WO2013013107A1 - Device for facilitating incentivizing patient compliance and/or health monitoring - Google Patents

Abstract

The present invention relates to systems and methods for assessing medication status in a subject. Optionally, the present systems comprise a display for displaying the code based on a detectable signal that indicates the presence, absence and/or amount of a medication indicator in a subject, and the present methods comprise a step of exchanging the code for a reward and/or an incentive.

Description

DEVICE FOR FACILITATING INCENTIVIZING PATIENT COMPLIANCE

AND/OR HEALTH MONITORING

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the priority benefit of U.S. provisional application Serial No. 61/509,910, filed July 20, 2011. This application also relates to U.S. provisional application Serial No. 61/509,929, filed July 20, 2011. The contents of both applications are incorporated by reference in their entireties.

TECHNICAL FIELD

[0002] The present invention relates to systems and methods for assessing medication status in a subject. Optionally, the present systems comprise a display for displaying a code based on a detectable signal that indicates the presence, absence and/or amount of a medication indicator in a subject, and the present methods comprise a step of exchanging the code for a reward and/or an incentive.

BACKGROUND OF THE INVENTION

[0003] Medication adherence and the lack thereof is a global problem of significant magnitude. For example, a large portion of hospitalizations are attributable to patients failing to fully complete their medication regimens as prescribed.

[0004] From a strictly objective perspective, the problem of medication adherence is a puzzling one. If the marginal cost of taking a medication is low or non-existent (i.e., the patient can obtain the medication at low or no cost), and not taking the medication might result in health consequences for the patient, it would seem that patients would take their medication. However, the quantity of patients who fully adhere to their treatment regimen is much lower than this logic would imply.

[0005] Subjects often respond to small incentives as an effective means of changing behavior. However, these small incentives must be combined with an effective monitoring mechanism, because subjects tend to respond poorly to systems that are easily fooled.

[0006] To address this problem, several solutions have been proposed. Some solutions opt to ignore the fact that patients may dissimulate having taken the medication and reward based on refill rate or patients asserting they have taken their medications. Other solutions opt to use some other behavior as a proxy for patients actually taking their medication. Pill boxes that count, register, and/or transmit the occasions on which they have been opened and closed, for example, use opening and closing the pill box as a proxy for the patient having taken the medication. Another proposed solution is to tag medications with a substance, compound, or digestible device that can be detected by some other means.

[0007] All of these existing solutions fall short on some level. Solutions that reward patients based on refill rate or assertions of adherence may be vulnerable to patients who now have an incentive to be disingenuous about their actual behavior. Solutions that rely on indirect measures of adherence, such as patients opening and closing pill bottles, fall short on at least three points, firstly in that they are ultimately incentivizing the behavior that is rewarded (opening and closing the pill bottle, for example) as opposed to the patient actually taking the medication, secondly because they do not provide a means that translates well across different ways of packaging and delivering medications (such as blister packs or liquid medication), and thirdly because they quickly become cumbersome for those patients taking multiple medications. Solutions that try to create a new metric of adherence by adding a detectable substance, compound, or digestible device to the medication may face an immensely challenging regulatory framework in which the detectable element must be separately shown to not interact negatively with each targeted medication, and face a further uphill battle in that they do not provide an easy solution for capturing the adherence patterns of patients using multiple medications at the same time: if more than one medication is tagged with the same substance, compound, or digestible device it becomes impossible to distinguish which of those medications the patient might be taking. [0008] Up to date, a system that would rely on direct measures of adherence (e.g. , the presence of medication, medication metabolite, or other health markers in the patient's blood, urine, saliva, sweat, etc.) has not been practical for a home-based setting, as these tests have generally been expensive, invasive, and/or required laboratory training to be carried out. Solution-based assays marketed for at-home usage that provide a direct measure of adherence may be cumbersome in format, not generalizable across conditions, expensive to produce, and/or difficult to interpret effectively.

[0009] The present invention addresses this and the related need in the art by providing an easy to use, often disposable, direct measure that can be used to convey information corresponding to the presence, absence, or amount of medication indicator present in a subject. Because it provides a direct measure, it can further be more effectively used in a program to incentivize or encourage patients to submit their results and/or take their medication as prescribed.

BRIEF SUMMARY OF THE INVENTION

[0010] In one aspect, the present invention is directed to a system for assessing medication status in a subject, which system comprises: a) a test device for generating a detectable signal that indicates the presence, absence and/or amount of a medication indicator in a subject; b) a sensor for sensing the detectable signal from the test device; c) a

microprocessor for algorithmically converting the sensed signal from the sensor to a code that corresponds to the presence, absence and/or amount of the medication indicator in the subject; and d) optionally a display for displaying the code.

[0011] In another aspect, the present invention is directed to a method for assessing medication status in a subject, which method comprises: a) providing for the above system; b) generating, on the test device of the system, a detectable signal that indicates the presence, absence and/or amount of a medication indicator in a subject ; c) sensing the detectable signal from the test device using the sensor of the system; d) algorithmically converting the sensed signal from the sensor to a code that corresponds to the presence, absence and/or amount of the medication indicator in the subject using the microprocessor of the system; and e) optionally displaying the code on the display of the system.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 shows a cut— -away side view of an exemplary system

(Embodiment 1 described in U.S. provisional application Serial No. 61/509,910) ('910 application). The portion of the drawing marked as "A" represents a display in the exemplary system. The portion of the drawing marked "B" represents a microcontroller in the exemplary system. The portion of the drawing marked as "C" represents a sensor in the exemplary system, in a colorimetric sensor embodiment. The portion of the drawing marked as "D" represents a sample assay in the exemplary system, in a lateral flow assay

embodiment.

[0013] Figure 2 shows a cut— -away top view of an exemplary system

(Embodiment 1 described in the '910 application). The portion of the drawing marked as "A" represents a display in the exemplary system. The portion of the drawing marked "B" represents a microcontroller in the exemplary system. The portion of the drawing marked as "C" represents a sensor in the exemplary system, in a colorimetric sensor embodiment. The portion of the drawing marked as "D" represents a sample assay in the exemplary system, in a lateral flow assay embodiment.

[0014] Figure 3 shows a cut— -away side view of an exemplary device

(Embodiment 8 described in the '910 application). The portion of the drawing marked as "A" represents an optional display referenced in Embodiment 9 of the '910 application. The portion of the drawing marked "B" represents a microcontroller referenced in Embodiment 8 of the '910 application. The portion of the drawing marked as "C" represents a sensor referenced in Embodiment 8, in the colorimetric sensor embodiment referenced in

Embodiment 11 of the '910 application. The portion of the drawing marked as "D" represents a sample assay referenced in Embodiment 8, in the lateral flow assay embodiment referenced in Embodiment 10 of the '910 application. The portion of the drawing marked as "E" represents a digital transmission component referenced in Embodiment 8, in the mobile telephone network— accessing embodiment referenced in Embodiment 12 of the'910 application.

[0015] Figure 4 shows a cut— -away top view of the device described in

Embodiment 8 of the'910 application. The portion of the drawing marked as "A" represents an optional display referenced in Embodiment 9 of the'910 application. The portion of the drawing marked "B" represents a microcontroller referenced in Embodiment 8. The portion of the drawing marked as "C" represents a sensor referenced in Embodiment 8, in the colorimetric sensor embodiment referenced in Embodiment 11 of the'910 application. The portion of the drawing marked as "D" represents a sample assay referenced in Embodiment 8, in the lateral flow assay embodiment referenced in Embodiment 10 of the'910 application. The portion of the drawing marked as "E" represents a digital transmission component referenced in Embodiment 8, in the mobile telephone network— -accessing embodiment referenced in Embodiment 12 of the'910 application.

[0016] Figure 5 depicts a biochemical assay that indicates the presence, absence or quantity of at least one target molecule or compound in a liquid sample. This exemplary embodiment produces a reward code based on the outcome of an assay such as this one. In terms of its usage, the liquid sample is put into contact with a membrane wick seen on the left-hand side of the figure. This membrane draws a sample into the plastic housing, where it mixes with a conjugate inside the housing that allows it to produce a visible signal indicating the presence, absence, and/or amount of target molecule or compound by the presence, absence, or intensity of the visible signal produced. In the assay used for this embodiment of the exemplary device, the presence, absence, or quantity of a target molecule or compound is indicated by the presence, absence, or intensity of the blue stripe seen in the window in the plastic housing. The presence, absence, or intensity of the blue stripe(s) that appear(s) in this window serve(s) as an indicator of the presence, absence, or quantity of at least one target molecule or compound present in the sample.

[0017] Figure 6 depicts an exemplary device described in the present application. The assay depicted in Figure 5 is inserted into the cream-colored cylindrical reader seen on the left-hand side of this Figure, with the assay's wick remaining outside and the window in which the visible signal(s) is/are produced inserted inside the cylinder. This cylinder contains a physical switch to detect when an assay has been inserted and light emitting diodes (LEDs) and optical sensors that are arranged to fit over the portion of the assay where the stripe(s) indicating presence, absence, or quantity of the target molecule or compound appear when the assay is inserted in the device. The optical sensors in this embodiment cause a voltage to vary depending on the presence, absence, or intensity of the stripes located underneath the sensors. Changes in voltage may thus be used as an indicator of the presence, absence, or quantity of the target molecule or compound in the sample.

