EP2525910B1 - Pipettenspitzen - Google Patents

Pipettenspitzen Download PDF

Info

Publication number
EP2525910B1
EP2525910B1 EP11735265.8A EP11735265A EP2525910B1 EP 2525910 B1 EP2525910 B1 EP 2525910B1 EP 11735265 A EP11735265 A EP 11735265A EP 2525910 B1 EP2525910 B1 EP 2525910B1
Authority
EP
European Patent Office
Prior art keywords
pipette tip
pipette
tip
ribs
tips
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP11735265.8A
Other languages
English (en)
French (fr)
Other versions
EP2525910A2 (de
EP2525910A4 (de
Inventor
Sean Michael Callahan
Arta Motadel
Phillip Chad Hairfield
Peter Paul Blaszcak
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biotix Inc
Original Assignee
Biotix Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biotix Inc filed Critical Biotix Inc
Priority to EP20209898.4A priority Critical patent/EP3831489A1/de
Priority claimed from PCT/US2011/022129 external-priority patent/WO2011091308A2/en
Publication of EP2525910A2 publication Critical patent/EP2525910A2/de
Publication of EP2525910A4 publication Critical patent/EP2525910A4/de
Application granted granted Critical
Publication of EP2525910B1 publication Critical patent/EP2525910B1/de
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/02—Burettes; Pipettes
    • B01L3/0275—Interchangeable or disposable dispensing tips
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0681—Filter
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/12—Specific details about materials
    • B01L2300/123—Flexible; Elastomeric
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/02—Burettes; Pipettes
    • B01L3/0275—Interchangeable or disposable dispensing tips
    • B01L3/0279—Interchangeable or disposable dispensing tips co-operating with positive ejection means

