WO1998003677A2 - Pit-1 gene polymorphism and trait selection in animals - Google Patents
Pit-1 gene polymorphism and trait selection in animals Download PDFInfo
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- WO1998003677A2 WO1998003677A2 PCT/EP1997/003939 EP9703939W WO9803677A2 WO 1998003677 A2 WO1998003677 A2 WO 1998003677A2 EP 9703939 W EP9703939 W EP 9703939W WO 9803677 A2 WO9803677 A2 WO 9803677A2
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6881—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for tissue or cell typing, e.g. human leukocyte antigen [HLA] probes
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/124—Animal traits, i.e. production traits, including athletic performance or the like
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/156—Polymorphic or mutational markers
Definitions
- the present invention relates to a genetic marker associated with different conformational traits More specifically, the present invention describes a process wherein a polymorphism in a P ⁇ t-1 gene is used to determine traits in animals such as milk production and muscularity with ease
- selection process involves a geneological evaluation of the mammals history over a long period of time This evaluation is based on various traits of the mammal or animal such as birth weight, growth weight, build, muscle strength, firmness, marbling, color, and
- the somatotropin system has several genes that may play a role in the control of particular traits in animals since this system is associated with growth, lactation, reproduction and immunity
- the somatotropin system is quite complicated and involves at a hypothalamic level, somatoc ⁇ nin and somatostatin, at a pituitary level, pituitary-specific transcription factor (P ⁇ t-1 ) which is responsible for growth hormone expression in mammals, at a hepatic level, growth hormone receptor and growth hormone plasmatic transport protein, and at a cellular level, growth hormone receptor, insulin-growth factor- and insulin growth factor transport protein
- the present invention involves the selection of a gene, the pituitary- specific transcription factor (hereinafter referred to as P ⁇ t-1 ) that can act as a genetic marker to characterize specific traits in animals
- P ⁇ t-1 is a member of the POU family of homeo-domain transcription factors and plays an important role in developmental processes
- the POU- domam was originally identified as a highly conserved region of 150 to 160 ammo acids found in three mammalian transcription factors, P ⁇ t-1 , Oct-1 , Oct- 2 and also in the product of nematode gene unc-86 (Herr et al , Genes & Dev 2: 1513 (1988), Ruvkun and Finnery, Cell 64 475 (1991 ))
- P ⁇ t-1 is a pituitary-specific transcription factor that regulates growth hormone, activates prolactin and has a role in pituitary cell differentiation and proliferation (Stei ⁇ felder et al , P N A S , USA 88 3130 (1991 ) Mutations in the P ⁇ t-1 gene responsible for the dwarf phenotypes of the Snell and Jackson mice and lead to anterior pituitary hypoplasia (Li et al , Nature 347 528 (1992)) Moreover, it has been shown that the inhibition of P ⁇ t-1 synthesis leads to a decrease in prolactin and growth hormone (GH) expression and to a dramatic decrease in cell proliferation in GH and prolactin producing cell lines (McCormick et al , Nature 345 829 (1990))
- GH prolactin and growth hormone
- the present invention overcomes the disadvantages of the current methods of trait selection in animals by providing a scientific basis for selection of traits by use of a genetic marker
- the process described in the present invention can be used to characterize superior milk producing animals from animals having meat producing characteristics
- a polymorphism in the P ⁇ t-1 gene can be used to characterize traits such as milk production and muscularity in animals
- Two alleles, A and B were distinguished for the P ⁇ t-1 gene responsible for the activation of prolactin and growth hormone gene expression
- the AA pattern was less frequent than the AB or BB pattern
- the significant superiority of the P ⁇ t-1 AB pattern or AA pattern over the BB pattern was observed for milk, protein and angularity
- the BB genotype pattern was associated with animal muscularity
- the present invention provides a process to characterize animals having superior milk production traits or muscularity traits
- the present invention provides genetically engineered animals that have superior milk production, angularity, fat, protein or muscularity traits
- the present invention provides a method to identify a polymorphism present in the P ⁇ t-1 gene which polymorphism can be utilized to select superior traits in animals for angularity, fat, muscularity protein or milk production
- the present invention relates to a genetic marker used to distinguish amongst animals a trait for milk producing capabilities or meat producing capabilities said genetic marker comprising a mutation in a fragment of a P ⁇ t-1 gene, wherein three allele patterns are observed, the fully mutated pattern being indicative
- the marker characteristic of milk producing capabilities is called AA for its homozygous state of the allele and the marker characteristic of meat producing capabilities is called BB for its homozygous state
- sequences of alleles A and B differ only by one transition from the Adenosi ⁇ e in position 1178 of the sequence of Figure 2 in P ⁇ t-1 AA to a guanine in P ⁇ t-1 BB, as demonstrated by the inventors by experiments shown in Example B
- the three allele patterns are distinguished after digestion with a restriction endonuclease, which cleaves the mutated P ⁇ t-1 gene fragment and not the non-mutated P ⁇ t-1 gene fragment, the fully digested pattern being indicative of a trait for muscularity in said animal, while the intermediate digested/non-digested pattern or the fully non-digested pattern being indicative of a milk producing trait in said animal.
