DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claims 1, 2, 4, 6-17, 19-27 and 29-32 are pending.
Election/Restrictions
Applicant’s election of Species in the reply filed on 05/27/2025 is acknowledged.
Applicant’s election of species of:
Species Election I: Species a, opposite substrate configuration - the SPR sensor surface is disposed at the first substrate, and the plurality of reaction electrodes are disposed at the second substrate opposite the first substrate (claim 11);
Species Election II: Species b, Chemical Coupling (claim 30)
Species Election III: Species b, between two or multiple surfaces configuration - the SPR sensor surface is disposed between a first reaction electrode and a second reaction electrode. (Claims 19-23)
Species Election III(b): Species b2: circular oscillation (claim 23)
as the species election in the reply filed on 05/27/2025, without traverse, is further acknowledged.
Interview Summary - Clarification of Elected Species
A telephonic interview was conducted on 05/06/2026 with Applicant to clarify a potential structural conflict regarding the species elected in the reply filed on 05/27/2025.
Initially, the Examiner noted that the elected structural configuration of Species I(a) (electrodes on an opposite substrate from the sensor, as in claim 11) and Species III(b) (the sensor is disposed between the electrodes, as in claims 19-23) appeared to represent mutually exclusive species under MPEP § 806.04(e).
During the interview, Applicant clarified that the "between" language in claims 19-23 does not require the sensor and electrodes to be on the same plane. Applicant explained that, as depicted in the top-down view of Figure 6, the SPR sensor surface can sit laterally "between" the reaction electrodes while remaining vertically separated on an opposite substrate (as depicted in Figure 5A).
Applicant further clarified that the truly conflicting "adjacent" or coplanar configuration (where the sensor and electrodes share the exact same substrate) corresponds to withdrawn claim 12, which remains properly withdrawn.
With this clarification on the record, the Examiner agrees that the elected configurations of Species I(a) and Species III(b) are not mutually exclusive. Therefore, the prosecution of the case will proceed on the merits with the elected species encompassing claims 11 and 19-23, interpreted such that the "between" spatial relationship in claims 19-23 encompasses the "opposite surface" configuration of claim 11.
The Examiner thanks Applicant for their time and the helpful clarification of the instant embodiments.
Applicant has withdrawn the claims based on the non-elected species.
Applicant’s reply does include an identification of the claims reading on the elected species. However, and additionally, as Applicant has elected the above species, claims 1, 2, 4, 6-11, 19, 20, 22, 23, 24-27 and 29-32 read on the elected species.
Claims 12-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election has been treated as an election without traverse in the reply filed on 05/27/2025 as noted above.
Claim(s) 12-17 has/have been withdrawn. Claim(s) 3, 5, 18, 28, and 33-86 has/have been canceled. Claims 1, 2, 4, 6-11, 19, 20, 22, 23, 24-27 and 29-32 are subject to examination below.
Priority
The present application was filed on 03/24/2021. Acknowledgment is made of the present application as a proper National Stage (371) entry of PCT Application No. PCT/IB20/19057540, filed 09/06/2019, which claims benefit under 35 U.S.C. 119(e) to priority provisional application. No. 62/727,934, filed on 6 Sep. 2018 and to and to provisional application No. 62/854,103, filed on 05/29/2019.
Information Disclosure Statement
The Information Disclosure Statement(s) (IDS), entered on Apr 20 2021, Oct 30 2024, and Apr 23 2025 is/are in compliance with the provisions of 37 CFR 1.97 and has/have been considered in full/part. A signed copy of list of references cited from the/each IDS is included with this Office Action.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(B) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim(s) 1, 2, 4, 6-11, 19, 20, 22, 23, 24-27 and 29-32 is/are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 1 recites the limitation(s) "disposed in relation to the plurality of actuators" in line(s) 5. This/these recitation(s) render(s) the claim indefinite, it is unclear what the structural relationship the claim intends to comprise, the recitation fails to specifically define what is the structural relation of the sensor media to the plurality of actuators, the specification does not further define what the "disposed in relation" intends to comprise.
Claim 1 recites the limitation(s) "the plurality of droplet actuators are operative to induce movement of the fluid droplet relative to the sensor media while in contact with the sensor media" in line(s) 6-7. This/these recitation(s) render(s) the claim indefinite, it is unclear what the structural relation between the recited components are, in other words it is unclear how the fluid droplet is structurally or specially defined “relative to” the sensor media while in contact with the sensor media, the specification does not further define what the " in relation" intends to comprise.
Claim 6 recites the limitation(s) "sensitive to binding" in line(s) 2. This/these recitation(s) render(s) the claim indefinite, it is unclear what “sensitive to binding” intends to comprise, whether it is the capture molecule which is sensitive to binding or is it the ligand, or the sensor media. Although the specification describes "sensitive to binding" ([0008]), in the same context as the recitation, it does not clarify which of the components are "sensitive to binding," and what this recitation intendeds to comprise. For example, does the binding of the analyte cause a subsequent conformational change of the ligand, which in turn cause an optical signal to change? Or does this occur at the capture molecule, or does the binding of the analyte which causes the formation of the complex analyte-capture molecule-ligand-sensor media cause a change due to being a larger complex (than without the analyte) which makes the system "sensitive to binding."
Claim 8 recites the limitation(s) "in relation to the plurality of reaction electrodes" in line 2. This/these recitation(s) render(s) the claim indefinite, it is unclear what the structural relation the recitation "in relation" intends to comprise, between the sensor surface and the electrodes. Although the specification discloses for example that “The SPR sensor surface may be disposed at the first substrate, and the plurality of reaction electrodes may be disposed at the second substrate opposite the first substrate. Alternatively, the SPR sensor surface may be disposed at the first substrate, and the plurality of reaction electrodes may be disposed at the first substrate” ([0009]), and that “the SPR sensor surface may be disposed between a first reaction electrode and a second reaction electrode” ([0011]) (among other configurations), these disclosures are not recited in the instant claim, and the claim does not clearly define what configuration “in relation” intends to claim, it is unclear what is the structural relationship between the sensor surface and the electrodes.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to performthe recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitation(s) is/are:
Claim limitation of “droplet actuators operative to perform droplet operations on a fluid droplet” and “droplet actuators are operative to induce movement of the fluid droplet relative to the sensor media” in claim 1, which has/have been interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because it uses/they use a generic placeholder “operative to” coupled with functional language “perform droplet operations on a fluid droplet” and “induce movement of the fluid droplet relative to the sensor media” without reciting sufficient structure to achieve the function. Furthermore, the generic placeholder is not preceded by a specific structural modifier.
