CA1065305A - PROCESS FOR THE ENRICHMENT OF THE PREGNANCY-SPECIFIC .beta.1-GLYCOPROTEIN - Google Patents
PROCESS FOR THE ENRICHMENT OF THE PREGNANCY-SPECIFIC .beta.1-GLYCOPROTEINInfo
- Publication number
- CA1065305A CA1065305A CA250,426A CA250426A CA1065305A CA 1065305 A CA1065305 A CA 1065305A CA 250426 A CA250426 A CA 250426A CA 1065305 A CA1065305 A CA 1065305A
- Authority
- CA
- Canada
- Prior art keywords
- glycoprotein
- pregnancy
- carrier
- specific
- beta
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4715—Pregnancy proteins, e.g. placenta proteins, alpha-feto-protein, pregnancy specific beta glycoprotein
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
- G01N33/76—Human chorionic gonadotropin including luteinising hormone, follicle stimulating hormone, thyroid stimulating hormone or their receptors
Abstract
Abstract of the disclosure:
Process for the enrichment of the pregnancy-specific .beta.1-gylco-protein (SP1) from blood serum, urine or placenta extracts, which comprises contracting the starting material at a pH-value of between 4 and 9 with an antibody against the pregnancy-spe-cific .beta.1-glycoprotein, said antibody being bound onto an in-soluble carrier, separating the carrier containing the SP1 in bound form from the liquid phase and in order to isolate the SP1 treating the carrier with an aqueous medium at a pH-value of from 2 to 4 or with the solution of a substance which disso-ciatos a protein molecule at a pH-value of from 4 to 9.
Process for the enrichment of the pregnancy-specific .beta.1-gylco-protein (SP1) from blood serum, urine or placenta extracts, which comprises contracting the starting material at a pH-value of between 4 and 9 with an antibody against the pregnancy-spe-cific .beta.1-glycoprotein, said antibody being bound onto an in-soluble carrier, separating the carrier containing the SP1 in bound form from the liquid phase and in order to isolate the SP1 treating the carrier with an aqueous medium at a pH-value of from 2 to 4 or with the solution of a substance which disso-ciatos a protein molecule at a pH-value of from 4 to 9.
Description
GermanPatent Application laid open to public inspection DOS 21 57 610 describes a glycoprotein which occurs in the pla-centa and is called "Pregnancy-specific ~l-glycoprotein" (herein-after referred to as SPl). Said Patent Application furthermore describes a process for the isolation of this glycoprotein.
Now, we have found a process which permits the isolation of the pregnancy-specific Bl-glycoprotein with better yield and higher purity.
The process of the invention comprises contacting blood serum, urine or the extract of placentas at a pH-value of bet-ween 4 and 9 with an antibody against the pregnancy-specific ~l-glycoprotein, which antibody is bound onto an insoluble carrier, separating this carrier onto which the said glycoprotein has then fixed from the liquid phase and, in order to isolate the glyco-protein, treating the carrier with an aqueous medium having a pH-value of 2 to 4 or with a solution of a substance that disso-ciates protein molecules at a pH-value of 4 to 9, preferably at about a pH-value of 7.
In this process, the pregnancy-specific ~l-glycoprotein is isolated from its solutions by specific immuno-adsorption with the aid of a carrier which contains the corresponding anti-body in insoluble form.
An antibody which can be fixed in known manner onto a solid carrier can be prepared by immunizing animals with the pregnancy-specific ~l-glycoprotein. The blood of the animals so treated is worked up in known manner to obtain the immuno-globulin fraction. The anti-SPl-serum so isolated is then bound to suitable carriers. Such processes are described, for example in Ann. Rev. Biochem. 40 (1971) 259; Naturwissenschaften 58 . - 2 -(1971) 389 or Nature 214 (1967) 1302. Particularly suitable are highly polymeric carbohydrates such as cellulose or agar, syn-thetic resins such as polyacryloamide or copolymers of ethylene/-~eic acid anhydride. Even glass particles may be used ascarriers.
A particularly preferred carrier material is purified agarose in the form of small spheres of a diameter of about 20 to 200 um, onto which the antibodies against SPl are fixed covalently accord-ing to the last of the above-mentioned methods.
