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 .
Response to Amendment
The Amendment filed 12/04/2025 has been entered. Claims 1-3, 7-21 remain pending in the application. Claims 13-20 are previously withdrawn and claims 4-6 are previously canceled. Claims 1-3, 7-12, and 21 are examined herein.
Status of Objections and Rejections
The objection to the drawings has been withdrawn.
The rejection of claims 1-3, 9, and 21 under 35 U.S.C. 103 as being unpatentable over Yasuda in view of Adamopoulou is maintained. The rejection of claims 7-12 is maintained based upon dependency of all of the limitations of claim 1.
Response to Arguments
Applicant’s arguments, see pp. 6-7, filed 12/04/2025, with respect to the objection to the drawings have been fully considered and are persuasive. The rejection of the drawings has been withdrawn.
The Applicant references the instant specification to describe how Figs. 12A-12G depict layering of the claimed device from a base plate, followed by the mixing device and injection device. Applicant argues that these figures clearly show the connection points between outlets of the injection device and the inlets of the mixing device.
The Examiner agrees.
The instant claims seem to describe the injection device configuration of that in Figs. 3-4 and the mixing device of Figs. 9-11. The layered pattern structurally depicts how the injection device outlets, Si, lay above and connect to the inlets of the serpentine mixing device as shown in the transition from Figs. 12D-12E. Although the inlets are not shown on the mixing device of the drawings, the instant publication (US 20220119443 A1) states that there can simply be holes on the injection device and mixing device that are put into contact with one another and serve as the outlets and inlets ([0113]). Applicant’s explanation of the layout of the drawings is therefore persuasive and the rejection of the drawings has been withdrawn.
Applicant’s arguments, see pp. 7-12, filed 12/04/2025, with respect to the rejection of claims 1-3, 9, 21 under 35 U.S.C. 103 as being unpatentable over Yasuda et. al (US 20080087336 A1), in view of Adamopoulou (“Experimental and numerical study of band-broadening effects associated with analyte transfer in microfluidic devices for spatial two-dimensional liquid chromatography created by additive manufacturing”; 2019), have been fully considered but they are not persuasive.
Applicant argues (p. 8), that the injection device of Yasuda has two injection channels with two inlets. Applicant states that the first channel has an inlet 621a with four transportation paths and four outlets 101a, 102a, 103a, and 104a, and the second channel has an inlet 621b with four transportation paths and four outlets 101b, 102b, 103b, and 104b as shown in Figs. 3A-3C. Applicant therefore asserts that “The injection device of the present invention comprising an injection channel differs from the injection device of Yasuda, at least in that the injection channel is provided with at least one inlet for a precipitation agent composition and a plurality of outlets on the external surface of the injection channel grouped as distinct injection zones distributed along the injection channel. This is because this claim feature requires that the outlets (grouped as distinct injection zones) should belong to the same injection channel”.
The Examiner respectfully disagrees.
The Examiner describes the inlet 621 (which includes both inlets 621a and 621b) to be the inlet of the injection channel, the injection channel to be transportation paths L11-L14(…L1N) of both rows of the injection device, and the plurality of outlets to be 101a-104a and 101b-104b from both rows of the injection device. The Applicant references Fig. 3B which shows a cross section of the top row of the injection device in 3A and interprets the associated inlet in Fig. 3B to be from 621a only. However the inlet in Fig. 3B is clearly labeled “621,” which can therefore be representative of either row. The Examiner therefore links branching paths L11-L14(…L1N) from the combined rows to be the injection channel with at least one inlet (621a or 621b), a first and second outlet (e.g. 101a and 102a), and two or more distinct zones (e.g. 101a and 101b). The injection channel is functionally capable of satisfying the intended use of receiving a precipitation agent composition (See MPEP 2114)(Yasuda, [0002]). The injection device of Yasuda therefore meets the limitations of claim 1.