[0018] In this embodiment, the circuitry in this cream-colored cylindrical reader, where voltages vary depending on the presence, absence, or quantity of at least one target molecule or compound in the sample, is connected to an Atmel 1045 Atmega 168 20pu integrated circuit (IC) chip. This chip is used to assess the presence, absence, or quantity of at least one target molecule or compound in the sample based on the voltages observed, to produce at least one code to reflect the presence, absence, or quantity of target molecule or compound in the sample as indicated by the voltages observed, and to provide the code(s) containing this information to be used as part of a reward program. This integrated circuit can be seen in the breadboard circuitry in the center of this Figure. The black USB cable used to program the integrated circuit can be seen at the top of this Figure. This integrated circuit is also connected to a Hainan Qinghua LCD Technology Development Co. Ltd.

UC204A-204A-YP-RB-N-LB-YG LCD display, which in this Figure has been folded up to reveal the circuitry beneath it, such that it is roughly perpendicular to the white surface behind it, and from the angle of the camera lens in this Figure resembles a black bar. This view reveals the side of this LCD panel; the front of this display panel can be seen in subsequent Figures. A standard 9-volt battery used to power the circuitry can be seen on the surface behind the display panel.

[0019] Figure 7 depicts the front of the Hainan Qinghua LCD Technology

Development Co. Ltd. UC204A-204A- YP-RB -N-LB - YG LCD display immediately after this embodiment of the Adherean device has been turned on. The cream-colored cylinder on the left-hand side contains a physical switch to detect the insertion of an assay and circuitry using LEDs and optical sensors to produce voltages that vary depending on the presence, absence, or quantity of at least one sample present in the sample, as indicated in this embodiment by the presence, absence, or intensity of at least one stripe on the assay being read. The circuitry to produce a code based on the voltages observed is directly beneath this display as depicted in Figure 6. In Figure 7, the wires sustaining the LCD have been folded down to reveal the front of the LCD panel, such that the panel is roughly parallel to the white surface behind it.

[0020] Figure 8 depicts the display panel when the voltages observed reflect a state in which the physical switch indicating the insertion of an assay has not been depressed. As such, in this state the device is ready for the insertion of an assay. To reflect this, in this embodiment the device has been programmed to display "Please insert your test strip" on the Hainan Qinghua LCD Technology Development Co. Ltd. UC204A-204A-YP-RB-N-LB-YG LCD display.

[0021] Figure 9 depicts the display panel immediately after the voltages observed reflect a state in which the physical switch indicating the insertion of an assay has been depressed. To reflect this, in this embodiment the device has been programmed to display "Checking Test Result" on the Hainan Qinghua LCD Technology Development Co. Ltd. UC204A-204A-YP-RB-N-LB-YG LCD display.

[0022] Figure 10 depicts the display panel providing a code that has been generated based on the presence, absence, or quantity of a target molecule or compound present in a sample, for use in a rewards program. In this embodiment the integrated circuit has been programmed to provide a valid code (in this image "JDS AEK") based on the voltages that indicate the presence, absence, or quantity of at least one target molecule or compound in the sample. By means of submitting this code, information is conveyed regarding the timing of the code's production and the presence, absence, or quantity of the target molecule or compound present in the sample. This prototype embodiment was constructed to convey one valid code (in this case "JDS AEK") in response to one valid assay outcome in one time period (in this case all time subsequent to 8:06 pm, June 17, 2011). Because the receiving entity has information about possible valid codes and the way the codes are generated, in this embodiment "JDS AEK" is known to be the only valid code, and its transmission is taken to indicate the development of a valid assay. This code further conveys the information that the test was taken on or after June 17, 2011 because the device was documented as having been first turned on that date. The reward code in this embodiment is only provided if the observed voltages indicate the presence of a stripe indicating the presence of the target molecule or compound in the sample at a given concentration.

[0023] Figure 11 depicts the display panel in a state where this embodiment of the device has detected that an assay has been inserted, but the presence, absence, or intensity of stripes reveals a situation other than that in which the patient has inserted a valid assay indicating the desired presence, absence, or quantity of a target molecule or compound in a sample. This might be because the assay has already been used, as indicated by the observation that the optical sensors are producing voltages that reflect already-developed stripes when the assay is inserted, or because the sample simply does not reflect the desired presence, absence, or quantity of the target molecule or compound in the sample. To reflect this anomalous state, in this embodiment the device has been programmed to display "Please See Leaflet" on the Hainan Qinghua LCD Technology Development Co. Ltd.

UC204A-204A-YP-RB-N-LB-YG LCD display. DETAILED DESCRIPTION OF THE INVENTION

[0024] For clarity of disclosure, and not by way of limitation, the detailed description of the invention is divided into the subsections that follow.

A. Definitions

[0025] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entireties. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in the patents, applications, published applications and other publications that are herein incorporated by reference, the definition set forth in this section prevails over the definition that is

incorporated herein by reference.

[0026] As used herein, "a" or "an" means "at least one" or "one or more."

[0027] As used herein, a "binding reagent" refers to any substance that binds to an analyte with desired affinity and/or specificity. Non-limiting examples of the binding reagent include cells, cellular organelles, viruses, particles, microparticles, molecules, or an aggregate or complex thereof, or an aggregate or complex of molecules. Exemplary binding reagents can be an amino acid, a peptide, a protein, e.g., an antibody or receptor, a nucleoside, a nucleotide, an oligonucleotide, a nucleic acid, e.g., DNA or RNA, a vitamin, a

monosaccharide, an oligosaccharide, a carbohydrate, a lipid, an aptamer and a complex thereof.

[0028] As used herein, the term "specifically binds" refers to the specificity of a binding reagent, e.g., an antibody, such that it preferentially binds to a defined analyte.

Recognition by a binding reagent or an antibody of a particular analyte in the presence of other potential targets or interfering substances is one characteristic of such binding. In some embodiments, a binding reagent that specifically binds to an analyte avoids binding to other interfering moiety or moieties in the sample to be tested. [0029] As used herein the term "avoids binding" refers to the specificity of particular binding reagents, e.g., antibodies or antibody fragments. Binding reagents, antibodies or antibody fragments that avoid binding to a particular moiety generally contain a specificity such that a large percentage of the particular moiety would not be bound by such binding reagents, antibodies or antibody fragments. This percentage generally lies within the acceptable cross reactivity percentage with interfering moieties of assays utilizing the binding reagents or antibodies directed to detecting a specific target. Frequently, the binding reagents, antibodies or antibody fragments of the present disclosure avoid binding greater than about 90% of an interfering moiety, although higher percentages are clearly

contemplated and preferred. For example, binding reagents, antibodies or antibody fragments of the present disclosure avoid binding about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, and about 99% or more of an interfering moiety. Less occasionally, binding reagents, antibodies or antibody fragments of the present disclosure avoid binding greater than about 70%, or greater than about 75%, or greater than about 80%, or greater than about 85% of an interfering moiety.

[0030] An "antibody" is an immunoglobulin molecule capable of specific binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule, and can be an immunoglobulin of any class, e.g., IgG, IgM, IgA, IgD and IgE. IgY, which is the major antibody type in avian species such as chicken, is also included within the definition. As used herein, the term encompasses not only intact polyclonal or monoclonal antibodies, but also fragments thereof (such as Fab, Fab', F(ab')2, Fv), single chain (ScFv), mutants thereof, naturally occurring variants, fusion proteins comprising an antibody portion with an antigen recognition site of the required specificity, humanized antibodies, chimeric antibodies, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site of the required specificity. [0031] As used herein, "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the antibodies comprising the population are identical except for possible naturally occurring mutations that are present in minor amounts. As used herein, a "monoclonal antibody" further refers to functional fragments of monoclonal antibodies.

[0032] As used herein, the term "antigen" refers to a target molecule that is specifically bound by an antibody through its antigen recognition site. The antigen may be monovalent or polyvalent, i.e., it may have one or more epitopes recognized by one or more antibodies. Examples of kinds of antigens that can be recognized by antibodies include polypeptides, oligosaccharides, glycoproteins, polynucleotides, lipids, or small molecules, etc.

[0033] As used herein, "mammal" refers to any of the mammalian class of species. Frequently, the term "mammal," as used herein, refers to humans, human subjects or human patients. Also frequently, the term "mammal," as used herein, refers to non-human mammalian subjects.

[0034] As used herein, the term "subject" is not limited to a specific species or sample type. For example, the term "subject" may refer to a patient, and frequently a human patient. However, this term is not limited to humans and thus encompasses a variety of mammalian or non-mammal species.

[0035] As used herein the term "sample" refers to anything which may contain an analyte for which an analyte assay is desired. The sample may be a biological sample, such as a biological fluid or a biological tissue. Examples of biological fluids include urine, blood, plasma, serum, saliva, semen, stool, sputum, cerebral spinal fluid, tears, mucus, amniotic fluid or the like. Biological tissues are aggregate of cells, usually of a particular kind together with their intercellular substance that form one of the structural materials of a human, animal, plant, bacterial, fungal or viral structure, including connective, epithelium, muscle and nerve tissues. Examples of biological tissues also include organs, tumors, lymph nodes, arteries and individual cell(s).

