Title of Invention

AN AIR DISPLACEMENT PIPETTE .

Abstract

An air displacement pipette (10) having axially spaced annular sealing and substantially cylindrical lateral support zones (36, 38) and regions (46, 48) on the pipette's mounting shaft and tip respectively, in combination with means (52) for insuring uniform depth of mounting shaft penetration into the pipette tip to maintain uniform tip interference with the mounting shaft as successive tips are mounted on and ejected from the mounting shaft whereby the pipette tip is easily and firmly mountable on and easily ejectable from the pipette tip mounting shaft by the application of axial mounting and ejection forces of about two pounds and one pound, respectively.

Full Text

PIPETTE WITH IMPROVED PIPETTE TIP AND MOUNTING SHAFT Related Application This application is a continuation-in-part application of United States Patent Application serial number 09/188,031 filed November 6, 1998, assigned to the same assxgnee as the this patent application. Background of Invention The present invention relates to improvements in pipettes and, more particularly, to air displacement pipettes including a novel mounting shaft and a unique pipette tip tailored to the mounting shaft such that the tip is easily insertable by a pipette user onto the shaft to a fluid tight position in which the tip is secured against undesired lateral rocking on or displacement from the shaft and, after use, is easily ejectable from the shaft by the pipette user; such tip insertion and ejection requiring the pipette user to only exert axial tip insertion and ejection forces of about one pound or less thereby substantially eliminating all risk of repetitive motion injury to the pipette user. The use of pipette devices for the transfer and dispensing of precise quantities of fluids in analytical systems is well known as is the use of disposable tip members for such pipettes. Disposable tiPs accommodate the serial use of such pipette devices in the transfer of different fluids without carryover or contamination. Generally speaking, disposable pipette tips are formed of a plastic material and are of a hollow, elongated, generally conical shape with an open proximal end for receiving and releasably mating with tne distal end of an elongated generally conical pipette tip mounting shaft of a pipette device. Ideally, the disposable tip should slide easily onto the mounting shaft to an axial position adjacent a lower end of a tip ejection mechanism of the pipette device. Thus located, the pipette tip should be laterally stable on the shaft, free from external rocking relative to the shaft (as during "touching off), and should form a fluid tight annular seal with the mounting shaft. Then when it is desired to replace the tip with a new tip, the .pipette tip should be easily removed from the mounting shaft by operation of the tip ejection mechanism. To meet the desired sealing criteria for disposable pipette tips on pipette tip mounting shafts, the inner surface and side walls of the proximal portions of most pipette tips axe axially tapered at a one to one and a half degree greater angle than the distal end of the pipette tip mounting shaft and form an axially elongated frusto-conical annular sealing band. The sealing band is dimensioned to stretch outwardly ("hoop stretch") as the distal end of the elongated generally conical pipette tip mounting shaft is forced into the proximal end of the tip to firmly seat the tip on the shaft and to create an axially elongated annular fluid right seal between the sealing band and the mounting shaft. Other pipette tips, such as those described in United States patents 4,748,859 and 4,824,641, include a plurality Of axially spaced cbmpressible annular sealing rings on an inner surface of the proximal end portion of such tips. The rings create multiple axially spaced fluid tight annular seals between the outer surface of the pipette tip mounting shaft and the inner surface of the proximal end portion of the tip which by virtue of the axially spaced rings is laterally stabilized against undesired rocking on the shaft during touching off. Usually, in mounting a pipette tip on a mounting shaft of a pipette, a user, exerting a downward force of between twelve and fifteen pounds, drives the mounting shaft axially into the tip a distance which to the user seems sufficient to create (i) a fluid tight seal between the tip and (ii) the desired lateral stability for the tip on the shaft. On occasion, in a mistaken attempt to improve the lateral stability of a pipette tip on a mounting shaft, a user will exert a downward insertion force (e.g. eighteen to twenty-five pounds) on the shaft sufficient to axially drive the tip on the shaft until an upper surface of the tip engages or is wedged into the ejector arm or cone of the tip ejector mechanism of the pipette. The contact between a lower surface of the tip ejector arm or cone and the upper surface of the tip, however, only provides a minimal resistance to rocking cf the tip on the shaft and hence only results in a minimal increase in the lateral stability of the tip on the shaft. Further, since most pipette tips are formed of a relatively rigid plastic material, the annular stretching cf the pipette tip required to accommodate movement cf the tip onto the shaft particularly to a point where it engages the lower surface cf the tip ejector or cone is difficult to achieve. In fact, the axial forces which must be exerted on a conventional pipette to achieve such a positioning of the tip on the pipette tip mounting shaft exceed twelve and may be as great as twenty pounds, which is difficult for many pipette tip users to generate. Of course, with most pipette, tip designs, the greater the axial, force exerted in seating a pipette tip on a pipette mounting shaft, the greater the force required to eject the tip from the mounting shaft. Thus, while the insertion of a pipette tip onto a mounting shaft until it reaches a position against a lower surface of a pipette tip ejector mechanism provides a minimum increase in the lateral stability of the tip on the shaft, it works against the design criteria for disposable pipette tips that they be easily removable from the shaft when it is desired to replace the tip. In fact, the design criteria for disposable pipette tips that they be stably mountable on and form a fluid tight seal with a pipette mounting shaft is more easily achieved than the design criteria that disposable pipette tips slide easily cntc a pipetta tip mounting shaft to an axial location forming a fluid tight seal and then be easily removable from the mounting shaft when it is desired to replace the tip. In these regards, the pipette tip mounting shafts of devices for pipetting volumes of liquid in different ranges have different external shape. For example, the distal end of standard pipette tip mounting shafts of pipettes for pipetting liquids in volumes greater than 500 microliters (large volume pipettes) commonly have a downward and inward axial taper of about one and one half to two and one half degrees per side from the longitudinal axis of the mounting shaft. On the other hand, the distal end of the mounting shafts of moderate to relatively small volume pipette devices (250 microliters and less) commonly have a downward and inward axial taper of about two to five degrees per side from the longitudinal axis of the mounting shaft so that the nose of the shaft will hit the inner wall of the pipette tip and cause hoop stretching thereof before the side of the shaft engages the inner wall of the tip. Therefore, while the design criteria that a large volume pipette tip be easily mountable on and easily removable from the mounting shaft of a large volume pipette device may be achieved by including a proximal end portion having a side wall of reduced wall thickness is in the large volume pipette tip described in United States patent 5,779,984, issued July 14, 1998, such a thin wall design vill not result in a pipette tip that satisfies the easy mount and ejection design criteria of moderate and small volume pipette tips which must firmly mount on pipette tip mounting shafts having an inward taper of two degrees and above. The same is true of the pipette tip design disclosed in United States parent 4,072,330 which includes a frusto-conical sealing region having a thin side wall. As previously stared, standard small and moderate volume pipette tips include a frusto-conical annular sealing band or inner surface for engaging and sealing with the tapered distal end of a pipette tip mounting shaft. The angle of taper of the sealing surface usually approximates (e.g. one and one-half degrees