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F a l l 

3 - 2 0 0 7 

Trends In 

Bio/Pharmaceutical 

Industry 

Table of Content 

Letter from Editor Leping Li /2 

Biopharma News 

Digest 

Drug Discovery & 

Development 

Triumphal return of “haigui”: IPo of Wuxi PharmaTech in us /3 

Leping Li 

commenTary 

The Keys to Ge li and Wuxi PharmaTech’s success /6 

Guoliang Yu 

“made-in-china”: Fda approved First Generic drug from china 

under the yallow skin: the First asian Genome completed /8 

IP Law ready for Primetime in us? an overview of the regulatory and 

Patent environment for Follow-on Biologics / 0 

Y. Philip Zhang 

关于知识产权促进医药创新的政策思考 / 7 

周和平 

2006年中国中药资源研究与学科建设进展 /23 

段金廒,吕洁丽,宿树兰, 周荣汉 

label free Technology for drug research /34 

Ye Fang 

development of hepatitis B Therapeutic Vaccine /40 

Lizhen He 

Conference Reports Tianjin Bioeco conference /46 

Job Market /48 

Sci-tech Park nanjing high-Tech Zone /26 

Advertisement Wuzhong Pharma Park /39 

Biorad laboratories 

millipore corporation /50 

morrison and Foerster /22 

cisBio / 6 

Trends In BIo/PharmaceuTIcal IndusTry | 3-2007

Trends in Bio/Pharmaceutical Industry 

Editor Board of 

Trend in 

Bio/Pharmaceutical 

Industry 

Editor in Chief 

John Wang 

Novartis, USA 

Board of Scientlfic Editors 

Feng Gen-sheng 

Burnham Inst. 

USA 

han Jun 

Novartis, USA 

li Bin 

Chempartner, China 

li hui 

Pfizer, USA 

li leping 

Amgen, USA 

liu chuan 

J&J, USA 

mo chengjun 

Medimmune, USA 

shi li 

Merck, USA 

Wang deqian 

Bayer, USA 

Wei yingfei 

Elixirin,USA 

Wu Jinzi 

Ambrilia, Canada 

Wu ruifang 

CJND, China 

yang dajun 

Ascera, USA 

yang Pei 

Sunesis, USA 

yang naibo 

MDS, USA 

yu Guoliang 

Epitomics, USA 

Art Director 

li Xiaojun 

CA State, USA 

TBI online 

www.cabsweb.org 

Contact us: 

TBI@CABSweb.org 

2 Trends In BIo/PharmaceuTIcal IndusTry | 3-2007 

Letter from Editor 

Dear Readers of TBI, 

As you have come to expect, our journal continues to 

bring useful information covering a broad range of 

topics in biopharmaceutical fields with a strong favor 

of bridging the information flow between the United 

States and China. With a good mix of news digest and 

commentary and review articles, I hope you will find 

this issue of particular interest to you. 

The biopharmaceutical fields continue to be very 

dynamic and fast moving. A lot have happened over 

the past a few months. One of the significant developments 

was the successful initial public offering of 

Wuxi PharmaTech (ticker symbol: WX). The astonishing 

development of the company was briefly recapped 

in the article which I have opportunity to provide. I find it particularly refreshing in 

reading the commentary by Guo-Liang Yu, in which he gives an in-depth analysis of the 

factors that might have contributed to the impressive growth of the business and the 

successful debut of Wuxi PharmaTech at the New York Stock Exchange. News Commentary 

is a Column we would like to incorporate more frequently into the future issues. 

Another interesting challenge we often encounter in the rapid changing landscape of the 

biomedical and biopharmaceutical fields is the new terminologies and vocabularies. The 

need to communicate accurately in both English and Chinese, has never been greater. In 

this issue we have introduced a testing case, called “Say it in Chinese”. Please let us hear 

your input on how we can make it more useful and have a broader coverage. 

Intellectual property (IP) is the life line of a biopharmaceutical business. This topic is 

well represented in this issue. A timely discussion concerning follow-on biologics, or 

biosimilars, is given by Phillip Zhang. The article by Heping Zhou deals with the relationship 

between IP protection and innovation. He also expresses his views on how policy 

setting, under the circumstances that are most relevant to the Chinese pharmaceutical 

business, can allow for adequate IP protection while stimulating, rather than hindering, 

creativity and innovation. 

