrophoretic separation in the microfluidic chip/ESI system of Li to arrive at the claimed invention. As prior art, Li and Gentalen demonstrate that the integrated gas channel combined with the presence of an electrospray ionization orifice on a single microfluidic chip does not demonstrate a technical contribution not present in the art.
Pg. 3 of the remarks notes that the claims have been amended to clarify that the electrospray ionization orifice and gas outlet orifice are disposed on an edge of the substrate adjacent to each other. No arguments are presented. The clarifying amendment does not overcome the cited art of record because Li teaches these features (see Lee, Fig. 2).
The remarks at the bottom of pg. 3 to pg. 4 recite that the specification discloses certain benefits provided by the invention of the instant application and argues that these features are not taught or suggested by the cited art. The claims, as written, do not require these features, therefore the arguments are found to be unpersuasive.
Pg. 4-5 of the remarks recites that the neither Li nor Gentalen teach or suggest the newly added limitation that the flow rates of the gas and liquid can be controlled to achieve a volumetric flow rate ratio of 1000:1 to 1,000,000:1. In view of this amendment to the claim, a new ground of rejection is made in view of Li and Bajic, et. al. (US 20160225601 A1) with support from MPEP 2144 (see 103 rejection below). The arguments with respect to Molla are deemed moot.
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 § 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, 4-7, 15-28 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 recites “a gas outlet orifice disposed on an edge of the substrate adjacent to the electrospray ionization orifice” is indefinite because it is unclear if the “an edge of the substrate is the same or different to the “an edge…of the substrate” presented in an earlier limitation of the claim.
Claims 4-7 and 15-28 are rejected by virtue of their dependence on claim 1.
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.
Claims 1, 4-7, 15-16, 18-21, and 23-28 are rejected under 35 U.S.C. 103 as being unpatentable over Li (US 20070257190 A1) in view of Gentalen (US 20170176386 A1) and Bajic, et. al. (US 20160225601 A1), hereinafter Bajic.
Regarding claim 1, Li teaches a microfluidic chip (microfluidic chip 3, [0028]) comprising:
a) a substrate (substrate [0028], central layer 13), wherein the substrate comprises:
i) a fluid channel (analyte channel 15, [0037], Fig. 2) comprising a distal end (end of analyte channel 15 at first end 9, [0037], Fig. 2) that is in fluid communication with an electrospray ionization orifice (spray tip 10, [0037], Fig. 2-5) wherein the electrospray ionization orifice is disposed on an edge or corner or tip of the substrate (spray tip 10 is disposed on an edge/tip of substrate as seen in Fig. 2); and
ii) a gas channel (first gas channel 17 or second gas channel 19, [0037], Fig. 2) comprising a distal end (end of gas channel at first end 9, [0037], Fig. 2) that is in fluid communication with a gas outlet orifice disposed on an edge of the substrate adjacent to the electrospray ionization orifice (gas channels make orifice at first end 9 (an edge of the substrate) adjacent to spray tip 10, [0037], Figs. 2-5);
wherein the gas outlet orifice is configured to perform nebulization of the separated sample expelled from the electrospray ionization orifice ([0044]).
wherein an angle between the distal end of the fluid channel and the distal end of the gas channel ranges from about 0 degrees to about 30 degrees (the channels are oriented parallel (0 degrees) to each other at first end 9, [0037], Fig. 2), and wherein a flow rate of gas in the gas channel and flow rate of liquid in the fluid channel can be controlled (Li teaches in [0037] that each of the channels may be designed for carrying various volumes, flow rates, and pressures. Li demonstrates this capability because Li states that these parameters (volumes, flow rates, pressures) can be designed and improved based on the samples that are employed, indicating the capacity for control and that optimal flow rate ratios are capable of being achieved.)
