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 Arguments
Applicant’s arguments, see Remarks page 8, filed 06 May 2026, with respect to the rejections under 112(b) have been fully considered and are persuasive in light of the claims. The 112(b) rejection of claims 7 – 12 has been withdrawn.
Applicant’s arguments, see Remarks page 8, filed 06 May 2026, with respect to the rejections of claims 7 – 10 under 35 U.S.C. 103 have been fully considered and are persuasive in light of amendments. Therefore, the rejection has been withdrawn. However, upon further consideration, a new grounds of rejection is made in view of Klas et al in view of Handique et al, and further in view of Matsumoto et al (US 20190301993 A1).
Regarding applicant’s amendment to independent claim 7 to recite “wherein […] the microfluidic channel is a single channel,” the examiner believes this to be an obvious modification of Klas et al, per MPEP 2144.04(II)’s recitation that elimination of an element and its function is obvious if the function is not desired. The prior art of both Klas et al and Handique et al use additional microfluidic channels to add sheath fluid or trigger fluid to the sample prior to entering the detection channel. If using additional fluids to modify the flow properties of a liquid is not desired, it would have been obvious to one of ordinary skill in the art to eliminate those additional channels.
Regarding applicant’s amendment to independent claim 7 to recite “a sample loading apparatus regulates the sample reservoir to stop loading the sample into the first end of the microfluidic channel” and “the sample loading apparatus regulates the sample flow to restart or to continue to flow in the microfluidic channel,” the examiner agrees that this step is not explicitly disclosed in the prior art previously made of record. Further search necessitated by this amendment returns the prior art of Matsumoto et al, which teaches a method of flow cytometry using discrete flow control, as discussed in the detailed rejection of amended claim 7.
Status of Claims
Applicant's amendments to the claims filed 06 May 2026 have been entered. Applicant's remarks filed 06 May 2026 are acknowledged.
Claims 7 and 11 are in status “Currently amended.” Claims 8 – 10 are in status “Previously presented.” Claims 1 – 7 and 12 are canceled.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 7 – 10 are rejected under 35 U.S.C. 103 as being unpatentable over Klas et al (US 20220163438 A1) in view of Handique et al (US 20190064168 A1, first cited in the office action dated 11 February 2025) and further in view of Matsumoto et al (US 20190301993 A1).
With regards to claim 7, Klas et al teaches;
The claimed “A method for detecting and collecting target biological particles” has been read on the taught ([0003], “…the present invention relates to systems and methods in a flow cytometer-based system for analyzing, handling, and processing fluids and components or particles in the sample.”);
The claimed “a liquid tank is provided for receiving the sample that is discharged from the second end of the microfluidic channel” has been read on the taught ([0197], “After processing, the fluid sample is collected in the automatic fluid collection system 14, or may automatically be diverted into a waste collection tube, reservoir, or container.”);
The claimed wherein the dilution apparatus further comprises “a sample tray assembly” has been read on the taught ([0025], “…the modular flow cytometry system may comprise […] a sample mixing and collection module…”; the sample mixing and collection module reads on a sample tray assembly.);
Klas et al does not explicitly teach a sample tray, but does teach a collection vessel in a sample tray assembly, as read on the taught ([0031], “…the sample mixing and collection module may comprise […] a set of collection tubes... One of the collection tubes can be positioned below the microfluidic chip such that the processed sample is collected in said collection tube.”);
Klas et al additionally teaches that the collection vessel may be filled prior to the addition of the sample, as read on the taught ([0354], “For example, the media may be buffered media that is in the tube prior to adding sample or added along with the sample.”);
“Wherein the second end of the microfluidic channel is distant to a liquid level of the diluter in the collection vessel” has been read on the taught ([0355], “The processed sample then drips, drops, or drains down, by operation of fluid pressure and/or gravity, through one or more channels or openings and into a sample collection tube.”; The sample dripping reads on the second end of the microfluidic channel being distant to a liquid level of the diluter.);
The claimed “providing a dilution apparatus” and “wherein the dilution apparatus comprises a microfluidic channel” have been read on the taught ([0026], “…the modular flow cytometry system for processing a sample may comprise […] a sample pathway module comprising a microfluidic module having at least one microfluidic channel…”);
The claimed wherein the dilution apparatus further comprises “a first optical detection module” has been read on the taught ([0025], “…the modular flow cytometry system may comprise […] an interrogation module…”; [0385], “… the interrogation module including a detector…”);
The claimed wherein “the microfluidic channel has a first end and a second end, wherein the first end of the microfluidic channel is connected to a sample reservoir” and “the sample in the sample reservoir flows into the microfluidic channel through the first end of the microfluidic channel and flows out through the second end of the microfluidic channel” have been read on the taught ([0239], “A channel 854 in the microfluidic module body 851 directs a sample fluid […] into a sample input 884, through a sample channel 885, into a common channel 886, through a detection region 887, and out through one or more outlets…”);