We are fortunate to have several informative review papers covering a variety of research 

topics in this issue. The paper co-authored by Professor Duan et al focuses on Traditional 

Chinese Medicine. In addition to providing a survey on the resource distribution, 

cultivation and production of herb medicine, the status of natural product chemistry, 

phytochemistry research in conjunction with management of the medicinal herbs is assessed. 

Lizhen He gives a detailed account on the different approaches and the challenges 

in the development of HBV therapeutic vaccines. Ye Fang, an expert on the technology 

of label-free optical biosensors, introduces to us the powerful new tool and its application 

in both biochemical and cell-based assays at many stages of the drug discovery 

process. 

Last but not least, writing this letter gives me an opportunity to thank all of you for your 

efforts and supports to the TBI journal by contributing articles and being loyal readers. 

I would also like to take this time to thank the Executive Council members of CABS for 

choosing me to serve as the next CABS President. Together, we will be successful. 

Truly Yours, 

Leping Li

BIOPHARMA NEWS DIGEST 

Triumphal Return of “Haigui”: 

IPO of Wuxi PharmaTech in US 

The spectacular initial public offering (IPO) of WuXi PharmaTech 

(Cayman) Inc. at the New York Stock Exchange 

(NYSE) on August 9, 2007 has been the topic of hot discussions 

in both the pharmaceutical and the financial worlds. 

The successful IPO was another major milestone in the still 

developing story of the company. Wuxi PharmaTech is no 

stranger to our readers, as its story was created by one of our 

own and we have had close associations through activities 

organized by our CABS organization and through business 

relation at the organizations we are serving, it is worthy of 

taking another close look at the astonishing story at this 

juncture. 

Wuxi PharmaTech was founded in December 2000 in 

Shanghai, China, by Ge Li and his business partners. Ge Li, 

who has been serving as Chairman of the Board and Chief 

Executive Officer, graduated from Peking University and 

obtained his Ph.D. in organic chemistry from Columbia 

University. He was one of the founding scientists of Pharmacopeia, 

Inc. one of world's pioneering companies in the 

field of combinatorial chemistry based in Princeton, New 

Jersey. Dr. Li returned to China after spending twelve years in 

the United States and established Wuxi PharmaTech., initially 

focusing on producing libraries of drug-like compounds 

for screening against various biological targets and building 

blocks that were attractive to pharmaceutical companies 

to generate targeted compound libraries of them own. The 

company’s business continues evolving based on the changing 

business demands and the building up of infrastructure 

and capacity. But at all stages of the company’s growth, Dr. 

Li paid special attention to quality and reputation by assembling 

a high-caliber and dedicated management & scientific 

team that is well-versed in western techniques and styles. One 

notable example was the recruitment of Shuhui Chen as its 

Chief Scientific Officer in 2004 from Eli Lily and Company. 

Dr. Chen has built a very successful career in the pharmaceutical 

industries as a medicinal chemist after obtaining his 

Biopharma News Digest 

WuXi PharmaTech (Cayman) 

Inc. Announces 

Closing Of Initial Public 

Offering 

14 Aug 2007, 05:20 PM ET 


Inc. announced the 

closing of its initial public 

offering of 15,167,326 

American Depositary 

Shares (ADSs), including 

1,978,347 ADSs issued 

in connection with the 

exercise of the over-allotment 

option in full. The 

Company's ADSs commenced 

trading on the New 

York Stock Exchange on 

August 9, 2007 under the 

symbol 'WX'. Credit Suisse 

Securities (USA) LLC and 

J.P. Morgan Securities Inc. 

acted as lead underwriters 

and joint book-runners and 

Jefferies & Company, Inc. 

acted as a co-manager in 

the offering. 

Trends In BIo/PharmaceuTIcal IndusTry | 3-2007 3


About: Dr. Ge Li 

Dr. Ge Li has served as 


Inc's Chief Executive 

Officer since inception and 

Chairman since early 2004. 

Before forming Wuxi PharmaTech, 

Dr. Li was one of 

the founding scientists of 

Pharmacopeia, Inc., a Nasdaq 

listed company based 

in Princeton, New Jersey. 

Dr. Li received a bachelor's 

degree in chemistry from 

Peking University, and a 

master's degree and a Ph.D. 

in organic chemistry from 

Columbia University. 


Ph.D. in organic chemistry from Yale University. Led by a business-savvy 

and western-trained management team, WuXi PharmaTech continues 

strengthening itself by attracting many strong professionals from home 

and abroad. 

In the short seven years, Wuxi PharmaTech has established itself as the 

preferred choice of CROs in the pharmaceutical and biotech sector. 