greater than) that of the mounting shaft (e.g. two to five degrees). Thinning the side wall cf the standard small and moderate volume pipette tips in the region of such a sealing band does little to reduce the mounting and ejection forces required to move such a tip to a sealing location and then eject the pipette tip from the mounting shaft. In forming the desired annular seal, the frusto-conical annular region is required to stretch like a hoop (hoop stretch) outwardly normal to the mating sloping surface of the pipette tip mounting shaft. Large reactive forces in the tip material resist such hoop stretching and require the exertion of large axial forces (eg. ten or more pounds) on the tip in order to mount the tip on the mounting shaft and create the necessary annular fluid tight seal. Such reactive forces increase as the tip is driven toward the tip ejection mechanism of the associated pipette device. Further, disposable pipette tips are commonly mounted and stored in sterilizable racks. Such racks commonly include a support tray having an array of holes for receiving distal ends of pipette tips to vertically orient the pipette tips in a spaced rectilinear pattern with open proximal ends of the tips exposed to receive the mounting shafts of a pipette device onto which the pipette tips are to be mounted. For example, to mount the disposable pipette tips contained in a tip rack on the shafts of a multi-channel pipette, the pipette device is placed over the rack with its several mounting shafts aligned with the open proximal ends of an aligned series of the pipette tips. After a slight initial insertion of the mounting shafts into the open proximal ends of the aligned pipette tips, a relatively large downward force is exerted on the pipette device to drive the mounting shafts into the tip members. The pipette tips are thus very firmly seated on the mounting shafts and are lifted from the rack with upward movement of the multi-channel pipette. Unfortunately, in practice, such multiple pipette tip mounting procedures often result in some of the pipette tips being mounted at different axial locations on some of the mounting shafts. In an attempt to eliminate such non-uniform mounting of pipette tips on the several channels of a multi channel pipette, users often rock the pipette as the mounting shafts are driven by axial forces approximating 12 to 15 pound per channel into the tips supported by a pipette tip rack to drive the tips toward the lower surface of the tip ejector mechanism of the pipette. Moreover, the more firmly a tip is mounted or wedged on the mounting shaft of the pipette device, the greater the axial force which a pipette user must generate by thumb and hand action tc eject the tip from the shaft when a tip replacement is desired. In practice, it is not uncommon for axial forces approximating ten pounds per pipette channel to be generated by the pipette users thumb and hand in driving a tip from a mounting shaft. Over several and repeated ejection operations, particularly with multi-channel pipettes where the generation of substantially greater axial forces is required, the thumb and hand of the user become physically stressed often resulting in repetitive stress injury to the thumb and hand and in extreme cases, carpal tunnel syndrome. Still further, standard pipette tips as well as those illustrated in United States patent 4,072,330 depend solely upon -he sealing region of the pipette tip to both create the annular fluid tight seal and to provide the stable lateral mounting of the tip to the shaft sufficient to resist rocking as during touching off. The structure of such pipette tips do not provide such lateral mounting stability and but for those rare instances where the tips are jammed upward against the bottom of the pipette tip ejector arm or cone, minimal lateral stability cf the tip on the shaft is achieved. In an effort to improve lateral stability and retention cf pipette tips on the mounting shafts of some pipettes, some manufacturers include O-rings on and encircling the tip mounting shafts of their pipettes. For example, the Brinkmann Instrument Co. indicates for its Transferpipette 8/12 that such O-rings ensure that all tips stay firmly mounted during use. However, there is a rapid wearing of such O-rings with repeated insertion of the associated mounting shafts into and ejection of pipette tips from such shafts. With such wear, the tips no longer stay firmly mounted during use and wear particles from the O-rings can contaminate fluid samples handled by the associated pipettes. In an effort to reduce the hand and finger forces which a pipette user must generate to eject a tip from the mounting shaft of a pipette, other pipette manufacturers such as LabSystems have developed and include in some of their pipettes gear and ratchet mechanisms for amplifying the user generated forces to eject pipette tips from their mounting shafts. Unfortunately, such mechanisms are costly and add undesired size and weight to the pipettes. More recently, to meet the previously described ideal characteristics and criteria for a pipette tip, there has been developed an improved plastic pipette tip which is mountable on and ejectable from a standard pipette mounting shaft of an air displacement pipette by application of an axial mounting force of less than six pounds and an axial ejection force as small as three pounds. The improved pipette tip is described ir. the concurrently filed United States patent application, Serial Number 09/188,030, entitled "Easy Eject Pipette Tip". As there described, to meet the mountability and ease of ejection criteria for disposable pipette tips, the improved pipette tip, hereinafter referred to as the "Soft Seal" tip, includes an open tubular proximal end portion comprising an enlarged frusto- conical open top tapering downwardly and inwardly to join at an annular sealing region to a hollow substantially cylindrical mid- portion of the pipette tip. The open top has an inner diameter sufficient to axially • receive the distal end of a standard pipette tip mounting shaft. The annular sealing region is formed by the transition or line of connection of the frusto-conical open top to the mid-portion of the pipette and includes an annular sidewall having a thickness in a range of .20 to .50 mm. The mid-portion has an inner diameter at the sealing region which is less than the diameter of the pipette mounting shaft, a thin resilient annular side wall having a thickness in a range of .20 to .50 mm and an axial length in a range of .25 to .65 cm. Thus, while the distal end of the mounting shaft fits into the enlarged open end of the pipette tip, the frusto—conical outer surface of the mounting shaft engages the inner surface of the sealing region at the bottom of the open top of the pipette tip to stretch the annular sealing region or line radially outward as the mounting shaft is inserted into the proximal portion, thereby creating a fluid tight seal between the sealing zone and the sealing region. In addition to the proximal portion, the improved pipette tip includes a tubular distal portion extending from the mid-portion and terminating in a relatively narrow distal end opening for passing fluid into and from the tip upon operation of the pipette device. Finally, the improved pipette tip preferably includes lateral stabilizing means on its inner surface adjacent the sealing region for engaging the outer surface of the mounting shaft as it is inserted into the proximal portion to laterally stabilize the tip on the shaft. Such lateral stabilising means preferably comprises at least three circumferentially spaced contacts extending inwardly from the inner surface of the proximal portion of the tip adjacent the sealing region for engaging the outer surface of the mounting shaft as it is inserted into the proximal portion to laterally stabilise the tip on the shaft. In this regard, the diametric spacing of the contacts is such that the contacts lightly engage and allow the distal end of the shaft to pass with no hoop stretching of the sidewalls from which the contacts extend. In this manner, the contacts combine with the sealing region to provide lateral support for the pipette tip on the mounting shaft and prevent the pipette tip from moving laterally when lateral external forces are exerted on the distal portion of the tip as during touching off. While the improved pipette tip as described above represents a substantial improvement over standard pipette tips with respect to the axial forces which are required to mount the tip on and eject the tip from a pipette mounting shaft, there is a continuing need to still further reduce the risk of