Although Li teaches isoelectric focusing and electrophoretic separation of a sample comprising a mixture of analytes in the fluid channel, Li does not teach that this performed by a separation channel of the fluid channel on the substrate (Instead, Li teaches a connected but external system for doing so, [0027], [0047], Fig. 1 where 2 is the optional separation system before going to microfluidic chip 3). As such, Li does not explicitly teach the limitation wherein the fluid channel comprises a separation channel configured to perform an isoelectric focusing or electrophoretic separation of a sample comprising a mixture of analytes in the fluid channel.
Gentalen teaches wherein the fluid channel comprises a separation channel configured to perform an isoelectric focusing or electrophoretic separation of a sample comprising a mixture of analytes in the fluid channel (Channels 116 and 124, [0045]).
Gentalen modifies Li by suggesting the fluid channel of the substrate comprises a separation channel configured to perform isoelectric separations of a sample comprising a mixture of analytes in the fluid channel.
Since both inventions are directed to characterization of analyte mixtures, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teachings of Gentalen because the configuration allows the channels to be used to separate and/or enrich an analyte and/or a portion of an analyte, (Gentalen, [0045]).
Although Li teaches that the flow rate of gas in the gas channel and flow rate of liquid in the fluid channel can be controlled, Li does not explicitly teach a ratio of volumetric flow rates for the gas and liquid ranges from 1000:1 to 1,000,000:1.
Bajic teaches a ratio of volumetric flow rates for the gas and liquid ranges from 1000:1 to 1,000,000:1 ([0042] teaches a liquid flow rate of > 200 µL/min (which, in converted units is > 0.012 L/Hr) and a nebulizer gas flow rate in the range 80-150 L/Hr. These flow rates give ratios (6,667:1 to 12,500:1) that are within the claimed range. See MPEP 2144.05 I. which recites “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.”).
Bajic modifies Li by suggesting a ratio of volumetric flow rates for the gas and liquid within the claimed range.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teachings of Bajic because setting the flow rates as suggested by Bajic allows a mass spectrometer to be used in an optimum manner and with optimum sensitivity by an inexperienced user, (Bajic, [0044]).
Additionally, optimizing the gas and liquid flow rates and resulting flow rate ratio is well within the bounds of normal experimentation. See MPEP 2144.05 II (A). “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to dis-cover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Furthermore, “[a] particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation.” In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977). In the case at hand, Bajic teaches that a liquid flow rate > 200 uL/min and a gas flow rate in the range 80-150 L/Hr, allows the mass spectrometer to be used in an optimum manner with optimum sensitivity by an inexperienced user. As such, Bajic identifies the gas and liquid flow rates and their relative values as a variable which achieves a recognized result, i.e., optimum sensitivity. Accordingly, it would have been obvious to one of ordinary skill in the art before the effective time of filing to optimize the gas and liquid flow rates in Li to meet the ratio of volumetric flow rates for the gas and liquid ranges from 1000:1 to 1,000,000:1 since it is not inventive to dis-cover the optimum or workable ranges by routine experimentation.
Regarding claim 4, Li teaches wherein the substrate comprises two or more gas channels, each of which comprises a distal end that is in fluid communication with a gas outlet orifice (gas channel 17 and gas channel 19 have orifices at first end 9, [0037], Fig. 2-5).
Regarding claim 5, Li teaches wherein the two or more gas outlet orifices are disposed adjacent to and symmetrically about the electrospray ionization orifice ([0038], Fig. 2-5).
Regarding claim 6, Li does not teach wherein the angle ranges from about 10 degrees to about 20 degrees.
Gentalen teaches wherein the angle ranges from about 10 degrees to about 20 degrees (Fig. 1 shows gas channels 106 and 140 at an angle with confluence 126 (a fluid channel). The angle appears to be about or close to the claimed range. Additionally, changing the angle between the distal ends of the gas and fluid channels represents an obvious change in shape that does not establish patentability.)
