Title of Invention	GONADOTROPINS WITH NON NATIVE DISULFIDE BRIDGES
Abstract	The present invention relates to gonadotropins consisting of an a and β subunit, said gonadotropins comprising non-native disulfide bridges, preferably non-native intersubunit disulfide bridges. The gonadotropins according to the invention have improved stability. The present invention furthermore provides for pharmaceutical compositions comprising said gonadotropins.

Full Text

DESK-MAT WITH KEYBOARD INSTRUMENT BACKGROUND OF THE INVENTION Field of the Invention This invention relates to a desk-mat with keyboard instrument, particularly a desk-mat provided with a keyboard instrument in a desk-pad to be used for desks of all kinds, by which schoolchildren can practice music easily, cleasantly and cheerfully in their own- family. Description of the Prior Art The prior art of desk-mat with a touch switch type keyboard instrument of this kind is composed of a transparent surface plate made of flexible plastic materials and a substrate member comprising an upper plate and a lower plate disposed under said transparent plate, wherein the upper plate is provided with a lower cavity on its lower portion for receiving the keyboard and an upper cavity on its upper portion for receiving a thin type battery, a speaker and an IC (integrated circuit) and wherein the keyboard received in the lower cavity is connected to the battery, speaker and IC by means of conductors. The conventional desk-mat with keyboard instrument as described above is very poor in its sound volume because of its thin type speaker which is confined to a kind of "toy" or "recreation", making it difficult to use as keyboard •instrument for the very proper purpose thereof, and further, as the electric power is easily exhausted in a short time because of a flat and small battery, it is difficult to perform music in a long time and it makes very troublesome to get frequently the battery changed. Further because of the small battery, it prevents to make the size of keyboard itself larger and the small keyboard is not proper for any auditory training. Summary of the Invention Accordingly, an object of this invention is to provide a desk-mat with a keyboard instrument most suitable for proper music training having a long useful life and a good sound volume as proper keyboard instrument and for a proper writing purpose for schoolchildren desk pads. The desk-mat with a keyboard instrument according to this invention comprises a rectangular mat member and a container box-body member fixed on a side of said mat member, said mat member being composed of a cushion sheet made of resilient materials and disposed as bottom ply, an insulator sheet disposed immediately on said cushion sheet, a conductor sheet having conductors .joined thereon and laid immediately on said insulator sheet, a keyboard printed sheet on which the keyboard is printed and laminated on said conductor sheet, and a transparent sheet through which the keyboard of said keyboard printed sheet can be seen, said container box-body being provided with an IC member connected to the conductors of said conductor sheet and with a speaker connected to said IC member, further said container box-body being also provided to the side portion of said container box-body with a jack for inserting the plug of DC adapter connected to a domestic AC power source, and to the surface of said box-body with a switch fixed between the jack and the IC member. BRIEF EXPLANATION OF THE DRAWINGS Fig. 1 shows a perspective view of a desk-mat with a keyboard instrument according to this invention laid on the top plate of a writing desk; Fig. 2 shows a plan view of the desk-mat itself; Fig. 3 shows a longitudinal sectional view along a line A-A of Fig. 2; Fig. 4 shows a longitudinal sectional view along a line B-B of Fig. 2; and Fig. 5 shows a plan view of the conductor sheet. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The preferred embodiments of the present invention will be described in detail in reference to the attached drawings. A desk-mat with a keyboard instrument according to this invention is composed of a mat member 3 in a rectangular form and a container box-body 2 mounted in a side of said, mat member 3 as shown in Fig. 1 and 2. The mat member 3 is provided with a cushion sheet 10 made of resilient materials as bottom ply. The cushion sheet is covered with an insulator sheet 13 and a conductor sheet 14 having conductors of small diameter joined thereon is laminated immediately on the insulator sheet 13. The insulator sheet 13 and the conductor sheet 14 are not extended wholly over the cushion sheet 10 but only partly confined upto the center portion thereof as shown in Fig. 2 from the economical point of view. A keyboard printed sheet 11, on which the keyboard member 9 is printed with any kind of colors desired, is laminated on the conductor sheet 14 and the conductors 15 of the conductor sheet 14 are connected to the keyboard member 9 of the keyboard printed sheet 11. The keyboard printed sheet 11 is laminated with a transparent sheet 12 so that the keyboard member 9 can be seen through from the surface of the mat member. The container box-body 2 is fixed vertically to one side either right or left side of the mat member 3 and contains an IC member 6 connected to the conductors 15 of the conductor sheet 14 and a speaker 7 connected to said IC member 6. A jack 8 is fixed on the side of the container box-body 2 for inserting a plug 17 of a DC adapter 18 connected to a domestic AC power source, thereby the desk-mat with keyboard instrument may be connected to the the power source and a switch 5 for switching on and off the power source is mounted on the surface of the container box-body 2. Further, the container box-body 2" is provided with a container saucer 16 for pencils/ball-point pens, etc., in the other portion of the surface thereof. Reference numeral 20 indicates a desk for schoolchildren on which the desk-mat with keyboard according to this invention is laid. The desk-mat with keyboard instrument according to this invention is laid as shown in Fig. 1 on the top plate of the desk for schoolchildren in which conditions the writing work can be conducted on the mat member 3. In the case of practicing the keyboard instrument, for example, the schoolchild can insert the plug 17 of DC adapter 18 into the jack 8 mounted on the side of the container box body 2 for connection to the power source via operating switch 5 on the surface thereof, thereby getting electricity turned on, then by pressing the keyboard member 9 down from the top of the transparent sheet 12, touch-switches can make the IC member 6 operate and also make the speaker 7~produce a volume of sound to be used for music learning. In the desk-mat with keyboard instrument of this invention, the schoolchildren can not only make writing " operation like the conventional desk-mats, but make practical musical training by means of the keyboard operation. Further, a large sized keyboard and a large capacity speaker can now be provided in the mat member and in the container box-body respectively, then it can be used as keyboard instrument properly for a long period of time and most suitably for the musical training as well. On the other hand, a cushion sheet made of resilient materials is used as bottom ply and an insulator sheet is also provided. Therefore, the conductors and the conductor sheet can safely be protected. Further, the conductor sheet is arranged smaller in area than that of the mat member, thereby the total length of conductors can be much shorter for connection to the IC member which is now very economical. WE CLAIM: 1. Gonadotropins consisting of an a subunit and a β subunit, characterised in that said gonadotropins comprise one or more non-native disulfide bridges. 2. Gonadotropins according to claim 1, characterised in that the non-native disulfide bridges are intersubunit disulfide bridges. 3. Gonadotropins according to claim 1, characterized in that said gonadotropins comprise a non-native disulfide bridge between one or more of the amino acid pairs (Phe al8 Cys - He a25 Cys), (Gin a20 Cys - Ala a23 Cys), (Ser a34 Cys - Ser a57 Cys), (Thr a39 Cys - Thr a54 Cys), (Ala 4. Gonadotropins according to any of the claims 1-3, characterized in that the β subunit is the β subunit of hCG. 5. Gonadotropins according to claim 4, characterized in that said gonadotropins comprise a non-native intersubunit disulfide bridge between one or more of the amino acid pairs (Gin a5 Cys - Arg P8 Cys), (Pro a24 Cys - Gly P71 Cys), (Met a29 Cys - Met p41 Cys), (Arg a35 Cys - Ala P35 Cys), (Tyr a37 Cys -lie P33 Cys), (Lys a51 Cys - Asp p99 Cys) and (His a90 Cys - Cys Py Cys). 