Variable focus optical devices, in particular lenses, can include a cavity at least partially defined by a flexible member (2), which may be retained between engaging portions of a frame member (8) and a ring member (12), such that a peripheral region of the membrane is caused to change direction, more than twice. The engaging portions of the ring and frame may be high-friction surfaces. In addition, methods of filling a cavity of a lens with transparent fluid, methods of adjusting the pressure of fluid in the cavity, and methods of sealing such a cavity are described, as well the use of such lenses in adjustable spectacles.

The present invention relates to improvements in the field of variable focus optical devices, in particular variable focus lenses, for example of the type in which the optical power of the lens is variable by varying the volume and/or pressure of a transparent fluid within a transparent envelope.
Variable focus lenses are known and have been described for example in GB 2183059, GB 2184562 and W096/38744. However, to date, despite the many examples of variable focus lenses described in the prior art, none have achieved widespread commercial acceptance as an alternative to fixed-focus ground glass or plastic lenses.
It is believed that the failure of known variable focus lenses to gain commercial acceptance is due to a number of factors. For example, many known such lenses suffer from leakage of the fluid from the envelope in use. Furthermore, many known such lenses suffer from poor optical quality due to the mounting arrangement of the flexible membrane and/or the material chosen for the membrane. A further contributor to the poor optical quality of known lenses has been the fluid selected to fill the envelope, which has had a less than optimal transparency or homogeneity of refractive index. An additional reason for the non-acceptance of known lenses has been their complex and bulky configuration which has lead to a poor aesthetic effect, for example when the known lenses have been mounted in spectacles, and has also increased the cost of such spectacles to a level which is not competitive with traditional fixed-focus lenses.
The present invention seeks to provide a variable focus lens and a method of making a variable focus lens, embodiments of which overcome at least some of the problems of known variable focus lenses, whereby a more commercially attractive product can be achieved. It also seeks to provide eyewear incorporating variable focus lenses.
According to an invention disclosed herein, there is provided a variable locus lens comprising a transparent envelope at least partially defined by a flexible, transparent membrane and containing a transparent fluid, a frame member engaging one face of the flexible membrane and a ring member engaging an opposite face of the flexible membrane, the ring member and the frame member being urged towards each other by retaining means, wherein the respective surfaces of the frame member and the ring member that engage the flexible membrane are substantially complementary and profiled so as to cause a peripheral region of the flexible membrane to change direction more than once.
It has been realised by the applicant that, in order to obtain a high optical quality of the membrane, the membrane should be held under tension at all times. Furthermore, it has been found by the applicant that the membrane, when under tension, and particularly when formed of preferred materials such as Mylar tends to form its own seal against the frame member or ring member.
The profiles of the engaging surfaces of the frame member and the ring member allow the flexible membrane to be retained under tension on the frame member simply by the action of the engaging surfaces. In this way the construction of the variable focus lens is considerably simplified in comparison to known such lenses.
The profiles of the engaging surfaces may be stepped or comprise one or more projections and complementary recess(es). The portions of the engaging surfaces substantially perpendicular to the plane of the unstretched membrane will tend to frictionally engage the membrane as the ring member is urged towards the frame member by the retaining means. Such frictional engagement will tend to stretch the membrane on the frame member, ensuring that the membrane is under tension.
In a particularly advantageous arrangement, the engaging surfaces comprise at least one oblique surface which increases in radial extent towards the frame member. In this way, as the ring member is urged towards the frame member by the retaining means, friction between, the oblique surface of the ring member and the flexible membrane tends to urge the periphery of the membrane radially outwardly, thereby increasing the tension in the membrane, i.e. stretching the membrane.
The ring member and frame member may be of a material or materials which is/are sufficiently rigid to positively interengage with each other and to ensure that the ring member and frame member can maintain the flexible membrane under tension. The material of the ring member and frame member is preferably also lightweight to facilitate the incorporation of lenses described herein in spectacles. Thus, the ring member and frame member may be made, for example, of a high impact resistant plastics material, or of aluminium, or of titanium.
It is generally advantageous to maximise the friction between the engaging surfaces and the membrane, not only to maximise the stretching effect described above, but also to ensure that the membrane is securely held by the ring member and the frame in the assembled lens. Preferably therefore, at least one of the surfaces is a high friction surface.
This in itself is believed to be new and thus according to an invention disclosed herein there is provided a variable focus lens comprising a transparent envelope at least partially defined by a flexible, transparent membrane and containing a transparent fluid, a frame member engaging one face of the flexible membrane and a ring member engaging an opposite face of the flexible membrane, the ring member and the frame member being urged towards each other by retaining means, wherein the respective surfaces of the frame member and the ring member that engage the flexible membrane are substantially complementary and at least one of the surfaces is a high friction surface.
For example, one or more of the frame member and the ring member may be made of a material having a high coefficient of friction at its surface. Alternatively, at least one of the engaging surfaces may have been roughened or expanded to increase its surface friction.
In a preferred arrangement, however, at least one of the engaging surfaces is provided with a coating of high friction material. A particularly preferred material for this coating is rubber or a synthetic elastomer, as this has been found by the applicant to engage well with the preferred materials for the membrane, such as Mylar.
A further advantage of providing at least one of the engaging surfaces with a coating of rubber or synthetic elastomer is that the rubber or elastomer tends to form a high integrity fluid seal at the interface between the engaging surface and the membrane.
Thus, according to an invention defined herein there is provided a variable focus lens comprising a transparent envelope at least partially defined by a flexible, transparent membrane and containing a transparent fluid, a frame member engaging one face of the flexible membrane and a ring member engaging an opposite face of the flexible membrane, the ring member and the frame member being urged towards each other by retaining means, wherein at least one of the engaging surfaces is provided with a coating of rubber or synthetic elastomer.
It has been found by the applicant that the coating need only be thin, in order to achieve an advantageous effect. For example, the coating may have thickness of less than 100 μm, or less than 50 μm, or less than 20 pm or even less than 10 μm.
Preferably, the coating is provided on the engaging surface that engages the face of the membrane which also forms an inner surface of the envelope, so that the sealing interface aids in the containment of the fluid. This surface will generally be provided on the frame member. Of course, both engaging surfaces may be provided with a coating.
The peripheral shape of the ring member, and also of the frame member, may be chosen as required. For example, the members may have a circular, otral, elliptical, or other closed curve, peripheral shape.
The frame member may comprise a rigid transparent window forming a wall of the envelope. The rigid window may be of any suitable material, for example glass, or a plastics material, such as polycarbonate. Indeed, for ease of manufacture, the frame member may be made entirely of such transparent material. Alternatively, the rigid window may form a part of the frame member, for example being bonded to and/or enclosed by an annular frame.
The frame member may be provided with a second engaging surface engaging a second membrane. In this case, a second ring member may be provided with a second engaging surface for engaging the second membrane. The second engaging surface may be opposed to the first engaging surface of the frame member. The second membrane may define a wall of the envelope.
Alternatively, the first ring member may be provided with a second engaging surface engaging a second membrane. Again, a second ring member may be provided with a second engaging surface for engaging the second membrane. The second engaging surface may be opposed to the first engaging surface of the first ring member. The second membrane may define a wall of the envelope.
The first and second membranes may be formed from a single membrane web, although preferably the first and second membranes are discrete.
A duct may be provided through a wall of the envelope, preferable a radially outer wall, which duct is in communication with the envelope. Such a duct will allow fluid to be removed from or introduced to the envelope in order that the volume and/or pressure of the fluid in the envelope may be varied to vary the power of the lens.
The duct may be formed by a pre-formed bore, or drilled, in one or more of the first or second ring members or the frame member.
The duct may be provided with suitable closure means to prevent leakage of fluid from the envelope through the duct. Such closure means may be as described in W096/38744, or may be a rubber or elastomer bung penetrable by a needle of a syringe and capable of self-sealing on removal of the needle. Alternatively, a valve may be provided in the duct, arranged so that the duct is normally closed, but capable of being opened by, for example, the needle of a syringe. In one embodiment, the valve comprises a ball urged by a spring against an annular seat. To vary the pressure of fluid in the envelope, a needle of a syringe or similar is inserted through the centre of the seat, thus displacing the ball. Fluid can be then be introduced into or removed from the envelope to vary the pressure therein. When the needle is retracted, the spring urges the ball against the seat again to close the valve and seal the duct.
