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 .
Election/Restrictions
2. Applicant’s election of Group I – claims 1, 2, 7, 8, 11-18, 21-26, 37-39, 42-48, 50, 51, 57, and 58 in the reply filed on 6/1/26 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 3, 4, 6, 9, 10, 19, 20, 27-36, 40, 41, 49, and 52-56 are withdrawn.
Claim Rejections - 35 USC § 112
3. 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.
4. Claims 2 is 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 is vague and confusing because it recites a “stain agent” coated on one or both of the sample contact areas of the plates in claim 1 but then goes on to recite a “staining liquid”. Claim 1 recites a “staining liquid” on one or both of the plates. The inconsistency in “stain agent” vs “staining liquid” in claims 1 and 2 is confusing. Are these separate reagents or the same reagent?
Double Patenting
5. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
6. Claims 1, 7, 8, 12, 13, 16-18, 22-26, 37, 39, 42-44, 47, 48, 50, 51, 57, and 58 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-133 of U.S. Patent No. 10,132,794. Although the claims at issue are not identical, they are not patentably distinct from each other because patent ‘794 claims a device that anticipates the instant invention. The labeled specific binding reagents and cell stain on the plates read on a staining liquid.
Patent ‘794 claims:
1. A device for collecting and analyzing vapor condensate (VC) sample comprising:
a collection plate and cover plate, wherein:
i. the plates are movable relative to each other into different configurations;
ii. one or both plates are flexible;
iii. each of the plates has, on its respective surface, a sample contact area for contacting a vapor condensate (VC) sample that contains an analyte;
iv. one or both of the plates comprise spacers that are fixed with a respective plate, wherein the spacers have a predetermined substantially uniform height and a predetermined constant inter-space distance and wherein at least one of the spacers is inside the sample contact area;
wherein one of the configurations is an open configuration, in which: the two plates are
either completely or partially separated apart, the spacing between the plates is not regulated by the spacers, and the VC sample is deposited on one or both of the plates; and
wherein another of the configurations is a closed configuration which is configured after the VC sample deposition in the open configuration; and in the closed configuration: at least a part of the VC sample is between the two plates and in contact with the two plates, and has a highly uniform thickness that is regulated by the spacers and the two sample surface of the plates and is equal to or less than 30 µm with a small variation.
2. The device of claim 1, wherein the device further comprises a dry reagent coated on one or both of the plates.
3. The device of claim 2, wherein the dry binding site comprises a capture reagent.
4. The device of claim 2, wherein the dry binding site comprises an antibody or nucleic acid.
5. The device of claim 2, wherein the releasable dry reagent is a cell stain.
6. The device of claim 1, wherein the device further comprises, on one or both plates, a releasable dry reagent and a release time control material that delays the time that the releasable dry regent is released into the sample.
7. The device of claim 6, wherein the releasable dry reagent is a labeled reagent.
8. The device of claim 6, wherein the releasable dry reagent is a fluorescently labeled reagent.
9. The device of claim 6, wherein the releasable dry reagent is a fluorescently labeled antibody.
10. The device of claim 1, wherein the device further comprises, on one or both plates, a dry binding site that has a predetermined area, wherein the dry binding site binds to and immobilizes an analyte in the sample.
11. The device of claim 6, wherein the release time control material delays the time that the dry regent starts to be released into the sample by at least 3 seconds.
12. The device of claim 1, wherein the device further comprises, on one or both plates, one or a plurality of dry binding sites and/or one or a plurality of reagent sites.
13. The device of claim 1, wherein the sample is exhale breath condensate.
14. The device of claim 1, wherein the sample is a vapor from a biological sample, an environmental sample, a chemical sample, or a clinical sample.
15. The device of claim 1, wherein the analyte comprises a molecule (e.g., a protein, peptides, DNA, RNA, nucleic acid, or other molecules), cells, tissues, viruses, or nanoparticles with different shapes.
16. The device of claim 1, wherein the analyte comprises volatile organic compounds (VOCs).
17. The device of claim 1, wherein the analyte comprises nitrogen, oxygen, CO2, H2O, or inert gases.
18. The device of claim 1, wherein the analyte is stained.
19. The device of claim 1, wherein on one of the surfaces that contacts the sample, it further comprises an enclosure-spacer that encloses a partial or entire VC sample deposited on the collection plate.
20. The device of claim 1, wherein the highly uniform thickness has a value equal to or less than 0.5 µm.
21. The device of claim 1, wherein the highly uniform thickness has a value in the range of 0.5 µm to 1 µm.
22. The device of claim 1, wherein the highly uniform thickness has a value in the range of 1 µm to 2 µm.
23. The device of claim 1, wherein the highly uniform thickness has a value in the range of 2 µm to 10 µm.
24. The device of claim 1, wherein the highly uniform thickness has a value in the range of 10 µm to 20 µm.
25. The device of claim 1, wherein the highly uniform thickness has a value in the range of 20 µm to 30 µm.
26. The device of claim 1, wherein the thickness of the at least a part of VC sample at the closed configuration is larger than the thickness of VC sample deposited on the collection plate at the open configuration.
27. The device of claim 1, wherein the thickness of the at least a part of the VC sample at the closed configuration is less than the thickness of the VC sample deposited on the collection plate at the open configuration.
28. The device of claim 1, wherein the spacers are fixed on a plate by directly embossing the plate or injection molding of the plate.
29. The device of claim 1, wherein the materials of the plate and the spacers are selected from polystyrene, PMMA, PC, COC, COP, and another plastic.
30. The device of claim 1, wherein the inter-spacer distance is in the range of 1 µm to 200 µm.
31. The device of claim 1, wherein the inter-spacer distance is in the range of 200 µm to 1000 µm.
32. The device of claim 1, wherein the VC sample is an exhaled breath condensate from a human or an animal.
33. The device of claim 1, wherein the spacers regulating the layer of uniform thickness have a filling factor of at least 1%, wherein the filling factor is the ratio of the spacer area in contact with the layer of uniform thickness to the total plate area in contact with the layer of uniform thickness.
34. The device of claim 1, wherein for spacers regulating the layer of uniform thickness, the Young's modulus of the spacers times the filling factor of the spacers is equal or larger than 10 MPa, wherein the filling factor is the ratio of the spacer area in contact with the layer of uniform thickness to the total plate area in contact with the layer of uniform thickness.
35. The device of claim 1, wherein for a flexible plate, the thickness of the flexible plate times the Young's modulus of the flexible plate is in the range 60 to 750 GPa-um.
36. The device of claim 1, wherein for a flexible plate, the fourth power of the interspacer-distance (ISD) divided by the thickness of the flexible plate (h) and the Young's modulus (E) of the flexible plate, ISD.sup.4/(hE), is equal to or less than 10.sup.6 µm.sup.3/GPa.
37. The device of claim 1, wherein one or both plates comprises a location marker, either on a surface of or inside the plate, that provides information of a location of the plate.
38. The device of claim 1, wherein one or both plates comprises a scale marker, either on a surface of or inside the plate, that provides information of a lateral dimension of a structure of the sample and/or the plate.
39. The device of claim 1, wherein one or both plates comprises an imaging marker, either on surface of or inside the plate, that assists imaging of the sample.
40. The device of claim 1, wherein the spacers function as a location marker, a scale marker, an imaging marker, or any combination thereof.
41. The device of claim 1, wherein the average thickness of the layer of uniform thickness is about equal to a minimum dimension of the analyte in the sample.
42. The device of claim 1, wherein the inter-spacer distance is in the range of 1 µm to 50 µm.
43. The device of claim 1, wherein the inter-spacer distance is in the range of 50 µm to 120 µm.
44. The device of claim 1, wherein the inter-spacer distance is in the range of 120 um to 200 um.
45. The device of claim 1, wherein the inter-spacer distance is substantially periodic.
46. The device of claim 1, wherein the spacers are pillars with a cross-sectional shape selected from round, polygonal, circular, square, rectangular, oval, elliptical, and any combination of the same.
47. The device of claim 1, wherein the spacers have a pillar shape and have a substantially flat top surface, wherein, for each spacer, the ratio of the lateral dimension of the spacer to its height is at least 1.
48. The device of claim 1, wherein for each spacer, the ratio of the lateral dimension of the spacer to its height is at least 1.
49. The device of claim 1, wherein a minimum lateral dimension of spacer is less than or substantially equal to the minimum dimension of the analyte in the sample.
50. The device of claim 1, wherein a minimum lateral dimension of spacer is in the range of 0.5 µm to 100 µm.
51. The device of claim 1, wherein a minimum lateral dimension of spacer is in the range of 0.5 um to 10 um.
52. The device of claim 1, wherein the spacers have a density of at least 100/mm2.
53. The device of claim 1, wherein the spacers have a density of at least 1000/mm2.
54. The device of claim 1, wherein at least one of the plates is transparent.
55. The device of claim 1, wherein at least one of the plates is made from a flexible polymer.
56. The device of claim 1, wherein, for a pressure that compresses the plates, the spacers are not compressible and/or, independently, only one of the plates is flexible.
