DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-8 and 10-14 are pending and under examination.
Claims 9 has been canceled.
Response to Amendment
The claim amendments received on 07/23/2026 have overcome the 112(b) rejection(s) set forth in the Non-Final Office Action mailed on 02/23/2026. Therefore, the 112(b) rejection(s) have been withdrawn.
The 101 rejection(s) have been modified to address the amended claims.
Based on the amended claims and remarks, the previous prior art rejection over Kwon has been modified to address the claim amendments (see below).
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-8 and 10-14 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Step 1: Claim 1 is directed toward a method.
Step 2A, Prong One: Identify the law of nature/natural phenomenon/abstract ideas.
Claim 1 recites the abstract ideas “generate a first curve of area covered by illuminated pixels vs. time for a formation of a platelet aggregate and a second curve of area covered by illuminated pixels vs. time for a fibrin information”, “generating a first curve of average fluorescence intensity vs. time for the formation of the platelet aggregate and a second curve of average fluorescence intensity vs. time for the fibrin formation”, “generating a first integrated density curve defined as the product of area and fluorescence intensity vs. time for the formation of the platelet aggregate and a second integrated density curve defined as the product of area and fluorescence intensity vs. time for the fibrin formation”, “generating a curve of particle number vs. time, in which the number of particles is given by the number of platelet aggregates comprising more than 2 illuminated pixels”, “generating a curve of particle size vs. time, in which the particle size is given by the average size of the platelet aggregates comprising more than 2 illuminated pixels”, “generating values of maximum slope, defined as relative maximum points of a first derivative function calculated for the curves of the parameter obtained in one or more of steps e), f), g), h) and i)” “generating values of maximum acceleration, defined as relative maximum points of a second derivative function calculated for the curves of the parameter obtained in one or more of steps e), f), g), h) and i)”, “generating values of F/P ratio, defined as the ratio of the areas under the curve (AUCs) of fibrin to the AUCs of the platelets of the parameter obtained in one or more of steps e), f) and g)”, “generating a lag time value representing the fibrin formation time defined as a time corresponding to a first occurrence of five consecutive images in which the value of the measured area related to fibrin is > 1% of a maximum peak value of the curve”, “generating the AUC (Area Under the Curve) values given by the area under the curve of the parameter obtained in one or more of steps e), f), g), h) and i)”, “comparing one or more of the generated values of AUC, area under the curve of a fluorescence intensity curve (AUC MGV), area under the curve of an integrated density curve (AUC ID), and Lag Time with corresponding reference values”, and “determining, based on the comparison, at least one of: an efficacy of an anticoagulant or antiplatelet treatment, a risk of thrombogenesis, or a risk of blood coagulation defects in the subject” which are mental processes and/or mathematical concepts between variables or numbers and could be performed by a human person or by pen and paper or by a generic computer, but do not preclude the steps from being considered an abstract idea. See MPEP 2106.04(a)(2) subsections (I) and (III).
Step 2A, Prong Two: Has the abstract idea been integrated into a particular practical application?
No. Upon generating the curve/values and determining an efficacy or risk based on a comparison of the curve/values to reference values, no further action is performed, and therefore is not a particular practical application.
Claim 1 also recites treating a whole blood sample with an anti-coagulant substance, a recalcification solution, and fluorescent probes with different emission frequencies for marking platelets and fibrin, perfusing the blood sample through a device having a cytoadhesive substance, and acquiring a series of fluorescent images. However, acquiring images from a sample has been treated is interpreted as extra-solution activity incidental to the primary process as mere data gathering which is not considered significantly more than the abstract idea, and generally linking the use of a judicial exception to a particular technological environment or field of use in which to apply the judicial exception, but does not amount to significantly more than the exception itself and cannot integrate the judicial exception into a practical application (see MPEP § 2106.05(g), Insignificant Extra-Solution Activity and MPEP § 2106.05(h), Field of Use and Technological Environment).
Step 2B: Does the claim recite any elements which are significantly more than the abstract idea?
Claim 1 recites treating a whole blood sample with an anti-coagulant substance, a recalcification solution, and fluorescent probes with different emission frequencies for marking platelets and fibrin, perfusing the blood sample through a device having a cytoadhesive substance, and acquiring a series of fluorescent images. These additional elements do not effectively transform or reduce the system to a different state or thing beyond such that the claims recite significantly more than well-understood, routine, and conventional activities previously known to the industry (See MPEP § 2106.05(c), Particular Transformation and MPEP § 2106.05(d), Well-Understood, Routine, Conventional Activity) as evidenced by Kwon (US 2023/0393120 having a Provisional Application filing date of October 30, 2020 – hereinafter “Kwon”) and Verdoold (WO 2017/093266A2 – hereinafter “Verdoold”). Kwon and Verdoold disclose treating a whole blood sample with an anti-coagulant substance, a recalcification solution, and fluorescent probes with different emission frequencies for marking platelets and fibrin, perfusing the blood sample through a device having a cytoadhesive substance, and acquiring a series of fluorescent images (Kwon; figs. 1B, 1C & 2B-2E, [0032-0036, 0039, 0041-0042, 0046-0048, 0050, 0053-0055, 0066, 0069-0070, 0074-0076, 0079-0081, 0090] and Verdoold; fig. 6, pp. 5-6, 11, 15, 24, 35-36). Additionally, data gathering in conjunction with the abstract ideas (mental processes and mathematical concepts) is not enough to transform the nature of the claim into "significantly more" than the judicial exception.
