CA2025530A1 - Porcine lactoferrin amino acid and cdna sequence and methods - Google Patents
Porcine lactoferrin amino acid and cdna sequence and methodsInfo
- Publication number
- CA2025530A1 CA2025530A1 CA002025530A CA2025530A CA2025530A1 CA 2025530 A1 CA2025530 A1 CA 2025530A1 CA 002025530 A CA002025530 A CA 002025530A CA 2025530 A CA2025530 A CA 2025530A CA 2025530 A1 CA2025530 A1 CA 2025530A1
- Authority
- CA
- Canada
- Prior art keywords
- cdna sequence
- sequence
- lactoferrin
- porcine
- cdna
- 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.)
- Abandoned
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
- C07K14/79—Transferrins, e.g. lactoferrins, ovotransferrins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/02—Fusion polypeptide containing a localisation/targetting motif containing a signal sequence
Abstract
ABSTRACT
A cDNA sequence for porcine lactoferrin (pLF) protein and corresponding amino acid sequence has been discovered.
The cDNA sequence can be used to prepare recombinant pig lactoferrin products for therapeutic and nutritional appli-cations. Regions of the cDNA such as the Fe binding sites can be used to make a pLF polypeptide product.
A cDNA sequence for porcine lactoferrin (pLF) protein and corresponding amino acid sequence has been discovered.
The cDNA sequence can be used to prepare recombinant pig lactoferrin products for therapeutic and nutritional appli-cations. Regions of the cDNA such as the Fe binding sites can be used to make a pLF polypeptide product.
Description
, ~ 2 3 ~ ~
P~TENT
PORCINE ~ACTOFERRIN AMINO ACID AND
cDNA SEQUENCE AND MET~ODS
BACRGROUND OF THE INVENTION
This application is related, in part, to Serial No.
348,270, entitled "Human Lactoferrin cDNA Sequence", filed May 5, 1389.
Lactoferrin is an iron-binding glycoprotein found in i~ -milk and other secretions and body fluids. It is one of a nul~er of iron binding proteins, sometimes referred t~ as transferrins, and is involved in iron binding and delivery in mammals.
Lactoferrin has been implicated as a factor in resis-tance against enteritis infections in suckled newborns.
These bacteriocidal/bacteriostatic actions are considered to be due, in part, to the iron binding properties of the protein. Lactoferrin decreases the iron availability to iron requiring microorganisms and thereby interferes with their growth and reproduction. Lactoferrin is also con-sid:red to have antiviral properties and other potential therapeutic applications.
~ uman lactoferrin (hLF) has been studied and the amino acids and cDNA has been seq,uenced. The protein has a high affinity for iron with two Fe3 cations binding sites per molecule. Bovine lactoferrin has been isolated and is used as a milk additive. A protein identified as mouse lacto- ;
transferrin has been isolated. The CDNA sequence and deduced amino acids have been reported. Pentecost and Teng, "Lactotransferrin Is The Major Estrogen Inducible Protein of Mouse Uterine Secretions", 262 J. Biol. Chem., pp. 10134-10139 (1987).
Pig lactoferrin (pLF) has not been sequenced for amino acids or nucleotides. Piglets suffer from anemia; there- `
PATENT
fore, an enhanced iron delivery system would be valuable.
~lso, therapeutic uses of lactoferrins have been reported which would benefit humans and animals.
SUMMARY OF TIIE INVENTION
The invention is the cDNA sequence for the partial porcine or pig lactoferrin 1PLF) protein which includes two iron binding sites. The porcine cDN~ sequence lacks about 105 nucleotides from the coding sequence in the second iron binding domain of the mature protein. The cDNA sequence does not code for the entire protein but for a substantial part of the protein. Part of the cDNA sequence may be used to code a polypeptide with the entire iron binding domain closest to the N-terminal end of the protein.
A complete cDNA sequence includes nucleotides coding for a secretion signal peptide which enables the mature pLF
to cross the cell membrane~ The nucleotide sequence for the porcine cDNA coding the secretion signal peptide is incom-plete. ~owever, the signal peptide for hLF can be used with the porcine nucleotide sequence.