Definitions

  • the technology relates in part to pipette tips and methods for using them.
  • Pipette tips are utilized in a variety of industries that have a requirement for handling fluids, and are used in facilities including medical laboratories and research laboratories, for example. In many instances pipette tips are used in large numbers, and often are utilized for processing many samples and/or adding many reagents to samples, for example.
  • Pipette tips often are substantially cone-shaped with an aperture at one end that can engage a dispensing device, and another relatively smaller aperture at the other end that can receive and emit fluid.
  • Pipette tips generally are manufactured from a moldable plastic, such as polypropylene, for example. Pipette tips are made in a number of sizes to allow for accurate and reproducible liquid handling for volumes ranging from nanoliters to milliliters.
  • Pipette tips can be utilized in conjunction with a variety of dispensing devices, including manual dispensers (e.g., pipettors) and automated dispensers.
  • a dispenser is a device that, when attached to the upper end of a pipette tip (the larger opening end), applies negative pressure to acquire fluids, and applies positive pressure to dispense fluids.
  • the lower or distal portion of a dispenser (typically referred to as the barrel or nozzle) is placed in contact with the upper end of the pipette tip and held in place by pressing the barrel or nozzle of the dispenser into the upper end of the pipette tip. The combination then can be used to manipulate liquid samples.
  • the pipette tip has a rigid distal end portion, which has been lengthened to provide an elongated, ultra thin integral extension.
  • the wall thickness of the rigid portion is within the range of 0.0381 cm to 0.0508 cm, whereas the wall thickness of the extension, terminating in tapered edge, is within the range of 0.01016 cm to 0.0254 cm, for proper flexibility coupled with sufficient wall integrity to prevent occlusion of the central passage.
  • the invention provides a pipette tip as set out in claim 1.
  • pipette tips comprising a proximal region and a distal region, where the proximal region comprises an exterior surface and an annular flange at the proximal terminus of the proximal region, the proximal region comprises a first set of axially oriented ribs and a second set of axially oriented ribs, the ribs of the first set and the second set are circumferentially spaced and alternately spaced around the exterior surface of the proximal region, and ribs of the first set have a maximum thickness greater than the maximum thickness of ribs of the second set.
  • the distal region wall thickness tapers from (a) a point at or between (i) about the junction of the proximal region and distal region to (ii) about one-quarter of the axial distance from the terminus of the distal region to the junction, to (b) the distal region terminus, and the wall thickness at the distal region terminus is about 0.01016 cm (0.0040 inches) to about 0.01397 cm (0.0055 inches).
  • pipette tips comprising a proximal region and a distal region, where the proximal region comprises an exterior surface and an annular flange at the proximal terminus of the proximal region, the distal region wall thickness tapers from (a) a point at or between (i) about the junction of the proximal region and distal region to (ii) about one-quarter of the axial distance from the terminus of the distal region to the junction, to (b) the distal region terminus, and the wall thickness at the distal region terminus is about 0.01016 cm (0.0040 inches) to about 0.01397 cm (0.0055 inches).
  • the proximal region comprises a first set of axially oriented ribs and a second set of axially oriented ribs.
  • the ribs of the first set and the second set are circumferentially spaced and alternately spaced around the exterior surface of the proximal region.
  • ribs of the first set have a maximum thickness greater than the maximum thickness of ribs of the second set.
  • Some pipette tip embodiments can comprise rib sets of differing thickness disposed on, or co-extensive with, the flexible proximal region.
  • ribs can have a profile shape selected from an arc, pyramid, flat, rectangle, semi-circular, stepped, triangle, rhombus, parallelogram, trapezoid, and the like, and combinations thereof.
  • ribs can be disposed at a particular distance below the flange terminal opening of the pipette tip (e.g., the top boundary of each section of increased thickness can be offset from the edge of the pipette tip).
  • a pipette tip sometimes includes a region of increased thickness (e.g., ribs) at an outer or exterior surface of the proximal region of the pipette tip, while retaining a substantially smooth inner surface in the proximal region, in specific embodiments.
  • a region of increased thickness e.g., ribs
  • one or more ribs may be coextensive with a portion of the flange, (ii) one or more ribs may be coextensive with the flange/proximal region junction, (iii) one or more ribs may terminate at a point on the proximal region before the flange/proximal region junction, (iv) one or more ribs may be coextensive with the junction between the proximal region and the distal region of the pipette tip, (v) one or more ribs may terminate at a point on the proximal region before the junction between the proximal region and the distal region of the pipette tip, or combinations of the foregoing, in some embodiments.
  • the proximal region may comprise a frustum-shaped cavity within the interior of the proximal region.
  • the frustum-shaped cavity can be substantially smooth.
  • the frustum-shaped cavity may comprise an optional annular groove.
  • the wall thickness at the distal region terminus is about 0.010922 cm (0.0043 inches) to about 0.0127 cm (0.0050 inches). In certain embodiments, the wall thickness at the distal region terminus is about 0.011176 cm (0.0044 inches) to about 0.012446 cm (0.0049 inches). In some embodiments, the interior surface of the distal region is substantially smooth, and in certain embodiments, the exterior surface of the distal region comprises a step.
  • each rib of the first set alternates with each rib of the second set.
  • one end of ribs in the first set, one end of ribs in the second set, or one end of ribs in the first and the second set is co-extensive with, or terminates at, the flange.
  • one end of ribs in the first set, one end of ribs in the second set, or one end of ribs in the first and the second set is co-extensive with, or terminates at the junction between the flange and proximal region.
  • one end of ribs in the first set, one end of ribs in the second set, or one end of ribs in the first and the second set is co-extensive with, or terminates at the junction between the proximal region and the distal region.
  • pipette tips comprising a proximal region and a distal region, where the proximal region has an average softness rating of less than about 7.78 N (1.75 pounds) of force.
  • softness rating is the amount of force required to deflect a surface of the pipette tip (e.g., deflection force) a given distance from a starting or resting position.
  • the force for a softness rating is measured by pressing on the side of a pipette tip, often in the proximal region of the pipette tip, towards the axis extending longitudinally from the distal region terminus to the proximal region terminus (e.g., Example 1).
  • the softness rating is a mean, nominal, average, maximum or minimum value.
  • pipette tips described herein have a mean, nominal or average deflection force to deflect a pipette tip a given amount from the resting position of below about 7.78 N (1.75 pounds) of force, below about 7.56 N (1.70 pounds) of force, below about 7.34 N (1.65 pounds) of force, below about 7.12 N (1.60 pounds) of force, below about 6.89 N (1.55 pounds) of force, below about 6.67 N (1.50 pounds) of force, below about 6.45 N (1.45 pounds) of force, below about 6.23 N (1.40 pounds) of force, below about 6.01 N (1.35 pounds) of force, below about 5.78 N (1.30 pounds) of force, below about 5.56 N (1.25 pounds) of force, below about 5.34 N (1.20 pounds) of force, below about 5.12 N (1.15 pounds) of force, and below about 4.89 N (1.10 pounds) of force required for deflection
  • a pipette tip proximal region has a minimal deflection force of about 4.76 N (1.07 pounds). In certain embodiments, a pipette tip proximal region has a maximal deflection force of about 7.78 N (1.75 pounds).
  • a pipette tip has a deflection force in the range of between about 4.76 N (1.07 pounds) and about 5.60 N (1.26 pounds) (e.g., about 4.76 N (1.07 pounds), about 4.80 N (1.08 pounds), about 4.85 N (1.09 pounds), about 4.89 N (1.10 pounds), about 4.94 N (1.11 pounds), about 4.98 N (1.12 pounds), about 5.03 N (1.13 pounds), about 5.07 N (1.14 pounds), about 5.12 N (1.15 pounds), about 5.16 N (1.16 pounds), about 5.20 N (1.17 pounds), about 5.25 N (1.18 pounds), about 5.29 N (1.19 pounds), about 5.34 N (1.20 pounds), about 5.38 N (1.21 pounds), about 5.43 N (1.22 pounds), about 5.47 N (1.23 pounds), about 5.52 N (1.24 pounds), about 5.56 N (1.25 pounds), and about 5.60 N (1.26 pounds) of force).
  • pipette tips comprising a proximal region and a distal region, where the proximal region comprises an exterior surface and an annular flange at the proximal terminus of the proximal region, the proximal region comprises a first set of axially oriented ribs and a second set of axially oriented ribs, the ribs of the first set and the second set are circumferentially spaced and alternately spaced around the exterior surface of the proximal region, and ribs of the first set have a maximum thickness greater than the maximum thickness of ribs of the second set.
  • the distal region wall thickness tapers from (a) a point at or between (i) about the junction of the proximal region and distal region to (ii) about one-quarter of the axial distance from the terminus of the distal region to the junction, to (b) the distal region terminus, the wall thickness at the distal region terminus is about 0.01016 cm (0.0040 inches) to about 0.01397 cm (0.0055 inches), and the proximal region is deflected by a known amount from its starting or resting position by a deflection force of less than 7.78 N (1.75 pounds). In certain embodiments, the proximal region is deflected by a known amount from the starting position by a deflection force between about 4.76 N (1.07 pounds) and about 5.60 N (1.26 pounds).
  • pipette tips comprising a proximal region and a distal region
  • the proximal region comprises an exterior surface and an annular flange at the proximal terminus of the proximal region
  • the distal region wall thickness tapers from (a) a point at or between (i) about the junction of the proximal region and distal region to (ii) about one-quarter of the axial distance from the terminus of the distal region to the junction, to (b) the distal region terminus
  • the wall thickness at the distal region terminus is about 0.01016 cm (0.0040 inches) to about 0.01397 cm (0.0055 inches)
  • the proximal region is deflected a by a known amount from its starting or resting position by a deflection force of less than 7.78 N (1.75 pounds).
  • the proximal region is deflected by a known amount from the starting position by a deflection force between about 4.76 N (1.07 pounds) and about 5.60 N (1.26 pounds).
  • the proximal region comprises a first set of axially oriented ribs and a second set of axially oriented ribs.
  • the ribs of the first set and the second set are circumferentially spaced and alternately spaced around the exterior surface of the proximal region.
  • ribs of the first set have a maximum thickness greater than the maximum thickness of ribs of the second set.
  • pipette tips comprising a proximal region and a distal region, where the proximal region comprises an exterior surface and an annular flange at the proximal terminus of the proximal region, the proximal region comprises a plurality of axially oriented ribs, a thickness of the proximal region is about 0.0127 cm (0.005 inches) to about 0.0381 cm (0.015 inches), the thickness is (i) at or near a sealing zone for a dispensing device, and (ii) at a portion between the ribs, the ribs or portion thereof extend over the sealing zone, and the proximal region is deflected by a known amount from its starting or resting position by a deflection force of less than 7.78 N (1.75 pounds). In certain embodiments, the proximal region is deflected by a known amount from the starting position by a deflection force between about 4.76 N (1.07 pounds) and about 5.60 N (1
  • a method of using a pipette tip comprising: (a) inserting a pipettor into a pipette tip, and (b) contacting the pipette tip with a fluid, where the pipette tip comprises a proximal region and a distal region, and further where the proximal region comprises an exterior surface and an annular flange at the proximal terminus of the proximal region, the proximal region comprises a first set of axially oriented ribs and a second set of axially oriented ribs, the ribs of the first set and the second set are circumferentially spaced and alternately spaced around the exterior surface of the proximal region, and ribs of the first set have a maximum thickness greater than the maximum thickness of ribs of the second set.
  • a pipette tip comprising: (a) inserting a pipettor into a pipette tip, and (b) contacting the pipette tip with a fluid, where the pipette tip comprises a proximal region and a distal region, the proximal region comprises an exterior surface and an annular flange at the proximal terminus of the proximal region, and further where the distal region wall thickness tapers from (a) a point at or between (i) about the junction of the proximal region and distal region to (ii) about one-quarter of the axial distance from the terminus of the distal region to the junction, to (b) the distal region terminus, and the wall thickness at the distal region terminus is about 0.01016 cm (0.0040 inches) to about 0.01397 cm (0.0055 inches).
  • a method for measuring improved pipetting efficiency comprising: (a) applying a pipette tip to a pipettor, (b) aspirating a solution, (c) dispensing the solution into a receptacle, and (d) ejecting the pipette tip from the pipettor, where the average time to complete 3 cycles of steps (a) to (d) is about 20.88 seconds or less.
  • the thickness of the tip wall at the distal region terminus is 0.01397 cm (0.0055 inches) or less.
  • the average time to complete a single cycle of steps (a) to (d) is about 6.7 seconds or less.
  • dispensing includes touching the distal terminus of the pipette tip to a wall of the receptacle after the fluid is dispensed from the interior of the tip.
  • a pipette tip having a wall thickness at the distal region terminus of about 0.01016 cm (0.0040 inches) to about 0.01397 cm (0.0055 inches) is configured to retain less than 0.065% of the fluid drawn into the pipette tip, after the fluid is dispensed (e.g., less than about 0.065%, 0.060%, 0.055%, 0.050%, 0.045%, 0.040%, 0.035%, 0.030%, 0.025%, 0.020%, 0.015%, 0.010%, 0.0095%, 0.0090%, 0.0085%, 0.0080%, 0.0075%, 0.0070%, 0.0065%, 0.0060%, 0.0055%, 0.0050%, 0.0045%, 0.0040%, 0.0035%, 0.0030%, 0.0025%, 0.0020%, 0.0015%, 0.0010%, 0.00095%, 0.00090%, 0.00085%, 0.00080%, 0.00075%, 0.00070%, 0.00065%, 0.00060
  • the pipette tip retains between about 0.00010% and about 0.00015% (e.g., about 0.00011%, 0.00012%, 0.00013%, or 0.00014%) of the fluid drawn into the tip, after the fluid is dispensed. In some embodiments, the pipette tip is configured to retain no more than 0.00012% of the fluid drawn into the tip, after the fluid is dispensed.
  • a method for dispensing fluid from a pipette tip comprising, (a) drawing a volume of fluid into a pipette tip having a wall thickness at the distal region terminus of about 0.01016 cm (0.0040 inches) to about 0.01397 cm (0.0055 inches), and (b) dispensing the fluid from the pipette tip, where the pipette tip retains less than 0.065% of the volume of the fluid that was drawn into the pipette tip, and in some embodiments, the pipette tip is configured to retain no more than 0.00012% of the volume of the fluid that was drawn into the pipette tip, after the fluid is dispensed.
  • the percentage of the fluid drawn into the pipette tip that is retained after dispensing is determined by weight, and in certain embodiments, the percentage of the fluid drawn into the pipette tip that is retained after dispensing is determined using a plurality of pipette tips.
  • the method optionally comprises one or more of (i) applying a pipette tip to a pipettor prior to step (a), (ii) visually inspecting the pipette tip after step (b), (iii) ejecting the pipette tip from the pipettor after step (b), and (iv) combinations thereof.
  • less than 3.72% of a plurality of pipette tips having a wall thickness at the distal region terminus of about 0.01016 cm (0.0040 inches) to about 0.01397 cm (0.0055 inches) retain a portion of the liquid drawn into the pipette tips after the liquid is dispensed (e.g., less than 3.72%, 3.70%, 3.65%, 3.60%, 3.55%, 3.50%, 3.45%, 3.40%, 3.35%, 3.30%, 3.25%, 3.20%, 3.15%, 3.10%, 3.05%, 3.00%, 2.95%, 2.90%, 2.80%, 2.70%, 2.60%, 2.50%, 2.40%, 2.30%, 2.20%, 2.10%, 2.00%, 1.90%, 1.80%, 1.70%, 1.60%, 1.50%, 1.40%, 1.35%, 1.30%, 1.25%, 1.20%, 1.15%, 1.10%, 1.05%, 1.00%, 0.95%, 0.90%, 0.85%
  • between about 0.05% and about 1.0% of the plurality of pipette tips having a wall thickness at the distal region terminus of about 0.01016 cm (0.0040 inches) to about 0.01397 cm (0.0055 inches) retain a portion of the liquid drawn into pipette tips after the liquid is dispensed. In certain embodiments, between about 0.15% and about 0.30% of the plurality of pipette tips having a wall thickness at the distal region terminus of about 0.01016 cm (0.0040 inches) to about 0.01397 cm (0.0055 inches) retain a portion of the liquid drawn into pipette tip after the liquid is dispensed.
  • between about 0.20% and about 0.26% of the plurality of pipette tips having a wall thickness at the distal region terminus of about 0.01016 cm (0.0040 inches) to about 0.01397 cm (0.0055 inches) retain a portion of the liquid drawn into pipette tips after the liquid is dispensed.
  • a method for dispensing fluid from a pipette tip comprising, (a) drawing fluid into a plurality of pipette tips having a wall thickness at the distal region terminus of about 0.01016 cm (0.0040 inches) to about 0.01397 cm (0.0055 inches), and (b) dispensing the fluid from the pipette tips, where less than 3.72% of the pipette tips retain a portion of the liquid drawn into pipette tips after the liquid is dispensed.
  • a method for dispensing fluid from a pipette tip comprising (a) drawing fluid into a plurality of pipette tips having a wall thickness at the distal region terminus of about 0.01016 cm (0.0040 inches) to about 0.01397 cm (0.0055 inches), and (b) dispensing the fluid from the pipette tips, where between about 0.15% and about 0.30% of the pipette tips retain a portion of the liquid drawn into pipette tips after the liquid is dispensed, and in certain embodiments, between about 0.20% and about 0.26% of the pipette tips retain a portion of the liquid drawn into pipette tips after the liquid is dispensed.
  • the number of pipette tips that retain liquid after dispensing is determined by visual inspection.
  • the method optionally comprises one or more of (i) applying a pipette tip to a pipettor prior to step (a), (ii) visually inspecting the pipette tip after step (b), (iii) ejecting the pipette tip from the pipettor after step (b), and (iv) combinations thereof.
  • a pipette tip having a wall thickness at the distal region terminus of about 0.01016 cm (0.0040 inches) to about 0.01397 cm (0.0055 inches) contributes to a reduction of between about 20% and about 90% in the average time to complete a cycle of steps in a fluid manipulation procedure (e.g., about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or up to about 90%).