- the restriction e ⁇ donuclease utilized is H ⁇ nf ⁇ .
- the three allele patterns are distinguished using probes which overlap the mutated region in said Pit-1 gene, one probe being specific for the mutated Pit-1 gene and another one being specific for the non-mutated P ⁇ t-1 gene.
- the present invention relates to a process for detecting certain traits in an animal, said process comprising the steps of
- detection is accomplished by using restriction endonucleases. In another particular embodiment of the present invention, detection is accomplished by using probes which overlap the mutated gene in said Pit-1 gene, more particularly the 1 178 position.
- the present invention relates to genetically engineered animals that have the characteristic traits described in the present invention.
- Fig. 1 is an electrophoretic gel illustrating the PCR/Restnction Fragment Length Polymorphism patterns using the restriction enzymes Hinf ⁇ on the Pit-1 gene observed in Holstem-Friesian and Simmental Bulls The sizes of digested fragments are on the left, and the patterns are at the top Fragment length (in kilobases) was estimated relative to the DNA size markers ⁇ X174 DNA/Haelll fragments
- Figure 2 is the sequence of bovine P ⁇ t-1 cDNA
- Figure 3 is an electrophoretic pattern illustrating the PCR amplification products obtained after amplification with following primers lines 1 -3-5 Pit 1 AA and Pit 1 B, lines 2-4-6 Pit 1 BB and Pit 1 B
- the "animal” encompasses all mammals, avians and fish including but not limited to, cows, bulls, goats, pigs, sheep, chickens and the like
- the invention is easily transposable from one specie to another
- the instant invention can be used in human beings to determine traits such as capacity to metabolize growth hormone
- polymorphism refers to the simultaneous occurrence in the population of genomes showing allelic variations as seen either in alleles producing different phenotypes or in changes in DNA affecting the restriction pattern
- the term “trait” encompasses any characteristic, especially one that distinguishes one animal from another
- angularity means an objective criteria used to identify specific traits of an animal in relation to specific measurements which can be taken on the animal's body The measurements are taken on the animal with respect to certain morphological characteristics
- the pelvic bones and muscles surrounding the pelvic bones of an animal are measured to determine whether they are projecting or not A scale can then
- muscleity encompasses animals that are better meat producers that can be slaughtered for their meat than milk producers
- the present invention relates to the use of a P ⁇ t-1 gene polymorphism as a potential marker for genetic variations in animals
- P ⁇ t-1 codes for a factor of transcription in a cell and any mutation of this gene can alter by diminution or augmentation the capacity of transcription thus resulting in polymorphisms which effect the outcome of different traits in an animal
- the P ⁇ t-1 gene was previously identified in a 13-kb bovine genomic library by Woolard et al , supra A 13-kb clone was isolated from this library by using a bovine P ⁇ t-1 cDNA, which is labeled, as a probe of
- the first step in identifying a mutation in the P ⁇ t-1 gene in an animal is to obtain a sample from the animal such as, but not limited to semen, blood, a cells, biopsy tissues, feces and the like Genomic DNA can then be extracted for the specimens obtained using methods known in the art as described by Sambrook et al , Molecular Cloning, A Laboratory Manual, second edition 1 989 However, it is preferable to extract the genomic DNA using the procedure described in Walsh, Biotechniques, 10 506 ( 1991 ) for semen or the procedure for blood as described
- PCR primers are used to amplify by standard procedures a fragment that includes the P ⁇ t-1 gene
- PCR primers can be utilized that would permit the amplification of the P ⁇ t-1 sequence and the method in isolating the particular clone which would identify such primers
- the PCR primers can be designed from intron V and exon 6 of a fragment containing the polymorphism of the P ⁇ t-1 gene, such as the 451 -bp fragment described by Woolard et a
- Amplification of the P ⁇ t-1 fragment can be performed using standard
- the following conditions for the PCR reaction can be employed between 88°C to 98°C for 10 to 15 minutes, and between 90°C to 100°C for about 1 minute, followed by between 25 to 50 cycles at between 90°C to 100°C for 20 to 40 seconds, 40°C to 60°C for 1 to 5 minutes, and 68°C to 80°C for about 1 to 5 minutes