repetitive motion injuries to pipette users and a continuing desire to further minimize the axial forces which are required to stably mount a pipette tip on and eject a pipette tip from a pipette mounting shaft. The present invention satisfies that need. Summary of Invention, To meet the heretofore unattainable ideal criteria that disposable plastic pipette tips (i) be easily mountable on a pipette tip. mounting shaft to form a fluid tight connection with the shaft which is so secure that the tip will not rock laterally on or accidently dislodge from the shaft during normal pipette use and (ii) then be easily ejectable from the mounting shaft by application of minimal axial mounting and ejection forces, e.g. forces approaching one pound or less, the present invention has adopted a unique approach. It incorporates in an air displacement pipette the concept of axially spaced annular sealing and substantially cylindrical lateral support zones and regions on the pipette's mounting shaft and tip, respectively. Further, it provides means for insuring uniform depth of mounting shaft penetration into the pipette tip to maintain uniform tip interference with the mounting shaft as successive tips are mounted on and ejected from the mounting shaft. In particular, the present invention comprises a combination of a pipette tip mounting shaft and pipette tip in an air displacement pipette. The mounting shaft comprises an axially elongated body including a distal end and annular or substantially cylindrical and axially spaced outer surface regions defining an annular sealing zone and an annular lateral support zone. The pipette tip is an elongated tube comprising an open proximal end, an open conical distal end and annular or substantially cylindrical and axially spaced inner surface regions defining an annular sealing region and an annular lateral support region. The outer diameter of the annular sealing zone of the annular sealing region on the pipette tip and the sidewall of the tip in the area of the annular sealing region is sufficiently thin that the annular sealing region expands slightly to form an interference fit and air tight seal between the mounting shaft and the pipette tip when the sealing penetrates the sealing region. The axial spacing of the sealing and support zones is substantially equal to the axial spacing of the sealing and support regions. Also, the outer diameter of the lateral support zone is slightly less than or substantially equal to the inner diameter of the lateral support region over at least some portion of the circumference of the support zone. This allows for some minimal contact between the support zone and region without creating a secondary air tight seal which would result in an undesired increase in the axial forces required to mount and eject the pipette tip on and from the shaft. With such a structural configuration, as the sealing zone penetrates the sealing region, the support region receives the support zone and provides lateral support therefor which prevents transverse rocking of the pipette tip on the mounting shaft as might otherwise occur during touching off of the pipette tip and an accompanying undesired dislodging of the tip from the shaft. Further/ the preferred embodiment of the present invention includes the aforementioned controlled interference air tight fit and mating annular lateral support zone and region as well cooperative means on the pipette and pipette tip for limiting the axial travel of the tip on the mounting shaft. This insures uniform depth of mounting shaft penetration into the pipette tip to maintain uniform the desired tip interference with the mounting shaft as successive tips are mounted on and ejected from the mounting shaft and is to be distinguished from the pipette tip shoulder structure of previously mentioned United States patent 4,824,641. Because of the above described cooperative structural features of the pipette tip and mounting shaft, the pipette tip combination of the present invention has proven to only require axial pipette tip mounting and ejection forces substantially equal to or less than one pound and to provide a stable air-tight seal of the tip on the shaft which is secure against undesired lateral rocking of the pipette tip on the mounting shaft. Thus, the combination comprising the present invention requires a pipette user to generate so little hand and thumb force that repeated mounting and ejection of such pipette tips is unlikely to result in repetitive stress injury. Further, for pipette tip and shaft combinations wherein the interference fit between the sealing zone and region is about .075 mm to about .2 mm and the wall thickness of the pipette tip in the sealing region is between .2 and .5 mm, it has been discovered that the desired minimal tip mounting and ejection forces associated with the present invention still may be achieved and the lateral stability of the tip on the shaft further enchanced when there is a small interference fit between the support region and zone. The small interference fit is provided by the lateral support region of the tip having an inner diameter which is slightly less than the outer diameter of the lateral support zone of the shaft, e.g. Less than .075 mm. Further, when the shaft and tip are concentric and substantailly circular in the support zone and region, a secondary air tight seal may be created between the support zone and region without creating an undesired increase in the axial forces required to mount and eject the tip on and from the shaft. Brief Description of the accompanying drawings Fig.l is a side view of a standard manual pipette having a pipette tip mounted of a mounting shaft adjacent a lower end of a tip ejector mechanism of the pipette. Fig- 2 is a cross sectional side view of one embodiment, of the pipette tip and mounting shaft combination of the present invention. Fig. 3 is an enlarged fragmentary section side view of the sealing region within the circle 3 for the piperts tip of Fig. 2. Fig. 4 is an enlarged fragmentary side view of an upper portion of the pipette tip and mounting shaft combination of Fig. 2 showing the fluid tight seal between the sealing region and sealing zone, the mating relationship of the lateral support region and zone and a preferred embodiment of the cooperative means including a shoulder on the pipette tip for limiting mounting shaft penetration into the tip. Fig. 5 is an enlarged fragmentary side view similar to Fig. 4 in addition showing a first alternative embodiment of the cooperative means including a shoulder on the mounting shaft for limiting mounting shaft penetration into the tip. Fig. 6 is an enlarged fragmentary side view similar to Fig. 2 in addition showing a second alternative embodiment of the cooperative means including a lower end of the pipette tip ejector of a pipette for limiting mounting shaft penetration into the tip. Fig. 7 is a cross sectional side view of an alternative embodiment of the pipette tip and mounting shaft combination of the present invention including a mounting shaft extension for reducing air volume effects associated with air displacement pipettes. Fig. 8 is a graph comparing the forces required to insert and eject a pipette tip of the pipette tip/mounting shaft combination of the present invention onto and from the mounting shaft with the insertion and ejection forces for a standard pipette tip on a standard mounting shaft and the insertion and ejection forces for the "Soft Seal" pipette tip and standard mounting shaft described in the concurrently filed patent application Serial Number Fig. 9 is a graph comparing the travel of the pipette tip of the pipette tip/mounting shaft combination of the present invention onto the mounting shaft with travel of a standard pipette tip and "soft seal" tip onto a standard pipette mounting shaft in response to different pipette tip insertion forces. Fig. 10 is a graph comparing the lateral stability of a pipette tip of the pipette tip/mounting shaft combination of the present invention on the mounting shaft with the lateral stability of a standard pipette tip and "soft seal" tip on a standard mounting shaft for tips mounted with different pipette tip insertion forces. Fig. 11 resembles Fig. 4 and is an enlarged fragmentary side view of an upper portion of and alternative embodiment of the pipette tip and mounting shaft combination of Fig. 2 showing an axial reversal of the locations of the fluid tight seal between the sealing region and sealing zone and the mating relationship of the lateral support region and zone, the sealing zone and region being adjacent the preferred embodiment of the cooperative means including a shoulder on the pipette tip for limiting mounting shaft penetration into the tip and the support zone and region being remote form the cooperative means. Fig. 12 resembles Fig. 5 and is an enlarged fragmentary side view similar to Fig. 11 showing the axial reversal of the sealing zone and region relative to the support zone and region in addition showing the first alternative embodiment of the cooperative means including a shoulder on the mounting shaft for limiting mounting shaft penetration into the tip, the support zone and region being adjacent the cooperative means and the sealing zone and region being remote from the cooperative means. Fig*. 