57. The device of any of claim 1, wherein the flexible plate has a thickness in the range of 10 µm to 200 µm.
58. The device of claim 1, wherein the variation is less than 30%.
59. The device of claim 1, wherein the variation is less than 10%.
60. The device of claim 1, wherein the variation is less than 5%.
61. The device of claim 1, wherein the collection and cover plates are connected and are configured to be changed from the open configuration to the closed configuration by folding the plates.
62. The device of claim 1, wherein the collection and cover plates are connected by a hinge and are configured to be changed from the open configuration to the closed configuration by folding the plates along the hinge.
63. The device of claim 1, wherein the collection and cover plates are connected by a hinge that is a separate material to the plates, and are configured to be changed from the open configuration to the closed configuration by folding the plates along the hinge.
64. The device of claim 1, wherein the collection and cover plates are made in a single piece of material and are configured to be changed from the open configuration to the closed configuration by folding the plates.
65. The device of claim 1, wherein the layer of uniform thickness of the sample is uniform over a lateral area that is at least 100 µm2.
66. The device of claim 1, wherein the layer of uniform thickness of the sample is uniform over a lateral area that is at least 1 mm2.
67. The device of claim 1, wherein the device is configured to analyze the sample in 60 seconds or less.
68. The device of claim 1, wherein at the closed configuration, the final sample thickness device is configured to analyze the sample in 60 seconds or less.
69. The device of claim 1, wherein the device further comprises, on one or both of the plates, one or a plurality of amplification sites that are each capable of amplifying a signal from the analyte or a label of the analyte when the analyte or label is within 500 nm from the amplification site.
70. The device of claim 1, wherein at the closed configuration, the final sample thickness device is configured to analyze the sample in 10 seconds or less.
71. The device of claim 1, wherein the collection or cover plate further comprises, on its surface, a first predetermined assay site and a second predetermined assay site, wherein the distance between the edges of the assay site is substantially larger than the thickness of the uniform thickness layer when the plates are in the closed position, wherein at least a part of the uniform thickness layer is over the predetermined assay sites, and wherein the sample has one or a plurality of analytes that are capable of diffusing in the sample.
72. The device of claim 1, wherein the collection or cover plate has, on its surface, at least three analyte assay sites, and the distance between the edges of any two neighboring assay sites is substantially larger than the thickness of the uniform thickness layer when the plates are in the closed position, wherein at least a part of the uniform thickness layer is over the assay sites, and wherein the sample has one or a plurality of analytes that are capable of diffusing in the sample.
73. The device of claim 1, wherein the collection or cover plate has, on its surface, at least two neighboring analyte assay sites that are not separated by a distance that is substantially larger than the thickness of the uniform thickness layer when the plates are in the closed position, wherein at least a part of the uniform thickness layer is over the assay sites, and wherein the sample has one or a plurality of analytes that are capable of diffusing in the sample.
74. The device of claim 1, wherein the device further comprises a detector that is an optical detector for detecting an optical signal.
75. The device of claim 1, wherein the device further comprises a detector that is an electrical detector for detecting an electric signal.
76. The device of claim 1, wherein the thickness of the at least a part of the VC sample at the closed configuration is less than the thickness of the VC sample deposited on the collection plate at the open configuration.
77. A system for rapidly analyzing a vapor condensation sample using a mobile phone comprising:
(a) a device of claim 1; and
(b) a mobile communication device comprising:
i. one or a plurality of cameras for the detecting signal and/or imaging the vapor condensate sample; and
ii. electronics, signal processors, hardware and software for receiving and/or processing the detected signal and/or the image of the vapor condensate sample and for remote communication.
78. The system of claim 77, further comprising: (d) a housing configured to hold the sample and to be mounted to the mobile communication device.
79. The system of claim 78, wherein the housing comprises optics for facilitating the imaging and/or signal processing of the sample by the mobile communication device, and a mount configured to hold the optics on the mobile communication device.
80. The system of claim 78, wherein an element of the optics in the housing is movable relative to the housing.
81. The system of claim 77, wherein the system further comprises a light source from either the mobile communication device or an external source.
82. The system of claim 77, wherein one of the plates has a binding site that binds the analyte, wherein at least part of the uniform sample thickness layer is over the binding site, and is substantially less than the average lateral linear dimension of the binding site.
83. The system of claim 77, wherein the mobile communication device is configured to communicate test results to a medical professional, a medical facility or an insurance company.
84. The system of claim 77, wherein the mobile communication device is further configured to communicate information on the test and the subject with the medical professional, medical facility or insurance company.
85. The system of claim 77, wherein the mobile communication device is further configured to communicate information of the test to a cloud network, and the cloud network is configured to process the information to refine the test results.
86. The system of claim 77, wherein the mobile communication device is further configured to communicate information of the test and the subject to a cloud network, the cloud network is configured to process the information to refine the test results, and the refined test results will send back the subject.
87. The system of claim 77, wherein the mobile communication device is configured to receive a prescription, diagnosis or a recommendation from a medical professional.
88. The system of claim 77, wherein the mobile communication device is configured with hardware and software to:
(a) capture an image of the sample;
(b) analyze a test location and a control location in in image; and
(c) compare a value obtained from analysis of the test location to a threshold value that characterizes the rapid diagnostic test.
89. The system of claim 77, wherein at least one of the plates comprises a storage site in which assay reagents are stored.
90. The system of claim 77, at least one of the cameras reads a signal from the device.
91. The system of claim 77, wherein the mobile communication device communicates with the remote location via a wifi or cellular network.
92. The system of claim 77, wherein the mobile communication device is a mobile phone.
93. A method for rapidly analyzing an analyte in a sample using a mobile phone, comprising:
(a) depositing a sample on the device of claim 77;
(b) assaying an analyte in the sample deposited on the device to generate a result; and
(c) communicating the result from the mobile communication device to a location remote from the mobile communication device.
94. The method of claim 93, wherein the analyte comprises a molecule (e.g., a protein, peptides, DNA, RNA, nucleic acid, or other molecule), cells, tissues, viruses, or nanoparticles with different shapes.
95. The method of claim 93, wherein the analyte comprises white blood cell, red blood cell and platelets.
96. The method of claim 93, wherein the method comprises: analyzing the results at the remote location to provide an analyzed result; and communicating the analyzed result from the remote location to the mobile communication device.
97. The method of claim 93, wherein the analysis is done by a medical professional at a remote location.
98. The method of claim 93, wherein the mobile communication device receives a prescription, diagnosis or a recommendation from a medical professional at a remote location.
99. The method of claim 93, wherein the thickness of the at least a part of VC sample at the closed configuration is larger than the thickness of VC sample deposited on the collection plate at the open configuration.
100. The method of claim 93, wherein the assaying step comprises detecting an analyte in the sample.
101. The method of claim 93, wherein the analyte is a biomarker.
102. The method of claim 93, wherein the analyte is a protein, nucleic acid, cell, or metabolite.
103. The method of claim 93, wherein the assay done in step (b) is a binding assay or a biochemical assay.
104. A method for analyzing an analyte in a vapor condensate sample comprising:
obtaining a device of claim 1;
depositing the vapor condensate sample onto one or both plates of the device;
placing the plates in the closed configuration and applying an external force over at least part of the plates; and
analyzing the analyte in the layer of uniform thickness while the plates are in the closed configuration.
105. The method for analyzing an analyte in a vapor condensate sample, wherein the method comprises:
(a) obtaining a sample;
(b) obtaining the device of claim 1 wherein the spacers have:
i. a shape of pillar with substantially uniform cross-section and a flat top surface;
ii. a ratio of the width to the height equal or larger than one;
iii. a predetermined constant inter-spacer distance that is in the range of 10 µm to 200 µm; and
iv. a filling factor of equal to 1% or larger; and
(c) depositing the sample on one or both of the plates when the plates are configured in the open configuration;
(d), after (c), using the two plates to compress at least part of the sample into the layer of substantially uniform thickness that has an average value equal to or less than 30 um with a variation of less than 10%, wherein the compressing comprises: bringing the two plates together; and conformable pressing, either in parallel or sequentially, an area of at least one of the plates to press the plates together to a closed configuration, wherein the conformable pressing generates a substantially uniform pressure on the plates over the at least part of the sample, and the pressing spreads the at least part of the sample laterally between the sample contact surfaces of the plates, and wherein the closed configuration is a configuration in which the spacing between the plates in the layer of uniform thickness region is regulated by the spacers; and
(e) analyzing the analyte in the layer of uniform thickness while the plates are the closed configuration; wherein the filling factor is the ratio of the spacer contact area to the total plate area; wherein a conformable pressing is a method that makes the pressure applied over an area is substantially constant regardless the shape variation of the outer surfaces of the plates; and wherein the parallel pressing applies the pressures on the intended area at the same time, and a sequential pressing applies the pressure on a part of the intended area and gradually move to other area.
106. The method of claim 105, wherein the analyzing step comprises counting the analyte in the sample.
107. The method of claim 106, wherein the imaging and counting is done by: i. illuminating the cells in the layer of uniform thickness; ii. taking one or more images of the cells using a CCD or CMOS sensor; iii. identifying cells in the image using a computer; and iv. counting a number of cells in an area of the image.