Claim 2 recites the analytical device comprises reference marks. However, these additional elements do not effectively transform or reduce the system to a different state or thing beyond such that the claims recite significantly more than well-understood, routine, and conventional activities previously known to the industry (See MPEP § 2106.05(c), Particular Transformation and MPEP § 2106.05(d), Well-Understood, Routine, Conventional Activity) as evidenced by Kwon. Kwon disclose the analytical device comprises reference marks (Colwell; figs. 2F-2G, [0054, 0056]).
Claims 3 further limits the anti-coagulant substance to heparin or citrate salts. However, these additional elements do not effectively transform or reduce the system to a different state or thing beyond such that the claims recite significantly more than well-understood, routine, and conventional activities previously known to the industry (See MPEP § 2106.05(c), Particular Transformation and MPEP § 2106.05(d), Well-Understood, Routine, Conventional Activity) as evidenced by Kwon. Kwon disclose the anti-coagulant substance as citrate salts (Kwon; [0037, 0039, 0079, 0080]).
Claims 4 & 14 further limit the fluorescent probes for marking platelets and fibrin. However, these additional elements do not effectively transform or reduce the system to a different state or thing beyond such that the claims recite significantly more than well-understood, routine, and conventional activities previously known to the industry (See MPEP § 2106.05(c), Particular Transformation and MPEP § 2106.05(d), Well-Understood, Routine, Conventional Activity) as evidenced by Kwon. Kwon disclose fluorescent probes having different emission frequencies for detecting platelets and fibrin; figs. 2B-2E, [0054-0055, 0075, 0079, 0081]. Furthermore, Ahearn et al. (US 2007/0178536 – hereinafter “Ahearn”) and Ruggeri et al. (US 2019/0127442 – hereinafter “Ruggeri”) teach the explicit excitation and emission wavelengths (Ahearn; [0041] and Ruggeri; [0135]).
Claims 5 and 12 further limits the recalcification solution to calcium chloride/salt. However, these additional elements do not effectively transform or reduce the system to a different state or thing beyond such that the claims recite significantly more than well-understood, routine, and conventional activities previously known to the industry (See MPEP § 2106.05(c), Particular Transformation and MPEP § 2106.05(d), Well-Understood, Routine, Conventional Activity) as evidenced by Kwon. Kwon disclose the anti-coagulant substance as citrate salts (Kwon; [0037, 0039, 0079, 0080]).
Claims 6 and 13 further limit the perfusion chamber as comprising a microchannel section configured to obtain a specific shear rate. However, these additional elements do not effectively transform or reduce the system to a different state or thing beyond such that the claims recite significantly more than well-understood, routine, and conventional activities previously known to the industry (See MPEP § 2106.05(c), Particular Transformation and MPEP § 2106.05(d), Well-Understood, Routine, Conventional Activity) as evidenced by Kwon. Kwon disclose a microfluidic channel configured to emulate venous vessels and arterial vessels (Kwon; [0036, 0048, 0053, 0071]).
Claim 7 further limits the cytoadhesive substance of the perfusion chamber. However, these additional elements do not effectively transform or reduce the system to a different state or thing beyond such that the claims recite significantly more than well-understood, routine, and conventional activities previously known to the industry (See MPEP § 2106.05(c), Particular Transformation and MPEP § 2106.05(d), Well-Understood, Routine, Conventional Activity) as evidenced by Kwon. Kwon disclose the cytoadhesive substance comprise collagen hydrogel with tissue factor (figs. 1B & 1C, [0033-0035, 0041, 0047-0048, 0050, 0055, 0070, 0075-0076]).
Claim 8 recites the cytoadhesive substance is placed on a glass slide facing the perfusion chamber, said glass slide forming a surface of the perfusion chamber. However, these additional elements do not effectively transform or reduce the system to a different state or thing beyond such that the claims recite significantly more than well-understood, routine, and conventional activities previously known to the industry (See MPEP § 2106.05(c), Particular Transformation and MPEP § 2106.05(d), Well-Understood, Routine, Conventional Activity) as evidenced by Kwon. Kwon disclose the device constructed on or of glass (figs. 1B, [0030]).
Claims 10 and 11 recites the abstract idea of “1) dynamic evaluation of the efficacy of an anticoagulant or antiplatelet treatment on a subject taking one or more therapies” and “comparing the values of said parameters calculated in step 1) with reference values” (step 2A prong 1), but does not integrate the exception under 2A prong 2 because data gathering and generally linking the use of a judicial exception to a particular technological environment or field of use in which to apply the judicial exception do not integrate the judicial exception into a particular practical application because data gathering is merely insignificant extra-solution activity. See MPEP § 2106.05(g), Insignificant Extra-Solution Activity and § 2106.05(f), Mere Instructions To Apply an Exception.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-3, 5-8, and 10-13 are rejected under 35 U.S.C. 103 as being unpatentable over Kwon (US 2023/0393120 having a Provisional Application filing date of October 30, 2020 – hereinafter “Kwon”).