13 resembles Fig. 6 and is an enlarged fragmentary side view similar to Fig. 11 showing the axial reversal of the sealing zone and region relative to the support zone and region in addition to showing the second alternative embodiment of the cooperative means including a lower end of the pipette tip ejector of a pipette for limiting mounting shaft penetration into the tip. Fig. 14 resembles Fig. 4 is an enlarged fragaentary side view of an upper portion of the pipette tip and mounting shaft combination of Fig. 2 showing the fluid tight seal formed by an interference fit between the sealing region and sealing zone, a small interference fit between the lateral support region and zone and a preferred embodiment of the cooperative means including a shoulder on the pipette tip for limiting mounting shaft penetration into the tip. Fig. 15 is an enlarged fragmentary side view similar to Fig. 5 in addition showing the small interference fit between the lateral support region of the tip and the lateral support zone of the shaft to provide enhanced lateral support for the tip on the shaft. Fig. 16 resembles Fig. 6 in addition showing the small interference fit between the lateral support region of the tip and the lateral support zone of the shaft to provide enhanced lateral support for the tip on the shaft. Fig. 17 resembles Fig. 7 in addition showing the small interference fit between the lateral support region of the tip and the lateral support zone of the shaft to provide enhanced lateral support for the tip on the shaft. Fig. 18 resembles Fig. 11 in addition showing the small interference fit between the lateral support region of the tip and the lateral support zone of the shaft to provide enhanced lateral support for the tip on the shaft. Fig. 19 resembles Fig. 12 in addition showing the small interference fit between the lateral support region of the tip and the lateral support zone of the shaft to provide enhanced lateral support for the tip on the shaft. Fig. 20 resembles Fig. 12 in addition showing the small interference fit between the lateral support region of the tip and the lateral support zone of the shaft to provide enhanced lateral support for the tip on the shaft. Detailed Description of Invention Fig. 1 illustrates a standard manual pipette resembling the PIPETMAN pipette sold exclusively in the United States by the Rainin Instrument Co. Inc., assignee of the present invention. The manual pipette is designated in fig. 1 by the number 10 and includes a pipette tip ejector mechanism 12 described in United States patent 3,991,617 issued November 16, 1976, which is incorporated nerexn oy tnxs reference. The pipette 10 comprises a push button 14 connected by a rod 16 to a piston (not shown) located in the body or housing 18 of the pipette. The push button 14 may be depressed by a user exerting a downward force on the push button to cause downward movement of the piston of the pipette. When the push button 14 is released, a quantity of liquid to be sampled is sucked into a disposable pipette tip 20 releasably secured to a lower end of a pipette tip mounting shaft 22 of the pipette. The sample then may be transferred into another vessel by once more exerting a downward force on the push button 14. After such use, it is common practice to eject the pipette tip 20 from the mounting shaft 22 and replace it with a new pipette tip for repeated operation of the pipette 10 in aspirating and dispensing a new sample fluid. The pipetre tip ejector mechanism 12 is employed to eject the tip 20 from the mounting shaft 22. In this respect, the mechanism 12 comprises a push button 24 connected to a rod located in a passage (not shown) provided in an upper part of the hand holdable housing 18 of the pipette 10. The passage and rod. are arranged so as to be able to impart to the rod a movement of translation parallel to an axis of the pipette in opposition to a spring (not shown) normally urging the rod in an upward position. A removable tip ejector member or arm 26 including a tubular upper end extends from a lower end of the rod and from the rod follows the general exterior contour of the housing 18 of the pipette to terminate in a sleeve 28. The sleeve 28 encircles a conical lower end 30 of the pipette tip mounting shaft 22 which tightly receives the upper end of the disposable pipette tip 20. To eject the pipette tip 20 from the lower end of the mounting shaft 22, a user grips the pipette housing 18 and using his or her thumb presses downward on the push button 24. The downward force on the push button is translated by the rod to the tip ejector arm 26 and hence to the sleeve 28 which presses down on an upper end of the pipette tip. When the downward force transferred by the sleeve 28 exceeds the friction between the pipette tip 20 and the mounting shaft 22, the pipette tip is propelled from the mounting shaft. Upon a release of the push button 24, the spring returns the tip ejector mechanism 12 to its normal position with the sleeve spaced slightly from the upper end of a replacement pipette tip which is inserted onto the mounting shaft 22 readying the pipette 10 for its next aspiration and dispensing operation. As previously stated, for standard small and moderate volume pipettes, the pipette tip mounting shaft 22 has an inward axial taper of between two and five degrees from the longitudinal axis of the mounting shaft. As also previously stated, standard small and moderate volume pipettes tips for use with such standard pipette tip mounting shafts include a relatively long frustoccnical annular sealing band or inner surface contiguous with the open proximal end of the tip for engaging and sealing with the frusto-conical distal end of the pipette tip mounting shaft to provide lateral stability for the tip on the shaft. The angle of taper of the sealing surface is usually within about one degree of the two to five degrees inward taper of the mounting shaft and the length of the sealing surface on the shaft is such that in forming the annular seal the tip is also fairly stable on the shaft. In forming the desired annular seal, the frusto conical annular sealing region along with the balance of the open proximal end of the pipette tip is required to stretch like a hoop outwardly normal to the mating sloping surface of the pipette tip mounting shaft. Because of the length of the sealing region and the relatively thick sidewall of the standard tip, large plastic forces in the tip material which resist such outward hoop stretching and require exertion of large axial forces on the tip in order to mount the standard tip on the mounting shaft and create the necessary annular fluid tight seal. Often, axial forces between 12 and 15 pounds are required to mount a standard pipette tip on a standard mounting shaft and create the desired fluid tight seal. Such axial forces are generated by the hand and forearm of a pipette user in exerting a pipette tip mounting shaft into a pipette tip usually held in a pipette tip mounting rack. Of course, when it is desired to eject such a firmly mounted tip from a pipette tip mounting shaft, an axial force of approximately ten (10) pounds must be exerted on the upper edge of the pipette tip to overcome the friction forces between the pipette tip and shaft and to eject the tip from the shaft. The relationship between tip insertion and tip ejection forces is depicted by the curve 60 in Fig. 8 for a standard 250 ml pipette tip, the tip insertion forces increasing from 0 to about 20 pounds at a point 62 where the tip engages an ejection mechanism of the associated pipette device. As previously described, the downward tip ejection forces are exerted by the pipette user pressing downward with his or her thumb on the top of the push button 24 to translate axial force through the ejector arm 26 to the top of the pipette tip 20. As indicated in Fig. 8, to eject the standard pipette tip from its associated mounting shaft requires the pipette user to generate an axial ejection force of about 12 pounds. Over the course of several