ZA200607575B - Optimized expression of HPV 52 L1 in yeast - Google Patents

Optimized expression of HPV 52 L1 in yeast

Info

Publication number: ZA200607575B
Authority: ZA; South Africa
Prior art keywords: hpv; yeast; optimized expression; optimized; expression
Prior art date: 2004-03-24

Application number

ZA200607575A

Other languages

English (en)

Inventor

Janine T Bryan

Michelle K Brownlow

Loren D Schultz

Kathrin U Jansen

Original Assignee

Merck & Co Inc

Priority date (The priority date 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 date listed.)

2004-03-24

Filing date

2006-09-11

Publication date

2008-08-27

2006-09-11 Application filed by Merck & Co Inc filed Critical Merck & Co Inc

2008-08-27 Publication of ZA200607575B publication Critical patent/ZA200607575B/xx

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
- C07K14/01—DNA viruses
- C07K14/025—Papovaviridae, e.g. papillomavirus, polyomavirus, SV40, BK virus, JC virus
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
- C12N7/04—Inactivation or attenuation; Producing viral sub-units
- C12N7/045—Pseudoviral particles; Non infectious pseudovirions, e.g. genetically engineered
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/525—Virus
- A61K2039/5258—Virus-like particles
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/20011—Papillomaviridae
- C12N2710/20022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/20011—Papillomaviridae
- C12N2710/20023—Virus like particles [VLP]

Landscapes

Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Virology (AREA)
Medicinal Chemistry (AREA)
General Health & Medical Sciences (AREA)
Genetics & Genomics (AREA)
Biochemistry (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Zoology (AREA)
Molecular Biology (AREA)
Wood Science & Technology (AREA)
Immunology (AREA)
Gastroenterology & Hepatology (AREA)
Proteomics, Peptides & Aminoacids (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
Animal Behavior & Ethology (AREA)
Biophysics (AREA)
Pharmacology & Pharmacy (AREA)
Biotechnology (AREA)
Microbiology (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
General Engineering & Computer Science (AREA)
Biomedical Technology (AREA)
Oncology (AREA)
Communicable Diseases (AREA)
Mycology (AREA)
Epidemiology (AREA)
Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Micro-Organisms Or Cultivation Processes Thereof (AREA)
Preparation Of Compounds By Using Micro-Organisms (AREA)
Peptides Or Proteins (AREA)
Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

ZA200607575A 2004-03-24 2006-09-11 Optimized expression of HPV 52 L1 in yeast ZA200607575B (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
US55592604P	2004-03-24	2004-03-24

Publications (1)

Publication Number	Publication Date
ZA200607575B true ZA200607575B (en)	2008-08-27

Family

ID=34964085

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
ZA200607575A ZA200607575B (en)	2004-03-24	2006-09-11	Optimized expression of HPV 52 L1 in yeast

Country Status (31)

Country	Link
US (2)	US7700103B2 (el)
EP (1)	EP1730175B1 (el)
JP (1)	JP4833962B2 (el)
KR (1)	KR101203403B1 (el)
CN (1)	CN1934131B (el)
AR (1)	AR048191A1 (el)
AT (1)	ATE466022T1 (el)
AU (1)	AU2005230907C1 (el)
BE (1)	BE2015C066I2 (el)
BR (1)	BRPI0509079B8 (el)
CA (1)	CA2560487C (el)
CY (2)	CY1110349T1 (el)
DE (1)	DE602005020913D1 (el)
DK (1)	DK1730175T3 (el)
ES (1)	ES2343255T3 (el)
FR (1)	FR15C0085I2 (el)
HU (1)	HUS1500062I1 (el)
IL (1)	IL178140A (el)
LT (2)	LTPA2015050I1 (el)
LU (1)	LU92903I2 (el)
MY (1)	MY148656A (el)
NL (1)	NL300777I2 (el)
NO (3)	NO338055B1 (el)
NZ (1)	NZ549898A (el)
PL (1)	PL1730175T3 (el)
PT (1)	PT1730175E (el)
RU (1)	RU2373219C2 (el)
SI (1)	SI1730175T1 (el)
TW (1)	TWI349036B (el)
WO (1)	WO2005097821A1 (el)
ZA (1)	ZA200607575B (el)