It has been found by the applicant that, with preferred transparent fluids such as silicone oil, which is relatively viscous, such a duct must be relatively large in order to enable efficient filling of the lens. One way in which the effective size of such a duct may be increased, is by providing a plurality of ducts in a wall of the envelope.
This in itself is believed to be new, and thus according to an invention disclosed herein, there is provided a variable focus lens comprising a transparent envelope at least partially defined by a flexible, transparent membrane and containing a transparent fluid, and a plurality of ducts provided in a wall of the envelope for introducing fluid into the envelope.
The plurality of ducts may be provided with respective closure means, for example as described above, or may be provided with a single closure means for a plurality of ducts. The ducts may be distributed about the periphery of the lens, but in a preferred arrangement the ducts are proximately grouped.
As an alternative to providing a plurality of ducts, it is possible to provide a single duct having a large cross-section. It will be appreciated that the maximum width of the duct in the direction of the axis of the lens is limited by the thickness of the wall of the envelope which forms the lens. However, the crosssectional area of the duct can be increased by forming the duct such that its width perpendicular to the axis of the lens is greater than its width parallel to the axis of the lens.
The retaining means may be any suitable means, for example screws, clips and the like. Respective retaining means may be provided for each of said first and second ring members.
In a preferred arrangement, the retaining means take the form of a deformable portion of one of the frame member and the ring member, arranged to be deformed, for example crimped, over the other of the frame member and the ring member. In this case, the deformable portion may be of metal, such as aluminium, stainless steel or titanium.
Advantageously, the retaining means may be provided by a pair of spectacles or similar device, into which the lens is to be mounted.
The transparent fluid retained within the envelope may be any suitable fluid, for example silicone oil, such as 703 type silicone oil.
The fluid may be communicated to the envelope by means of a suitable pump, for example a syringe.
However, it has been realised by the applicant that a simple syringe is not ideal as a pump for varying the focus of the lens. One reason for this is that the plunger of the syringe is difficult to control accurately. For example, static friction between the piston and the syringe barrel must be overcome before the plunger moves, such that pressure applied to the plunger tends to build up until the static friction is overcome, at which point the plunger moves relatively rapidly.
Thus, according to an invention disclosed herein, there is provided a pump for a variable focus lens comprising a fluid chamber having an outlet port and a linearly movable member arranged to vary the effective volume of the fluid chamber, wherein locating means are provided for locating the movable member in a plurality of discrete positions.
In a simple arrangement the locating means may be in the form of two stops arranged to limit the movement of the movable member, for example a piston or plunger, to a range having end points defined by respective stops. The end points may correspond respectively to a first predetermined power of the lens, for example for the correction of myopia of a user, and a second predetermined power of the lens, for example for correction of hypermetropia or presbyopia of a user. In this way a bifocal lens may be produced which can be adjusted by the user for reading and close work or distance vision.
The stops may be variable in their positions, for example for initial setting of two levels of power for the lens, and may be lockable in a selected position.
The locating means may comprise a series of locators, for example teeth of a rack or the like, which may be engaged by a suitable mating member, in order that the movable member is adjustable step-wise.
It has also been found preferable by the applicant for users of variable focus lenses, for example users of spectacles incorporating variable focus lenses, to control the focus of the lenses by a rotational movement rather than a linear movement such as that of the piston of a syringe.
Thus, according to an invention disclosed herein, there is provided a pump for a variable focus lens comprising a fluid chamber having an outlet port and means for linearly varying the volume of the fluid chamber in response to a rotational movement of a control member.
The pump may comprise a pinion coupled for rotation with a control knob and engaging a rack coupled for linear movement to a piston provided in the fluid chamber. Alternatively, a piston received within the fluid chamber may be provided on a threaded shaft, the shaft engaging with a complementary threaded collar, such that the collar or the shaft may be rotated to cause the piston to move linearly within the fluid chamber. Alternatively, the interior of the fluid chamber may be threaded, and the periphery of the piston may be provided with a complementary thread such that rotation of the piston causes linear movement thereof within the fluid chamber.
In a presently preferred arrangement, a barrel member is provided having a threaded exterior, circumferential wall, and a fluid port defined in an end wall thereof. The barrel member is received within a cap member provided with a complementary interior thread and an end wall opposed to the end wall of the barrel member. The fluid chamber is defined by the volume enclosed by the connected barrel and cap members. According to this arrangement, as the cap member and barrel member are rotated relative to each other the cap moves away from or towards the end face of the barrel member, thereby linearly increasing or reducing the volume of the fluid chamber. The cap member may optionally be provided with a piston mounted in fixed relation to its end face and received within the barrel member. In this case, the fluid chamber is defined between the end face of the barrel member and the piston, and relative rotation of the barrel member and cap member causes the piston to reduce the effective volume of the fluid chamber.
Locating means as described above may be provided in the context of a rotational control member.
According to an invention disclosed herein, there is provided a variable focus lens in combination with a pump as described herein.
In a preferred arrangement, two variable focus lenses are provided in a spectacle frame. A single pump may be provided, although it is preferred for a respective pump to be provided for each lens, so that each lens is independently variable.
The pump(s) may be provided on the arms of the spectacle frames, for example at the ends of the arms, so that they are hidden by the ears in use.
Channels may be provided in the spectacle frame, for example in the arms, for fluid communication between the lenses and the pump(s).
The pump(s) may be arranged to be detachable from the spectacles, for example permanently detachable after an initial setting operation of the focus of the lenses. The pump(s) may be arranged to be detachable from the spectacles such that when the pump(s) is/are detached the fluid communication channels are automatically closed off, for example by means of a valve.
In a preferred embodiment, a pair of spectacles has two pumps, one for each lens, with each pump being removably attached to an arm of the spectacles. Fluid communication between each pump and its respective lens is achieved by means of flexible tubing extending from the pump to the lens. The flexible tubing is received in a channel in the frame of the spectacles for at least part of its length. When the user has set the focus of the lens, the tubing is closed and cut, and the pump and the portion of the tubing attached thereto is detached and discarded.
In one particularly preferred form, a part of the tubing connecting the lens and the pump is received in a channel formed in the main frame of the spectacles, preferably in the side facing the user. The tubing projects from this recess beyond the side of the spectacles to join the pump attached to the arm of the spectacles.
The tubing can be closed in any suitable manner. However, it is preferred for the tubing to be clamped closed, for example by means of a screw urging the sides of the tubing together. In a preferred form, a screw is provided in a passage in the frame of the spectacles, perpendicular to and intersecting the channel in which the tubing is received. On the opposite side of the channel from the screw is a member which extends across the channel in the form of a bridge. When it is desired to close the tubing, the screw is screwed into the passage, and the end of the screw compresses the tubing against the member to close it. The part of the tubing which projects beyond the end of the channel can then be removed, for example by cutting it so that its end lies flush with the side of the frame.
In a particularly preferred embodiment, the member is formed by a part of the hinge attaching the arm to the main frame. This helps to retain the tubing in the channel, and avoids the need to provide a separate member.
As an alternative, the tubing could be closed by compression means other than a screw. For example, the frame may be provided with a button, which when depressed compresses the tubing against a member to close it. The button pay be arranged such that it latches when it is depressed, to ensure that the tubing remains closed. In addition, the button can be provided with means for retaining it in its original position, to prevent accidental operation. These means may take the form of a protuberance on the button, which fits into a corresponding recess in the frame.
In addition, means can be provided in the spectacles to allow the tubing to be cut. For example, a button carrying a blade may be provided, the blade severing the tubing when the button is depressed. This button may be provided separately; however, it is preferred that the button which closes the tubing and the button which cuts it are combined, so that the tubing can be closed and cut in a single movement. This simplifies the process of setting the spectacles to a desired focus.
As mentioned in W096/38744, the lenses can be pre-filled with fluid during their manufacture. The pumps then need only contain a sufficient amount of fluid to allow the adjustment of the focus of the lenses.
It will be appreciated that it is very important for the lens to be completely filled with fluid, with no air bubbles in the lens. The presence of air bubbles is extremely distracting for the wearer of the spectacles.
A number of approaches can be taken to filling the lens so as to avoid the presence of air bubbles in the filled lens. For example, in one method which has proved effective, some of the air in the envelope of the lens is first sucked out, and then a similar amount of fluid is injected. The cycle of air removal followed by fluid injection is then repeated as necessary until the lens is filled with fluid.