For the isolation of SPl from solutions, which additionally contain other proteins and carbohydrates, for example placental extracts or serum or urine of pregnant women, the mentioned starting material is contacted with the adsorbent carrying the antibody, while adjusting the pH-value to >4. In order to pre-vent denaturation of the proteins, it is advisable to chose a pH-value which is not higher than 9. The salt concentration of the solution is not critical. However, conditions should be avoided under which the linkage between antigens and antibodies would be loosened. It is preferred to use an aqueous solution which contains neutral salts and/or the buffer substances usually employed in biochemical reactions, in particular sodium chloride, phosphate buffers, tris-hydroxymethylaminomethane or other known buffer substances, for example those described in Biochemistry 5 (1966) 472. The concentration of these substances is suitable in the range of from 0.01 to 2 moles/l. The ratio of protein solution to adsorbent is suitable in the range of from 1:1 to 10:1, preferably 2:1. The adsorbent should be in 10~5305 contact with the protein solution for 0.1 to 5 hours to permit linkage of the antibodies with the antigens.
The adsorbent is then separated from the solution by centri-fugation or filtration and washed several times with a neutral salt solution in order to eliminate excess salts and unspeci-fically adsorbed impurities.
The elution of SPl from the antibody-containing carrier can be effected in known manner by measures which cause dissociation of antigen-antibody linkages. For example, the elution may be carried out by introducing the carrier into an aqueous medium having a pH-value of <4, preferably between 2 and 4. The corres-ponding solution should contain salts and suitable buffer sub-stances in a suitable concentration, preferably from 0.2 to 8 moles/l.
It is advisable to stir the dispersion of the adsorbent in this solution for 0.1 to 2 hours, during which time the SPl is desorbed from the immuno-adsorbent. After separation of the adsorbent, the pH-value of the solution containing the SPl is adjusted to about neutral (6 to 8). If desired, the solution may be subjected to a further purification operation, for example to adsorption on hydroxy-apatite.
The elution of SPl from the antibody-containing carrier may also be carried out with the aid of substances that dissociate proteins, for example solutions of urea or solutions of so-called chaotroPic salts such as NaN03, NaBr, NaC104, CF3COONa, NaSCN
or CC13COONa. The concentration of these salts in the elution medium is suitably 0.2 to 8 moles/l. In order to remove from the solution, after desorption of the SPl, the substances which dissociate protein molecules and to separate the adsorbent, the solution can be dialyzed against a neutral salt solution or a buffer solution having a concentration of from 0.1 to 1 mole/l.
The SPl obtained by the above-described process has purity of 60 to 95%. It can be enriched to more than 99% by further purification operations.
The following Example illustrates the process of the invention.
EXAMPLE:
Isolation of the pregnancy-specific ~l-glycoprotein from its solutions by immuno-adsorption An amino-adsorbent suitable for the specific linkage of the pregnancy-specific ~l-glycoprotein was obtained by covalently binding anti-pregnancy-specific Bl-glycoprotein-immunoglo-bulins on a suitable carrier. The immuno-adsorbent used in the present example was prepared by fixing 1.75 g of a protein isolated from the immuno-globulin fraction of an anti-pregnancy-specific ~l-glycoprotein rabbit serum onto 175 g of Sepharose (R) 4 B (Pharmacia Uppsala), which had been activated with 21.8 g of BrCn (Axen, R., Porath, J., Ernbach, S. : Nature 214, 1302 (1967)). With the aid of this immuno-adsorbent, the pregnancy-specific ~l-glycoprotein was isolated from the extracts of pla-centas according to the following process:
The placental extract containing the pregnancy-specific ~1-glycoprotein was first dialyzed against 0.1 m of a buffer of trishydroxymethylaminomethane and hydrochloric acid (pH 8.0), which contained 1.0 mole/liter of NaCl and 1 g/liter of sodium azide. This solution was combined with the carrier-bound anti-pregnancy-specific ~l-glycoprotein-immunoglobulin, the whole was stirred for 2hours at 4C and the adsorbent with the bound pregnancy-specific ~l-glycoprotein was filtered off with suction. The adsorbent was then washed with 2 x 250 ml of the 0.1 m trishydroxymethylaminomethane-hydrochloric acid buffer solution and subsequently with 2 x 250 ml of a physiological NaCl solution (~.9% strength); the pregnancy-specific ~l-glyco-protein was finally eluted from the adsorbent by a six-fold treatment of the adsorbent each time for 20 minutes with 400 ml of a 0.5 m glycine-HCl buffer that had a pH-value of 2.5. The combined eluates were adjusted to pH 7.0 by means of lN-NaOH
and concentrated to 10 ml on an ultra-filter. The solution con-taining the pregnancy-specific ~l-glycoprotein was rendered free from salt by a dialysis against water and eventually lyophilized.