Families Citing this family (26)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US7858098B2 (en) *	2002-12-20	2010-12-28	Glaxosmithkline Biologicals, S.A.	Vaccine
CN1869215B (zh) *	2006-05-19	2012-07-04	长春百克生物科技股份公司	一种制备人乳头瘤病毒的病毒样颗粒的方法
US7709010B2 (en)	2007-03-09	2010-05-04	Merck Sharp & Dohme Corp.	Papillomavirus vaccine compositions
MX344751B (es)	2007-11-23	2017-01-05	Shanghai Zerun Biotechnology Co Ltd	Genes que codifican para la proteina l1 mayor de la capside del virus del papiloma humano y uso de los mismos.
CN101440371B (zh) *	2007-11-23	2012-09-05	上海泽润生物科技有限公司	一种16型人乳头状瘤病毒主要衣壳蛋白l1基因
MX375965B (es) *	2010-05-14	2025-03-07	Baxalta Inc	Genes ospa quimericos, proteinas, y metodos para usar los mismos.
WO2011149897A1 (en)	2010-05-25	2011-12-01	Qiagen Gaithersburg, Inc.	Fast results hybrid capture assay and associated strategically-truncated probes
IN2013CN00536A (el)	2010-07-02	2015-07-03	Univ Xiamen
US8361720B2 (en)	2010-11-15	2013-01-29	Exact Sciences Corporation	Real time cleavage assay
EP2646559A2 (en)	2010-12-03	2013-10-09	MS Technologies, LLC	Optimized expression of glyphosate resistance encoding nucleic acid molecules in plant cells
CN102154325B (zh) *	2011-01-01	2013-08-21	上海生物制品研究所有限责任公司	针对人乳头瘤状病毒的疫苗及其制法和用途
RU2445357C1 (ru) *	2011-02-15	2012-03-20	Закрытое акционерное общество научно-производственная компания "Комбиотех"	Рекомбинантный штамм дрожжей pichia angusta - продуцент капсидного белка l1 вируса папилломы человека типа 16
RU2445358C1 (ru) *	2011-02-15	2012-03-20	Закрытое акционерное общество научно-производственная компания "Комбиотех"	Рекомбинантный штамм дрожжей pichia angusta - продуцент капсидного белка l1 вируса папилломы человека типа 18
CN110484554B (zh) *	2013-04-26	2024-04-16	北京安百胜生物科技有限公司	用汉逊酵母表达系统产生hpv52 l1蛋白的方法
CN104164374B (zh) *	2013-05-17	2019-10-22	北京安百胜生物科技有限公司	用汉逊酵母表达系统产生hpv31 l1蛋白的方法
US9782470B2 (en)	2013-10-16	2017-10-10	Merck Sharp & Dohme Corp.	Method of obtaining thermostable dried vaccine formulations
CN104878022A (zh) *	2015-04-27	2015-09-02	段青姣	编码hpv58l1、hpv52l1蛋白的核苷酸序列及其应用
CN106701796B (zh) *	2015-08-12	2021-11-16	北京康乐卫士生物技术股份有限公司	52型重组人乳头瘤病毒病毒样颗粒及其制备方法
CN109750049B (zh) *	2017-11-07	2023-08-18	上海泽润生物科技有限公司	重组人乳头瘤病毒52亚型蛋白表达
PE20230493A1 (es)	2020-02-14	2023-03-23	Merck Sharp And Dohme Llc	Vacuna contra hpv
CN114539365B (zh) *	2020-11-26	2023-12-01	中国医学科学院基础医学研究所	一种改造的人乳头瘤病毒52型l1蛋白及其用途
CN113073105B (zh) *	2021-03-23	2023-06-13	重庆博唯佰泰生物制药有限公司	一种表达hpv 56l1的多核苷酸序列及其表达载体、宿主细胞和应用
CN113549634B (zh) *	2021-06-07	2023-03-31	郑州大学	编码可溶性hpv58 l1蛋白的基因及其重组质粒的构建与应用
TW202313658A (zh)	2021-08-06	2023-04-01	美商默沙東有限責任公司	Hpv疫苗
WO2023023152A1 (en)	2021-08-19	2023-02-23	Merck Sharp & Dohme Llc	Thermostable lipid nanoparticle and methods of use thereof
TW202513091A (zh)	2023-06-09	2025-04-01	美商默沙東有限責任公司	用於人類乳突病毒疫苗之奈米乳液佐劑組合物