108. The method of claim 105, wherein the method further comprises removing the external force after the plates are in the closed configuration; and imaging the analytes in the layer of uniform thickness while the plates are the closed configuration; and counting a number of analytes or the labels in an area of the image.
109. The method of claim 105, wherein the method comprises removing the external force after the plates are in the closed configuration; and measuring optical signal in the layer of uniform thickness while the plates are in the closed configuration.
110. The method of claim 105, wherein the inter-spacer distance is in the range of 20 µm to 200 µm.
111. The method of claim 105, wherein the inter-spacer distance is in the range of 5 µm to 20 µm.
112. The method of claim 105, wherein a product of the filling factor and the Young's modulus of the spacer is 2 MPa or larger.
113. The method of claim 105, wherein the surface variation is less than 50 nm.
114. The method of claim 105, further comprising a step of calculating the concentration of an analyte in the relevant volume of sample, wherein the calculation is based on the relevant sample volume defined by the predetermined area of the storage site, the uniform sample thickness at the closed configuration, and the amount of target entity detected.
115. The method of claim 105, wherein the external force is provided by human hand.
116. The method of claim 105, wherein the device it future comprises a dry reagent coated on one or both plates.
117. The method of claim 105, wherein the layer of uniform thickness of the sample has a thickness uniformity of up to +/-5%.
118. The method of claim 105, wherein the spacers are pillars with a cross-sectional shape selected from round, polygonal, circular, square, rectangular, oval, elliptical, or any combination of the same.
119. The method of claim 105, wherein the spacing between the spacers is approximately the minimum dimension of the analyte.
120. The method of claim 105, wherein one or both plate sample contact surfaces comprises one or a plurality of amplification sites that are each capable of amplifying a signal from the analyte or a label of the analyte when the analyte or label is within 500 nm from an amplification site.
121. The method of claim 105, wherein the sample is exhale breath condensate.
122. The method of claim 105, wherein the sample is a vapor from a biological sample, an environmental sample, a chemical sample, or clinical sample.
123. The method of claim 105, wherein the analyte comprises a molecule (e.g., a protein, peptides, DNA, RNA, nucleic acid, or other molecules), cells, tissues, viruses, and nanoparticles with different shapes.
124. The method of claim 105 wherein the analyte comprises volatile organic compounds (VOCs).
125. The method of claim 105, wherein the analyte comprises nitrogen, oxygen, CO2, H2O, and inert gases.
126. The method of claim 105 wherein the analyte is stained.
127. The method of claim 105, wherein on one of the sample surface, it further comprises an enclosure-spacer that encloses a partial or entire VC samples deposited on the collection plate.
128. The method of claim 105, wherein the highly uniform thickness has a value equal to or less than 0.5 µm.
129. The method of claim 105, wherein the highly uniform thickness has a value in the range of 0.5 µm to 1 µm.
130. The method of claim 105, wherein the highly uniform thickness has a value in the range of 1 µm to 2 µm.
131. The method of claim 105, wherein the highly uniform thickness has a value in the range of 2 µm to 10 µm.
132. The method of claim 105, wherein the highly uniform thickness has a value in the range of 10 µm to 20 µm.
133. The method of claim 105, wherein the highly uniform thickness has a value in the range of 20 µm to 30 µm.
7. Claims 1, 7, 8, 12-18, 21, 22, 24-26, 37, 39, 42-44, 47, 48, 50, 51, 57, and 58 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-156 of U.S. Patent No. 10,605,805. Although the claims at issue are not identical, they are not patentably distinct from each other because patent ‘805 claims a method for analyzing tissue, including staining, with essentially the same limitations as the instant method and recites using a device with the same limitations as the instant device.
Patent ‘805 claims:
1. A method for analyzing a sample comprising:
a. obtaining a device comprising:
a first plate and a second plate, wherein:
i. the plates are movable relative to each other into different configurations, including an open configuration and a closed configuration;
ii. one or both plates are flexible;
iii. each of the plates has, on its respective surface, a sample contact area for contacting a sample that contains an analyte;
iv. one or both of the plates comprise spacers that are fixed with a respective plate, wherein the spacers have pillar shape, a substantially flat top surface, a predetermined substantially uniform height and a predetermined constant inter-spacer distance, and wherein at least one of the spacers is inside the sample contact area; and
v. the fourth power of the inter-spacer distance (ISD) divided by the thickness (h) and the Young's modulus (E) of the flexible plate (ISD4/(hE)) is 5.times.10.sup.5 um.sup.3/GPa or less;
b. depositing the sample onto one or both plates of the device in an open configuration;
wherein in an open configuration, the two plates are separated apart, the spacing between the plates is not regulated by the spacers, and the sample is deposited on one or both of the plates; and
c. after b, placing the plates in the closed configuration by applying an external force over at least part of the plates, wherein in the closed configuration, at least part of the sample is compressed by the two plates into a layer of uniform thickness and is substantially stagnant relative to the plates, wherein the uniform thickness of the layer is confined by the inner surfaces of the two plates and is regulated by the plates and the spacers, and has a thickness equal to or less than 250 µm; and
d. analyzing the layer of uniform thickness while the plates are in the closed configuration.
2. The method of claim 1, further comprising: imaging cells in the sample in the layer of uniform thickness while the plates are in the closed configuration to form an image; and counting a number of cells in an area of the image.
3. The method of claim 1, wherein the inter-spacer distance is in the range of 20 µm to 200 µm.
4. The method of claim 1, wherein the inter-spacer distance is in the range of 5 µm to 20 µm.
5. The method of claim 1, wherein the sample is undiluted whole blood into which no anticoagulant has been added.
6. The method of claim 1, wherein the depositing step is done by: pricking the skin of a human thereby releasing a droplet of blood onto the skin and contacting the droplet of blood with one or both of the plates without use of a blood transfer tool.
7. The method of claim 1, wherein the analyzing step comprise counting the number of red blood cells.
8. The method of claim 1, wherein the device further comprises scale markers, wherein the scale markers comprise at least a pair of the scale-markers that are separated by a known distance.
9. The method of claim 1, wherein the analyzing step comprises counting the number of red blood cells, white blood cells, neutrophils, lymphocytes, monocytes, eosinophils or basophils.
10. The method of claim 2, wherein the imaging and counting is done by: i. illuminating the cells in the layer of uniform thickness; ii. taking one or more images of the cells using a CCD or CMOS sensor; iii. identifying cells in the image using a computer; and iv. counting a number of cells in an area of the image.
11. The method of claim 1, wherein the external force is provided by human hand.
12. The method of claim 1, further comprising measuring sodium, potassium, chloride, bicarbonate, blood urea, nitrogen, magnesium, creatinine, glucose, calcium, HDL cholesterol LDL cholesterol levels and/or triglyceride levels in the layer of uniform thickness.
13. The method of claim 1, wherein the device further comprises a dry reagent coated on one or both plates.
14. The method of claim 1, wherein the layer of uniform thickness sample has a thickness uniformity of up to +/-5%.
15. The method of claim 1, wherein the spacers are pillars with a cross-sectional shape selected from round, polygonal, circular, square, rectangular, oval, elliptical, or any combination of the same.
16. The method of claim 1, wherein the spacing between the spacers is approximately an average thickness of red blood cells.
17. The method of claim 1, wherein the analyzing step comprises imaging cells in the blood.
18. The method of claim 2, wherein the blood cells comprise red blood cells, white blood cells, or platelets.
19. The method of claim 1, wherein the analyzing comprises imaging cancer cells, viruses, or bacteria in the blood.
20. The method of claim 1, wherein the analyzing comprises detecting proteins or nucleic acids.
21. The method of claim 2, wherein imaging the blood cells comprises measuring hemocytes, comprising determining of the sample thickness using the spacer, determining the lateral area by imaging, and calculating the area of red blood cells using the 2D image.
22. The method of claim 2, wherein the imaging the blood cells comprises measuring the red cell concentration in the blood.
23. The method of claim 2, wherein the imaging the blood comprises measuring the white blood cell concentration in the blood.
24. The method of claim 2, wherein the imaging the blood comprises measuring the platelet concentration in the blood.
25. The method of claim 1, wherein the sample is a blood, the analytes are blood cells, and the uniform thickness of the layer is 1.9 um-2.2 um.
26. The method of claim 1, wherein the external force is applied by human hand.
27. The method of claim 1, wherein the external force is by human hand, and the uniform sample thickness has a variation of 50% or less.
28. The method of claim 1, wherein at least a portion of the inner surface of one plate or both plate is hydrophilic.
29. The method of claim 1, wherein the sample is deposited directly from a subject to the plate without using any transferring devices.
30. The method of claim 1, wherein the sample maintains the same sample thickness in the closed configuration after some or all of the external force is removed.
31. The method of claim 1, wherein the spacers have pillar shape and nearly uniform cross-section.
32. The method of claim 1, wherein the fourth power of the inter-spacer-distance (ISD) divided by the thickness (h) and the Young's modulus (E) of the flexible plate (ISD.sup.4/(hE)) is 5.times.10.sup.6 um.sup.3/GPa or less.