  • a method for dispensing fluid from a pipette tip comprising (a) drawing a volume of fluid into a pipette tip having a wall thickness at the distal region terminus of about 0.01016 cm (0.0040 inches) to about 0.01397 cm (0.0055 inches), and (b) dispensing the fluid from the pipette tip, where the pipette tip contributes to a reduction of between about 20% and about 90% in the average time to complete a cycle of steps in a method for dispensing fluid from a pipette tip.
  • the method optionally comprises one or more of (i) applying a pipette tip to a pipettor prior to step (a), (ii) visually inspecting the pipette tip after step (b), (iii) ejecting the pipette tip from the pipettor after step (b), and (iv) combinations thereof.
  • a method of manufacturing a pipette tip comprising: (a) contacting a pipette tip mold with a molten polymer, and releasing the formed pipette tip from the mold after cooling, where the pipette tip comprises a proximal region and a distal region, and further where the proximal region comprises an exterior surface and an annular flange at the proximal terminus of the proximal region, the proximal region comprises a first set of axially oriented ribs and a second set of axially oriented ribs, the ribs of the first set and the second set are circumferentially spaced and alternately spaced around the exterior surface of the proximal region, and ribs of the first set have a maximum thickness greater than the maximum thickness of ribs of the second set.
  • a pipette tip comprising: (a) contacting a pipette tip mold with a molten polymer, and releasing the formed pipette tip from the mold after cooling, where the pipette tip comprises a proximal region and a distal region, and further where the proximal region comprises an exterior surface and an annular flange at the proximal terminus of the proximal region, the distal region wall thickness tapers from (a) a point at or between (i) about the junction of the proximal region and distal region to (ii) about one-quarter of the axial distance from the terminus of the distal region to the junction, to (b) the distal region terminus, and the wall thickness at the distal region terminus is about 0.01016 cm (0.0040 inches) to about 0.01397 cm (0.0055 inches).
  • pipette tips comprising a proximal region and a distal region, where the proximal region comprises an exterior surface and an annular flange at the proximal terminus of the proximal region, the proximal region comprises a plurality of axially oriented ribs; a thickness of the proximal region is about 0.0127 cm (0.005 inches) to about 0.0381 cm (0.015 inches); the thickness is (i) at or near a sealing zone for a dispensing device, and (ii) at a portion between the ribs; and the ribs or portion thereof extend over the sealing zone.
  • One end of ribs is co-extensive with, or terminates at, the flange, in certain embodiments. At times, one end of ribs is co-extensive with, or terminates at, the junction between the flange and the proximal region. Sometimes one end of ribs is co-extensive with, or terminates at, the junction between the proximal region and the distal region. In certain embodiments, the ribs extend from the junction of the flange and proximal region to the junction of the proximal and distal regions.
  • the distal region wall thickness tapers from (a) a point at or between (i) about the junction of the proximal region and distal region to (ii) about one-quarter of the axial distance from the terminus of the distal region to the junction, to (b) the distal region terminus, and the wall thickness at the distal region terminus is about 0.01016 cm (0.0040 inches) to about 0.01397 cm (0.0055 inches).
  • the wall thickness at the distal region terminus sometimes is about 0.010922 cm (0.0043 inches) to about 0.0127 cm (0.0050 inches), and at times is about 0.011176 cm (0.0044 inches) to about 0.012446 cm (0.0049 inches).
  • the interior surface of the distal region is substantially smooth, and sometimes the exterior surface of the distal region comprises a step.
  • the proximal region sometimes comprises a frustum-shaped cavity within the interior of the proximal region, and at the frustum-shaped cavity is substantially smooth and, in some embodiments, comprises an optional annular groove.
  • the thickness of the proximal region is about 0.01778 cm (0.007) inches to about 0.003302 cm (0.0013 inches),
  • the maximum thickness of the ribs is about 0.09398 cm (0.037 inches) to about 0.1524 cm (0.060 inches), is about 0.04064 cm (0.016 inches) to about 0.06858 cm (0.027 inches), is about 0.0381 cm (0.015 inches) to about 0.0635 cm (0.025 inches), is about 0.02794 cm (0.011 inches) to about 0.05334 cm (0.021 inches) or is about 0.00762 cm (0.003 inches) to about 0.02286 cm (0.009 inches). Also included are methods of manufacturing and using such pipette tips, described in greater detail hereafter.
  • the pipette tip is a unitary construction. In certain embodiments, the pipette tip is made of not made of an elastomer. In some embodiments, the interior surface of the proximal region does not include an internal shelf. In certain embodiments, the internal surface of the proximal region has a continuous circumferential thickness. In some embodiments, the internal surface of the proximal region does not have a continuous axial thickness. In certain embodiments, the internal surface of the proximal region provides a continuous contact zone. In some embodiments, the internal surface of the proximal region does not include internal spaced contact points.
  • pipette tip embodiments described herein may afford particular advantages to some users.
  • one or more of the structural features described may be incorporated into a pipette tip embodiment in one or more combinations. Incorporation of a structural feature can result in an advantage described hereafter, in certain instances.
  • Pipette tip embodiments described herein can be of any overall geometry useful for dispensing fluids in combination with a dispensing device.
  • the pipette tips described herein also can be of any volume useful for dispensing fluids in combination with a dispensing device.
  • Non-limiting examples of volumes useful for dispensing fluids in combination with a dispensing device, and described as non-limiting embodiments herein, include pipette tips configured in sizes that hold from 0 to 10 microliters, 0 to 20 microliters, 1 to 100 microliters, 1 to 200 microliters, 1 to 300 microliters, and from 1 to 1250 microliters, for example.
  • the volumes pipette tips described herein can manipulate are larger than the volume designation given that particular pipette tip.
  • a pipette tip designated as suitable to manipulate volumes up to 300 microliters can sometimes be used to manipulate volumes up to about 1%, 2%, 3%, 5%, 10%, 15% or sometimes as much as up to about 20% larger than the designated pipette tip volume.
  • pipette tips may differ, and certain pipette tips can comprise a continuous tapered wall forming a central channel or tube that is roughly circular in horizontal cross section, in some embodiments.
  • a pipette tip can have any cross-sectional geometry that results in a tip that (i) provides suitable flow characteristics, and (ii) can be fitted to a dispenser (e.g., pipette), for example.
  • pipette tips comprise a proximal region 15 and a distal region 20 (e.g., FIGS. 1A-1D ).
  • Proximal region 15 comprises an outer or exterior surface upon which regions of increased thickness (e.g., ribs) are disposed, in some embodiments.
  • proximal region 15 comprises an annular flange at the proximal terminus of the proximal region.
  • the bore of the top-most portion of the central channel or tube generally is wide enough to accept a particular dispenser apparatus (e.g., nozzle, barrel).
  • Pipette tips described herein often taper from the widest point at the top-most portion of the pipette tip (pipette proximal end or end that engages a dispenser), to a narrow opening at the bottom most portion of the pipette tip (pipette distal end used to acquire or dispel fluid).
  • a pipette tip wall includes two or more taper angles.
  • pipette tips described herein are of unitary construction.
  • Proximal region 15 also comprises an interior or inner surface.
  • the inner surface of the pipette tip sometimes forms a tapered continuous wall, in some embodiments, and in certain embodiments, the external wall may assume an appearance ranging from a continuous taper to a stepped taper or a combination of smooth taper with external protrusions.
  • the interior surface of proximal region 15 is smooth and does not include an internal shelf. That is, the inner surface of proximal region 15 does not have internal walls or protrusions that stop the axial insertion of a pipette tip barrel or nozzle.
  • the inner surface of proximal region 15 provides a continuous contact zone (e.g., sealing zone), for engagement of a pipettor nozzle or barrel. In some embodiments, the inner surface of proximal region 15 does not include internal spaced contact points.
  • a pipette tip can have (i) an overall length of about 2,794 cm (1.10 inches) to about 8.89 cm (3.50 inches) (e.g., about 3.175, 3.81, 4.445, 5.08, 5.715, 6.35, 6.985, 7.62, 8.225 cm (1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, 3.00, 3.25 inches)); (ii) a fluid-emitting distal section terminus having an inner diameter of about 0.0254 cm (0.01 inches) to about 0.0762 cm (0.03 inches) (e.g., about 0.0381, 0.0508, 0.0635 cm (0.015, 0.020, 0.025 inches)) and an outer diameter of about 0.0508 cm (0.02 inches) to about 1.778 cm (0.7 inches) (e.g., about 0.0635 cm, 0.0762 cm, 0.1016 cm, 0.127 cm, 0.1524 cm (0.025, 0.03, 0.04, 0.05, 0.06 inches)
  • the wall of the proximal section of a pipette tip described herein sometimes is continuously tapered from the top portion, to a narrower terminus.
  • the top portion generally is open and often is shaped to receive a pipette tip engagement portion of a dispensing device.
  • the wall of a proximal section in some embodiments, forms a stepped tapered surface.
  • the angle of each taper in the proximal section is between about zero degrees to about thirty degrees from the central longitudinal vertical axis of the pipette tip (e.g., about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ,11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 degrees), in certain embodiments.
  • the wall thickness of a proximal section may be constant over the length of the section, or may vary with the length of the proximal section (e.g., the wall of the proximal section closer to the distal section of the pipette tip may be thicker or thinner than the wall closer to the top of the proximal section; the thickness may continuously thicken or thin over the length of the wall).
  • the walls of proximal region 15 do not have a continuous axial thickness. That is, the thickness of the walls in proximal region 15 sometimes decreases axially towards the midpoint of proximal region 15, then increases axially from the midpoint towards the junction of proximal region 15 and distal region 20.
  • the walls of proximal thickness 15 have a continuous circumferential thickness. That is, the thickness of the walls in proximal region 15, as viewed in a particular cross section, do not vary in thickness.
  • a proximal section of a pipette tip may contain a filter, insert or other material.
  • the wall of the distal section of a pipette tip sometimes is continuously tapered from the wider portion, which is in effective connection with the proximal section, to a narrower terminus.
  • the wall of the distal section in some embodiments, forms a stepped tapered surface.
  • the angle of each taper in a distal section is between about zero degrees to about thirty degrees from the central longitudinal vertical axis of the pipette tip (e.g., about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 degrees), in certain embodiments.
  • the wall of the distal section forms stepped vertical sections.
  • the wall thickness of a distal section may be constant along the length of the section, or may vary with the length of the section (e.g., the wall of the distal section closer to the proximal section of the pipette tip may be thicker or thinner than the wall closer to the distal section terminus; the thickness may continuously thicken or thin over the length of the wall).
  • the distal section of a pipette tip generally terminates in an aperture through which fluid passes into or out of the distal portion.
  • the interior surface of the distal region is substantially smooth.
  • the exterior surface of the distal region comprises a step.
  • a distal section of a pipette tip may contain a filter, insert or other material.
  • Certain pipette tip embodiments can include a flared lead-in surface at the end of the proximal region.
  • Certain pipette tip embodiments may include a flange (e.g., annular flange) at the end of each pipette tip in the proximal region.
  • the flange may be flared, and the lead-in diameter of the flange can allow for dispenser engagement tolerance, which is relevant for multi-dispenser applications, for example.
  • Such a flange can provide a larger contact zone for engaging a pipettor nozzle, and can increase the probability of a sealing engagement between the dispenser nozzle not coaxially aligned with a pipette tip by guiding the axial center of the pipette tip to axial center of the dispenser nozzle.
  • An annular flange also can provide pipette tip rigidity in addition to facilitating dispenser alignment.
  • pipette tips described herein include an annular flange at the proximal terminus of the proximal region.
  • FIGS. 1A and 1B An example of a flared lead-in surface and flange is illustrated in FIGS. 1A and 1B (e.g., 60, 65 and 70).
  • Some pipette tip embodiments can include a distal region having a tapered wall thickness and terminating with a "knife edge” thickness.
  • the term "knife edge” or “blade,” as used herein refers to an edge resulting from a continuous taper of a pipette wall surface.
  • the taper can be established by the inner surface disposed at a different angle than the outer surface along all or a portion of the axial length of the distal region.
  • the surfaces form a sharply defined single contiguous edge or boundary of minimal thickness.
  • This feature can reduce the area of the surface to which liquid droplets can adhere, and also may reduce the surface tension between the tip and the droplets, thereby reducing the probability and frequency with which droplets may adhere to the discharge aperture of the pipette tips.
  • This feature also can reduce the number of times a user needs to touch a pipette tip to a surface to remove a droplet adhered to the pipette tip, which sometimes is referred to as "touching off.”
  • This feature also may increase precision and accuracy in manual or automated applications ("precision” and "accuracy” are described in further detail below).
  • minimal thickness refers to a value representative of the limits of current and future manufacturing and molding capabilities. Factors such as plastic viscosity and flow characteristics, as well as plastic hardeners (e.g., currently available plasticizers or hardeners, or plasticizers yet to be formulated) also may contribute to the minimal thickness attainable for pipette tips described herein. Therefore, thicknesses described herein for pipette tip walls of the distal opening (e.g. the edge or blade walls of the opening) sometimes are at the current limit of molding and manufacturing technology, and it is possible that future molding, manufacturing and plastics technology will result in lesser thicknesses.
  • plastic viscosity and flow characteristics as well as plastic hardeners (e.g., currently available plasticizers or hardeners, or plasticizers yet to be formulated) also may contribute to the minimal thickness attainable for pipette tips described herein. Therefore, thicknesses described herein for pipette tip walls of the distal opening (e.g. the edge or blade walls of the opening) sometimes are at
  • the lower (or distal) about one-quarter of the distance 40 from the distal region terminus 50 to the junction 30, may comprise a distal terminus 50 featuring a knife or blade edge wall thickness 53 in the range of about 0.01016 cm (0.0040 inches) to about 0.01397 cm (0.0055 inches) thick.
  • the wall thickness 53 at distal terminus 50 can resemble a blade or knife edge and can be about 0.01016 cm (0.0040 inches), 0.010414 cm (0.0041 inches), 0.010668 cm (0.0042 inches), 0.010922 cm (0.0043 inches),.0.011176 cm (0.0044 inches), 0.01143 cm (0.0045 inches), 0.011684 cm (0.0046 inches), 0.011938 cm (0.0047 inches), 0.012192 cm (0.0048 inches), 0.012446 cm (0.0049 inches), 0.0127 cm (0.0050 inches), 0.012954 cm (0.0051 inches), 0.013208 cm (0.0052 inches), 0.013462 cm (0.0053 inches), 0.013716 cm (0.0054 inches), or about 0.01397 cm (0.0055 inches) thick, in certain embodiments.
  • the wall thickness at the distal region terminus is about 0.010922 cm (0.0043 inches) to about 0.0127 cm (0.0050 inches). In certain embodiments, the wall thickness at the distal region terminus is about 0.011176 cm (0.0044 inches) to about 0.012446 cm (0.0049 inches). In certain embodiments, the distal region comprises a wall thickness that tapers from (a) a point at or between (i) about the junction of the proximal region and distal region 30 to (ii) about one quarter of the axial distance 40 from the terminus of the distal region to the junction 30, to (b) the distal region terminus 50, as illustrated in FIG. 1A .
  • a knife edge or blade feature may reduce the area of the surface to which liquid droplets can adhere, and also may reduce the surface tension between the tip and the droplets, thereby reducing the probability and frequency with which droplets may adhere to the discharge aperture of the pipette tips.
  • the "inverse taper" (e.g., the taper of the inner surface caused by the thinning of the distal terminus, while the outer surface taper remains constant) of the blade feature may cause drops of liquid to become less likely to adhere to the pipette tip while being dispelled from the pipette tip due to the combination of increased drop surface area and surface tension (e.g., the drop is stretched due to the internal inverse taper) and decreased pipette tip inner surface area, in some embodiments.
  • the combination of increased drop surface area and surface tension combined with the decreased pipette tip surface area enables the efficient release of liquid droplets from the surfaces of the pipette tip.
  • This feature also may lessen the number of times a user needs to touch a pipette tip to a surface to remove a droplet adhered to the pipette tip, and also may increase precision and accuracy in manual or automated applications. Reducing the number of times a user needs to touch off may help increase throughput of samples (e.g., time savings), increase accuracy of sample delivery (e.g., delivery of entire sample or reagent), and decrease costs (e.g., fewer repetitive injury claims, higher sample throughput, and fewer repeated samples due to pipetting error or inaccuracy).
  • time savings associated with the combination of blade feature, flange feature and flexible region feature is described in the Examples section herein.
  • the term "user" as used herein refers to a person or extension under the direct or indirect control of a person (e.g., a pipettor, an automated device, an automated device controlled by a computer).
  • a pipette tip can comprise one or more flexible features.
  • a pipette tip includes a section of flexible thickness (e.g., proximal region) that sometimes also can include axially oriented alternating regions of increased thickness (e.g., axially oriented ribs or sets of ribs).
  • the ribs comprise a first set and a second set of axially oriented ribs.
  • the axially oriented ribs can be alternately spaced and circumferentially spaced around the external surface of the proximal region of the pipette tip.
  • a terminus of a dispenser often sealingly engages an inner portion of a pipette tip at a sealing zone, which generally is located a particular distance from the proximal terminus of the pipette tip.
  • a sealing zone in certain embodiments is disposed a particular distance below the terminal opening of the pipette tip (e.g., the sealing zone is offset from the edge of the pipette tip).