The present invention of the cDNA sequence can be used ~ ~-to prepare a recombinant porcine lactoferrin product, thus making available a source for therapeutic and nutritional applications. The cDNA sequence of this invention can be used in an appropriate cloning vehicle to replicate the cDNA
sequence. Also, part or all of the cDNA can be incorporated into a vectorisystem for expression. This invention is not limited to any particular uses of the cDNA. The inclusion of a substantial part of the lactoferrin gene with expres-sion should improve an animal's disease resistance to bacterial and viral infection. The tissue specific expres-sion of lactoferrin in mammary glands, for instance, would impart the bacteriocidal and viracidal benefit of the expressed gene to young feeding on the milk and would provide a production means for the secreted protein for therapeutic use.
P~TENT
PORCINE ~ACTOFERRIN AMINO ACID AND
cDNA SEQUENCE AND MET~ODS
BACRGROUND OF THE INVENTION
This application is related, in part, to Serial No.
348,270, entitled "Human Lactoferrin cDNA Sequence", filed May 5, 1389.
Lactoferrin is an iron-binding glycoprotein found in i~ -milk and other secretions and body fluids. It is one of a nul~er of iron binding proteins, sometimes referred t~ as transferrins, and is involved in iron binding and delivery in mammals.
Lactoferrin has been implicated as a factor in resis-tance against enteritis infections in suckled newborns.
These bacteriocidal/bacteriostatic actions are considered to be due, in part, to the iron binding properties of the protein. Lactoferrin decreases the iron availability to iron requiring microorganisms and thereby interferes with their growth and reproduction. Lactoferrin is also con-sid:red to have antiviral properties and other potential therapeutic applications.
~ uman lactoferrin (hLF) has been studied and the amino acids and cDNA has been seq,uenced. The protein has a high affinity for iron with two Fe3 cations binding sites per molecule. Bovine lactoferrin has been isolated and is used as a milk additive. A protein identified as mouse lacto- ;
transferrin has been isolated. The CDNA sequence and deduced amino acids have been reported. Pentecost and Teng, "Lactotransferrin Is The Major Estrogen Inducible Protein of Mouse Uterine Secretions", 262 J. Biol. Chem., pp. 10134-10139 (1987).
Pig lactoferrin (pLF) has not been sequenced for amino acids or nucleotides. Piglets suffer from anemia; there- `
PATENT
fore, an enhanced iron delivery system would be valuable.
~lso, therapeutic uses of lactoferrins have been reported which would benefit humans and animals.
SUMMARY OF TIIE INVENTION
The invention is the cDNA sequence for the partial porcine or pig lactoferrin 1PLF) protein which includes two iron binding sites. The porcine cDN~ sequence lacks about 105 nucleotides from the coding sequence in the second iron binding domain of the mature protein. The cDNA sequence does not code for the entire protein but for a substantial part of the protein. Part of the cDNA sequence may be used to code a polypeptide with the entire iron binding domain closest to the N-terminal end of the protein.
A complete cDNA sequence includes nucleotides coding for a secretion signal peptide which enables the mature pLF
to cross the cell membrane~ The nucleotide sequence for the porcine cDNA coding the secretion signal peptide is incom-plete. ~owever, the signal peptide for hLF can be used with the porcine nucleotide sequence.
The present invention of the cDNA sequence can be used ~ ~-to prepare a recombinant porcine lactoferrin product, thus making available a source for therapeutic and nutritional applications. The cDNA sequence of this invention can be used in an appropriate cloning vehicle to replicate the cDNA
sequence. Also, part or all of the cDNA can be incorporated into a vectorisystem for expression. This invention is not limited to any particular uses of the cDNA. The inclusion of a substantial part of the lactoferrin gene with expres-sion should improve an animal's disease resistance to bacterial and viral infection. The tissue specific expres-sion of lactoferrin in mammary glands, for instance, would impart the bacteriocidal and viracidal benefit of the expressed gene to young feeding on the milk and would provide a production means for the secreted protein for therapeutic use.