- the last step may encompass a cycle at between 68°C to 80°C for 8 to 12 minutes
- restriction enzymes include, but are not limited to Bam ⁇ , EcoRI, Smal, Hmf ⁇ and the like See, for example those enzymes described in Sambrook et al ,s ⁇ pra It is of particular interest to use a restriction endonuclease which cleaves the mutated allele of the P ⁇ t-1 gene and does not cleave the non- mutated allele of the P ⁇ t-1 gene
- Htnf ⁇ is utilized
- the sample is then electrophoresed on agarose gels and identified with a stain such as, for example ethidium bromide, however any stain can be used that identifies the fragments
- SCCP(s ⁇ ngle stranded conformation polymorphism) is also a method known in the art that can identify a mutation or mutations in the isolated genomic P ⁇ t-1 fragment This method is based on PCR amplification, using similar primers as those described above. The amplified fragment is then labeled with a label such as 32 P or with any other appropriate radioactive label The radiolabeled fragment is then denatured, for example by heating and then subjected to quick cooling After cooling, the fragment is then electrophoresed using non-denatured technique and then audioradiographed
- DGGE denaturing gradient gel electrophoresis
- Another method that can be used to detect the mutation in the P ⁇ t-1 gene utilizes primers that overlap the mutated region of the P ⁇ t-1 gene More preferably, two separate amplification reactions are performed on the extracted genomic DNA sample using two sets of primers one set containing a primer which overlaps and is specific for the mutated P ⁇ t-1 gene, another set containing a primer which overlaps and is specific for the non- mutated P ⁇ t-1 gene Even more preferably, the primers used are labeled so that the amplification product can be easily visualized
- the tested genomic DNA contains a homozygous mutated P ⁇ t-1 gene (two mutated alleles)
- only the amplification reaction using the probe specific for the mutated region will produce a signal (i e , an amplification product)
- the two amplification reactions will produce a signal (an amplification product)
- the tested genomic DNA contains a
- the visualization can be very easy
- the probes are radiolabelled visualization is obtained by electrophoresis
- immediate visualization is obtained
- the test can be carried out in very simple devices, such as plates Samples of the genomic DNA are introduced into 2 wells, one with the labeled set of probes containing one probe which overlaps the P ⁇ t-1 gene mutation and is specific for the mutated P ⁇ t-1 gene, one with the set of probes containing one probe which overlaps the P ⁇ t-1 gene mutation and is specific for the non-mutated P ⁇ t-1 gene
- the labelling appears directly in the plates and can be analyzed by automated devices
- the second primer used in each of the set of probes is selected in such a way as to enable amplification of a product containing from 200 to 400 bp More preferably 320-370 bp
- Such second primers can be for instance selected from the following primers gac agggaaagtg atatagaaag ggagataga (P ⁇ t-1 B)
- each of the primers is preferably comprised between 20 and 40 bases, more preferably between 25 and 35
- the position of the probe which overlap the mutated region (the mutation) can vary
- the two couples of primers are ca gagagaaaaa cgggtgaaga caagcat a (P ⁇ t-1 AA) gac agggaaagtg atatagaaag ggagataga (P ⁇ t-1 B) for the AA genotype, characteristic of milk producing capabilities and
- the alleles and allelic patterns are then identified and statistical analysis is then performed to determine the specific traits evidenced by the identification of the alleles More specifically, any statistical program that can identify daughter yield variations (DYD) and deregressed proofs (DRP) can be utilized It is preferable to perform the statistical analysis using the MIXED procedure of SAS ( User's Guide Statistics, Version 6, 4th ed SAS Inst , Inc Cary, N C (1990), Technical Report P 229 SAS I ⁇ st , Inc , Cary, N C (1992)
- the statistical analysis used in the present invention is discussed in detail in the examples below
- a kit containing extraction materials for genomic DNA, the PCR primers having SEQ ID NOS 1 and 2 (illustrated above), the materials necessary to visualize the mutation such as electrophoretic gels and the like The content of the kit may vary depending upon the detection methods utilized, which are discussed in detail above
- primers that overlap the mutation in the P ⁇ t-1 gene are also encompassed by the present invention.