The claimed “providing a sample that contains the target biological particles by the sample reservoir” has been read on the taught ([0236], “In a flow cytometry system, when processing a biological fluid sample, the fluid 824 may be a semen sample, and the fluid reservoir 822 may be a sample tube.”);
The claimed “wherein the sample tray assembly comprises at least one sample tray for receiving a sample discharged through the second end of the microfluidic channel” has been read on the taught ([0236], “In a flow cytometry system, when processing a biological fluid sample, the fluid 824 may be a semen sample, and the fluid reservoir 822 may be a sample tube.”);
The claimed wherein “the first optical detection module provides a first optical pathway that penetrates through the microfluidic channel and is adapted to detect at least one of the target biological particles that passes through the microfluidic channel” has been read on the taught ([0334], “…one or more electromagnetic radiation emitters are directed at or to the chip using an optical pathway… The detection module collects or detects emissions from particles or components in the sample to identify one or more characteristics of the particles or components, such as an amount or type of DNA, and to provide feedback to the system and/or an operator.”);
The claimed “when the first optical detection module does not detect that the sample contains the target biological particles passing through the microfluidic channel, the sample is discharged from the second end of the microfluidic channel into the waste liquid tank” has been read on the taught ([0079], “Based on meeting a set of criteria or parameters, the processed sample is permitted to flow into a sample catch tube disposed on the sample mixing system or is diverted into a waste collection container.”; [0176], “Further examples of the automated features of the system include the auto-dump module which allows for the processed sample stream to be redirected to a waste collection…”);
“When the first optical detection module detects any of the target biological particles passing through the microfluidic channel, […] controlling the sample tray assembly to provide and move the collection reservoir to an opening of the second end of the microfluidic channel” has been read on the taught ([0335], “The actuator operates to move the diverter in or out of the path of a processed sample exiting the chip to either permit the sample to pass into a collection tube 5130 or to cause the sample to be diverted into a waste collection container or area.”; [0336], “The rotary base 5110 rotates in an arcuate path […] to rotate sample collection tubes on the base into a sample collection path.”);
“After a sample with the target biological particles passes through the microfluidic channel and the second end of the microfluidic channel, the target biological particles are loaded to the collection reservoir” has been read on the taught ([0335], “The actuator operates to move the diverter in or out of the path of a processed sample exiting the chip to either permit the sample to pass into a collection tube 5130…”).
While Klas et al does not explicitly teach “a diluter supplying device”, MPEP 2144.04(III) states that “… broadly providing an automatic or mechanical means to replace a manual activity which accomplished the same result is not sufficient to distinguish over the prior art.” As providing a diluter supplying device to load the sample tray with media prior to loading the target biological particles accomplishes the same result as loading the sample tray with diluter by hand, the claim language is not sufficient to distinguish the instant invention over the prior art of Klas et al.
While Klas et al does not explicitly teach wherein “the microfluidic channel is a single channel,” this modification to Klas et al would be obvious to one of ordinary skill in the art. According to MPEP 2144.04(II), elimination of an element and its function is obvious if the function is not desired; please see In re Larson, 340 F.2d 965, 144 USPQ 347 (CCPA 1965). Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the microfluidic device of Klas et al to have a single microfluidic reservoir rather than one which incorporates a sheath fluid, for the predictable benefit of simplified manufacturing.
However, Klas et al does not explicitly disclose a sample tray; providing a selectively capturing apparatus, wherein the selectively capturing apparatus comprises a second optical detection module and a capturing device; the at least one sample tray is controlled to move the selectively capturing apparatus and locate at a position where the second optical detection module corresponds to the at least one sample tray; the second optical detection module is adapted to scan, identify, and locate an accurate position of each of the target biological particles on the at least one sample tray; the capturing device is connected to the second optical detection module by a signal; after the second optical detection module locates the accurate position of each of the target biological particles on at the at least one sample tray, controlling the capturing device to move to the accurate position of each of the target biological particle and capture the target biological particle; the capturing device is controlled to load the target biological particle that is captured to a collection plate; or when the first optical detection module detects any of the target biological particles passing through the microfluidic channel, a sample loading apparatus regulates the sample reservoir to stop loading the sample into the first end of the microfluidic channel; and the sample loading apparatus regulates the sample flow to restart or continue to flow in the microfluidic channel.