5 ~3~j PATENT
The gene can be placed in the appropriate cloning vector for the production of a synthetic pLF product. The pLF polypeptide produced by recombinant methods can be used in a variety of products including feed, therapeutic addi-tives to enhance iron transport and delivery and for the viracidal and bacteriocidal qualities, additives for eye- --drops, contact lens and o~her eye care solutions, topical skin care products, ear drops, mouthwashes, chewing gum and toothpaste. The recombinant pLF polypeptide product would provide a safe, naturally occurring product which can be topically applied as well as ingested safely.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is the number cDNA sequence from 5' to 3' end with the partial porcine signal peptide sequence and the partial mature porcine lactoferrin protein sequence and untranslated regions with corresponding deduced amino acids.
Fig. 2 is a cDNA sequence from 5' to 3' end and corre~
sponding amino acids starting with part of the untranslated hLF, hLF signal peptide sequence, the mature porcine lacto-ferrin nucleotide sequence and the untranslated pLF cDNA at the 3' end.
DETAILED DESCRIPTION OF THE INVENTION ~ -The cDNA sequence for the porcine lactoferrin gene including iron-binding sites for two iron binding domains is shown in Fig. 1. The sequence in Fig. 1 starting at the 5' end includes an untranslated region of undetermined length which is not sequenced shown as "NNNNNNNNNN". The next sequence from the 5' end is a signal peptide for secretion for pLF lacking two amino acids. The signal peptide is not part of the mature pLF but is necessary for effective secretion of the protein. The following portion of the cDNA ;~
sequence in Fig. 1 starting with the nucleotides coding for amino acid number 20 alanine is the full cDNA sequence for the first iron binding domain of pLF.
The gene can be placed in the appropriate cloning vector for the production of a synthetic pLF product. The pLF polypeptide produced by recombinant methods can be used in a variety of products including feed, therapeutic addi-tives to enhance iron transport and delivery and for the viracidal and bacteriocidal qualities, additives for eye- --drops, contact lens and o~her eye care solutions, topical skin care products, ear drops, mouthwashes, chewing gum and toothpaste. The recombinant pLF polypeptide product would provide a safe, naturally occurring product which can be topically applied as well as ingested safely.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is the number cDNA sequence from 5' to 3' end with the partial porcine signal peptide sequence and the partial mature porcine lactoferrin protein sequence and untranslated regions with corresponding deduced amino acids.
Fig. 2 is a cDNA sequence from 5' to 3' end and corre~
sponding amino acids starting with part of the untranslated hLF, hLF signal peptide sequence, the mature porcine lacto-ferrin nucleotide sequence and the untranslated pLF cDNA at the 3' end.
DETAILED DESCRIPTION OF THE INVENTION ~ -The cDNA sequence for the porcine lactoferrin gene including iron-binding sites for two iron binding domains is shown in Fig. 1. The sequence in Fig. 1 starting at the 5' end includes an untranslated region of undetermined length which is not sequenced shown as "NNNNNNNNNN". The next sequence from the 5' end is a signal peptide for secretion for pLF lacking two amino acids. The signal peptide is not part of the mature pLF but is necessary for effective secretion of the protein. The following portion of the cDNA ;~
sequence in Fig. 1 starting with the nucleotides coding for amino acid number 20 alanine is the full cDNA sequence for the first iron binding domain of pLF.
-3- ~ -': "''. .' PATENT
The iron binding domains require an adequate number of amino acids in sequence for three dimensional confirmation to align the iron molecule with tlle binding sites. Tlle iron binding sites closest to the N-terminal end of pLF are disclosed. The full functional domain is shown in Fig. 1.
A polypeptide product may be prepared using the sequence shown in Fig. 1 for the complete iron binding N-terminal end of the protein.
The amino acids asparagine, tyrosine, tyrosine and histidine, numbers 77, 107, 204 and 268, respectively, are iron binding sites of the first domain closest to the N-terminal end of the protein. The cDNA sequence has been determined up to the corresponding nucleotide for the amino acid asparagine, number 463. Thereafter, about 105 nucleotides have not been determined.