In an alternative method, a needle whose external diameter is less than the internal diameter of the duct is used to inject the fluid. The gap between the needle and the needle allows air in the lens to escape as fluid is injected. Fluid can still be injected through the needle while it is being withdrawn from the duct.
It is also preferred for the fluid used to fill the lens to be degassed prior to filling, to reduce. the chance of bubbles forming in the lens after filling.
Filling the lens will normally involve injection of a relatively viscous fluid through a narrow passageway. The filling process can be facilitated by heating the fluid prior to injection, so as to reduce its viscosity.
The variable focus lens described herein may be provided with at least one transparent, protective cover for the or each flexible membrane. The cover may be, for example, a rigid sheet of transparent material, for example glass or a plastics material such as polycarbonate. The protective cover may be mounted, for example bonded, to the ring member or the frame member.
As mentioned above it has been found by the applicant that in order to obtain a desired optical quality of a variable focus lens it is important that the membrane is maintained under tension. For this purpose it is advantageous to form the membrane from a heat-shrinkable plastics material.
Thus, according to an invention disclosed herein, there is provided a method of making a variable focus lens having a flexible, transparent membrane supported in a frame, wherein the membrane is heat treated while held in the frame to increase the tension in the membrane.
It has been found by the applicant that, at least with preferred materials for the membrane, e.g. Mylar, heat treatment of the membrane causes the membrane material to contract and thereby increase the tension in the membrane.
The membrane may be treated using any suitable source of heat, and in a preferred arrangement the heat is provided by a source of hot air, such as a hair dryer, a hot air gun or a fan heater.
According to an invention disclosed herein, there is provided a method of making a variable focus lens having a flexible, transparent membrane supported in a frame, wherein the membrane is pre-tensioned, and the frame is mounted to the membrane while the membrane is pre-tensioned. In this way, a convenient method of ensuring that the membrane is in tension on the frame is provided.
Any suitable means may be provided for pre-tensioning the membrane. For example, the principles for tensioning the membrane disclosed in GB 2184562 and 2183059 may be applied in this novel way to the pre-tensioning of the membrane.
The frame may be a frame as disclosed elsewhere herein.
The variable focus lens described above is of course suitable for use in spectacles. However, it can also be used on any form of eyewear where it may be desired to incorporate corrective optics, including but not limited to sunglasses, swimming goggles, skiing goggles, squash glasses, sports eyewear in general, welding masks, welding goggles, laboratory goggles, and protective eyewear in general. The lens may be provided as an insert, or may have means for attachment to the outside of the eyewear.
If the lens is to be used in sunglasses, then the material of the membranes or the fluid itself could be tinted. Further, it is possible to use metallized. Mylar, which reflects a portion of the light. incident thereon and transmits the remainder, as the material of the outer membrane, thereby providing reflective sunglasses.
The lens described and illustrated herein may be utilised in an optical apparatus constructed and arranged to be adjusted as described and claimed in W096/38744.
The lens shown in FIG. 2 comprises first and second transparent, flexible membranes 2 which are tensioned and which define therebetween an envelope 30 in which a transparent fluid 4, such as silicone oil, is contained. In the embodiment illustrated the membranes 2 are of Mylar, for example, 23 μm Type D Mylar.
The membranes 2 are held in tension by a support 6. The support 6 defines the periphery of the lens, and of the envelope 30, and is arranged to hold the flexible membranes 2 under tension. The support 6 is also arranged to seal the lens.
As can be seen from FIG. 1, the support 6 is formed by interengaging a frame member 8 and first and second ring members 10,12 of aluminum. In this respect, the frame member 8 has a radially extending flange 14 which is stepped as indicated at 16. The frame member 8 also has an axially extending rim 18. The first ring member 10 has a radially outwardly projecting portion 20 defining a first step 22 which cooperates with the step 16 of the frame member 8 and a second step 24 which cooperates with a step 26 of the second ring member 12. The second ring member 12 has a recess 28 arranged radially outwardly therein.
Where the completed lens is to have a generally circular periphery, for example, a first membrane 2, which is circular, is positioned to extend within the frame member 8 such that its periphery extends along the radial flange 14 thereof. The first ring member 10 is then supported within the frame member 8 such that the complementary steps 16 and 22 thereof interengage. This interengagement positions the first ring member 10 relative to the frame member 8. The interengagement also bends the peripheral circumference of the first membrane 2 through two different directions as is clearly shown in FIG. 1.
A second circular membrane 2 is then positioned across the frame member 8 such that its periphery extends along the upper radially extending surface of the first ring member 10. Thereafter, the second ring member 12 is positioned such that the steps 24 and 26 of the first and second ring members 10,12 cooperate to retain the second ring member 12 in position within the frame member 8, and to bend the periphery of the second membrane 2 through two directions. The tolerances of the members 8,10,12 are chosen such that even when the arrangement is in the interengaged position shown in FIG. 1, the two membranes 2 are firmly held by the interengaged members.
The construction has the considerable advantage that the circular membranes 2 do not have to be produced to close tolerances. Each circular membrane 2 can be cut to be generally circular and to have a diameter which is somewhat larger than is required. In its turn, each membrane 2 is positioned as described above and held by the interengagement of the corresponding ring members 10, 12. Any excess material of the membrane 2 can then be trimmed simply using a knife with the ring members 10,12 acting as guides.
To complete the construction of the lens it is necessary to ensure that the frame member and the first and second ring members 8,10,12 are secured together such that the peripheries of the membranes 2 are firmly retained to seal the lens and to prevent any leakage from the envelope 30 defined between the two membranes 2. In the embodiment illustrated, the retention of the membranes 2 is achieved by crimping and deforming the frame member 8. In this respect, the upstanding, axially extending, free end of the limb 18 of the frame member 8 is bent over to be received within the recess 28 of the second ring member 12. Any excess material deformed from the ring 8 during this crimping operation is received within an annular space 32 which is defined between the radially outward peripheries of the first and second ring members 10 and 12, and the inner periphery of the limb 18 of the frame member 8.
Once the lens has been constructed, as shown in FIG. 1, and with the frame member 8 deformed to secure the structure, a duct 34 is drilled through the frame 6 into the envelope 30. The envelope 30 can then be filled with the transparent fluid 4 through the duct 34. With 703 silicone oil as the fluid, the resultant lens achieves a focal length range of at least −6 to +10 dioptres, and the range −10 to +10 dioptres should be achievable. Of course, it will be appreciated that, in an alternative embodiment, the rings are formed with ducts before they are assembled.
Fluid may be introduced into the envelope 30 by way of the duct 34 and retained therein by use, for example, of ducts, plugs and sealing means as described in W096/38744. In an embodiment, the lens is pre-filled at this stage with the fluid 4 and an appropriate material is provided in the duct 34 to seal the envelope 30. However, the material sealing the duct 34 is preferably penetrable by a syringe, for example, so that the pressure of the fluid 4 within the envelope 30 can be adjusted. As an alternative, a self-sealing valve could be positioned in the duct, as described above.
In the embodiment shown, the two axially outer surfaces of the lens are each protected by a sheet 36 of a polycarbonate. Each polycarbonate sheet 36, for example, may be about ½ millimetre thick. It will be appreciated that these sheets 36 are arranged to extend substantially parallel to each other. The circumferential periphery of each of the sheets 36 may be fixed to the annular frame 6 in any appropriate manner. For example, the sheets 36 may be adhered to the frame 6. Additionally and/or alternatively, a plastics material frame (not shown) of a pair of spectacles, for example, may be arranged to receive the annular frame 6 in a manner to retain the sheets against the annular frame 6 in the position of FIG. 2.
FIG. 3 shows a fluid-filled lens according to a different arrangement. In this case there is only a single ring member 12 which has an oblique engaging surface 38 complimentary to the oblique engaging surface 40 of the frame member 8. A single flexible, membrane 2 is held between these engaging surfaces 38,40, which are urged together by retaining means in the form of a crimped limb 18 of the frame member 8. A wall of the envelope containing the transparent fluid 4 is provided by a polycarbonate window 42 received by the annular part 44 of the frame member 8.