33. The method of claim 1, wherein the fourth power of the inter-spacer distance (ISD) divided by the thickness (h) and the Young's modulus (E) of the flexible plate (ISD.sup.4/(hE)) is 5.times.10.sup.5 um.sup.3/GPa or less.
34. The method of claim 1, wherein the spacers have pillar shape, a substantially flat top surface, a predetermined substantially uniform height, and a predetermined constant inter-spacer distance that is at least about 2 times larger than the size of the analyte, wherein the Young's modulus of the spacers times the filling factor of the spacers is equal or larger than 2 MPa, wherein the filling factor is the ratio of the spacer contact area to the total plate area, and wherein, for each spacer, the ratio of the lateral dimension of the spacer to its height is at least 1 (one).
35. The method of claim 1, wherein the spacers have pillar shape, a substantially flat top surface, a predetermined substantially uniform height, and a predetermined constant inter-spacer distance that is at least about 2 times larger than the size of the analyte, wherein the Young's modulus of the spacers times the filling factor of the spacers is equal or larger than 2 MPa, wherein the filling factor is the ratio of the spacer contact area to the total plate area, and wherein, for each spacer, the ratio of the lateral dimension of the spacer to its height is at least 1 (one), wherein the fourth power of the inter-spacer-distance (ISD) divided by the thickness (h) and the Young's modulus (E) of the flexible plate (ISD.sup.4/(hE)) is 5.times.10.sup.6 um.sup.3/GPa or less; wherein the sample is blood; wherein the analytes is red blood cell, white blood cell, or platelets; and wherein the uniform thickness of the layer is in a range of 1.8 um to 2.6 um.
36. The method of claim 1, wherein the analyte is a protein, a peptide, a nucleic acid, a synthetic compound, or an inorganic compound.
37. The method of claim 1, wherein the sample that is deposited on one or both of the plates has an unknown volume.
38. The method of claim 1, wherein the analyte correlates with the stage of a disease.
39. The method of claim 1, wherein the sample is from a patient having an infectious and parasitic disease, an injury, a cardiovascular disease, a cancer, a mental disorder, a neuropsychiatric disorder, a pulmonary disease, a renal disease, or other organic disease.
40. The method of claim 1, further comprising detecting or quantifying a microorganism.
41. The method of claim 1, wherein the sample comprises a virus, a fungus, or a bacteria.
42. The method of claim 1, further comprising detecting or quantifying one or more chemical compounds or biological samples that pose a hazard to food safety or national security.
43. The method of claim 1, wherein the analyte is a vital parameter of a medical or physiological monitor.
44. The method of claim 1, wherein the method provides a measurement of glucose, blood, oxygen level, and/or total blood count.
45. The method of claim 1, wherein the method comprises detecting and/or quantifying specific DNA or RNA from a biosample.
46. The method of claim 1, comparing further comprising DNA sequencing.
47. The method of claim 1, further comprising detecting a reaction product.
48. The method of claim 1, wherein the sample comprises cells, tissue, bodily fluid, or stool.
49. The method of claim 1, wherein the method comprises detecting a protein, a peptide, a nucleic acid, a synthetic compound, or an inorganic compound.
50. The method of claim 1, wherein the sample is the sample in a human sample, a veterinary sample, an agriculture sample, a food sample, an environment sample, or a drug testing sample.
51. The method of claim 1, wherein the sample is a biological sample selected from blood, serum, plasma, a nasal swab, a nasopharyngeal wash, saliva, urine, gastric fluid, spinal fluid, tears, stool, mucus, sweat, earwax, oil, a glandular secretion, cerebral spinal fluid, tissue, semen, vaginal fluid, interstitial fluids derived from tumorous tissue, ocular fluids, spinal fluid, a throat swab, breath, hair, finger nails, skin, biopsy, placental fluid, amniotic fluid, cord blood, lymphatic fluids, cavity fluids, sputum, pus, microbiota, meconium, breast milk, exhaled condensate nasopharyngeal wash, nasal swab, throat swab, stool samples, hair, finger nail, ear wax, breath, connective tissue, muscle tissue, nervous tissue, epithelial tissue, cartilage, cancerous sample, and bone.
52. The method of claim 1, wherein the sample is blood.
53. The method of claim 1, wherein the sample is a biological sample, an environmental sample, a chemical sample, or a clinical sample.
54. The method of claim 1, wherein the analyzing step comprises measuring: i. luminescence selected from photoluminescence, electroluminescence, and electrochemiluminescence, ii. surface Raman scattering, iii. electrical impedance selected from resistance, capacitance, and inductance, or iv. any combination of i-iii.
55. The method of claim 1, wherein the analyzing step comprises reading, image analysis, or counting of the analyte, or a combination of thereof.
56. The method of claim 1, wherein the sample contains one or plurality of analytes, and one or both plate sample contact areas comprise one or a plurality of binding sites that each binds and immobilize a respective analyte.
57. The method of claim 1, wherein one or both plate sample contact areas comprise one or a plurality of storage sites that each stores a reagent or reagents, wherein the reagent(s) dissolve and diffuse in the sample during or after step (c).
58. The method of claim 1, wherein one or both plate sample contact areas comprises one or a plurality of amplification sites that are each capable of amplifying a signal from the analyte or a label of the analyte when the analyte or label is within 500 nm from an amplification site.
59. The method of claim 1, wherein: i. one or both plate sample contact areas comprise one or a plurality of binding sites that each binds and immobilize a respective analyte; or ii. one or both plate sample contact areas comprise, one or a plurality of storage sites that each stores a reagent or reagents; wherein the reagent(s) dissolve and diffuse in the sample during or after step (c), and wherein the sample contains one or plurality of analytes; or iii. one or a plurality of amplification sites that are each capable of amplifying a signal from the analyte or a label of the analyte when the analyte or label is 500 nm from the amplification site; or iv. any combination of i to iii.
60. The method of claim 1, wherein the sample is a liquid biological sample selected from amniotic fluid, aqueous humour, vitreous humour, blood (e.g., whole blood, fractionated blood, plasma or serum), breast milk, cerebrospinal fluid (CSF), cerumen (earwax), chyle, chime, endolymph, perilymph, feces, breath, gastric acid, gastric juice, lymph, mucus (including nasal drainage and phlegm), pericardial fluid, peritoneal fluid, pleural fluid, pus, rheum, saliva, exhaled breath condensates, sebum, semen, sputum, sweat, synovial fluid, tears, vomit, prostatic fluid, nipple aspirate fluid, lachrymal fluid, perspiration, cheek swabs, cell lysate, gastrointestinal fluid, biopsy tissue and urine.
61. The method of claim 1, wherein the spacers are in a periodic array.
62. The method of claim 1, wherein the spacers are arranged in a periodic array, and wherein the periodic array has a triangular lattice, square lattice, diamond lattice, pentagonal lattice, hexagonal lattice, heptagonal lattice, octagonal lattice, nonagonal lattice, or a decagonal lattice.
63. The method of claim 1, wherein the analyte is a protein, peptides, DNA, RNA, nucleic acid, molecules, cells, tissues, viruses, nanoparticles with different shapes, or a combination thereof.
64. The method of claim 1, wherein the analyte comprises a stained cell.
65. The method of claim 1, wherein the analyte comprises a stained cell comprising neutrophils, lymphocytes, monocytes, eosinophils or basophils.
66. The method of claim 1, wherein the analyte comprises a stained analyte, wherein the stain comprising acridine Orange dye.
67. The method of claim 1, wherein the analyte is selected from the group consisting of a cell, a blood cell, a red blood cell, a white blood cell, a granulocyte, a neutrophil, an eosinophil, a basophil, a lymphocyte, a monocyte, a platelet, a cancer cell, a virus, a bacteria, a fungus, a protein, a nucleic acid, a DNA molecule, an RNA molecule, an miRNA molecule, an mRNA molecule, a hemocyte, a peptide, a polypeptide, a tissue, a nanoparticle, a drug metabolite, a lipid, a carbohydrate, a hormone, a vitamin, a combination thereof, a fragment thereof, and a combination thereof.
68. The method of claim 1, wherein the analyte is measured by using an label that is selected from the group consisting of a light-emitting label, a fluorescent label, a dye, a quantum dot, a luminescent label, electro-luminescent label, a chemi-luminescent label, a bead, an electromagnetic radiation emitter, an optical label, an electric label, enzymes that can be used to generate an optical or electrical signal, a nanoparticle, a colorimetric label, an enzyme-linked reagent, a multicolor reagent, and an avidin-streptavidin associated detection reagent.