  • a sealing zone often is a point at which a fluid tight, frictional and/or sealing engagement occurs between a pipette tip and a dispenser.
  • a sealing zone is axially coextensive with a region of flexible thickness and/or increased thickness (e.g., ribs) in some embodiments.
  • the proximal region comprises a sealing zone.
  • a sealing zone provides a continuous contact zone for frictional and/or sealing engagement between a pipette tip and a dispenser.
  • a flexible region e.g., flexible thickness
  • a pipette tip proximal region e.g., at a sealing zone
  • a pipette tip sometimes includes a flexible proximal region where the softness or flexibility allows deflection of the proximal region when a deflecting force is applied.
  • the softness or flexibility sometimes is referred to as a "softness rating" or a "flexibility rating.” Any suitable method can be used to measure pipette tip flexibility in the flexible region of a pipette tip.
  • Non-limiting examples of tests that can be utilized to measure pipette tip flexibility include a deformation test, a pipette tip engagement test, a pipette tip ejection test, the like and combinations thereof.
  • a pipette tip deformation test sometimes includes the use of a force gauge to press down on an outer surface (e.g., proximal outer surface, distal outer surface, proximal and distal outer surfaces) of the pipette tip, and the force necessary to cause deformation of the normal pipette tip shape by a predetermined amount, is recorded.
  • Pipette tip engagement and ejection experiments sometimes includes the use of digital force gauges to measure the amount of force exerted during pipette/pipette tip engagement and pipette tip ejection. Examples of experiments performed to measure pipette tip deflection (softness of tip), engagement force and ejection force are presented in the Examples.
  • a pipette tip generally is affixed to a dispensing device by inserting a portion of the dispenser (e.g., dispenser barrel, tip or nozzle) into the proximal or receiving end of a pipette tip with a downward or axial force.
  • the downward force applied to the dispenser that can securely engage the pipette tip may be less than pipette tips currently manufactured.
  • a proximal region having flexible thickness e.g., in the sealing zone) can reduce the amount of axial force required to engage and/or disengage a pipette tip to a dispenser.
  • Non-limiting examples of reduced axial forces include an average, mean or nominal axial force reduction of about 20% to about 80% of the force required to engage standard inflexible pipette tips (e.g., about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% of the force required to engage pipette tips currently manufactured).
  • a non-limiting example of a manufactured inflexible pipette tip that can be used as a standard against which to compare mean or nominal axial force reduction, is manufactured by Eppendorf International (e.g., Eppendorf Dualfilter 100 microliter tip, USA/CDN Catalog No. 022491237).
  • circumferentially spaced regions of increased thickness e.g., axially oriented ribs or sets of ribs
  • Radial expansion and segmental expansion can allow for a secure, fluid tight sealing engagement of a pipette tip with different dispensers having disparate nozzle or barrel diameters.
  • Radial and segmental expansion properties can be a result of circumferentially spaced alternating regions of thicker and thinner ribs, in some embodiments.
  • Certain flexible features described herein can reduce costs and injuries associated with repetitive motions, and increase efficiency, precision and accuracy of pipette tip use. For example, reducing the axial force required for engagement and/or disengagement of a pipette tip with a dispenser. Also, reducing the frequency of "touching off” can reduce the number of repetitive motions associated with using pipette tips.
  • a proximal region comprises a wall thickness of about 0.0127 cm (0.005 inches) to about 0.0381 cm (0.015 inches) at or near the sealing zone (e.g., about 0.01524, 0.01778, 0.02286, 0.0254 0.02794, 0.03048, 0.03302, 0.03356 cm (0.006, 0.007, 0.008, 0.009, 0.010, 0.011, 0.012, 0.013, 0.014 inches)).
  • the proximal region comprises a wall thickness of about 0.02032 cm (0.008 inches) to about 0.03048 cm (0.012 inches) or about 0.02286 cm (0.009 inches) to about 0.02794 cm (0.011 inches).
  • the latter-referenced wall thickness is measured at a point of the proximal region where there are no ribs (e.g., a point between ribs). Such a thickness measurement sometimes is measured at or near where callout 70 in FIG. 2 meets the pipette tip proximal region, for example.
  • the thickness of proximal region 15 gradually increases below the sealing zone towards the proximal region/distal region junction. Without being limited by theory, the increased thickness below the sealing zone may limit the travel of a dispenser past the sealing zone, due to the larger force required to insert the dispenser past the sealing zone as a result of a thicker, less flexible area in the proximal region.
  • the wall thickness at the junction of the proximal region and the distal region, measured from the interior surface to the exterior surface of the pipette tip is about 0.04318 cm (0.017 inches) to about 0.0762 cm (0.030 inches) thick (e.g., about 0.04572, 0.04826, 0.0508, 0.05334, 0.05588, 0.05842, 0.06096, 0.0635, 0.06604, 0.06858, 0.07112, 0.07366 cm (0.018, 0.019, 0.020, 0.021, 0.022, 0.023, 0.024, 0.025, 0.026, 0.027, 0.028, 0.029 inches)).
  • the wall thickness at this junction is about 0.05588 cm (0.022 inches) to about 0,06858 cm (0.027 inches) thick, or about 0.05842 cm (0.023 inches) to about 0.06604 cm (0.026 inches) thick.
  • the step from the exterior surface of the distal region to the exterior surface of the proximal region at the proximal region/distal region junction is about 0,0076.2 cm (0.003 inches) to about 0.02032 cm (0.008 inches) thick (e.g., about 0.01016, 0.0127, 0.01524, 0.01778 cm (0.004, 0.005, 0.006, 0.007 inches) thick). This step is located at about the position in FIG. 2 where callout 72 meets the pipette tip.
  • the proximal region comprises a first set of axially extended ribs (e.g., 80) and a second set of axially extended ribs (e.g., 85).
  • Axially extended ribs which also are referred to herein as "axially oriented ribs," are longer in the direction of the pipette tip axis, where the axis extends from the center of the proximal region terminus cross section to the center of the distal region terminus cross section.
  • Axially extended ribs are shorter in the radial, circumferential direction around the pipette tip.
  • the longer length of axially extended ribs is parallel to the pipette tip axis.
  • the longer length of axially extended ribs is at an angle with respect to the pipette tip axis, which angle sometimes is between about zero to ten degrees from such axis.
  • one or more ribs are longer than other ribs on a pipette tip. Ribs of the first set sometimes are longer than ribs of the second set, and in certain embodiments, ribs of the first set are shorter than ribs of the second set. In certain embodiments, the axial length of one or more ribs (e.g., all ribs) is substantially equal to the axial length of the proximal region (e.g., proximal region 15, illustrated in FIG. 2 and FIG. 3 ).
  • a pipette tip comprises a set of axially extended ribs circumferentially spaced around the external surface of the proximal region of the pipette tip.
  • ribs of a first set and a second set are circumferentially spaced and alternately spaced around the external surface of the proximal region.
  • the terms "alternately spaced”, “spaced alternately,” “alternates” and grammatical equivalents thereof, when used to describe spacing between ribs, or sets of ribs, can refer to one or more ribs of the first set or first type between two ribs of the second set or second type, or one or more ribs of the second set or second type between two ribs of the first set or first type, and combinations of the foregoing.
  • Ribs there can be one or more circumferential spacing distances between ribs (e.g., ribs may be spaced equidistant from one another or may be spaced with different distances). Ribs may be patterned around the proximal region of a pipette tip in a regular pattern (e.g., all ribs are equidistantly spaced, some ribs are equidistantly spaced) in some embodiments, and in certain embodiments, ribs are spaced in an irregular pattern. In some embodiments, all ribs are equidistant from one another along a circumference of the pipette tip, and thereby are spaced regularly along the circumference.
  • a pipette tip may include any suitable number of ribs that confer proximal region flexibility.
  • pipette tips comprise about 4 or more ribs, and sometimes about 6 to about 60 ribs (e.g., about 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 ribs).
  • a pipette tip includes a total of about 8 to about 16 ribs.
  • a pipette tip comprises a number of ribs in a first set equal to the number of ribs in a second set. In some embodiments, a pipette tip includes about 3 to about 20 ribs of a first set and about 3 to about 20 ribs of a second set.
  • Ribs on a pipette tip have a particular thickness (e.g., height measured from the exterior surface of the pipette tip proximal region; height measured from the surface to which callout 70 in FIG. 2 connects) and a particular width (e.g., the width of the face to which callout 85 in FIG.2 connects).
  • the maximum thickness of a rib is about 0.1524 cm (0.060 inches), and sometimes the maximum thickness of a rib is about 0.09398 cm (0.037 inches) to about 0.1524 cm (0.060 inches) (e.g., about 0.09652, 0.09906, 0.1016, 0.10414, 0.10668, 0.10922, 0.11176, 0.1143, 0.11684, 0.11938, 0.12192, 0.12446, 0.1270, 0.12954, 0.13208, 0.13462, 0.13716, 0.1397, 0.14224, 0.14478, 0.14732, 0.14986 cm (0.038, 0.039, 0.040, 0.041, 0.042, 0.043, 0.044, 0.045, 0.046, 0.047, 0.048, 0.049, 0.050, 0.051, 0.052, 0.053, 0.054, 0.055, 0.056, 0.057, 0.058, 0.059 inches) thick).
  • the maximum thickness of a rib is about 0.04064 cm (0.016 inches) to about 0.06858 cm (0.027 inches) thick (e.g., about 0.04318, 0.04572, 0.04826, 0.0508, 0.05334, 0.05588, 0.05842, 0.06096, 0.0635, 0.06604 cm (0.017, 0.018, 0.019, 0.020, 0.021, 0.022, 0.023, 0.024, 0.025, 0.026 inches) thick), and sometimes the maximum thickness of a rib is about 0.02794 cm (0.011 inches) to about 0.05334 cm (0.021 inches) thick (e.g., about (0.03048, 0.03302, 0.03356, 0.0381, 0.04064, 0.04318, 0.04572, 0.04826, 0.0508 cm (0.012, 0.013, 0.014, 0.015, 0.016, 0.017, 0.018, 0.019, 0.020 inches) thick).
  • the foregoing thickness can be applicable to a first set of ribs, and if a second set of ribs is present on a pipette tip, the second set of ribs often have a smaller maximum thickness.
  • the maximum thickness sometimes is about 0.00762 cm (0.003 inches) to about 0.0228.6 ⁇ cm (0.009 inches) thick (e.g., about 0.0101.6, 0.0127, 0.0152.4, 0.0177.8, 0.0203.2, 0.0228.6 cm (0.004, 0.005, 0.006, 0.007, 0.008, 0.009 inches) thick).
  • the first set of ribs have a maximum thickness about 2-fold to about 10-fold greater than the maximum thickness of the second set of ribs (e.g., about 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold greater).
  • the width of ribs on a pipette tip sometimes is about 0.0381 cm (0.015 inches) to about 0.0635 cm (0.025 inches) (e.g., about 0.0406.4, 0.0431.8, 0.0457.2, 0.0482.6, 0.0508, 0.0533.4, 0.0558.8, 0.0584.2, 0.0609.6 cm ( 0.016, 0.017, 0.018, 0.019, 0.020, 0.021, 0.022, 0.023, 0.024 inches)).
  • the maximum thickness of a rib is about 1.2-fold to about 7-fold greater than the wall thickness of the pipette tip at or near the sealing zone (e.g., about 2-fold, 3-fold, 4-fold, 5- fold, 6-fold greater).
  • the pipette tip wall thickness at or near the sealing zone sometimes is about 1.2-fold to about 2.0-fold thicker than the maximum thickness of the ribs in the second set (e.g., about 1.2, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9-fold thicker).
  • ribs of a first set have a maximum thickness greater than the maximum thickness of ribs of a second set.
  • ribs of a first set e.g. 80
  • mean thickness greater than the mean thickness of ribs of a second set (e.g. 85).
  • ribs of the first set have a nominal thickness greater than the nominal thickness of ribs of the second set, and in some embodiments, ribs of the first set have an average thickness greater than the average thickness of ribs of the second set.
  • the thickness at or near the proximal terminus of the distal region is substantially similar to the thickness at or near the distal terminus of the proximal region.
  • Ribs can have any useful profile shape, as seen from the side or the end, with the proviso the shape is suitable for adding rigidity to proximal region 15 flexible thickness 70.
  • profile shapes that can be utilized for ribs in pipette tips described herein include arc, pyramid, flat, rectangle, semi-circular, stepped, rhombus, parallelogram, trapezoid and the like, and combinations of the foregoing.
  • the size and shape of the distal terminus of ribs 80 and 85 also provides additional surface area for seating engagement with a pipette tip rack or a nested pipette tip.
  • ribs can be configured to have additional termini 83 (e.g., ribs with a stepped shape or profile, not shown in FIG. 2 , but see termini 283 and 383 in FIGS. 5 and 6 , respectively).
  • additional termini 83 e.g., ribs with a stepped shape or profile, not shown in FIG. 2 , but see termini 283 and 383 in FIGS. 5 and 6 , respectively.
  • one end of ribs in the first set, one end of ribs in the second set, or one end of ribs in the first and the second set is co-extensive with, or terminates at, the flange. In some embodiments, one end of ribs in the first set, one end of ribs in the second set, or one end of ribs in the first and the second set is co-extensive with, or terminates at the junction between the flange and proximal region.
  • one end of ribs in the first set, one end of ribs in the second set, or one end of ribs in the first and the second set is co-extensive with, or terminates at the junction between the proximal region and the distal region.
  • one end of ribs in the first set, of ribs in the second set, or of ribs in the first set and the second set extend from the junction of the flange and proximal region to the junction of the proximal and distal regions.
  • one or more (e.g., all) ribs on a pipette tip extend over the sealing zone.
  • FIG. 1A and FIG. 2 show certain rib embodiments. Extending axially from near the base of flange 60 to junction 30, and spaced circumferentially around the external surface of proximal region 15, are alternating ribs 80 and 85 or rib sets, in some embodiments. Alternating ribs 80, 85 often have different maximum, mean, average or nominal thicknesses.
  • proximal region 15 may comprise flexible thickness 70 with alternating regions of first rib thickness (e.g., ribs of the first set) 80 and second rib thickness (e.g., ribs of the second set) 85 on the exterior surfaceof proximal region 15.
  • the circumferential and axial midpoint of the alternating ribs are spaced around a circumference of the pipette tip proximal region.
  • the thickness of proximal region 15 flexible thickness 70 can vary. In certain embodiments, the thickness can taper from a from a less flexible to a more flexible thickness (e.g., to about 0.02032 cm (0.008 inches) to about 0.03048 cm (0.012 inches) or about 0.02286 cm (0.009 inches) to about 0.02794 cm (0.011 inches)).
  • the thickness of proximal region 15 can gradually increase from a more flexible thickness to a less flexible thickness (e.g., about 0.05588 cm (0.022 inches) to about 0.06858 cm (0.027 inches) thick, or about 0.05842 cm (0.023 inches) to about 0.06604 cm (0.026 inches) thick) towards the distal end of proximal region 15, at or near junction 30.
  • the thickness of proximal region 15 flexible thickness 70 can taper towards the sealing zone and gradually increase towards junction 30.
  • the thickness of proximal region 15 flexible thickness 70 can remain constant.
  • the thickness of proximal region 15 flexible thickness 70 does not have a continuous axial thickness in the region of the sealing zone.
  • proximal region 15 flexible thickness 70 and the regions of increased thickness in ribs 80 and 85 may allow some radial and/or segmental expansion to accommodate, and sealingly engage, the leading edge of an inserted pipette nozzle or barrel, while also reducing the axial force required to achieve said sealing engagement. Illustrated in FIGS. 4B-4D are the heights and widths of alternating ribs 80, 85 at each lower successive cross-section in proximal region 15.
  • the increase in the height (e.g., protrusion above proximal region 15 flexible thickness 70) and width along the axial length of the ribs provides for an increase in rigidity towards the distal portion of the proximal region near junction 30, thereby providing a lower zone, in the proximal region, past which an engaging pipettor nozzle cannot be inserted, without the application of excessive downward axial forces.
  • the term "excessive downward axial forces" as used herein refers to the application of sufficient force to cause physical damage or deformation of the pipette tip, such that the pipette tip is no longer capable of functioning for its intended purpose.
  • the radial and/or segmental expansion that accommodates, and sealingly engages the leading edge of an inserted pipette nozzle, can be attributed to the flexible thickness of the proximal region.
  • the flexible thickness can be rated in terms of its softness or flexibility.
  • the softness or flexibility can be measured as pounds of force required for deflection, and in certain embodiments, the softness or flexibility can be measured as grams of force required for deflection, tip insertion or tip ejection.
  • a non-limiting method of measuring softness or flexibility is determining the amount of force required to cause a predetermined amount of deflection in the proximal region of the pipette tip, using a digital force gauge, and is described in further detail in Example 1.
  • pipette tips described herein sometimes have a mean, nominal or average deflection force to deflect a pipette tip a given (e.g., defined) amount from the resting position of below about 7.78 N (1.75 pounds) of force, below about 7.56 N (1.70 pounds) of force, below about 7.34 N (1.65 pounds) of force, below about 7.12 N (1.60 pounds) of force, below about 6.89 N (1.55 pounds) of force, below about 6.67 N (1.50 pounds) of force, below about 6.45 N (1.45 pounds) of force, below about 6.23 N (1.40 pounds) of force, below about 6.01 N (1.35 pounds) of force, below about 5.78 N (1.30 pounds) of force, below about 5.56 N (1.25 pounds) of force, below about 5.34 N (1.20 pounds) of force, below about 5.12 N (1.15 pounds) of force, and below about 4.89 N (1.10 pounds) of force required for deflection of the pipette tip proximal region.
  • a pipette tip proximal region has a minimal deflection force of about 4.76 N (1.07 pounds). In certain embodiments, a pipette tip proximal region has a maximal deflection force of about 7.78 N (1.75 pounds).
  • a pipette tip has a deflection force in the range of between about 4.76 N (1.07 pounds) and about 5.60 N (1.26 pounds) (e.g., about 4.76 N (1.07 pounds), about 4.80 N (1.08 pounds), about 4.85 N (1.09 pounds), about 4.89 N (1.10 pounds), about 4.94 N (1.11 pounds), about 4.98 N (1.12 pounds), about 5.03 N (1.13 pounds), about 5.07 N (1.14 pounds), about 5.12 N (1.15 pounds), about 5.16 N (1.16 pounds), about 5.20 N (1.17 pounds), about 5.25 N (1.18 pounds), about 5.29 N (1.19 pounds), about 5.34 N (1.20 pounds), about 5.38 N (1.21 pounds), about 5.43 N (1.22 pounds), about 5.47 N (1.23 pounds), about 5.52 N (1.24 pounds), about 5.56 N (1.25 pounds), and about 5.60 N (1.26 pounds) of force).
  • regions of increased wall thickness may help retain tip integrity under circumstances where excess downward axial forces are applied, for example.