Because this/these claim limitation(s) is/are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
Claim(s) 1, 2, 4, 6-11, 19, 20, 22, 23, 24-27 and 29-32 has/have been interpreted to cover the corresponding structure described in the specification that achieves the claimed function, and equivalents thereof.
A review of the specification shows that there is no specific description, definition, or disclosure of what the structure of "droplet actuators” “operative to” as discussed above specifically comprises. The closest disclosures are as follows:
[0005] “a plurality of droplet actuators operative to perform droplet operations on a fluid droplet in the DMF portion and a reaction portion comprising sensor media that is disposed in relation to the plurality of droplet actuators, wherein the plurality of droplet actuators are operative to induce movement of the fluid droplet relative to the sensor media”
[0007] “For instance, in an example, the plurality of droplet actuators may comprise reaction electrodes. The plurality of reaction electrodes may perform droplet operations by electrowetting”
Therefore, the structures described comprise: droplet actuators; those structures known to those of ordinary skill in the art at the time of the invention which are capable of performing the function of “droplet actuators operative to perform droplet operations on a fluid droplet” and “droplet actuators are operative to induce movement of
the fluid droplet” will be interpreted to cover the corresponding structure that achieves the claimed function.
If applicant wishes to provide further explanation or dispute the examiner’s interpretation of the corresponding structure, applicant must identify the corresponding structure with reference to the specification by page and line number, and to the drawing, if any, by reference characters in response to this Office action.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
Since the claim limitation(s) invokes 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 2, 4, and 6-10 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Malic et al. (US 2010/0045995 A1).
Regarding claim 1:
Malic et al. discloses a cartridge for use with an instrument to perform measurement of a fluid. See Abstract and [0004] where Malic et al. teaches a "system and method for molecule detection uses a surface plasmon resonance (SPR) system" including a "microfluidic sample support", which constitutes a cartridge designed for the introduction of fluid samples to a detector.
Malic et al. discloses a digital microfluidics (DMF) portion comprising a plurality of droplet actuators operative to perform droplet operations on a fluid droplet in the DMF portion. See Abstract and [0004] where Malic et al. teaches a "digital microfluidic control system" such as an electrowetting-on-dielectric (EWOD) chip comprising a "plurality of control electrodes" to selectively displace and position fluid droplets.
Malic et al. discloses a reaction portion comprising sensor media that is disposed in relation to the plurality of droplet actuators. See [0004], [0006], [0017], where Malic et al. teaches an SPR assembly having a metal electrode in electrical contact with a plurality of metal "detection spots" having nanostructures to enhance the SPR signal, wherein these detection spots serve as the sensor media, and further teaches the microfluidic system is one "by which the droplets may be selectively displaced and positioned relative to the detection spots".
Malic et al. further discloses wherein the plurality of droplet actuators are operative to induce movement of the fluid droplet relative to the sensor media while in contact with the sensor media. See [0017], [0020], and Figure 3 where Malic et al. teaches the electrodes selectively displace the droplet and move it from its original position along a path to the detection spots.
Regarding claim 2, Malic et al. teaches:
that the plurality of droplet actuators comprise a plurality of reaction electrodes. See [0004], [0019], and [0024] where Malic et al. teaches a "microfluidic control system" that "makes use of an electrowetting-on-dielectric (EWOD) structure" including "a plurality of control electrodes embedded in an insulating dielectric layer", wherein these control electrodes constitute the claimed reaction electrodes.
Malic et al. also discloses that the plurality of reaction electrodes perform droplet operations by electrowetting. See [0004]-[0007], [0023], [0025], and [0029] where Malic et al. teaches the "microfluidic control system comprises an electrowetting-on-dielectric (EWOD) structure" and see [0023], [0025], and [0029] where Malic et al. describes "EWOD droplet actuation" where "The motion of the droplet is achieved by Voltage applied to a specific grid point".
Regarding claim 4, Malic et al. teaches:
That the sensor media comprises surface plasmon resonance (SPR) sensor media. See [0004]-[0007] and [0019]-[0021] where Malic et al. teaches a "system and method for molecule detection" that "uses a surface plasmon resonance (SPR) system with detection spots" and further describes "metal detection spots" with "nanostructures" that constitute the claimed SPR sensor media.
Malic et al. discloses wherein the SPR sensor media is functionalized with a capture molecule. See [0032]-[0033] where Malic et al. teaches "Bio-interface functionalization" in which "[s]amples, such as DNA or proteins can be chemically derivatized to bind to the electrode surface," and provides the example that "thiol modified ss-DNA probes can be covalently attached to gold," wherein the ss-DNA probes constitute the claimed capture molecule.
Malic et al. discloses to which a target molecule of an analyte fluid binds. See [0034] and [0036] where Malic et al. teaches the system is "used for studying molecular interactions such as DNA hybridization, antibody-antigen interactions," representing the binding of a target molecule.
Malic et al. discloses to change an optical signal of the SPR sensor media. See [0020], [0021], and [0028] where Malic et al. teaches that the nanostructures "enhance the SPR signal" and describes an "enhancement of the electromagnetic field at the interface resulting in a larger angular shift of the SPR spectrum dip," which constitutes a change in the optical signal of the SPR sensor media.
Regarding claim 6, Malic et al. teaches : That the capture molecule comprises a ligand immobilized on the SPR sensor media. See [0032] and [0033] where Malic et al. teaches "Bio-interface functionalization" where "thiol modified ss-DNA probes can be covalently attached to gold," wherein the ss-DNA probes covalently attached to the gold detection spots constitute the claimed ligand immobilized on the SPR sensor media.
Malic et al. discloses that the system is sensitive to binding with the target molecule of the analyte fluid. See [0034] and [0036] where Malic et al. teaches the system is "used for studying molecular interactions such as DNA hybridization, antibody-antigen interactions," representing the target molecule binding to the capture molecule.
Malic et al. discloses to change an optical property of the SPR sensor media resulting in the change of the optical signal of the SPR sensor media. See [0020], [0021], and [0028] where Malic et al. teaches the binding results in an "enhancement of the electromagnetic field at the interface resulting in a larger angular shift of the SPR spectrum dip," which constitutes changing an optical property and resulting in the change of the optical signal of the SPR sensor media.