repeated ejection operations, the thumb and hand of the user will become physically stressed. This often results in repetitive motion injury to the thumb and hand and in extreme cases carpal tunnel syndrome. •K\ J^ In an att:efflPi: Zo overcome such problems, the previously "10^ W referred to Soft. Seal pipette tip design described in the \ Xp^'''^'- « jdr*' \* developed. As depicted.by the curve 70 in Fig. 8, the Soft Seal ^ pipette, tip design allows for the easy and firm mounting of a )r JJT pipette tip on a mounting -shaft and the easy ejection of the . pipette;:;tip ..from the mounting shaft by the..application of axial mo.unting of about six (6) pounds and axial ejection forces of about three applied force necessary to insert and eject the Soft Seal tip to and from a location on a standard pipette mounting shaft where the tip engages the tip ejection mechanism of an associated pipette. The substantial reduction in tip insertion and ejection forces associated with the Soft Seal pipette tip when compared to those of a standard pipette tip is clear from a comparison of curve 70 to curve 60. As previously indicated, the present invention provides a novel mounting shaft and unique pipette tip tailored to the mounting shaft such that the tip is even more easily insertable ^»y a pipette user onto the shaft to a fluid tight position in which the tip is secured against undesired lateral rocking on or displacement from the shaft and, which after use, is even more easily ejectable from the shaft by the pipette user. Such tip insertion and ejection operations require the pipette user to only exert axial tip insertion and ejection forces of about one pound or less, thereby substantially reducing all risk of repetitive motion injury to the pipette user. As depicted by the curve 80 in Fig. 8 the design of the present invention, referred hereinafter as the "LTS" tip and/or shaft, allows for the easy and firm mounting of the pipette tip of the present invention on its associated mounting shaft and the easy ejection of the pipette tip from the mounting shaft by the application of axial mounting and ejection forces of about one (1) pound. In Fig. 8, the point 82 depicts the applied force necessary to insert and eject the LTS tip to and from a location on the mounting shaft of the present invention where the tip engages a. tip insertion shoulder for limiting penetration of the shaft into the tip. As will be described hereinafter, in different embodiments of the present invention, such a shoulder comprises a shoulder on the tip or on the shaft or the base of a tip ejection mechanism of the associated pipette. The substantial reduction in tip insertion and ejection forces associated with the LTS pipette tip when compared with the Soft Seal tip and the standard pipette tip is clear from a comparison of the curve 80 to the curves 70 and 60 in Fig. 8. In Fig. 9, the relationship between the pipette tip insertion force and the distance traveled by a tip on an associated pipette tip mounting shaft is graphically depicted for 250 ml LTS, Soft Seal and standard pipette tips. The curves 100 and 110 depict the relationship between insertion force and the travel of the Soft Seal and standard pipetre rips on standard mounting shafts respectively- In this regard, the travel of Sofz Seal and standard pipette tips is limited by the pipette tip ejection mechanism engaging the pipette tip as depicted by points 102 and 112 respectively. The curve 90 depicrs the relationship between insertion force and LTS pipette tip travel on an LTS mounting shaft. The travel of the LTS pipette tip is limited by the previously referred to shoulder engaging the LTS tip as depicted by point 92 on curve 90. The substantial increase in tip travel per unit of insertion force associated with the LTS pipette tip of the present invention when compared to the Soft Seal and the standard pipette tip is clear from a comparison of curves 90, 100 and 110 in Fig. 9. In Pig. 10, the relation between the pipette tip insertion force and the lateral stability of a pipette tip on its associated shaft is graphically depicted for 250 microliter LTS, Soft Seal, and standard pipette tips. For the standard and Soft Seal pipette tips, the axial location of the pipette tip on the standard pipette tip mounting shaft is the point where the pipette forms a air tight seal with the mounting shaft and is near or against the bottom of the pipette tip ejection mechanism for the associated pipette. For the LTS pipette tip, the axial location of the tip is defined by the previously referred to shoulder. Each pipette tip was tested for stability by "touching off" the pipette tip during normal pipette use. That is, upon aspirating a volume of liquid into the distal of the pipette tip, the pipette is moved to a receptacle where the distal end of the tip is placed at an incline against the side of the receptacle and at least a portion of the aspirated volume of liquid is dispensed by operation of the pipette. During such a positioning of the pipette tip, the distal end is touching the side of the receptacle (e.g. "touching off"). During that time, lateral forces are exerted on the distal end of the pipette tip which tend to rock the tip on its mounting shaft. The number of cycles of "touching off" required to dislodge the pipette tip from its associated mounting shaft for different insertion forces is depicted in Fig. 10. The curve 120 depicts the relationship of insertion force to lateral stability for a standard pipette tip while curve 130 depicts the relationship for a Soft Seal pipette tip. The curve 140 depicts the relationship of insertion force to lateral stability for the LTS tip of the present invention. From Fig. 10 it is to be noted that the lateral stability of the LTS tip is substantially constant at above 50 cycles of "touching off" before the LTS tip dislodges from its associated mounting shaft. This uniform stability extends from an insertion force of approximately 1 pound. For the standard pipette tip and Soft. Seal tip, lateral stabilities approaching that of the LTS pipette tip are only achieved with insertion forces apDroaching or exceeding 15 pounds. For more normal insertion forces of about 10 pounds, the standard and Soft Seal pipette tips dislodge from their associated mounting -shafts at about. 25 cycles cf "touching off". Thus, Fig. 10 clearly depicts the improved lateral stability for the LTS pipette tip on its associated mounting shaft when compared with standard and Soft Seal pipette tips of comparable volume. A preferred embodiment of the structure of the pipetta tip and mounting shaft ..combination of the present invention is depicted in Fig. 2 and shown in enlarged detail in Fig. 4. As there illustrated, the mounting shaft 32 comprises an axially elongated body including a distal end 34 and annular or a substantially cylindrical and axially spaced outer surface regions defining an annular sealing zone 36 adjacent the distal end 34 and an annular lateral support zone 38 on the distal end 34 near the end of the shaft 32. The pipette tip is represented by the numeral 40 and is an elongated plastic tube comprising an open proximal end 42, an open conical distal end 44 and annular or substantially cylindrical and axially spaced inner surface- regions defining an annular sealing region 46 and an annular lateral support region 48 for mating with the sealing and support zones 36 and 38 respectively, on the mounting shaft 32. As used herein, "substantially cylindrical" means an annular surface having an axial taper of one and one-half degrees or less. Fig. 3 illustrates in enlarged detail a preferred embodiment of the sealing region 46 and comprises the portion of the pipette tip 40 of Fig. 2 within the circle 3. As shown, the sealing region. 