Gentalen modifies Li by suggesting that the angle between the distal end of the fluid channel and the distal end of the gas channel ranges from about 10 degrees to about 20 degrees.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teachings of Gentalen because although Gentalen does not explicitly specify the angle between 106/140 and 126, Figure 1 presents a configuration showing said angle, and this angle appears to be similar to the claimed range of 10 degrees to 20 degrees. MPEP 2144.05 teaches the obviousness of similar and overlapping ranges, amounts, and proportions. Furthermore, a change in shape is obvious absent persuasive evidence that the particular configuration is significant (See In re Dailey, 357 F.2d 669, 149 USPQ 47 (CCPA 1966)). Since the specification of the instant application has not shown the particular angle to be significant, it would be obvious to change the shape of the invention by adjusting the angle between the distal ends of the gas channel and fluid channel.
Regarding claim 7, Li does not teach wherein the angle is about 15±5 degrees.
Gentalen teaches wherein the angle is about 15±5 degrees (Fig. 1 shows gas channels 106 and 140 at an angle with confluence 126 (a fluid channel). The angle appears to be about or close to the claimed range. Additionally, changing the angle between the distal ends of the gas and fluid channels represents an obvious change in shape that does not establish patentability.)
Gentalen modifies Li by suggesting that the angle between the distal end of the fluid channel and the distal end of the gas channel is about 15±5 degrees.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teachings of Gentalen because although Gentalen does not explicitly specify the angle between 106/140 and 126, Figure 1 presents a configuration showing said angle, and this angle appears to be similar to the claimed range of about 15±5 degrees. MPEP 2144.05 teaches the obviousness of similar and overlapping ranges, amounts, and proportions. Furthermore, a change in shape is obvious absent persuasive evidence that the particular configuration is significant (See In re Dailey, 357 F.2d 669, 149 USPQ 47 (CCPA 1966)). Since the specification of the instant application has not shown the particular angle to be significant, it would be obvious to change the shape of the invention by adjusting the angle between the distal ends of the gas channel and fluid channel.
Regarding claim 15, Li teaches wherein the fluid channel has a width ranging from about 20 µm to about 600 µm ([0044] teaches dimensions of the analyte channel between 10 to 200 µm). Li renders the claimed invention obvious because “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.” See MPEP 2144.05 I.
Regarding claim 16, Li teaches wherein the fluid channel has a depth ranging from about 10 µm to about 100 µm ([0044] teaches dimensions of the analyte channel between 10 to 200 µm). Li renders the claimed invention obvious because “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.” See MPEP 2144.05 I.
Regarding claim 18, Li teaches wherein the electrospray ionization orifice has a substantially square, rectangular, circular, ovoid, or lozenge-shaped cross- section (spray tip 10 has a square cross-section as seen in Fig. 2).
Regarding claim 19, Li teaches wherein the electrospray ionization orifice has a maximum cross-sectional dimension ranging from about 10 µm to about 100 µm ([0044] teaches dimensions of the analyte channel between 10 to 200 µm). Li renders the claimed invention obvious because “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.” See MPEP 2144.05 I.
Regarding claim 20, Li teaches wherein the gas channel has a width ranging from about 20 µm to about 200 µm ([0044] teaches dimensions of the gas channel ranging from 10 µm to 200 µm). Li renders the claimed invention obvious because “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.” See MPEP 2144.05 I.
Regarding claim 21, Li teaches wherein the gas channel has a depth ranging from about 10 µm to about 100 µm ([0044] teaches dimensions of the gas channel ranging from 10 µm to 200 µm). Li renders the claimed invention obvious because “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.” See MPEP 2144.05 I.
Regarding claim 23, Li teaches wherein the gas outlet orifice has a substantially square, rectangular, circular, ovoid, or lozenge-shaped cross-section (see Fig. 2 which shows cross-section of gas outlet orifice having substantially ovoid or rectangular shape).