FIG. 4 shows a pump for a variable focus lens in the form of a modified singe having a barrel 45 and a piston 48 mounted on a piston rod 50. The piston rod 50 is provided along one side with a rack of teeth. A collar 52 is clipped to the rim of the barrel 46 and the shaft 50 passes through a central aperture defined in the collar. A tooth of the collar projects into the aperture and engages the teeth of the shaft 50, such that the shaft 50, and hence the piston 48, is movable step-wise through a series of discrete locations defined by the teeth of the shaft 50.
Stops 56 are clipped to the shaft 50 and have complementary teeth which engage the teeth of the shaft 50 and maintain the stops 56 in position relative to the shaft. The stops 56 engage the collar 52 when the shaft 50 is at either end of the range of movement defined by the stops 56.
FIG. 5 shows another pump for a variable focus lens. The pump comprises a cylindrical barrel 58 with a threaded exterior and cap 60 with a complementary threaded interior engaging the thread of the barrel 58. Between the barrel and the cap is defined a fluid chamber 62. As the barrel and cap are rotated relative to each other the effective volume of the fluid chamber 62 is varied Bo that fluid can be forced out of or sucked through a fluid port 64 defined in an end face of the barrel 58.
FIG. 6 shows a further pump use with a variable focus lens. Again, this pump is in the form of a modified syringe, having a barrel 70 and a piston 72 mounted on a piston rod 74, which has a rack 76 of teeth on one side. Passing through the barrel is an axle 78, on which a pinion gear 80 is mounted. The pinion 80 meshes with the rack 76. Attached to an end of the axle, which projects beyond the barrel, is a wheel 82 (partly shown in phantom), which can be rotated by a user. Rotation of the wheel 820 in turn rotates the pinion 80, which drives the rack 76 and thus moves the piston 72 in the barrel 70. Fluid can thus be forced out of and sucked into the barrel, to vary the pressure in the lens, simply by rotating the wheel. Of course, other forms of gearing can be used to link the wheel to the piston rod.
FIG. 7 shows a part of a pair of spectacles 100 employing two variable focus lenses. As will be seen, one of the lenses 102 is connected to a pump 104, removably attached to an arm 106 of the spectacles, by a length of tubing 108. The other lens is also provided with a pump in an analogous manner. The pumps can be of the form described above, although it will be appreciated that any suitable form of pump can be used.
The area of attachment between the main frame 110 of the spectacles and the arm 106 is shown in more detail in FIG. 8. It will be seen that the tubing 108 extends from the lens through a channel 112 formed in the frame 110 and open towards the rear (ie the side facing the wearer) thereof. Part of the hinge (shown schematically as 114) is fixed to either side of the channel, and extends across it in the manner of a bridge.
The frame also includes a threaded passage 116, as shown in FIG. 9, which accommodates a screw 118. The threaded passage 116 opens into the channel 112, and is aligned with the part 114 of the hinge which bridges the channel.
In use, the pressure inside the lens, and thus its focus, is adjusted by means of the pump 104. When the desired focus has been achieved, the screw 118 is screwed into the passage 116 to close the tubing 108. In particular, the end of the screw 118 clamps the tubing 108 against the part 114 of the hinge which bridges the channel. The screw is preferably screwed in and out by means of an Allen key, although of course any form of screw may be used.
Once the tubing 108 is clamped closed, the pump 104 is detached from the arm/106 of the spectacles, and the tubing is cut as indicated at 120, flush with the edge of the frame 110. The same process is repeated for the other lens.
An alternative arrangement for closing and cutting the tubing 108 is shown in FIG. 10. Here, the tubing is closed by means of a projection 122 attached to a button 124, which slides in an opening in the frame. When the button 124 is depressed, the projection 122 presses the tubing against the part 114 of the hinge of the spectacles, thus closing it. The button can be provided with means to latch it in its closed position, as shown at 126 and 128. The button can also be provided with means (not shown) to retain it in its original position until it is pressed.
In addition, the button 124 can be provided with a blade 130 for cutting the tubing. The blade 130 and tubing 108 are arranged such that the blade only cuts the tubing after the tubing has been closed by the projection 122. A single depression of the button thus serves to close the tubing and cut it.
The button 124 has been shown in the front face of the frame 110 of the spectacles. However, it will be appreciated that it could also be arranged in the top face of the frame of the spectacles. The member would then bear against a side wall of the channel 112 to close the tubing.
The features described herein may be used either separately or in any suitable combination. It will be appreciated that alterations and modifications may be made to the embodiments described and illustrated herein within the scope of this application.
For example, although the much mention has been made herein of variable focus lenses, the advantageous features described herein may also be applied to other optical devices. For example, by providing a suitable silvered surface in the lens described herein, a mirror of variable focus may be/manufactured in accordance with the present disclosure. The silvered surface may be applied to the flexible membrane, or may be applied to a rigid surface viewed through the flexible membrane. Of course, in the case of a silvered flexible membrane, it is not necessary for the fluid within the envelope to be transparent, as light is not required to pass through it in use. Indeed, the optical properties of the fluid in this case are irrelevant and the fluid may be opaque.


A paint activity tray has a first section with a workspace at least partly surrounded by a channel for holding excess water and a second section with recesses holding containers for water and watercolor paint blocks. A container with a handle holding paint brushes to drip dry is provided in one embodiment. The paint activity tray protects surrounding area from spills and drips since all of the components for making a watercolor painting are contiguous, and the containers for water and paint are securely held in recesses of the tray.

The present invention relates generally to the field of children""s activity toys and in particular to a new and useful paint tray activity desk for reducing messes associated with paints and being easier to clean after use.
Watercolor paints are a source of enjoyment and creativity for children in particular. Watercolor paints are good for use by children because they usually do not require more than washing with water or wiping with a damp cloth to clean a child who deposits some of the paint on their body instead of a sheet of paper or other suitable substrate.
But, watercolors can still be messy. A cup or other container of water is usually needed to dip a brush in to both activate a watercolor paint pigment and clean brush for use with a different color. Thus, the container can be tipped and spilled, or drips will occur as the brush is moved from the water to the paints and to the substrate.
Activity toys or sets for children sometimes include paints. One known activity toy including paints is a paint-by-numbers kit. U.S. Pat. No. 4,416,632 describes one such paint-by-numbers kit having a plurality of paints in aligned recesses of a tray in combination with substrate bearing a line drawing picture. The tray includes a shelf with printed numbers on one side; each number identifies one of the paints. The picture has corresponding printed numbers indicating which one of the paints is used to color an area of the picture. A single brush is provided with the kit for depositing the paints on the picture. The tray includes two cradle holders extending from the shelf for holding the brush.
Paint-by-numbers kits like that of U.S. Pat. No. 4,416,632 do not include any support for the substrate bearing the line drawing picture. Further, as is usual for these kits, neither of the paint tray nor the water container disclosed by the patent include structure for catching water drips or spills. It is common to spread newspapers or other protective layers of paper below the substrate to prevent messes or damage from spilled paints.
Other painting toy sets simply include a tray of watercolor paint pigments in solid form within indentations on the tray. Some paint sets include a brush with the paint tray. To use the paints, the brush is wetted in water, and used to activate the pigments in one or more of the trays. Color is picked up on the brush, and used to paint on a sheet of paper or other substrate. The brush is cleaned by dipping in water. Typically, only one brush having a plurality of elongated bristles bound in a cylinder is provided in such paint sets.
U.S. Pat. No. 5,318,171 discloses a watercolor paint kit having several brushes of varying sizes, a paint block holder containing several blocks of paint pigment, and a water tray. The kit is provided as a case which can be folded closed for carrying. The brushes are provided for wetting on a cover sponge of the water tray, contacting one or more of the paint blocks to pick up color, and then making a painting on a suitable substrate. The brushes are formed from blades covered by a layer of foam. The brushes are sized so that a different number of the paint blocks is contacted at once by each of the brushes, thereby picking up one or multiple colors, depending on the brush width.
The kit of U.S. Pat. No. 5,318,171 does not include a substrate, or any area for holding a substrate, being painted. The paint blocks can be separated from the adhesive holding them in their respective slots for replacing, but the paint block holder and the water tray are both fixed in the kit and are not removable. Thus, to clean the holders in the kit, the entire case must be cleaned at once.
It is desirable to have an activity kit which includes a workspace that helps prevent water and paint from dripping or spilling onto other surfaces. No children""s activity kits are known which include a mess prevention workspace or an easily cleaned workspace, as well as holders for paints, brushes and water.