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
CA1339729C (en) *	1988-10-26	1998-03-17	Wayne D. Lancaster	Human papillomavirus type 52 dna sequences and methods for employing thesame
US5821087A (en)	1995-03-30	1998-10-13	Merck & Co., Inc.	Production of recombinant human papillomavirus type II protein utilizing papillomavirus 6/11 hybrid DNA
IL117591A0 (en)	1995-03-30	1996-07-23	Merck & Co Inc	Synthetic DNA encoding human papillomavirus type 11 L1 protein
JP2001512308A (ja)	1997-02-07	2001-08-21	メルクエンドカンパニーインコーポレーテッド	合成ｈｉｖｇａｇ遺伝子
WO1999002694A1 (en)	1997-07-09	1999-01-21	The University Of Queensland	Nucleic acid sequence and method for selectively expressing a protein in a target cell or tissue
PL347472A1 (en) *	1998-08-14	2002-04-08	Merck & Co Inc	Process for purifying human papillomavirus virus-like particles
EP1105157B1 (en)	1998-08-14	2006-11-02	Merck & Co., Inc.	Protein delivery system using human papillomavirus virus-like particles
SE514982C2 (sv) *	1999-09-30	2001-05-28	Active Biotech Ab	Bärare innehållande ett huvudkapsidprotein L1 från humant papillomavirus samt dess användning
ATE284898T1 (de)	1999-08-25	2005-01-15	Merck & Co Inc	Synthetische papillomavirus gene, welche für expression in menschlichen zellen optimiert sind
US6436402B1 (en)	1999-10-15	2002-08-20	Merck & Co., Inc.	Process for making human papillomavirus virus-like particles with improved properties
ES2277605T3 (es)	2000-07-21	2007-07-16	Glaxo Group Limited	Secuencias de papilomavirus de codones optimizados.
US20030226155A1 (en) *	2001-08-30	2003-12-04	Biorexis Pharmaceutical Corporation	Modified transferrin-antibody fusion proteins
AU2004224335B2 (en)	2003-03-24	2010-01-28	Merck Sharp & Dohme Llc	Optimized expression of HPV 31 L1 in yeast
MY140664A (en) *	2003-09-29	2010-01-15	Merck Sharp & Dohme	Optimized expression of hpv 45 l1 in yeast
MY139500A (en)	2003-11-12	2009-10-30	Merck Sharp & Dohme	Optimized expression of hpv 58 l1 in yeast

2005
- 2005-03-18 PL PL05725933T patent/PL1730175T3/pl unknown
- 2005-03-18 WO PCT/US2005/009199 patent/WO2005097821A1/en active Application Filing
- 2005-03-18 NZ NZ549898A patent/NZ549898A/en not_active IP Right Cessation
- 2005-03-18 TW TW094108431A patent/TWI349036B/zh active
- 2005-03-18 KR KR1020067019673A patent/KR101203403B1/ko not_active Expired - Lifetime
- 2005-03-18 AT AT05725933T patent/ATE466022T1/de active
- 2005-03-18 ES ES05725933T patent/ES2343255T3/es not_active Expired - Lifetime
- 2005-03-18 EP EP05725933A patent/EP1730175B1/en not_active Expired - Lifetime
- 2005-03-18 JP JP2007505032A patent/JP4833962B2/ja not_active Expired - Lifetime
- 2005-03-18 BR BRPI0509079A patent/BRPI0509079B8/pt not_active IP Right Cessation
- 2005-03-18 MY MYPI20051180A patent/MY148656A/en unknown
- 2005-03-18 RU RU2006137363/13A patent/RU2373219C2/ru active
- 2005-03-18 DE DE602005020913T patent/DE602005020913D1/de not_active Expired - Lifetime
- 2005-03-18 CA CA2560487A patent/CA2560487C/en not_active Expired - Lifetime
- 2005-03-18 AU AU2005230907A patent/AU2005230907C1/en active Active
- 2005-03-18 SI SI200531052T patent/SI1730175T1/sl unknown
- 2005-03-18 DK DK05725933.5T patent/DK1730175T3/da active
- 2005-03-18 PT PT05725933T patent/PT1730175E/pt unknown
- 2005-03-18 CN CN2005800095956A patent/CN1934131B/zh not_active Expired - Lifetime
- 2005-03-18 US US10/594,064 patent/US7700103B2/en active Active
- 2005-03-23 AR ARP050101174A patent/AR048191A1/es active IP Right Grant
2006
- 2006-09-11 ZA ZA200607575A patent/ZA200607575B/xx unknown
- 2006-09-17 IL IL178140A patent/IL178140A/en active IP Right Grant
- 2006-10-23 NO NO20064815A patent/NO338055B1/no active Protection Beyond IP Right Term
2009
- 2009-10-14 US US12/578,995 patent/US7744892B2/en not_active Expired - Lifetime
2010
- 2010-07-26 CY CY20101100698T patent/CY1110349T1/el unknown
2015
- 2015-11-30 NL NL300777C patent/NL300777I2/nl unknown
- 2015-12-02 HU HUS1500062C patent/HUS1500062I1/hu unknown
- 2015-12-04 FR FR15C0085C patent/FR15C0085I2/fr active Active
- 2015-12-07 CY CY2015052C patent/CY2015052I1/el unknown
- 2015-12-08 LT LTPA2015050D patent/LTPA2015050I1/lt unknown
- 2015-12-08 LU LU92903C patent/LU92903I2/xx unknown
- 2015-12-08 LT LTPA2015050C patent/LTC1730175I2/lt unknown
- 2015-12-09 BE BE2015C066C patent/BE2015C066I2/nl unknown
2017
- 2017-01-20 NO NO2017005C patent/NO2017005I1/no unknown
2022
- 2022-11-30 NO NO2022050C patent/NO2022050I1/no unknown

