EP0303602A4 - Enzymatisches syntheseverfahren. - Google Patents
Enzymatisches syntheseverfahren.Info
- Publication number
- EP0303602A4 EP0303602A4 EP19870902325 EP87902325A EP0303602A4 EP 0303602 A4 EP0303602 A4 EP 0303602A4 EP 19870902325 EP19870902325 EP 19870902325 EP 87902325 A EP87902325 A EP 87902325A EP 0303602 A4 EP0303602 A4 EP 0303602A4
- Authority
- EP
- European Patent Office
- Prior art keywords
- amino acid
- ester
- derivative
- benzyl
- peptide
- 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.)
- Withdrawn
Links
- 230000015572 biosynthetic process Effects 0.000 title description 16
- 238000003786 synthesis reaction Methods 0.000 title description 10
- 230000002255 enzymatic effect Effects 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 26
- 229940024606 amino acid Drugs 0.000 claims abstract description 18
- 150000001413 amino acids Chemical class 0.000 claims abstract description 18
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 16
- 108091005804 Peptidases Proteins 0.000 claims abstract description 12
- 102000035195 Peptidases Human genes 0.000 claims abstract description 12
- 235000019833 protease Nutrition 0.000 claims abstract description 12
- 150000003573 thiols Chemical class 0.000 claims abstract description 12
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims abstract description 10
- 229940009098 aspartate Drugs 0.000 claims abstract description 10
- 229930195712 glutamate Natural products 0.000 claims abstract description 9
- 150000003862 amino acid derivatives Chemical class 0.000 claims abstract description 8
- 150000001412 amines Chemical class 0.000 claims abstract description 7
- 150000002148 esters Chemical class 0.000 claims abstract description 7
- 125000000729 N-terminal amino-acid group Chemical group 0.000 claims abstract description 4
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 4
- 125000003118 aryl group Chemical group 0.000 claims abstract description 4
- 125000001165 hydrophobic group Chemical group 0.000 claims abstract description 4
- 239000004365 Protease Substances 0.000 claims description 12
- 108090000526 Papain Proteins 0.000 claims description 11
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 11
- 235000019834 papain Nutrition 0.000 claims description 10
- 229940055729 papain Drugs 0.000 claims description 10
- 108010011485 Aspartame Proteins 0.000 claims description 9
- 239000000605 aspartame Substances 0.000 claims description 9
- 229960003438 aspartame Drugs 0.000 claims description 9
- 235000010357 aspartame Nutrition 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 210000004899 c-terminal region Anatomy 0.000 claims description 7
- ZPVDKMKHRJFPMC-QHCPKHFHSA-N dibenzyl (2s)-2-(phenylmethoxycarbonylamino)butanedioate Chemical compound N([C@@H](CC(=O)OCC=1C=CC=CC=1)C(=O)OCC=1C=CC=CC=1)C(=O)OCC1=CC=CC=C1 ZPVDKMKHRJFPMC-QHCPKHFHSA-N 0.000 claims description 7
- 229940049906 glutamate Drugs 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- VSDUZFOSJDMAFZ-VIFPVBQESA-N methyl L-phenylalaninate Chemical compound COC(=O)[C@@H](N)CC1=CC=CC=C1 VSDUZFOSJDMAFZ-VIFPVBQESA-N 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- 108090001069 Chymopapain Proteins 0.000 claims description 3
- ISWQCIVKKSOKNN-UHFFFAOYSA-L Tiron Chemical compound [Na+].[Na+].OC1=CC(S([O-])(=O)=O)=CC(S([O-])(=O)=O)=C1O ISWQCIVKKSOKNN-UHFFFAOYSA-L 0.000 claims description 3
- 229960002976 chymopapain Drugs 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- -1 benzyloxycarboxyl Chemical group 0.000 claims 2
- 101710097834 Thiol protease Proteins 0.000 claims 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 abstract description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 abstract description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 abstract description 2
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 abstract description 2
- 229960002591 hydroxyproline Drugs 0.000 abstract description 2
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 25
- 235000001014 amino acid Nutrition 0.000 description 12
- 239000000047 product Substances 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethyl mercaptane Natural products CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 108090000371 Esterases Proteins 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010647 peptide synthesis reaction Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- XYXYXSKSTZAEJW-VIFPVBQESA-N (2s)-2-(phenylmethoxycarbonylamino)butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 XYXYXSKSTZAEJW-VIFPVBQESA-N 0.000 description 1
- PVFCXMDXBIEMQG-JTQLQIEISA-N (2s)-2-(phenylmethoxycarbonylamino)pentanedioic acid Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 PVFCXMDXBIEMQG-JTQLQIEISA-N 0.000 description 1
- MGOGKPMIZGEGOZ-REOHCLBHSA-N (2s)-2-amino-3-hydroxypropanamide Chemical compound OC[C@H](N)C(N)=O MGOGKPMIZGEGOZ-REOHCLBHSA-N 0.000 description 1