69. The method of claim 1, wherein the analyte is measured by using an label comprising a fluorescent label that is selected from the group consisting of IRDye800CW, Alexa 790, Dylight 800, fluorescein, fluorescein isothiocyanate, succinimidyl esters of carboxyfluorescein, succinimidyl esters of fluorescein, 5-isomer of fluorescein dichlorotriazine, caged carboxyfluorescein-alanine-carboxamide, Oregon Green 488, Oregon Green 514, Lucifer Yellow, acridine Orange, rhodamine, tetramethylrhodamine, Texas Red, propidium iodide, JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazoylcarbocyanine iodide), tetrabromorhodamine 123, rhodamine 6G, TMRM (tetramethyl rhodamine methyl ester), TMRE (tetramethyl rhodamine ethyl ester), tetramethylrosamine, rhodamine B, 4-dimethylaminotetramethylrosamine, green fluorescent protein, blue-shifted green fluorescent protein, cyan-shifted green fluorescent protein, red-shifted green fluorescent protein, yellow-shifted green fluorescent protein, 4-acetamido-4'-isothiocyanatostilbene-2,2'disulfonic acid, acridine, acridine isothiocyanate, 5-(2'-aminoethyl)aminonaphthalene-1-sulfonic acid (EDANS), 4-amino-N-[3-vinylsulfonyl)phenyl]naphth-alimide-3,5 disulfonate, N-(4-anilino-1-naphthyl)maleimide, anthranilamide, 4,4-difluoro-5-(2-thienyl)-4-bora-3a,4a diaza-5-indacene-3-propioni-c acid BODIPY, cascade blue, Brilliant Yellow, coumarin, 7-amino-4-methylcoumarin (AMC, Coumarin 120),7-amino-4-trifluoromethylcoumarin (Coumarin 151), cyanine dyes, cyanosine, 4',6-diaminidino-2-phenylindole (DAPI), 5',5''-dibromopyrogallol-sulfonaphthalein (Bromopyrogallol Red), 7-diethylamino-3-(4'-isothiocyanatophenyl)-4-methylcoumarin, diethylenetriaamine pentaacetate, 4,4'-diisothiocyanatodihydro-stilbene-2-,2'-disulfonic acid, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, 5-(dimethylamino]naphthalene-1-sulfonyl chloride (DNS, dansylchloride), 4-dimethylaminophenylazophenyl-4'-isothiocyanate (DABITC), eosin, eosin isothiocyanate, erythrosin, erythrosin B, isothiocyanate, ethidium, fluorescein, 5-carboxyfluorescein (FAM),5-(4,6-dichlorotriazin-2-yl)amino-fluorescein (DTAF), 2',7'dimethoxy-4'5'-dichloro-6-carboxyfluorescein (JOE), fluorescein isothiocyanate, QFITC, (XRITC), fluorescamine, IR144, IR1446, Malachite Green isothiocyanate, 4-methylumbelli-feroneortho cresolphthalein, nitrotyrosine, pararosaniline, Phenol Red, B-phycoerythrin, o-phthaldialdehyde, pyrene, pyrene butyrate, succinimidyl 1-pyrene, butyrate quantum dots, Reactive Red 4 (Cibacron.TM. Brilliant Red 3B-A) rhodamine, 6-carboxy-X-rhodamine (ROX), 6-carboxyrhodamine (R6G), lissamine rhodamine B sulfonyl chloride rhodamine (Rhod), rhodamine B, rhodamine 123, rhodamine X isothiocyanate, sulforhodamine B, sulforhodamine 101, sulfonyl chloride derivative of sulforhodamine 101 (Texas Red), N,N,N',N'-tetramethyl-6-carboxyrhodamine (TAMRA), tetramethyl rhodamine, tetramethyl hodamine isothiocyanate (TRITC), riboflavin, 5-(2'-aminoethyl) aminonaphthalene-1-sulfonic acid (EDANS), 4-(4'-dimethylaminophenylazo)benzoic acid (DABCYL), rosolic acid, CAL Fluor Orange 560, terbium chelate derivatives, Cy 3, Cy 5, Cy 5.5, Cy 7, IRD 700, IRD 800, La Jolla Blue, phthalo cyanine, naphthalo cyanine, coumarin, xanthene dyes such as rhodols, resorufins, bimanes, acridines, isoindoles, dansyl dyes, aminophthalic hydrazides such as luminol, isoluminol derivatives, aminophthalimides, aminonaphthalimides, aminobenzofurans, aminoquinolines, dicyanohydroquinones, fluorescent europium, terbium complexes, a green fluorescent protein (GFP), a GFP derived from Aequoria victoria, a "humanized" derivative such as Enhanced GFP, a GFP from Renilla reniformis, Renilla mulleri, Ptilosarcus guernyi, "humanized" recombinant GFP (hrGFP), a combination thereof, a fragment thereof, and a combination thereof.
70. The method of claim 2, wherein the imaging and counting is done by: i. illuminating the blood cells in the layer of uniform thickness; ii. taking one or more images of the blood cells using a CCD or CMOS sensor; iii. identifying cells in the image using a computer; and iv. counting a number of blood cells in an area of the image.
71. The method of claim 1, wherein the analyzing comprises measuring hemocytes, comprising determining the sample thickness using the spacer, determining the lateral area by imaging, and calculating the area of red blood cells using the 2D image.
72. The method of claim 1, wherein the device further comprises an imager, wherein the imager images the spacers and the images are used to assist the quantification of a relevant volume of the sample.
73. The method of claim 1, wherein the device further comprises: a plurality of scale marks, an imager, and a processing device, wherein: at least a portion of the plurality of scale marks comprises the spacers that are periodically arranged; the imager images the scale marks and the device; and the processing device processes one or more images imaged by the imager.
74. The method of claim 1, wherein the sample is a biological sample selected from the group consisting of blood, serum, plasma, a nasal swab, a nasopharyngeal wash, saliva, urine, gastric fluid, spinal fluid, tears, stool, mucus, sweat, earwax, oil, a glandular secretion, cerebral spinal fluid, tissue, semen, vaginal fluid, interstitial fluids derived from tumorous tissue, ocular fluids, spinal fluid, a throat swab, breath, hair, finger nails, skin, biopsy, placental fluid, amniotic fluid, cord blood, lymphatic fluids, cavity fluids, sputum, pus, microbiota, meconium, breast milk, exhaled condensate nasopharyngeal wash, nasal swab, throat swab, stool samples, hair, finger nail, ear wax, breath, connective tissue, muscle tissue, nervous tissue, epithelial tissue, cartilage, cancerous sample, and bone.
75. The method of claim 1, wherein the sample includes an analyte selected from proteins, peptides, nucleic acids, synthetic compounds, and inorganic compounds.
76. The method of claim 1, wherein the device further comprises a measurement device, wherein the measurement device detects and/or quantifies the analyte by measuring a signal related to the analyte, wherein the signal is an optical signal, electrical signal, mechanical signal, chemi-physical signal, or any combination of thereof.
77. The method of claim 1, wherein the device further comprises a measurement device, wherein the measurement device detects and/or quantifies the analyte by measuring an optical signal related to the analyte, wherein the optical signal comprising light reflection, scattering, transmission, absorption, spectrum, color, emission, intensity, wavelength, location, polarization, luminescence, fluorescence, electroluminescence, chemiluminescence, electrochemiluminescence, or any combination of thereof.
78. The method of claim 1, wherein the device further comprises a measurement device, wherein the measurement device detects and/or quantifies the analyte by measuring an electric signal related to the analyte, wherein the electrical signal comprising charge, current, impedance, capacitance, resistance, or any combination of thereof.
79. The method of claim 1, wherein the device further comprises a measurement device, wherein the measurement device detects and/or quantifies the analyte by measuring a mechanical signal related to the analyte, wherein the mechanical signal comprising mechanical wave, sound wave, shock wave, or vibration.
80. The method of claim 1, wherein the device further comprises a measurement device, wherein the measurement device detects and/or quantifies the analyte by measuring a chemi-physical signal related to the analyte, wherein he chemi-physical signal includes, but not limited to, PH value, ions, heat, gas bubbles, color change, that are generated in a reaction.
81. The method of claim 1, wherein the sample is a blood, the analytes are blood cells, and the uniform thickness of the layer is 1.9 um to 2.2 um.
82. The method of claim 1, wherein the external force is applied by a human hand.
83. The method of claim 1, wherein the external force is by a human hand, and the uniform sample thickness has a variation of 50% or less.
84. The method of claim 1, wherein at least a portion of the inner surface of one plate or both plates is hydrophilic.
85. The method of claim 1, wherein the sample is deposited directly from a subject to the plate without using any transferring devices.
86. The method of claim 1, wherein the sample maintains the same sample thickness in the closed configuration after some or all of the external force is removed.
87. The method of claim 1, wherein the spacers have a pillar shape and a nearly uniform cross-section.
88. The method of claim 1, wherein the fourth power of the inter-spacer distance (ISD) divided by the thickness (h) and the Young's modulus (E) of the flexible plate (ISD.sup.4/(hE)) is 5.times.10.sup.5 um.sup.3/GPa or less.
89. The method of claim 1, wherein the spacers have a pillar shape, a substantially flat top surface, a predetermined substantially uniform height, and a predetermined constant inter-spacer distance that is at least about 2 times larger than the size of the analyte, wherein the Young's modulus of the spacers times the filling factor of the spacers is equal or larger than 2 MPa, wherein the filling factor is the ratio of the spacer contact area to the total plate area, and wherein, for each spacer, the ratio of the lateral dimension of the spacer to its height is at least 1 (one).