[0036] As used herein the term "isolated" refers to material removed from its original environment, and/or is altered from its natural state. For example, an isolated polypeptide could be coupled to a carrier, and still be "isolated" because that polypeptide is not in its original environment.

[0037] As used herein, high-throughput screening (HTS) refers to processes that test a large number of samples, such as samples of diverse chemical structures against disease targets to identify "hits" (see, e.g., Broach, et al., High throughput screening for drug discovery, Nature, 384: 14-16 (1996); Janzen, et al., High throughput screening as a discovery tool in the pharmaceutical industry, Lab Robotics Automation: 8261-265 (1996); Fernandes, P.B., Letter from the society president, /. Biomol. Screening, 2: 1 (1997); Burbaum, et al., New technologies for high-throughput screening, Curr. Opin. Chem. Biol., 7:72-78 (1997)). HTS operations are highly automated and computerized to handle sample preparation, assay procedures and the subsequent processing of large volumes of data.

[0038] The terms "polypeptide", "oligopeptide", "peptide" and "protein" are used interchangeably herein to refer to polymers of amino acids of any length, e.g., at least 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, 1,000 or more amino acids. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids, etc.), as well as other modifications known in the art.

[0039] The terms "polynucleotide," "oligonucleotide," "nucleic acid" and "nucleic acid molecule" are used interchangeably herein to refer to a polymeric form of nucleotides of any length, e.g., at least 8, 9, 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, 1,000 or more nucleotides, and may comprise ribonucleotides, deoxyribonucleotides, analogs thereof, or mixtures thereof. This term refers only to the primary structure of the molecule. Thus, the term includes triple-, double- and single- stranded deoxyribonucleic acid ("DNA"), as well as triple-, double- and single- stranded ribonucleic acid ("RNA"). It also includes modified, for example by alkylation, and/or by capping, and unmodified forms of the polynucleotide. More particularly, the terms "polynucleotide," "oligonucleotide," "nucleic acid" and "nucleic acid molecule" include polydeoxyribonucleotides (containing 2-deoxy-D-ribose), polyribonucleotides (containing D-ribose), including tRNA, rRNA, hRNA, and mRNA, whether spliced or unspliced, any other type of polynucleotide which is an N- or C-glycoside of a purine or pyrimidine base, and other polymers containing normucleotidic backbones, for example, polyamide {e.g. , peptide nucleic acids ("PNAs")) and polymorpholino

(commercially available from the Anti-Virals, Inc., Corvallis, OR., as Neugene) polymers, and other synthetic sequence- specific nucleic acid polymers providing that the polymers contain nucleobases in a configuration which allows for base pairing and base stacking, such as is found in DNA and RNA. Thus, these terms include, for example, 3'-deoxy-2',5'-DNA, oligodeoxyribonucleotide N3' to P5' phosphoramidates, 2'-0-alkyl-substituted RNA, hybrids between DNA and RNA or between PNAs and DNA or RNA, and also include known types of modifications, for example, labels, alkylation, "caps," substitution of one or more of the nucleotides with an analog, intemucleotide modifications such as, for example, those with uncharged linkages {e.g. , methyl phosphonates, phosphotriesters, phosphoramidates, carbamates, etc.), with negatively charged linkages {e.g. , phosphorothioates,

phosphorodithioates, etc.), and with positively charged linkages {e.g.,

aminoalkylphosphoramidates, aminoalkylphosphotriesters), those containing pendant moieties, such as, for example, proteins (including enzymes {e.g. nucleases), toxins, antibodies, signal peptides, poly-L-lysine, etc.), those with intercalators {e.g., acridine, psoralen, etc.), those containing chelates (of, e.g. , metals, radioactive metals, boron, oxidative metals, etc.), those containing alkylators, those with modified linkages (e.g., alpha anomeric nucleic acids, etc.), as well as unmodified forms of the polynucleotide or oligonucleotide.

[0040] It will be appreciated that, as used herein, the terms "nucleoside" and "nucleotide" will include those moieties which contain not only the known purine and pyrimidine bases, but also other heterocyclic bases which have been modified. Such modifications include methylated purines or pyrimidines, acylated purines or pyrimidines, or other heterocycles. Modified nucleosides or nucleotides can also include modifications on the sugar moiety, e.g. , wherein one or more of the hydroxyl groups are replaced with halogen, aliphatic groups, or are functionalized as ethers, amines, or the like. The term "nucleotidic unit" is intended to encompass nucleosides and nucleotides.

[0041] "Nucleic acid probe" and "probe" are used interchangeably and refer to a structure comprising a polynucleotide, as defined above, that contains a nucleic acid sequence that can bind to a corresponding target. The polynucleotide regions of probes may be composed of DNA, and/or RNA, and/or synthetic nucleotide analogs.

[0042] As used herein, "complementary or matched" means that two nucleic acid sequences have at least 50% sequence identity. Preferably, the two nucleic acid sequences have at least 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% of sequence identity. "Complementary or matched" also means that two nucleic acid sequences can hybridize under low, middle and/or high stringency condition(s).

[0043] As used herein, "substantially complementary or substantially matched" means that two nucleic acid sequences have at least 90% sequence identity. Preferably, the two nucleic acid sequences have at least 95%, 96%, 97%, 98%, 99% or 100% of sequence identity. Alternatively, "substantially complementary or substantially matched" means that two nucleic acid sequences can hybridize under high stringency condition(s).

[0044] In general, the stability of a hybrid is a function of the ion concentration and temperature. Typically, a hybridization reaction is performed under conditions of lower stringency, followed by washes of varying, but higher, stringency. Moderately stringent hybridization refers to conditions that permit a nucleic acid molecule such as a probe to bind a complementary nucleic acid molecule. The hybridized nucleic acid molecules generally have at least 60% identity, including for example at least any of 70%, 75%, 80%, 85%, 90%, or 95% identity. Moderately stringent conditions are conditions equivalent to hybridization in 50% formamide, 5x Denhardt' s solution, 5x SSPE, 0.2% SDS at 42°C, followed by washing in 0.2x SSPE, 0.2% SDS, at 42°C. High stringency conditions can be provided, for example, by hybridization in 50% formamide, 5x Denhardt' s solution, 5x SSPE, 0.2% SDS at 42°C, followed by washing in 0. lx SSPE, and 0.1% SDS at 65°C. Low stringency hybridization refers to conditions equivalent to hybridization in 10% formamide, 5x

Denhardt' s solution, 6x SSPE, 0.2% SDS at 22°C, followed by washing in lx SSPE, 0.2% SDS, at 37°C. Denhardt' s solution contains 1% Ficoll, 1% polyvinylpyrolidone, and 1% bovine serum albumin (BSA). 20x SSPE (sodium chloride, sodium phosphate, ethylene diamide tetraacetic acid (EDTA)) contains 3M sodium chloride, 0.2M sodium phosphate, and 0.025 M EDTA. Other suitable moderate stringency and high stringency hybridization buffers and conditions are well known to those of skill in the art and are described, for example, in Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Press, Plainview, N.Y. (1989); and Ausubel et al., Short Protocols in Molecular Biology, 4th ed., John Wiley & Sons (1999).

[0045] Alternatively, substantial complementarity exists when an RNA or DNA strand will hybridize under selective hybridization conditions to its complement. Typically, selective hybridization will occur when there is at least about 65% complementary over a stretch of at least 14 to 25 nucleotides, preferably at least about 75%, more preferably at least about 90% complementary. See Kanehisa (1984) Nucleic Acids Res. 12:203-215.

[0046] As used herein, "biological sample" refers to any sample obtained from a living or viral source or other source of macromolecules and biomolecules, and includes any cell type or tissue of a subject from which nucleic acid or protein or other macromolecule can be obtained. The biological sample can be a sample obtained directly from a biological source or a sample that is processed. For example, isolated nucleic acids that are amplified constitute a biological sample. Biological samples include, but are not limited to, body fluids, such as blood, plasma, serum, cerebrospinal fluid, synovial fluid, urine and sweat, tissue and organ samples from animals and plants and processed samples derived therefrom. Also included are soil and water samples and other environmental samples, viruses, bacteria, fungi, algae, protozoa and components thereof.

[0047] It is understood that aspects and embodiments of the invention described herein include "consisting" and/or "consisting essentially of aspects and embodiments.

[0048] Throughout this disclosure, various aspects of this invention are presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0049] Other objects, advantages and features of the present invention will become apparent from the following specification taken in conjunction with the accompanying drawings.

B. Systems for assessing medication status in a subject

[0050] In one aspect, the present disclosure provides for a system for assessing medication status in a subject, which system comprises: a) a test device for generating a detectable signal that indicates the presence, absence and/or amount of a medication indicator in a subject; b) a sensor for sensing the detectable signal from the test device; c) a microprocessor for algorithmically converting the sensed signal from the sensor to a code that corresponds to the presence, absence and/or amount of the medication indicator in the subject; and d) optionally a display for displaying the code.