Regarding claim 1, Kwon disclose an ex vivo method for analyzing a coagulation function of a subject's blood sample (Kwon; [0006]), comprising the following steps:
a) providing a whole-blood sample taken from a subject and added with an anti- coagulant substance (Kwon; [0036, 0042, 0053, 0066, 0070, 0079, 0090];
b) treating the blood sample of step a) with a solution comprising fluorescent probes for marking platelets and for marking fibrin capable of binding to platelets and fibrin and emitting fluorescent light on two different emission frequencies (Kwon; antibodies were fluorescently labeled using the Alexa Fluor antibody labeling kits (488, 568, and 647). The fluorescently-labeled antibodies were used to detect platelets (a-CD61-568), P-selectin (a-CD62P-647), and fibrin (a-Fibrin-488); figs. 2B-2E, [0054-0055, 0075, 0079, 0081]) and of a recalcification solution of the blood sample, wherein the two solutions are separated or combined in a single reagent (Kwon; whole blood was recalcified in the presence of corn trypsin inhibitor and a buffer solution; [0039, 0053, 0079, 0080]);
c) introducing said recalcified blood sample into an analytical device having at least one perfusion chamber (Kwon disclose a blood vessel-on-a-chip microdevice having an intravascular channel 105 for introducing recalcified whole blood sample; figs. 1B & 1C, [0036, 0039, 0042, 0047-0048, 0053, 0055, 0066, 0079-0081, 0090]), in which at least one wall comprises a transparent material comprising a cytoadhesive substance (Kwon disclose the microdevice is optically transparent to allow a user to observe the dynamic process of bleeding and measure the kinetics of platelet accumulation in real-time, where the middle chamber comprise collagen hydrogel containing tissue factor 109; figs. 1B & 1C, [0033-0035, 0041, 0047-0048, 0050, 0055, 0070, 0075-0076]), the blood sample being made to flow into the perfusion chamber in known and measurable flow conditions (Kwon disclose flowing the whole blood through the intravascular channel at a shear rate to recapitulate or emulate the native vascular system; [0032, 0036, 0046, 0048, 0053, 0069-0070, 0074]) comprising controlled physiological flow conditions that simulate physiological conditions in venous vessels and arterial vessels (Kwon; [0036, 0048, 0053, 0066, 0071]) and maintaining the perfusion chamber at a temperature of about 37˚C while the blood sample flows through the perfusion chamber to simulate physiological conditions of the subject (Kwon; [0025, 0070, 0077-0078]);
d) during blood flow in the perfusion chamber, alternately acquiring at least two series of fluorescence images, so that at least one series of fluorescence images is acquired at an emission wavelength characteristic of the fluorescent probe for platelets and at least one other series of fluorescence images is acquired at another emission wavelength characteristic of the fluorescent probe for fibrin (Kwon; figs. 2B-2E, [0054-0055]);
e) binarizing the pixels of the acquired images for the platelets and for the fibrin, to generate a first curve of area covered by illuminated pixels vs. time for a formation of a platelet aggregate and a second curve of area covered by illuminated pixels vs. time for a fibrin formation (Kwon; fig. 2B-2I, 3A-3G, [0054-0061]);
the method comprising at least one step selected from:
f) generating a first curve of average fluorescence intensity vs. time for the formation of the platelet aggregate and a second curve of average fluorescence intensity vs. time for the fibrin formation (Kwon; fig. 2G, 2H, 2I, 5F, [0054-0058, 0068, 0081, 0084]);
g) generating a first integrated density curve defined as the product of area and fluorescence intensity vs. time for the formation of the platelet aggregate and a second integrated density curve defined as the product of area and fluorescence intensity vs. time for the fibrin formation (Kwon; fig. 2G, 2H, 2I, 5F, [0054-0058, 0068, 0081, 0084]);
h) generating a curve of particle number vs. time, in which the number of particles is given by a number of platelet aggregates comprising more than 2 illuminated pixels (Kwon; fig. 2G, 2H, 2I, 5F, [0054-0058, 0068, 0081, 0084]);
i) generating a curve of particle size vs. time, in which the particle size is given by an average size of the platelet aggregates comprising more than 2 illuminated pixels (Kwon; fig. 2G, 2H, 2I, 5F, [0054-0058, 0068, 0081, 0084]);
j) generating values of maximum slope, defined as relative maximum points of a first derivative function calculated for the curves of the parameter obtained in one or more of steps e), f), g), h) and i) (Kwon; fig. 2G, 2H, 2I, 5F, [0054-0058, 0068, 0081, 0084]);
k) generating values of maximum acceleration, defined as relative maximum points of a second derivative function calculated for the curves of the parameter obtained in one or more of steps e), f), g), h) and i) (Kwon; fig. 2G, 2H, 2I, 5F, [0054-0058, 0068, 0081, 0084]);
l) generating values of F/P ratio, defined as the ratio of the areas under the curve (AUCs) of fibrin to the AUCs of the platelets of the parameter obtained in one or more of steps e), f) and g) (Kwon; fig. 2G, 2H, 2I, 5F, [0054-0058, 0068, 0081, 0084]);
the method further comprising the steps of:
m) generating a lag time value representing a fibrin formation time defined as a time corresponding to which the value of the measured area related to fibrin is a maximum peak value of the curve (Kwon; fig. 2G, 2H, 2I, 5F, [0054-0058, 0068, 0081, 0084]);
n) generating the AUC (Area Under the Curve) values given by the area under the curve of the parameter obtained in one or more of steps e), f), g), h) and i) (Kwon; fig. 2G, 2H, 2I, 5F, [0054-0058, 0068, 0081, 0084]);