6. Gonadotropins according to claim 4 or 5, characterized in that said gonadotropins comprise a non-native disulfide bridge between one or more of the amino acid pairs (Pro p4 Cys - Pro p7 Cys), (Pro pi 1 Cys - Thr P32 Cys), (Pro p 11 Cys - Ala P85 Cys), (Thr P32 Cys - Ala P85 Cys), (Arg P60 Cys -Ser p87 Cys), (Arg P60 Cys - Gin p89 Cys), (Asp P61 Cys - Leu p86 Cys), (Asp p61 Cys - Ser P87 Cys), (Ser p66 Cys - Ser P81 Cys) and (Leu p69 Cys -Pro p78 Cys). 7. Gonadotropins according to any of the claims 1-3, characterized in that the P subunit is the P subunit of LH. 8. Gonadotropin according to claim 7, characterized in that said gonadotropins comprise a non-native intersubunit disulfide bridge between one or more of the amino acid pairs (Gin oc5 Cys - Trp P8 Cys), (Pro oc24 Cys - Gly 371 Cys), (Met a29 Cys - Met p41 Cys), (Arg a35 Cys - Ala p35 Cys), (Tyr a37 Cys -He P33 Cys), (Lys a51 Cys - Asp 399 Cys) and (His a90 Cys - Cys Py Cys). 9. Gonadotropins according to claim 7 or 8, characterized in that said gonadotropins comprise a non-native disulfide bridge between one or more of the amino acid pairs (Pro p4 Cys - Pro P7 Cys), (Pro pi 1 Cys - Thr p32 Cys), (Pro pi 1 Cys - Ala P85 Cys), (Thr P32 Cys - Ala p85 Cys), (Arg P60 Cys -Ser P87 Cys), (Arg P60 Cys - Arg P89 Cys), (Asp p61 Cys - Leu P86 Cys), (Asp p61 Cys - Ser p87 Cys), (Ser p66 Cys - Ser p81 Cys) and (Leu p69 Cys -Pro p78 Cys). 10. Gonadotropins according to any of the claims 1-3, characterized in that the β subunit is the β subunit of FSH. 11. Gonadotropins according to claim 10, characterized in that said gonadotropins comprise a non-native intersubunit disulfide bridge between one or more of the amino acid pairs (Gin a5 Cys - Ser (J2 Cys), (Pro a24 Cys - Gly P65 Cys), (Met a29 Cys - Arg 035 Cys), (Arg a35 Cys - Ala P29 Cys), (Tyr a37 Cys - Trp P27 Cys), (Lys a51 Cys - Asp P93 Cys) and (His a90 Cys - Cys py Cys). 12. Gonadotropins according to claim 10 or 11, characterized in that said gonadotropins comprise a non-native disulfide bridge between one or more of the amino acid pairs (Leu p5 Cys - Thr P26 Cys), (Leu p5 Cys - Ala P79 Cys), (Thr P26 Cys - Ala P79 Cys), (Lys P54 Cys - Gin P81 Cys), (Lys p54 Cys - His P83 Cys), (Glu p55 Cys - Thr P80 Cys), (Glu P55 Cys - Gin P81 Cys), (Thr P60 Cys - Thr p75 Cys) and (Val p63 Cys - Ser P72 Cys). 13. Gonadotropins according to any of the claims 1-3, characterized in that the P subunit is the P subunit of TSH. 14. Gonadotropins according to claim 13, charcterized in that said gonadotropins comprise a non-native intersubunit disulfide bridge between one or more of the amino acid pairs (Gin a5 Cys - Phe β 1 Cys), (Pro a24 Cys - Gly P66 Cys), (Met a29 Cys - Arg P34 Cys), (Arg a35 Cys - Ala p28 Cys), (Tyr ot37 Cys -He p26 Cys), (Lys a51 Cys - Asp P94 Cys) and (His a90 Cys - Cys Py Cys). 15. Gonadotropins according to claim 13 or 14, characterized in that said gonadotropins comprise a non-native disulfide bridge between one or more of the amino acid pairs (Pro p4 Cys - Thr p25 Cys), (Pro p4 Cys - Ala P80 Cys), (Thr P25 Cys - Ala P80 Cys), (Arg 055 Cys - Ser p82 Cys), (Arg P55 Cys -Lys p84 Cys), (Asp p56 Cys - Leu J381 Cys), (Asp P56 Cys - Ser p82 Cys), (Thr P61 Cys - Ser p76 Cys) and (lie P64 Cys - Pro p73 Cys). 16. Pharmaceutical composition comprising one or more of the gonadotropins according to claim 1-15 and a pharmaceutical acceptable carrier.

Documents:

1834-mas-1996 abstract.pdf

1834-mas-1996 assignment.pdf

1834-mas-1996 claims.pdf

1834-mas-1996 correspondence-others.pdf

1834-mas-1996 correspondence-po.pdf

1834-mas-1996 description(complete).pdf

1834-mas-1996 drawings.pdf

1834-mas-1996 form-1.pdf

1834-mas-1996 form-18.pdf

1834-mas-1996 form-26.pdf

1834-mas-1996 form-4.pdf

1834-mas-1996 form-6.pdf

1834-mas-1996 petition.pdf