[0051] Any suitable test devices can be used in the present systems. For example, test devices for an enzyme-linked immunosorbent assay (ELISA), immunoblotting, immunoprecipitation, radioimmunoassay (RIA), immunostaining, latex agglutination, indirect hemagglutination assay (IHA), complement fixation, indirect immunofluorescent assay (IFA), nephelometry, flow cytometry assay, plasmon resonance assay, chemiluminescence assay, lateral flow assay, u-capture assay, inhibition assay and avidity assay can be used.

[0052] In some embodiments, lateral flow test devices can be used. Any suitable lateral flow test devices can be used in the present systems. For example, the lateral flow test devices and assays disclosed and/or claimed in the U.S. patent Nos. 3,641,235, 3,959,078, 3,966,897, 4,094,647, 4,168,146, 4,299,916, 4,347,312, 4,366,241, 4,391,904, 4,425,438, 4,517,288, 4,960,691, 5,141,875, 4,857,453, 5,073,484, 4,695,554, 4,703,017, 4,743,560, 5,075,078, 5,591,645, 5,656,448, RE 38,430 E, 5,602,040, 6,017,767, 6,319,676, 6,352,862, 6,485,982, 5,120,643, 4,956,302, RE 39,664 E, 5,252,496, 5,514,602, 7,238,538 B2,

7,175,992 B2, 6,770,487 B2, 5,712,170, 5,275,785, 5,504,013, 6,156,271, 6,187,269,

6,399,398, 7,317,532, EP 0,149,168 Al, EP 0,323,605 Al, EP 0,250,137 A2, GB 1,526,708, WO99/40438, and in U.S. provisional application Serial No. 61/509,929, can be used.

[0053] In some embodiments, an exemplary lateral flow test device comprises a porous matrix that comprises a test reagent at a test location on said porous matrix, wherein a liquid sample derived from a subject flows laterally along said test device and passes said test location to form a detectable signal to indicate presence, absence and/or amount of a medication indicator in said subject that can be used to assess medication status in said subject.

[0054] In one specific embodiment, the medication indicator to be detected comprises or is an antigen, the binding reagent on the test device comprises or is an antibody or an aptamer. Preferably, the antibody or aptamer specifically binds to the medication indicator.

[0055] In one example, the test device is used in a sandwich assay format, in which a binding reagent, e.g. , an antibody or aptamer, is used as a reagent at the test location, and another binding reagent having a detectable label is also used to form a labeled binding reagent- medication indicator - binding reagent or antibody or aptamer sandwich at the test location to generate readout signals. Alternatively, a binding reagent is used as a reagent at the test location, and an antibody or aptamer having a detectable label is also used to form a labeled antibody or aptamer - medication indicator - binding reagent sandwich at the test location to generate readout signals. In one example, the sandwich assay uses two antibodies or aptamers, one as the capture reagent and the other as the labeled reagent.

[0056] The test device can also be used in a competition assay format. In one example, a binding reagent, e.g., an antibody or aptamer, is used as a capture reagent at the test location. A medication indicator or a medication indicator analog having a detectable label, either added in a liquid or previously dried on the test device and redissolved or resuspended by a liquid, will compete with a medication indicator in a sample to bind to the capture reagent at the test location. In another example, a medication indicator or a medication indicator analog is used as a capture reagent at the test location. A binding reagent, e.g. , an antibody or aptamer, having a detectable label, is either added in a liquid or previously dried on the test device and redissolved or resuspended by a liquid. A medication indicator in a sample will compete with the medication indicator or the medication indicator analog at the test location for binding to the binding reagent, e.g. , an antibody or aptamer, having a detectable label.

[0057] The test reagent can be any suitable substance. In some embodiments, the test reagent is capable of binding to a medication indicator or another binding reagent that is capable of binding to a medication indicator. Preferably, the test reagent is capable of specifically binding to a medication indicator or another binding reagent that is capable of binding or specific binding to a medication indicator. In other embodiments, the test reagent is a medication indicator or a medication indicator analog that competes with a medication indicator in the liquid sample for binding to a binding reagent for the medication indicator.

[0058] In some embodiments, the test reagent is an inorganic molecule, an organic molecule or a complex thereof. Exemplary organic molecules include an amino acid, a peptide, a protein, a nucleoside, a nucleotide, an oligonucleotide, a nucleic acid, a vitamin, a monosaccharide, an oligosaccharide, a carbohydrate, a lipid and a complex thereof. In some embodiments, the protein is an antigen or an antibody.

[0059] The matrix can comprise or be made of any suitable material. In some embodiments, the matrix comprises nitrocellulose, glass fiber, polypropylene, polyethylene (preferably of very high molecular weight), polyvinylidene flouride, ethylene vinylacetate, acrylonitrile and/or polytetrafluoro-ethylene. See e.g., U.S. patent No. 6,187,598. It can be advantageous to pre-treat the membrane with a surface-active agent during manufacture, as this can reduce any inherent hydrophobicity in the membrane and therefore enhance its ability to take up and deliver a moist sample or liquid rapidly and efficiently. The matrix can also be made from paper or other cellulosic materials. In some embodiments, the matrix comprises or is made of nitrocellulose or glass fiber.

[0060] The matrix can also be in any suitable form or shape. In some

embodiments, the matrix is in the form a strip or a circle. The matrix can also comprise or be made of any suitable number of element. In some embodiments, the matrix is a single element or comprises multiple elements.

[0061] The present test devices can comprise any suitable additional elements. In some embodiments, the test device can further comprise a sample application element upstream from and in fluid communication with the matrix. In other embodiments, the test device can further comprise a liquid absorption element downstream from and in fluid communication with the matrix. In still other embodiments, the test device can further comprise a control zone comprising means for indicating proper flow of the liquid sample and/or a valid test result. In yet other embodiments, at least a portion of the matrix is supported by a solid backing. In yet other embodiments, the entire matrix is supported by a solid backing.

[0062] In some embodiments, a labeled reagent can be dried on the test device and the dried labeled reagent can be redissolved or resuspended by a liquid, e.g., a sample liquid and/or additional liquid, and transported laterally through the test device to generate readout, control and/or other signals. For example, a portion of the matrix, upstream from the test location, can comprise a dried, labeled reagent, the labeled reagent capable of being moved by a liquid sample and/or a further liquid to the test location and/or a control location to generate a detectable signal.

[0063] The dried, labeled reagent can be located at any suitable places on the test device. In one example, the dried, labeled reagent is located downstream from a sample or liquid application place on the test device. In another example, the dried, labeled reagent is located upstream from a sample or liquid application place on the test device.

[0064] The type of the labeled reagent can be determined based on the intended assay formats. For example, if the test device is to be used in a sandwich assay, the labeled reagent should be capable of binding, and preferably capable of specifically binding, to the analyte or a target, or another substance that binds to the analyte or the target. The same labeled reagent can also be used for certain competitive binding assays. For other types of the competitive binding assays, the labeled reagent should be an analyte or an analyte analog linked to a detectable label.

[0065] In some embodiments, a portion of the matrix, upstream from the test location, comprises a dried, labeled reagent, the labeled reagent being capable of being moved by a liquid sample and/or a further liquid to the test location and/or a control location to generate a detectable signal. The dried, labeled reagent can be located downstream from a sample application place on the test device. Alternatively, the dried, labeled reagent can be located upstream from a sample application place on the test device. [0066] In some embodiments, the test can further comprise, upstream from the test location, a conjugate element that comprises a dried, labeled reagent, the labeled reagent being capable of moved by a liquid sample and/or a further liquid to the test location and/or a control location to generate a detectable signal. The conjugate element can be located downstream from a sample application place on the test device. Alternatively, the conjugate element can be located upstream from a sample application place on the test device.

[0067] In some embodiments, the labeled reagent binds, and preferably specifically binds, to a medication indicator in the liquid sample. In other embodiments, the labeled reagent competes with a medication indicator in the liquid sample for binding to a binding reagent for the medication indicator at the test location.

[0068] Any suitable label can be used. The label can be a soluble label, such as a colorimetric, radioactive, enzymatic, luminescent or fluorescent label. The label can also be a particle or particulate label, such as a particulate direct label, or a colored particle label. Exemplary particle or particulate labels include colloidal gold label, latex particle label, nanoparticle label and quantum dot label. Depending on the specific configurations, the labels such as colorimetric, radioactive, enzymatic, luminescent or fluorescent label, can be either a soluble label or a particle or particulate label.

[0069] In some embodiments, the labeled reagent is dried in the presence of a material that stabilizes the labeled reagent, facilitates solubilization or resuspension of the labeled reagent in a liquid, and/or facilitates mobility of the labeled reagent. Any suitable material can be used. For example, the material can be a protein, e.g., a meta-soluble protein, a peptide, a polysaccharide, a sugar, e.g., sucrose, a polymer, a gelatin or a detergent. See e.g., U.S. patent Nos. 5,120,643 and 6,187,598.

[0070] The present test devices can be used with any suitable liquid. In one example, a sample liquid alone is used to transport a medication indicator and/or the labeled reagent to the test location. In another example, a developing liquid is used to transport a medication indicator and/or the labeled reagent to the test location. [0071] In some embodiments, the test device can further comprise a housing that covers at least a portion of the test device, wherein the housing comprises a sample or liquid application port to allow sample or liquid application upstream from or to the test location and an optic opening around the test location and/or the control location to allow signal detection at the test location and/or the control location. The optic opening can be achieved in any suitable way. For example, the optic opening can simply be an open space.