o) comparing one or more of the generated values of AUC, area under the curve of a fluorescence intensity curve (AUC MGV), area under the curve of an integrated density curve (AUC ID), and Lag Time with corresponding reference values (Kwon disclose comparing the platelet and fibrin deposition before adding the target drug with the measured platelet and fibrin deposition after adding the target drug; fig. 3F, [0013, 0061]. The device provides means for evaluating adverse effects of anticoagulatns and antiplate agents used for treating or preventing thrombotic events in the arterial and venous circulations by comparing injury-induced platelet and fibrin deposition when the devices were perfused with drug-containing whole blood. Hirudin analysis showed no statistically significant changes in platelet accumulation and activation as compared to control without the drug. However, Hirudin drastically reduced fibrin accumulation, illustrating its efficacy as a thrombin inhibitor where platelet aggregates blocked the extravascular opening. Analysis included an injury closure score ranging between 0 and 2, which corresponds to fully open and fully closed, respectively. The results indicating the adverse effects of Hirudin on the formation of competent hemostatic plugs ; fig. 5A-5F, [0066-0068]); and
p) determining, based on the comparison, at least one of: an efficacy of an anticoagulant or antiplatelet treatment, a risk of thrombogenesis, or a risk of blood coagulation defects in the subject (Kwon disclose comparing the platelet and fibrin deposition before adding the target drug with the measured platelet and fibrin deposition after adding the target drug; fig. 3F, [0013, 0061]. The device provides means for evaluating adverse effects of anticoagulants and antiplatelet agents used for treating or preventing thrombotic events in the arterial and venous circulations by comparing injury-induced platelet and fibrin deposition when the devices were perfused with drug-containing whole blood. Hirudin analysis showed no statistically significant changes in platelet accumulation and activation as compared to control without the drug. However, Hirudin drastically reduced fibrin accumulation, illustrating its efficacy as a thrombin inhibitor where platelet aggregates blocked the extravascular opening. Analysis included an injury closure score ranging between 0 and 2, which corresponds to fully open and fully closed, respectively. The results indicate the adverse effects of Hirudin on the formation of competent hemostatic plugs; fig. 5A-5F, [0066-0068]).
Kwon does not explicitly disclose the lag time value representing the fibrin formation time defined as a time corresponding to a first occurrence of five consecutive images in which the value of the measured area related to fibrin is > 1% of a maximum peak value of the curve.
However, Kwon does teach generating a time lag value range representing the fibrin formation time defined as a time within a few minutes of injury when platelets began to form small aggregates over time (Kwon; fig. 2G, 2H, 2I, 5F, [0054-0058, 0068, 0081, 0084]).
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the lag time value range representing the fibrin formation of Kwon with the lag time value range defined as a time corresponding to a first occurrence of five consecutive images in which the value of the measured area related to fibrin is >1% of a maximum peak value of the curve, because defining the lag time value range to correspond to a first occurrence of five consecutive images in which the value of the measured area related to fibrin is >1% of a maximum peak value of the curve would allow a quantifiable threshold value to be established to show changes over time in the formation of fibrin over the course of the method while eliminating trivial datasets during the time within a few minutes of injury when plates had yet to form small aggregates or the time after fibrin formation cease forming small aggregates. Further, a prima facie case of obviousness is established when “the claimed range and the prior art range do not overlap but are close enough such that one skill in the art would have expected them to have the same properties.” In re Peterson, 315 F. 3d at 1329, citing Titanium Metals Crop. V. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). In this case, Kwon teaches the fibrin is measured from 0% to an upward bound over approximately 9 minutes which overlaps with images corresponding to a value of the measured area when fibrin is >1% of a maximum peak of the curve. One of ordinary skill in the art would have expected this modification could have been performed with a reasonable expectation of success since Kwon disclose the formation of small aggregates at 2 minutes and image analysis for select data points (Kwon; figs. 2B-2E & 2G-2I, [0055, 0084]).
Regarding claim 2, modified Kwon teach the method according to claim 1 above, wherein the analytical device comprises reference marks configured to identify a height at which a surface is located on which an adhesion phenomenon of the platelets and fibrin will occur (Kwon teach identifying a region of interest in the vessel wall and plotting the fluorescence intensity aver over the length of the region of interest in terms of negative and positive distances; figs. 2F-2G, [0054, 0056]).
Regarding claim 3, modified Kwon teach the method according to claim 1 above, wherein said anti-coagulant substance is heparin or citrate salts (Kwon; [0037, 0039, 0079, 0080]).
Regarding claim 5, modified Kwon teach the method according to claim 1 above, wherein the recalcification of the blood sample is conducted by adding a quantity of calcium salt (Kwon; [0079]).
Regarding claim 6, modified Kwon teach the method according to claim 1 above, wherein the perfusion chamber comprises at least one microchannel section configured so as to obtain a shear rate, to simulate physiological conditions in the venous vessels(Kwon; [0036, 0048, 0053]), and at least one microchannel section configured so as to obtain a shear rate, to simulate physiological conditions in the arterial vessels (Kwon; [0071]).
Modified Kwon does not explicitly teach a shear rate between 150 sec-1 and 500 sec-1, to simulate the venous vessels or a shear rate between 1000 sec-1 and 2000 sec-1, to simulate the arterial vessels.
However, Kwon does teach perfusion in the intravascular channel at a venous shear rate of 100 sec-1 (Kwon; [0053]), and parallel chambers to recreate arterial conditions by changing hemodynamic parameters such as the flow rate; [0071]).
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify shear rate of Kwon to be between 150 sec-1 and 500 sec-1, to simulate the venous vessels or between 1000 sec-1 and 2000 sec-1, to simulate the arterial vessels, because adjusting the shear rate to be between 150 sec-1 and 500 sec-1, to simulate the venous vessels or between 1000 sec-1 and 2000 sec-1, to simulate the arterial vessels would allow the method and device of Kwon to emulate conditions in venous vessels or arterial vessels having different dimensions or to emulate fluids having different viscosities. Further, a prima facie case of obviousness is established when “the claimed range and the prior art range do not overlap but are close enough such that one skill in the art would have expected them to have the same properties.” In re Peterson, 315 F. 3d at 1329, citing Titanium Metals Crop. V. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). One of ordinary skill in the art would have expected this modification could have been performed with a reasonable expectation of success since Kwon disclose emulating venous vessels and arterials vessels by changing flow rates.
Regarding claim 7, modified Kwon teach the method according to claim 1 above, wherein the at least one perfusion chamber comprises at least one cytoadhesive substance on a surface thereof or on part thereof, said at least one cytoadhesive substance being selected from type I fibrillar Collagen, type I/III Collagen, type VI Collagen, PG-M/versican (vascular), Perlecan Fibronectin, Laminin-1, Vitronectin, Decorin, Biglycan, Fibulin-1, Tenascin-C, Lumican, Thrombospondin-1, emilin and tissue factor (Kwon disclose the microdevice is optically transparent to allow a user to observe the dynamic process of bleeding and measure the kinetics of platelet accumulation in real-time, where the middle chamber comprise collagen hydrogel containing tissue factor 109; figs. 1B & 1C, [0033-0035, 0041, 0047-0048, 0050, 0055, 0070, 0075-0076]).
Regarding claim 8, modified Kwon teach the method according to claim 7 above, wherein said at least one cytoadhesive substance is placed on a surface of a glass slide facing the perfusion chamber, said glass slide forming the surface of the at least one perfusion chamber which comprises the at least one cytoadhesive substance (Kwon; fig. 1B, [0030]).
Regarding claim 10, modified Kwon teach the method according to claim 1 above, for the ex-vivo evaluation of the efficacy of an anticoagulant or antiplatelet treatment on the subject taking one or more therapies, comprising the following steps:
1) dynamic evaluation of the parameters of AUC Area, AUC MGV, AUC ID and Lag Time on the whole-blood sample of said subject, in which the values of said parameters refer to an 8-bit acquisition system (The modification of the lag time value range representing the fibrin formation of Kwon with the lag time value range defined as a time corresponding to a first occurrence of five consecutive images in which the value of the measured area related to fibrin is >1% of a maximum peak value of the curve has previously been discussed in claim 1 above. Kwon disclose dynamic evaluation of the efficacy of an anticoagulant and antiplatelet treatment; figs. 5A-5F, [0015, 0042, 0066-0070, 0081]);
2) comparing the values of said parameters calculated in step 1) with reference values (The modification of the lag time value range representing the fibrin formation of Kwon with the lag time value range defined as a time corresponding to a first occurrence of five consecutive images in which the value of the measured area related to fibrin is >1% of a maximum peak value of the curve has previously been discussed in claim 1 above. Kwon disclose dynamic evaluation of the efficacy of an anticoagulant and antiplatelet treatment; figs. 5A-5F, [0015, 0042, 0066-0070]), in which
if the subject's platelet AUC Area is <4.4x107, and/or
if the subject's platelet AUC MGV is <3.0x104, and/or
if the subject's platelet AUC ID is <5.4x109, and/or
if the subject's fibrin AUC Area is <4.7x107, and/or
if the subject's fibrin AUC MGV is <2.7x104, and/or
if the subject's fibrin AUC ID is <7.0x109, and/or
if the subject's Lag Time is >210 s,
then the subject is likely to be under therapy and said therapy has a medium or high probability of being effective.
Note: “if… then…” are all contingent limitations and do not necessarily have to occur.
The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met. For example, assume a method claim requires step A if a first condition happens and step B if a second condition happens. If the claimed invention may be practiced without either the first or second condition happening, then neither step A or B is required by the broadest reasonable interpretation of the claim. If the claimed invention requires the first condition to occur, then the broadest reasonable interpretation of the claim requires step A. If the claimed invention requires both the first and second conditions to occur, then the broadest reasonable interpretation of the claim requires both steps A and B. (See MPEP 2111.04).
Claim limitation “if… then…” is a limitation that requires a condition where the sample platelet or fibrin parameter is less than or greater than a threshold value. Since the method may be practiced by the sample platelet or fibrin parameter being within a threshold value, the above limitation is not required.
Regarding claim 11, modified Kwon teach the method according to claim 1 above, for the ex-vivo evaluation of the risk of thrombogenesis or coagulation defects in the subject not undergoing drug therapy, comprising the following steps:
1A) dynamic evaluation of the parameters of AUC Area, AUC MGV, AUC ID and Lag Time on the whole-blood sample of said subject, in which the values of said parameters refer to an 8-bit acquisition system (The modification of the lag time value range representing the fibrin formation of Kwon with the lag time value range defined as a time corresponding to a first occurrence of five consecutive images in which the value of the measured area related to fibrin is >1% of a maximum peak value of the curve has previously been discussed in claim 1 above. Kwon disclose dynamic evaluation of the efficacy of an anticoagulant and antiplatelet treatment; figs. 5A-5F, [0015, 0042, 0066-0070, 0081]);
2A) comparing the values of said parameters calculated in step 1A) with reference values (The modification of the lag time value range representing the fibrin formation of Kwon with the lag time value range defined as a time corresponding to a first occurrence of five consecutive images in which the value of the measured area related to fibrin is >1% of a maximum peak value of the curve has previously been discussed in claim 1 above. Kwon disclose dynamic evaluation of the efficacy of an anticoagulant and antiplatelet treatment; figs. 5A-5F, [0015, 0042, 0066-0070]), in which
if the subject's platelet AUC Area is <4.4x107, and/or
if the subject's platelet AUC MGV is <3.0x104, and/or
if the subject's platelet AUC ID is <5.4x109, and/or
if the subject's fibrin AUC Area is <4.7x107, and/or
if the subject's fibrin AUC MGV is <2.7x104, and/or
if the subject's fibrin AUC ID is <7.0x109, and/or
if the subject's Lag Time is >210 s,
then said subject has a medium or high risk probability of blood coagulation defects;
or:
if the subject's platelet AUC Area is >4.4x107, and/or
if the subject's platelet AUC MGV is >3.0x104, and/or
if the subject's platelet AUC ID is >5.4x109, and/or
if the subject's fibrin AUC Area is >4.7x107, and/or
if the subject's fibrin AUC MGV is >2.7x104, and/or
if the subject's fibrin AUC ID is >7.0x109, and/or
if the subject's Lag Time is <210 s,
then said subject has a medium or high risk probability of thrombogenesis.
Note: “if… then…” are all contingent limitations and do not necessarily have to occur.
The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met. For example, assume a method claim requires step A if a first condition happens and step B if a second condition happens. If the claimed invention may be practiced without either the first or second condition happening, then neither step A or B is required by the broadest reasonable interpretation of the claim. If the claimed invention requires the first condition to occur, then the broadest reasonable interpretation of the claim requires step A. If the claimed invention requires both the first and second conditions to occur, then the broadest reasonable interpretation of the claim requires both steps A and B. (See MPEP 2111.04).
Claim limitation “if… then…” is a limitation that requires a condition where the sample platelet or fibrin parameter is less than or greater than a threshold value. Since the method may be practiced by the sample platelet or fibrin parameter being within a threshold value, the above limitation is not required.
Regarding claim 12, modified Kwon disclose the method according to claim 1 above, wherein the recalcification of the blood sample is conducted by adding a quantity of calcium chloride (Kwon; [0079]).
Regarding claim 13, modified Kwon teach the method according to claim 1 above, wherein the perfusion chamber comprises at least one microchannel section configured to obtain a shear rate to simulate the physiological conditions in the venous vessels (Kwon; [0036, 0048, 0053]), and at least one microchannel section configured to obtain a shear rate to simulate the physiological conditions in the arterial vessels (Kwon; [0071]).
Modified Kwon does not explicitly teach a shear rate of about 300 sec-1 to simulate the venous vessels or a shear rate of about 1500 sec-1 to simulate the arterial vessels.
However, Kwon does teach perfusion in the intravascular channel at a venous shear rate of 100 sec-1 (Kwon; [0053]), and parallel chambers to recreate arterial conditions by changing hemodynamic parameters such as the flow rate (Kwon; [0071]).
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify shear rate of Kwon to be about 300 sec-1 to simulate the venous vessels or about 1500 sec-1 to simulate the arterial vessels, because adjusting the shear rate to be about 300 sec-1 to simulate the venous vessels or about 1500 sec-1 to simulate the arterial vessels would allow the method and device of Kwon to emulate conditions in venous vessels or arterial vessels having different dimensions or to emulate fluids having different viscosities. Further, a prima facie case of obviousness is established when “the claimed range and the prior art range do not overlap but are close enough such that one skill in the art would have expected them to have the same properties.” In re Peterson, 315 F. 3d at 1329, citing Titanium Metals Crop. V. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). One of ordinary skill in the art would have expected this modification could have been performed with a reasonable expectation of success since Kwon disclose emulating venous vessels and arterials vessels by changing flow rates.
Claims 4 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Kwon in view of Ahearn et al. (US 2007/0178536 – hereinafter “Ahearn”), and further in view of Ruggeri et al. (US 2019/0127442 – hereinafter “Ruggeri”).
Regarding claim 4, modified Kwon teach the method according to claim 1 above, wherein the fluorescent probes used in step b) are:
for marking platelets, a quinacrine probe having an excitation wavelength of about 488 nm and an emission wavelength of about 510 nm, or an antiplatelet antibody or a derivative thereof, conjugated with a fluorescent molecule, having an excitation wavelength (Kwon; antibodies were fluorescently labeled using the Alexa Fluor antibody labeling kits (488, 568, and 647). The fluorescently-labeled antibodies were used to detect platelets (a-CD61-568), P-selectin (a-CD62P-647), and fibrin (a-Fibrin-488); figs. 2B-2E, [0054-0055, 0075, 0079, 0081]);
for marking fibrin, an antifibrin antibody conjugated with a fluorescent molecule, having an excitation wavelength (Kwon; antibodies were fluorescently labeled using the Alexa Fluor antibody labeling kits (488, 568, and 647). The fluorescently-labeled antibodies were used to detect platelets (a-CD61-568), P-selectin (a-CD62P-647), and fibrin (a-Fibrin-488); figs. 2B-2E, [0054-0055, 0075, 0079, 0081]).
Modified Kwon does not teach for marking platelets, the antiplatelet antibody conjugated with a fluorescent molecule having an excitation wavelength of about 495 nm and an emission wavelength of about 519 nm. However, Ahearn teach the analogous art of marking platelets using an antiplatelet antibody conjugated with a fluorescent molecule having an excitation wavelength of about 495 nm and an emission wavelength of about 519 nm (Ahearn; [0041]). It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the fluorescent molecule to mark platelets of modified Kwon to be Alexa Fluor 488, as taught by Ahearn, because Ahear teach the Alexa Fluor 488 fluorescent molecule allows detection for flow cytometry (Ahearn; [0041]). One of ordinary skill in the art would have expected this modification could have been performed with a reasonable expectation of success since modified Kwon and Ahearn both teach fluorescent detection of platelets using tagged antibodies.
Modified Kwon does not teach for marking fibrin, the fluorescent molecule, having an excitation wavelength of about 556 nm and an emission wavelength of about 573 nm. However, Ruggeri teach the analogous art of marking fibrin using a fluorescent molecule comprising Alexa Fluor 546 (Ruggeri; [0135]). It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the fluorescent molecule to mark fibrin of modified Kwon to be Alexa Fluor 546, as taught by Ruggeri, because Ruggeri teaching marking fibrin with Alexa Fluor 546 allows visualization specific for the B chain of human fibrin (HB-8545; ATCC) (Ruggeri; [0135]). One of ordinary skill in the art would have expected this modification could have been performed with a reasonable expectation of success since modified Kwon and Ruggeri both teach fluorescent detection of fibrin using fluorescent molecules.
Regarding claim 14, modified Kwon teach the method according to claim 1 above, wherein the fluorescent probes used in step b) are:
for marking platelets, a quinacrine probe having an excitation wavelength of about 488 nm and an emission wavelength of about 510 nm, or an antiplatelet antibody or a derivative thereof comprising Fab, or antigen binding fragment, conjugated with a fluorescent molecule, having an excitation wavelength (Kwon; antibodies were fluorescently labeled using the Alexa Fluor antibody labeling kits (488, 568, and 647). The fluorescently-labeled antibodies were used to detect platelets (a-CD61-568), P-selectin (a-CD62P-647), and fibrin (a-Fibrin-488); figs. 2B-2E, [0054-0055, 0075, 0079, 0081]);
for marking fibrin, an antifibrin antibody conjugated with a fluorescent molecule, having an excitation wavelength.
Modified Kwon does not teach for marking platelets, the antiplatelet antibody conjugated with a fluorescent molecule having an excitation wavelength of about 495 nm and an emission wavelength of about 519 nm. However, Ahearn teach the analogous art of an antiplatelet antibody conjugated with a fluorescent molecule, having an excitation wavelength of about 495 nm and an emission wavelength of about 519 nm (Ahearn; [0041]). It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the fluorescent molecule of modified Kwon to be Alexa Fluor 488, as taught by Ahearn, because Ahear teach the Alexa Fluor 488 fluorescent molecule allows detection for flow cytometry (Ahearn; [0041]). One of ordinary skill in the art would have expected this modification could have been performed with a reasonable expectation of success since modified Kwon and Ahearn both teach fluorescent detection of platelets using tagged antibodies.
Modified Kwon does not teach for marking fibrin, the fluorescent molecule having an excitation wavelength of about 556 nm and an emission wavelength of about 573 nm. However, Ruggeri teach the analogous art of marking fibrin using a fluorescent molecule comprising Alexa Fluor 546 (Ruggeri; [0135]). It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the fluorescent molecule to mark fibrin of modified Kwon to be Alexa Fluor 546, as taught by Ruggeri, because Ruggeri teaching marking fibrin with Alexa Fluor 546 allows visualization specific for the B chain of human fibrin (HB-8545; ATCC) (Ruggeri; [0135]). One of ordinary skill in the art would have expected this modification could have been performed with a reasonable expectation of success since modified Kwon and Ruggeri both teach fluorescent detection of fibrin using fluorescent molecules.
Response to Arguments
Applicants’ remarks, filed 07/23/2026, have been fully considered.
Applicant argues, see pages 9-11 of their remarks, towards the 101 rejection(s), that amended claim 1 does not stop at generating curves or numerical values. The claims now affirmatively requires comparing generated values with reference values and determining result based on the comparison. Applicant argues that the claims require treating whole-blood sample which integrates any alleged mathematical concept into a practical application. The examiner respectfully disagrees.
The amended limitations of comparing one or more of the generated values and determining an efficacy/risk are abstract ideas. These abstract ideas are mental processes that could be performed by a human person by pen and paper or by a black box computer. A user could, in their mind, compare one or more values and determine an efficacy or a risk based on the comparison. However, the abstract idea (comparing/determining) itself cannot be the alleged improvement in a particular technology. See MPEP 2106.05(a) paragraphs 4-7. The additional elements of acquiring images from a sample has been treated is interpreted as extra-solution activity incidental to the primary process as mere data gathering which is not considered significantly more than the abstract idea, and generally linking the use of a judicial exception to a particular technological environment or field of use in which to apply the judicial exception, but does not amount to significantly more than the exception itself and cannot integrate the judicial exception into a practical application (see MPEP § 2106.05(g), Insignificant Extra-Solution Activity and MPEP § 2106.05(h), Field of Use and Technological Environment). Accordingly, the claim does not integrate the abstract into a practical application.
Applicant argues on pages 11-13 of their remarks towards the 103 rejection over Kwon, that Kwon does not teach the amended clinical comparison and determination framework. The examiner respectfully disagrees.
Kwon disclose comparing the platelet and fibrin deposition before adding the target drug with the measured platelet and fibrin deposition after adding the target drug at 37 degrees C; fig. 3F, [0013, 0061, 0078, 0082]. The device provides means for evaluating adverse effects of anticoagulants and antiplatelet agents used for treating or preventing thrombotic events in the arterial and venous circulations by comparing injury-induced platelet and fibrin deposition when the devices were perfused with drug-containing whole blood. Hirudin analysis showed no statistically significant changes in platelet accumulation and activation as compared to control without the drug. However, Hirudin drastically reduced fibrin accumulation, illustrating its efficacy as a thrombin inhibitor where platelet aggregates blocked the extravascular opening. Analysis included an injury closure score ranging between 0 and 2, which corresponds to fully open and fully closed, respectively. The results indicate the adverse effects of Hirudin on the formation of competent hemostatic plugs; fig. 5A-5F, [0066-0068]. Accordingly, Kwon discloses the clinical comparison and determination framework of amended claim 1.
Applicants’ arguments, see pages 13-15 of their remarks towards Verdoold cited in the 101 rejection are moot because applicants argue Verdool does not render the claims obvious under 35 USC 103. However, the examiner notes that Verdoold was not used as the prior art rejection and was only used to support that the claims do not amount to significantly more under step 2B of the 35 USC 101 rejection. Thus, the prior art rejection does not rely on Verdoold for teaching any of the argued limitations.
Citations to art
In the above citations to documents in the art, an effort has been made to specifically cite representative passages, however rejections are in reference to the entirety of each document relied upon. Other passages, not specifically cited, may apply as well.
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 extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CURTIS A THOMPSON whose telephone number is (571)272-0648. The examiner can normally be reached on M-F: 7:00 a.m. - 5:00 p.m..
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.
E-mail communication Authorization
Per updated USPTO Internet usage policies, Applicant and/or applicant’s representative is encouraged to authorize the USPTO examiner to discuss any subject matter concerning the above application via Internet e-mail communications. See MPEP 502.03. To approve such communications, Applicant must provide written authorization for e-mail communication by submitting the following statement via EFS Web (using PTO/SB/439) or Central Fax (571-273-8300):
Recognizing that Internet communications are not secure, I hereby authorize the USPTO to communicate with the undersigned and practitioners in accordance with 37 CFR 1.33 and 37 CFR 1.34 concerning any subject matter of this application by video conferencing, instant messaging, or electronic mail. I understand that a copy of these communications will be made of record in the application file.
Written authorizations submitted to the Examiner via e-mail are NOT proper. Written authorizations must be submitted via EFS-Web (using PTO/SB/439) or Central Fax (571-273-8300). A paper copy of e-mail correspondence will be placed in the patent application when appropriate. E-mails from the USPTO are for the sole use of the intended recipient, and may contain information subject to the confidentiality requirement set forth in 35 USC § 122. See also MPEP 502.03.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Charles Capozzi can be reached at 571-270-3638. 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.
/C.A.T./Examiner, Art Unit 1798
/BENJAMIN R WHATLEY/Primary Examiner, Art Unit 1798
Prosecution Insights