It is an object of the present invention to provide a self-contained paint tray kit for reducing messes and making cleanup after use easier.
Yet another object of the invention is to provide a children""s activity desk having a mess prevention workspace integrated with tool and material supply holders.
A further object of the invention is to provide an easily cleaned art activity desk having removable tool and supply holders combined with a workspace.
Another object of the invention is to provide a paint tray kit which forms a unitary work space area, but is easily separable into component parts for cleaning or storage.
Accordingly, a children""s paint tray activity desk of the invention has a base tray with distinct areas for removable tool and supply holders, and a workspace. The workspace holds a piece of paper or other suitable substrate for applying watercolor paints to make a picture. The workspace is surrounded by a channel, or moat, inside the tray. The sides of the workspace are designed to permit excess water to naturally drain from the workspace into the channel. The workspace may be sloped slightly toward drain holes in the workspace sides to encourage water to drain into the channel.
The tool and supply holders include a water reservoir, a paint tray and a drip tray. Each of the tool and supply holders has a handle extending over the top with slots for receiving brushes, squeegees, rollers, sponge brushes, or other painting tools. One or more of the brushes, squeegees, rollers, sponge brushes or other tools are provided with the activity desk. The brush and tool handles may each have a groove for mating with the holder handle slots and making a more secure fit.
The base tray is preferably unitary, but may be separable into one section containing the removable tool and supply holders, and a second section with the workspace and surrounding channel. In this embodiment, the sections are preferably locked together during use to form a single activity desk. Separable embodiments of the base tray are more easily stored or carried on car trips while providing the same benefits of the unitary tray construction when assembled.
In an alternate configuration of the activity desk, only a paint holder and water supply reservoir are removably held in recesses in the base tray. A workspace is provided adjacent the paint holder and water reservoir recesses, with a channel around the front and one side of the workspace.
In a further alternate construction, the base tray has a ridged lip surrounding a flat, level workspace, but no drain. The ridged lip contains the excess water until the base tray is cleaned. The tool and supply holders may be supported in an integral portion of the base tray or a detachable second section.
Many different brushes and other paint applicators are available for use with the invention. Brushes include conventional bristle brushes, sponge brushes of different shapes and texture, squeegee brushes, or wiper blades, and rollers may all be used with the activity desk of the invention. The brushes are sized to have different widths, so that a varying number of colors of paint will be picked up when a wet brush is rubbed on the aligned paint blocks in the paint holder. For example, some brushes may be one paint block wide, while others may be two, three, four or more paint blocks wide.
The paint blocks of the invention are supported within the paint holder with the lower surface of the paint blocks held above the bottom of the paint holder. The spacing improves the life of the paint blocks, as excess water used to activate the paint blocks does not erode the block bottoms. The paint blocks are preferably removable from the paint holder for cleaning or rearranging the color order. The paint blocks are removably supported directly by the paint holder or are supported in individual cartridges removably connected with the paint holder.
When using wider brushes with the invention, a child can make rainbow type pictures with multiple colors at once on a paper held in the workspace. Plaid patterns are easily made using wider brushes to paint intersecting lines of multiple colors. At the same time, excess water is kept almost entirely within the confines of the activity desk by the base tray walls, the channel or moat around the workspace, and the contiguous water reservoir, paint holders and drip tray. The child has no need to pass the brush over any area other than the activity desk and its components.
Cleaning the activity desk is easy, as the water reservoir, paint holders and drip tray are all removable from the base tray, so that they can be emptied into a sink or other drain without having to lift the entire tray at once. Further, the paint blocks can be lifted from the paint holder to even more easily clean the paint holder and also extend the life of the paints. The components can be individually washed, if desired, and then replaced in their recesses in the tray.
The various features of novelty which characterize the invention are pointed out with particularity in the claims annexed to and forming a part of this disclosure. For a better understanding of the invention, its operating advantages and specific objects attained by its uses, reference is made to the accompanying drawings and descriptive matter in which a preferred embodiment of the invention is illustrated.


Catalytic monoclonal antibodies (abzymes) with selective protease activity in the pathologies characterized by the presence of plaques and fibrillar aggregates with protein component; methods for the preparation thereof and the use thereof as medicaments in the treatment of pathologies such as Alzheimer""s disease, amyloidosis, atherosclerosis, prions diseases.

The present invention relates to catalytic monoclonal antibodies, in particular with protease activity, for the selective lysis of the protein component of plaques and aggregates related to pathological conditions.
Alzheimer""s Disease
Alzheimer""s disease (AD) is a degenerative disease which affects central nervous system, mainly at the level of those areas related to the intellectual functions, causing necrosis of the neuronal cells and, as a consequence, the progressive loss of cognitive, mental and mnemonic abilities of the concerned patients with inevitably fatal outcome.
AD, which can be diagnosed definitely only by autopsy, is characterized by pathological structures which can be distinguished in:
senile or amyloid plaques, localized in the extracellular space, which deposit in the brain and in the walls of cerebral blood vessels;
neurofibrillar tangles localized inside the cells.
The formation of said structures causes a remarkable loss of neurons in neocortex, hippocampus and other related structures, with a great reduction of the neurotransmitter concentration. Said effects are due to the toxicity determined both directly and indirectly by the cited neuro-pathological structures and the neuron death results, in its turn, in the progressive loss of the cognitive capacities.
The anatomic-pathological structures cited above consist of specific components:
1xe2x80x94xcex2-amyloid Peptide (Axcex2, A4, A4xcex2, xcex2,xcex2-peptide), which derives by the processing of the amyloid precursor protein (xcex2APP), and is a mixture of a small group of peptides, 28 to 43 amino acid long, arranged in planar sheet structures.
2xe2x80x94Apolipoprotein E (Apo E)
3xe2x80x94Protein tau.
Axcex2 peptide is the main component of amyloid plaques; at least two different forms of plaques exist, which are likely to represent two subsequent steps of the Axcex2 polymerization process:
a) diffused or preamyloid plaques, which consist of amorphous, non Congo-philic deposits of insoluble Axcex2, with few amyloid depositions, containing few reactive astrocytes or microglia; these are usually localized in brain""s gray matter and apparently do not cause remarkable effects on the adjacent tissues;
b) senile or neuritic plaques which consist of a core of fibrillar, Congo-philic deposits of Axcex2, containing reactive astrocytes or microglia and surrounded by degenerative, dystrophic neurites
Protein tau associated with microtubules, in the hyperphosphorylated form, is the major component of the neurofibrillar tangles. These are usually formed by paired helical filaments (PHF) which, in their turn, derive from microtubule associated: proteins (MAPs) and consist of an abnormal accumulation in the degenerative neurons of cytoskeletal proteins with specific biochemical and antigenic properties. Under normal conditions MAPs probably regulate movement and stabilize the arrangement of neurons during the growth of axons and of dendrites.
ApoE is present in combination with the amyloid plaques, with the neurofibrillar forms and with the amyloid deposits of cerebral vases. ApoE could play a biochemical role in the development of AD, related to its capability of binding Axcex2. ApoE supposedly plays the role of molecular carrier and it could assist in sequestrating Axcex2 in the plaques.
Early AD genetic analysis revealed mutations of some genes on different chromosomes.
In correlation with the characteristic presence of Axcex2, a mutation of the gene which codifies for xcex2APP has been identified on chromosome 21, at the levels of codons 717 and 670/671. A punctiform mutation at said levels can change the xcex2APP processing, preventing the physiological cleavage in non-aggregating peptides and favouring, on the contrary, the amyloidogenic pathway. It should, however, be noted that only a small percentage of early cases of familial AD (4-5%) has been related to mutations on chromosome 21.
A second mutation strictly related with familial, early AD, has been identified on the long arm of chromosome 14. On the involved gene, named S182, at least 15 different mutations were detected, related with familial AD, said mutations appearing in 80% of the early AD cases. The product of gene S182 is a membrane integral protein, whose function has not yet been clarified.
A third gene, whose mutation is related with about 15% of the cases of familial early AD, is localized on chromosome 1 and is named STM2. The function of the protein codified by said gene is not yet known, but it seems to cause an increase in the production of xcex2 amyloid.