Alternatively, the optic opening can be a transparent cover.

[0072] In other embodiments, the housing can cover the entire test device. In still other embodiments, at least a portion of the sample receiving portion of the matrix or the sample application element is not covered by the housing and a sample or liquid is applied to the portion of the sample receiving portion of the matrix or the sample application element outside the housing and then transported to the test location and/or control location. The housing can comprise any suitable material. For example, the housing can comprise a plastic material.

[0073] The present test devices can be used to assess medication status in any suitable subject. In some embodiments, the present test devices can be used to assess medication status in a human. In other embodiments, the present test devices can be used to assess medication status in an animal, e.g. , a non-human mammal.

[0074] The present test devices can be used to assess medication status in a suitable subject by assessing any suitable medication indicator from the subject. In some

embodiments, the medication indicator is a medication metabolite, an unmetabolized medication, or an indicator of over medication, under medication or medication failure.

[0075] In some embodiments, the present invention provides for a test device wherein the liquid or sample has moved laterally along the test device to generate a detectable signal at the test location.

[0076] Any suitable sensors or readers can be used in the present systems and methods. For example, the sensors or readers disclosed and/or claimed in the U.S. patent Nos. 7,371,582 B2, 6,267,722 Bl, 6,830,731 Bl can be used in the present systems and methods. In some embodiments, the sensor can be a laser based sensor. See e.g., U.S. Patent Nos. 7,371,582, 7,476,549, 7,633,620 and 7,815,853. In other embodiments, the sensor can be a LED based sensor. In still other embodiments, the sensor can be a colorimetric sensor.

[0077] The sensed signal from the sensor can be converted to a code that corresponds to the presence, absence and/or amount of a medication indicator in a subject algorithmically by a microprocessor in any suitable manner. For example, an algorithm can be used to convert the signal received from the sensor into a code or codes that represent a quantity of information corresponding to the presence, absence, and/or amount of a medication indicator or medication indicators present in the subject, such that this

information may be subsequently transmitted, interpreted, and/or recorded by a human or machine. The algorithm may further contain information about a time or time window in which the signal is received.

[0078] In one embodiment, the algorithm is used to produce a code or codes if the signal received from the sensor corresponds to some level of medication indicator that is present in the subject and not to produce a code or codes if the sensor indicates an absence of a medication indicator present in the subject. In another embodiment, the algorithm is used to produce a code or codes if the signal received from the sensor corresponds to some level of a medication indicator present in the subject and produce a different code or codes if the sensor indicates an absence of the medication indicator present in the subject.

Binary

[0079] In one embodiment, the signal received from the sensor may be used as a binary metric of the presence or absence of a medication indicator present in the subject, whereby the fact that a signal that is above or below a given threshold is used to represent the categorical presence or absence of the medication indicator in the subject. Quantitative

[0080] In another embodiment, the signal received from the sensor may be used as a quantitative or semi-quantitative metric of the amount of a medication indicator present in the signal, whereby the signal's presence, absence, or level is used to represent the quantity of medication indicator present in the subject, either by means of a continuous variable corresponding to the amount of signal observed or by means of a discrete variable

corresponding to a level of signal observed.

Time

[0081] In one embodiment, the algorithm may further incorporate, as part of a code or codes, information corresponding to the time period in which the signal is received. In a related embodiment, the algorithm may incorporate, as part of a code or codes, information corresponding to the calendar date and time period in which the signal is received. In another related embodiment, the algorithm may incorporate, as part of a code or codes, information corresponding to a device- specific or subject- specific time period in which the signal is received, e.g. , the amount of time since the device was first turned on, the amount of time since the device was last connected to or synchronized with another device, the amount of time since the last signal was observed, or other such device-specific or subject- specific details.

Purely Formulaic Binary One Code

[0082] In one embodiment, the algorithm may use a purely formulaic approach to generating the code or codes corresponding with the presence of some level of a medication indicator. Such an approach might include the direct representation of the time or time period in which the signal was received if the signal received from the sensor corresponds to some level of a medication indicator that is present in the subject and not to produce a code or codes if the sensor indicates an absence of the medication indicator present in the subject. For example, upon receiving a signal corresponding to the presence of a medication indicator in the sample the algorithm might produce "2012.07.20.10.00" as a code, which code might correspond to observing a signal corresponding to some level of medication indicator that is present in the subject on July 20, 2012, at 10:00am.

Purely Formulaic Quantitative One Code

[0083] In a related embodiment, the algorithm may use a purely formulaic approach to generating the code or codes corresponding with a quantitative or

semi-quantitative level of a medication present in the sample. Such an approach might include the direct representation of the time or time period in which the signal was received if the signal received from the sensor corresponds to some level of a medication indicator that is present in the subject and not to produce a code or codes if the sensor indicates an absence of a medication indicator present in the subject. For example, upon receiving a signal corresponding to a quantity of medication indicator in the sample defined as "9" the algorithm might produce "2012.07.20.10.00.09" as a code, which code might correspond to observing a signal corresponding to a quantity or level of medication indicator defined as "9" that is present in the subject on July 20, 2012, at 10:00am.

Purely Formulaic Binary Two-Code

[0084] In another related embodiment, the algorithm may use a purely formulaic approach to generate a code or codes if the signal received from the sensor corresponds to some level of a medication indicator that is present in the subject and a different code or codes if the sensor indicates an absence of the medication indicator present in the subject. Such an approach might include the direct representation of the time or time period in which the signal was received if the signal received from the sensor corresponds to some level of a medication indicator that is present in the subject and not to produce a code or codes if the sensor indicates an absence of the medication indicator present in the subject. For example, upon receiving a signal corresponding to the presence of a medication indicator in the sample, the algorithm might produce "2012.07.20.10.00.1" as a code, which code might correspond to observing a signal corresponding to some level of the medication indicator that is present in the subject on July 20, 2012, at 10:00am, and upon receiving a signal corresponding to an absence of medication indicator in the sample the algorithm might produce

"2012.07.20.10.00.0" as a code, which code might correspond to observing a signal corresponding to an absence of the medication indicator that is present in the subject on July 20, 2012, at 10:00am.

Purely Formulaic Quantitative Two-Code

[0085] In another related embodiment, the algorithm may use a purely formulaic approach to generate the code or codes corresponding with a quantitative or semi-quantitative level of a medication present in the sample and a different code or codes if the sensor indicates an absence of the medication indicator present in the subject. Such an approach might include the direct representation of the time or time period in which the signal was received if the signal received from the sensor corresponds to some level of a medication indicator that is present in the subject and not to produce a code or codes if the sensor indicates an absence of the medication indicator present in the subject. For example, upon receiving a signal corresponding to a quantity defined as a large amount of medication indicator in the sample, corresponding to a 9 on a quantitative or semi-quantitative scale ranging from 0 to 9, the algorithm might produce "2012.07.20.10.00.09" as a code, which code might correspond to observing a signal corresponding to a quantity or level of medication indicator defined as "9" that is present in the subject on July 20, 2012, at

10:00am., and upon receiving a signal corresponding to an absence of medication indicator in the sample the algorithm might produce "2012.07.20.10.00.0" as a code, which code might correspond to observing a signal corresponding to an absence of the medication indicator that is present in the subject on July 20, 2012, at 10:00am. Combination Formula/Hardcoded Binary One Code

[0086] In one embodiment, the algorithm may use an approach combining formulas and an amount of predetermined information, either as a seed to a formula, or seed or key to a system such as embedded RSA encryption or another encryption protocol, or as a lookup table, to generate a code or codes if the signal received from the sensor corresponds to some level of medication indicator that is present in the subject and not to produce a code or codes if the sensor indicates an absence of medication indicator present in the subject. For example, a simple combination of formulas and predetermined information might be to add a predetermined seed (such as "1") to each number of the date and time. With this simple combination of predetermined information and formulas, upon receiving a signal

corresponding to the presence of medication indicator in the sample, the algorithm might produce "2013.08.21.11.01" as a code, which code might correspond to observing a signal corresponding to some level of medication indicator that is present in the subject on July 20, 2012, at 10:00am.

Combination Formula/Hardcoded Quantitative One Code

[0087] In a related embodiment, the algorithm may use an approach combining formulas and an amount of predetermined information, either as a seed to a formula, or seed or key to a system such as embedded RSA encryption or another encryption protocol, or as a lookup table, to generate a code or codes corresponding with a quantitative or

semi-quantitative level of medication present in the sample and not to produce a code or codes if the sensor indicates an absence of the medication indicator present in the subject. For example, a simple combination of formulas and predetermined information might be to add a predetermined seed (such as "1") to each number of the date and time and a

quantitative or semi-quantitative representation of the level or amount of sample present in the subject. With this simple combination of predetermined information and formulas, upon receiving a signal corresponding to a quantity defined as a large amount of medication indicator in the sample, corresponding to a 9 on a quantitative or semi-quantitative scale ranging from 0 to 9, the algorithm might produce "2013.08.21.11.01.10" as a code, which code might correspond to observing a signal corresponding to a quantity or level of medication indicator defined as "9" that is present in the subject on July 20, 2012, at

10:00am.