46 is formed by an inwardly extending substantially V- shaped bead 49 extending radially inward from the sidewall 50 of the pipette tip 40. The innermost surface of the bead 49 forms a very narrow annular sealing band or line for engaging the substantially cylindrical sealing zone 36 of the pipette tip mounting shaft 32 to form the previously described air-tight seal between the tip and mounting shaft. As illustrated in Fig. 4, the outer diameter of the annular sealing zone 36 is slightly greater than the inner diameter of the annular sealing region 46 on the pipette tip 40 and the sidewall 50 of the tip in the area of the annular sealing region 46 is sufficiently thin that the annular sealing region expands slightly to form an interference fit and air tight seal between the mounting shaft 32 and the pipette tip 40 when the sealing zone 36 penetrates the sealing region 46. In practice, it has been found that the desired interference fit is formed when the difference in the outer diameter of the annular sealing zone and the inner diameter of the annular sealing region is at least .075 millimeters (mm). further, it has been found that in practice that the wall thickness of the pipette tip in the area of the sealing region 46 is preferably between .20 and .50 mm. As illustrated in Figs. 2 and 4, the axial spacing of the sealing and support zones is substantially equal to the axial spacing of the sealing and support regions- Also, the outer diameter of the lateral support zone 38 is slightly less than or substantially equal to the inner diameter of the lateral support: region over at least some portion of the circumference of the support zone. This allows for some minimal contact between the • support zone and region without creating a secondary air tight seal which would result in an undesired increase in the axial forces required to mount and eject the pipette tip on and from the shaft. With such a structural configuration, as the sealing zone 36 penetrates the sealing region 46, the support region 48 receives the support zone 38 and provides lateral support therefor which prevents transverse rocking of the pipette tip 40 on the mounting shaft 32 as might otherwise occur during "touching off" of the pipette tip and an accompanying undesired dislodging of the tip from the shaft. In these regards, it is preferred that the axial spacing of the mating lateral support zone 38 and region 48 from the sealing zone and region 36,46 is substantially equal to the inner diameter of the pipette tip 40 in the support region. Such a length relationship provides excellent lateral stability for the pipette tip 40 on the mounting shaft 32. Further, as illustrated- in Figs. 2 and 4, the present invention includes cooperative means 52 on the pipette of the present invention and the pipette tip 40 for limiting the axial travel of the tip on the mounting shaft 32. This insures uniform depth of mounting shaft penetration into the pipette tip to maintain uniform tip interference with the mounting shaft as successive tips are mounted on and ejected from the mounting shaft. In the embodiment illustrated in Figs. 2 and 4, such cooperative means 52 comprises an annular, upwardly facing, inwardly directed shoulder 53 on the inner surface of the pipette tip 40 immediately adjacent the lateral support region 48. The shoulder 53 is designed such that an upper surface thereof engages a downwardly facing surface such as the bottom 54 of the distal end 34 of the mounting shaft 32 at an outer circumferential portion thereof Alternate embodiments of the cooperative means 52 are depicted in Fig. 5 and Fig. 6. In Fig. 5, the cooperative means 52 comprises an outwardly directed downwardly facing annular shoulder 53' on the pipette tip mounting shaft 32 which upon insertion of the shaft into the open proximal 42 of the tip engages the upper annular edge 56 of the tip to halt further penetration of the shaft into the tip. In Fig. 6, the cooperative means 52 is depicted as comprising a bottom 58 of the sleeve 28 of the pipette tip ejector mechanism 26 illustrated and described with respect to Fig. 1. When the bottom surface 58 engages the upper annular edge 56 of the pipette tip 40, further penetration of the mounting shaft 32 into the pipette is halted. While in the foregoing, particular preferred embodiments of the pipette tip of the present invention have been described and illustrated in detail, changes and modifications may be made without departing from the spirit of the present invention. For example, Fig. 7 depicts an alternate embodiment cf the present invention which include the cooperative means 52 as depicted in Figs. 2 and 4. In addition to the structure of Figs. 2 and 4, the embodiment of Fig. 7 includes an elongated substantially cylindrical extension 62 from the bottom cf the distal end portion 34 of the mounting shaft 32. The extension 62 is coaxial with the mounting shaft and includes an outer sidewall 63 spaced from the inner surface of the pipette tip 40. The extension 62 functions to decrease the air volume captured in the pipette of the present invention and reduces the air volume effects commonly associated with air displacement pipettes. Further, Figs. 11, 12 and 13 depict alternative embodiments of the present invention where the sealing zone 36 and region 46 and the support zone 46 and region 48 are axially reversed from the locations illustrated in Figs. 4, 5 and 6 respectively. As shown in Figs. 11, the sealing zone 36 and region 46 are adjacent the cooperative means 52 while the support zone 38 and region 48 are remote from the cooperative means 52. In Figs. 12 and 13, the sealing zone 36 and region 46 are adjacent the cooperative means 52 and the support zone 38 and region 48 are remote form the cooperative means 52. Still further, Figs. 14, 15, 16, 17, 18, 19 and 20 resemble Figs. 4, 5, 6, 7, 11, 12 and 13 respectively and show alternative embodiments of the present invention where there is a small interference fit between the lateral support region 4 8 and support zone 38 to further enhance the lateral stability of the tip 40 on the shaft 32 without introducing an undesired increase in the axial forces required to mount and eject the tip from the shaft. In this regard, and as illustrated in each of Figs. 14- 20, it has been discovered that for pipette tip and shaft combinations wherein the interference fit between the sealing zone 36 and region 46 is about .075 mm to about .2 mm and the wall thickness of the pipette tip in the sealing region 46 and in the lateral support region 48 is between .2 and .5 mm, the lateral stability of the tip 40 on the shaft 32 can be further enhanced while maintaining the desired minimal tip mounting and ejection forces associated with the present invention when their is a small interference fit between the support region and zone. The small interference is provided by the lateral support region 48 of the tip 40 having an inner diameter which is slightly less than the outer diameter of the lateral support zone 38 of the shaft 32, eg. less than .075 mm. Further, when the shaft 32 and tip 40 are concentric and substantially circular in the support zone 38 and region 48, a secondary air tight seal may be created between the support zone and region without creating an undesired increase in the axial forces required to mount and eject the tip We claim 1. A pipette (10) comprising a pipette tip mounting shaft (32) and a pipette tip (40) characterized in that the shaft and tip include axially and substantially equally spaced and mating annular sealing and substantially cylindrical lateral support zones (36, 38) and regions (46, 48), respectively, The annular sealing region (46) comprising a single axially narrow annular inner sealing surface (49) on a sidewall (50) of the pipette tip which in the sealing region is sufficiently thin that the sealing region will expand slightly and form a single air tight seal for the pipette tip on the mounting shaft between the sealing surface (49) and the sealing zone (36) on the mounting shaft (32) when the sealing zone (36) penetrates the sealing region (46) and the substantially cylindrical lateral support region (38) of the pipette tip (40) having an inner diameter equal to or slightly greater than an outer diameter of the mounting shaft (32) in the lateral support zone (38) to form an air-tight seal-free lateral support for the pipette tip on the mounting shaft as the sealing zone (36) penetrates the sealing region (46) to form the single air-tight seal for the pipette tip on the mounting shaft. 2. The pipette as claimed in claim 1 wherein the annular inner sealing surface (49) comprises a narrow surface inward of and on on and from the shaft In the embodiments of Figs. 14-17 the small interference fit is provided fay controlling the axial taper of the sidewall of the tip between the sealing region and zone to taper slightly inwardly in a downward direction such that the sidewall of the tip engages the outside cf the shaft in the support zone. In the embodiments of Figs. 18-20 the small interference fit is provided by controlling the axial taper of the distal end of the shaft to taper slightly outward in an upward direction such that the outside of the shaft engages the inside of the tip in the support region. Accordingly, the present invention is to be limited in scope only by the terms in the following claims. the sidewall (50) of the pipette tip (40) shaped to form a line or edge seal against the sealing zone (36) of the mounting shaft. 