Regarding claim 7, Malic et al. discloses::
That the change of the optical properties comprises a change in the optical signal resulting from light interacting with the SPR sensor media. See [0005], [0017], and [0021] where Malic et al. teaches an "SPR assembly" that includes an "SPR beam source 16 and a CCD array 18 for detection of the SPR signal," and describes that the nanostructures "enhance the SPR signal" yielding an "enhancement of the electromagnetic field at the interface resulting in a larger angular shift of the SPR spectrum dip," wherein this angular shift of the beam source light constitutes the claimed change in the optical signal resulting from light interacting with the SPR sensor media.
Regarding claim 8: Malic et al. discloses the cartridge of claim 1, further comprising an SPR sensor surface disposed in the reaction portion and in relation to the plurality of reaction electrodes. See [0004] and [0005] where Malic et al. teaches an "SPR assembly having a metal electrode in electrical contact with a plurality of metal detection spots" acting as the SPR sensor surface, and further teaches a "microfluidic control system" with "a plurality of control electrodes" where the droplets are "selectively displaced and positioned relative to the detection spots."
Malic et al. discloses wherein the SPR sensor media is disposed on the SPR sensor surface. See [0013] and [0018] where Malic et al. teaches "a glass or plastic substrate 20 that is transparent to SPR signals and a ground electrode 22, which is a conductive material such as gold," and that "[a]djacent to the ground electrode is a hydrophobic coating interspersed with detection spots," where "the detection spots are each made up of a group of conductive nanostructures," wherein the conductive nanostructures constitute the SPR sensor media disposed on the detection spots.
Malic et al. discloses and wherein the droplet is contactingly engageable with the SPR sensor surface by operation of the plurality of reaction electrodes. See [0004], [0005], [0019], [0023], [0030], where Malic et al. teaches the droplets reside in a "space between" plates that contact the droplets, and that "electrical potentials may be selectively placed at certain control electrodes so as to move a sample droplet to a desired location relative to the plate surface" by "voltage applied to a specific grid point" in order to selectively displace and position the droplets relative to the detection spots.
Malic et al.’s teaching that the "microfluidic control system is used by which the droplets may be selectively displaced and positioned relative to the detection spots" (e.g. [0004]), and that “electrical potentials may be selectively placed at certain control electrodes so as to move a sample droplet to a desired location relative to the plate surface” (e.g. [0019]), read on the recitation that the droplet is contactingly engageable with the SPR sensor surface. Malic et al. also teaches that the droplets reside in a "space between" plates that contact the droplets (see [0005], [0030])The movement of the droplet is achieved by "voltage applied to a specific grid point" (see [0023]) (i.e. by operation of electrodes). These teachings demonstrate that the droplet is contactingly engageable with the SPR sensor surface by operation of the plurality of reaction electrodes.
Regarding claim 9, Malic et al. explicitly teaches that discloses that the SPR sensor media comprises one of nanosized structures distributed on the sensor surface or a continuous film comprising nano-sized features. See [0006], [0021], [0028], and Figure 4 where Malic et al. teaches "an SPR sample support apparatus is provided that has an electrode connected to detection spots that each includes a plurality of nanostructures" and details that these "nanostructures may be of different shapes, such as nano-pillars, nano-posts, non-spots, nano-dots, nano-particles, nano-brushes or nano-prisms," and further describes "nanopatterns (nanostructures) to enhance the SPR signal" including "scanning electron microscope images of pillar nanostructures."
Regarding claim 10, Malic et al. discloses that the reaction portion comprises a first substrate and second substrate. See [0017]-[0019], [0026]-[0029], where Malic et al. teaches a "microfluidic sample support includes two plates," referred to as a "first plate" and a "second plate" or a “top plate” and “bottom plate,” constituting the first and second substrates.
Malic et al. discloses that the substrates are disposed in spaced-apart relation to define a reaction chamber therebetween. See [0005] where Malic et al. teaches that the "two plates may be positioned adjacent to each other with a space between them within which the fluid droplets reside," defining the reaction chamber.
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.
Claim(s) 19, 20, 22, and 23 is/are rejected under U.S.C. 103(a) as being unpatentable over Malic et al. (US 2010/0045995 A1) in view of Srinivasan et al. (US 2007/0275415 A1).
Regarding claim 19: Malic et al. discloses the cartridge as discussed supra. and discloses an SPR assembly having a metal electrode in electrical contact with a plurality of metal detection spots constituting the SPR sensor surface, and a microfluidic control system comprising an electrowetting-on-dielectric (EWOD) structure having a plurality of control electrodes embedded in a plate. See [0004], [0005], [0026], and [0027] where Malic et al. teaches these elements as discussed supra. Malic et al. further discloses that "based on the optimum electrodes configuration, their respective geometry and required separation to achieve the desired droplet actuation pathway, photolithographic masks can be designed" (See [0025]).
Malic et al. does not explicitly teach: that the SPR sensor surface is disposed between a first reaction electrode and a second reaction electrode.
However, Srinivasan et al. discloses: a device for executing various biochemical protocols using discrete droplets (droplet microactuators) comprising SPR detection, see at [0022], [0023], [0055], [0202], [0222], and [0533], and further discloses a method for conducting droplet operations, including mixing and agitating droplets using electrode-mediated movement, see at [0064], [0076], [0375].
Srinivasan et al. also discloses that the SPR sensor surface is disposed between electrodes, a first reaction electrode and a second reaction electrode. See [0195], [0217], and [0533] where Srinivasan et al. teaches a device for executing biochemical protocols comprising SPR detection where an analyte "may itself be immobilized on the surface of a droplet microactuator," where this surface constitutes the claimed SPR sensor surface on which "optical reflectivity of the gold changes very sensitively with the presence of biomolecules." Srinivasan et al. further discloses "mixing and agitating droplets" using electrodes configured for "conducting droplet operations on a surface of the substrate," wherein conducting these operations over the immobilized sensor surface inherently places the surface between the actuating reaction electrodes. Because Srinivasan et al. also teaches that the droplet microactuator system incorporating SPR detection wherein binding/sensor surfaces are strategically disposed among and between actuating electrodes to facilitate droplet operations directly on the surface, see at [0064], [0076], [0195], [0217], [0375], [0533], where Srinivasan discloses the electrode-mediated movement where droplets are mixed and agitated in contact with immobilized binding surfaces, which therefore teaches that the the sensor surface is between the electrodes
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention to modify the SPR sample support apparatus comprising an SPR sensor surface and multiple reaction electrodes, as taught by Malic et al., by disposing the sensor surface between a first and second reaction electrode, as enabled by the general design principles of droplet microactuators taught by Srinivasan et al. in order to enable efficient agitation and mixing of the fluid droplet over the sensor surface, because Srinivasan et al. teaches that droplet operations include "mixing a droplet" and "agitating a droplet”, see at Srinivasan et al. [0064], [0076], [0375], and discloses using electrodes, which benefit from the strategic placement of sensing elements in relation to electrodes for optimal fluid interaction, and because Malic et al. teaches that the optimization of electrode configurations, see at Malic et al. [0025]).