In the analogous art of methods for detecting and collecting target biological particles, Handique et al teaches the following:
The claimed “a sample tray” has been read on the taught (Fig 3, substrate 110 including array of wells 120);
The claimed “providing a selectively capturing apparatus” has been read on the taught (Figure 1, system 100; Figure 21, method 200; After capturing the population of target cells, Block S210 can optionally include gathering information from […] and locating the captured cells in Block S216. Block S216 is preferably achieved using the imaging subsystem 194 described in Section 1, but can be achieved using any other method and/or component of the system 100.” System 100 reads on the selectively capturing apparatus.);
The claimed “wherein the selectively capturing apparatus comprises a second optical detection module” has been read on the taught (Figure 1, imaging subsystem 194; [0095], “The system 100 can additionally include an imaging subsystem 194 that functions to image the contents of the set of wells, and can further function to distinguish target objects […] captured in the set of wells from other cells or objects in the sample…”);
The claimed apparatus further comprising “a capturing device” has been read on the taught ([0101], "The system 100 can further include an extraction module (e.g., cell retrieval subsystem) that functions to extract at least one of a single cell and a cell cluster from a well 128 of the array.");
The claimed “the sample tray is controlled to move to the selectively capturing apparatus and locate at a position where the second optical detection module corresponds to the sample tray” has been read on the taught ([0114], “Block S210 recites receiving a population of target cells into an array of wells.” [0053] clarifies that receiving a population of target cells into an array of wells includes positioning the array of wells relative to system 100, “…the substrate 110 can be attached to a substrate platform 105 that functions to reversibly attach and align the substrate to a […] stage upon which assays are performed, wherein the stage can be used to physically adjust the position of the substrate within the system 100 to improve access of the array of wells to other elements of the system, such as the imaging subsystem 194.”);
The claimed “the second optical detection module is adapted to scan, identify, and locate an accurate position of each of the target biological particles on the sample tray” has been read on the taught ([0129], “After capturing the population of target cells, Block S210 can optionally include gathering information from the captured cells, including identifying, quantifying, and locating the captured cells in Block S216. Block S216 is preferably achieved using the imaging subsystem 194...”);
The claimed “the capturing device is connected to the second optical detection module by a signal” has been read on the taught ([0147], “…the extraction module can be used in operation with the imaging subsystem […] based on imaging feedback.” The imaging feedback reads on connection via a signal);
The claimed “after the second optical detection module locates the accurate position of each of the target biological particles on the sample tray, controlling the capturing device to move to the accurate position of each of the target biological particle and capture the target biological particle” has been read on the taught (Figure 18, block 230 recites “Re-distributing a subset of partially retained particles across the array of wells.”; [0129], “… Block S210 can optionally include […] locating the captured cells in Block S216… The information obtained in Block S216 can further be used to inform, modify, and/or adjust settings for subsequent or concurrent steps in method 200.” Block 230 is a subsequent step that can be modified with the location information; [0104] clarifies that the extraction module can move to the target particle, “The extraction module can be configured to facilitate advancement of a particle extractor to a well 128 containing a cell/particle cluster of interest, for instance, with an actuation subsystem.”; [0147] supports the step including the capturing device capturing the particle, “the extraction module can be used in operation with the imaging subsystem to retrieve one or more particles from a well...”);
The claimed “then, the capturing device is controlled to load the target biological particle that is captured to a collection plate” has been read on the taught (Figure 18, block 230, reads on loading a captured target biological particle to a new well among an array of wells. [0147] recites that the capturing device can be used for this purpose, “…the extraction module can be used in operation with the imaging subsystem to retrieve one or more particles from a well containing more than one particle and dispense them into another well containing no beads, based on imaging feedback.”; [0048] clarifies that the system can operate with multiple arrays of wells, “…the components of the system can be configured with any numerosity to accommodate any suitable number of arrays.”; Distribution one or more particles and dispensing them into another on a suitable number of arrays via the extraction module reads on the capturing device loading the target biological particle to a collection plate).
Handique et al additionally teaches that different reagents can be added at different times in a workflow in an automated fashion, as read on the taught ([0106], “According to one or more workflows, […] the correct types and volumes of materials (e.g., reagents/samples) are added to or removed from the sample processing cartridge at the correct times in an automated fashion.”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of particle separation of Klas et al with the method of particle separation as taught by Handique et al, in order to use a microfluidic method with an increased probability that a given droplet contains a single cell of interest from a sample (Nassef et al, [0172], “The microfluidic nature of the technology allows for the volume of a single collection droplet to be decreased. Minimizing the volume of the collection droplets increases the probability that a given droplet contains exactly one isolated particle.”) for efficient subsequent cell capture (Handique et al, [0004], “The system and method described herein address these limitations by integrating functions such as single-cell capture […] in order to enable more advanced biochemical processes to be performed on individual […] thereby vastly improving capture efficiency for desired cells…”).