While its core business initially was in the areas of providing synthetic 

chemistry support in the lead discovery and lead optimization segment 

of the drug discovery process, the chemistry services has expanded all 

the way to process R&D and bulk manufacture of active pharmaceutical 

ingredients. As the trend of outsourcing to the East continues under the 

pressure of increasing cost and time efficiency, Wuxi PharmaTech has 

broadened its business to meet the demands of its global partners. This 

year, WuXi PharmaTech is also expanding its outsourcing to include animal 

testing, where not only are cost differentials pronounced, but a more 

permissive ethical climate exists as Shanghai, at this stage, is beyond the 

reach of animal rights groups. Today its operations are grouped into two 

segments: laboratory services, consisting of discovery chemistry, service 

biology, analytical, pharmaceutical development and process development 

services, and research manufacturing, focusing on manufacturing 

of advanced intermediates and active pharmaceutical ingredients for 

R&D use. 

The trend of outsourcing and to China continues trending up. The growing 

opportunity also brings fierce competition. To stay ahead, the company 

has recognized that it is essential to win the trust and confidence of 

its customers particularly in the areas of service quality and high regard 

for intellectual property protection. Today, they have been doing well. In 

addition to being recognized by its many global partners as evidenced by 

the awards and expanding business, Wuxi PharmaTech has been recognized 

by the entire business world, including being named one of the top 

103 National Innovative Companies awarded by the Ministry of Science 

and Technology. The company has been among the Deloitte Technology 

Fast 500 Asia Pacific competition three consecutive years since 2003 and 

voted one of Red Herring Asia 100 private enterprises in 2005. 

Wuxi PharmaTech has produced spectacular growth over its short history. 

The rapid revenue growth and world-class reputation are without 

doubt contributing to the build up of it high valuation. Based on what 

was disclosed in the company’s financial picture in the prospectus, given 

the story behind the company and investors’ large appetites for all things 

Chinese – the need for biopharma to outsource its early discovery operations 

at low cost – Wuxi PharmaTech (WX) is a compelling story of 

investment.

About Wuxi PharmaTechs 

Founded in December 2000 and based in Shanghai, WuXi PharmaTech is the leading 

China-based pharmaceutical and biotechnology R&D outsourcing company. As a 

research-driven and customer-focused company, WuXi PharmaTech offers global pharmaceutical 

and biotechnology companies a broad and integrated portfolio of laboratory 

and manufacturing services ranging from discovery chemistry to biological services and 

manufacturing of APIs for R&D use. 

WuXi PharmaTech assists its global partners in shortening the cycle and lowering the cost 

of drug discovery and development by providing cost-effective and efficient outsourcing 

solutions. Our management team consists of Western-trained Ph.D.s and MBAs with 

experience in drug R&D methodologies and Western-style business practices. Collectively, 

our senior management has more than 100 patents pending or granted, published more 

than 500 publications and has an average of 10 years of experience working in major 

international pharmaceutical and biotechnology companies. 

With over 1,300 scientific staff members, a 630,000 sq. ft. Shanghai Waigaoqiao Free 

Trade Zone research facility, a 220,000 sq. ft. cGMP-quality manufacturing plant in 

Jinshan District, Shanghai, and a new 130,000 sq. ft. Tianjin research facility, WuXi 

PharmaTech is well-positioned to offer its customers high quality services along the drug 

discovery value chain. In 2006, WuXi PharmaTech's customers included 9 of the top 10 

pharmaceutical companies in the world, as measured by 2006 total revenues. 




The Keys To Ge Li And Wuxi Pharma 

Tech’s Success 

Guo-Liang Yu 

On August 14, 2007, Wuxi PharmaTech surprised many 

entrepreneurs and technologists who share the same dream 

as Ge’s by his company’s astonishing successful initial public 

offering in New York Stock Exchange. On September 10, 

Wuxi PharmaTech (WX, NYSE) reached a market capitalization 

of $1.7 billions after 7 years of operation. It took 

more than ten years for Amgen and Genentech to reach 

the same market capitalization. While we all cheer for Ge’s 

success and wish to be the next in line, many come to me 

asking the following questions. 

What are the key elements behind Wuxi PharmaTech’s 

success? How many other Chinese biotechnology companies 

can follow the suite? What can we all learn from Ge’s 

success? 