One would have been motivated to modify the SPR sample support apparatus of Malic et al. by disposing the sensor surface for example on the surface of the electrodes between a first and second reaction electrode, as taught by Srinivasan et al., to enable efficient agitation and mixing of the fluid droplet directly over the sensor surface, thereby enhancing mass transport and improving detection kinetics. This is because Malic et al. teaches that electrode configurations can be optimized for desired droplet actuation pathways (see [0025]), and Srinivasan et al. teaches that droplet actuators perform "mixing a droplet" and "agitating a droplet" using electrodes (see at [0064], [0076], [0375]). A person of ordinary skill in the art would recognize that placing the sensor surface directly within the active area of droplet manipulation between two actuating electrodes would be a predictable design choice to directly influence and maximize the interaction of the fluid droplet with the sensor for improved assay performance, yielding a reasonable expectation of success.
Regarding claim 20, Malic et al. teaches, as discussed supra, a device for introducing fluid samples to a multichannel surface plasmon resonance (SPR) detector, and a method for selectively displacing and positioning fluid droplets relative to detection spots for SPR detection, see at [0004]. The reference also discloses a DMF cartridge comprising an SPR sensor surface and a plurality of reaction electrodes, see [0004], [0005], [0026], [0027].: where Malic.et al. discloses an SPR assembly having a metal electrode in electrical contact with a plurality of metal detection spots (SPR sensor surface), and a microfluidic control system comprising an electrowetting-on-dielectric (EWOD) structure having a plurality of control electrodes (serving as reaction electrodes) to displace and position fluid droplets.
Malic et al. does not explicitly teach: the first reaction electrode and the second reaction electrode are alternately activated to induce oscillation of the droplet between the first reaction electrode and the second reaction electrode to induce the movement of the fluid droplet relative to the SPR sensor surface.
Srinivasan et al., who teaches droplet-based assays on a droplet actuator, further explicitly teaches a method for agitating or mixing a droplet by inducing repeated movement.
Srinivasan et al. discloses wherein the first reaction electrode and the second reaction electrode are alternately activated to induce oscillation of the droplet. See [0374], [0375], [0380], and [0469] where Srinivasan et al. teaches "activating and deactivating" multiple electrodes to cause movement of the droplet in desired programmed sequences, and further teaches that "a series of successive transfers will transport droplets along the path or network of control electrodes" by "varying the patterns of voltage activation," wherein applying this cyclical activation and deactivation to a path of adjacent electrodes constitutes alternately activating them to induce oscillation of the droplet. Srinivasan et al. further discloses this oscillation is used to induce the movement of the fluid droplet relative to the SPR sensor surface. See [0447] and [0533] where Srinivasan et al. teaches a droplet is "rapidly and cyclically deformed in place by activating and deactivating the electrode" to mix and agitate the droplet over the surface plasmon resonance (SPR) sensing surface. Also see [0380] where the reference discloses varying Patterns of Voltage Activation for Movement: and that "A series of successive transfers will transport droplets along the path or network of control electrodes. In addition to transport, other operations including merging, splitting, mixing and dispensing of droplets can be accomplished in the same manner by varying the patterns of Voltage activation"
Likewise, the recitation "Induce oscillation of the droplet between the first reaction electrode and the second reaction electrode", is taught because as explained supra, the general teaching of "successive transfers" and "varying patterns of Voltage activation" for transport on a path of electrodes, when applied to a path with only two electrodes, directly leads to back-and-forth movement, which is an oscillation. This movement is a known method to achieve "mixing" or "agitating a droplet", see [0380] and [0447].
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention to modify the SPR sample support apparatus comprising an SPR sensor surface and multiple reaction electrodes, as taught by Malic et al., by having the at least two microacuator electrodes activated and deactivated sequentially in other words by having the first reaction electrode and the second reaction electrode alternately activated to induce oscillation of the droplet to induce movement relative to the SPR sensor surface, as taught by Srinivasan et al. in order to produce sequential movement for example between the first and second electrodes which would induce oscillation of the droplet between the first reaction electrode and the second reaction electrode to induce the movement of the fluid droplet, and to have this movement relative to the SPR sensor as taught by Srinivasan et al., in order to enhance mixing and mass transport of analytes to the SPR sensor surface, thereby improving reaction kinetics and detection sensitivity. Because Srinivasan et al. teaches that droplet operations comprise "agitating a droplet" (see [0153]) using electrodes with "varying the patterns of voltage activation" ([0380]) to effect "successive transfers" along a path of electrodes; a person having ordinary skill in the art would recognize that when a path consists of two electrodes, "successive transfers" or "varying patterns of Voltage activation" would involve alternately activating these two electrodes, thereby inducing a back-and-forth oscillation of the droplet between them, a known technique for enhancing agitation and mixing in microfluidics for improved sensor interaction and detection.
One of ordinary skill in the art would be motivated to apply said modification in order to thoroughly mix the droplet contents and continuously agitate the fluid relative to the sensor surface to enhance binding efficiency and mass transport (as explicitly taught by Srinivasan et al. see [0375]). Furthermore, one of ordinary skill in the art would have a reasonable expectation of success because shuttling/oscillating droplets via alternating electrode activation is a standard, predictable method of operation in digital microfluidics. In addition, a person of ordinary skill in the art would recognize that alternately activating these electrodes induces a back-and-forth oscillation of the droplet between them, which is a known and predictable technique for enhancing agitation and mixing in microfluidics for improved sensor interaction.
Regarding claims 22 and 23,
Malic et al. discloses the cartridge of claim 20, as discussed supra, wherein the SPR sensor surface is disposed between three or more reaction electrodes. See [0019] and Figure 2 where Malic et al. teaches "a series of control electrodes 30" organized in a "two-dimensional array," constituting three or more reaction electrodes.