However, Klas et al in view of Handique et al does not explicitly disclose when the first optical detection module detects any of the target biological particles passing through the microfluidic channel, a sample loading apparatus regulates the sample reservoir to stop loading the sample into the first end of the microfluidic channel; and the sample loading apparatus regulates the sample flow to restart or continue to flow in the microfluidic channel.
In the analogous art of flow cytometry particle detection methods, Matsumoto et al teaches;
The claimed “when the first optical detection module detects any of the target biological particles passing through the microfluidic channel, a sample loading apparatus regulates the sample reservoir to stop loading the sample into the first end of the microfluidic channel […] and the sample loading apparatus regulates the sample flow to restart or continue to flow in the microfluidic channel” has been read on the taught ([0026], “…the flow velocity measuring device 200 may measure the flow velocity based on the optical characteristics of the particles flowing through the flow cell 10.”; [0016], “The flow cytometer also includes a control unit 302 that causes the sample liquid to be fed to the flow cell 10 by the sample liquid feeding unit 20 when the information on the flow velocity satisfies the criterion, and does not cause the sample liquid to be fed to the flow cell 10 by the sample feeding unit 20 when the information on the flow velocity does not satisfy the criterion.”; The flow velocity measuring device based on particles reads on detecting target biological particles passing through the channel. The control unit feeding or not feeding sample liquid based on a criterion reads on regulating the sample reservoir to stop loading sample.”
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of particle detection and separation as taught by Klas et al in view of Handique et al with the flow control method taught by Matsumoto et al, for the predictable benefit of minimizing sample waste (Matsumoto et al, [0017], “According to the above flow cytometer, it is possible to control the sample liquid feeding unit 20 so that the sample liquid is not wasted.”).
With regards to claim 8, the method of claim 7 is obvious over Klas et al in view of Handique et al and further in view of Matsumoto et al.
Klas et al additionally teaches;
The claimed “wherein the first optical detection module comprises a first light source and a first optical detector” has been read on the taught ([0262], “The flow cytometry apparatus or microfluidic device may further comprise a laser configured to emit electromagnetic radiation along a beam path to the particle interrogation location and a detector configured to detect an emission from the particle.”);
The claimed “the first light source and the first optical detector are disposed at two planes that are not parallel to the microfluidic channel, respectively, so that the first optical pathway passes through the microfluidic channel” has been read on the taught ([0275], “With reference now to FIG. 25A, a block diagram of an opto-mechanical system 3400 for positioning a set of laser assemblies 3410 comprising a detection laser assembly 3430 […]on the opposite side of a detection assembly 3450... The opto-mechanical system 3400 is used to detect certain characteristics of particles […] passing through an action or interrogation area 3404 in a flow path 3402 of a flow cytometer system, such as in a channel of a microfluidic chip.”; Figure 25A shows that the light source 3430 and detection assembly 3450 are an opposite sides of microfluidic channel 3402.).
With regards to claim 9, the method of claim 7 is obvious over Klas et al in view of Handique et al and further in view of Matsumoto et al.
The prior art of Klas et al in view of Handique et al does not explicitly teach the claimed distances between the second end of the microfluidic channel, bottom surface of a slot on the at least one sample tray, height of the diluter, or distance between the second end of the microfluidic channel and the liquid level of the diluter. However, according to MPEP 2144.04(IV)(A), changes in size or proportion do not render a claimed invention distinct from the prior art device provided that “…a device having the claimed relative dimensions would not perform differently than the prior art device.” See In Gardner v. TEC Syst., Inc., 725 F.2d 1338, 220 USPQ 777 (Fed. Cir. 1984), cert. denied, 469 U.S. 830, 225 USPQ 232 (1984).
The specification of the instant application notes in [0024] that the only purpose of the recited dimensions is to avoid retaining the sample droplet on the end of the microfluidic channel, and to reduce the impact on biological particles when the droplet falls. Klas et al explicitly teaches that the channel drips into the collection vessel, as read on ([0355], “The processed sample then drips, drops, or drains down, by operation of fluid pressure and/or gravity, through one or more channels or openings and into a sample collection tube.”). Accordingly, the device as taught by Klas et al in view of Handique et al does not function differently than the claimed invention.
As such, the method of claim 9 is not distinct over Klas et al in view of Handique et al.
With regards to claim 10, the method of claim 7 is obvious over Klas et al in view of Handique et al and further in view of Matsumoto et al.
Klas et al additionally teaches;
The claimed “wherein a mixing device makes the target biological particle be evenly distributed in the at least one sample tray” has been read on the taught ([0354], “The dispensing instrument can dispense a sample into one of the collection tubes 5130 as the rotary base moves in the arcuate path. In a preferred embodiment, the collection tube 5130 receiving the sample remains under a dispensing path of the dispensing instrument as said collection tube 5130 moves in the arcuate path, thereby mixing the sample in the collection tube 5130. […] The media is mixed or agitated to maintain buffering and control a degree of buffering.”).