  • alternating ribs may aid in providing a better sealing engagement by ensuring the correct longitudinal axis alignment of the pipettor barrel and the sealing zone in proximal region 15.
  • the additional rigidity offered by ribs 80, 85 may direct the advancing pipettor barrel into the correct alignment to ensure a fluid tight, sealing engagement of pipette tip embodiment 10 and a pipettor nozzle or barrel.
  • the co-extensive bottom or terminus surfaces of proximal region 15 flexible thickness 70 and ribs 80, 85 (e.g., rib termini 82 and 90, respectively), near junction 30, can provide a seating support surface 72.
  • the terminus surfaces are configured to have a width sufficient to overlap the diameter of the openings commonly found in many commercially available pipette tip storage units, and can therefore interact with pipette tip rack, pipette card or pipette box, support surfaces to provide seating engagement.
  • the pipette tip embodiments described herein are configured in a manner compatible with many commercially available pipette tip storage systems, in some embodiments.
  • a pipette cycle frequently includes the steps of (a) applying a pipette tip to a pipettor, (b) aspirating a solution, (c) dispensing the solution into a receptacle, and (d) ejecting the pipette tip from the pipettor.
  • dispensing optionally includes one or more of (i) touching the distal terminus of the pipette tip to a wall of the receptacle after the fluid is dispensed from the interior of the tip, (ii) visual inspection of the tip to determine if any liquid adhered to the tip, or (iii) touching the distal terminus of the pipette tip to a wall of the receptacle after the fluid is dispensed from the interior of the tip and visual inspection of the tip to determine if any liquid adhered to the tip.
  • Pipetting efficiency sometimes can be measured by the time required to complete one, two, three, four, five or more pipetting cycles involving steps (a) to (d).
  • pipetting efficiency is measured by determining the average time required to complete three full cycles of steps (a) to (d).
  • step (c) includes touching the distal terminus of the pipette tip to a wall of the receptacle after the fluid is dispensed from the interior of the tip.
  • the average time to compete three cycles of steps (a) to (d) is 20.88 seconds or less (e.g., about 20.88 seconds or less, about 20.80 seconds or less, about 20.75 seconds or less, about 20.70 seconds or less, about 20.65 seconds or less, about 20.60 seconds or less, about 20.55 seconds or less, about 20.50 seconds or less, about 20.45 seconds or less, about 20.40 seconds or less, about 20.35 seconds or less, about 20.30 seconds or less, about 20.25 seconds or less, about 20.20 seconds or less, about 20.15 seconds or less, about 20.10 seconds or less, or about 20.00 seconds or less).
  • the average time to complete a single cycle of steps (a) to (d) is about 6.7 seconds or less (e.g., about 6.7 seconds or less, about 6.6 seconds or less, or about 6.5 seconds or less).
  • the average time to complete a single cycle of steps (a) to (d) can be determined by taking the average time to complete 3 cycles of steps (a) to (d) and dividing by 3, to arrive at the average time required to complete a single cycle.
  • the average time to complete a single cycle of steps (a) to (d) can be determined by taking the average time to complete any number of cycles and diving the time by the number of cycles.
  • a method for manipulating a solution using pipette tips described herein comprising: (a) applying a pipette tip to a pipettor, (b) aspirating a solution, (c) dispensing the solution into a receptacle, and (d) ejecting the pipette tip from the pipettor, where the average time to complete 3 cycles of steps (a) to (d) is about 20.88 seconds or less. In some embodiments the average time to complete a single cycle of steps (a) to (d) is about 6.7 seconds or less.
  • dispensing includes touching the distal terminus of the pipette tip to a wall of the receptacle after the fluid is dispensed from the interior of the tip.
  • Measurements of pipetting efficiency can provide data allowing the results of modifications to pipette tip shape, features or materials to be quantified.
  • Pipetting efficiency can be measured using the pipetting cycle tests described herein or using other methods of measurement known to a user. Accordingly, also provided herein is a method for measuring improved pipetting efficiency, comprising: (a) applying a pipette tip to a pipettor, (b) aspirating a solution, (c) dispensing the solution into a receptacle, and (d) ejecting the pipette tip from the pipettor, wherein achieving an average time to complete 3 cycles of steps (a) to (d) in about 20.88 seconds or less is indicative of improved pipetting efficiency.
  • dispensing includes touching the distal terminus of the pipette tip to a wall of the receptacle and/or visually inspecting the pipette tip for liquid, after the fluid is dispensed from the interior of the tip.
  • Example 5 and FIGS. 16 and 17 present data indicative of the average time to complete 3 pipette cycles for pipette tips described herein, as compared to custom and generic pipette tips. Tips described herein provide time savings advantages that, when scaled to the number of pipette tip cycles performed by a user on a daily, weekly, monthly and/or yearly basis, can provide significant time and cost savings. Custom and generic pipette tips are further described in the Examples.
  • the combination of features of pipette tips described herein contributes to a reduction in the average time required to complete one or more pipetting cycles of between about 20% and about 90%.
  • the reduction in time is due, in whole or in part, to a reduction in the amount of fluid that remains with the pipette tip.
  • the pipette tip blade tip feature contributes to the reduction in liquid retained by the pipette tip.
  • the fluid retained by the pipette tip is less than about 0.065% of the liquid drawn into the tip after the liquid is dispensed.
  • the fluid retained by the pipette tip is no more than 0.00012% of the liquid drawn into the tip after the liquid is dispensed.
  • less than 3.72% of the pipette tips described herein, utilized in a pipetting cycle retain a portion of the liquid drawn into the pipette tips after the liquid is dispelled. In some embodiments, no more than 0.00012% of the pipette tips described herein, utilized in a pipetting cycle, retain a portion of the liquid drawn into the pipette tips after the liquid is dispelled. In certain embodiments, about 3.72% or less of the pipette tips described herein, utilized in a pipetting cycle, retain less than about 0.065% of the liquid drawn into the tips after the liquid is dispensed.
  • Pipette tip embodiments also may comprise one or more of the following features illustrated in FIGS. 1A-D and FIG. 2 : step(s) 55 along the outer surface of the distal region 20; region of inner surface where wall taper of the inner and outer surfaces reaches 0 degrees and the wall surfaces become parallel 57; flange 60; flange rim 65; flange lead-in surface 67; proximal region flexible thickness 70 that extends from the junction 75 of flange 60 and proximal region 15 to the junction 30 of proximal region 15 and distal region 20.
  • the interior surface 130 of the distal region 20 is substantially smooth, as illustrated in FIGS. 1C-1D.
  • FIG. 1B provides a side view of 200 microliter pipette tip embodiment 10, highlighted with line 1C-1C that denotes the cross-section presented in FIG. 1C .
  • FIG. 1 B features are labeled identically to the features presented in FIG. 1A .
  • FIG. 1C illustrates the substantially smooth interior surface 130 of the distal region 20, and also highlights detail area 1D, which is presented in FIG. 1D .
  • Pipette embodiment 10 may comprise annular groove 120 on the interior surface of proximal region 15 (see FIG. 1C ). Annular groove 120 may provide a region of increased surface area for interaction with a mold core pin, as described below in further detail.
  • FIG. 1D is an enlarged view of the detail area highlighted in FIG. 1C . Illustrated in FIG. 1D is a gradually decreasing taper. The decreasing taper is denoted by the change in taper from about 4.2 degrees to about 2.7 degrees. The decrease in taper continues until the taper angle reaches 0 at or near region 57, in the range of about 0.02032 cm (0.008 inches) to about 0.03048 cm (0.012 inches) from distal region terminus 50.
  • the region of 0 degree taper 57 (e.g., the region where the inner and outer walls become essentially parallel, for example) can be about 0.02032 cm (0.008 inches), about 0.02286 cm (0.009 inches), about 0.0254 cm (0.010 inches), about 0.02794 cm (0.011 inches) or about 0.03048 cm (0.012 inches) from distal region terminus 50.
  • This region starting approximately 0.0254 cm (0.01 inches) from distal terminus 50 and ending at distal terminus 50, defines the knife edge or blade region of pipette tip embodiment 10.
  • the region where the taper ends is highlighted as a line 57 denoting the point where the inner and outer walls become essentially parallel (e.g., taper angle becomes 0 degrees).
  • the distal terminus region wall 53 thickness in this area was described above, and in the embodiment illustrated in FIG. 1D is about 0.011176 cm (0.0044 inches) thick.
  • the exterior surface of the distal region may comprise a step. In certain embodiments, the exterior surface of the distal region may comprise more than one step. Exterior surface step(s) 55 can aid in visual assessment of the uptake or delivery of sample or reagent by providing external visual volumetric gradations, which allow the user to determine if sample has been successfully acquired or expelled, and can allow the user to visually determine how much sample has been delivered, in reverse pipetting applications for example.
  • Reverse pipetting is the process whereby a pipettor plunger is depressed to its fully depressed position, and sample is taken up. Taking up sample in this manner allows more than the preset volume to be taken up. The preset volume of sample is then delivered by depressing the plunger to the first stop.
  • This technique can be useful for delivering a sample or reagent to many tubes, where the possibility of cross contamination is minimal (e.g., when pipetting the initial reagent or liquid into a tube, during reaction set up).
  • Proximal region 15 also may comprise a frustum-shaped cavity within the interior of proximal region 15, in certain embodiments, as illustrated in FIGS. 4A-4D.
  • FIGS. 4A-4D illustrate a view looking down the top of various cross-sections of pipette tip embodiment 10. The areas, in proximal region 15, in which the cross-sections are taken, are illustrated in FIG. 3 as lines; A-A, B-B, C-C, and D-D. Also illustrated in FIG. 4A-4D (and not previously described) are proximal region inner surface 100, flange tapered inner surface 110, and annular groove 120. In some embodiments, the frustum-shaped cavity is substantially smooth.
  • the frustum-shaped cavity comprises an optional annular groove 120.
  • annular groove 120 is an area of increased surface area formed during the molding process that corresponds to a portion of the mold core pin.
  • the core pin often forms the internal surfaces of the object to be molded, for example the pipette tips described herein.
  • the distance between the core pin and the mold cavity e.g., the part of the mold that forms the outer surface of the object determines the thickness of the object to be molded (e.g., pipette tip).
  • the shape of the core pin can offer an increased surface area upon which the cooling pipette tip (e.g., specifically annular groove 120) may find purchase and therefore remain in contact with the core pin during cooling and separation from the portion of the mold that forms the pipette tip outer surface, which in turn may facilitate release and ejection of the pipette tip from the mold core after cooling of the pipette tip.
  • Annular groove 120 resides on the interior surface 100 of proximal region 15.
  • the sealing zone which is located in the proximal region of a pipette tip, sometimes is located at a position in the pipette tip interior proximal of the annular groove 120, sometimes is located at a position distal to annular groove 120, and sometimes is located in the same region as annular groove 120.
  • the proximal region also may be in connection with an annular flange 60 at the proximal terminus of proximal region 15.
  • Flange 60 at the proximal terminus of pipette tip 10 in proximal region 15 may be flared, and the lead-in surface 67 (see FIG. 4A ) diameter of the flange 60 can allow for pipettor engagement tolerance in multi-pipettor applications.
  • Flange 60 can provide a larger contact zone for engaging a pipettor nozzle, and can increase the probability of a sealing engagement between a pipettor nozzle not coaxially aligned with a pipette tip by guiding the axial center of the pipette tip to the axial center of the pipettor nozzle.
  • the edge of the flange 60 also may provide pipette tip rigidity, in some embodiments, and also may facilitate pipette entry and seating, in certain embodiments.
  • the pipette tip embodiments described herein can be configured in any volume.
  • Multiple features and properties described for 200 microliter pipette tip embodiment 10 are also common to the pipette tips configured in different sizes, such as 10 microliter, 300 microliter and 1250 microliter pipette tips, for example (referred to herein after as 10 microliter pipette tip, 300 microliter pipette tip and 1250 microliter pipette tip, respectively). Therefore, while FIGS. 1A-1D , 2 , 3 and 4A-4D often pertain to 200 microliter pipette tips, certain features illustrated in FIGS.
  • 1A-1D , 2 , 3 and 4A-4D are related to features of 10 microliter, 300 microliter and 1250 microliter pipette tip embodiments, and similar reference characters are utilized in FIGS. 5-8 .
  • the distal region terminus is referenced as 50 in FIGS. 1A-1D
  • 10 microliter pipette tip embodiment 200 has distal region terminus 250, in FIG. 5 .
  • 10 microliter and 10 microliter extra long pipette tip embodiments 200 and 300 may comprise one or more of the following features illustrated in FIG. 5 and FIG. 6 : proximal region 215, 315; distal region 220, 320; junction between distal region and proximal region 230, 330; tapered junction surface 232; region 240, 340 that is about one-quarter of the distance from the distal region terminus to the junction; distal region terminus 250, 350; blade or knife edge wall thickness 253, 353 at distal region terminus; step(s) 355; flange 260, 360; flange rim 265, 365; proximal region flexible thickness 270, 370 that extends from the junction 275, 375 of flange 260, 360 and proximal region 215, 315 to junction 230, 330 of proximal region 215, 315 and distal region 220, 320.
  • Proximal region 215, 315, between junctions 275, 375 and 230, 330 sometimes can include alternating ribs 280, 380 and 285, 385, which can end in rib termini. Illustrated in FIGS. 5 and 6 are ribs ending in termini 282, 283, and 290.
  • 300 microliter pipette tip embodiment 400 may comprise one or more of the following features illustrated in FIG. 7 : proximal region 415; distal region 420; junction between distal region and proximal region 430; tapered junction surface 432 (not shown); region 440 that is about one-quarter of the distance from the distal region terminus to the junction; distal region terminus 450; blade or knife edge wall thickness 453 at distal region terminus; step(s) 455; flange 460; flange rim 465; proximal region flexible thickness 470 that extends from the junction 475 of flange 460 and proximal region 415 to junction 430 of proximal region 415 and distal region 420.
  • Proximal region 415, between junctions 475 and 430 sometimes can include alternating ribs 480 and 485, which can end in rib termini. Illustrated in FIG. 7 are ribs ending in termini 482 and 490.
  • 1250 microliter pipette tip embodiment 500 may comprise one or more of the following features illustrated in FIG. 8 : proximal region 515; distal region 520; junction between distal region and proximal region 530; tapered junction surface 532 (not shown); region 540 that is about one-quarter of the distance from the distal region terminus to the junction; distal region terminus 550; blade or knife edge wall thickness 553 at distal region terminus; step(s) 555; flange 560; flange rim 565; proximal region flexible thickness 570 that extends from the junction 575 of flange 560 and proximal region 515 to junction 530 of proximal region 515 and distal region 520.
  • Proximal region 515, between junctions 575 and 530 sometimes can include alternating ribs 580 and 585, which can end in rib termini. Illustrated in FIG. 8 are ribs ending in termini 582 and 590.
  • the 10 microliter, 300 microliter and 1250 microliter pipette tip embodiments also may comprise features and properties illustrated or described for 200 microliter pipette tip embodiment 10, but not illustrated in FIGS. 5-8 .
  • 10 microliter pipette tip embodiment 200 may also comprise, a smooth inner distal or proximal surface, as illustrated in FIGS. 1C and 1D .
  • the 10 microliter, 300 microliter and 1250 microliter pipette tip embodiments also may comprise a smooth distal inner surface.
  • the 10 microliter, 300 microliter and 1250 microliter pipette tip embodiments also may comprise; a region of 0 degree taper about 0.0254 cm (0.01 inches) above the distal region terminus 20; flexibility contributed by proximal wall thickness 70; rigidity contributed by alternating regions of increased thickness in rib 80, 85 regions and the lower portion of the proximal region, co-extensive rib and proximal region termini that provide for seating engagement with pipette tip storage units and the like.
  • all features and properties described for the 200 microliter pipette tip embodiment, and applicable to the 10 microliter, 300 microliter and 1250 microliter pipette tip embodiments are understood to be incorporated into the 10 microliter, 300 microliter and 1250 microliter pipette tip embodiments.
  • features such as the smooth inner surface (e.g., 100 and 130) or annular groove 120, which are not shown in certain embodiments, are understood to be adaptable, and can be included in certain embodiments where they are not shown.
  • pipette tips may comprise one or more of a filter component and/or an insert component.
  • a filter component and/or insert component may be located in any suitable portion of a pipette tip, and sometimes is located in a proximal portion of a pipette tip near a pipette tip aperture that can engage a dispensing device.
  • a filter component and/or insert component sometimes also can be located in a distal portion of the pipette tip near a pipette tip aperture that can engage a fluid.
  • a filter can be of any shape (e.g., plug, disk; U.S. Patent Nos.
  • a filter may be porous, non-porous, hydrophobic, hydrophilic or a combination thereof.
  • a filter in some embodiments may include vertically oriented pores, and the pore size may be regular or irregular.
  • Pores of a filter may include a material (e.g., granular material) that can expand and plug pores when contacted with aerosol (e.g., U.S. Patent No. 5,156,811 ).
  • a filter may include nominal, average or mean pore sizes of about 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, or 0.05 micrometers, for example.
  • a section of a pipette tip also may include an insert or material that can interact with a molecule of interest, such as a biomolecule.
  • the insert or material may be located in any suitable location for interaction with a molecule of interest, and sometimes is located in the distal section of a pipette tip (e.g., a material or a terminus of an insert may be located at or near the terminal aperture of the distal section).
  • An insert may comprises one or more components that include, without limitation, multicapillaries (e.g., US 2007/0017870 ), fibers (e.g., randomly oriented or stacked, parallel orientation), and beads (e.g., silica gel, glass (e.g. controlled-pore glass (CPG)), nylon, Sephadex®, Sepharose®, cellulose, a metal surface (e.g. steel, gold, silver, aluminum, silicon and copper), a magnetic material, a plastic material (e.g., polyethylene, polypropylene, polyamide, polyester, polyvinylidenedifluoride (PVDF)), Wang resin, Merrifield resin or Dynabeads®).