- BEXAJIYIQICKDL-HRDPVCSZSA-N (2s)-2-aminobutanedioic acid;methyl (2s)-2-amino-3-phenylpropanoate Chemical compound OC(=O)[C@@H](N)CC(O)=O.COC(=O)[C@@H](N)CC1=CC=CC=C1 BEXAJIYIQICKDL-HRDPVCSZSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- QCTFKEJEIMPOLW-JURCDPSOSA-N Ala-Ile-Phe Chemical compound C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 QCTFKEJEIMPOLW-JURCDPSOSA-N 0.000 description 1
- 108010004032 Bromelains Proteins 0.000 description 1
- 102000005600 Cathepsins Human genes 0.000 description 1
- 108010084457 Cathepsins Proteins 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000270 Ficain Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- 108090000794 Streptopain Proteins 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 239000008122 artificial sweetener Substances 0.000 description 1
- 150000001509 aspartic acid derivatives Chemical class 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 235000019835 bromelain Nutrition 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- ROBXZHNBBCHEIQ-BYPYZUCNSA-N ethyl (2s)-2-aminopropanoate Chemical compound CCOC(=O)[C@H](C)N ROBXZHNBBCHEIQ-BYPYZUCNSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000019836 ficin Nutrition 0.000 description 1
- POTUGHMKJGOKRI-UHFFFAOYSA-N ficin Chemical compound FI=CI=N POTUGHMKJGOKRI-UHFFFAOYSA-N 0.000 description 1
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P21/00—Preparation of peptides or proteins
- C12P21/02—Preparation of peptides or proteins having a known sequence of two or more amino acids, e.g. glutathione
Definitions
- the present invention relates to a method of linking either an aspartate or glutamate radical to the N-terminal of an amino acid or derivative thereof.
- This method is applicable for amino acids, with the exception of proline or hydroxy-proline, and is functional regardless of whether the amino acid is in isolation or present as the N-terminal residue of a peptide.
- the method is therefore useful in peptide synthesis.
- This method is particularly applicable to the production of the artificial sweetening agent known under the generic name of aspartame. Aspartame was first discovered in 1966 and is a dipeptide of the following structure:
- A. and A_ are amino acids or peptides.
- thiol proteinases were able to catalyse the reaction between Z-L-aspartic acid dibenzyl ester and L-phenylalanine methyl ester to form a derivate of aspartame, Z-L-aspartyl(/J-benzyl ester) -L-phenylalanine methyl ester (Z is an abbreviation used in the art that refers to benzyoxycarbonyl) . Further work has shown that this method is applicable to linking either aspartate or glutamate to the N-terminal of an amino acid derivative or peptide.
- the reaction takes advantage of the esterase activity of the thiol proteinase giving rise to a much faster and more efficient reaction than results from the use of prior art processes involving condensation reactions.
- the use of an aspartate or glutamate derivative with a free carboxyl group is a different and less efficient method with a reaction time of days as compared to minutes.
- the use of the esterase activity does not generate a free carboxyl group, rather, in the enzyme-C-component complex the ester of the C-component is cleaved by a nucleophilic attack by the amino group of the incoming N-component during formation of the peptide bond.
- the present invention consists in a method for the addition of an aspartate or glutamate radical to the N-terminal of an amino acid, wherein said amino acid exists either singly, as a derivative having a C-terminal 'o protective group, or as the N-terminal residue of a peptide, said method comprising the following steps: reacting, in the presence of a thiol proteinase, a compound of a general formula:
- n is either 1 or 2
- B- is any group capable of forming an ester linkage
- B- is any group capable of forming an ester 3o linkage and cleavable by the thiol proteinase
- X is an aliphatic or aromatic hydrophobic group, with an amino acid or derivative thereof or a peptide, the amino acid derivative having a C-terminal protective group, to obtain a compound of the following general formula:
- A is a residue of said amino acid or derivative thereof or said peptide, and optionally removing the X and B, groups from the molecule.
- the thiol proteinase is either papain or chymopapain, n is 1, X is benzyloxycarbonyl (known in the art as Z) , B, and B-, -2- . ⁇ are both benzyl groups, A is a methyl ester of phenylalanine and a hydrogenation process is used to remove the Z and B, benzyl group from the reaction product to produce aspartame.
- Thiol proteinases have been well characterized in the literature (e.g. Advances in Enzymology Vol. 53 pp 239-306) , and include the enzymes papain, chymopapain, ficin, bromelain, cathepsins B and C and Streptococcal proteinase. Apart from Z there are a number of other aliphatic or aromatic hydrophobic groups which could be used in this invention. These include t-BOC, B ' .poc, and Fmoc. The use and characteristics of these compounds has been described in the literature by Schechter I and Berger A (Biochem. Biphys. Res. Comm. Vol. 27 pp 157-162) and by Fruton J.S.