Applicant argues (p. 10), “The device of Adamopoulou for liquid-phase chromatography consists of three parts with specific geometries (part. 1, introduction p.78), which are intended to cooperate together. This is further illustrated by the microfluidic device being produced as a single piece by 3D printing (Figure 2 in the article, and Figure 1 in Supporting Information). Thus, it would not be obvious for the skilled person to extract only one part of the microfluidic device of Adamopoulou (i.e. the flow distributor) and couple it with the injection device of Yasuda. Adamopoulou is directed to a fully integrated device”.
“Furthermore, Yasuda describes an embodiment in which the first fluid and the second fluid flow through the injection device (1007, Fig. 12). Both liquids combine and mix with each other in the reaction vessel (1008, Fig. 12), located in the lower part of the injection device (paragraph [0140], p. 8). The mixture is then collected in a recovery tank 1010 (paragraph [0141], p. 8). Therefore, the injection device of Yasuda is not intended to be combined with a mixing device as claimed and there would be no reason for the skilled person to artificially couple the device of Yasuda with only part of the device of Adamopoulou.
In response to applicant's argument that it would not be obvious to combine the injection device of Yasuda with only the mixing device of Adamopoulou since the apparatus of Adamopoulou is 3D printed as a single device, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
The Examiner respectfully disagrees.
Modifying the injection device of Yasuda by guiding its outlets to the inlets of the mixing device of Adamopoulou would still be expected to yield the predictable results of an even more uniformly distributed mixture of fluids downstream. Fig. 12 of Yasuda shows the injection device 1007 spraying and mixing the fluids from outlets (e.g., 101a, 101b) into a reacting vessel 1008. There is no structure between the outlets of the injection device and the inlet of the reaction vessel 1008 (Yasuda, [0140]). One of ordinary skill in the art would have recognized that providing channels like the mixing device from Adamopoulou would help to guide the mixture and create even more uniformity of the fluids due to turbulent velocity within the channels of the mixing device. The fluid streams of Yasuda are already positioned in a vertical flow path which is in the same orientation as the mixing device channels 2D of Adamopoulou. Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to have combined the two references to provide a more structured apparatus for maximum fluid mixing (See MPEP 2143(I)(A)).
Applicant argues (p. 10-11), “Yasuda and Adamopoulou are not analogous art. It cannot be the case that any and all devices wherein liquids flow are deemed analogous. The purpose of Yasuda is to process fluids which react and produce solid matter when mixed (paragraph [0002]). In contrast, Adamopoulou relates to a liquid chromatography device; accordingly, what is considered by the examiner to be the mixing channel in Adamopoulou is in fact intended to be filled with a stationary phase to induce chromatographic separation. These are two entirely different contexts, and this is an
additional reason why the skilled person would not combine Yasuda with Adamopoulou without the benefit of hindsight.
In response to applicant's argument that Adamopoulou is nonanalogous art, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, Adamopoulou is in the same field of endeavor for flow dynamics and analyte transfer in a microfluidic device (Title and Abstract). Yasuda and Adamopoulou also solve the same technical problem of flow distribution from a branched upper stream to a downstream structure. Additionally, the device of Yasuda is not limited to the intended use of reacting and producing solid matter; Yasuda states there to be an alternative motivation which is to simply uniformly mix two fluids ([0018]). Additionally, the Examiner does not rely upon Adamopoulou to teach the stationary phase packing but rather only to teach a mixing device channeling structure with a compatible interface to an injection channel. Adamopoulou even demonstrates that fluid flow mixing can still occur between both devices when there is no stationary phase present (simulations were conducted for both an empty 1D channel and for a 1D channel containing a stationary-phase material; (p. 79, col. 1, ll. 3-4)(See Fig. 6). Therefore, the combination of Yasuda’s injection device and Adamopoulou’s mixing device would have yielded the predictable result of uniformly mixed fluids.
Applicant argues (p. 11), “The apparatus of Adamopoulou comprises a number of outlets evenly spaced along the external surface of the mixing channel (Figure 1A), while the injection device of Yasuda
includes two rows of outlets (Fig. 3A). Therefore, if the injection device of Yasuda were to be coupled with the mixing device of Adamopoulou, the skilled person would obtain an apparatus wherein each of the plurality of outlets of the injection device is not connected to a respective secondary inlet of the plurality of secondary inlets of the mixing channel (as required by claim 1). In fact, only one row of outlets of the injection device of Yasuda would be connected to inlets of the mixing channel of Adamopoulou.
The Examiner respectfully disagrees.
Under broadest reasonable interpretation, the claim language of “respective secondary inlet” allows multiple injection device outlets to connect to one mixing device inlet. For example, Fig. 12 of Yasuda shows the injection device 1007 outputting two fluid streams at opposing angles that come together to form one mixture stream. This would correspond to both fluids from outlets 101a and 101b of Fig. 3B. After a combined stream is created from the two outlets, the respective mixing device inlet would accommodate this single stream. This pattern would then repeat for outlets 102a and 102b with the next mixing device inlet. The instant publication (US 20220119443 A1) does not demonstrate the criticality of a one-to-one outlet/inlet connection that would yield unpredictable results ([0037]). Uniform fluid distribution would also be expected when combining the devices of Yasuda and Adamopoulou and a person of ordinary skill in the art would have been motivated to make the combination (See MPEP 2143(I)(A)).
In conclusion, the rejection of claim 1 under 35 U.S.C. 103 is maintained. The rejection of claims 7-12 is maintained based upon dependency of all of the limitations of claim 1.
Claim Interpretation
The claims contain limitations which are directed to intended uses or capabilities of the claimed invention. These limitations are only given patentable weight to the extent which effects the structure of the claimed invention. Please see MPEP 2114. Note that functional limitations are emphasized in italics herein.
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 1-3, 9, 21 are rejected under 35 U.S.C. 103 as being unpatentable over Yasuda et. al (US 20080087336 A1), in view of Adamopoulou (“Experimental and numerical study of band-broadening effects associated with analyte transfer in microfluidic devices for spatial two-dimensional liquid chromatography created by additive manufacturing”; 2019).
Regarding claim 1, Yasuda teaches an apparatus (a fluid-processing apparatus; [0084]; Figs. 3A-3C) for the purification of biomolecules (the fluid-processing apparatus is functionally capable of purifying biomolecules), comprising:
- an injection device (The apparatus illustrated in FIGS. 3A and 3B; [0079]) comprising an injection channel (branching transportation paths; [0080]; L11-L14(…L1N) in Fig. 3B), the injection channel being provided with at least one inlet (inlet 621; [0080]) for a precipitation agent composition (the inlet is functionally capable of receiving a precipitation agent composition) and a plurality of outlets (101a-102a and 101b-102b; See Fig. 3A) on an external surface of the injection channel (Figs. 3A-3C; [0081]-[0094] discloses outlets (101a-102a and 101b-102b) formed in a nozzle substrate (131-132) that terminate at the external face of the substrate (135), thereby being located on the external surface of the injection channel and configured to discharge fluid to the outside environment),
subsets of the plurality of outlets (See the columns of outlets in Fig. 3A) grouped as distinct zones distributed along the injection channel (Zone 101a-101b, Zone 102a-102b in Fig. 3A), wherein
(i) the injection device comprises two or more distinct zones (See the sections of Fig. 3A that include “a pair of the outlets (for instance 101a and 101b,” and 102a-102b),
(ii) each distinct zone comprises two or more outlets (101a-101b and 102a-102b),
(iii) each outlet has a geometric center (the geometric center is the midpoint between the two outlets in each zone in Fig. 3A),
(iv) each outlet of the plurality of outlets is located such that a maximum distance between geometric centers of any two outlets within a given zone is less than a minimum distance between geometric centers of a first outlet and a second outlet of the plurality of outlets, where the first outlet belongs to the given zone and the second outlet belongs to any distinct zone different from the given zone (See Fig. 3A, which shows a shorter distance between 101a and 101b than between 101a and 102a, for example).
Yasuda is silent to teaching:
- a mixing device comprising a mixing channel provided with at least one main inlet for a composition to be purified and at least one main outlet, as well as a plurality of secondary inlets;
wherein the injection device and the mixing device are coupled such that each of the plurality of outlets of the injection device is connected to a respective secondary inlet of the plurality of secondary inlets of the mixing channel.
Adamopoulou teaches:
- a mixing device (See 1D in, 1D channel, 1D out, and 2D out in Fig. 1A) comprising a mixing channel (1D channel; Fig. 1A) provided with at least one main inlet (1D in; Fig. 1A) for a composition to be purified (the main inlet is functionally capable of receiving a composition to be purified since a “1D injection” is possible; page 79, line 18) and at least one main outlet (1D out; Fig. 1A), as well as a plurality of secondary inlets (Fig. 1A shows 8 junctures between the flow distributor and the 1D channel where the outlets of the flow distributor meet the secondary inlets to the 1D channel);
wherein the injection device (2D in and flow distributor of Fig. 1A) and the mixing device (See 1D in, 1D channel, 1D out, and 2D out in Fig. 1A) are coupled such that each of the plurality of outlets of the injection device is connected to a respective secondary inlet of the plurality of secondary inlets of the mixing channel (Fig. 1A shows 8 junctures between the flow distributor and the 1D channel where the outlets of the flow distributor meet the secondary inlets to the 1D channel).
Adamopoulou is considered to be analogous to the claimed invention because it is in the same field of endeavor for flow dynamics and analyte transfer in a microfluidic device (Title and Abstract). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have coupled the injection device taught by Yasuda with the mixing device taught by Adamopoulou in order to provide uniform fluid injection into a structured downstream distribution network for better analyte transfer. Yasuda ensures equalized pressure and uniform injection across multiple outlets (Abstract) while Adamopoulou teaches how to direct such distributed flows into parallel planar (1D) and stacked (2D) channels to achieve efficient mixing and analyte separation (Abstract, Fig. 1A). One of ordinary skill would have been motivated to combine these elements because it represents a predictable use of known components to improve uniformity and scalability of mixing devices in fluid purification systems, each functioning the same as they would separately (See MPEP 2143(I)(A)).
Regarding claim 2, Modified Yasuda teaches the apparatus according to claim 1, wherein the injection channel comprises from 2 to 40 outlets (see 4 outlets 101a-102a and 101b-102b in Fig. 3B).
Regarding claim 3, Modified Yasuda teaches the apparatus according to claim 2, wherein the injection channel comprises from 2 to 20 outlets (see 4 outlets 101a-102a and 101b-102b in Fig. 3B).
Regarding claim 9, Modified Yasuda teaches the apparatus according to claim 1, comprising only one pump connected to the injection device (“a fluid is introduced into a branching path formed in a branching path substrate 131 through a tube connector 129a with a pump,” wherein 129a of Fig. 2 corresponds to 621a of Fig. 3 as a part of the injection device).
Regarding claim 21, Modified Yasuda teaches the apparatus according to claim 1, wherein the injection device further comprises one or more isolated outlets on the external surface of the injection channel (104a or 104b would be isolated since they are furthest away from injector 621 as shown in Fig. 3B. This is consistent with the description of “isolated” in paragraph [0083] of the instant specification).
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Yasuda et. al (US 20080087336 A1), in view of Adamopoulou (“Experimental and numerical study of band-broadening effects associated with analyte transfer in microfluidic devices for spatial two-dimensional liquid chromatography created by additive manufacturing”; 2019), as applied to claim 1 above, and in further view of Masoudi et al. (US 20210349065 A1, claiming benefit to provisional application US63022965 with an EFD of 20200511).
Regarding claim 7, Modified Yasuda teaches the apparatus according to claim 1.
Modified Yasuda fails to teach the mixing device is configured as a coiled conduit.
Masoudi teaches a coiled conduit (a channel having an essentially helical flow path 11; [0081]; Figs. 4-5).
Masoudi is considered to be analogous to the claimed invention because it is in the same field of endeavor for flow dynamics and analyte transfer in a microfluidic device ([0003],[0241]). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the mixing device taught by Yasuda in view of Adamopoulou by substituting the 2D outlet channels (Adamopoulou, Fig. 1A) with the coiled conduits taught by Masoudi in order to intensify mixing efficiency at laminar flow conditions ([0134],[0131]). One of ordinary skill in the art would have recognized that replacing Adamopoulou’s straight channels with Masoudi’s coiled conduits would be a predictable way to improve mixing uniformity of the injected streams since “dean vortices are known to be good mixers” (Masoudi, [0131])(See MPEP 2143(I)(B)).
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Yasuda et. al (US 20080087336 A1), in view of Adamopoulou (“Experimental and numerical study of band-broadening effects associated with analyte transfer in microfluidic devices for spatial two-dimensional liquid chromatography created by additive manufacturing”; 2019), as applied to claim 1 above, and in further view of Tonkovich et al. (US 20070246106 A1).
Regarding claim 8, Modified Yasuda teaches the apparatus according to claim 1.
Modified Yasuda fails to teach the mixing channel is formed of a plurality of intersecting linear segments.
Tonkovich teaches a plurality of intersecting linear segments (flow distribution channel; Title; [0112]; Table 1; Fig. 16).
Tonkovich is considered to be analogous to the claimed invention because it is in the same field of endeavor for flow distribution in a microfluidic device (Title, Abstract). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the mixing device taught by Yasuda in view of Adamopoulou by substituting the 1D channel (Adamopoulou, Fig. 1A) with the intersecting linear segments channel taught by Tonkovich in order to equalize flow distribution and promote efficient mixing in processing manifolds (Tonkovich, [0004]]). Making this substitution would yield the predictable result of “uniform flow distribution” using well known serpentine or intersecting linear segment channeling (Tonkovich, [0006])(See MPEP 2143(I)(B)).
Claims 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Yasuda et. al (US 20080087336 A1), in view of Adamopoulou (“Experimental and numerical study of band-broadening effects associated with analyte transfer in microfluidic devices for spatial two-dimensional liquid chromatography created by additive manufacturing”; 2019), as applied to claim 1 above, and in further view of Jung et al. (US 20080181821 A1).
Regarding claim 10, Modified Yasuda teaches the apparatus according to claim 1.
Modified Yasuda teaches the fails to teach a set comprising at least one biomolecule and at least one impurity, and a composition comprising at least one precipitation agent.
Jung teaches a set (System 100; [0106]; Fig. 1) comprising at least one biomolecule (antibodies may be coupled to a substrate within a microfluidic chip 108; [0138]; Fig. 1) and at least one impurity (antibody fragments; [0147]), and a composition comprising at least one precipitation agent (“reagents used for polypeptide precipitation,” wherein “microfluidic chips 108 may include one or more reagent inputs 114”; [0106][0082];Fig. 1).
Jung is considered to be analogous to the claimed invention because it is in the same field of endeavor for practical applications of a microfluidic device. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the injection-mixing apparatus of Yasuda in view of Adamopoulou with the sample-reagent processing system of Jung in order to achieve predictable purification of biomolecules on-chip. Such a combination merely applies known reagents, biomolecules, and impurity handling methods in a known apparatus for their established functions, yielding the expected result of impurity removal from biomolecules (See MPEP 2143(I)(A)).
Regarding claim 11, Modified Yasuda teaches the set according to claim 10, wherein the biomolecule is chosen from a protein and a nucleic acid (“aptamers that are immobilized on an array,” wherein “aptamers may include polynucleotides (e.g., deoxyribonucleic acid; ribonucleic acid”; [0113];120 of Fig. 1) and/or wherein the impurity is chosen from double stranded DNA, host cell proteins, high molecular weight impurities, low molecular weight impurities, and antibody fragments, or aggregates; and/or wherein the precipitation agent is chosen from caprylic acid, polyethylene glycol, calcium chloride, zinc chloride, ethanol, isopropanol and combinations thereof.
Regarding claim 12, Modified Yasuda teaches the set according to claim 11, wherein the biomolecule is an antibody (antibodies may be coupled to a substrate within a microfluidic chip 108; [0138]; Fig. 1).
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 extension fee 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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/V.S./Examiner, Art Unit 1758
/MARIS R KESSEL/Supervisory Patent Examiner, Art Unit 1758