For the remainder of Fig. 1 approximate nucleotide number and amino acid numbers are assigned for convenience of reference. The omitted nucleotide bases are represented as repeated "N's" and are in the region of the second iron binding domain. However, the iron binding sites for the domain nearest the carboxy terminus of the protein are identified for the second domain as amino acids asparagine, tyrosine, tyrosine and histidine, numbers 409, 448, 540 and 609, respectively. Starting at glutamine, numbered as amino acid 499 of Fig. 1, the corresponding cDNA sequence for pLF
is complete for the rest of the mature protein including the carboxy terminal end of the protein. The cDNA sequence continues to the '3 end with an untranslated region staxting at nucleotide number 2068.
The pLF cDNA and amino acid sequence to the nearly complete signal peptide, mature protein and untranslated region is shown in Fig. 1. The pLF cDNA disclosed does not code the entire protein. However, a polypeptide coded by the cDNA of the invention can include only the functional domain around the iron binding sites useful in iron delivery or any other useful amino acid sequence. It is not the intention to limit the`invention to the entire cDNA sequence `
shown in Fig. 1. Any useful pLF polypeptide product coded ~ ~3 ~ s ~j PATENT
by all or part of the cDNA sequence is included in this invention. Similarly, any portion of the cDNA sequence used with an expression vector to code a useful polypeptide is part of this invention. One or more of the cDNA sequences for the functional iron binding domains may be placed in a vector for expression. The cDNA sequence disclosed is a map from which to select the nucleotide sequence to code for the desired pLF polypeptide product. There are no limitations intended for the use of the cDNA sequence to produce a useful polypeptide.
The sequence in Fig. 2 is an example of the use o~ cDNA
sequence coding the mature pLF from Fig. 1 in combination with the entire sequence coding for the human secretion signal peptide for hLF. The mature pLF cDNA sequer.ce or parts thereof can be joined with the hLF signal peptide to `;
create a new polypeptide of this invention.
In Fig. 2, a short portion of untranslated hLF from the 5' end, "GACCGCAGAC", is shown at the beginning of the cDNA
sequence. The numbering of the nucleotide bases starts at the 5' untranslated end. The sequence in Fig. 2 ends with an untranslated pLF cDNA at the 3' end. It is not necessary to use the untranslated cDNA at either the 3' or the 5' end to prepare a polypeptide of this invention. The human signal portion will effect secretion of the mature porcine lactoferrin polypeptide. The human signal peptide and corresponding cDNA sequence is:
ATC AAA CTT. GTC TTC CTC GTC CTG Cl'G TTC Cl'C GGG CCC CTC GGA CTG TGT CTG GCT
met ly9 leu val phe leu val leu leu phe leu gly ala leu gly leu cys leu ala ~ .
The nucleotide sequence analysis was performed on cDNA
isolated from a porcine mammary cDNA library. The library yielded two cDNA clones with sequences for analysis. One clone contained a sequence 1391 base pairs (bp) in length and included all but two amino acids of pLF secretion signal peptide sequence. Also, the 1391 bp clone contained the first 463 amino acids of mature pLF and encoded the complete -N-terminal iron bindiny domain.
.
~ ~ t~
PATENT
The second cDNA sequence was 801 base pairs in length.
It encoded the carboxy-terminal 162 amino acids of mature pLF followed by 238 nucleotides of the 3' untranslated region.
. . ' ~ . "f' ::
':
' ` , , ' .
'' "'"
. , ", ' .
.
The iron binding domains require an adequate number of amino acids in sequence for three dimensional confirmation to align the iron molecule with tlle binding sites. Tlle iron binding sites closest to the N-terminal end of pLF are disclosed. The full functional domain is shown in Fig. 1.
A polypeptide product may be prepared using the sequence shown in Fig. 1 for the complete iron binding N-terminal end of the protein.
The amino acids asparagine, tyrosine, tyrosine and histidine, numbers 77, 107, 204 and 268, respectively, are iron binding sites of the first domain closest to the N-terminal end of the protein. The cDNA sequence has been determined up to the corresponding nucleotide for the amino acid asparagine, number 463. Thereafter, about 105 nucleotides have not been determined.