  • multicapillaries e.g., US 2007/0017870
  • fibers e.g., randomly oriented or stacked, parallel orientation
  • beads e.g., silica gel, glass (e.g. controlled-pore glass (CPG)), nylon, Sephadex®, Sepharose®, cellulose, a
  • Beads may be sintered (e.g., sintered glass beads) or may be free (e.g., between one or two barriers (e.g., filter, frit)).
  • Each insert may be coated or derivitized (e.g., covalently or non-covalently modified) with a molecule that can interact with (e.g., bind to) a molecule of interest (e.g., C18, nickel, affinity substrate).
  • Pipette tips can be manufactured from a commercially suitable material.
  • Pipette tips often are manufactured from one or more moldable materials, independently selected from those that include, without limitation, polypropylene (PP), polyethylene (PE), high-density polyethylene (HDPE), low-density polyethylene (LDPE), polyethylene teraphthalate (PET), polyvinyl chloride (PVC), polytetrafluoroethylene (PTFE), polystyrene (PS), high-density polystyrene, acrylnitrile butadiene styrene copolymers, crosslinked polysiloxanes, polyurethanes, (meth)acrylate-based polymers, cellulose and cellulose derivatives, polycarbonates, ABS, tetrafluoroethylene polymers, corresponding copolymers, plastics with higher flow and lower viscosity or a combination of two or more of the foregoing, and the like.
  • PP polypropylene
  • PE polyethylene
  • Non-limiting examples of plastics with higher flow and lower viscosity include, any suitable material having a hardness characterized by one or more of the following properties, in certain embodiments: a melt flow rate (230 degrees Celsius at 2.16 kg) of about 30 to about 75 grams per 10 minutes using an ASTM D 1238 test method; a tensile strength at yield of about 26.89 MPa to about 34.47 MPa (3900 to about 5000 pounds per square inch) using an ASTM D 638 test method; a tensile elongation at yield of about 7 to about 14% using an ASTM D 638 test method; a flexural modulus at 1% sectant of about 758.42 MPa to about 1654.74 MPa (110,000 to about 240,000 pounds per square inch) using an ASTM D 790 test method; a notched Izod impact strength (23 degrees Celsius) of about 0.4 to about 4.0 foot pounds per inch using an ASTM D 256 test method; and/or a heat deflection temperature (at 0.455 MPa) of
  • a material used to construct the distal section and/or axial projections include moldable materials in some embodiments.
  • Non-limiting examples of materials that can be used to manufacture the distal section and/or axial projections include polypropylene, polystyrene, polyethylene, polycarbonate, and the like, and mixtures thereof.
  • pipette tips described herein are not made from an elastomer. Materials suitable for use in embodiments described herein, and methods for manufacture using those materials have been described in United States Provisional Patent Application No. 61/144,031, filed on January 12, 2009 , and entitled "FLEXIBLE PIPETTE TIPS".
  • a pipette tip also may include one or more antimicrobial materials.
  • An antimicrobial material may be coated on a surface (e.g., inner and/or outer surface) or impregnated in a moldable material, in some embodiments.
  • One or more portions or sections, or all portions and sections, of a pipette tip or other pipette tip tray component may include one or more antimicrobial materials.
  • anti-microbial agents or substances may be added to the moldable plastic during the manufacture process.
  • the anti-microbial agent or substance can be an anti-microbial metal.
  • anti-microbial agents may be useful in (i) decreasing the amount of microbes present in or on a device, (ii) decreasing the probability that microbes reside in or on a device, and/or (iii) decreasing the probability that microbes form a biofilm in or on a device, for example.
  • Antimicrobial materials include, without limitation, metals, halogenated hydrocarbons, quaternary salts and sulfur compounds.
  • Non-limiting examples of metals with anti-microbial properties are silver, gold, platinum, palladium, copper, iridium (i.e. the noble metals), tin, antimony, bismuth, zinc cadmium, chromium, and thallium.
  • the afore-mentioned metal ions are believed to exert their effects by disrupting respiration and electron transport systems upon absorption into bacterial or fungal cells.
  • a commercially accessible form of silver that can be utilized in devices described herein is SMARTSILVER NovaResin.
  • SMARTSILVER NovaResin is a brand of antimicrobial master batch additives designed for use in a wide range of polymer application.
  • SMARTSILVER NovaResin additives may be delivered as concentrated silver-containing master batch pellets to facilitate handling and processing. NovaResin is designed to provide optimum productivity in a wide range of processes, including fiber extrusion, injection molding, film extrusion and foaming.
  • anti-microbial substances or agents include, without limitation, inorganic particles such as barium sulfate, calcium sulfate, strontium sulfate, titanium oxide, aluminum oxide, silicon oxide, zeolites, mica, talcum, and kaolin.
  • inorganic particles such as barium sulfate, calcium sulfate, strontium sulfate, titanium oxide, aluminum oxide, silicon oxide, zeolites, mica, talcum, and kaolin.
  • Halogenated hydrocarbons include, without limitation, halogenated derivatives of salicylanilides (e.g., 5-bromo-salicylanilide; 4',5-dibromo-salicylanilide; 3,4',5-tribromo-salicylanilide; 6-chloro-salicylanilide; 4'5-dichloro-salicylanilide; 3,4'5-trichloro-salicylanilide; 4',5-diiodo-salicylanilide; 3,4',5-triiodo-salicylanilide; 5-chloro-3'-trifluoromethyl-salicylanilide; 5-chloro-2'-trifluoromethyl-salicylanilide; 3,5-dibromo-3'-trifluoromethyl-salicylanilide; 3-chloro-4-bromo-4'-trifluoromethyl-salicylanilide; 2',5-d
  • Halogenated hydrocarbons also can include, without limitation, carbanilides (e.g., 3,4,4'-trichloro-carbanilide (TRICLOCARBAN); 3,3',4-trichloro derivatives; 3-trifluoromethyl-4,4'-dichlorocarbanilide and the like).
  • carbanilides e.g., 3,4,4'-trichloro-carbanilide (TRICLOCARBAN); 3,3',4-trichloro derivatives; 3-trifluoromethyl-4,4'-dichlorocarbanilide and the like.
  • Halogenated hydrocarbons include also, without limitation, bisphenols (e.g., 2,2'-methylenebis(4-chlorophenol); 2,2'-methylenebis(4,5-dichlorophenol); 2,2'-methylenebis(3,4,6-trichlorophenol); 2,2'-thiobis(4,6-dichlorophenol); 2,2'-diketobis(4-bromophenol); 2,2'-methylenebis(4-chloro-6-isopropylphenol); 2,2'-isopropylidenebis(6-sec-butyl-4-chlorophenol) and the like).
  • bisphenols e.g., 2,2'-methylenebis(4-chlorophenol); 2,2'-methylenebis(4,5-dichlorophenol); 2,2'-methylenebis(3,4,6-trichlorophenol); 2,2'-thiobis(4,6-dichlorophenol); 2,2'-diketobis(4-bromophenol); 2,2'-m
  • halogenated mono-and poly-alkyl and aralkyl phenols e.g., methyl-p-chlorophenol; ethyl-p-chlorophenol; n-propyl-p-chlorophenol; n-butyl-p-chlorophenol; n-amyl-p-chlorophenol; sec-amyl-p-chlorophenol; n-hexyl-p-chlorophenol; cyclohexyl-p-chlorophenol; n-heptyl-p- chlorophenol; n-octyl-p-chlorophenol; o-chlorophenol; methyl-o-chlorophenol; ethyl-o-chlorophenol; n-propyl-o-chlorophenol; n-butyl-o-chlorophenol; n-amyl-o-chlorophenol; tert-amyl-
  • Halogenated hydrocarbons also include, without limitation, chlorinated phenols (e.g., parachlorometaxylenol, p-chloro-o-benzylphenol and dichlorophenol); cresols (e.g., p-chloro-m-cresol), pyrocatechol; p-chlorothymol; hexachlorophene; tetrachlorophene; dichlorophene; 2,3-dihydroxy-5,5'-dichlorophenyl sulfide; 2,2'-dihydroxy-3,3',5,5'-tetrachlorodiphenyl sulfide; 2,2'-dihydroxy-3,3',5,5',6,6'-hexachlorodiphenyl sulfide and 3,3'-dibromo-5,5'-dichloro-2,2'-dihydroxydiphenylamine).
  • chlorinated phenols e.g., par
  • Halogenated hydrocarbons also may include, without limitation, resorcinol derivatives (e.g., p-chlorobenzyl-resorcinol; 5-chloro-2, 4- dihydroxy-di-phenyl methane; 4'-chloro-2, 4-dihydroxydiphenyl methane; 5-bromo-2,4- dihydroxydiphenyl methane; 4'-bromo-2, 4-dihydroxydiphenyl methane), diphenyl ethers, anilides of thiophene carboxylic acids, chlorhexidines, and the like.
  • resorcinol derivatives e.g., p-chlorobenzyl-resorcinol
  • 4'-chloro-2, 4-dihydroxydiphenyl methane 5-bromo-2,4- dihydroxydiphenyl methane
  • Quaternary salts include, without limitation, ammonium compounds that include alkyl ammonium, pyridinum, and isoquinolinium salts (e.g., 2,2'-methylenebis(4-chlorophenol); 2,2'-methylenebis(4,5-dichlorophenol); 2,2'-methylenebis(3,4,6-trichlorophenol); 2,2'-thiobis(4,6-dichlorophenol); 2,2'-diketobis(4-bromophenol); 2,2'-methylenebis(4-chloro-6-isopropylphenol); 2,2'-isopropylidenebis(6-sec-butyl-4-chlorophenol); cetyl pyridinium chloride; diisobutylphenoxyethoxyethyldimethylbenzyl ammonium chloride; N-methyl-N- (2- hydroxyethyl)-N-(2-hydroxydodecyl)-N-benzyl ammonium chloride; cet
  • Sulfur active compounds include, without limitation, thiuram sulfides and dithiocarbamates, for example (e.g., disodium ethylene bis-dithiocarbamate (Nabam); diammonium ethylene bis-dithiocarbamate (amabam); Zn ethylene bis-dithiocarbamate (ziram); Fe ethylene bis-dithiocarbamate (ferbam); Mn ethylene bis-dithiocarbamate (manzate); tetramrethyl thiuram disulfide; tetrabenzyl thiuram disulfide; tetraethyl thiuram disulfide; tetramethyl thiuram sulfide, and the like).
  • Nabam disodium ethylene bis-dithiocarbamate
  • amabam diammonium ethylene bis-dithiocarbamate
  • Zn ethylene bis-dithiocarbamate ziram
  • an antimicrobial material comprises one or more of 4',5-dibromosalicylanilide; 3,4',5-tribromosalicylanilide; 3,4',5-trichlorosalicylanilide; 3,4,4'-trichlorocarbanilide; 3-trifluoromethyl4,4'-dichlorocarbanilide; 2,2'-methylenebis(3,4,6-trichlorophenol); 2,4,4'-trichloro-2'-hydroxydiphenyl ether; Tyrothricin; N-methyl-N-(2-hydroxyethyl-N-(2-hydroxydodecyl)-N-benzylammonium chloride; cetyl pyridinium chloride; 2,3',5-tribromosalicylanilide; chlorohexidine digluconate; chlorohexidine diacetate; 4',5-dibromosalicylanilide; 3,4,4'-trichlorocarbanilide; 2,4,4'
  • a pipette tip may comprise any type of electrically conductive material, such as a conductive metal for example.
  • electrically conductive metals include platinum (Pt), palladium (Pd), copper (Cu), nickel (Ni), silver (Ag) and gold (Au).
  • the metals may be in any form in or on a pipette tip, for example, such as metal flakes, metal powder, metal strands or coating of metal.
  • Electrically conductive materials, or portions thereof, may be any material that can contain movable electric charges, such as carbon for example.
  • a pipette tip comprises about 5% to about 40% or more carbon by weight (e.g., 7-10%, 9-12%, 11-14%, 13-16%, 15-18%, 17-20%, 19-22%, 21-24%, 23-26%, 25-28%, 27-30%, 29-32%, 32-34%, 33-36%, or 35-38% carbon by weight).
  • Methods for manufacturing components comprising an anti-static member have been described in United States Provisional Patent Application No. 61/147,065, filed on January 23, 2009 , and entitled "ANTI-STATIC PIPETTE TIP TRAYS".
  • Pipette tip “precision” refers to the ability of a plurality of pipette tips to deliver about the same volume of fluid, with a relatively small standard deviation, for a given dispenser (e.g., pipette tips stated to deliver 200 microliters of fluid consistently deliver about 197 microliters of fluid).
  • Pipette tip “accuracy” refers to the ability of a plurality of pipette tips to deliver a particular volume of fluid (e.g., pipette tips stated to deliver 200 microliters of fluid deliver, in practice, about 200 microliters of fluid).
  • One measure of pipette tip precision is a calculated percent "coefficient of variation," which also is referred to herein as "CV" and discussed in greater detail hereafter.
  • Coefficient of variation can be calculated for a pipette tip lot in a variety of manners.
  • percent CV equals (a) the quotient of (i) standard deviation in volume dispensed from the pipette tips, divided by (ii) the average volume dispensed from the pipette tips, (b) multiplied by 100.
  • a CV value often is calculated for a particular lot of pipette tips.
  • One of many protocols can be selected for collecting pipette tips in the lot to calculate a CV value.
  • Random pipette tips may be selected from a lot after a manufacturing run is completed in some embodiments, and in certain embodiments, pipette tips are collected at different time points during the manufacturing run of the lot (e.g., pipette tips are collected at time points during the manufacture run at regular intervals).
  • water is dispensed from pipette tips of a particular lot using one dispensing device, and volume of each dispensed amount is weighed. The average and standard deviation of all weighed aliquots of water then can be calculated in such embodiments.
  • liquid containing a dye is dispensed from each pipette tip into a well of a tray having an array of wells.
  • the average volume can be determined from the weight of the plate containing the dispensed liquid less the weight of the plate before liquid was dispensed.
  • the standard deviation in volume dispensed into each well can be determined by optically determining the volume in each well by the amount of dye in each well (e.g., using a light, fluorescence, luminescence or absorbance detector in a plate reader).
  • pipette tip embodiments described herein can deliver a volume of double distilled water with a CV of 10% or less, when the pipettor is set at a low or minimum volume.
  • pipette tips described herein can deliver a volume of double distilled water with a CV of 5% or less, when the pipettor is set at a high or maximum volume. The precision and accuracy measurements of the pipette tips is dependent on the condition and calibration of the pipettor being tested with the tips described herein.
  • accuracy and CV values for the pipette tip embodiments described herein can range between 1% and 10% depending on the volume at which the pipettor is tested, and the condition and calibration of the pipettor (e.g., CV of 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or less).
  • Pipette tips frequently are used in conjunction with a pipetting device (manual or automated) to take up, transport or deliver precise volumes of liquids or reagents.
  • suitably configured pipette tips also can be used to prepare or isolate biomolecules of interest (e.g., nucleic acids, proteins, antibodies and the like).
  • a biomolecule of interest can be contained in a biological fluid or biological preparation with a fluid component.
  • a method of using a pipette tip comprising (a) inserting a pipettor into a pipette tip, and (b) contacting the pipette tip with a fluid, where the pipette tip comprises a proximal region and a distal region, and further where the proximal region comprises a first set of axially oriented ribs and a second set of axially oriented ribs, the ribs of the first set and the second set are circumferentially spaced and alternately spaced around the proximal region, and ribs of the first set have a maximum thickness greater than the maximum thickness of ribs of the second set.
  • a pipette tip comprising, (a) inserting a pipettor into a pipette tip, and (b) contacting the pipette tip with a fluid, where the pipette tip comprises a proximal region and a distal region, and further where the distal region wall thickness tapers from (a) a point at or between (i) about the junction of the proximal region and distal region to (ii) about one-quarter of the axial distance from the terminus of the distal region to the junction, to (b) the distal region terminus, and the wall thickness at the distal region terminus is about 0.01016 cm (0.0040 inches) to about 0.01397 cm (0.0055 inches).
  • the wall thickness of the tip at the distal region terminus is 0.01397 cm (0.0055 inches) or less. In some embodiments, the wall thickness at the distal region terminus is about 0.010922 cm (0.0043 inches) to about 0.0127 cm (0.0050 inches). In certain embodiments, the wall thickness at the distal region terminus is about 0.011167 cm (0.0044 inches) to about 0.012446 cm (0.0049 inches).
  • Pipette tips may be manufactured by injection molding.
  • pipette tips described herein are injection molded as a unitary construct.
  • Injection molding is a manufacturing process for producing objects (e.g., pipette tips, for example) from thermoplastic (e.g., nylon, polypropylene, polyethylene, polystyrene and the like, for example) and thermosetting plastic (e.g., epoxy and phenolics, for example) materials.
  • the plastic material of choice often is fed into a heated barrel, mixed, and forced into a mold cavity where it cools and hardens to the configuration of the mold cavity.
  • the melted material sometimes is forced or injected into the mold cavity, through openings (e.g., a sprue), under pressure.
  • a pressure injection method ensures the complete filling of the mold with the melted plastic. After the mold cools, the mold portions are separated, and the molded object is ejected.
  • additional additives can be included in the plastic or heated barrel to give the final product additional properties (e.g., anti-microbial, or anti-static properties, for example).
  • the mold is configured to hold the molten plastic in the correct geometry to yield the desired product upon cooling of the plastic.
  • Injection molds sometimes are made of two or more parts, and comprise a core pin.
  • the core pin sometimes can determine the thickness of the object wall, as the distance between the core pin and the outer mold portion is the wall thickness. Molds are typically designed so that the molded part reliably remains on the core pin when the mold opens, after cooling.
  • the core pin sometimes can be referred to as the ejector side of the mold. The part can then fall freely away from the mold when ejected from the core pin, or ejector side of the mold.
  • ejector pins and/or an ejector sleeve push the pipette tip from the core pin.
  • a mold for manufacturing a device by an injection mold process which comprises a body that forms an exterior portion of the device and a member that forms an inner surface of the device, where the member comprises an irregular surface that results in a portion of the inner surface that is irregular (e.g., annular groove 120).
  • the member is a core pin for forming the inner surface of a pipette tip.
  • a method for manufacturing a pipette tip comprising (a) contacting a pipette tip mold with a molten polymer, and releasing the formed pipette tip from the mold after cooling, where the pipette tip comprises a proximal region and a distal region, and further where the proximal region comprises an exterior surface and an annular flange at the proximal terminus of the proximal region, the proximal region comprises a first set of axially oriented ribs and a second set of axially oriented ribs, the ribs of the first set and the second set are circumferentially spaced and alternately spaced around the exterior surface of the proximal region, and ribs of the first set have a maximum thickness greater than the maximum thickness of ribs of the second set.
  • a pipette tip comprising, (a) contacting a pipette tip mold with a molten polymer, and releasing the formed pipette tip from the mold after cooling, where the pipette tip comprises a proximal region and a distal region, and further where the proximal region comprises an exterior surface and an annular flange at the proximal terminus of the proximal region, the distal region wall thickness tapers from (a) a point at or between (i) about the junction of the proximal region and distal region to (ii) about one-quarter of the axial distance from the terminus of the distal region to the junction, to (b) the distal region terminus, and the wall thickness at the distal region terminus is about 0.01016 cm (0.0040 inches) to about 0.01397 cm (0.0055 inches).