Although Malic et al. teaches the structural features capable of being “alternately activated to induce oscillation of the droplet” (as discussed supra, see claim 20) and “between the three or more reaction electrodes to induce the movement of the fluid droplet” as in claim 22, and where the “the oscillation of the droplet between the three or more reaction electrodes is circular” as in claim 23, Malic et al. doesn’t describe the function of alternate activation between three or more reaction electrodes or an oscillation that comprises circular motion.
Srinivasan et al. discloses wherein the three or more reaction electrodes are alternately activated to induce oscillation of the droplet, and wherein the oscillation of the droplet between the three or more reaction electrodes is circular. See [0380] and [0447] where Srinivasan et al. teaches "varying the patterns of voltage activation" along a path or network of control electrodes to perform operations including "mixing" and "agitating a droplet," wherein applying sequential activation to a planar network of three or more electrodes inherently leads to a cyclical or circular movement of the fluid.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention to modify the SPR sample support apparatus comprising an SPR sensor surface and multiple reaction electrodes for example a two dimensional array of electrodes, as taught by Malic et al., by having the two or more microacuator electrodes or reaction electrodes, activated and deactivated sequentially by activating and deactivating three or more reaction electrodes sequentially to induce a circular oscillation of the fluid droplet relative to the SPR sensor surface, as taught by Srinivasan et al.(as in claim 22) in order to produce sequential movement for example between the two or more electrodes and to have this movement over the SPR sensor (i.e. relative to the SPR sensor surface), as taught by Srinivasan et al., in order to enhance mixing and mass transport of analytes to the SPR sensor surface, thereby improving reaction kinetics and detection sensitivity, because Srinivasan et al. teaches that droplet operations comprise "agitating a droplet" (see [0153]) using “two or more electrodes ([0375]) and having electrodes with "varying the patterns of voltage activation" ([0380]) to effect "successive transfers" along a path of electrodes; a person having ordinary skill in the art would recognize that when a path consists of two or more electrodes, "successive transfers" or "varying patterns of Voltage activation" would involve alternately activating two or more electrodes, in patterns comprising cyclical patterns, thereby inducing an oscillation of the droplet between them. It would have been obvious to one of ordinary skill in the art that if the electrodes are in a planar array format, as taught by Malic et al. (and as also disclosed in the instant specification), that the “successive transfers” taught by Srinivasan et al. would necessarily comprise a cycle of for example, for four electrodes in a planar array, the successive transfers would form a path comprising the effect of a circular movement (for example, successive transfers from electrodes 1-4 in a planar array, would comprise transfers from 1-2, 2-3, 3-4, 4-1 (one cycle) and succession back to 1-2, 2-3, 3-4, 4-1 (cycle 2), etc. etc.) which would cause the desired effect of the well known circular motion in a fluid for mixing a fluid, which is also a known technique for enhancing agitation and mixing in microfluidics for improved sensor interaction and detection. Furthermore, it is well-known in the field of microfluidics that circular motion or oscillation is a highly effective and predictable method for achieving thorough mixing within a confined droplet; a person having ordinary skill in the art would recognize the benefit of applying such a known mixing pattern (circular oscillation via coordinated electrode activation) to an SPR biosensing system to enhance analyte-sensor interaction and improve assay kinetics.
Claim(s) 24 is/are rejected under U.S.C. 103(a) as being unpatentable over Malic et al. (US 2010/0045995 A1) in view of Sista et al. (US 2015/0314293 A1) as motivated by Lu et al. (“Recent advances in biological detection with magnetic nanoparticles as a useful tool” Sci China Chem May (2015) Vol.58 No.5).
Regarding claim 24, Malic et al. teaches, as discussed supra:
That the sensor media comprises a plurality of sensor nanoparticles disposed in the reaction portion. See [0004] and [0006] where Malic et al. teaches an SPR assembly having a plurality of detection spots comprising nanostructures, specifically noting the "nanostructures may be of different shapes, such as nano-pillars, nano-posts, non-spots, nano-dots, nano-particles," where the droplets are selectively displaced and positioned relative to these detection spots where the reaction occurs.
Malic et al. explains that the microfluidic system is one "by which the droplets may be selectively displaced and positioned relative to the detection spots" (see [0004], [0017], claims 1, 11). In other words, Malic teaches that the sensor media comprises nanostructures.
Malic et al. doesn’t explicitly teach that the plurality of sensor nanoparticles are suspended in a sensor droplet.
However, Sista et al. discloses droplet actuator devices and methods employing magnetic beads. See [0006] and [0007] where Sista et al. teaches these elements, and that that the magnetic beads comprise nanoparticles ([0010]).
Sista et al. further discloses wherein the plurality of sensor nanoparticles are suspended in a sensor droplet. See [0010], [0012], [0013], and [0065] where Sista et al. teaches that the magnetic beads comprise nanoparticles, wherein "magnetically responsive beads" "are substantially restrained in position in a droplet" and are manipulated by the droplet actuator to perform operations "for improving the sensitivity of droplet detection," constituting a sensor droplet in a reaction portion.
Sista et al. also teaches that the droplet actuator manipulation of the droplets comprises “operations for improving the sensitivity of droplet detection” , see [0065] FIGS. 11A, 11B, and 11C where they illustrate side views of droplet actuator 1100 by which respective operations for improving the sensitivity of droplet detection may be performed. Droplet actuator 1100 includes a top plate 1110 and a bottom plate 1114 that are arranged having a gap 1118 therebetween. An arrangement of electrodes 1122, e.g., electrowetting electrodes, may be associated with bottom plate 1114 for performing droplet operations on a droplet”. These teachings that the droplet in which reside suspended magnetic nanoparticles and undergoes manipulation comprising improvement of detection, constitutes the reaction portion. Thus, Sista discloses a plurality of sensor nanoparticles (magnetic beads/nanoparticles) suspended in a sensor droplet disposed in the reaction portion.
Lu et al. teaches magnetic nanoparticles (MNPs) “with particular emphasis upon their applications in biological detection such as magnetic separation, sensing, catalysis, manipulation, and signal enhancer for SPR” (1st Pg, Pg. 793, right Col., last P), and that MNPs provide the advantage of improvement of SPR signals, and teaches that “MNPs can be attracted and controlled by external magnetic fields to form an “aggregate” layer with a strong refractive index, which results in a notable SPR signal when sensing trace amounts of biological and chemical samples” (Pg. 804, Section 7 Signal enhancer for SPR).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention, to modify the sensor media comprising a sensor droplet disposed in the reaction portion, as taught by Malic et al., by having a plurality of sensor nanoparticles suspended in a sensor droplet, in the DMF assay, as taught by Sista et al., in order to enhance detection of analytes on the SPR sensor surface, and to improve its detection sensitivity, because Sista et al. teaches that being able to manipulate nanoparticles provide the advantage of improving the sensitivity of droplet detection (see [0065]).