- Examples of groups which can be substituted for benzyl at B, and/or B, are ethyl or methyl groups. However the rate of reaction in the case of production of aspartame is greater when B, and B- are both benzyl.
- the protective groups for the carboxyl ⁇ group of this amine component include alkoxy groups, substituted or unsubstituted benzyloxy groups, or amino groups.
- Reaction 1 part “a” was added to 9 parts “b” at room temperature and the pH maintained at 8.5. Synthesis was monitored by high pressure liquid chromatography (HPLC) . The reaction proceeded with approximately 70 to 80% efficiency in terms of the amount of '-a" used with a reaction time of approximately 2-3 hours.
- HPLC high pressure liquid chromatography
- This conversion was carried out by a hydrogenation reaction involving a palladium catalyst and hydrogen gas.
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Health & Medical Sciences (AREA)
- Zoology (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Peptides Or Proteins (AREA)
- Immobilizing And Processing Of Enzymes And Microorganisms (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU5408/86 | 1986-04-10 | ||
| AUPH540886 | 1986-04-10 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0303602A1 EP0303602A1 (de) | 1989-02-22 |
| EP0303602A4 true EP0303602A4 (de) | 1990-06-26 |
Family
ID=3771549
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP19870902325 Withdrawn EP0303602A4 (de) | 1986-04-10 | 1987-04-08 | Enzymatisches syntheseverfahren. |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0303602A4 (de) |
| JP (1) | JPH01501995A (de) |
| AU (1) | AU591557B2 (de) |
| WO (1) | WO1987006268A1 (de) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK72587D0 (da) * | 1987-02-13 | 1987-02-13 | Carlsberg Biotechnology Ltd | Fremgangsmaade til enzymatisk fremstilling af dipeptider |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1337086A (en) * | 1971-05-25 | 1973-11-14 | Tate & Lyle Ltd | Sweet substance |
| US4116768A (en) * | 1975-04-29 | 1978-09-26 | (Zaidanhojin) Sagami Chemical Research Center | Process for producing a peptide |
| US4086136A (en) * | 1975-10-23 | 1978-04-25 | (Zaidanhojin) Sagami Chemical Research Center | Process for producing a peptide using a serine or thiol proteinase |
| FI70597C (fi) * | 1979-04-06 | 1986-09-24 | Carlsberg Biotechnology Ltd | Foerfarande foer enzymatisk framstaellning av peptider |
| CH647550A5 (fr) * | 1979-12-28 | 1985-01-31 | Nestle Sa | Procede de preparation d'une oligo-l-methionine par voie enzymatique et utilisation. |
| IE52242B1 (en) * | 1981-02-02 | 1987-08-19 | Searle & Co | Preparation of amino protected-l-aspartyl-l-phenylalanine alkyl ester |
-
1987
- 1987-04-08 EP EP19870902325 patent/EP0303602A4/de not_active Withdrawn
- 1987-04-08 JP JP62502329A patent/JPH01501995A/ja active Pending
- 1987-04-08 WO PCT/AU1987/000092 patent/WO1987006268A1/en not_active Ceased
- 1987-04-08 AU AU72365/87A patent/AU591557B2/en not_active Ceased
Non-Patent Citations (4)
| Title |
|---|
| CHEMICAL ABSTRACTS, vol. 100, no. 1, 2nd January 1984, page 420, abstract no. 4787t, Columbus, Ohio, US; & JP-A-58 146 295 (SAGAMI CHEMICAL RESEARCH CENTER INSTITUTE OF PHYSICAL AND CHEMICAL RESEARCH) 31-08-1983 * |
| CHEMICAL ABSTRACTS, vol. 103, no. 23, 9th December 1985, page 579, abstract no. 194943y, Columbus, Ohio, US; & JP-A-60 41 499 (ASAHI CHEMICAL INDUSTRY CO., LTD) 05-03-1985 * |
| CHEMICAL ABSTRACTS, vol. 91, no. 17, 22nd October 1979, page 696, abstract no. 141244y, Columbus, Ohio, US; & JP-A-79 64 692 (SHIONOGI AND CO., LTD) 24-05-1979 * |
| See also references of WO8706268A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0303602A1 (de) | 1989-02-22 |
| AU7236587A (en) | 1987-11-09 |
| WO1987006268A1 (en) | 1987-10-22 |
| JPH01501995A (ja) | 1989-07-13 |
| AU591557B2 (en) | 1989-12-07 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
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| 17P | Request for examination filed |
Effective date: 19880926 |
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| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE FR GB IT LI LU NL SE |
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| A4 | Supplementary search report drawn up and despatched |
Effective date: 19900626 |
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| 17Q | First examination report despatched |
Effective date: 19920304 |
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| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
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| 18D | Application deemed to be withdrawn |
Effective date: 19920915 |
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| RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: WHITTAKER, ROBERT, GEORGE |