Also Published As

Publication number	Publication date
BE2015C066I2 (el)	2024-08-08
LTC1730175I2 (lt)	2017-05-10
FR15C0085I2 (fr)	2016-11-25
CN1934131B (zh)	2010-12-29
DK1730175T3 (da)	2010-08-23
CY2015052I2 (el)	2016-06-22
PT1730175E (pt)	2010-06-25
AU2005230907A1 (en)	2005-10-20
RU2006137363A (ru)	2008-04-27
NL300777I1 (el)	2015-12-29
EP1730175B1 (en)	2010-04-28
IL178140A (en)	2010-11-30
US7700103B2 (en)	2010-04-20
US7744892B2 (en)	2010-06-29
CY1110349T1 (el)	2015-04-29
JP2007530040A (ja)	2007-11-01
NL300777I2 (el)	2015-12-29
LTPA2015050I1 (lt)	2016-01-11
CA2560487C (en)	2013-01-29
CY2015052I1 (el)	2016-06-22
AR048191A1 (es)	2006-04-05
PL1730175T3 (pl)	2010-09-30
US20080226660A1 (en)	2008-09-18
WO2005097821A1 (en)	2005-10-20
JP4833962B2 (ja)	2011-12-07
CN1934131A (zh)	2007-03-21
HUS1500062I1 (hu)	2017-07-28
TW200602490A (en)	2006-01-16
US20100035818A1 (en)	2010-02-11
DE602005020913D1 (de)	2010-06-10
NO20064815L (no)	2006-10-23
RU2373219C2 (ru)	2009-11-20
AU2005230907B2 (en)	2011-05-19
NO338055B1 (no)	2016-07-25
NO2022050I1 (no)	2022-11-30
EP1730175A1 (en)	2006-12-13
CA2560487A1 (en)	2005-10-20
KR101203403B1 (ko)	2012-11-21
BRPI0509079B1 (pt)	2020-05-19
SI1730175T1 (sl)	2010-08-31
BRPI0509079A (pt)	2007-08-21
BRPI0509079B8 (pt)	2021-07-06
NZ549898A (en)	2009-06-26
AU2005230907C1 (en)	2016-07-28
MY148656A (en)	2013-05-15
ES2343255T3 (es)	2010-07-27
LU92903I2 (fr)	2016-03-08
IL178140A0 (en)	2006-12-31
TWI349036B (en)	2011-09-21
ATE466022T1 (de)	2010-05-15
FR15C0085I1 (el)	2016-08-01
KR20060134120A (ko)	2006-12-27
NO2017005I1 (no)	2017-01-20

Publication	Publication Date	Title
HUS1500062I1 (hu)	2017-07-28	HPV 52 L1 optimalizált expresszáltatása élesztõben
HUS1500064I1 (hu)	2016-02-29	HPV58 L1 optimalizált expressziója élesztõben
HUS1500063I1 (hu)	2016-02-29	HPV 45 L1 optimalizált expresszáltatása élesztõben
IL238365A0 (en)	2015-06-30	Cholesterol-producing yeast strains and their uses
GB2409265B8 (en)	2009-01-09	Improvements In and Relating to Stoves
GB0406835D0 (en)	2004-04-28	Improvements in and relating to implants
SI1745123T1 (sl)	2012-10-30	Sevi kvasa, ki proizvajajo holesterol, in njihove uporabe
GB0423648D0 (en)	2004-11-24	Improvements in and relating to comparison
GB0523108D0 (en)	2005-12-21	Improvements relating to foundations and floors
HK1103764A (zh)	2007-12-28	茚滿醯基醯胺刺激紫杉植物次級代謝的用途
GB0425796D0 (en)	2004-12-22	Improvements in and relating to electrodes
GB0407717D0 (en)	2004-05-12	Improvements in and relating to implants
GB0406832D0 (en)	2004-04-28	Improvements in and relating to implants
GB0406851D0 (en)	2004-04-28	Improvements in and relating to implants