- the invention also relates to a primer comprising from 20 to 40 bases, which is complementary to a region of the P ⁇ t-1 gene having a mutation
- the invention also embraces sets of primers which allow the amplification of a region of 200 to 400 bases in the P ⁇ t-1 gene, wherein said region contains a mutation
- the following primers are encompassed in the present invention ca gagagaaaaa cgggtgaaga caagcat a (P ⁇ t-1 AA) ca gagagaaaaa cgggtgaaga caagcat g (P ⁇ t-1 BB) gac agggaaagtg atatagaaag ggagataga (P ⁇ t-1 B)
- Genomic DNA of 89 commercially available registered Italian Holstem- F ⁇ esian bulls was extracted from semen as described by Lucy et al , Domest Amm Endocnnol 10 325 (1993)
- the RFLP at the P ⁇ t-1 gene using Htn ⁇ restriction enzyme was revealed by PCR analysis adapted from Woolard et al , supra
- the PCR primers were designed from intron V and exon 6
- the sequences of the primers used were 5'-AAACCATCATCTCCCTTCTT-3' (SEQ ID NO 1 ) and 5'-AATGTACAATGTGCCTTCTGAG-3' (SEQ ID NO.2)
- These primers were used to amplify by standard procedures a 451 -bp fragment form the genomic DNA in 50- ⁇ L reaction volumes containing 2 mM MgCI 2 Conditions were 94 5°C, 10 mm , and 94°C, 1 mm , followed by 35 cycles of 95°C, 30 s, 56°C, 1 m
- V QEQ'
- E is a diagonal matrix of eigenvalues
- Q a matrix of eigenvectors
- PCR/RFLP The PCR product was 451 bp in length Digestion of the PCR product with Hm ⁇ revealed two alleles the A allele not digested with H ⁇ nf ⁇ and yielding a 451 bp fragment and the B allele cut at one restriction site and generating two fragments of 244 and 207 bp in length as described by Woollard et al ,s ⁇ pra ( Figure 1 )
- the frequencies of the three pattern AA, AB, and BB were 2 2%, 31 5% and 66 3%
- the frequencies of the A and B alleles were estimated by a maximum likelihood approach with 18 8% for A and 81 2% for B
- Table 3 shows the linear contrasts and standard errors between the three P ⁇ t-1 pattern Therefore the highly significant contrasts (P ⁇ 0 01 ) observed for rear legs seem to be more due to the fact that the typed AA animals are extreme on this trait than to a real biological reason Highly significant contrasts between AB and BB patterns were found for milk and protein yield (P ⁇ 0 01 ) Significant contrasts were observed for fat c5 ⁇ percentage and angularity ( P ⁇ 0 05) The AB pattern or AA pattern was superior for milk, protein yield and angularity and inferior for fat percentage These results can be interpreted as resulting from a single positive action of the heterozygote AB or AA on milk yield, thereby influencing protein yield positively and not fat yield which gives the observed negative influence on fat percentage The influence of P ⁇ t-1 on angularity is in this context not very surprising as this linear trait is considered being strongly related to milk yield
- Body depth 0.108 1.076 0.562 1.061 0.454 0.332
- results from the canonical decomposition of the correlation matrix are in table V
- the first and the second canonical trait explain 90% of the total variance Especially the last canonical trait was not very informative
- Table 5 gives also the eigenvectors and the relative importance of the different traits in each eigenvector
- the first canonical trait is a combination of all four traits with relative influences between 15% for angularity and 30% for protein
- the second canonical trait however is more specifically linked to angularity with a
- Table 6 shows the linear contrasts and standard-errors observed for the four canonical traits Against the expectations the first and the second canonical traits were found very highly significant (P ⁇ 0 001 ) and the fourth was slightly significant (P ⁇ 0 05) for the contrasts between the AB and BB pattern This result showed that P ⁇ t-1 could have more than one action
- the first canonical trait is more specifically linked to angularity
- the last trait reflected the equilibrium between milk and protein yields
- table 7 gives the values of the contrasts and the standard errors expressed on the original scales
- the backtransformed contrasts were very important for milk, fat and protein for the first canonical contrast All were also positive with AB animals superior to BB animals
- the AB were inferior for milk, fat and protein and superior for angularity This indicates again that the influence of P ⁇ t-1 on angularity seems to be important, first through the link between yields and angularity, but also directly on angularity with a