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Klas et al (US 20220163438 A1) in view of Handique et al (US 20190064168 A1, first cited in the office action dated 11 February 2025) in view of Vercruysse (US 20200018684 A1, first cited in the office action dated 11 February 2025) and further in view of Matsumoto et al (US 20190301993 A1).
With regards to claim 11, Klas et al teaches;
The claimed “A method for detecting and collecting target biological particles” has been read on the taught ([0003], “…the present invention relates to systems and methods in a flow cytometer-based system for analyzing, handling, and processing fluids and components or particles in the sample.”);
The claimed “providing a dilution apparatus” and “wherein the dilution apparatus comprises a microfluidic channel” have been read on the taught ([0026], “…the modular flow cytometry system for processing a sample may comprise […] a sample pathway module comprising a microfluidic module having at least one microfluidic channel…”);
The claimed wherein the dilution apparatus further comprises “a sample tray assembly” has been read on the taught ([0025], “…the modular flow cytometry system may comprise […] a sample mixing and collection module…”; the sample mixing and collection module reads on a sample tray assembly.);
Klas et al does not explicitly teach a sample tray, but does teach a collection vessel in a sample tray assembly, as read on the taught ([0031], “…the sample mixing and collection module may comprise […] a set of collection tubes... One of the collection tubes can be positioned below the microfluidic chip such that the processed sample is collected in said collection tube.”);
The claimed wherein the dilution apparatus further comprises “a first optical detection module” has been read on the taught ([0025], “…the modular flow cytometry system may comprise […] an interrogation module…”; [0385], “… the interrogation module including a detector…”);
The claimed wherein “the microfluidic channel has a first end and a second end, wherein the first end of the microfluidic channel is connected to a sample reservoir” and “the sample in the sample reservoir flows into the microfluidic channel through the first end of the microfluidic channel and flows out through the second end of the microfluidic channel” have been read on the taught ([0239], “A channel 854 in the microfluidic module body 851 directs a sample fluid […] into a sample input 884, through a sample channel 885, into a common channel 886, through a detection region 887, and out through one or more outlets…”);
The claimed “providing a sample that contains the target biological particles by the sample reservoir” has been read on the taught ([0236], “In a flow cytometry system, when processing a biological fluid sample, the fluid 824 may be a semen sample, and the fluid reservoir 822 may be a sample tube.”);
The claimed “a waste liquid tank is provided for receiving the sample that is discharged from the second end of the microfluidic channel” has been read on the taught ([0197], “After processing, the fluid sample is collected in the automatic fluid collection system 14, or may automatically be diverted into a waste collection tube, reservoir, or container.”);
The claimed wherein “the first optical detection module provides a first optical pathway that penetrates through the microfluidic channel and is adapted to detect at least one of the target biological particles that passes through the microfluidic channel” has been read on the taught ([0334], “…one or more electromagnetic radiation emitters are directed at or to the chip using an optical pathway… The detection module collects or detects emissions from particles or components in the sample to identify one or more characteristics of the particles or components, such as an amount or type of DNA, and to provide feedback to the system and/or an operator.”);
The claimed “when the first optical detection module does not detect that the sample contains the target biological particles passing through the microfluidic channel, the sample is discharged from the second end of the microfluidic channel into the waste liquid tank” has been read on the taught ([0079], “Based on meeting a set of criteria or parameters, the processed sample is permitted to flow into a sample catch tube disposed on the sample mixing system or is diverted into a waste collection container.”; [0176], “Further examples of the automated features of the system include the auto-dump module which allows for the processed sample stream to be redirected to a waste collection…”;
Regarding the limitation, “wherein the dilution apparatus comprises a diluter supplying device, the diluter supplying device adds a diluter into the at least one sample tray”;
Klas et al teaches that the collection vessel may be filled prior to the addition of the sample, as read on the taught ([0354], “For example, the media may be buffered media that is in the tube prior to adding sample or added along with the sample.”);
While Klas et al does not explicitly teach “a diluter supplying device”, MPEP 2144.04(III) states that “… broadly providing an automatic or mechanical means to replace a manual activity which accomplished the same result is not sufficient to distinguish over the prior art.” As providing a diluter supplying device to load the sample tray with media prior to loading the target biological particles accomplishes the same result as loading the sample tray with diluter by hand, the claim language is not sufficient to distinguish the instant invention over the prior art of Klas et al.