For the remainder of Fig. 1 approximate nucleotide number and amino acid numbers are assigned for convenience of reference. The omitted nucleotide bases are represented as repeated "N's" and are in the region of the second iron binding domain. However, the iron binding sites for the domain nearest the carboxy terminus of the protein are identified for the second domain as amino acids asparagine, tyrosine, tyrosine and histidine, numbers 409, 448, 540 and 609, respectively. Starting at glutamine, numbered as amino acid 499 of Fig. 1, the corresponding cDNA sequence for pLF
is complete for the rest of the mature protein including the carboxy terminal end of the protein. The cDNA sequence continues to the '3 end with an untranslated region staxting at nucleotide number 2068.
The pLF cDNA and amino acid sequence to the nearly complete signal peptide, mature protein and untranslated region is shown in Fig. 1. The pLF cDNA disclosed does not code the entire protein. However, a polypeptide coded by the cDNA of the invention can include only the functional domain around the iron binding sites useful in iron delivery or any other useful amino acid sequence. It is not the intention to limit the`invention to the entire cDNA sequence `
shown in Fig. 1. Any useful pLF polypeptide product coded ~ ~3 ~ s ~j PATENT
by all or part of the cDNA sequence is included in this invention. Similarly, any portion of the cDNA sequence used with an expression vector to code a useful polypeptide is part of this invention. One or more of the cDNA sequences for the functional iron binding domains may be placed in a vector for expression. The cDNA sequence disclosed is a map from which to select the nucleotide sequence to code for the desired pLF polypeptide product. There are no limitations intended for the use of the cDNA sequence to produce a useful polypeptide.
The sequence in Fig. 2 is an example of the use o~ cDNA
sequence coding the mature pLF from Fig. 1 in combination with the entire sequence coding for the human secretion signal peptide for hLF. The mature pLF cDNA sequer.ce or parts thereof can be joined with the hLF signal peptide to `;
create a new polypeptide of this invention.
In Fig. 2, a short portion of untranslated hLF from the 5' end, "GACCGCAGAC", is shown at the beginning of the cDNA
sequence. The numbering of the nucleotide bases starts at the 5' untranslated end. The sequence in Fig. 2 ends with an untranslated pLF cDNA at the 3' end. It is not necessary to use the untranslated cDNA at either the 3' or the 5' end to prepare a polypeptide of this invention. The human signal portion will effect secretion of the mature porcine lactoferrin polypeptide. The human signal peptide and corresponding cDNA sequence is:
ATC AAA CTT. GTC TTC CTC GTC CTG Cl'G TTC Cl'C GGG CCC CTC GGA CTG TGT CTG GCT
met ly9 leu val phe leu val leu leu phe leu gly ala leu gly leu cys leu ala ~ .
The nucleotide sequence analysis was performed on cDNA
isolated from a porcine mammary cDNA library. The library yielded two cDNA clones with sequences for analysis. One clone contained a sequence 1391 base pairs (bp) in length and included all but two amino acids of pLF secretion signal peptide sequence. Also, the 1391 bp clone contained the first 463 amino acids of mature pLF and encoded the complete -N-terminal iron bindiny domain.
.
~ ~ t~
PATENT
The second cDNA sequence was 801 base pairs in length.
It encoded the carboxy-terminal 162 amino acids of mature pLF followed by 238 nucleotides of the 3' untranslated region.
. . ' ~ . "f' ::
':
' ` , , ' .
'' "'"
. , ", ' .
.
-6~
Claims (11)
1. A cDNA sequence coding for the partial porcine lactoferrin protein, said DNA sequence comprising the sequence of Fig. 1.
2. A synthetic porcine lactoferrin product comprising a polypeptide from the cDNA sequence of Fig. 1.
3. A synthetic porcine lactoferrin product comprising a polypeptide sequence corresponding to a selected portion of the cDNA sequence of Fig. 1.
4. A method to produce synthetic porcine lactoferrin product comprising the steps of incorporating the cDNA
sequence of Fig. 1 in a vector; and expressing the porcine lactoferrin product.
sequence of Fig. 1 in a vector; and expressing the porcine lactoferrin product.
