US007195878B2
`
`(12)
`
`United States Patent
`Cleator
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,195,878 B2
`Mar. 27, 2007
`
`(54) DEVICE AND METHOD FOR FECAL
`TESTING
`(75) Inventor: Iain G. M. Cleator, Vancouver (CA)
`(73) Assignee: Cryo-Genomics, Vancouver (CA)
`(*) Notice:
`Subject to any disclaimer, the term of this
`past iss, so listed under 35
`M
`YW-
`y
`ayS.
`
`(21) Appl. No.: 10/953,273
`
`(22) Filed:
`
`Sep. 30, 2004
`
`(65)
`
`Prior Publication Data
`US 2006/OO684OO A1
`Mar. 30, 2006
`
`eaC)
`
`8/1993 Steinbiss et al. .............. 422.61
`5,238,847 A
`5,264,181 A 11/1993 Schreiber
`5,310,680 A
`5/1994 Baker et al.
`3. t A
`E.
`et al.
`3.
`ck
`E. E. al. ................... 435/6
`3. R ck 1939. St. al.
`435,912
`6,627,414 B2
`9/2003 Billing-Medel et al.
`2003/01388.19 A1* 7/2003 Gong et al. .................... 435/6
`2003/0138941 A1* 7/2003 Gong et al. ...
`... 435/287.2
`2005/0277204 A1* 12/2005 Hollis et al. ................ 436,518
`2006/0029972 A1
`2/2006 Lorenz .......................... 435/6
`
`CA
`
`FOREIGN PATENT DOCUMENTS
`2 286 328
`10, 1998
`OTHER PUBLICATIONS
`
`(51) Int. Cl.
`CI2O I/68
`CI2M I/00
`C7H 2L/02
`C7H 2L/04
`(52) U.S. Cl
`
`(56)
`
`Mandel, J.S., et al: “Reducing Mortality from Colorectal Cancer by
`Screening for Fecal Occult Blood”; The New England Journal of
`(2006.01)
`Medicine; vol. 328, No. 19; May 13, 1993; pp. 1365-1371.
`(2006.01)
`Winawer, S.J.; "Colorectal Cancer Screening Comes of Age'; The
`(2006.01)
`New England Journal of Medicine; Vool. 328, No. 19; May 13,
`(2006.01)
`435/6.435/283.1536/23.1: 'PP ''''''
`s
`s 536,243
`* cited by examiner
`(58) Field of Classification Search .................... 435/6,
`Primary Examiner Ethan Whisenant
`435/283.1; 536/23.1, 24.3
`(74) Attorney, Agent, or Firm Nixon & Vanderhye
`See application file for complete search history.
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`... 23,253
`3.996,006 A 12/1976 Pagano ........
`... 422/56
`4,225,557 A
`9, 1980 Hartlet al. ..
`... 422.61
`4,259,964 A
`4, 1981 Levine ..............
`... 422/58
`4,365,970 A 12, 1982 Lawrence et al.
`4,367,750 A
`1/1983 Levine ........................ 422.61
`4,578,358 A
`3/1986 OkSman et al. ............... 436.66
`4,645,743 A
`2f1987 Baker et al. ....
`... 436.66
`4,742,002 A
`5/1988 Guadagno .......
`435/28
`4,789,629 A 12/1988 Baker et al. ....
`435/7
`4,808.379 A
`2, 1989 Wardlaw et al. .............. 422/56
`5,100,619 A
`3, 1992 Baker et al.
`5,106,582 A
`4, 1992 Baker
`5,171,529 A 12/1992 Schreiber
`5, 182,191 A
`1/1993 Fan et al. ..................... 422.61
`5,196,167 A
`3/1993 Guadagno et al. .....
`422.56
`
`
`
`ABSTRACT
`(57)
`A specimen testing device having a first panel with at least
`two apertures, a second panel with at least two apertures
`opposite the apertures in said first panel, a sheet disposed
`between the first and second panels for receiving a specimen
`through the apertures, the sheet in the apertures in said first
`panel having first, second and third portions disposed on
`opposite sides of a longitudinal axis of the apertures. First
`aperture covers are mounted on the first panel and overlie the
`apertures in the first panel. Second aperture covers are
`mounted on the second panel and overlie the apertures in the
`second panel. The first and second aperture covers in the first
`and second panels are movable independently of each other
`to expose the first, second and third portions of the sheet.
`
`24 Claims, 5 Drawing Sheets
`
`Geneoscopy Exhibit 1049, Page 1
`
`