“Wherein the second end of the microfluidic channel is distant to a liquid level of the diluter in the collection vessel” has been read on the taught ([0355], “The processed sample then drips, drops, or drains down, by operation of fluid pressure and/or gravity, through one or more channels or openings and into a sample collection tube.”; The sample dripping reads on the second end of the microfluidic channel being distant to a liquid level of the diluter.);
“When the first optical detection module detects any of the target biological particles passing through the microfluidic channel, controlling the sample tray assembly to provide and move the collection reservoir to an opening of the second end of the microfluidic channel” has been read on the taught ([0335], “The actuator operates to move the diverter in or out of the path of a processed sample exiting the chip to either permit the sample to pass into a collection tube 5130 or to cause the sample to be diverted into a waste collection container or area.”; [0336], “The rotary base 5110 rotates in an arcuate path […] to rotate sample collection tubes on the base into a sample collection path.”);
The claimed “after a sample with the target biological particles passes through the microfluidic channel and the second end of the microfluidic channel, the target biological particles are loaded to the sample tray and the sample droplet discharged through the second end of the microfluidic channel could smoothly drip into the diluter” has been read on the taught ([0355], “The sample is inserted into the flow cytometer, is processed by one or more systems or elements of the flow cytometer, and is expelled through one or more outlets at a terminal end of the flow cytometer… The processed sample then drips, drops, or drains down, by operation of fluid pressure and/or gravity, through one or more channels or openings and into a sample collection tube.”; See also [0562], which clarifies that the microfluidic chip is part of the flow cytometry system and forms a sample pathway with an inlet and an outlet.);
While Klas et al does not explicitly teach wherein “the microfluidic channel is a single channel,” this modification to Klas et al would be obvious to one of ordinary skill in the art. According to MPEP 2144.04(II), elimination of an element and its function is obvious if the function is not desired; please see In re Larson, 340 F.2d 965, 144 USPQ 347 (CCPA 1965). Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the microfluidic device of Klas et al to have a single microfluidic reservoir rather than one which incorporates a sheath fluid, for the predictable benefit of simplified manufacturing.
However, Klas et al does not explicitly disclose a sample tray; providing a selectively capturing apparatus, wherein the selectively capturing apparatus comprises a second optical detection module and a capturing device; the at least one sample tray is controlled to move the selectively capturing apparatus and locate at a position where the second optical detection module corresponds to the at least one sample tray; the second optical detection module is adapted to scan, identify, and locate an accurate position of each of the target biological particles on the at least one sample tray; the capturing device is connected to the second optical detection module by a signal; after the second optical detection module locates the accurate position of each of the target biological particles on at the at least one sample tray, controlling the capturing device to move to the accurate position of each of the target biological particle and capture the target biological particle; the capturing device is controlled to load the target biological particle that is captured to a collection plate; when the first optical detection module detects any of the target biological particles passing through the microfluidic channel, a sample loading apparatus regulates the sample reservoir to stop loading the sample into the first end of the microfluidic channel; and the sample loading apparatus regulates the sample flow to restart or continue to flow in the microfluidic channel.
In the analogous art of methods for detecting and collecting target biological particles, Handique et al teaches the following:
The claimed “a sample tray” has been read on the taught (Fig 3, substrate 110 including array of wells 120);
The claimed “providing a selectively capturing apparatus” has been read on the taught (Figure 1, system 100; Figure 21, method 200; After capturing the population of target cells, Block S210 can optionally include gathering information from […] and locating the captured cells in Block S216. Block S216 is preferably achieved using the imaging subsystem 194 described in Section 1, but can be achieved using any other method and/or component of the system 100.” System 100 reads on the selectively capturing apparatus.);
The claimed “wherein the selectively capturing apparatus comprises a second optical detection module” has been read on the taught (Figure 1, imaging subsystem 194; [0095], “The system 100 can additionally include an imaging subsystem 194 that functions to image the contents of the set of wells, and can further function to distinguish target objects […] captured in the set of wells from other cells or objects in the sample…”);
The claimed apparatus further comprising “a capturing device” has been read on the taught ([0101], "The system 100 can further include an extraction module (e.g., cell retrieval subsystem) that functions to extract at least one of a single cell and a cell cluster from a well 128 of the array.");
The claimed “the sample tray is controlled to move to the selectively capturing apparatus and locate at a position where the second optical detection module corresponds to the sample tray” has been read on the taught ([0114], “Block S210 recites receiving a population of target cells into an array of wells.” [0053] clarifies that receiving a population of target cells into an array of wells includes positioning the array of wells relative to system 100, “…the substrate 110 can be attached to a substrate platform 105 that functions to reversibly attach and align the substrate to a […] stage upon which assays are performed, wherein the stage can be used to physically adjust the position of the substrate within the system 100 to improve access of the array of wells to other elements of the system, such as the imaging subsystem 194.”);
The claimed “the second optical detection module is adapted to scan, identify, and locate an accurate position of each of the target biological particles on the sample tray” has been read on the taught ([0129], “After capturing the population of target cells, Block S210 can optionally include gathering information from the captured cells, including identifying, quantifying, and locating the captured cells in Block S216. Block S216 is preferably achieved using the imaging subsystem 194...”);
The claimed “the capturing device is connected to the second optical detection module by a signal” has been read on the taught ([0147], “…the extraction module can be used in operation with the imaging subsystem […] based on imaging feedback.” The imaging feedback reads on connection via a signal);