5. A portion of the cDNA sequence coding for the partial porcine lactoferrin product of claim 1 comprising regions of the DNA sequence of Fig. 1 containing at least one of the iron binding domains.
6. A synthetic porcine lactoferrin product comprising a polypeptide including at least one of the iron binding domains of Fig. 1.
7. A method to produce synthetic porcine lactoferrin product comprising utilizing the cDNA sequence of Fig. 1 including at least one Fe binding domain and expressing the porcine lactoferrin product.
8. A cDNA sequence comprising the cDNA sequence for the human lactoferrin secretion signal peptide and the mature porcine lactoferrin cDNA sequence of Fig. 2.
9. A synthetic polypeptide comprising the human lactoferrin secretion signal peptide of Fig. 2 and a select-ed part of of the partial mature porcine lactoferrin protein of Fig. 2.
10. A synthetic polypeptide of claim 9 wherein the portion of the partial mature porcine lactoferrin protein includes at least one iron binding domain.
11. A method to produce a synthetic polypeptide utliz-ing the cDNA sequence described in claim 9 and producing with a vector the synthetic porcine lactoferrin product with the human lactoferrin secretion signal peptide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US41388089A | 1989-09-28 | 1989-09-28 | |
| US413,880 | 1989-09-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2025530A1 true CA2025530A1 (en) | 1991-03-29 |
Family
ID=23639053
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002025530A Abandoned CA2025530A1 (en) | 1989-09-28 | 1990-09-17 | Porcine lactoferrin amino acid and cdna sequence and methods |
Country Status (5)
| Country | Link |
|---|---|
| AU (1) | AU6406590A (en) |
| CA (1) | CA2025530A1 (en) |
| IE (1) | IE903471A1 (en) |
| IL (1) | IL95697A0 (en) |
| WO (1) | WO1991005045A1 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6100054A (en) * | 1989-05-05 | 2000-08-08 | Baylor College Of Medicine | Production for recombinant lactoferrin and lactoferrin polypeptides using DNA sequences in various organisms |
| IL94183A (en) | 1989-05-05 | 2003-09-17 | Baylor College Medicine | cDNA SEQUENCE CODING FOR HUMAN LACTOFERRIN PROTEIN OR PORTION THEREOF AND LACTOFERRIN PROTEIN PRODUCED FROM SAID SEQUENCE |
| US5849881A (en) * | 1989-05-05 | 1998-12-15 | Baylor College Medicine | Production of recombinant lactoferrin and lactoferrin polypeptides using cDNA sequences in various organisms |
| US5571691A (en) * | 1989-05-05 | 1996-11-05 | Baylor College Of Medicine | Production of recombinant lactoferrin and lactoferrin polypeptides using CDNA sequences in various organisms |
| US5571697A (en) * | 1989-05-05 | 1996-11-05 | Baylor College Of Medicine Texas Medical Center | Expression of processed recombinant lactoferrin and lactoferrin polypeptide fragments from a fusion product in Aspergillus |
| US5766939A (en) * | 1989-05-05 | 1998-06-16 | Baylor College Of Medicine | Production of recombinant lactoferrin and lactoferrin polypeptides using CDNA sequences in various organisms |
| JP3312946B2 (en) * | 1993-03-04 | 2002-08-12 | 雪印乳業株式会社 | Virus infection / growth inhibitor |
| US6111081A (en) * | 1996-05-31 | 2000-08-29 | Baylor College Of Medicine | Lactoferrin variants and uses thereof |
-
1990
- 1990-09-14 WO PCT/US1990/005245 patent/WO1991005045A1/en unknown
- 1990-09-14 IL IL95697A patent/IL95697A0/en unknown
- 1990-09-14 AU AU64065/90A patent/AU6406590A/en not_active Abandoned
- 1990-09-17 CA CA002025530A patent/CA2025530A1/en not_active Abandoned
- 1990-09-27 IE IE347190A patent/IE903471A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL95697A0 (en) | 1991-06-30 |
| IE903471A1 (en) | 1991-04-10 |
| WO1991005045A1 (en) | 1991-04-18 |
| AU6406590A (en) | 1991-04-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |