DETAILED ACTION
Election/Restrictions
Applicant's election with traverse of group II comprising claims 10-20 and species A comprising claim 14, in the reply filed on 07/23/2026 is acknowledged.
Applicant’s arguments traversing the lack-of-unity requirement have been considered but are not persuasive.
Applicant argues that Clime is “fundamentally incapable of adjusting an isopycnic surface of fractionated liquids,” and that Clime could not dispense Ficoll until a desired fraction is aligned with the extraction channel because the Ficoll would fall from above and disrupt the already-formed fractions. Applicant further argues that claims 1 and 10 are “strongly linked technologically, although not linguistically.”
These arguments are not persuasive because the lack-of-unity requirement did not rely on Clime as teaching the full method of claim 1, including the step of dispensing a medium until the desired fraction is aligned with the extraction channel. Rather, Clime was cited to show that the common subject matter shared by Groups I and II—namely, a fractionation column/separation chamber and a medium chamber/Ficoll storage—is known in the prior art and therefore does not constitute a “special technical feature” defining a contribution over the prior art. The original requirement explained that Group I and Group II commonly require a fractionation column and a medium chamber, but that those features are not special technical features in view of Clime’s separation chamber and Ficoll storage.
Applicant’s arguments regarding Clime’s inability to perform the pressure-controlled alignment step of claim 1 actually support the Office’s position. The feature that appears to distinguish Group I is the method step of operating an off-chip flow control to vary pressure to dispense a characterized-density medium into the column until a desired fraction is aligned with an extraction channel. However, that method step is not recited in claim 10 or the other Group II chip/system/kit claims. Claim 10 is directed to a chip structure having a fractionation column, extraction channel, transit chamber, medium chamber, ports, and hydrodynamic resistive element, and does not require operating the chip to vary pressure until a desired fraction is aligned with the extraction channel.
Nor does Applicant’s amendment to withdrawn claim 1 overcome the lack of unity. Although amended claim 1 now includes structural alternatives relating to a U-shaped column or distal coupling for receiving a higher-density medium, claim 1 still requires the pressure-controlled alignment operation, whereas claim 10 does not. The mere fact that claims 1 and 10 may share certain structural features does not establish unity unless those shared features are the same or corresponding special technical features. Here, the shared structural features do not define the contribution of both groups over the prior art; the pressure-controlled alignment operation is present in Group I but absent from Group II.
Accordingly, Group I and Group II remain not so linked as to form a single general inventive concept because they do not share the same or corresponding special technical feature. The lack-of-unity requirement is therefore maintained. The requirement is still deemed proper and is therefore made FINAL.
In a telephone interview on 08/03/2026, Applicant’s representative clarified that the statement in the Remarks electing “claim group I” was a typographical error, and that Applicant intended to elect Group II and Species A. This clarification is consistent with the claim listing, in which claims 1-9 are marked withdrawn and claims 10–20 remain pending for examination. Accordingly, claims 1-9 are withdrawn from consideration as drawn to non-elected Group I, and claim 15 is withdrawn from consideration as drawn to non-elected Species B. Claims 10-14 and 16-20 are examined as elected Group II, Species A.
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.
Claims 10, 13-14, and 16-20 are rejected under 35 U.S.C. 103 as being unpatentable over Clime et al. (Microfluidics and Nanofluidics, 2019) (Clime) in view of Veres et al. (US 2017/0036208) (Veres).
Regarding claim 10, Clime teaches a centrifugal microfluidic chip for mounting to a centrifuge for rotation about an axis of the centrifuge, the chip having a microfluidic network comprising a fractionation column extending between a proximal point and a distal point relative to the axis. Clime teaches using active pneumatic pumping technology “to separate blood components using density fractionation,” wherein a metered volume of density-gradient medium, Ficoll, is transferred into a separation chamber, blood is added into the separation chamber, and the blood is centrifuged to separate its components (Clime, p. 18, Fig. 12). Clime’s separation chamber corresponds to the claimed fractionation column because it receives the sample and density-gradient medium and separates the sample into density-based fractions during centrifugation.
Clime teaches an extraction channel meeting the column between the proximal and distal points, through which fluid is removed from the column, or blocked, during centrifugation, depending upon a pressure at a second port of the chip. Clime teaches that RBCs sediment beyond the position of the “plasma extraction channel” after about 10 minutes, and that a 250 µL plasma fraction located at the upper part of the separation chamber is transferred to an external container by applying air pressure (page 18, par 1).
Clime does not expressly teach all of the claimed pressure-port/chamber details. However, Veres teaches a centrifugal microfluidic chip controller having pressurized fluid supply lines coupled to chip ports (abstract). Veres teaches that the controller includes pressurized fluid supply lines ending at ports for sealed coupling to a chip port, with electronically controlled valves for selectively opening or closing the port to the pressure chamber(abstract). Veres further teaches that the valves are flow-control devices for selectively controlling delivery of the pressurized fluid supply through the port (par [0018]). Veres also teaches that the controller may be mounted to a centrifuge blade while concurrently mounting the microfluidic chip so that the mounting and chip are rotatable by the centrifuge (par [0020]).
Clime in view of Veres teaches a transit chamber having an ingress, and an egress coupled to the column, and a third port in fluid communication with the transit chamber. Veres teaches a reverse-flow pumping structure having two chambers, where fluid is forced through a bottom exit that communicates with a top chamber, and the top chamber is vented to prevent air-plug resistance (par [0093]). The top chamber of Veres corresponds to the claimed transit chamber, the bottom exit/inlet path corresponds to the ingress, the chamber outlet/fluid communication path corresponds to the egress, and the vent/pneumatic connection corresponds to the third port.
Clime in view of Veres teaches a first medium chamber operably coupled to a fourth port of the chip and to the ingress, such that a change in pressure at the fourth port relative to a pressure in the transit chamber can be used to draw fluid from the medium chamber into the transit chamber during centrifugation. Clime teaches a density-gradient medium reservoir containing Ficoll and transferring a metered 400 µL volume of Ficoll into the separation chamber (page 18, Fig. 12). Veres teaches applying pressure to a channel to move a liquid from a first reservoir connected with the channel to a second reservoir (par [0032]; claim 38). Veres further teaches that instead of pushing fluid, a pneumatic line can apply negative pressure, in which case fluid is pulled (par [0091]), and in reverse-flow pumping, negative pressure at the top-chamber vent can equivalently be used (par [0093]). Thus, it would have been obvious to use Veres’s pressure-controlled chamber/port arrangement to transfer Clime’s Ficoll medium from a medium chamber through an intermediate/transit chamber into the separation chamber during centrifugation.
Clime in view of Veres teaches a hydrodynamic resistive element between the column and medium chamber that limits flow therebetween during centrifugation. Veres teaches that liquid displacement in a rotating pneumatic microfluidic chip depends on applied pneumatic pressure, centrifuge rotation speed, liquid density, meniscus positions, and the hydraulic resistance of the fluidic path (Fig. 12, par [0090]. Veres further teaches a siphon/serpentine structure in which fluid is stably held regardless of centrifugation until pressure is supplied (par [0091]). These teachings correspond to or render obvious a hydrodynamic resistive element between the medium chamber and column for limiting flow during centrifugation until pneumatic actuation occurs.
Clime in view of Veres teaches the elected Species A alternative, wherein the transit chamber is coupled to the column axis distally of the extraction channel. Clime teaches that Ficoll density-gradient medium is transferred into the separation chamber and that the blood sample is layered on top of the Ficoll, while the plasma fraction is located at the upper part of the separation chamber and extracted through the plasma extraction channel (Fig. 12, page 18). Therefore, the density-medium supply path/transit path is on the axis-distal side of the plasma extraction region in Clime’s centrifugal separation arrangement.
It would have been obvious to one of ordinary skill in the art to modify Clime’s automated centrifugal blood-fractionation cartridge to use Veres’s pressure-controlled port, valve, vented chamber, and hydraulic-resistance-based flow-control structures. The motivation would have been to provide predictable, programmable, and independently controlled pneumatic transfer of density-gradient medium and extracted plasma during centrifugation, as suggested by Veres’s pressure-controlled centrifugal chip architecture. The combination merely applies Veres’s known pneumatic chip-control system for its intended purpose—controlling fluid movement in a rotating microfluidic chip—to Clime’s known automated density-fractionation cartridge.
Regarding claim 13, Clime in view of Veres teaches or suggests wherein a volumetric capacity of the medium chamber is at least half a volume of the column that lies axis proximal of the extraction channel. Clime teaches transferring a metered 400 µL volume of Ficoll density-gradient medium into a 1 mL separation chamber and later transferring a 250 µL plasma fraction from the upper part of the separation chamber (Fig. 12, page 18, par 0). It would have been obvious to size the density-medium chamber/reservoir to hold a volume sufficient to perform the intended density-gradient separation and plasma extraction, including a volume at least half of the relevant axis-proximal extraction region, because Clime expressly teaches selecting metered Ficoll and plasma volumes for the automated fractionation process.
Regarding claim 14, Clime in view of Veres teaches the chip of claim 10 as part of a centrifugal microfluidic system, wherein the supply chamber contains a medium having a density higher than that of an intended fractionated sample, and the transit chamber is coupled to the column axis distally of the extraction channel. Clime teaches Ficoll as the density-gradient medium, blood layered on top of the Ficoll, and plasma located in the upper part of the separation chamber for extraction through the plasma extraction channel (Fig. 12, page 18). Thus, Clime teaches the elected higher-density medium/distal-coupling species.
Regarding claim 16, Clime in view of Veres teaches the chip of claim 10 mounted to a microfluidic chip controller with respective pressurized fluid supply lines coupled to the second and fourth ports of the chip, and respective flow controllers for controlling pressures thereat, the microfluidic chip controller and chip being mountable to a centrifuge for rotation about an axis thereof. Veres teaches mounting a microfluidic chip control system and microfluidic chip to a centrifuge so that the chip and at least part of the control system rotate with the centrifuge, providing a pressurized fluid supply, coupling a pressurized fluid supply line to a chip port, and operating a flow-control device to selectively control pressure supplied to the chip (par [0020], claim 36). Veres also teaches multiple independently controlled valves and multiple pressure supply lines coupled to chip ports (par [0057]-[0059]).