Regarding claim 24, Li teaches wherein the gas outlet orifice has a maximum cross-sectional dimension ranging from about 10 µm to about 50 µm ([0044] teaches cross-sectional dimension of the end of the gas channel of around 10 µm). Li renders the claimed invention obvious because “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.” See MPEP 2144.05 I.
Regarding claim 25, Li teaches wherein the gas outlet orifice is disposed within 100 µm of the electrospray ionization orifice ([0044] teaches the gas channel places 20 to 500 µm behind the end of the analyte channel). Li renders the claimed invention obvious because “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.” See MPEP 2144.05 I.
Regarding claim 26, Li teaches wherein the gas outlet orifice is disposed within 50 µm of the electrospray ionization orifice ([0044] teaches the gas channel places 20 to 500 µm behind the end of the analyte channel). Li renders the claimed invention obvious because “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.” See MPEP 2144.05 I.
Regarding claim 27, Li teaches/renders obvious wherein the gas outlet orifice is disposed within 15 µm of the electrospray ionization orifice ([0044] teaches the gas channel is placed 20 to 500 µm behind the end of the analyte channel. The dimension of 20 µm is similar to 15 µm such that the claimed dimension is obvious (See MPEP 2144.05 I). Further, in Fig. 2, the horizontal distance between the gas outlet orifice and electrospray ionization orifice appears to be smaller than the distance that the gas outlet orifice is behind the electrospray ionization orifice. Consequently, Fig. 2 shows that this horizontal dimension could be less than 20µm based on the description and figure. See also [0019]).
Regarding claim 28, Li teaches wherein the substrate is fabricated from glass, silicon, a polymer, or any combination thereof ([0039] teaches glass or polymer).
Claims 17 and 22 are is rejected under 35 U.S.C. 103 as being unpatentable over Li (US 20070257190 A1) in view of Gentalen (US 20170176386 A1) and Bajic (US 20160225601 A1), further in view of Yu, et. al. (C. Yu, X. Qian, Y. Chen, Q. Yu, K. Ni, X. Wang. Microfluidic self-aspiration sonic-spray ionization chip with single and dual ionization channels for mass spectrometry. RSC Adv. 2016. 6. 50180-50189.)
Regarding claim 17, Li in view of Gentalen and Bajic n does not explicitly teach wherein the fluid channel has a length ranging from about 0.25 cm to about 30 cm.
Yu teaches wherein the fluid channel has a length ranging from about 0.25 cm to about 30 cm (Fig. 1 shows the liquid and gas channels on the microfluidic chip. The zoomed in portion shown in the green box of Fig. 1 is on the micrometer scale, so it is clear that the full channel lengths would be on the centimeter scale. Additionally, the silicon wafer template of the microfluidic chip is disclosed to be 3 inches (see (1) of “Fabrication of the microfluidic chip), where 3 inches = 7.62 cm. Based on these dimensions, it is clear that the length of the fluid channel, which extends along a significant portion of the chip, would be within the claimed range.).
The combination renders the claimed invention obvious because “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.” See MPEP 2144.05 I.
Regarding claim 22, Lin in view of Gentalen and Bajic does not explicitly teach wherein the gas channel has a length ranging from about 0.2 cm to about 20 cm.
Yu teaches wherein the gas channel has a length ranging from about 0.2 cm to about 20 cm (Fig. 1 shows the liquid and gas channels on the microfluidic chip. The zoomed in portion shown in the green box of Fig. 1 is on the micrometer scale, so it is clear that the full channel lengths would be on the centimeter scale. Additionally, the silicon wafer template of the microfluidic chip is disclosed to be 3 inches (see (1) of “Fabrication of the microfluidic chip), where 3 inches = 7.62 cm. Based on these dimensions, it is clear that the length of the gas channel, which extends along a significant portion of the chip, would be within the claimed range.).
The combination renders the claimed invention obvious because “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.” See MPEP 2144.05 I.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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LAURA E TANDY
Examiner
Art Unit 2881
/DAVID E SMITH/Examiner, Art Unit 2881