The claimed “after the second optical detection module locates the accurate position of each of the target biological particles on the sample tray, controlling the capturing device to move to the accurate position of each of the target biological particle and capture the target biological particle” has been read on the taught (Figure 18, block 230 recites “Re-distributing a subset of partially retained particles across the array of wells.”; [0129], “… Block S210 can optionally include […] locating the captured cells in Block S216… The information obtained in Block S216 can further be used to inform, modify, and/or adjust settings for subsequent or concurrent steps in method 200.” Block 230 is a subsequent step that can be modified with the location information; [0104] clarifies that the extraction module can move to the target particle, “The extraction module can be configured to facilitate advancement of a particle extractor to a well 128 containing a cell/particle cluster of interest, for instance, with an actuation subsystem.”; [0147] supports the step including the capturing device capturing the particle, “the extraction module can be used in operation with the imaging subsystem to retrieve one or more particles from a well...”);
The claimed “then, the capturing device is controlled to load the target biological particle that is captured to a collection plate” has been read on the taught (Figure 18, block 230, reads on loading a captured target biological particle to a new well among an array of wells. [0147] recites that the capturing device can be used for this purpose, “…the extraction module can be used in operation with the imaging subsystem to retrieve one or more particles from a well containing more than one particle and dispense them into another well containing no beads, based on imaging feedback.”; [0048] clarifies that the system can operate with multiple arrays of wells, “…the components of the system can be configured with any numerosity to accommodate any suitable number of arrays.”; Distribution one or more particles and dispensing them into another on a suitable number of arrays via the extraction module reads on the capturing device loading the target biological particle to a collection plate).
However, Klas et al in view of Handique et al does not explicitly disclose wherein the second optical detection module comprises a second light source, a lens assembly, a photomultiplier, and a charge-coupled device; the second light source generates a second optical pathway and a third optical pathway; the second optical pathway is started from the second light source and passes through the at least one sample tray and the lens assembly to the photomultiplier; the third optical pathway is started from the second light source and passes through the at least one sample tray and the lens assembly to the charge-coupled device; wherein when the target biological particles absorb excitation light emitted by the second light source, the target biological particles emit an emission light; the emission light enters the charge-coupled device along the third optical pathway; the charge-coupled device receives the emission light and captures an image of the target biological particles that emit the emission light, wherein the emission light enters the second photomultiplier along the second optical pathway, after the second photomultiplier receives the emission light, the second photomultiplier records the intensity of the emission light of the target biological particles; when the first optical detection module detects any of the target biological particles passing through the microfluidic channel, a sample loading apparatus regulates the sample reservoir to stop loading the sample into the first end of the microfluidic channel; and the sample loading apparatus regulates the sample flow to restart or continue to flow in the microfluidic channel.
In the analogous art of devices for testing analytes which include optical detection modules, Vercruysse teaches the following:
The claimed “a sample tray” has been read on the taught (Figure 1, substrate 105; [0059], “The present invention includes a substrate integrating the means for providing analytes to the region of interest and the means for focusing and/or collimating radiation emanating from the region of interest.”);
The claimed “an optical detection module” has been read on the taught (abstract, “It is an object of embodiments of the present invention to provide a fast, reliable and compact optical detector…”) comprising;
The claimed “a light source” has been read on the taught ([0093], “The sensing system can be coupled to at least one irradiation source or radiation carrier for generating an excitation radiation beam for exciting the particles to be characterized.”);
The claimed “a lens assembly” has been read on the taught (Figure 1, lens system 120; [0060]; “In some embodiments, a lens system comprising different thin lenses (e.g. Fresnel lenses with different designs, thin film lenses) may be attached to a surface of the substrate.”);
The claimed “a detector including a photomultiplier” has been read on the taught (Figure 1, detector system 130; [0081], “Such suitable detectors may comprise […] photomultipliers (e.g. Si-PMT), etc.”);
The claimed “a detector including a CCD” has been read on the taught (Figure 1, detector system 130; [0081], “Such suitable detectors may comprise CCD pixels...”);
The claimed “a detector array comprising multiple detectors” has been read on the taught (Figure 2, detection system 230; [0068], “The particle sensor may then comprise a plurality of detectors for detecting different wavelengths.”; [0070], “…the optical system can be optimized to transmit […] different wavelengths […] towards a different detector, for example by adapting each lens to each wavelength and aligning each lens to a different detector.”);
The claimed “a second optical pathway started from the second light source and passes through the sample tray and lens assembly to the photomultiplier” has been read on the taught (Figure 2, deflected radiation 111, lens system 120; [0078], “A portion of this radiation travels downwards the transparent substrate 105 and encounters the […] lens system 120 … These lenses deflect radiation 111, 112 to each of the different detectors 131, 132 in a detection system…”; Figure 1 shows individual detectors 131 and 132.);
The claimed “a third optical pathway started from the second light source and passes through the sample tray and the lens assembly to the charge-coupled device” has been read on the taught (Figure 2, deflected radiation 112, lens system 120; [0078], “A portion of this radiation travels downwards the transparent substrate 105 and encounters the […] lens system 120 … These lenses deflect radiation 111, 112 to each of the different detectors 131, 132 in a detection system…”; Figure 1 shows individual detector 131 and 132.);
Please see annotated figure 2 below showing separate optical pathways as taught by Vercruysse.