If desired, the SPl-solution could be further purified, for example, by the following processes: the concentrate was dia-lyzed against a 0.005 m sodium phosphate buffer having a pH-value of 6.8 and/or purified by chromatography on hydroxyl-apatite. Thereby, the plasma-proteins bound unspecifically to the immuno-adsorbent and eluted later on were adsorbed onto the hydroxyl-apatite, while the eluate contained the pregnancy-spe-cific Bl-glycoprotein in a highly purified form (purity >99%).
The same method was applied using the pregnancy-specific ~l-glycoprotein isolated from the serum or urine of pregnant women.
Now, we have found a process which permits the isolation of the pregnancy-specific Bl-glycoprotein with better yield and higher purity.
The process of the invention comprises contacting blood serum, urine or the extract of placentas at a pH-value of bet-ween 4 and 9 with an antibody against the pregnancy-specific ~l-glycoprotein, which antibody is bound onto an insoluble carrier, separating this carrier onto which the said glycoprotein has then fixed from the liquid phase and, in order to isolate the glyco-protein, treating the carrier with an aqueous medium having a pH-value of 2 to 4 or with a solution of a substance that disso-ciates protein molecules at a pH-value of 4 to 9, preferably at about a pH-value of 7.
In this process, the pregnancy-specific ~l-glycoprotein is isolated from its solutions by specific immuno-adsorption with the aid of a carrier which contains the corresponding anti-body in insoluble form.
An antibody which can be fixed in known manner onto a solid carrier can be prepared by immunizing animals with the pregnancy-specific ~l-glycoprotein. The blood of the animals so treated is worked up in known manner to obtain the immuno-globulin fraction. The anti-SPl-serum so isolated is then bound to suitable carriers. Such processes are described, for example in Ann. Rev. Biochem. 40 (1971) 259; Naturwissenschaften 58 . - 2 -(1971) 389 or Nature 214 (1967) 1302. Particularly suitable are highly polymeric carbohydrates such as cellulose or agar, syn-thetic resins such as polyacryloamide or copolymers of ethylene/-~eic acid anhydride. Even glass particles may be used ascarriers.
A particularly preferred carrier material is purified agarose in the form of small spheres of a diameter of about 20 to 200 um, onto which the antibodies against SPl are fixed covalently accord-ing to the last of the above-mentioned methods.
For the isolation of SPl from solutions, which additionally contain other proteins and carbohydrates, for example placental extracts or serum or urine of pregnant women, the mentioned starting material is contacted with the adsorbent carrying the antibody, while adjusting the pH-value to >4. In order to pre-vent denaturation of the proteins, it is advisable to chose a pH-value which is not higher than 9. The salt concentration of the solution is not critical. However, conditions should be avoided under which the linkage between antigens and antibodies would be loosened. It is preferred to use an aqueous solution which contains neutral salts and/or the buffer substances usually employed in biochemical reactions, in particular sodium chloride, phosphate buffers, tris-hydroxymethylaminomethane or other known buffer substances, for example those described in Biochemistry 5 (1966) 472. The concentration of these substances is suitable in the range of from 0.01 to 2 moles/l. The ratio of protein solution to adsorbent is suitable in the range of from 1:1 to 10:1, preferably 2:1. The adsorbent should be in 10~5305 contact with the protein solution for 0.1 to 5 hours to permit linkage of the antibodies with the antigens.
The adsorbent is then separated from the solution by centri-fugation or filtration and washed several times with a neutral salt solution in order to eliminate excess salts and unspeci-fically adsorbed impurities.
The elution of SPl from the antibody-containing carrier can be effected in known manner by measures which cause dissociation of antigen-antibody linkages. For example, the elution may be carried out by introducing the carrier into an aqueous medium having a pH-value of <4, preferably between 2 and 4. The corres-ponding solution should contain salts and suitable buffer sub-stances in a suitable concentration, preferably from 0.2 to 8 moles/l.
It is advisable to stir the dispersion of the adsorbent in this solution for 0.1 to 2 hours, during which time the SPl is desorbed from the immuno-adsorbent. After separation of the adsorbent, the pH-value of the solution containing the SPl is adjusted to about neutral (6 to 8). If desired, the solution may be subjected to a further purification operation, for example to adsorption on hydroxy-apatite.
The elution of SPl from the antibody-containing carrier may also be carried out with the aid of substances that dissociate proteins, for example solutions of urea or solutions of so-called chaotroPic salts such as NaN03, NaBr, NaC104, CF3COONa, NaSCN
or CC13COONa. The concentration of these salts in the elution medium is suitably 0.2 to 8 moles/l. In order to remove from the solution, after desorption of the SPl, the substances which dissociate protein molecules and to separate the adsorbent, the solution can be dialyzed against a neutral salt solution or a buffer solution having a concentration of from 0.1 to 1 mole/l.