One would have been motivated to modify the sensor media comprising a sensor droplet disposed in the reaction portion, as taught by Malic et al., by having a plurality of sensor nanoparticles suspended in a sensor droplet, as taught by Sista et al., because Lu et al. teaches that the inclusion of magnetic nanoparticles in SPR detection provides the desired advantage of enhacement of the SPR signal (see abstract, Pg. 804, Section 7 Signal enhancer for SPR).
A person of ordinary skill in the art, seeking to implement a sensitive, optical detection method for the DMF/magnetic particle assay platform taught by Malic et al. and Sista et al., would have been motivated to combine these teachings for the following reasons:
The review by Lu et al. articulates a known challenge and solution in the art. Lu et al. teaches that magnetic nanoparticles (MNPs) are useful in various biological detection methods and highlights their specific application as a "signal enhancer for SPR". Lu et al. explains that using MNPs can result in a "notable SPR signal when sensing trace amounts of biological and chemical samples". Motivated by the explicit teaching in Lu et al. to use magnetic nanoparticles for SPR signal enhancement, one of ordinary skill in the art at the effective filing date of the invention, would have found it an obvious design choice to include magnetic nanoparticles in the droplets taught by the Sista et al. system with the well-known nanoparticles described by Lu et al. This would predictably result in an assay with a magnetically controllable workflow and a highly sensitive, optically amplified SPR readout. This represents the application of known technologies for their recognized purposes to achieve an expected and predictable result.
One would have been motivated to make this combination to enhance the optical signal and detection sensitivity of the SPR sensor surface, because Lu et al. explicitly teaches that the inclusion of magnetic nanoparticles in SPR detection provides the highly desired advantage of enhancing the SPR signal. A person of ordinary skill in the art, seeking to implement a sensitive, optical detection method for the DMF platform taught by Malic et al. and Sista et al., would have found it an obvious and predictable design choice to include magnetic nanoparticles suspended in the droplets to achieve the well-known SPR signal amplification described by Lu et al. This would predictably result in an assay with a magnetically controllable workflow and a highly sensitive, optically amplified readout.
Claim(s) 25-27 and 29-32 is/are rejected under U.S.C. 103(a) as being unpatentable over Malic et al. (US 2010/0045995 A1) in view of Sista et al. (US 2015/0314293 A1) as motivated by Lu et al. (“Recent advances in biological detection with magnetic nanoparticles as a useful tool” Sci China Chem May (2015) Vol.58 No.5), as applied to claim 24 above, and further in view of Srinivasan et al. (US 2007/0275415 A1).
Regarding claim 25, Malic et al., Sista et al. and Lu et al. teach, as discussed supra: sensor media comprising a sensor droplet disposed in a reaction portion having a plurality of sensor nanoparticles suspended in the sensor droplet. Sista et al., as discussed supra teaches: a device for performing droplet operations using magnetic beads/nanoparticles in a droplet actuator; and manipulating magnetically responsive beads in a fluid droplet. The reference also teaches: a biosensor comprising a suspension of magnetic nanoparticles suspended in a liquid droplet in the reaction portion (as established for Claim 24).
Malic et al., Sista et al. and Lu et al. teach do not explicitly teach: the fluid droplet is merged with the sensor droplet to form a reacted droplet.
Srinivasan et al. teaches, as discussed supra: a device for executing various biochemical protocols using discrete droplets (droplet microactuators) comprising SPR detection ([0022], [0023], [0055], [0202], [0222], [0533]); a method for conducting droplet operations, including mixing and agitating droplets using electrode-mediated movement (see [0064], [0076], [0375]). The reference also discloses wherein the fluid droplet is merged with the sensor droplet to form a reacted droplet. See [0064], [0263], [0375], and [0439] where Srinivasan et al. teaches that the method for conducting droplet operations explicitly comprises "merging or combining two or more droplets into a single droplet" to facilitate biochemical and affinity-based reactions.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention to modify the droplet actuator system for suspended nanoparticles, as taught by Malic et al., Sista et al. and Lu et al., by merging a fluid droplet with a sensor droplet (containing the suspended nanoparticles) to form a reacted droplet for optical measurement, as taught by Sista et al., in order to enable efficient reaction initiation and measurement within a microfluidic environment, because Srinivasan et al. teaches that merging droplets is a fundamental droplet operation used in biochemical protocols to combine reagents or samples for reaction and subsequent analysis. One would have been motivated to combine the fluid droplet with the droplet comprising the nanoparticles (the sensor droplet) because doing so would yield a resulting droplet with the analyte enhanced with nanoparticles, and this would to form a reacted droplet which can be used for enhanced measurement of the optical signal of the SPR sensor media in the reacted droplet, because Lu et al. teaches that using MNPs (magnetic nanoparticles) can result in a "notable SPR signal when sensing trace amounts of biological and chemical samples". Motivated by the explicit teaching in Lu et al. to use magnetic nanoparticles for SPR signal enhancement, the skilled artisan would have found it an obvious design choice to merge an analyte droplet (a fluid droplet) with magnetic nanoparticles in the droplets (i.e. a sensor droplet) taught by the Sista et al. system with the well-known nanoparticles described by Sista et al. and Lu et al. This would predictably result in an assay with a magnetically controllable workflow in the resultant reactant droplet, and a highly sensitive, optically amplified SPR readout.
One would have been further motivated to merge the droplets to enable efficient reaction initiation and measurement within a microfluidic environment, because Srinivasan et al. teaches that merging droplets is a fundamental operation used in biochemical protocols to combine reagents for subsequent analysis. One of ordinary skill in the art would have predictably recognized that merging an analyte droplet with the magnetic nanoparticle droplet taught by Sista et al. would form a reacted droplet capable of yielding the notably enhanced SPR signal taught by Lu et al.
Regarding claim 26, Malic et al., Sista et al. and Lu et al. teach, as discussed supra: sensor media comprising a sensor droplet disposed in a reaction portion having a plurality of sensor nanoparticles suspended in the sensor droplet. Sista et al., as discussed supra teaches: a device for performing droplet operations using magnetic beads/nanoparticles and that nanoparticles are suspended within a droplet.