Combination Formulaic/Hardcoded Binary Two Codes

[0088] In a related embodiment, the algorithm may use an approach combining formulas and an amount of predetermined information or information directly input into the algorithm by human or machine, either as a seed to a formula, or seed or key to a system such as embedded RSA encryption or another encryption protocol, or as a lookup table, to generate a code or codes if the signal received from the sensor corresponds to some level of medication indicator that is present in the subject and a different code or codes if the sensor indicates an absence of the medication indicator present in the subject. Such an approach might include a modified or direct representation of the time or time period in which the signal was received if the signal received from the sensor corresponds to some level of medication indicator that is present in the subject and a different code or codes if the sensor indicates an absence of the medication indicator present in the subject. For example, a simple combination of formulas and predetermined information might be to add a

predetermined seed (such as "1") to each number of the date and time. With this simple combination of predetermined information and formulas, upon receiving a signal

corresponding to the presence of medication indicator in the sample the algorithm might produce "2013.08.21.11.01.2" as a code, which code might correspond to observing a signal corresponding to some level of medication indicator that is present in the subject on July 20, 2012, at 10:00am, and upon receiving a signal corresponding to an absence of the medication indicator in the sample the algorithm might produce "2013.08.21.11.01.1" as a code, which code might correspond to observing a signal corresponding to an absence of the medication indicator that is present in the subject on July 20, 2012, at 10:00am.

Combination Formulaic/Hardcoded Quantitative Two Codes

[0089] In a related embodiment, the algorithm may use an approach combining formulas and an amount of predetermined information or information directly input into the algorithm by human or machine, either as a seed to a formula, or seed or key to a system such as embedded RSA encryption or another encryption protocol, or as a lookup table, to generate a code or codes corresponding with a quantitative or semi-quantitative level of medication present in the sample and a different code or codes if the sensor indicates an absence of medication indicator present in the subject. Such an approach might include a modified or direct representation of the time or time period in which the signal was received if the signal received from the sensor corresponds to some level of medication indicator that is present in the subject and a different code or codes if the sensor indicates an absence of the medication indicator present in the subject. For example, a simple combination of formulas and predetermined information might be to add a predetermined seed (such as "1") to each number of the date and time and a quantitative or semi-quantitative representation of the level or amount of sample present in the subject. With this simple combination of predetermined information and formulas, upon receiving a signal corresponding to a quantity defined as a large amount of medication indicator in the sample, corresponding to a 9 on a quantitative or semi-quantitative scale ranging from 0 to 9, the algorithm might produce

"2013.08.21.11.01.10" as a code, which code might correspond to observing a signal corresponding to a quantity or level of medication indicator defined as "9" that is present in the subject on July 20, 2012, at 10:00am, and upon receiving a signal corresponding to an absence of the medication indicator in the sample the algorithm might produce

"2013.08.21.11.01.1" as a code, which code might correspond to observing a signal corresponding to an absence of the medication indicator that is present in the subject on or about July 20, 2012, at 10:00am.

Purely Hardcoded Binary One Code

[0090] In one embodiment, the algorithm may use solely predetermined

information or information directly input into the algorithm by human or machine, either as a seed to a formula, or seed or key to a system such as embedded RSA encryption or another encryption protocol, or as a lookup table, to generate a code or codes if the signal received from the sensors corresponds to some level of medication indicator that is present in the subject and not to produce a code or codes if the sensor indicates an absence of medication indicator present in the subject. For example, a simple use of predetermined information might be to assign a predetermined code to each hour, day, year, or other time period subsequent to the device's first being turned on. For example, the time period of one hour immediately subsequent to the device's first being turned on might be assigned a

predetermined code of "AAA", the time period of one hour immediately subsequent to that might be assigned a predetermined code of "AAB", the time period of one hour immediately subsequent to that might be assigned a predetermined code of "A AC", and all time subsequent to that might be assigned a code of "AAD". With this predetermined

information, upon receiving a signal corresponding to the presence of medication indicator in the sample, at a time less than 1 hour after the system was first turned on, the algorithm might produce "AAA" as a code, which code might correspond to observing a signal corresponding to some level of medication indicator that is present in the subject at a time that is between the time when the device was first turned on and one hour immediately subsequent to that.

Purely Hardcoded Semi-Quantitative One Code

[0091] In another related embodiment, the algorithm may use solely predetermined information or information directly input into the algorithm by human or machine, either as a seed to a formula, or seed or key to a system such as embedded RSA encryption or another encryption protocol, or as a lookup table, to generate a code or codes corresponding with a quantitative or semi-quantitative level of medication indicator present in the subject and not to produce a code or codes if the sensor indicates an absence of medication indicator present in the subject. For example, a simple use of predetermined information might be to assign a predetermined code to each possible medication level for each hour, day, year, or other time period subsequent to the device's first being turned on. For example, a level or amount of signal corresponding to a level of medication indicator defined as "1" for the time period of one hour immediately subsequent to the device's first being turned on might be assigned a predetermined code of "AAA", a level or amount of signal corresponding to a level of medication indicator defined as "2" for the time period of one hour immediately subsequent to the device's first being turned on might be assigned a predetermined code of "AAB", a level or amount of signal corresponding to a level of medication indicator defined as "3" for the time period of one hour immediately subsequent to the device's first being turned on might be assigned a predetermined code of "AAC", and levels greater than 0 for all time subsequent to that might be assigned a code of "AAD". With this predetermined information, upon receiving a signal corresponding to a level or quantity of medication indicator defined as "1" in the sample, at a time less than 1 hour after the system was first turned on, the algorithm might produce "AAA" as a code, which code might correspond to observing a signal corresponding to a level or quantity of medication indicator defined as "1" present in the subject at a time that is between the time when the device was first turned on and one hour immediately subsequent to that.

Purely Hardcoded Binary Two Codes

[0092] In a related embodiment, the algorithm may use solely predetermined information or information directly input into the algorithm by human or machine, either as a seed to a formula, or seed or key to a system such as embedded RSA encryption or another encryption protocol, or as a lookup table, to generate a code or codes if the signal received from the sensor corresponds to some level of medication indicator that is present in the subject and a different code or codes if the sensor indicates an absence of the medication indicator present in the subject. For example, a simple use of predetermined information might be to assign predetermined codes or sets of codes to each hour, day, year, or other time period subsequent to the device's first being turned on, with a code or codes to correspond to the signal received from the sensor corresponding to some level of medication indicator that is present in the subject and another different code or codes if the sensor indicates an absence of the medication indicator present in the subject. For example, the time period of one hour immediately subsequent to the device's first being turned on might be assigned a

predetermined code of "AAA" if the signal received from the sensor corresponds to some level of medication indicator that is present in the subject and "BBA" if the sensor indicates an absence of the medication indicator present in the subject, the time period of one hour immediately subsequent to that might be assigned a predetermined code of "AAB" if the signal received from the sensor corresponds to some level of medication indicator that is present in the subject and "BBB" if the sensor indicates an absence of the medication indicator present in the subject, the time period of one hour immediately subsequent to that might be assigned a predetermined code of "AAC" if the signal received from the sensor corresponds to some level of medication indicator that is present in the subject and "BBC" if the sensor indicates an absence of the medication indicator present in the subject, and all time subsequent to that might be assigned a code of "AAD" if the signal received from the sensor corresponds to some level of medication indicator that is present in the subject and "BBD" if the sensor indicates an absence of the medication indicator present in the subject. With this predetermined information, upon receiving a signal corresponding to the presence of medication indicator in the sample, at a time less than 1 hour after the system was first turned on, the algorithm might produce "AAA" as a code, which code might correspond to observing a signal corresponding to some level of medication indicator that is present in the subject at a time that is between the time when the device was first turned on and one hour immediately subsequent to that. Upon receiving a signal corresponding to the absence of the medication indicator in the sample, at a time less than 1 hour after the system was first turned on, this same algorithm might produce "BBA" as a code, which code might correspond to observing a signal corresponding to an absence of the medication indicator that is present in the subject at a time that is between the time when the device was first turned on and one hour immediately subsequent to that.