3. The pipette as claimed in claim 1 further comprising means (52) for insuring uniform depth of mounting shaft penetration into the pipette tip to maintain a uniform tip interference with the mounting shaft as successive tips are mounted on an ejected from the mounting shaft. 4. A combination of a pipette tip (40) and a pipette tip mounting shaft (32) in a pipette (10) characterized in that: the pipette tip mounting shaft (32) comprises an axially elongated body including a distal end (34) and annular or substantially cylindrical and axially spaced outer surface regions defining an annular sealing zone (36) and an annular lateral support zone (38); and the pipette tip (40) comprises an elongated tube comprising an open proximal end (42), an open conical distal end (44) and annular or substantially cylindrical and axially spaced inner surface regions defining an annular sealing region (46) and an annular lateral support region (48) for mating with the sealing zone (36) and lateral support zone (38) respectively, the axial spacing of the sealing zone (36) and the lateral support zone (38) on the shaft (32) being substantially equal to the axial spacing of the sealing region (46) and the lateral support region (48) on the tip (40). the annular sealing region comprising an axially narrow annular inner sealing surface (49) on a sidewall (50) of the pipette tip which in the sealing region (46) is sufficiently thin that the sealing region. will expand slightly and form a single air tight seal between the sealing surface (49) and the sealing zone (36) on the mounting shaft when the sealing zone (36) penetrates the sealing region (46) and the substantially cylindrical lateral support region (38) of the pipette tip (40) having an inner diameter equal to or greater than an outer diameter of the mounting shaft (32) in the lateral support zone (38) to form an air tight seal free lateral support for the pipette tip on the mounting shaft as the sealing zone (36) penetrates the sealing region (46) to form the single air-tight seal for the pipette tip on the mounting shaft. 5. The pipette as claimed in claim 4 wherein the annular inner sealing surface (49) comprises a narrow surface inward of and on the sidewall (50) of the pipette tip (40). 6. The combination as claimed in claim 4 wherein the annular sealing zone (36) on the mounting shaft (32) has an outer diameter slightly greater than an inner diameter of the annular sealing region (46) on the pipette tip. 7. The combination as claimed in claim 6 wherein: the annular lateral support zone (38) on the mounting shaft (32) has an outer diameter which is slightly greater than an inner diameter of the annular support region (48) on the pipette tip; and the pipette tip (40) in an area including the annular lateral support region (48) includes a sidewall which is sufficiently thin that the lateral support region expands slightly to form a small interference fit between the mounting shaft and the pipette tip when the lateral support zone (38) penetrates the lateral support region. 8. The combination as claimed in claim 7 wherein the annular inner sealing surface (49) comprises a narrow surface inward of and on the sidewall (50) of the pipette tip (40). 9. The combination as claimed in claim 7 wherein the sidewall of pipette tip in the sealing region (46) and in the support region (48) has a thickness of between .2 and .5 mm. 10. The combination as claimed in claim 9 wherein the sealing region (46) has an inner diameter which is about .075 mm to about .2 mm less that the outer diameter of the sealing zone (36) and wherein the support region (48) has an inner diameter which is less than outer diameter of the support zone (38) by .075 mm or less. 11. The combination as claimed in claim 6 wherein the sidewall (50) in the sealing region (46) has a thickness of between .2 and .5 mm. 12. The combination as claimed in claim 6 wherein the sealing region (46) has an inner diameter which is at least .075 mm less that the outer diameter of the sealing zone (36). 13. The combination as claimed in claim 4 wherein the axial spacing of the lateral support zona and ragion from tha sealing zona and ragion is substantially equal to an innar diameter of tha pipatta tip in tha support ragion. 14. Tha combination as claimed in claim 4 further including cooperating means (52) on the pipette shaft and pipette tip for limiting the axial travel of the tip on the mounting shaft to insure uniform depth of mounting shaft penetration into the pipette tip to maintain uniform tip interference with the mounting shaft as successive tips are mounted on and ejected from the mounting shaft. 15. A pipette tip mounting shaft (32) designed to releasably receive and support a pipette tip (40) including annular or substantially cylindrical and axially spaced inner surface regions definining an annular sealing region (46) and an annular lateral support region (48), the pipette tip mounting shaft comprising an axially elongated body for axially receiving such a pipette tip, the axially elongated body comprising a proximal end portion for support by a pipette (10) to extend axially therefrom, and a distal and (34) remote from the proximal end portion and being characterized by: a substantially cylindrical outer surface region on the axially extending body adjacent the distal end (34) or the proximal end of the shaft and defining an annular sealing zone (36) for mating with the annular sealing region (46) within the pipette tip (40), and a substantially cylindrical outer surface region on the axially elongated body axially spaced from the annular sealing zone (36) and defining an annular lateral supprt zone (38) for mating with the annular lateral support region(48) within the pipette tip (40) and having an outer diameter equal to or slightly less than the inner diameter of the lateral support region (48). 16. A pipette tip (40) wherein the tip comprises an elongated tube comprising an open proximal end (42), an open conical distal end (44) and annular or substantially cylindrical and axially spaced inner surface regions defining an annular sealing region (46) and an annular lateral support region (48) for mating with annular or substantially cylindrical and axially spaced outer surface regions defining an annular sealing zone (36) and an annular lateral support zone (38) of a pipette tip mounting shaft (32), the annular sealing region (46) comprising a narrow annular inner sealing surface (49) on a sidewall (50) of the pipette tip which in the sealing region (46> is sufficiently thin that the sealing region will expand slightly to form an interference fit and air tight seal between the scaling surface (49) and the scaling zona (36) on the mounting shaft whan the scaling zona penetrates tha scaling region. 17. The pipatta tip as claimed in claim 16 wherein the annular inner sealing surface (49) comprises a narrow surface inward of and on the sidewall (30) of the pipette tip (40). 18. The pipette tip as claimed in claim 16 or 17 further including an upwardly facing shoulder (S3) on an inner surface of the pipette tip below the lateral support region (48) for engaging a lower surface (94) of a distal end of the pipette tip mounting shaft (32) to limit penetration of the shaft into the pipette tip. 19. The pipette tip as claimed in any of claims 16-18 wherein: the sidewall of pipette tip in the sealing region (46) and in the support region (48) has a thickness of between .2 and .5mm the sealing region (46) of the tip (4 ) has an inner diameter which is about .079 mm to about .2 mm less than an outer diameter of tha sealing zona (36) of tha shaft (32) and tha support ragion (48) of tha tip (40) has an inntr diameter which is lass than an outtr diamatar of tha support zona (38) of tha shaft (32) by .075 mm to lass. 20. Tha pipatta tip as claimed in claim 19 wherein tha support ragion (48) of tha pipatta tip (40) and tha support zona (38) of tha mounting shaft (32) ara substantially circular and concentric to craata a secondary air tight seal batwaan tha support zona and ragion as the shaft panatratas tha tip. An air displacement pipette (10) having axially spaced annular sealing and substantially cylindrical lateral support zones (36, 38) and regions (46, 48) on the pipette's mounting shaft and tip respectively, in combination with means (52) for insuring uniform depth of mounting shaft penetration into the pipette tip to maintain uniform tip interference with the mounting shaft as successive tips are mounted on and ejected from the mounting shaft whereby the pipette tip is easily and firmly mountable on and easily ejectable from the pipette tip mounting shaft by the application of axial mounting and ejection forces of about two pounds and one pound, respectively.