1. Strong leadership team. It was said “idea is cheap, 

execution is the key and team wins”. Since the beginning, 

Ge surrounded himself with good partners such 

as Xiaozhong Liu (Excutive Vice President), Tao Lin 

(Vice President, Internal Operation) and Zhaohui Zhang 

(Vice President, Domestic Marketing). Together, this 

team formulated a business strategy, developed a sound 

business plan and faithfully executed the plan. Under Ge’s 

leadership, each team member takes the responsibilities in 

his respective area and collectively forms a fully integrated 

functional team that is essential for the rapid growth of 

the company. Without the team efforts, it is impossible to 

command the explosive growth WuXi PharmaTech has 

experienced. 

2. Focused business model. Service model may not be as 

attractive in the Western countries than those of product 

development companies. However, it is a totally different 

story in China. Among more than 400 biotech companies 

in Zhangjiang, most are founded by oversea returnees, 

about 80% of are now CROs. About two years ago, 

I visited Wuxi PharmaTech and had a very interesting 

discussion with Ge. My concern was that a “service only” 

business has less value than a product company and is 

difficult to be sustainable. While Ge acknowledged my 


About the author: dr. 

Guo-liang is currently the 

chairman and President of 

epitomics, Inc. an emerging 

biotech company dedicated to 

the development of innovative 

next-generation monoclonal 

antibodies. Before starting 

epitomics, he was the senior 

Vice-President of research 

and development in mendel 

Biotechnology Inc. dr. yu 

has broad technological and 

scientific experiences in many 

aspects of biotechnology. his 

interests cover genomics, 

molecular biology, genetics, 

immunology, cancer biology, 

and plant physiology and drug 

discovery. he is co-inventor 

and co-author of over 00 patents 

and scientific articles. 

dr. yu received Ph.d. degree 

in molecular Biology from 

the university of california, 

Berkeley and B.s. degree 

in Biochemistry from Fudan 

university, china. Guo-liang 

conducted his Post-doctoral 

training in dr. Frederick ausubel’s 

laboratory at the harvard 

medical school. dr. yu founded 

chinese Biopharmaceutical association 

(cBa) headquartered 

in Washington dc and is an 

executive member of several 

professional organizations in 

u.s and china.


opinion, he emphasized the importance of “not to compete with the customers”. It is proven today 

that his strategy has worked well since a large number of outsourcing deals have been signed with 

large pharmaceutical companies. 

Service business completely depends on outstanding customer satisfaction, i.e., the ability to address 

customer’s needs and concerns, especially when China is still viewed as a risky place for intellectual 

property protections. Wuxi has done an excellent job making the customers comfortable about IP 

protection by investing in the infrastructure to ensure fire-walls between the service teams performing 

for different companies. Proper documentation, real time data transfer and customer communications 

have been in place to ensure happy customers. 

3. Driving growth as suppose to profit. A business is meant to make profit. However, it is always a 

challenge for biotech companies to manage cash flow and focus on revenue growth. To be able to 

continuously find the cash that it is necessary to keep the company going is one of the main challenges 

to the CEO. There are three types of cash sources: investors who buy the stocks, customers 

who pay for services and products, and loans that need to be paid back. The company has to 

do well in order to attract venture investors. The best kind of cash is revenue flow although it is 

not easy to generate revenue and keep growing it to a critical level, especially at early stage of the 

company with weak credibility. Ge and his team did everything necessary to ensure the success of 

the initial projects for customers. Rumor said that they even used two people to perform one FTE 

(full time equivalent) work. With good reputation on the capability and delivery, the business grew 

steadier and faster. In the last 5 years Wuxi had an average growth of 100% per year. To achieve 

such impressive revenue growth, Wuxi must have reinvested all profit back to growing of revenue. 

Not until last year the company started to make a profit. For the second quarter of 2007, Wuxi had 

a net profit of $7M with revenue of $40M. Such a rapid growth has never been heard of in biotech 

history. 

4. Simplicity in technology and business. Wuxi is now recognized as the best and the largest chemistry 

outsourcing place. It is unusual to have a simple and scalable technical platform in the biotech drug 

development industry. Medicinal chemistry is an ideal technology platform to be adopted in China. 

It is easy to execute, easy to replicate and easy to train staff. In China, probably true in other places 

too, critical mass is important to have the cost benefits. Normally, an operation of 20 people can 

hardly bring the cost down due to the low efficiency and productivity. However, when the number 

of scientific staff increases to great than 50, the efficiency starts to bring the cost benefits and 

operation efficiency. The simplicity of technology platform also makes the business relatively easy 

to operate and manage because the outsource work can be tracked and priced in a uniform way. It 

also makes the sales and marketing job easy. Although each program from different customers is 

different, the process in which the works are performed is the same. In essence, the sales team sells 

service as if selling “vacation packages”. This takes out the operational risks and pre-set customer 

expectations. 