As far as senile AD is concerned, this could be the result of oligogenic mutations. This has been observed to be related to mutations on chromosome 19, in particular against the gene encoding for ApoE.
xcex2APP is a transmembrane glycoprotein (695-770 aa) which for the most part protrudes in the extracellular space. The physiological processing of xcex2APP consists in the cleavage by the enzyme xcex1-secretase within the Axcex2 sequence, immediately outside the transmembrane region (aa 16), with formation and release of (AAPs) amyloid soluble forms in the extracellular fluid. The action of xcex1-secretase, therefore, prevents the formation of Axcex2. The amino acid sequence of xcex2APP corresponding to Axcex2 is localized in part in the extracellular space and in part in the membrane (the 28 aa from the amino-terminal to the transmembrane single domain of the precursor, plus the first 11-15 residues of the transmembrane domain). The xcex2APP expression and APPs release are modulated by neurotrophic factors and by cytokines. The expression of xcex2APP increases when the neuronal differentiation takes place and APPs can affect the neurite growth and neuron survival in cell cultures. The function of xcex2APP is not clear: apparently it can play an adhesive/receptor role and be involved in synaptic plasticity. APPs control [Ca2+]i and modify the Ca2+ response to glutamate. APPs are transported along the axon and are then released in the synapses by the growing axon cones and by the axon terminals.
In short, the functions of xcex2APP and of APPs are:
regulation of cell proliferation in non-neuronal cells,
cellular adhesion,
promotion of neuron survival,
protection from excito-toxycity or from ischemic damages,
regulation of neuron growth,
regulation of calcium intracellular levels.
When the degradation of xcex2APP does not take place physiologically, either due to the presence of the punctiform mutation or to the attack by enzymes different from xcex1-secretase or to an excessive production of xcex2APP, amyloidogenic fragments form, i.e. insoluble fragments of Axcex2, with a planar xcex2-sheet structure, aggregate in more and more complex fibrous formations until insoluble extracellular amyloid plaques are formed (Cummings, Neuroscience 48:763 (1992); Kuo, Neurobiol. Aging 14:547-560 (1993)).
In the core of neuritic plaques, a prevalent Axcex2 form 42 amino acid long has been identified, namely Axcex21-42 (Rohrer, Proc. Natl. Acad. Sci. 90:10836-10840 (1993); Gravina, J. Biol. Chem. 270: 7013-7016 (1995); Motter, Ann. Neurol. 38: 643-648 (1995); Cummings, Neurobiol. Aging. 17: 653-659 (1996). This fragment, besides being the major component of amyloid plaques, is, among the various fragments, the one with the highest amyloidogenic characteristics, i.e. it is highly capable of associating in more and more complex aggregates and of forming fibrils. A more hydrophobic domain has, in fact, been evidenced on the Axcex21-42 molecule which seems to be critical for the assemblage of amyloid fibrils, in that it increases the aggregation rate thereof (Pike, J. Neuroscience 13:1676 (1993); Axcex21-42 could therefore play a more important role than the shorter fragments in the formation of plaques. Following the formation of the first fibrillar aggregates consisting of Axcex21-42, other shorter fragments also aggregate in the plaques; Axcex21-42 would therefore serve as a nucleation core for the aggregation.
Axcex21-42 is deposited early and selectively in the senile plaques and this is a steady characteristic of all of the AD forms. Axcex21-42 aggregates in fibrils and, already at this stage, i.e. before the fibrils are deposited in the amyloid plaques, the fibrils themselves can start the neurodegenerative process and also induce hyperphosphorylation of protein tau. The C-terminal amino acid is apparently critical for the aggregation of the peptide (Jarrett, Biochemistry 32:4693-4697 (1993).
A direct relationship exists between peptide aggregation and neurotoxic potentiality. Axcex2 has, in fact, a direct toxic effect on in vitro human neurons and such toxicity is directly proportional to the aggregation state. Axcex2 accumulates in or on the plasmatic membrane (it is incorporated in the double lipid layer) wherein it forms selective flow channels for Ca2+, thereby causing a structural change in the plasmatic membrane, with formation of specific channels altering Ca2+ permeability. The ionic channels canal activity would therefore be at the bottom of Axcex2 neurotoxic effect.
The effects of Axcex2 can thus be summarized:
alteration of neurite growth,
increase in neurons vulnerability to excitotoxicity,
destabilization of the neuronal calcium homeostasis,
toxicity consequent to aggregation,
formation of pores for Ca2+ transport in the membrane,
promotion of the release of pro-inflammatory cytokines.
At present, no pharmacological therapies against AD exist. The only marketed medicament bearing said indication is Tacrine (INN), an acetylcholinesterase inhibitor, whose pharmacological activity is based on the block of the catabolism of the neurotransmitter acetylcholine.
The current therapeutical approaches based on xcex2 peptide turn to different strategies:
inhibition of the enzymes involved in the amyloidogenic pathway (xcex2-secretase),
products which either block Axcex2-induced neurotoxicity or stabilize neuronal cells preventing their sensitization to intracellular calcium,
Axcex2 ionic channels blockers or modifiers,
compounds inhibiting Axcex2 aggregation, even modifying the hydrophobic domain which apparently causes the amyloidogenic properties.
Atherosclerosis
Atherosclerosis is an extremely complex and variable pathology wherein some components of different nature deposit in plaques adhering to the intima of blood vessels. Said formations cause a local damage to the vessel and an increase in the circulatory resistances with a consequent pressure increase, as well as a decrease in the blood afflux to organs and tissues and therefore a functional decompensation.
Histologic characterization of the atherosclerotic plaques has not yet completely been defined: the parameters responsible for the evolution of the plaque, the mechanisms of formation and the evolution stages are still partly not clear and vary depending on determinant factors such as age, sex, diet and environment. The study of morphology and composition of complex atheromatous plaques, extracted from patients subjected to peripheral surgery, showed a remarkable heterogenicity in the chemical/biological composition of the aggregates: some formations mainly consist of lipoproteins and lipids, others of inflammation cells, others of fibrous capsules, others, most complex, of neo-formed vases.
On the other hand, the early formation stages of the atheromratous plaques have apparently some common characteristics: in particular, the presence of lipoproteins of the LDL group (Hoff HF et al. J. Lipid Res 34: 789-798 (1993); Srinivasan SR et al. Atherosclerosis 38: 137-147 (1981); Piotrowski JJ Life Sci. 58: 735-740 (1996)) seems to represent a common structural characteristic of atheromatous plaques in the early stage of deposition.
Westermark and colleagues (Am. J. Pathol. 147: 1186-1192 (1995) evidenced that amyloid deposits in aorta intima are very common in combination with atherosclerotic pathologies and aging. These researchers purified a fibrillar protein present in the extracellular deposits from patients with atherosclerosis: said protein is the N-terminal fragment 69 amino acids long of apolipoprotein A1.
At present, no effective pharmacological therapies for the treatment of the early phases of the formation of atheromatous plaques exist. Whereas surgery is the choice strategy when complex, evolved plaques are present, the patients known to be disposed to atherosclerosis cannot receive suitable preventive therapies.
Amyloidosis
Monoclonal gammapathies or plasma-cell dyscrasias are a group of clinically and biochemically different. diseases characterized by the abnormal proliferation of a cell clone normally involved in immunoglobulins synthesis.
The immunochemical characteristic of these diseases is the presence of structurally and electrophoretically homogeneous (monoclonal) immunoglobulins or of polypeptidic subunits thereof in the patient""s serum or urines.
Some of these conditions are asymptomatic and apparently stable, others, such as multiple myeloma and amyloidosis, are progressive and fatal.
The etiology of monoclonal gammapathies is unknown.
Amyloidosis consists of a group of biochemically and clinically heterogeneous conditions, which are usually characterized by the deposition of proteins in fibrillar form in the tissues. Such an accumulation causes functional damage to the involved organs with an often fatal outcome.
More particularly, AL amyloidosis is due to the deposition of fibrils formed by fragments of immunoglobulin light chains. This amyloidosis is distinguished in primary amyloidosis, if the plasma-cell clone is not very large and amyloidosis associated with multiple myeloma.
AL amyloidosis is one of the most serious plasma-cell dyscrasias for which no effective treatments exist. The progress of the disease is quick and fatal, with a mean survival of only 12 months.