`

`U.S. Patent
`
`Mar. 27, 2007
`
`Sheet 1 of 5
`
`US 7,195,878 B2
`
`
`
`
`
`le. S
`
`ve
`vis
`
`Auoeuoqe epuAoud
`:pese eleC
`
`?A???SOd ),
`
`?A???SOCH Z
`
`?A???SOd IIV/
`
`Auo)eloqeelou Aoud
`:pe)SeeleO
`
`O
`
`f
`
`Xe-
`
`Deuould :Aq peg|ONJOOOO
`:Aq peyoNuee
`Deuould
`
`| -61-I
`
`Geneoscopy Exhibit 1049, Page 2
`
`

`

`U.S. Patent
`
`Mar. 27, 2007
`
`Sheet 2 of 5
`
`US 7,195,878 B2
`
`74
`
`75
`
`77
`
`79
`
`Fig. 2
`
`Geneoscopy Exhibit 1049, Page 3
`
`

`

`U.S. Patent
`
`Mar. 27, 2007
`
`Sheet 3 of 5
`
`US 7,195,878 B2
`
`
`
`154
`
`v=
`
`Go
`LO
`
`156
`
`150
`
`158
`
`Geneoscopy Exhibit 1049, Page 4
`
`

`

`U.S. Patent
`
`Mar. 27, 2007
`
`Sheet 4 of 5
`
`US 7,195,878 B2
`
`
`
`Geneoscopy Exhibit 1049, Page 5
`
`

`

`U.S. Patent
`
`Mar. 27, 2007
`
`Sheet S of 5
`
`US 7,195,878 B2
`
`
`
`: pe)SeeleO
`
`JOOOO
`
`
`D] ea?Isod IIw
`DJ aa!!!sod z DJ ea?Isod !
`
`:pe)SeeleO
`
`le. OUZ
`
`Xe
`
`Deuould
`euould
`
`Aq peg|ONJOOOO
`:Aq pey).ONue)ed
`
`G -61-I
`
`Geneoscopy Exhibit 1049, Page 6
`
`