  • a method for manufacturing a device having an inner surface and an exterior surface comprises: (a) injecting a liquid polymer mixture into a mold that comprises a body that forms the exterior surface of the device and a member that forms the inner surface of the device, (b) curing the device in the mold (e.g., partially curing or fully curing), and (c) ejecting the device from the mold, where the member comprises an irregular surface (e.g., annular groove 120) that results in a portion of the inner surface of the device that is irregular.
  • the polymer mixture comprises a polymer and a material that can provide one or more of the following properties; anti-microbial activity, anti-static function, anti-foaming function and combinations thereof.
  • a "soft” or flexible pipette tip often will be easier to mount onto a pipettor than a "hard” or reduced flexibility pipette tip, thus offering several benefits, such as better fit, reduced insertion and/or ejection forces and the ability to fit a larger variety of pipettor nozzles (e.g., a more universal fit).
  • the flexibility or "softness" of pipette tips described herein was quantified and compared to competitors commercially available pipette tips.
  • a force gauge (Imada model DS2-44 force gauge) was mounted to a fixed aluminum base plate on a table top stand, and a lever with a handle was mounted to the force gauge, as shown in FIG. 9 .
  • the depth that the gauge can travel was fixed by incorporating a travel stop on the stand.
  • the travel stop was configured such that the depth the gauge could travel was fixed throughout the experiment so the only change measurable was the force required to depress each tip that same depth or travel distance.
  • Each tip was placed under the force gauge and the handle depressed. The force reading, in pounds, was then recorded.
  • Six different tip styles were used and five independent, randomly chosen, tips per style were tested. The tips were placed on top of the aluminum plate to ensure that the force used on the tip was not bending the tip.
  • the force required for deformation would therefore only change due to the stiffness or pliability of the individual tip.
  • the competitors tips tested included (designated as Tip 1, Tip 2, and the like); tip 1, 200 microliter with filter; tip 2, 100 microliter with filter; tip 3, 200 microliter with filter; tip 4, 100 microliter with filter; tip 5, 300 microliter without filter; and a 300 microliter non-filter pipette tip embodiment as described herein.
  • the results are presented graphically in FIG. 10 and in the table below. Results are presented as pounds of force.
  • 300 microliter non-filter pipette tips described herein are, on average, up to about 8 fold (e.g., between about 1.5 and about 8 fold; about 1.5 fold, about 2 fold, about 2.5 fold, about 3 fold, about 3.5 fold, about 4 fold, about 4.5 fold, about 5 fold, about 5.5 fold, about 6 fold, about 6.5 fold, about 7 fold, about 7.5 fold and about 8 fold) more flexible than some currently available competitor pipette tips.
  • about 8 fold e.g., between about 1.5 and about 8 fold; about 1.5 fold, about 2 fold, about 2.5 fold, about 3 fold, about 3.5 fold, about 4 fold, about 4.5 fold, about 5 fold, about 5.5 fold, about 6 fold, about 6.5 fold, about 7 fold, about 7.5 fold and about 8 fold
  • Pipette tips described herein were compared to custom tips manufactured by market leading pipette companies (e.g., for their brand of pipettor) and also to a popular generic pipette tip brand. Pipettors utilized in these experiments were designated pipette 1, pipette 2, pipette 3, pipette 4 and pipette 5, and corresponding custom tips for specific pipettors were similarly designated (e.g., pipette tip 1 was a custom tip for pipettor 1, pipette tip 2 was a custom tip for pipettor 2, etc). The generic pipette tip was designated as "generic”. Pipette tips described herein were designated "TDH”.
  • Ergonomic testing was accomplished using a combination of objective and subjective measurement techniques.
  • the experimental design included appropriate sampling methods (e.g., multiple trials, pipettor and pipette tip randomization, and the like) to allow a valid statistical analysis of product performance. Video and photographic documentation of the testing also was collected.
  • test subjects Prior to the start of testing, participants completed a background survey regarding pipetting experience and a musculoskeletal stress survey of aches, pains or discomfort experienced at work. Anthropometric measurements also were collected.
  • the test subjects included 3 women and 8 men with pipetting experience (11 total).
  • the participants included scientists, research technicians, biologists, a chemist and graduate students.
  • the average age of the participants was 25.9 years and participants had been using pipettes for an average of 4.0 years, for an average of up to 3.3 hrs/day.
  • Each test participant completed a series of pipetting tasks using each of the following tip types; (a) a tip as described herein, (b) a custom tip for a specific brand of pipettor, and (c) a generic tip, selected for its popularity. Each tip was tested using the 5 different pipettor brands. Each participant also was monitored using electomyographic (EMG) data collection, as shown in FIG. 11 . Standardized calibration routines were utilized to ensure accuracy of sampling.
  • EMG electomyographic
  • EMG electromyography
  • EMG Five muscle groups from the pipetting arm were monitored by EMG. Representative EMG tracings are shown in FIG. 13 .
  • the muscle groups monitored included the major muscles involved in hand/finger exertions (e.g., forearm flexor and extensor muscles), the interosseous muscles of the thumb, the bicep, and trapezius muscles.
  • a calibration routine was conducted at the start of testing to obtain the MVC for each participants' muscles.
  • the corresponding EMG signals were scaled using the MVC to obtain the percent of muscle exertion associated with each subsequent test (%MVC).
  • the applied muscle effort levels were analyzed to determine the physical requirements associated with each pipette and tip combination.
  • cycle time to complete the task was measured as a gauge of product efficiency, ease of use and productivity.
  • the results were statistically analyzed to determine differences in performance between the products.
  • cycle time e.g., productivity rate in seconds
  • muscle work e.g., sum of the average exertion across the 5-muscle groups tested, % maximum voluntary contraction
  • average exertion e.g., the average level of muscle effort among the 5-muscle groups tested (%MVC)
  • peak e.g., the average peak level of exertion among the muscle groups tested (%MVC)
  • total work done e.g., the sum of the total exertions across all 5-muscle groups tested (%MVC)
  • Pipette tip effort across tasks was used as a measure of overall pipette tip performance. All pipettors with the exception of pipettor 3 were tested with all pipette tips. Pipettor 3 could not accept the generic tips, or tips as described herein.
  • FIG. 14 graphically illustrates the total muscle work done as a measure of tip performance. The measurements were taken for each of the 4 aspects of pipette tip usage (e.g., apply tip, aspirate liquid, dispense liquid and de-tip or eject tip). The results shown in FIG. 14 indicate that the tips as described herein, perform as well if not better than the generic and custom tips for each of the pipettors tested.
  • pipette tip usage e.g., apply tip, aspirate liquid, dispense liquid and de-tip or eject tip.
  • FIG. 15 graphically illustrates the total muscle work during a pipetting cycle as a measure of tip performance.
  • the results presented are the average of the muscle work measurements taken for full cycle testing and on/off testing.
  • the results shown in FIG. 15 indicate that tips described herein perform substantially better than generic tips and custom tips designed for a specific pipettor application.
  • Borg ratings below three e.g., "Moderate" generally are considered to be acceptable levels of exertion for tasks that have extended durations.
  • the Borg scale can be used as a subjective determination of the physical requirements associated with a task, and a relative comparison of products used to perform a given task.
  • FIGS. 18-22 The results of perceived exertion testing are presented graphically in FIGS. 18-22 . Generally, the results suggested that testing participants perceived the tips described herein as requiring the lowest, or next to lowest, physical effort among the tips tested.
  • FIG. 18 graphically represents the average overall ratings of perceived exertion for all pipette tips.
  • FIG. 19 graphically illustrated the perceived exertion ratings for all pipette tips tested using pipettor 2.
  • FIG. 20 graphically illustrated the perceived exertion ratings for all pipette tips tested using pipettor 4.
  • FIG. 21 graphically illustrated the perceived exertion ratings for all pipette tips tested using pipettor 5.
  • FIG. 22 graphically illustrated the perceived exertion ratings for all pipette tips tested using pipettor 1. Pipettor 3 was not tested in these experiments due to pipette tip fitment problems as noted herein.
  • a product performance survey was administered to each participant at the completion of each pipette/tip combination test.
  • the survey included six questions pertaining to the participants' perceptions of tip performance and ease of use and comfort.
  • a 10-point scale was utilized where 10 indicated the best response (e.g., exceptional performance) and 1 indicated the worst response (e.g., extremely poor performance).
  • the survey questions included; (1) effort to apply tip; (2) ease of aligning pipette on tip; (3) confidence that tip is sealed on pipettor; (4) effort to eject tip; (5) performance during "touch off”; and (6) overall comfort during use.
  • "Touching off' is the act of touching the dispensing end of the pipette tip against the bottom or sidewall of the liquid receptacle in order to remove the last drop of liquid that may adhere to the outer surface of the pipette tip.
  • the tips described herein received the highest (e.g., best) ratings by participants across each of the survey criteria.
  • the results of the subjective surveys are presented graphically in FIGS. 23-28 , and also are summarized in the table below.
  • FIG. 29 shows the results for effort to apply pipette tip to pipettor (e.g., "tip application effort” panel), effort to eject pipette tip from pipettor (e.g., "tip ejection effort” panel), and ease of aligning pipette tip with pipettor barrel (e.g., "ease of alignment” panel) for each pipette tip tested.
  • FIG. 29 shows the results for effort to apply pipette tip to pipettor (e.g., "tip application effort” panel), effort to eject pipette tip from pipettor (e.g., "tip ejection effort” panel), and ease of aligning pipette tip with pipettor barrel (e.g., "ease of alignment” panel) for each pipette tip tested.
  • FIG. 29 shows the results for effort to apply pipette tip to pipettor (e.g., "tip application effort” panel), effort to eject pipette tip from pipettor
  • FIGS. 29 and 30 show the results for overall comfort of a particular tip (e.g., "overall comfort” panel), overall speed and efficiency of task completion with a particular pipette tip (e.g., "speed/efficiency” panel), and overall preference of use (e.g., "overall preference panel") of a particular tip.
  • the results shown in FIGS. 29 and 30 indicate that the tips described herein were ranked as the most preferred in nearly all categories and was ranked similarly to the custom (e.g., brand specific) pipette tips in overall performance.
  • the popular generic tip selected due to is popularity ranked as least preferred in all categories used in pipette tip ranking.
  • Example 8 Pipette Tip Application and Ejection Forces.
  • Pipette tip application and ejection forces were measured using a digital force gauge. The forces were measured on the 200 microliter and 1000 microliter capacities for each brand of pipette tip tested.
  • the pipette tips tested were (i) the tips described herein, (ii) custom tips (e.g., brand specific), and (ii) the popular generic pipette tip.
  • the test results for pipette tips on each brand of pipettor are shown graphically in FIGS. 31-39 . The results shown for pipettor 3 only reflect the brand specific custom tip due to fitment of pipette tips as noted herein.
  • FIG. 31 shows the results of pipettor 1 with tips of the 200 microliter capacity.
  • FIG. 32 shows the results of pipettor 1 with tips of the 1000 microliter capacity.
  • FIG. 33 shows the results of pipettor 2 with tips of the 200 microliter capacity.
  • FIG 34 shows the results of pipettor 2 with tips of the 1000 microliter capacity.
  • FIG. 35 shows the results of pipettor 3 using only brand specific custom pipette tips in the 200 microliter and 1000 microliter capacities.
  • FIG. 36 shows the results of pipettor 4 with tips of the 200 microliter capacity.
  • FIG. 37 shows the results of pipettor 4 with tips of the 1000 microliter capacity.
  • FIG. 38 shows the results of pipettor 5 with tips of the 200 microliter capacity.
  • FIG. 39 shows the results of pipettor 5 with tips of the 1000 microliter capacity.
  • Tips described herein consistently resulted in shorter cycle times and often required less total and average muscle work. Tips described herein were significantly faster and/or required less effort than the custom and generic tips in the majority of all full cycle and on/off tests, performed with all 5 pipettors tested, measured at confidence intervals of either (p ⁇ 0.05) and (p ⁇ 0.1).
  • Tips described herein were perceived as requiring the lightest effort when used with pipettors 1, 2 and 4.
  • tips described herein were also perceived as requiring a lighter effort than the generic tips and similar level of effort when compared to the custom or brand specific tip for pipettor 5.
  • the overall perceived level of effort associated with tips described herein corresponded to a "Very weak" to "Weak" level of exertion.
  • tips described herein were consistently better than the other tips tested, when compared across all pipettor models. Additionally, tips described herein were consistently rated better than the custom and generic tips when used with pipettors 1, 2 and 4. Tips described herein were also rated better than generic tips when used in conjunction with pipettor 5 and were rated similarly to the custom tips for pipettor 5. Experienced pipette and pipette tip users ranked tips described herein as the "most preferred" in 5 of the 6 categories tested (e.g., tip application effort, tip ejection effort, ease of aligning pipette on tip, overall comfort to use and overall speed and efficiency).
  • Example 10 Comparison of pipetting accuracy and task productivity as measured by liquid retention and time required for task completion where minimizing sample loss is a factor
  • one 200 microliter pipettor e.g., the pipettor previously designated as the 200 microliter version of pipettor 2 was used to test the accuracy and time to completion of a specific pipetting cycle. The tests were carried out by the testing facility described herein. The pipettor was chosen due to it's performance in other tests described herein. Pipettor 2 was tested in conjunction with the tips described herein, the custom tips for pipettor 2, and the generic tips also previously tested.
  • the pipetting cycled used for this analysis included the following steps:
  • over-blow feature refers to the additional stroke of a pipettor plunger, which allows a user to fully dispense liquid by pushing the plunger past the position normally used for liquid aspiration. Collecting any remaining liquid on the end of the tips by touching the tip to a surface that is subsequently weighed, simulates the action described herein as "touching-off". Touching off is a process often used by pipettor users to ensure pipetting accuracy and substantially complete delivery of samples. A total of 430 pipette tips (e.g., equivalent to about 5 racks) of each type were tested using the pipetting cycle described above. Weight of liquid collected was measured on a Sartorius GD503 precision scale. The scale was calibrated prior to the test (Troemner, Certification number 547366W).
  • Tips described herein have been designed with features that provide the advantageous benefits of substantially complete sample delivery (e.g., blade feature) and ease of tip engagement and tip ejection (flexible, ribbed proximal region with flange).
  • the experiments presented herein demonstrate the advantageous benefits of the features of tips described herein.
  • the amount of liquid and the number of tips that retained liquid were measurements of the advantages of the blade tip feature, while the time to completion was a measurement of the combined benefits of the blade tip feature (reduced or eliminated the need for touching off) and the ease of pipette tip application and ejection.
  • the results indicate that the tips described herein (TDH) had the lowest amount of collectable fluid (e.g., fluid retained on the tip), were the tips least likely to retain fluid on the tip, and showed lowest time to completion due to the lack of fluid retained and ease of pipette tip engagement and disengagement.
  • the results and further analysis are presented in the tables below and in FIGS. 40-41 .
  • Tips described herein were compared to generic and pipettor 2 custom tips for fluid retained at the tip of the pipette tip. Tips described herein feature the "blade tip” design, whereas the tips of the generic and pipettor 2 custom tips do not feature the same distal terminal end.
  • the weights of collected liquid, after completing the pipetting cycle for 430 of each pipette tip type, is presented in the table below and graphically in FIG. 40 .
  • W the weight of liquid collected in grams
  • X the total weight of liquid pipetted (e.g., a constant for this experiment set at 200 microliters which is equivalent to 200 micrograms))
  • N the number of pipette tips sampled (e.g., a constant number for this experiment, a total of 430 tips of each type were tested).
  • [0.0555/(.2g)(430)] ⁇ 100 0.06453% or 0.065%.
  • the total percent of fluid that remained undelivered to the test samples (e.g., % error) gives an indication of pipetting accuracy, and tips described herein resulted in the least error (e.g., 0.00012% liquid retained).
  • the generic tips resulted in the greatest error (e.g., 0.312% liquid retained).
  • the custom tips performed better than the generic tips, (e.g., 0.065% liquid retained), however the custom tips showed a substantially larger liquid retention than tips described herein.
  • pipette tips described herein may contribute to a general increase in productivity seen by users of tips described herein, when compared to identical tasks performed using other pipette tips (e.g., the generic and/or pipettor specific custom designed, pipette tips). Increases in productivity can lead to cost benefits.
  • the time required to complete the sampling (e.g., utilizing 430 pipette tips) for each type of tip was measured during the accuracy test. Each tip was visually inspected following the dispensing step to determine if fluid remained on the tip. Samples that had fluid remaining were subjected to sample collection and weighing, including data entry at time of measurement, into a computer placed adjacent to the scale. The additional time for sample collection, weighing and data entry are reflected in the time to complete each pipette tip cycle. The results are presented graphically in FIG. 42 . Consistent with the other results presented in this example, tips described herein substantially outperformed the generic and pipettor specific pipette tips. The results indicate the time savings benefit is between about 20% and about 90%, for the pipetting cycle described.
  • proximal flexible region and blade tip distal region features provide significant reduction in (i) effort of use, (ii) time of pipetting task completion, and (iii) liquid retained with tip, all of which can contribute to operational cost savings, including claims for repetitive type injuries.
  • FIG 1A-1D FIG 2
  • FIG 3 Selected Features of FIG 1A-1D, FIG 2, FIG 3 and FIG 4A-4D