Purely Hardcoded Quantitative Two Codes

[0093] In a related embodiment, the algorithm may use solely predetermined information or information directly input into the algorithm by human or machine, either as a seed to a formula, or seed or key to a system such as embedded RSA encryption or another encryption protocol, or as a lookup table, to generate a code or codes if the signal received from the sensor corresponds to some level of medication indicator that is present in the subject and a different code or codes if the sensor indicates an absence of medication indicator present in the subject. For example, a simple use of predetermined information might be to assign two predetermined codes or sets of codes to each level of medication indicator for each hour, day, year, or other time period subsequent to the device's first being turned on, with a code or codes to correspond to the signal received from the sensors corresponding to some level of medication indicator that is present in the subject and another different code or codes if the sensor indicates an absence of the medication indicator present in the subject. For example, a level or amount of signal corresponding to a level of medication indicator defined as "1" for the time period of one hour immediately subsequent to the device's first being turned on might be assigned a predetermined code of "AAA", a level or amount of signal corresponding to a level of medication indicator defined as "2" for the time period of one hour immediately subsequent to the device's first being turned on might be assigned a predetermined code of "AAB", a level or amount of signal corresponding to a level of medication indicator defined as "3" for the time period of one hour immediately subsequent to the device's first being turned on might be assigned a predetermined code of "AAC", and levels greater than 0 for all time subsequent to that might be assigned a code of "AAD". The algorithm might similarly assign a predetermined code of "BBA" if the sensor indicates an absence of the medication indicator present in the subject for that same time period and "BBD" if the sensor indicates an absence of the medication indicator present in the subject for all time subsequent to that. With this predetermined information, upon receiving a signal corresponding to the presence of medication indicator in the sample at a level or quantity defined as "1", at a time less than 1 hour after the system was first turned on, the algorithm might produce "AAA" as a code, which code might correspond to observing a signal corresponding to some level of medication indicator that is present in the subject at a time that is between the time when the device was first turned on and one hour immediately subsequent to that. Upon receiving a signal corresponding to the absence of the medication indicator in the sample, at a time less than 1 hour after the system was first turned on, this same algorithm might produce "BBA" as a code, which code might correspond to observing a signal corresponding to an absence of the medication indicator that is present in the subject at a time that is between the time when the device was first turned on and one hour

immediately subsequent to that.

[0094] The code generated by the present systems can be used for any suitable purposes. For example, a code can be exchanged for a reward and/or an incentive.

[0095] In some embodiments, the present system can further comprise a

component for transmitting the code to a location. The component can transmit the code to any suitable location. For example, the component can transmit the code to a doctor's office, a pharmacy, a clinical lab, a hospital, a health care management company, an insurance company, or other centralized location.

[0096] The component can transmit the code to a location in any suitable manner. For example, the component can transmit the code to a location digitally. In another example, the component can digitally transmit the code to a location, e.g., a centralized location, via a cable, a phone line or wirelessly, e.g., via a mobile telephone network, or via internet connection, whether wired or wireless internet connection.

[0097] In some embodiments, the present systems can be used to assess medication status in a subject of the exemplary medications listed in the Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations (Current through March 2012) published by the U.S. Food and Drug Administration, the exemplary medications listed in The Merck Index (a U.S. publication, the printed 14th Edition, Whitehouse Station, N.J., USA) and its online version (The Merck Index Online^SM, Last Loaded on Web: Tuesday, May 01, 2012), and the exemplary medications listed in Biologies Products & Establishments published by the U.S. Food and Drug Administration.

C. Methods for assessing medication status in a subject

[0098] In another aspect, the present disclosure provides for a method for assessing medication status in a subject, which method comprises: a) providing for a system described in the above Section B; b) generating, on the test device of the system, a detectable signal that indicates the presence, absence and/or amount of a medication indicator in a subject ; c) sensing the detectable signal from the test device using the sensor of the system; d) algorithmically converting the sensed signal from the sensor to a code that corresponds to the presence, absence and/or amount of the medication indicator in the subject using the microprocessor of the system; and e) optionally displaying the code on the display of the system.

[0099] The detectable signal can be generated using any suitable test devices. For example, the detectable signal can be generated using an enzyme-linked immunosorbent assay (ELISA), immunoblotting, immunoprecipitation, radioimmunoassay (RIA),

immuno staining, latex agglutination, indirect hemagglutination assay (IHA), complement fixation, indirect immunofluorescent assay (IFA), nephelometry, flow cytometry assay, plasmon resonance assay, chemiluminescence assay, lateral flow assay, u-capture assay, inhibition assay and avidity assay can be used.

[00100] In some embodiments, the detectable signal can be generated using a lateral flow test device. Any suitable lateral flow test devices can be used in the present methods. For example, the lateral flow test devices and assays disclosed and/or claimed in the U.S. patent Nos. 3,641,235, 3,959,078, 3,966,897, 4,094,647, 4,168,146, 4,299,916, 4,347,312, 4,366,241, 4,391,904, 4,425,438, 4,517,288, 4,960,691, 5,141,875, 4,857,453, 5,073,484, 4,695,554, 4,703,017, 4,743,560, 5,075,078, 5,591,645, 5,656,448, RE 38,430 E, 5,602,040, 6,017,767, 6,319,676, 6,352,862, 6,485,982, 5,120,643, 4,956,302, RE 39,664 E, 5,252,496, 5,514,602, 7,238,538 B2, 7,175,992 B2, 6,770,487 B2, 5,712,170, 5,275,785, 5,504,013, 6,156,271, 6,187,269, 6,399,398, 7,317,532, EP 0,149,168 Al, EP 0,323,605 Al, EP

0,250,137 A2, GB 1,526,708, WO99/40438, and in U.S. provisional application Serial No. 61/509,929, can be used.

[00101] In some embodiments, the step(s) for generating a detectable signal using a lateral flow test device comprises: a) contacting a liquid sample derived from a subject with the test device described in above Section B, wherein the liquid sample is applied to a site of the test device upstream of the test location; b) transporting a medication indicator, if present in the liquid sample, and a labeled reagent to the test location; and c) assessing a detectable signal at the test location that indicates presence, absence and/or amount of the medication indicator in the subject to assess medication status in the subject.

[00102] In some embodiments, the liquid and the labeled reagent are premixed to form a mixture and the mixture is applied to the test device. For example, the labeled reagent can be provided or stored in a liquid and then can be premixed with a sample to form a mixture and the mixture is applied to the test device. In another example, the labeled reagent can be dried in a location or container not in fluid communication with the test device, e.g., in a test tube or well such as a microtiter plate well. In use, the sample liquid can be added to the container, e.g. , the test tube or well, to form the mixture and the mixture can then be applied to the test device.

[00103] In other embodiments, the test device comprises a dried labeled reagent before use and the dried labeled reagent is solubilized or resuspended, and transported to the test location by the liquid sample. The dried labeled reagent can be located at any suitable location on the test device. For example, the dried labeled reagent can be located

downstream from the sample application site, and the dried labeled reagent is solubilized or resuspended, and transported to the test location by the liquid sample. In another example, the dried labeled reagent can be located upstream from the sample application site, and the dried labeled reagent is solubilized or resuspended, and transported to the test location by another liquid.

[00104] In some embodiments, the labeled reagent is solubilized or resuspended, and transported to the test location by the liquid sample alone. In other embodiments, the medication indicator and/or labeled reagent is solubilized or resuspended, and transported to the test location by another liquid.

[00105] The present methods can be used to assess medication status in a suitable subject by assessing a medication indicator in any suitable sample. In some embodiments, the liquid sample is a body fluid sample, e.g., a whole blood, a serum, a plasma and a urine sample.

[00106] In some embodiments, the present methods can be used to assess

medication status in a subject by assessing presence or absence of a medication indicator in a sample. In other embodiments, the present methods can be used to assess medication status in a subject by quantifying or semi-quantifying the amount of a medication indicator in a liquid sample. In still other embodiments, the present methods can be used to assess medication status in a subject by assessing multiple medication indicators in a liquid sample.

[00107] The present methods can be used to detect a signal that indicates the presence, absence and/or amount of a medication indicator in a subject in any suitable sample. In some embodiments, the present methods can be used to detect a signal that indicates the presence, absence and/or amount of a medication indicator in a subject in body fluid sample, e.g. , a whole blood, a serum, a plasma and a urine sample.

[00108] The present methods can be used to detect a signal that indicates the presence, absence and/or amount of a medication indicator in any suitable subject. In some embodiments, the present methods can be used to detect a signal that indicates the presence, absence and/or amount of a medication indicator in a human. In other embodiments, the present methods can be used to detect a signal that indicates the presence, absence and/or amount of a medication indicator in an animal, e.g., a non-human mammal.

[00109] The sensed signal from the sensor can be converted to a code that corresponds to the presence, absence and/or amount of a medication indicator in a subject algorithmically by a microprocessor in any suitable manner. For example, the various embodiments for the conversion as described in the above Section B can be used.

[00110] The present methods can further comprise transmitting the code to a location. The present methods can transmit the code to any suitable location. For example, The present methods can transmit the code to a doctor' s office, a pharmacy, a clinical lab, a hospital, a health care management company, an insurance company, or other centralized location.

[00111] The present methods can transmit the code to a location in any suitable manner. For example, the present methods can transmit the code to a location digitally. In another example, the present methods can digitally transmit the code to a location, e.g., a centralized location, via a cable, a phone line or wirelessly, e.g. , via a mobile telephone network, or via internet connection, whether wired or wireless internet connection.

[00112] The present methods can comprise any suitable additional steps. For example, the present methods can further comprise exchanging the code for a reward and/or an incentive. [00113] The present methods can be used for any suitable purposes. For example, the present methods can be used for facilitating and/or incentivizing patient medication adherence and/or health monitoring.

[00114] In some embodiments, the present methods can be used to assess medication status in a subject of the exemplary medications listed in the Orange Book:

Approved Drug Products with Therapeutic Equivalence Evaluations (Current through March 2012) published by the U.S. Food and Drug Administration, the exemplary medications listed in The Merck Index (a U.S. publication, the printed 14th Edition, Whitehouse Station, N.J., USA) and its online version (The Merck Index Online^SM, Last Loaded on Web: Tuesday, May 01, 2012), and the exemplary medications listed in Biologies Products & Establishments published by the U.S. Food and Drug Administration.

D. Exemplary embodiments

[00115] In exemplary embodiments, the present invention relates to devices, kits, instruments, and methods to facilitate incentivizing patient compliance and/or health monitoring. A microprocessor and sensors are used in the assessment of a sample assay provided by the patient and also to return a code depending on the result of the assay. The code may then be transmitted to a centralized location in exchange for rewards or incentives distributed based on the information contained in the code.

[00116] In some embodiments, the present invention provides devices to facilitate incentivizing patient medication adherence and/or health monitoring. In one embodiment, the present invention provides a device for reading the outcome of a sample assay and returning a code to the user based on the outcome of the assay, which device comprises: at least one sensor to detect the presence, absence, and/or amount of response in a sample assay; at least one microprocessor to algorithmically translate the presence, absence, and/or amount of response in the sample assay to a code, which code contains at least information regarding the presence, absence, and/or amount of response in the sample assay; at least one display to provide this code to the device's user.

[00117] The sample assay can be conducted using any suitable test devices. In some embodiments, the sample assay can be conducted or read using a lateral flow assay.

[00118] Any suitable sensors can be used. In some embodiments, the sensor can be a colorimetric sensor.

[00119] In a related embodiment, the present invention is directed to a method for facilitating incentivizing patient medication adherence and/or health monitoring using the above device, which method comprises: a) carrying out a sample assay that responds to the presence, absence, and/or amount of at least one analyte in the sample; b) using at least one sensor to detect the presence, absence, and/or amount of response in the sample assay; c) using at least one microprocessor to translate the presence, absence, and/or amount of response in the sample assay to a code, which code contains at least information regarding the presence, absence, and/or amount of response in the sample assay; d) providing this code to the user via at least one display, such that the code may be transmitted to a centralized location.

[00120] The present methods can be used to detect a signal that indicates the presence, absence and/or amount of a medication indicator in a subject in any suitable sample. In some embodiments, the present methods can be used to detect a signal that indicates the presence, absence and/or amount of a medication indicator in a subject in body fluid sample, e.g. , a whole blood, a serum, a plasma and a urine sample.

[00121] The present methods can be used to detect a signal that indicates the presence, absence and/or amount of any suitable medication indicator in a subject such as medication metabolites, unmetabolized medication, ketones, glucose, transaminases, albumin, sarcosine, cancer markers, hepatotoxicity markers, nephrotoxicity markers.

[00122] The code can be used for any suitable purposes. For example, the code can be exchanged for rewards and/or incentives. [00123] In another embodiment, the present invention provides a device for reading the outcome of a sample assay and returning a code digitally to a centralized location based on the outcome of the assay, which device comprises: at least one sensor to detect the presence, absence, and/or amount of response in a sample assay; at least one microprocessor to algorithmically translate the presence, absence, and/or amount of response in the sample assay to a code, which code contains at least information regarding the presence, absence, and/or amount of response in the sample assay; at least one component to digitally transmit the code to a centralized location.

[00124] The device can comprise any suitable additional component. For example, the present device can additionally include at least one display to provide this code to the device's user.

[00125] The sample assay can be conducted using any suitable test devices. In some embodiments, the sample assay can be conducted or read using a lateral flow assay.

[00126] Any suitable sensors can be used. In some embodiments, the sensor can be a colorimetric sensor.

[00127] The present device can comprise any suitable component for data or signal transmission. For example, the present device can comprise a digital transmission component for data or signal transmission via any suitable means, e.g., via access a mobile telephone network.

[00128] In a related embodiment, the present invention provides a method for facilitating incentivizing patient medication adherence and/or health monitoring using the device in Embodiment 8 of the'910 application, which method comprises: a) carrying out a sample assay that responds to the presence, absence, and/or amount of analyte in the sample; b) using at least one sensor to detect the presence, absence, and/or amount of response in the sample assay; c) using at least one microprocessor to translate the presence, absence, and/or amount of response in the sample assay to at least a code, which code contains at least information regarding the presence, absence, and/or amount of response in the sample assay; d) digitally transmitting the code to a centralized location.

[00129] The present methods can be used to detect a signal that indicates the presence, absence and/or amount of a medication indicator in a subject in any suitable sample. In some embodiments, the present methods can be used to detect a signal that indicates the presence, absence and/or amount of a medication indicator in a subject in body fluid sample, e.g. , a whole blood, a serum, a plasma and a urine sample.

[00130] The present methods can be used to detect a signal that indicates the presence, absence and/or amount of any suitable medication indicator in a subject such as medication metabolites, unmetabolized medication, ketones, glucose, transaminases, albumin, sarcosine, cancer markers, hepatotoxicity markers, nephrotoxicity markers.

[00131] The code can be used for any suitable purposes. For example, the code can be exchanged for rewards and/or incentives.

[00132] Citation of the above publications or documents is not intended as an admission that any of the foregoing is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents.

Claims

CLAIMS The claimed invention is:

1. A system for assessing medication status in a subject, which system comprises: a) a test device for generating a detectable signal that indicates the presence, absence and/or amount of a medication indicator in a subject;

b) a sensor for sensing the detectable signal from the test device;

c) a microprocessor for algorithmically converting the sensed signal from the sensor to a code that corresponds to the presence, absence and/or amount of the medication indicator in the subject; and

d) optionally a display for displaying the code.

2. The system of claim 1, wherein the test device is a lateral flow test device.

3. The system of claim 2, wherein the test device comprises a porous matrix that comprises a test reagent at a test location on said porous matrix, wherein a liquid sample derived from a subject flows laterally along said test device and passes said test location to form a detectable signal to indicate presence, absence and/or amount of a medication indicator in said subject that can be used to assess medication status in said subject.

4. The system of claim 3, wherein the test reagent is capable of binding to a medication indicator or another binding reagent that is capable of binding to a medication indicator.

5. The system of claim 3, wherein the test reagent is capable of specifically binding to a medication indicator or another binding reagent that is capable of binding to a medication indicator.

6. The system of claim 3, wherein the test reagent is a medication indicator or a medication indicator analog that competes with a medication indicator in the liquid sample for binding to a binding reagent for the medication indicator.

7. The system of any of claims 1-6, wherein a portion of the matrix, upstream from the test location, comprises a dried, labeled reagent, the labeled reagent being capable of being moved by a liquid sample and/or a further liquid to the test location and/or a control location to generate a detectable signal.

8. The system of any of claims 1-6, wherein the test device further comprises, upstream from the test location, a conjugate element that comprises a dried, labeled reagent, the labeled reagent being capable of moved by a liquid sample and/or a further liquid to the test location and/or a control location to generate a detectable signal.

9. The system of any of claims 3-8, wherein the label is a soluble label.

10. The system of any of claims 3-8, wherein the label is a particle label, e.g. , a gold or latex particle label.

11. The system of any of claims 1- 10, wherein the medication indicator is a medication metabolite, an unmetabolized medication, or an indicator of over medication, under medication or medication failure.

12. The system of any of claims 1- 11, wherein the sensor is a laser or LED based sensor.

13. The system of any of claims 1- 12, wherein the sensor is a colorimetric sensor.

14. The system of any of claims 1- 13, wherein the code can be exchanged for a reward and/or an incentive.

15. The system of any of claims 1- 14, which further comprises a component for digitally transmitting the code to a location, e.g. , a centralized location.

16. The system of claim 15, wherein the component digitally transmits the code to a location, e.g. , a centralized location, via a cable, a phone line or wirelessly, e.g. , via a mobile telephone network, or via internet connection.

17. A method for assessing medication status in a subject, which method comprises: a) providing for a system of any of claims 1-16;

b) generating, on the test device of the system, a detectable signal that indicates the presence, absence and/or amount of a medication indicator in a subject ;

c) sensing the detectable signal from the test device using the sensor of the system; d) algorithmically converting the sensed signal from the sensor to a code that corresponds to the presence, absence and/or amount of the medication indicator in the subject using the microprocessor of the system; and

e) optionally displaying the code on the display of the system.

18. The method of claim 17, wherein the detectable signal that indicates the presence, absence and/or amount of a medication indicator in a subject is generated using a body fluid sample.

19. The method of claim 18, wherein the body fluid sample is selected from the group consisting of a whole blood, a serum, a plasma and a urine sample.

20. The method of any of claims 17- 19, wherein the subject is a human.

21. The method of any of claims 17- 19, wherein the subject is an animal.

22. The method of any of claims 17-21, further comprising digitally transmitting the code to a location, e.g. , a centralized location.

23. The method of claim 22, wherein the code is digitally transmitted to a location, e.g. , a centralized location, via a cable, a phone line or wirelessly, e.g. , via a mobile telephone network, or via internet connection.

24. The method of any of claims 17-23, further comprising exchanging the code for a reward and/or an incentive.

25. The method of any of claims 17-24, which is used for facilitating and/or incentivizing patient medication adherence and/or health monitoring.