`

`US 7,195,878 B2
`
`1.
`DEVICE AND METHOD FOR FECAL
`TESTING
`
`2
`positives and can be readily used in a doctor's office. The
`invention of the present application seeks to meet that need.
`
`The present invention relates to a device for testing fecal
`matter, and to a method of testing using Such a device.
`
`5
`
`BACKGROUND OF THE INVENTION
`
`15
`
`25
`
`It is well known that colorectal cancer and large polyps
`bleed into the stool. Use of guaiacum for the detection of 10
`blood was described in “The Scarlet Letter” by Sherlock
`Holmes as being sensitive but unreliable. The problem has
`been that guaiacum detects oxidizing agents of which blood
`is only one, and red meat and other oxidizing agents also can
`test positive.
`A typical form of fecal occult blood testing known as
`Hemoccult IIR utilizes a guaiac-treated test sheet upon
`which a specimen of fecal material is Smeared. A developing
`Solution is applied to the opposite side of the sheet yielding
`a blue color, which suggests that blood may be present in the
`fecal specimen. The drawback of this approach is that a high
`percentage of false positives is obtained from patients who
`in fact do not have a cancer or polyp. A false positive result
`in the test often results in expensive testing of patients who
`in fact have simply consumed a lot of meat just prior to the
`teSt.
`One approach to overcome the high incidence of false
`positives has been to make the test paper sensitive enough to
`detect up to 2% of blood but not sensitive enough to produce
`too many false positives. A disadvantage of this compromise
`approach is that because of the reduced sensitivity, a number
`of cancers and polyps are not detected.
`In an effort to increase sensitivity, the Hemoccult(R)
`SENSA system was devised (which results in detecting as
`35
`little as 1000 micrograms of blood per ml of stool). How
`ever, this system results in a higher incidence of false
`positives requiring unnecessary invasive tests.
`Alternative approaches to cutting down on false positives
`have involved placing patients on specific diets designed to
`restrict intake of animal proteins and other sources of false
`positives. Despite these efforts, large numbers of false
`positives still occur. One reason for this is the very long time
`it can take for food to pass through the bowel in certain
`patients.
`A specific test for human hemoglobin has been devised.
`This test the HemeSelect(R) test (now called Immudia
`spR)—theoretically registers only human hemoglobin and
`not animal blood from meat or other agents and therefore
`theoretically does not require the patient to be on a special
`diet. Another possible advantage is that human blood from
`the upper gastrointestinal tract may be digested by the time
`it reaches the stool and the only human blood detected would
`be that from the distal bowel. A serious drawback of the
`Immudia-spR test is that it is expensive for a screening test
`and requires specially trained individuals to perform and
`read the test.
`Devices and method for screening fecal occult blood
`specimens are described and claimed in U.S. Pat. Nos.
`5,747,344 and 5,948,687. The entire disclosures of those two
`patents are herein incorporated by reference.
`In recent years there have been significant advances in
`DNA/RNA testing of fecal matter. Present tests are very
`expensive often costing hundreds of dollars, and involve a
`whole stool specimen rather than a sample.
`A need continues to exist for an inexpensive and easy
`to-use fecal test which has a minimal incidence of false
`
`40
`
`45
`
`55
`
`60
`
`65
`
`SUMMARY OF THE INVENTION
`
`In accordance with one aspect of the present invention,
`there is provided a testing device including a first panel with
`three apertures in the first panel; a second panel with three
`apertures in the second panel opposite the three apertures in
`the first panel; a sheet disposed between the first and second
`panels for receiving a specimen through the apertures, the
`sheet in the apertures in the first panel having first and
`second and third portions disposed about a transverse axis of
`the apertures; first aperture covers mounted on the first panel
`and overlying the apertures in the first panel; second aper
`ture covers mounted on the second panel and overlying the
`apertures in the second panel, the first and second aperture
`covers being movable independently of each other to expose
`the first and second and third portions of the sheet. The first
`and second and third portions of the sheet are provided with
`indicating means for locating where specimen is to be placed
`on the sheet. The indicating means in the second portion is
`comprised of one or more Zones which are removable from
`said sheet, and may be defined by perforations. The indi
`cating means in the third portion is comprised of a Zone
`which is also removable from the sheet typically by way of
`perforations and is impregnated with one or more com
`pounds for preventing degradation of DNA/RNA in a
`sample applied to the third portion.
`According to a preferred aspect, the first and second
`panels are rectangular. In a further preferred aspect, the
`apertures in the first panel extend at right angles to the
`apertures in the second panel. The apertures may be rect
`angular, square, round or oval.
`Typically, the aperture covers in the first panel are
`hingedly mounted along a hinge line extending transversely
`of the first panel, and the aperture covers in the second panel
`are hingedly mounted along a hinge line extending longi
`tudinally of the second panel. The first, second and third
`portions of the sheet may be divided by one or more dividing
`regions, which may comprise a hydrophobic strip.
`In a further aspect, the first and second panels each have
`three apertures, with the three apertures in the second panel
`being opposite the three apertures in the first panel. Each of
`the three apertures in the first and second panels has a
`respective aperture cover which overlies portions of the
`sheet in each of the three apertures. The first and second
`panels typically have printed matter thereon, and an inner
`Surface of the first and second aperture covers is generally
`provided with a non-stick wax layer. The sheet may if
`desired be supported on a Support panel disposed between
`the first and second panels.
`In a further aspect, there is provided a method of analyz
`ing a specimen using a specimen-testing device as defined
`above. The method includes, comprises or consists essen
`tially of the steps of obtaining a specimen; opening a first
`aperture cover on the first panel to expose the first, second
`and third portions through an aperture; Smearing a portion of
`the specimen on the first, second and third portions through
`the aperture; closing the first aperture cover to overlie the
`aperture; opening a second aperture cover on the second
`panel to expose the first portion of the sheet carrying the
`specimen; and applying a reagent to the first portion of the
`sheet. A Zone of the second and third portions is typically
`removed from the sheet for further analysis. The specimen
`
`Geneoscopy Exhibit 1049, Page 7
`
`

`

`3
`may be a fecal specimen, a urine specimen, a blood speci
`men, a sputum specimen, a body fluid specimen or a
`DNA/RNA specimen.
`The sheet may be a single piece of paper, typically filter
`paper, and may be provided with one or more hydrophobic
`dividing strips separating the first, second and third portions
`to prevent or minimize possible leakage of developing
`solution from the one portion to the other portions. Alter
`natively, the first, second and third portions may be com
`prised of three separate pieces of filter paper each separated
`10
`by a hydrophobic barrier. The paper sheet may be impreg
`nated with reagent (e.g. guaiac) over the entire area thereof,
`or may be impregnated with reagent (guaiac) only on the
`first portion and plain unimpregnated filter paper for the
`second portion. The third portion is typically impregnated
`with a compound selected from pH buffers, antibiotic(s), a
`disaccharide Sugar (Such as Trehalose), a drying agent, a
`diffusion gel, antibodies to blood or DNA/RNA, and mix
`tures thereof. These compounds serve to stabilize DNA/
`RNA to reduce degeneration of the DNA/RNA.
`The paper is typically high quality cotton to facilitate
`preservation of DNA/RNA for analysis of the sample. The
`hydrophobic material may be wax or other suitable solid
`organic or inorganic material.
`In another preferred aspect, the first and second portions
`are provided with indicating means for locating where
`specimen is to be placed on the sheet through the apertures
`in the first panel, and where developing solution is to be
`placed through the apertures in the second panel. The
`indicating means may comprise printed circles or other
`shapes on the sheet as a visible indicator to the user of where
`to place the specimen. At least one of the indicating means,
`usually that in the second and third portions, is preferably
`comprised of a perforated Zone which is removable from the
`sheet.
`In accordance with a further aspect of the invention, the
`first panel has three apertures extending transversely of the
`first panel and the second panel has three apertures opposite
`the three apertures in the first panel, which extend longitu
`dinally of the second panel. In this embodiment, a Support
`panel for the sheet may be provided between the first and
`second panels with apertures corresponding to the apertures
`in the first panel. Each of the three apertures in the first panel
`has a respective cover hingedly mounted along a hinge line
`extending longitudinally of the longitudinal axis of the panel
`and overlying a respective aperture and respective first and
`second portions of the sheet. Each of the three apertures in
`the second panel has a respective cover which is hingedly
`mounted on the second panel along a hinge line extending
`longitudinally of the second panel and overlies the apertures.
`According to another preferred feature, the device may
`carry printed matter on the first panel Such as patient details
`and instructions for opening of the respective covers to
`reveal the apertures on which the specimen is Smeared.
`Printed matter may also be provided on the second panel,
`Such as instructions to the doctor for conducting testing of
`specimens.
`A further preferred feature of the device is that sticking of
`the cover to the specimen is prevented by providing the
`inside surfaces of the respective aperture covers with a
`non-stick coating. A typical example is a wax layer.
`The present invention enjoys numerous advantages. In
`particular, the device is embodied in one card which readily
`facilitates transference between the doctor and the patient
`and between the doctor and another testing location, such as
`a laboratory. The device is easy to use by the patient and is
`inexpensive to produce. A particularly important advantage
`
`45
`
`25
`
`30
`
`35
`
`40
`
`50
`
`55
`
`60
`
`65
`
`US 7,195,878 B2
`
`5
`
`15
`
`4
`is that the device allows a first test to be carried out by the
`doctor and, in the event that a specimen is positive, or
`DNA/RNA testing is indicated for other reasons such as
`family history or inflammatory bowel disease, Subsequent
`testing can be carried out on the same specimen.
`The methodology involves amplifying the DNA/RNA and
`testing for abnormalities after separating from bacterial and
`human DNA/RNA. In essence genomics, proteomics and
`laser flight technology are used to look for changes com
`pared to normal for tumor producing genes, tumor Suppres
`sor genes, whether they are expressed, biological markers,
`and a few genes and messengers which allow delay in the
`division of the nucleus to permit the gene material to be
`corrected or the cell to be destroyed (apoptosis) such as p23.
`Genomics permits testing using a micro-array chip and
`amplification fluorescent system for up to 20,000 amino acid
`sequences. Proteomics uses a gel diffusion technique and an
`applied electric current to delineate different molecular
`weight and charged proteins and further investigate those,
`which are not present in the same amount as the normal
`control. Chip and laser flight technology measures the
`characteristics of weight and charge using a flight technol
`ogy. Biological markers can be detected by immunoassay
`using antibodies.
`The third aperture consists of a high quality cotton paper
`with certain additives present. In order to preserve the stool
`specimen, the pH should be maintained at around neutral,
`for example 6.5-7.5, typically about 7.0. This is accom
`plished by using pH buffered paper which has been impreg
`nated with, for example, 50 ml 0.1 molar potassium dihy
`drogen phosphate and 29.1 ml of 0.1 molar NaOH. In order
`to prevent bacterial destruction of the DNA/RNA, use of a
`solution of an antibiotic such as Flagyl in a dilution 1:10
`is used to impregnate the paper. Cotton paper can be
`impregnated with magnesium carbonate as a drying agent.
`In order to preserve the DNA/RNA, Trehalose, a disaccha
`ride sugar, in a dilution 1:10" can be used to prevent the
`destruction of the DNA/RNA which occurs rapidly in
`untreated stool. The compounds allow for the protection and
`preservation of DNA/RNA for periods typically up to 11
`years. The nature of the compounds varies, depending on
`whether the specimen is stool or other biological fluid. For
`stool, the compound would for example include pH buffers,
`antibiotic(s), a disaccharide Sugar Such as Trehalose, a
`diffusion gel, antibodies to blood or DNA/RNA and a drying
`agent. The paper typically would be high quality cotton to
`facilitate DNA/RNA testing of the sample. The additives
`will vary depending on the Source of the specimen, but for
`stool would include pH and osmolarity buffers, antibiotic(s)
`and a disaccharide Sugar Such as Trehalose.
`If it were indicated to proceed with a DNA/RNA test, the
`rectangular perforated area would be removed and an eluate
`obtained using distilled water and buffers which would be
`used to look for DNA/RNA abnormalities. Examples of
`these abnormalities are mutant K-ras, p53 tumor suppressor
`gene, BAT-26 micro satellite instability marker, long DNA/
`RNA, APC (Adenomatous polyposis coli). The sensitivity of
`the current commercial version using whole stool is approxi
`mately 65% for Colo-rectal Cancer (CRC), 30–40% for
`advanced adenomas, and there is a specificity of 95%. The
`use of the third aperture adds to conditions detected by a two
`aperture system (two-tier test), since two entirely different
`methods of detecting cancer and polyps are involved. Thus,
`the two tier test identifies about 3% of the screened group of
`patients who have bleeding in the stool, and this will detect
`about 90% of cancers and 70% of adenomas. The third
`aperture will typically detect about 65% of the colo-rectal
`
`Geneoscopy Exhibit 1049, Page 8
`
`

`

`US 7,195,878 B2
`
`5
`cancers and 40% of polyps through the shedding of cancer
`cells and there will be an overlap in patients because the
`third aperture will detect some cancers and adenomas that
`are not bleeding at the time of testing. The high specificity
`of the second test will not add greatly to the 3% who require
`colonoscopy. The net result is a test with high sensitivity and
`specificity which avoids unnecessary expensive and inva
`sive tests as are carried out at present.
`
`5
`
`6
`FIG. 2 shows the inner sides 74, 79 of the panel 70. The
`surfaces 75, 77 are typically coated with a hydrophobic
`material, preferably a waterproof glue Such as wax contain
`ing an adhesive. The purpose of this hydrophobic material is
`to prevent contamination or mixing of individual specimens
`applied through an aperture into the region of an adjacent
`aperture. In this way, the risk of a specimen spreading and
`contacting other specimen(s) is minimized. The hydropho
`bic material also aids in minimizing Sticking of the covers to
`the specimen.
`FIG. 3 shows a sample receiving sheet 128 sized to be
`received between portions 80, 82 when folded over each
`other. Sheet 128 is typically made of an absorbent material,
`usually filter or high grade cotton paper, which is impreg
`nated with a reagent which will react with hemoglobin
`components from blood and a peroxide solution to form a
`colored compound. Examples of Suitable reagents are
`guaiac, tetramethyl benzidene, orthotoluidine and other
`similar chromogens. In the embodiment illustrated herein,
`the reagent impregnated in the sheet is guaiac. For DNA/
`RNA testing, the compounds will vary depending on the
`source of the specimen, but for stool would include pH and
`osmolarity buffers, antibiotic(s), a diffusion gel, antibodies
`to blood or DNA/RNA and a disaccharide sugar, such as
`Trehalose.
`To prevent seepage of reagent from one area to another,
`sheet 128 is provided with strips of hydrophobic material
`130, 131 such as wax extending longitudinally parallel to
`axis 132 and two strips of hydrophobic material 134, 136
`Such as wax extending transversely of axis 132 and crossing
`strips 130, 131. The intersecting pattern of strips 130, 131,
`134, 136 defines nine regions 138, 140, 142,144, 146, 148,
`154, 156, 158. Regions 144, 146,148 are each provided with
`indicating means 150, typically circular Zones shown in
`dashed outline, to assist the user in browsing where to Smear
`the sample on the sheet. The Zones may be provided with
`perforations 152 to enable the Zones to be removed from the
`sheet 128 for subsequent analysis. The sheet 128 may, if
`desired, be Supported on a Support member (not shown).
`The sheet 128 may be formed from one piece of absorbent
`paper with hydrophobic strips defining the regions 138, 140,
`142, 144, 146, 148, 154, 156, 158. Alternatively, the sheet
`128 may be constructed from different absorbent papers,
`each optionally containing different reagents, with the
`hydrophobic strips bonding the different papers together to
`form the sheet. In a further modification, the regions 138,
`140, 142, 144, 146, 148, 154, 156, 158 may be comprised of
`different paper(s) of varying textures, and carrying different
`colors of reagent. Each region is then bonded together with
`hydrophobic material to form the completed sheet 128.
`DNA/RNA stool specimens undergo considerable
`amounts of degradation/digestion. There has been some
`study of this aspect by the Department of Criminal Justice.
`Dr. Liane R. Martin, STR-Typing of Nuclear DNA/RNA for
`Human Fecal Matter Using the Qiagen QIAAMP(R) Stool
`Mini Kit, describes the difference between the theoretical
`yield of DNA/RNA (3.0x10-6.0x10 pg/ml stool. After a
`week, Swabbing or excision both yielded DNA/RNA under
`the conditions of water immersion (2 hours), air dried for a
`week, frozen for a week and processed without thawing. All
`alleles matched that of the subjects reference sample. This
`means that the stool collected in the way described in this
`test will be sufficient for testing. Additionally, work has been
`reported on preservation of stools in rare animals which
`provides the data for the additives suggested (Society for
`Conservation Biology, 16" Annual Meeting, Jul. 14–19,
`2002).
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`10
`
`FIG. 1 is a plan view of a device of the invention showing
`the outside configuration of the foldable sheet:
`FIG. 2 is a plan view of the inside configuration of the
`foldable panel of FIG. 1,
`FIG. 3 is a plan view of a simple receiving sheet which is
`positionable inside the foldable panel of FIG. 1 when the
`latter is folded;
`FIG. 4 is a perspective view of the embodiment in
`partially open configuration comprised of a foldable panel of
`FIGS. 1 and 2 and a sample receiving sheet of FIG. 3
`therebetween; and
`FIG. 5 is a plan view of a further embodiment showing the
`outside configuration of the foldable sheet.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`15
`
`25
`
`40
`
`45
`
`Referring to FIGS. 1 and 2, there is shown a foldable
`panel 70 of the invention. The panel is typically made of
`30
`paper or cardboard, but may also be fabricated of plastic.
`The panel has a first outer side 72 and an opposite inner side
`74. The panel 70 has a fold line 76 extending along a
`longitudinal axis 78 forming a first portion 80 on one side of
`the fold line and a second portion 82 of the other side of the
`35
`fold line. The first portion 80 is provided with three rectan
`gular apertures 84, 86, 88 extending transversely with
`respect to the longitudinal axis 78. Each aperture has a
`respective cover 90, 92, 94 hingedly mounted to the first
`portion 80 along a respective hinge line 96, 98, 100 extend
`ing transversely of the axis 78. Each cover 90, 92, 94 is
`hingedly movable independently of the others between
`closed and open positions.
`The second portion 82 includes three rectangular aper
`tures 102, 104, 105 extending longitudinally of the axis 78
`and opposite the transversely extending apertures 84, 86, 88.
`Aperture 102 is provided with a cover 106, aperture 104
`provided with a cover 107 and aperture 105 is provided with
`a cover 109. Covers 106, 107 and 109 are each hingedly
`mounted along a respective hinge line 110, 111, 112, each of
`50
`which extends longitudinally of the axis 78. Each cover 106,
`107, 109 is movable independently of the other between a
`closed portion and an open position.
`The first portion 80 is provided with locations 114 for
`completion of date(s) on which samples are collected from
`the patient and patient identifying information 116. In addi
`tion, each cover 90, 92, 94 is provided with specimen
`identification information 118 together optionally with
`instructions for application of a specimen sample after the
`cover is opened.
`The second portion 82 is provided with locations 120 for
`reporting results of testing, together with boxes 122 for
`completion of action taken with respect to the patient and/or
`doctor. The covers 106, 107, 109 are provided with respec
`tive information 124, 125, 126 regarding person or entity
`conducting analysis of the specimen. Tabs 115 are formed on
`each cover to assist the user in opening the cover.
`
`55
`
`60
`
`65
`
`Geneoscopy Exhibit 1049, Page 9
`
`

`

`US 7,195,878 B2
`
`10
`
`15
`
`25
`
`40
`
`7
`The term “texture' as used herein in connection with the
`sheet 128 means that the fibrous structure of the sheet
`material, e.g. paper, may be varied depending on the desired
`degree of adherence of the sample. The paper should be
`Sufficiently absorbent so that specimen does not easily
`separate from the sheet after application thereto, for example
`as the specimen dries out. Generally, the sheet (paper) is
`chosen such that the fibrous structure of the paper permits at
`least Some of the sample to permeate through the paper and
`be visible on the other side to that on which the specimen is
`applied. Generally, the sheet material should be such that at
`least about 20% by weight, for example about 25 to about
`50% by weight, of the specimen permeates through the sheet
`and is visible on the other side.
`FIG. 4 is a device of the invention constructed using a
`foldable panel 70 and a sheet 128. The device is constructed
`by placing a sheet 128 on an inside surface 74 with the
`regions 138, 140, 142, 144, 146, 148, 154, 156, 158 aligned
`with apertures 84, 86, 88. The panel 70 is then folded along
`fold line 76 to bring the inner surface 74, 79 into face-to-face
`contact with each other, sandwiching the sheet 128 therebe
`tween with regions in registration with apertures 84, 86, 88
`and apertures 102, 104,105. Adhesive present on surface 74
`or surface 79 or both permits the surfaces to be adhered to
`each other to maintain the resulting device in the folded
`closed state.
`FIG. 5 shows an embodiment similar to that shown in
`FIG. 1 except that the second panel 82" includes two
`rectangular apertures 102', 104 extending longitudinally of
`the axis 78' and opposite the transversely extending aper
`30
`tures 84', 86", 88. Aperture 102' is provided with a cover
`106, aperture 104' is provided with a cover 108. Covers 106
`and 108' are each hingedly mounted along a respective hinge
`line 110", 112', each of which extends longitudinally of the
`axis 78. Each cover 106', 108 is movable independently of
`35
`the other between a closed portion and an open portion.
`The first portion 80' is provided with locations 114" for
`completion of date(s) on which samples are collected from
`the patient and patient identifying information 116'. In
`addition, each cover 90", 92', 94' is provided with specimen
`identification information 118 together optionally with
`instructions for application of a specimen sample after the
`cover is opened.
`The second portion 82" is provided with locations 120' for
`reporting results of testing, together with boxes 122 for
`completion of action taken with respect to the patient and/or
`doctor. The covers 106' 108' are provided with respective
`information 124', 126' regarding person or entity conducting
`analysis of the specimen. Tabs 107" are formed on each cover
`to assist the user in opening the cover.
`The invention has been described with reference to analy
`sis of fecal samples for stool occult blood. However, the
`device may be used for Screening and testing of other
`biological specimens, for example blood and AIDS tests,
`urine tests, pregnancy tests and DNA/RNA tests. Other
`biological fluids can be usefully transported and conve
`niently stored on the DNA/RNA or third aperture which in
`this aspect could be a single window, or using that only or
`using the otherapertures for a preliminary sensitive but not
`specific test (inexpensive) to be followed, if positive, by the
`third aperture. Examples of this would be blood tests (genes
`for familial breast cancer, leukemia, other cancers, HIV,
`diabetes, morbid obesity, pregnancy, Hepatitis A,B,C) urine
`(pregnancy test, complications of pregnancy. Another aspect
`would be inexpensive storage of biological material—cen
`trifuged specimen of cells from urine, washings, asciitic fluid
`for later testing or us as a database (with patients informed
`
`45
`
`50
`
`55
`
`60
`
`65
`
`8
`consent). Another aspect would be storage of blood and
`other samples for DNA/RNA testing for specific disorders
`(heart disease, atherosclerosis, diabetes, morbid obesity.
`In use, where a fecal sample is to be analyzed, a cover 90
`on the first panel 80 of the device is opened and a fecal
`specimen is Smeared through the aperture on the first, second
`and third portions 138, 144 and 154 of the exposed sheet
`128. The cover is then closed. A second fecal sample taken
`at a different time as a result of a different bowel movement
`is then smeared onto the first, second and third portions 140,
`146, 156 of the sheet through the second aperture 86 on the
`first panel, and the cover 92 is closed. The third specimen
`from yet a different bowel movement at a different time is
`smeared onto the first, second and third portions 142, 148,
`158 through the third aperture 88 on the first panel and the
`cover 94 is closed.
`To conduct a first analysis, the cover 106 on the second
`panel 82 covering the first portions on which specimen has
`been applied is opened and developer Solution is applied to
`the circular Zone 150 of each first portion. If a specimen tests
`positive, as evidenced, for example, by the development of
`a blue color, the cover 104 on the second panel covering the
`second portions is opened together with the cover on the first
`panel, and the respective exposed perforated circular Zone
`150 of the second portion of the sheet carrying the positive
`specimen is removed with both covers open, e.g. by being
`punched out of the sheet, and subjected to further analysis
`(e.g. an immunochemical test).
`For DNA/RNA testing, the device is used as follows.
`Upon indication to proceed with DNA/RNA testing, the
`cover 105 is opened and the rectangular perforated area 154
`is removed and an eluate obtained using distilled water and
`buffers, which is analyzed for DNA/RNA abnormalities.
`Examples of such abnormalities are mutant K-ras, p53
`tumor suppressor gene, BAT-26 micro satellite instability
`marker, long DNA/RNA, APC. Colo-rectal cancer has many
`