Regarding claim 17, Clime in view of Veres teaches the mounted chip further comprising a camera and illumination equipment for imaging the chip during centrifugation, and a processor adapted to analyze the chip imaging to determine the isopycnic surface relative to the extraction channel in the column. Clime teaches extracting vertical color variations inside the separation chamber at regular intervals during centrifugation and using those image-derived variations to determine the temporal evolution of the separation process, including when RBCs sediment beyond the plasma extraction channel (page 18, par 1). Veres further teaches that sensors, including sensors for optical properties, may monitor chip operations and provide feedback for controlling chip operation, including flow control by valves (par [0027]).
Regarding claim 18, Clime in view of Veres teaches the chip of claim 10 in a kit with a supply of at least one medium of a characterized density of a desired isopycnic surface of a desired component to be extracted from a sample. Clime teaches a cartridge used with a supply of density-gradient medium, Ficoll, for extracting a desired plasma fraction from blood (Fig. 12, page 18). Veres also teaches a kit including a chip controller, tubing for connecting a microfluidic chip port with a supply line, a microfluidic chip, a centrifuge blade, and a centrifuge (par [0033]).
Regarding claim 19, Clime in view of Veres teaches the kit of claim 18 further comprising a centrifugal microfluidic chip controller with controllers for first and second pressurized fluid supplies, adapted for mounting the chip to a centrifuge, for spinning the chip and at least part of the controller on an axis of the centrifuge at a rate of at least 5 Hz. Veres teaches the chip controller and pressurized supply-line structure as discussed above. Clime teaches centrifuging the blood sample at 800 rpm (page 18, par 0), which corresponds to about 13.3 Hz and therefore satisfies the “at least 5 Hz” limitation.
Regarding claim 20, Clime in view of Veres teaches the kit of claim 19 assembled with the chip installed on the chip controller mounted to a centrifuge. Veres teaches mounting the microfluidic chip control system and microfluidic chip to the centrifuge so that the chip and at least part of the control system rotate together (par [0057]).
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Clime in view of Veres, and further in view of Banks (WO 2014/111721, IDS).
Regarding claim 11, Clime in view of Veres teaches the chip of claim 10, as discussed above, but does not expressly teach wherein the column is waisted, in that the column is narrower at the extraction channel than on average away from the extraction channel.
Banks teaches this feature. Banks teaches first and second separation chambers separated by a separation channel, and further teaches that the separation channel acts as a pinch-point to reduce liquid flow between the first and second separation chambers (page 3, lie 32-33). Banks also teaches that the pinch-point may be included in an embodiment having only one chamber by forming a narrow portion within the chamber. Banks further teaches that the separation channel or pinch-point reduces remixing of the fluid within the separation chambers after separation (page 3, line 33 to page 4, line 1).
It would have been obvious to modify Clime’s separation chamber/extraction-channel region to include the waisted/pinch-point geometry taught by Banks. The motivation would have been to reduce remixing after separation and improve extraction precision at the desired extraction location, as suggested by Banks.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Clime in view of Veres, and further in view of Moen et al. (PLOS One, 2016) (Moen).
Regarding claim 12, Clime in view of Veres teaches the chip of claim 10, as discussed above. Clime further teaches programmable liquid mixing and aliquoting using three dispensing reservoirs, a mixing chamber, and aliquot reservoirs, where the volumes dispensed from three different reservoirs are programmed, mixed, and transferred while the platform is rotating at high speed (page 14, Fig. 8). Clime further teaches that all liquid displacements are triggered by controlled air pressure and that arbitrary mixtures can be created from the three dispensing reservoirs (page 14). Veres similarly teaches a chip used to generate mixtures from up to three liquids using input reservoirs, independent pneumatic lines, a mixing chamber, constriction channels for controlled flow, and pressure-pulse control for precise volume transfer (par [0110]-[0111], Fig. 15).
To the extent Clime and Veres do not expressly identify the mixed liquids as density media having different densities, Moen teaches using multiple density media for centrifugal blood fractionation. Moen teaches a disk divided into eight lanes, each lane having five discrete density sections with ports for introducing density gradients and removing sample (page 2, Fig. 1). Moen further teaches that each section in the disk has a discrete density medium, and that sample constituents travel through the discrete density sections during centrifugation (page 4).
It would have been obvious to provide Clime’s centrifugal density-fractionation chip, as controlled by Veres, with multiple medium chambers or a mixing chamber coupled to multiple medium chambers for producing density media of different densities, as taught by Moen. The motivation would have been to provide selectable or programmable density-gradient media for separating different blood components while retaining Clime and Veres’s automated pressure-controlled centrifugal platform.
Conclusion
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/XIAOYUN R XU, Ph.D./ Primary Examiner, Art Unit 1797
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