90. The method of claim 1, wherein the spacers have a pillar shape, a substantially flat top surface, a predetermined substantially uniform height, and a predetermined constant inter-spacer distance that is at least about 2 times larger than the size of the analyte, wherein the Young's modulus of the spacers times the filling factor of the spacers is equal or larger than 2 MPa, wherein the filling factor is the ratio of the spacer contact area to the total plate area, and wherein, for each spacer, the ratio of the lateral dimension of the spacer to its height is at least 1 (one), wherein the fourth power of the inter-spacer-distance (ISD) divided by the thickness (h) and the Young's modulus (E) of the flexible plate (ISD.sup.4/(hE)) is 5.times.10.sup.6 um.sup.3/GPa or less; wherein the sample is blood; wherein the analytes is a red blood cell, a white blood cell, or platelets; and wherein the uniform thickness of the layer is in a range of 1.8 um to 2.6 um.
91. The method of claim 1, wherein the analyte is a protein, a peptide, a nucleic acid, a synthetic compound, or an inorganic compound.
92. The method of claim 1, wherein the analyte correlates with the stage of a disease.
93. The method of claim 1, wherein the sample is from a patient having an infectious and parasitic disease, an injury, a cardiovascular disease, a cancer, a mental disorder, a neuropsychiatric disorder, a pulmonary disease, a renal disease, or other organic disease.
94. The method of claim 1, further comprising detecting or quantifying a microorganism.
95. The method of claim 1, wherein the sample comprises a virus, fungus, or bacteria.
96. The method of claim 1, further comprising detecting or quantifying one or more chemical compounds or biological samples that pose a hazard to food safety or national security.
97. The method of claim 1, wherein the analyte is a vital parameter of a medical or physiological monitor.
98. The method of claim 1, wherein the method provides a measurement of glucose, blood, oxygen level, or total blood.
99. The method of claim 1, wherein the method comprises detecting or quantifying a specific DNA or RNA from a biosample.
100. The method of claim 1, wherein the method comprises comparing DNA sequences.
101. The method of claim 1, wherein the method comprises detecting a reaction product.
102. The method of claim 1, wherein the sample comprises cells, tissue, bodily fluid, or stool.
103. The method of claim 1, wherein the method comprises detecting a protein, a peptide, a nucleic acid, a synthetic compound, or an inorganic compound.
104. The method of claim 1, wherein the sample is the sample in a human sample, a veterinary sample, an agriculture sample, a food sample, an environmental sample, or a drug testing sample.
105. The method of claim 1, wherein the sample is a biological sample, an environmental sample, a chemical sample, or a clinical sample.
106. The method of claim 1, wherein the sample is not flowable.
107. The method of claim 1, wherein the method comprises imaging cells in the blood and counting the number of the cells.
108. The method of any prior claim, wherein the external force that pressed the device from an open configuration to a closed configuration is provided by human hand, and the sample thickness variation is 10% and less.
109. The method of claim 1, wherein one or both plates have a staining reagent and the sample is stained.
110. The method of claim 1, wherein the sample thickness is reduced to reduce the diffusion time of the reagent, wherein at the closed configuration, the device is configured to analyze the sample in 60 seconds or less.
111. The method of claim 1, wherein the reagent comprises capture agents, detection agents, chemical compounds, optical labels, radioactive labels, enzymes, antibodies, proteins, nucleic acids, DNA, RNA, lipids, carbohydrates, salts, metals, surfactants, solvents, or any combination thereof.
112. The method of claim 1, wherein: the sample is whole blood without liquid dilution; the spacers have a uniform height selected from 20 um to 30 um, the fourth power of the inter-spacer-distance (IDS) divided by the thickness (h) and the Young's modulus (E) of the flexible plate (ISD.sup.4/(hE)) is 5.times.10.sup.6 um.sup.3/GPa or less; the thickness of the flexible plate times the Young's modulus of the flexible plate is in the range of 60 to 750 GPa-um; and the analyte comprises a protein, nucleic acid, cell, or metabolite.
113. The method of claim 1, wherein: the sample is whole blood without liquid dilution, the spacers have a uniform height selected from 2 .mu.m to 5 .mu.m, the fourth power of the inter-spacer-distance (IDS) divided by the thickness (h) and the Young's modulus (E) of the flexible plate (ISD.sup.4/(hE)) is 5.times.10.sup.6 um.sup.3/GPa or less; the thickness of the flexible plate times the Young's modulus of the flexible plate is in the range of 60 to 750 GPa-um; and the analyte comprises a protein, nucleic acid, cell, or metabolite.
114. The method of claim 1, wherein a plate has multiple reagent sites, wherein the measurement time is longer than the assay saturation incubation time but less than a time for a significant inter-diffusion between two neighboring sites.
115. The method of claim 1, wherein the step of analyzing is performed without washing.
116. The method of claim 1, wherein the sample is tissue, and the reagent is a staining agent.
117. The method of claim 1, wherein the sample is a liquid, a solid, or a semi-solid.
118. The method of claim 1, wherein the sample is stained by immunohistochemical staining.
119. The method of claim 1, wherein the analyzing comprises imaging the sample and communicating the results using a mobile communication device, wherein the mobile communication device comprises: (i) one or a plurality of cameras for the detecting and/or imaging the sample; and (ii) signal processors, hardware, and software for receiving and/or processing a detected signal and/or an image of the sample and for remote communication.
120. The method of claim 1, wherein the analyzing comprises (a) taking, using an imager, one or more images of the sample between the plates, and (b) processing, using a processing device, the one or more images using an image processing algorithm, and wherein the image processing algorithm includes one or more selected from the group consisting of a particle count algorithm, a look up table (LUT) filter, a particle filter, a pattern recognition algorithm, a morphological determination algorithm, a histogram, a line profile, a topographical representation, a binary conversion, a color matching profile, or any combination thereof.
121. The method of claim 1, wherein the analyzing comprises (a) taking, using an imager, one or more images of the sample between the plates, and (b) processing, using a processing device, the one or more images, using a method comprising one or more selected from the group consisting of an image acquisition algorithm, an image processing algorithm, a user interface method that (i) facilitates interaction between a user and a computational device and (ii) serves as means for data collection, data transmission and analysis, a communication protocol, and a data processing algorithm.
122. The method of claim 1, wherein the analyzing comprises (a) taking, using an imager, one or more images of the sample between the plates, and (b) processing, using a processing device, the one or more images, using a method comprising one or more selected from the group consisting of detecting a signal from the sample, correcting raw data based on at least one of (i) mathematical manipulation, (ii) mathematical correction, and (iii) calibrations specific for the device or reagents used to examine the sample, calculating a value, calculating a concentration value, comparing, determining the accuracy of a test, determining outlying values or results, determining values or results above or below a normal or acceptable range, determining values or results indicative of an abnormal condition, determining two or more results which, together, indicate the presence of an abnormal condition, curve-fitting, using data as the basis of mathematical or analytical reasoning selected from the group consisting of deductive reasoning, inductive reasoning, Bayesian reasoning.
123. The method of claim 1, wherein the analyzing comprises (a) imaging, using an imager, the sample to generate data, and (b) processing, using a processing device, the data from the imager, wherein the processing comprises at least one selected from the group consisting of binning data, transforming data, transforming time domain data by Fourier Transform to frequency domain, and combining the data with additional data.
124. The method of claim 1, wherein the analyzing comprises (a) imaging, using an imager, the sample to generate data, and (b) processing, using a processing device, the data from the imager, wherein the processing comprises at least one selected from the group consisting of detecting a signal from a sample, correcting raw data based on at least one of (i) mathematical manipulation, (ii) mathematical correction, and (iii) calibrations specific for the device or reagents used to examine the sample, calculating a value, calculating a concentration value, comparing with a baseline, threshold, standard curve, historical data, or data from other sensors, determining the accuracy of a test, determining outlying values or results, determining values or results above or below a normal or acceptable range, determining values or results indicative of an abnormal condition, determining two or more results which, together, indicate the presence of an abnormal condition, curve-fitting, using data as the basis of mathematical or analytical reasoning selected from the group consisting of deductive reasoning, inductive reasoning, Bayesian reasoning.
125. The method of claim 1, wherein the analyzing comprises (a) imaging, using an imager, the sample to generate data, and (b) processing, using a processing device, the data from the imager, wherein the processing comprises comparing the processed data with a database stored in a device to retrieve instructions for a course of action to be performed by a subject.
126. The method of claim 1, wherein the analyzing comprises (a) imaging, using an imager, the sample to generate data, and (b) processing, using a processing device, the data from the imager, wherein the processing comprises determining an accuracy of a test.
127. The method of claim 119, wherein imaging the sample comprises imaging the spacers, wherein the spacers are in a periodic array, and the spacers are used as scale markers.
128. The method of claim 120, wherein taking the one or more images comprises imaging the spacers, wherein the spacers are in a periodic array, and the spacers are used as scale markers.
129. The method of claim 121, wherein taking the one or more images comprises imaging the spacers, wherein the spacers are in a periodic array, and the spacers are used as scale markers.
130. The method of claim 122, wherein taking the one or more images comprises imaging the spacers, wherein the spacers are in a periodic array, and the spacers are used as scale markers.
131. The method of claim 123, wherein imaging the sample comprises imaging the spacers, wherein the spacers are in a periodic array, and the spacers are used as scale markers.
132. The method of claim 124, wherein imaging the sample comprises imaging the spacers, wherein the spacers are in a periodic array, and the spacers are used as scale markers.
133. The method of claim 125, wherein imaging the sample comprises imaging the spacers, wherein the spacers are in a periodic array, and the spacers are used as scale markers.
134. The method of claim 126, wherein imaging the sample comprises imaging the spacers, wherein the spacers are in a periodic array, and the spacers are used as scale markers.
135. The method of claim 1, wherein the analyzing comprises (a) taking, using an imager, one or more images of the sample between the plates, and (b) scanning, using a scanner, different areas of the sample, wherein the spacers comprise a periodic array of spacers.
136. The method of claim 1, wherein the analyzing comprises (a) taking, using an imager, one or more images of the sample between the plates, and (b) scanning, using a scanner, different areas of the sample.
137. The method of claim 1, wherein the device further comprises, on one or both plates, a dry binding site that has a predetermined area, wherein the dry binding site binds to and immobilizes an analyte in the sample.
138. The method of claim 1, wherein the device further comprises, on one or both plates, a releasable dry reagent and a release time control material that delays the time that the releasable dry regent is released into the sample.
139. The method of claim 138, wherein the release time control material delays the time that the dry regent starts being released into the sample by at least 3 seconds.
140. The method of claim 138, wherein the regent comprises anticoagulant and/or staining reagent(s).
141. The method of claim 1, wherein the device further comprises, on one or both plates, one or a plurality of dry binding sites and/or one or a plurality of reagent sites.
142. The method of claim 1, wherein the device further comprises a dry reagent coated on one or both plates.
143. The method of claim 1, wherein the ratio of the inter-spacing distance of the spacers to the average width of the spacer is 2 or larger, and the filling factor of the spacers multiplied by the Young's modulus of the spacers is 2 MPa or larger, wherein the filling factor is the ratio of the spacer contact area to the total plate area.
144. The method of claim 1, wherein the analyte is stained.
145. The method of claim 1, wherein for spacers regulating the layer of uniform thickness, the Young's modulus of the spacers times the filling factor of the spacers is equal or larger than 10 MPa, wherein the filling factor is the ratio of the spacer contact area to the total plate area.
146. The method of claim 1, wherein the average thickness of the layer of uniform thickness is in the range of 1.8 µm to 2.6 µm and the sample is whole blood without a dilution by another liquid.
147. The method of claim 1, wherein the thickness of one of the plates times the Young's modulus of the plate is in the range 60 to 750 GPa-um.
148. The method of claim 1, wherein for a flexible plate, the fourth power of the inter-spacer-distance (ISD) divided by the thickness of the flexible plate (h) and the Young's modulus (E) of the flexible plate, ISD.sup.4/(hE), is equal to or less than 10.sup.6 um.sup.3/GPa.
149. The method of claim 1, wherein one or both plates comprises a location marker, either on a surface of or inside the plate, that provide information of a location of the plate.
150. The method of claim 1, wherein one or both plates comprises a scale marker, either on a surface of or inside the plate, that provide information of a lateral dimension of a structure of the sample and/or the plate.
151. The method of claim 1, wherein one or both plates comprises an imaging marker, either on surface of or inside the plate, that assists an imaging of the sample.
152. The method of claim 1, wherein the spacers function as a location marker, a scale marker, an imaging marker, or any combination of thereof.
153. The method of claim 1, wherein the average thickness of the layer of uniform thickness is in the range of 2 µm to 2.2 µm and the sample is blood.
154. The method of claim 1, wherein the average thickness of the layer of uniform thickness is in the range of 2.2 µm to 2.6 µm and the sample is blood.
155. The method of claim 1, wherein the average thickness of the layer of uniform thickness is in the range of 1.8 µm to 2 µm and the sample is blood.
156. The method of claim 1, wherein the average thickness of the layer of uniform thickness is in the range of 2.6 µm to 3.8 µm and the sample is blood.
8. Claims 1, 2, 7, 8, 11, 12, 14, 15, 18, 22, 24-26, 37-39, 42, 43, 47, 48, 57, and 58 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-33 of U.S. Patent No. 11,609,224. Although the claims at issue are not identical, they are not patentably distinct from each other because patent ‘224 claims a device and method of using the device that anticipates the instant invention. The device of patent ‘224 includes a cell stain, lysing agent (permeabilizing agent), detergent (transfer solution), release agent coated on the plates.
Patent ‘224 claims:
1. A device for analyzing an analyte in a liquid sample, comprising:
(a) an attachment member configured to attach the device to an apparatus that comprises a light source and a camera;
(b) a card slot configured to accommodate a sample card, wherein the sample card comprises two plates having a gap of 200 μm or less, that sandwich a liquid sample into a layer of uniform thickness, wherein when the sample card is inserted into the card slot, the sample is positioned under the view of the camera and the light source;
(c) an optical filter configured to filter light from the light source to form a first beam with a specific wavelength range, wherein a part of the first beam illuminates on the edge of the sample card and travels inside the sample card to illuminate the sample;
(d) a mirror configured to deflect a second part of the first beam to form a second beam that back-illuminates the sample in an oblique angle; and
(e) an absorber configured to absorb a remaining part of the first beam that has a substantial divergence angle.
2. The device of claim 1, further comprising a lens, wherein the lens is positioned on a front-side of the sample and the configuration of the mirror is configured to make the oblique angle is larger of the second part of the first beam than a collecting angle of the lens.
3. The device of claim 1, further comprising a wavelength filter positioned between the sample and the camera to pass fluorescence emitted by the sample in response to the oblique illumination.
4. The device of claim 1, wherein the sample card is supported by a sample holder comprising a planar structure, and wherein the receptacle sample slot is configured to position the planar structure to extend partially into a path of illumination light from the light source to couple illumination light into the planar structure.
5. A method for analyzing an analyte in a liquid sample using the device of claim 1, comprising:
(a) providing the device of claim 1;
(b) obtaining the liquid sample;
(c) compressing at least part of the sample into a layer of uniform thickness with a sample card,
(c) inserting the sample card into the device of claim 1;
(e) illuminating the sample with light from the light source wherein the sample card comprises: a first plate, a second plate, and spacers, wherein:
(i) the plates are movable relative to each other into different configurations;
(ii) one or both plates are flexible;
(iii) each of the plates comprises an inner surface that has a sample contact area for contacting a blood sample;
(iv) one or both of the plates comprise the spacers that are permanently fixed on the sample contact area of a respective plate;
(vi) the spacers have:
(a) a predetermined substantially uniform height that has a value selected in the range of 5 μm to 50 μm,
(b) a shape of pillar with a substantially uniform cross-section and a flat top surface;
(c) a ratio of the width to the height equal to or larger than one;
(d) a predetermined, fixed, non-random, inter-spacer distance that is in the range of 10 μm to 200 μm (micron);
(e) a filling factor of equal to 1% or larger, wherein the filling factor is the ratio of the spacer contact area (on the plate) to the total plate area; and
(f) the filling factor multiplies the Young's modulus of the spacer is equal to 2 MPa or larger;
wherein one of the configurations is an open configuration, in which: the two plates are partially or completely separated apart, the spacing between the plates is not regulated by the spacers, and the sample is deposited on one or both of the plates;
wherein another of the configurations is a closed configuration which is configured after the sample is deposited in the open configuration; and in the closed configuration: at least part of the sample is compressed by the two plates into a layer of highly uniform thickness and is substantially stagnant relative to the plates, wherein the uniform thickness of the layer is confined by the sample contact areas of the two plates and is regulated by the plates and the spacers.
6. The method of claim 5, further comprising:
(f) capturing images of the sample in the layer of uniform thickness with the camera;
(g) analyzing the images to enumerate the analyte in the images; and
(h) calculating the concentration of the analyte in the sample based on the uniform thickness, a field of view of the camera, analyte number, and a predetermined correction factor; wherein the field of view is the extent of the field in which the camera captures the images; wherein the correction factor is determined by a miscount ratio, which is dependent on the field of view, the uniform thickness, and properties of the analyte.
7. The method of claim 5, wherein the liquid sample is a blood sample, the method further comprises:
(a) depositing the blood sample on one or both of the plates when the plates are configured in the open configuration,
(b) after (a), forcing the two plates into a closed configuration; and
(c) capturing images of sample in the layer of uniform thickness while the plates are the closed configuration; and (
d) analyzing the images to determine the concentration of white blood cells in the sample.
8. The method of claim 7, wherein the step of analyzing the images comprises determining the respective number of white blood cells including neutrophils, lymphocytes, monocytes, eosinophils and basophils, through the counting of the cell number in the images and the analysis of the fluorescence color and shape for each white blood cell.
9. The method of claim 5, further comprising:
(a) analyzing the images to enumerate the analyte in the images,
(b) calculating the concentration of the analyte in the sample based on the uniform thickness, a field of view of the camera, the analyte enumeration, and a predetermined correction factor; wherein the field of view is the area of sample of which the camera captures the images; wherein the correction factor is determined by a miscount ratio, which is dependent on the field of view, the uniform thickness, and properties of the analyte.