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The claimed “wherein when the target biological particles absorb the excitation light emitted by the second light source, the target biological particles emit an emission light” has been read on the taught (Figure 1, excitation beam 100, analyte 109, radiation signal 110; [0003], “…detecting the labelled particles by irradiating them with an excitation source and detecting the fluorescent emission.”)
The claimed “the emission light enters the charge-coupled device along the third optical pathway” has been read on the taught (See annotated figure 2 above for schematic of third optical pathway; [0078], “These lenses deflect radiation 111, 112 to each of the different detectors 131, 132 in a detection system…”);
The claimed “the charge-coupled device receives the emission light and captures an image of the target biological particles that emit the emission light” has been read on the taught ([0081], “…the present invention allows obtaining fluorescent images of cells with subcellular resolution, by combination of fluorescent detectors and an excitation radiation adapted to illuminate the particles crossing the ROI with a predetermined resolution (e.g. a thin light sheet with a known thickness) and image the fluorescence received by the detectors… Such suitable detectors may comprise CCD pixels…”)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the second optical detection module as taught by Nassef et al in view of Handique et al in view of Spence et al with the fluorescence detection system as taught by Vercruysse, in order to make use of multiple fluorescent biomarkers for analytes of interest while reducing strain in the sensing system (Vercruysse, [0021], “In some embodiments adapted for fluorescence analysis of analytes attached to fluorescence biomarkers, different biomarkers and combinations thereof may be separately detected by each detector of the system, reducing strain in the sensing system…”).
However, Klas et al in view of Handique et al in view of Vercruysse does not explicitly disclose when the first optical detection module detects any of the target biological particles passing through the microfluidic channel, a sample loading apparatus regulates the sample reservoir to stop loading the sample into the first end of the microfluidic channel; and the sample loading apparatus regulates the sample flow to restart or continue to flow in the microfluidic channel.
In the analogous art of flow cytometry particle detection methods, Matsumoto et al teaches;
The claimed “when the first optical detection module detects any of the target biological particles passing through the microfluidic channel, a sample loading apparatus regulates the sample reservoir to stop loading the sample into the first end of the microfluidic channel […] and the sample loading apparatus regulates the sample flow to restart or continue to flow in the microfluidic channel” has been read on the taught ([0026], “…the flow velocity measuring device 200 may measure the flow velocity based on the optical characteristics of the particles flowing through the flow cell 10.”; [0016], “The flow cytometer also includes a control unit 302 that causes the sample liquid to be fed to the flow cell 10 by the sample liquid feeding unit 20 when the information on the flow velocity satisfies the criterion, and does not cause the sample liquid to be fed to the flow cell 10 by the sample feeding unit 20 when the information on the flow velocity does not satisfy the criterion.”; The flow velocity measuring device based on particles reads on detecting target biological particles passing through the channel. The control unit feeding or not feeding sample liquid based on a criterion reads on regulating the sample reservoir to stop loading sample.”
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of particle detection and separation as taught by Klas et al in view of Handique et al with the flow control method taught by Matsumoto et al, for the predictable benefit of minimizing sample waste (Matsumoto et al, [0017], “According to the above flow cytometer, it is possible to control the sample liquid feeding unit 20 so that the sample liquid is not wasted.”).
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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/ALISON CLAIRE GERHARD/ Examiner, Art Unit 1797 /LYLE ALEXANDER/ Supervisory Patent Examiner, Art Unit 1797
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