Prions Diseases
The term prion was brought in to define a class of particles responsible for the transmission of some neurodegenerative diseases such as Creutzfeld-Jakob disease; kuru, Gerstmann-Straussler-Scheinker (GSS) syndrome, familial fatal insomnia (FFI), bovine spongiform encephalopathy (BSE).
This type of pathologies is characterized by the accumulation in brain of a protease-resistant protein (PrPres), deriving from a protease-sensitive protein (PrPsen) of 33-35 kDa. The amino acid sequence of the two proteins is the same and they differ in the conformation. The clinical signs of the diseases coincide with the structural modification from PrPsen to PrPres, with accumulation of the latter in fibrillar structures. The histopathological characteristic of the nervous tissue from patients with prion diseases is, in fact, the presence of crystalline aggregates with a spherical structure localized at the post-synaptic evaginations. In crude brain extracts from infected rodents, fibrillar structures with a well defined morphology have been identified: two types of fibrils exist, formed by two or four helical sub-filaments; the rotation progress of the sub-filaments as well as the space among them are regular. This characteristic microscopical structure allows to distinguish between the aggregates present in prions diseases and those characterizing other diseases with plaque accumulations, such as Alzheimer""s disease. Prions are highly resistant to protease action and they are usually inactivated by chemical and physical means.
Some monoclonal antibodies are capable of catalysing chemical reactions involving components recognizable by the antibody itself. Catalytic monoclonal antibodies are named abzymes and are usually prepared by using as antigen the stable analogue of the transition state of the reaction to be catalysed by the abzyme itself.
For the preparation of abzymes with protease activity, the analogue of the transition state of the peptide bond between two selected amino acids is usually employed, i.e. a dipeptide analogue; on the other hand, an abzyme with a specific protease activity is obtained this way, and any proteins containing said dipeptide in its own sequence can be the target of the abzyme. To increase the antibody specificity, attempts to use immunogens in which no more than 8 amino acids linked to the dipeptide analogue are present have been made. Also in this case, however, the resulting specificity and selectivity could not assure the absence of cross reactions between the abzyme and other protein molecules different from the target.
Moreover, abzymes have up to now been produced for the purpose of increasing reaction rates. On the contrary, no abzymes produced in order to exert activities absent or deficient in the organism affected with one of the above described pathologies are known.
Abstract of the Invention
It has now surprisingly been found that catalytic monoclonal antibodies (in the following abzymes) with protease activity can be prepared without using the stable analogue of the transition state. Most unexpectedly, using as immunogen the protein agent responsible for or involved in pathologies characterized by plaques or aggregates with a protein component, abzymes with protease activity extremely selective towards the protein component of the plaque or of the aggregate characteristic of the concerned pathology can be obtained.
It is therefore an object of the present invention an abzyme or a fragment thereof or an engineerized fragment thereof which participates in the cleavage reaction of protein molecules whose presence, either in the free or in the aggregated form, is related to pathologies of various apparatuses and organs.
A further object of the present invention is a process for the preparation of said abzyme.
Still a further object of the present invention are pharmaceutical compositions containing said abzyme or a mixture of abzymes and medicaments useful for the treatment or the prevention of pathologies related to proteins in the free or aggregated form against various apparatuses and organs.
These and other objects of the invention, in the various embodiments there of, will be described in the following in greater detail also by means of examples.
Detailed Disclosure of the Invention.
According to the present invention, the abzyme has protease activity against protein molecules whose presence, either in the free or in the aggregated form, is related to pathologies of various apparatuses and organs.
As a rule, according to the present invention, the abzyme is obtained using directly its protein target as immunogen agent, with no need for a synthetic derivative of the analogue of the transition state.
The process comprises:
a) immunizing an animal with the target of the abzyme
b) obtaining the hybridoma
c) selecting the hybridomas for their catalytic activity.
The process for the preparation of the abzyme is effected with conventional techniques for the preparation of monoclonal antibodies, such as in vivo immunization, in vitro immunization and phage display.
The resulting antibody can be integer, or only the part of the molecule maintaining the catalytic activity can be isolated and used. The present invention also comprises any modification deriving from engineerization processes, such as single chain variable fragment (ScFv), or from modification processes, such as fragment antigen binding (Fab) and equivalent analogues.
In a first preferred embodiment, the abzyme is direct against Axcex21-42.
Said abzyme selectively recognizes the Axcex21-42 assembled in senile plaques and is capable of exerting a peptidase catalytic activity specifically against it, cleaving it into smaller fragments, which can easily be metabolized and which show no aggregating activities. Such an approach would allow for the treatment of patients both in early and late stages of the disease, although in the latter condition the neurodegenerative process is already advanced and irreversible.
It is essential for the abzyme against Axcex21-42 that the immunogen, i.e. the fragment itself of the xcex2 amyloid 1-42 fragment be in a xcex2-sheet conformation.
The intended use of the Axcex21-42 fragment as an immunogen agent is due to the fact that the core of the amyloid insoluble extracellular deposits consists mainly of Axcex21-42. Furthermore, Axcex21-42 is, among the various fragments, the one with the highest amyloidogenic properties, i.e. it is highly capable of associating into more and more complex aggregates and assembling in fibres. Axcex21-42 is, in fact, more hydrophobic than other fragments and its aggregation rate is higher.
The secondary structure of the peptide has been found to be of extreme importance for its neurotoxic activity (Simmons, Mol. Pharmacol. 45:373-379 (1994), and the 1-42 fragment exerts its action only after reaching the planar xcex2-sheet conformation. Considering that Axcex21-42 has a planar xcex2-sheet conformation also in the amyloid plaques, it is necessary to use the peptide in its secondary structure as the immunogen. Commercial Axcex21-42 (fresh) has a random coil structure; the xcex2-sheet conformation can be obtained by incubation of the fresh Axcex21-42 in aqueous solution for some days (aging): this treatment determines a conformational transition from random coil to xcex2-sheet (Simmons, 1994), obtaining aged
The immunogen can optionally be linked to a protein carrier, when the immunogen itself does not have sufficient size to evoke a suitable immune response or if this is considered useful in the practice of the present invention.
In a second preferred embodiment, the abzyme is directed against monoclonal immunoglobulins, or their polypeptidic subunits typical of monoclonal gammapathies, for example multiple myeloma and amyloidosis.
In a third preferred embodiment, the abzyme is directed against apolipoproteins, for example apo A and/or apo B, responsible for atherosclerosis.
In a fourth preferred embodiment, the abzyme is directed against prions.
A further aspect of the present invention relates to the method for the selection of hybridomas. Conventionally, hybridomas are selected with affinity techniques. Said techniques, however, do not select the abzymes on the basis of the catalytic activity so that the selected abzymes sometimes are not those having the best activity. According to the present invention, the selection is carried out contacting the hybridomas with a staining reactive which reveals that the concerned catalytic reaction has taken place. The detection of the reacted species can be carried out with conventional procedures, for example calorimetric or spectrophotometric techniques.

Catalytic monoclonal antibodies with protease activity for selective lysis of protein component of plaques aggregates pathological conditions


The system is a rebate program for the benefit of participating individuals such as wage earners. Participating individuals apply and are approved and are issued a card with an identifiable account number using credit approval systems. The card may include debit, smart card, customer loyalty and security features. The rebate is calculated and transferred to the participant""s account in a trust fund. The card may also be used to engage in other financial transactions. The system may include a wide range of retail merchants as well as professional services available to the participant. Funds are disbursed to the participant upon the occurrence of certain specified events.

The present invention relates to a financial system and more particularly relates to a financial processing system and method for directing a portion of a credit or other consumer transaction to a managed retirement or savings account of the participant. The system is of particular benefit to the wage earner who may not have adequately provided for retirement.
The current banking system is moving toward cashless devices for both consumer and commercial transactions. The most common of cashless devices is the credit card or xe2x80x9cplasticxe2x80x9d as it is commonly called. Credit cards are issued by banks and other organizations and trillions of dollars are charged on credit cards each year in the United States. Generally, the conventional credit card is issued by companies such as VISA, MASTERCARD, AMERICAN EXPRESS and the like which establish a network of participating merchants that accept the cards. Banks and other institutions service the accounts. The consumer can then charge goods and services at participating merchants and the participating merchants pay a percentage of the transaction, usually several percent, to the credit card company. In order to promote use of a particular credit card and to induce merchants to participate, credit card issuers rely on various marketing techniques. For example, some credit card companies offer special discounts to users of cards if they participate by buying particular products or services. Other card issuers such as DISCOVER card rebate a small percentage to the consumer, again typically in the order of several percent. Other types of promotional devices include credits based on credit card activity which may be used when purchasing large ticket items such as vehicles.