Documents:

IN-PCT-2001-476-KOL-(03-11-2011)-OTHER PATENT DOCUMENTS.pdf

IN-PCT-2001-476-KOL-FORM 27.pdf

IN-PCT-2001-476-KOL-FORM-27-1.pdf

IN-PCT-2001-476-KOL-FORM-27.pdf

in-pct-2001-476-kol-granted-abstract.pdf

in-pct-2001-476-kol-granted-assignment.pdf

in-pct-2001-476-kol-granted-claims.pdf

in-pct-2001-476-kol-granted-correspondence.pdf

in-pct-2001-476-kol-granted-description (complete).pdf

in-pct-2001-476-kol-granted-drawings.pdf

in-pct-2001-476-kol-granted-examination report.pdf

in-pct-2001-476-kol-granted-form 1.pdf

in-pct-2001-476-kol-granted-form 13.pdf

in-pct-2001-476-kol-granted-form 18.pdf

in-pct-2001-476-kol-granted-form 2.pdf

in-pct-2001-476-kol-granted-form 26.pdf

in-pct-2001-476-kol-granted-form 3.pdf

in-pct-2001-476-kol-granted-form 5.pdf

in-pct-2001-476-kol-granted-form 6.pdf

in-pct-2001-476-kol-granted-gpa.pdf

in-pct-2001-476-kol-granted-reply to examination report.pdf

in-pct-2001-476-kol-granted-specification.pdf

in-pct-2001-476-kol-granted-translated copy of priority document.pdf