Sista et al. further discloses wherein the movement induced by the plurality of droplet actuators is operative to mix the reacted droplet. See [0012] and [0013] where Sista et al. discloses “magnetically responsive beads” “are substantially restrained in position in a droplet”] which are manipulated by the droplet actuator, and discloses “Droplet operation” means any manipulation of a droplet on a droplet actuator. A droplet operation may, for example, include: loading a droplet into the droplet actuator; dispensing one or more droplets from a source droplet; splitting, separating or dividing a droplet into two or more droplets” “merging or combining two or more droplets into a single droplet; diluting a droplet; mixing a droplet.
Regarding claim 27, Malic et al., Sista et al. and Lu et al. teach, as discussed supra: sensor media comprising a sensor droplet disposed in a reaction portion having a plurality of sensor nanoparticles suspended in the sensor droplet. Sista et al. further discloses wherein each of the plurality of sensor nanoparticles is magnetically responsive. See [0006], [0007], [0010], and [0013] where Sista et al. teaches "droplet actuator devices and methods employing magnetic beads" that comprise nanoparticles, wherein the "magnetically responsive beads" are substantially restrained in position in a droplet.
Regarding claim 29, Malic et al., Sista et al. and Lu et al. teach, as discussed supra: sensor media comprising a sensor droplet disposed in a reaction portion having a plurality of sensor nanoparticles suspended in the sensor droplet. Sista et al. further teaches: that “For magnetically responsive beads, the magnetically responsive material may constitute substantially all of a bead or one component only of a bead. The remainder of the bead may include, among other things, polymeric material, coatings, and moieties which permit attachment of an assay regent.” ([0010]). In other words, Sista et al. teaches that a composite structure is in the definition of the bead:
• Composite Nature: Sista teaches that for magnetically responsive beads, the magnetically responsive material may constitute substantially all of a bead or "only one component of a bead" ([0010]). This teaching implies a complex structure where the magnetic function is separate from the remaining structure.
• Coupling/Functionalization: The reference further states that the remainder of the bead (i.e. nanoparticle) may include "polymeric material, coatings, and moieties which permit attachment of an assay reagent" ([0010]). "Moieties which permit attachment" covers the binding aspect of coupling required to link (i.e. tether) the functional part (assay reagent/sensing capability) to the underlying structure (which includes the magnetic component).
Although Sista et al. does not use the exact language "a magnetically responsive element tethered to the sensor nanoparticle", the teachings of a bead composite (more than one component) and of "Moieties which permit attachment" covers the binding aspect of coupling required to link (i.e. tether), read on the instant recitation because Sista teaches magnetically responsive beads which comprise a link and a composite structure. This further reads on the instant recitation because the instant specification discloses “ a separate magnetically responsive element 254 may be tethered to nanoparticle 232 to form a magnetically responsive nanoparticle 250. For example, magnetically responsive element 254 can be a magnetically responsive particle that is linked to nanoparticle 232 using physical or chemical coupling. In one example, magnetically responsive element 254 may be coupled to nanoparticle 232 using a linker” (see at instant [0147]).
In addition, Sista et al. discloses wherein each of the plurality of sensor nanoparticles comprise a magnetically responsive element tethered to the sensor nanoparticle. See [0010] where Sista et al. teaches that "magnetically responsive material may constitute substantially all of a bead or one component only of a bead," and further teaches that the remainder of the bead may include "polymeric material, coatings, and moieties which permit attachment of an assay reagent," wherein these moieties constitute a tether linking the magnetic element to the functional sensor particle.
Notwithstanding the above, it would have nonetheless been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention to modify the magnetically responsive sensor nanoparticles, as taught by Malic et al., Sista et al., and Lu et al. by configuring each of the sensor nanoparticles to comprise a magnetically responsive element tethered to the sensor nanoparticle, as taught by Sista et al. because Sista et al. teaches both a composite bead structure and "Moieties which permit attachment" which covers the chemical aspect of coupling required to link (i.e. tether). It would have been also prima facie obvious to apply said modification, in accordance to well-known general design choices for coupling a magnetic bead to a sensor particle, in order to impart magnetic manipulability to a sensing nanoparticle while maintaining and optimizing its sensing function, because Sista et al. explicitly teaches that magnetic material may comprise only one component of a bead as well as a bead composite as well as comprise linking moieties (i.e. tethering), providing motivation to combine distinct magnetic and sensing functionalities onto a single particle, which is achieved by tethering or coupling.
One would have been motivated to tether a magnetically responsive element to the sensor nanoparticle to impart magnetic manipulability to a sensing particle while optimizing its sensing function, as Sista et al. explicitly teaches that magnetic material may comprise only one component of a composite bead structure containing linking moieties.
Regarding claim 30, Malic et al., Sista et al. and Lu et al. teach, as discussed supra: sensor media comprising a sensor droplet disposed in a reaction portion having a plurality of sensor nanoparticles suspended in the sensor droplet.
Malic et al. further teaches that “Bio-interface functionalization can be optimized as a function of the molecules involved. Attachment of molecules to surfaces for SPR detection is known in the art” and that for example “specific chemistry for immobilization of biomolecules to a metal substrate that involves depositing an omega-modified alkanethiol monolayer on Substrate, UV photopatterning to create an array and contacting the monolayer with heterobifunctional linking compound via first moiety allowing the biomolecule immobilization. Another example” “describes biomolecule attachment chemistry involving polylysine” ([0033]).
Sista et al. further teaches: a sensor nanoparticle comprising a magnetically responsive element tethered to it (as made obvious by the combination for Claim 29).
Although Sista et al. does not explicitly teach that the taught linker attachment or binding of beads is a physically or chemically coupling.
Sista et al. however teaches: that the remainder of the bead may comprise “polymeric material, coatings, and Moieties which permit attachment" and that “the beads are typically used to bind to one or more target substances in a mixture of substances” ([0147], [0005]), and Malic et al. teaches chemical coupling, as discussed supra.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention to modify the sensor nanoparticles comprising a tethered magnetically responsive element, as taught by Malic et al., Sista et al., and Lu et al. (as modified for Claim 29), by physically or chemically coupling the magnetically responsive element to the sensor nanoparticle, as taught by Mallic et al. and the general knowledge in the art, in order to create a stable and functional composite nanoparticle with both sensing and magnetic manipulation capabilities, because Sista et al. teaches that moieties permit attachment ([0147]), and the principles of physical and chemical coupling are fundamental methods for creating composites or tethering elements in nanotechnology and molecular biology (as taught by Malic et al.); one of ordinary skill in the art would naturally employ such well-known coupling methods to achieve the tethered structure comprising chemical or physical coupling in the attachment of the particles. Furthermore, one would be motivated to have the attachment comprise chemical or physical coupling in accordance with well-known procedures for functionalization of particles since the steps are conventional and well understood as shown by those in the field as taught by Malic et al. and Sista et al.