In addition to the conventional credit card, other types of cards are used in commercial transactions. More and more, cards known as shopper loyalty cards and frequent shopper cards, are issued to customers by businesses such as grocery chains. These businesses promote use of these cards as a convenient alternative to paper coupons. The object of use of such cards, similar to the frequent flyer programs run by airlines, is to build loyalty by offering customers discounts. The customer presents the card to the merchant at the time of purchase and the card is scanned and certain items are then discounted. The advantage to the merchant is that such cards utilize a database eliminating the need for checkout cashiers to visually and electronically scan coupons. As mentioned above, such cards also build customer loyalty and also serve to obtain information on shoppers"" buying habits and demographics, therefore providing the grocery store valuable demographic and product information which will assist in its marketing of products.
Other types of cards are known as SMART cards or e-cards. These cards are an alternative to the use of hard currency and basically a SMART card stores funds digitally. SMART cards of the type produced by Productivity Enhancement Products of Laguna Hills, Calif. work like an automated teller. These cards are personalized and protected by an identification system, typically a PIN number or a photo. The cards function like cash with their value stored on a computer chip embedded on the card which stored value is reduced by the amount of the purchase at the time of use. Merchants may then use PC based cash registers to deduct payments from the cards. SMART cards can be used to buy items and cards of this type are commonly used by students for purchasing meals at university cafeterias and are promoted for use in making telephone calls.
Other types of financial cards commonly used are debit cards which are presented to a cashier and the card is electronically xe2x80x9cswipedxe2x80x9d. The user may then authorize a direct deduction from a checking account in the amount of the purchase or an amount which includes additional cash back to the user.
While many consumers actively use such cards, these same consumers are greatly concerned about the stability of the Social Security system and their own retirement. Studies show that the average worker has not adequately provided for his or her retirement. Further, the social security system is experiencing increasing financial problems. According to the trustees, the United States social security system will be insolvent by the year 2029. Currently Social Security taxes generate more revenue than the system pays out in benefits. The surplus theoretically accumulates in the social security trust fund. However, it is estimated that in the year 2012 the situation will reverse and the Social Security system will be obligated to pay out more in benefits than it collects in revenues. To continue to meet its obligations, the system will have to begin drawing on the surplus in the trust fund. In actuality the trust fund surplus is a fiction as the federal government has used the trust fund for other purposes and has over the years xe2x80x9cborrowedxe2x80x9d money from the trust fund to disguise the actual amount of the federal budget deficit. Effectively, the federal government has been borrowing from the social security fund and issuing IOU""s in the form of bonds to the Social Security fund. It is estimated that in 2012 the Social Security system will have to start turning in the bonds to the federal government to obtain cash needed to pay benefits, but the federal government has no cash or other asset and, therefore, the deficit will accelerate.
Even if the financial difficulties of the present Social Security system can be fixed, the system is not a sound investment for most Americans who contribute and is even worse for younger workers. Payroll taxes are high and even if today""s younger workers receive the promised benefits, those benefits will amount to a below-market return on their taxes. Today""s retirees generally get back all they have paid in to Social Security, plus a modest return, but when younger workers retire they will actually receive a negative rate of return which will be lower than the amount of contributions.
Based on these problems, there are various reforms that have been proposed one of which is the privatization of the Social Security fund.
Unlike private pensions and individual retirement accounts, the Social Security system does not invest the money it collects in stocks and bonds but pays those funds out as benefits the same year they are collected.
Accordingly, because of the deteriorating financial condition of the Social Security system, it becomes more and more incumbent upon individuals to plan for their own retirement to ensure a secure future. The present system is based on the underlying concept that merchants and credit card issuers would be willing as an inducement to pay a percentage of the transaction as a refund into a tax deferred fund for the benefit of the card holder.
Various rebate and refund systems can be found both in the prior art and patent literature. For example, U.S. Pat. No. 4,750,119 describes a purchasing system with a rebate feature which allows for the input of purchase orders and correlates transfer of funds from purchasers to vendors. A future benefit guarantor supplies the rebate factor which is input into the system. The system then computes and reports the rebate which is due in the future to each subscriber or purchaser. The system provides instructions to pay the vendors for selected goods and services and pay the future rebate guarantor a premium representing the purchase price of future guaranteed rebates. Preferably the premium is paid on a daily basis to the guarantor and a group annuity contract is funded.
U.S. Pat. No. 4,941,090 shows a centralized computer cash value accumulation system based on point of sale transactions with multiple merchants. The consumer""s account number and birth date are transmitted to a central system along with data identifying the merchant and a credit line determined by the merchant. At the central location, a cash value for that consumer is incremented by the credit value and a bill for that merchant is similarly incremented. Periodically the merchants are billed for the accumulated bill value. Also at selected intervals, consumers are given access to their respective accumulated cash values by either check or through funds dispensed electronically. Preferably the intervals are selected to correspond to the birth dates of the consumers.
U.S. Pat. No. 5,537,314 shows a credit accumulation and accessing system for a plurality of sponsors and participants. Under the control of an operational program, several tasks are accomplished including creating sub-directories for a single participant account so as to selectively associate the single account sub-directory with multiple sponsoring company accounts in deciphering and, accordingly at points of sale, calculating, posting and issuing discounts, raffle entries, store credit returns, points and cash values in accordance with the performance of participants. Award output devices provide consumers access to funds based upon the cash value in the consumer account and may include wire transfer, check, cash coupon, charge card balance reduction or catalog merchandise.
Accordingly, the present invention provides a processing system based on a retirement card for financial transactions which with some modification will utilize the existing financial structure and existing computer software and hardware so that over a period of time, a portion of funds spent by users utilizing the retirement card will be deposited into a depository such as a trust fund. Funds so deposited over the working life time of an individual will be allowed to accumulate and can only be withdrawn upon retirement or some other event such as medical emergency and either on a tax-free or tax deferred basis.
The present invention provides a system in which an individual is issued a special credit type card which is designated a xe2x80x9cRetirement Charge Cardxe2x80x9d (RCC). The user would have an identifiable account in a trust fund and the RCC would be issued by banks or other existing financial institutions. Individuals, upon consummating transactions such as credit purchases using the card, would be rewarded with a rebate in a predetermined about, which rebate would not go directly to the individual card holder but rather would be deposited into the card holder""s trust fund account. The invention contemplates using existing electronic credit and banking systems for approval both approving the issuance of cards and approving individual transactions.
The result would be that those using the cards would tend to be financially responsible individuals and therefore the rate of delinquency or loss on the cards to card issuers and businesses would be substantially reduced. Use of the cards would benefit businesses in that card holders would tend to make more purchases on their cards, thus increasing the revenue to the businesses and banks. The system may be implemented without additional legislation using existing technology, electronic communication and data processing systems.
As an additional feature, those businesses honoring the retirement cards could also be provided with conventional banking software and have one or more checkout locations at which the software is available creating a virtual banking system which would substantially reduce transaction costs to banking institutions. Thus, card holders could utilize these checkout locations when purchasing goods or services. Further, these locations could provide other banking services such as deposits, bill payment and the like, thus providing convenience to card holders and providing more convenient banking locations and reducing overhead and operating expenses to banks.
The retirement trust fund would issue periodic statements to the card holders setting forth the amount in the trust. The funds would be treated as trust funds and deposited in investments such as government securities, bonds, and perhaps blue chip stocks. As another aspect of the system, the individual retirement card holder could select from a menu of securities such as high growth stocks, bonds, government securities or blue chip stocks and select the particular areas in which the funds deposited to the card holder""s account would be invested.
Another significant advantage of the transaction system of the present invention is that the system inherently provides a safeguard for as inflation occurs over a period of time and as the card holder spends more, increased retirement savings will be effected as the rebate is based on a percentage of the amount spent.
The system further contemplates expanding services available to participants by providing additional services such as low cost loans, appraisal services, insurance services, provided by entities funded by the trust fund. Stock in these companies would be available to member participants.

Financial transaction system with retirement saving benefit