10. The method of claim 6, wherein the correction factor is used to back calculate the WBC count to WBC concentration to compensate the WBC miss counting in the process.
11. The method of claim 6, wherein the correction factor depending on the size of the gap between the two plates of the sample holder is used to back calculate the WBC count to WBC concentration to compensate the WBC miss counting in the process.
12. The method of claim 6, wherein the correction factor is used to back calculate the WBC count to WBC concentration to compensate other imperfection effect as WBC distribution in the process.
13. The device of claim 1, wherein the sample card comprises:
a first plate, a second plate, and spacers, wherein:
(i) the plates are movable relative to each other into different configurations;
(ii) one or both plates are flexible;
(iii) each of the plates comprises an inner surface that has a sample contact area for contacting a blood sample;
(iv) one or both of the plates comprise the spacers that are permanently fixed on the sample contact area of a respective plate;
(vi) the spacers have:
(a) a predetermined substantially uniform height that has a value selected in the range of 5 μm to 50 μm,
(b) the fourth power of the inter-spacer-distance (ISD) divided by the thickness (h) and the Young's modulus (E) of the flexible plate (ISD.sup.4/(hE)) is 5×10.sup.6 μm.sup.3/GPa, and
(c) the thickness of the flexible plate times the Young's modulus of the flexible plate is in the range 60 to 750 GPa-μm,
wherein one of the configurations is an open configuration, in which: the two plates are partially or completely separated apart, the spacing between the plates is not regulated by the spacers, and the sample is deposited on one or both of the plates;
another of the configurations is a closed configuration which is configured after the sample is deposited in the open configuration; and in the closed configuration: at least part of the sample is compressed by the two plates into a layer of highly uniform thickness and is substantially stagnant relative to the plates, wherein the uniform thickness of the layer is confined by the sample contact areas of the two plates and is regulated by the plates and the spacers.
14. The method of claim 1, wherein the analyte is white blood cells (WBCs).
15. The device of claim 1, wherein the gap has a size in the range of 2 μm to 150 μm.
16. The device of claim 1, wherein the gap has a size in the range of 5 μm to 50 μm.
17. The device of claim 1, wherein the gap has a size in the range of 2 μm to 30 μm.
18. The device of claim 1, wherein the gap has a size in the range of 2 μm to 15 μm.
19. The device of claim 1, wherein a field of view for counting and differentiating WBCs is in the range of 1 mm.sup.2 to 50 mm.sup.2.
20. The device of claim 1, further comprising an anti-conglutination agent that is coated inside the sample card, the anti-conglutination agent comprises ethylenediaminetetraacetic acid (EDTA), EDTA disodium, K.sub.2EDTA, or K.sub.3EDTA, citrate, heparin, or any combinations thereof.
21. The device of claim 1, further comprising a fluorescence reagent for detecting the analyte.
22. The device of claim 1, further comprising a cell stain agent coated inside the sample card, the cell stain agent comprises Wright's stain (Eosin, methylene blue), Giemsa stain (Eosin, methylene blue, and Azure B), May-Grunwald stain, Leishman's stain (“Polychromed” methylene blue (i.e. demethylated into various azures) and eosin), Erythrosine B stain (Erythrosine B), and other fluorescence stain including but not limit to Acridine orange dye, 3,3-dihexyloxacarbocyanine (DiOC6), Propidium Iodide (PI), Fluorescein Isothiocyanate (FITC) and Basic Orange 21 (B021) dye, Ethidium Bromide, Brilliant Sulfaflavine and a Stilbene Disulfonic Acid derivative, Erythrosine B or trypan blue, Hoechst 33342, Trihydrochloride, Trihydrate, or DAPI (4′,6-Diamidino-2-Phenylindole, Dihydrochloride), YOYO or any combinations thereof.
23. The device of claim 1, further comprising a cell lysing agent coated inside the sample card, the cell lysing agent comprises ammonium chloride, sodium bicarbonate, ethylenediaminetetraacetic acid (EDTA), acetic acid, citric acid, or other acid and base, or any combinations thereof.
24. The device of claim 1, further comprising an agent coated on the sample card, wherein the agent comprises Zwittergent, ASB-14, ASB-16, CHAPS, Cationic surfactant NN-[Tris(hydroxymethyl) methyl]-N-alkyl-N,N-dimethyl ammonium chloride (Ila), llb, llc, lld, CTAC, Tween 20, Tween 40, Tween 60, Tween 80, Sodium lauryl sulfate (SLS), ammonium lauryl sulfate, CTAB, sodium lauryl ether sulfate (SLES), sodium myreth sulfate, docusate, perfluorooctanesulfonate, alkyl-aryl ether phosphates, alkyl ether phosphates, CTAB, cetylpyridinium chloride (CPC), benzalkonium chloride (BAC), benzethonium chloride (BZT), dimethyldioctadecylammonium chloride, dioctadecyldimethlyammonium bromide (DODAB), cocamidopropyl hydroxysultaine, cocamidopropyl betaine, narrow-range ethoxylate, octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether, nonxynols, Triton X-100, polyethoxylated tallow amine, cocamide monoethanolamine, cocamide diethanolamine, poloxamers, glycerol monostearate, glycerol monolaurate, sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, decyl glucoside, lauryl glucoside, octyl glucoside, lauryldimethylamine oxide, dimethyl sulfoxide, or phosphine oxide.
25. The device of claim 1, further comprising agent coated on the device, wherein the agent comprises Pluronic F-127, Cremophor EL, Pluronic F-68, Myrj 52, Brij 35, sodium oleate, sodium dodecyl sulfate, Tween 20, Tween 40, Tween 60, Tween 80, SLS, CTAB, CTAC, Tamoxifen, saponin, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, lactic acid, ABS-14, ABS-16, anti-malaria drugs (quinine compounds), arsenic, dapsone, metals (chromium/chromates, platinum salts, nickel compounds, copper, lead, cis-platinum), nitrites, nitrofurantoin, penicillin, phenazopyridine (pyridium), rho immune globulin, ribavirin, sulfonamides, sulfones.
26. The device of claim 1, further comprising a release time control material icoated inside the device, wherein the release time control material comprises albumin, carbomers, carboxymethyl cellulose, carrageenan, chitosan, dextrin, polyethylene glycol, polyvinylpyrrolidone, or polyvinyl alcohol, or any combinations thereof.
27. The device of claim 1, further comprising a mobile device that comprises the camera and a light source.
28. The device of claim 1, further comprising a camera and a light source that provides the first beam.
29. The device of claim 1, further comprising an electronic hardware that comprises a machine learning model for analyzing the image and the analyte.
30. The device of claim 1, wherein the signal is a fluorescence signal.
31. The device of claim 1, wherein the device is configured to count neutrophils, eosinophils, basophils, lymphocytes, or monocytes.
32. The device of claim 13, wherein the spacers are periodic and have a period of less than 200 μm.
33. The device of claim 1, wherein the analyte is white blood cell, and wherein the device further comprises a hardware that contains a correction factor for correctly counting the white blood cell.
9. Claims 1, 2, 7, 8, 11-18, 21-26, 37-39, 42-48, 50, 51, 57, and 58 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-100 of U.S. Patent No. 11,326,989. Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-100 of patent ‘989 anticipate the instant invention being claimed.
10. Claims 1, 7, 8, 12-18, 22-26, 37, 39, 42-45, 46-48, 50, 51, 57, and 58 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-46 of U.S. Patent No. 11,543,408. Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-100 of patent ‘989 anticipate the instant invention being claimed.
11. Claims 1, 7, 8, 12, 13, 16-18, 22-26, 37, 39, 42-45, 46-48, 57, and 58 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-48 of U.S. Patent No. 11,883,824. Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-48 of patent ‘824 anticipate the instant invention being claimed. Claim 45 of patent ‘824 recites a cell staining reagent on the plates.
12. Claims 1, 7, 8, 12-18, 22-26, 37, 39, 42-45, 46-48, 50, 51, 57, and 58 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-43 of U.S. Patent No. 12,169,167. Although the claims at issue are not identical, they are not patentably distinct from each other because patent ‘167 claims a method of staining tissue that uses a device that anticipates the instant invention.
13. Claims 1, 2, 7, 8, 11-18, 22-26, 37-39, 42-48, 50, 51, 57, and 58 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,276,660. Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-20 of patent ‘660 anticipate the instant invention being claimed.
Allowable Subject Matter
14. Claims 1, 2, 7, 8, 11-18, 21-26, 37-39, 42-48, 50, 51, 57, and 58 are free of the prior art. Watanabe et al (US 2006/0246508 A1) is he closest prior art and teaches a device comprising first and second plates movable relative to each other, each of the plates having a sample contact area; spacers comprising an array of pillars with predetermined interspacer distance fixed on the first plate; (Par. 37, 42; Fig. 7B). However, Watanabe fails to teach a device with the specific limitations recited in the instant claims.
Conclusion
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTOPHER L CHIN whose telephone number is (571)272-0815. The examiner can normally be reached on Monday - Friday, 10:00am - 6:30pm.
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/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677
8/8/2026