One would have been motivated to physically or chemically couple the elements to create a stable and functional composite nanoparticle with both sensing and magnetic manipulation capabilities, as the principles of physical and chemical coupling are fundamental, predictable methods for creating composites in molecular biology as taught by Malic et al. and Sista et al.
Regarding claim 31, Malic et al., Sista et al. and Lu et al. teach, as discussed supra: sensor media comprising a sensor droplet disposed in a reaction portion having a plurality of sensor nanoparticles suspended in the sensor droplet comprising magnetic nanoparticles (i.e. magnetically responsive sensor nanoparticles in the reaction portion).
Sista et al. further discloses further comprising a magnet that is selectively operable to act on the magnetically responsive sensor nanoparticles to immobilize the sensor nanoparticles in the reaction portion to dispose the plurality of nanoparticles in a restrained position relative to the magnet. See [0006], [0036], [0084], and [0089] where Sista et al. teaches "employing magnetic forces for immobilizing magnetically responsive beads," detailing that a magnet "may be arranged in sufficient proximity to droplet operation electrodes to permit some degree of immobilization of the magnetically responsive beads," and further teaches the magnet may be "turned on and off electronically" or "moved away" to remove the influence of the magnetic field, constituting being selectively operable.
Regarding claim 32, Malic et al., Sista et al. and Lu et al. teach, as discussed supra: sensor media comprising a sensor droplet disposed in a reaction portion having a plurality of sensor nanoparticles suspended in the sensor droplet.
Sista et al. further discloses wherein the plurality of droplet actuators are operative to move fluid away from the sensor nanoparticles when the magnetically responsive sensor nanoparticles are immobilized by the magnet in the restrained position, and to move fluid into contact with the sensor nanoparticles when the magnetically responsive sensor nanoparticles are immobilized by the magnet in the restrained position. See [0006], [0013], [0041], [0042], and [0064] where Sista et al. teaches a "splitting operation" where the droplet is divided and fluid is "transporting a droplet away" from the immobilized beads without substantial loss of beads, and subsequently teaches a washing process involving the repetition of droplet merging where a "wash droplet" is transported to the site of the immobilized beads to move fluid into contact with the nanoparticles.
Pertinent Prior Art
The following prior art made of record (IDS references) and not relied upon is considered pertinent to applicant's disclosure:
Silva et al. (2016 NPL, “Gold coated magnetic nanoparticles: from preparation to surface modification for analytical and biomedical applications” Chem. Commun., 2016,
52, 7528): This review article teaches the creation and application of hybrid nanoparticles, specifically gold-coated magnetic nanoparticles. It explains that the magnetic core allows for manipulation and separation, while the gold shell provides plasmonic properties for use in SPR sensing.
Schrittwieser et al. (2012 NPL, “Modeling and Development of a Biosensor Based on Optical Relaxation Measurements of Hybrid Nanoparticles” ACSNANO VOL. 6 ’ NO. 1 ’ 791–801 ’ 2012) -
Rationale: The abstract describes "hybrid nanoparticles that combine both magnetic and optical anisotropic properties" using a cobalt core (magnetic) and a gold shell (plasmonic/optical). This is a direct teaching of a bifunctional nanoparticle for optical sensing, providing an excellent alternative to the Silva reference.
Wang et al. (NPL 2010, “Magnetic Nanoparticles (MNPs) enhanced biosensing by Surface Plasmon Resonance (SPR) for portable devices” Proc. of SPIE Vol. 7647 76470T-1) -
Rationale: demonstrates that magnetic nanoparticles can "greatly enhance the signal of surface plasmon resonance spectroscopy (SPR)." This provides a clear, articulated reason why a person of skill in the art would combine these technologies (MNPs and SPR).
Schotter et al. (NPL 2008, "Recognition of biomolecular interactions by plasmon resonance shifts in... magnetic nanoparticles" APPLIED PHYSICS LETTERS 93, 144105, 2008) -
Rationale: The abstract discusses using "composite nanoparticles consisting of a superparamagnetic core and a noble metal shell" for "direct plasmon-based optical detection." This is another strong teaching of the bifunctional nanoparticle concept.
Ha et al. (NPL 2018, "Recent Advances Incorporating Superparamagnetic Nanoparticles into Immunoassays" ACS Appl. Nano Mater. 2018, 1, 512−521) -
Rationale: Discusses using superparamagnetic nanoparticles (SPMNPs) to "increase detection capabilities of surface plasmon resonance."
Hainberger et al. (NPL 2014, "Integrated optical waveguide and nanoparticle based label-free molecular biosensing concepts" Proc. of SPIE Vol. 8933 893305-1) -
Rationale: This paper describes a "nanoparticle based approach relies on a plasmon-optical detection of... magnetic-core/gold-shell nanorods." This reinforces the existence and utility of bifunctional magnetic-plasmonic nanoparticles for sensing.
Tran et al. (NPL 2018, "Magnetoplasmonic Nanomaterials for Biosensing/Imaging and in Vitro/in Vivo Biousability" American Chemical Society Publications, DOI: 10.1021/acs.analchem.7b04255, Anal. Chem.) -
Rationale: The abstract describes composites "combining magnetic and plasmonic materials" (e.g., Iron/Gold). This review provides insight into the knowledge of a PHOSITA regarding these hybrid materials.
Chung et al. (US 2009/0033935 A1) - "Magneto-optic biosensor using bio-functionalized magnetized nanoparticles"
Rationale: explicitly applies the technology to a "micro-fluidic channel." While the detection is "polarized light scattering," it establishes the combination of magnetic nanoparticles, an optical readout, and a microfluidic environment.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANIELA E. FUENTES whose telephone number is (571) 270-0310. The examiner can normally be reached on Monday Thursday 9:00 a.m. - 3:00 p.m. EST. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy Nguyen can be reached on (571) 272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov
Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DANIELA E FUENTES/
Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 June 2, 2026
Prosecution Insights