The SPl obtained by the above-described process has purity of 60 to 95%. It can be enriched to more than 99% by further purification operations.
The following Example illustrates the process of the invention.
EXAMPLE:
Isolation of the pregnancy-specific ~l-glycoprotein from its solutions by immuno-adsorption An amino-adsorbent suitable for the specific linkage of the pregnancy-specific ~l-glycoprotein was obtained by covalently binding anti-pregnancy-specific Bl-glycoprotein-immunoglo-bulins on a suitable carrier. The immuno-adsorbent used in the present example was prepared by fixing 1.75 g of a protein isolated from the immuno-globulin fraction of an anti-pregnancy-specific ~l-glycoprotein rabbit serum onto 175 g of Sepharose (R) 4 B (Pharmacia Uppsala), which had been activated with 21.8 g of BrCn (Axen, R., Porath, J., Ernbach, S. : Nature 214, 1302 (1967)). With the aid of this immuno-adsorbent, the pregnancy-specific ~l-glycoprotein was isolated from the extracts of pla-centas according to the following process:
The placental extract containing the pregnancy-specific ~1-glycoprotein was first dialyzed against 0.1 m of a buffer of trishydroxymethylaminomethane and hydrochloric acid (pH 8.0), which contained 1.0 mole/liter of NaCl and 1 g/liter of sodium azide. This solution was combined with the carrier-bound anti-pregnancy-specific ~l-glycoprotein-immunoglobulin, the whole was stirred for 2hours at 4C and the adsorbent with the bound pregnancy-specific ~l-glycoprotein was filtered off with suction. The adsorbent was then washed with 2 x 250 ml of the 0.1 m trishydroxymethylaminomethane-hydrochloric acid buffer solution and subsequently with 2 x 250 ml of a physiological NaCl solution (~.9% strength); the pregnancy-specific ~l-glyco-protein was finally eluted from the adsorbent by a six-fold treatment of the adsorbent each time for 20 minutes with 400 ml of a 0.5 m glycine-HCl buffer that had a pH-value of 2.5. The combined eluates were adjusted to pH 7.0 by means of lN-NaOH
and concentrated to 10 ml on an ultra-filter. The solution con-taining the pregnancy-specific ~l-glycoprotein was rendered free from salt by a dialysis against water and eventually lyophilized.
If desired, the SPl-solution could be further purified, for example, by the following processes: the concentrate was dia-lyzed against a 0.005 m sodium phosphate buffer having a pH-value of 6.8 and/or purified by chromatography on hydroxyl-apatite. Thereby, the plasma-proteins bound unspecifically to the immuno-adsorbent and eluted later on were adsorbed onto the hydroxyl-apatite, while the eluate contained the pregnancy-spe-cific Bl-glycoprotein in a highly purified form (purity >99%).
The same method was applied using the pregnancy-specific ~l-glycoprotein isolated from the serum or urine of pregnant women.
Claims (4)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the enrichment of the pregnancy-specific .beta.1-glycoprotein from blood serum, urine or the extracts of placenta in which the blood serum, urine or the extracts are contacted at a pH of from 4 to 9 with an antibody against the pregnancy-specific .beta.1-glycoprotein, said antibody being bound onto an insoluble carrier, whereby the .beta.1-glycoprotein becomes bound to the carrier, the carrier is separated from the serum, urine or extracts, and the sep-arated carrier is treated to isolate the pregnancy-specific .beta.1-glycoprotein from the carrier.
2. A process as claimed in claim 1 in which the sep-arated carrier is treated with an aqueous solution at a pH of from 2 to 4 to isolate the pregnancy-specific .beta.1-glycoprotein.
3. A process as claimed in claim 1 in which the sep-arated carrier is treated with a solution of a substance which dissociates a protein molecule at a pH of from 4 to 9.