- Seguencing of the P ⁇ t-1 gene and characterization of a mutation This method generates separate populations of radiolabeled oligonucleotides that begin from a fixed point and terminate randomly at a fixed residue or combination of residues Because every base in the DNA has an equal chance of being a variable terminus, each population consists of a mixture of oligonucleotides whose lengths are determined by the location of a particular base along the length of the original DNA These populations of oligonucleotides are then resolved by electrophoresis under conditions that can disc ⁇ mate between individual DNAs that differ in length by as little as one nucleotide When the populations are loaded into adjacent lanes of a sequencing gel, the order of nucleotides along the DNA can be read directly from an autoradiographic image of the gel
- Ligase chain reaction employing just oligonucleotide probes and DNA ligase, is capable of detecting approximately 1000 copies of a specific target DNA sequence in the presence of a vast excess of other DNA sequence information Since the first description in 1989 (Backman and Wang, 1989, European Patent Application No 0 320 308, Royer et al , 989, European Patent Application No 0 324 616, Wallace, 1989, European Patent Application No 0 336 731 , Wu and Wallace, 1989, Genomics 4 560-569, Orgel, 1989 Richards and Jones, 1989) LCR has been improved by the employment of a thermostable DNA ligase in conjonction with non-radioactive detection (Bond et al , 1990)
- PCR polymerase chain reaction
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Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT97938846T ATE243264T1 (en) | 1996-07-22 | 1997-07-22 | PIT-1 GENE POLYMORPHISM AND TRAITS SELECTION IN ANIMALS |
JP54123997A JP4246262B2 (en) | 1996-07-22 | 1997-07-22 | PIT-1 gene polymorphism and animal trait selection |
CA002261157A CA2261157C (en) | 1996-07-22 | 1997-07-22 | Pit-1 gene polymorphism and trait selection in animals |
DE69722954T DE69722954T2 (en) | 1996-07-22 | 1997-07-22 | PIT-1 GENE POLYMORPHISM AND PROPERTY SELECTION IN ANIMALS |
EP97938846A EP0937160B1 (en) | 1996-07-22 | 1997-07-22 | Pit-1 gene polymorphism and trait selection in animals |
DK97938846T DK0937160T3 (en) | 1996-07-22 | 1997-07-22 | Pit-1 gene polymorphism and selection of traits in animals |
US09/236,268 US6492142B2 (en) | 1996-07-22 | 1999-01-22 | Pit-1 gene polymorphism and trait selection in animals |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP96401634A EP0821070A1 (en) | 1996-07-22 | 1996-07-22 | Pit-1 gene polymorphism and trait selection in animals |
EP96401634.9 | 1996-07-22 |
Related Child Applications (1)
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US09/236,268 Continuation US6492142B2 (en) | 1996-07-22 | 1999-01-22 | Pit-1 gene polymorphism and trait selection in animals |
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WO1998003677A2 true WO1998003677A2 (en) | 1998-01-29 |
WO1998003677A3 WO1998003677A3 (en) | 1998-04-23 |
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PCT/EP1997/003939 WO1998003677A2 (en) | 1996-07-22 | 1997-07-22 | Pit-1 gene polymorphism and trait selection in animals |
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US (1) | US6492142B2 (en) |
EP (2) | EP0821070A1 (en) |
AT (1) | ATE243264T1 (en) |
CA (1) | CA2261157C (en) |
DE (1) | DE69722954T2 (en) |
DK (1) | DK0937160T3 (en) |
ES (1) | ES2202637T3 (en) |
PT (1) | PT937160E (en) |
WO (1) | WO1998003677A2 (en) |
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WO1990010714A1 (en) * | 1989-03-15 | 1990-09-20 | Wisconsin Alumni Research Foundation | Genetic marker for superior milk production in dairy cattle |
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1996
- 1996-07-22 EP EP96401634A patent/EP0821070A1/en not_active Withdrawn
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1997
- 1997-07-22 CA CA002261157A patent/CA2261157C/en not_active Expired - Fee Related
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Also Published As
Publication number | Publication date |
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CA2261157C (en) | 2009-11-24 |
EP0937160B1 (en) | 2003-06-18 |
DE69722954T2 (en) | 2004-05-19 |
EP0937160A2 (en) | 1999-08-25 |
DK0937160T3 (en) | 2003-10-13 |
ES2202637T3 (en) | 2004-04-01 |
ATE243264T1 (en) | 2003-07-15 |
WO1998003677A3 (en) | 1998-04-23 |
EP0821070A1 (en) | 1998-01-28 |
DE69722954D1 (en) | 2003-07-24 |
US20010016315A1 (en) | 2001-08-23 |
PT937160E (en) | 2003-11-28 |
US6492142B2 (en) | 2002-12-10 |
CA2261157A1 (en) | 1998-01-29 |
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