Landscapes

  • Health & Medical Sciences (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Sampling And Sample Adjustment (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)
  • Devices For Use In Laboratory Experiments (AREA)

Claims (13)

  1. Pipettenspitze mit einem proximalen Bereich (15) und einem distalen Bereich (20), wobei der proximale Bereich (15) mehrere axial orientierte Rippen (80, 85) aufweist,
    wobei:
    der proximale Bereich (15) eine Außenfläche und einen Ringflansch (60) am proximalen Ende des proximalen Bereichs (15) aufweist;
    sich die Rippen (80, 85) jeweils vom Ringflansch (60) zu einem Übergang (30) zwischen dem proximalen Bereich (15) und dem distalen Bereich (20) erstrecken, der einem Rippenende (82, 90) entspricht;
    die Wanddicke des distalen Bereichs (20) kontinuierlich zuläuft von
    (a) einem Punkt am Rippenende (82, 90) oder einem Punkt zwischen dem Rippenende (82, 90) und einem Viertel des Axialabstands vom Ende (50) des distalen Bereichs (20) zum Rippenende (82, 90) zum
    (b) Ende (50) des distalen Bereichs und
    die Wanddicke (53) am Ende (50) des distalen Bereichs 0,01016 cm (0,0040 Inch) bis 0,01397 cm (0,0055 Inch) beträgt.
  2. Pipettenspitze nach Anspruch 1, wobei die Wanddicke (53) am Ende (50) des distalen Bereichs 0,011176 cm (0,0044 Inch) bis 0,012446 cm (0,0049 Inch) beträgt.
  3. Pipettenspitze nach Anspruch 1 oder 2, wobei die Wanddicke an oder nahe einem proximalen Ende des distalen Bereichs (120) der Wanddicke an oder nahe einem distalen Ende des proximalen Bereichs (15) im Wesentlichen ähnelt.
  4. Pipettenspitze nach einem der Ansprüche 1 bis 3, wobei der proximale Bereich (15) einen ersten Satz axial orientierter Rippen (80) und einen zweiten Satz axial orientierter Rippen (85) aufweist, wobei die Rippen (80) des ersten Satzes nicht mit den Rippen (85) des zweiten Satzes identisch sind.
  5. Pipettenspitze nach Anspruch 4, wobei die Rippen (80, 85) des ersten Satzes und des zweiten Satzes über den Umfang beabstandet und um den proximalen Bereich (15) abwechselnd beabstandet sind.
  6. Pipettenspitze nach Anspruch 4 oder 5, wobei Rippen (80) des ersten Satzes eine maximale Dicke haben, die größer als die maximale Dicke von Rippen (85) des zweiten Satzes ist.
  7. Pipettenspitze nach einem der Ansprüche 1 bis 6, die einen flexiblen proximalen Bereich und einen distalen Bereich aufweist, wobei der flexible proximale Bereich so konfiguriert ist, dass er über eine festgelegte Strecke aus einer Ruheposition durch eine Ablenkkraft unter 7,78 N (1,75 Pounds) abgelenkt wird.
  8. Pipettenspitze nach Anspruch 7, wobei der flexible proximale Bereich so konfiguriert ist, dass er über eine festgelegte Strecke aus der Ruheposition durch eine Ablenkkraft zwischen 4,76 N (1,07 Pounds) und 5,60 N (1,26 Pounds) abgelenkt wird.
  9. Pipettenspitze nach einem der Ansprüche 1 bis 8, wobei die Innenfläche des distalen Bereichs im Wesentlichen glatt ist.
  10. Pipettenspitze nach einem der Ansprüche 1 bis 9, wobei die Außenfläche des distalen Bereichs eine Stufe aufweist.
  11. Pipettenspitze nach einem der Ansprüche 1 bis 10, wobei der proximale Bereich einen kegelstumpfförmigen Hohlraum im Inneren des proximalen Bereichs aufweist.
  12. Pipettenspitze nach Anspruch 11, wobei der kegelstumpfförmige Hohlraum im Wesentlichen glatt ist.
  13. Pipettenspitze nach Anspruch 11 oder 12, wobei der kegelstumpfförmige Hohlraum eine Ringnut (120) aufweist.
EP11735265.8A 2010-01-22 2011-01-21 Pipettenspitzen Active EP2525910B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP20209898.4A EP3831489A1 (de) 2010-01-22 2011-01-21 Pipettenspitzen

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US29765810P 2010-01-22 2010-01-22
US35439810A 2010-01-22 2010-01-22
US41185910P 2010-11-09 2010-11-09
PCT/US2011/022129 WO2011091308A2 (en) 2010-01-22 2011-01-21 Pipette tips

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP20209898.4A Division EP3831489A1 (de) 2010-01-22 2011-01-21 Pipettenspitzen

Publications (3)

Publication Number Publication Date
EP2525910A2 EP2525910A2 (de) 2012-11-28
EP2525910A4 EP2525910A4 (de) 2015-07-22
EP2525910B1 true EP2525910B1 (de) 2020-12-09

Family

ID=47042251

Family Applications (2)

Application Number Title Priority Date Filing Date
EP20209898.4A Pending EP3831489A1 (de) 2010-01-22 2011-01-21 Pipettenspitzen
EP11735265.8A Active EP2525910B1 (de) 2010-01-22 2011-01-21 Pipettenspitzen

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP20209898.4A Pending EP3831489A1 (de) 2010-01-22 2011-01-21 Pipettenspitzen

Country Status (1)

Country Link
EP (2) EP3831489A1 (de)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2526135A (en) * 2014-05-15 2015-11-18 Stratec Biomedical Ag Tip geometry

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4212204A (en) * 1979-04-26 1980-07-15 St Amand Elmer F Pipette and method of making same
US4721680A (en) * 1986-08-11 1988-01-26 Multi-Technology, Inc. Methods of using micro pipette tips
US4748859A (en) * 1987-03-06 1988-06-07 Rainin Instrument Co., Inc. Disposable pipette tip
DE3824767A1 (de) * 1988-07-21 1990-02-01 Eppendorf Geraetebau Netheler Aufsteckbare pipettenspitze in form eines entsprechend einem aufsteckkopfstueck, insbesondere konus einer pipette, wenigstens abschnittsweise ausgefuehrten gefaesses
US5156811A (en) 1990-11-07 1992-10-20 Continental Laboratory Products, Inc. Pipette device
US5223225A (en) * 1991-05-17 1993-06-29 Bio 101 Scale-marked pipet tip for precision dispensing of fluids over a large range of volumes
US5232669A (en) * 1991-11-08 1993-08-03 Abbott Laboratories Pipette tip with self-aligning and self-sealing features
US7335337B1 (en) 2001-09-11 2008-02-26 Smith James C Ergonomic pipette tip and adapters
US20070017870A1 (en) 2003-09-30 2007-01-25 Belov Yuri P Multicapillary device for sample preparation
US20050255005A1 (en) * 2004-05-13 2005-11-17 Arta Motadel Stackable pipette tips having increased accuracy
JP2007271427A (ja) * 2006-03-31 2007-10-18 Sysmex Corp ピペットチップ
JP5129729B2 (ja) * 2008-02-08 2013-01-30 富士フイルム株式会社 ピペットチップ

Also Published As

Publication number Publication date
EP3831489A1 (de) 2021-06-09
EP2525910A2 (de) 2012-11-28
EP2525910A4 (de) 2015-07-22

Similar Documents

Publication Publication Date Title
US11590490B2 (en) Pipette tips
CA2787274C (en) Pipette tips
US9649636B2 (en) Pipette tip handling devices and methods
US9089845B2 (en) Anti-static pipette tip trays
EP2855021B1 (de) Vorrichtungen mit integrierten pipettenspitzen
US20100089938A1 (en) Pipette tip handling devices and methods
US20180238778A1 (en) Apparatus for spreading a fluid across a substrate and method of using the same
EP2525910B1 (de) Pipettenspitzen
EP2412440A1 (de) System und Verfahren zur Abgabe von Flüssigkeit aus einem Behälter und in einen Flüssigkeitsbehälter

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20120821

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
A4 Supplementary search report drawn up and despatched

Effective date: 20150619

RIC1 Information provided on ipc code assigned before grant

Ipc: G01N 1/10 20060101ALI20150615BHEP

Ipc: B01L 3/02 20060101AFI20150615BHEP

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BIOTIX, INC.

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20191028

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

RIC1 Information provided on ipc code assigned before grant

Ipc: B01L 3/02 20060101AFI20200519BHEP

INTG Intention to grant announced

Effective date: 20200619

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN GRANTED

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 1342854

Country of ref document: AT

Kind code of ref document: T

Effective date: 20201215

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602011069583

Country of ref document: DE

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210310

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201209

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201209

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210309

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 1342854

Country of ref document: AT

Kind code of ref document: T

Effective date: 20201209

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210309

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201209

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201209

REG Reference to a national code

Ref country code: NL

Ref legal event code: MP

Effective date: 20201209

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201209

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201209

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG9D

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201209

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201209

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201209

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201209

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201209

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201209

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210409

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201209

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201209

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602011069583

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210409

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201209

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210121

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20210131

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201209

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201209

26N No opposition filed

Effective date: 20210910

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201209

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201209

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201209

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210121

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210409

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210131

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20110121

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201209

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20231130

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20231212

Year of fee payment: 14

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201209

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20231128

Year of fee payment: 14

Ref country code: CH

Payment date: 20240201

Year of fee payment: 14