4. A process as claimed in claim 1, claim 2 or claim 3 in which the carrier comprises purified agarose in the form of small spheres having a diameter in the range of from 20 to 200 um.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/569,476 US4065445A (en) | 1971-09-29 | 1975-04-18 | Pregnancy-specific β1 -glycoprotein and process for isolating it |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1065305A true CA1065305A (en) | 1979-10-30 |
Family
ID=24275609
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA250,426A Expired CA1065305A (en) | 1975-04-18 | 1976-04-15 | PROCESS FOR THE ENRICHMENT OF THE PREGNANCY-SPECIFIC .beta.1-GLYCOPROTEIN |
| CA250,439A Expired CA1065307A (en) | 1975-04-18 | 1976-04-15 | PROCESS FOR THE PURIFICATION OF THE PREGNANCY-SPECIFIC .beta.1-GLYCOPROTEIN |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA250,439A Expired CA1065307A (en) | 1975-04-18 | 1976-04-15 | PROCESS FOR THE PURIFICATION OF THE PREGNANCY-SPECIFIC .beta.1-GLYCOPROTEIN |
Country Status (18)
| Country | Link |
|---|---|
| JP (2) | JPS51133408A (en) |
| AT (2) | AT344920B (en) |
| AU (2) | AU503342B2 (en) |
| BE (2) | BE840912A (en) |
| CA (2) | CA1065305A (en) |
| DE (1) | DE2612479A1 (en) |
| DK (2) | DK173576A (en) |
| ES (2) | ES446944A1 (en) |
| FI (2) | FI54486C (en) |
| FR (2) | FR2307816A1 (en) |
| GB (2) | GB1541453A (en) |
| IE (2) | IE42679B1 (en) |
| IT (1) | IT1060215B (en) |
| LU (2) | LU74783A1 (en) |
| NL (2) | NL7603903A (en) |
| NO (2) | NO145405C (en) |
| NZ (1) | NZ180619A (en) |
| SE (2) | SE7604483L (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2720704C2 (en) * | 1977-05-07 | 1986-09-25 | Behringwerke Ag, 3550 Marburg | New glycoprotein, process for its production and its uses |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5325030B2 (en) * | 1972-12-19 | 1978-07-24 |
-
1976
- 1976-03-24 DE DE19762612479 patent/DE2612479A1/en active Pending
- 1976-04-12 ES ES446944A patent/ES446944A1/en not_active Expired
- 1976-04-12 ES ES446939A patent/ES446939A1/en not_active Expired
- 1976-04-13 NL NL7603903A patent/NL7603903A/en not_active Application Discontinuation
- 1976-04-13 NL NL7603902A patent/NL7603902A/en not_active Application Discontinuation
- 1976-04-14 DK DK173576A patent/DK173576A/en active IP Right Grant
- 1976-04-14 NO NO761305A patent/NO145405C/en unknown
- 1976-04-14 DK DK173876A patent/DK173876A/en active IP Right Grant
- 1976-04-14 FI FI761016A patent/FI54486C/en not_active IP Right Cessation
- 1976-04-14 NO NO761306A patent/NO761306L/no unknown
- 1976-04-14 FI FI761017A patent/FI56184C/en not_active IP Right Cessation
- 1976-04-15 SE SE7604483A patent/SE7604483L/en not_active Application Discontinuation
- 1976-04-15 AU AU13082/76A patent/AU503342B2/en not_active Expired
- 1976-04-15 CA CA250,426A patent/CA1065305A/en not_active Expired
- 1976-04-15 IE IE818/76A patent/IE42679B1/en unknown
- 1976-04-15 IE IE817/76A patent/IE42566B1/en unknown
- 1976-04-15 GB GB15557/76A patent/GB1541453A/en not_active Expired
- 1976-04-15 GB GB15558/76A patent/GB1541454A/en not_active Expired
- 1976-04-15 SE SE7604484A patent/SE419340B/en unknown
- 1976-04-15 CA CA250,439A patent/CA1065307A/en not_active Expired
- 1976-04-15 NZ NZ180619A patent/NZ180619A/en unknown
- 1976-04-15 AU AU13081/76A patent/AU503288B2/en not_active Expired
- 1976-04-16 LU LU74783A patent/LU74783A1/xx unknown
- 1976-04-16 FR FR7611372A patent/FR2307816A1/en active Granted
- 1976-04-16 LU LU74782A patent/LU74782A1/xx unknown
- 1976-04-16 AT AT284176A patent/AT344920B/en not_active IP Right Cessation
- 1976-04-16 IT IT22445/76A patent/IT1060215B/en active
- 1976-04-16 FR FR7611367A patent/FR2307815A1/en active Granted
- 1976-04-16 AT AT284276A patent/AT344734B/en not_active IP Right Cessation
- 1976-04-17 JP JP51044151A patent/JPS51133408A/en active Pending
- 1976-04-17 JP JP51044152A patent/JPS51133406A/en active Granted
- 1976-04-20 BE BE166290A patent/BE840912A/en unknown
- 1976-04-20 BE BE166291A patent/BE840913A/en not_active IP Right Cessation
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