Obviously, there are many other important qualities and practices that contributed to Ge and his 

team’s success. Having a strong mentality to be the industry leader with the long term vision is one. 

To find the right market place and to be able to execute well is another. To be able to control all risks 

associated with the business and not let other things distract the main focus is also critical. Is it just 

luck? Is it because they are at the right place and the right moment? Maybe. But it is definitely much 

more than pure luck. 



NEVIRAPINE 

H3C 

N 

HN 

“Made-in-China”: 

FDA Approved First Generic Drug from China 

On July 10, 2007, FDA granted tentative approval for a generic formulation of 

nevirapine tablets, 200 mg, manufactured by Zhejiang Huahai Pharmaceutical 

Co. Ltd. of Zhejiang China, under expedited review provisions developed for 

US President's Emergency Plan for AIDS Relief. Huahai will be able to sell nevirapine 

in the United States after the patent on the drug expires in 2012. For now, 

Nevirapine is sold in the U.S. by Pfizer under the brand-name Viracept. 

*CD-ROM ILLUSTEO LECTURE NOTES ON TROPICAL MEDICINE 

N 

O 

N 


Nevirapine, also marketed under the trade name Viramune® 

(Boehringer Ingelheim ), is a non-nucleoside reverse transcriptase 

inhibitor 

(NNRTI) used to treat HIV-1 infection and AIDS . 

Pfizer's VIRACEPTÒ (nelfinavir mesylate) is an inhibitor of the human 

immunodeficiency virus (HIV ) protease . 

"Tentative Approval" means that FDA has concluded that a drug product has met all required 

quality, safety and efficacy standards, even though it may not yet be marketed in the U.S. because 

of existing patents and/or exclusivity rights. However, tentative approval does make the product 

eligible for consideration for purchase under the PEPFAR program. As with all generic applications, 

FDA conducts an on-site inspection of each manufacturing facility and of the facilities 

performing the bioequivalence studies prior to granting approval or tentative approval to these 

applications to evaluate the ability of the manufacturer to produce a quality product and to assess 

the quality of the bioequivalence data supporting the application. 

Zhejiang Huahai Pharmaceutical Co.,Ltd, was founded by Chen Baohua in January 1989 and located 

at Linhai Zhejiang, with an initial investment of around $5,000 and 12 employees mixing chemicals 

in a one-room warehouse. It is now one of leading modern large-scale pharmaceutical manufacturing 

enterprises in China with 2200 employees, Huahai used to focus on hypertension drugs but now makes 

a stable of generic medicines. Its sales tripled to 557 million yuan last year from 187 million Chinese 

yuan in 2002. The company's profit has more than doubled in that same period, rising to 110 million 

yuan. The stock price has also soared 

in recent years. 

According to Federation of Pharmaceutical 

Generic Associations, 

China API industry is currently estimated 

to be under 4.4% of world 

market and is expected tog grow to 

9.9% by 2010.

Under the Yellow Skin: 

The First Asian Genome Completed 

What genetic make-ups have made us the distinct “Yellow Race”? 

The answer has recently been revealed. In the 9th China Hi-Tech Fair, 

Beijing Genomics Institute - Shenzhen (BGI-SZ) and other units 

announced that the first genome sequence map of a Han-Chinese individual 

was worked out by a group of Chinese scientists. The work was 

underway at the Shenzhen Huada Gene Institute. Although the current 

project will not be a standard map, it is certain to be the first genome 

atlas of the yellow race. 

The First Asian Diploid Genome Project was named as " YanHuang 

(炎黄)No.1". Yan and Huang were the two earliest leaders of different tribes in ancient 

China. Chinese people generally believe that we are all the descendants of Yan and Huang. The 

project included 1000 individuals of Han nationality. 

Two currently available versions of human genome (the Human Genome Sequencing Consortium 

version and the Celera version) are both composites from multiple individuals. Recent 

publications of J. Craig Venter and James Watson’s genomes have started the emerging era of 

individual genome. 

Genomic accuracy is critical for medical research. For example, about 2,000 genes have been 

linked to human diseases. Among them, 1,500 have been identified in clinical diagnosis in the 

United States. However, the Chinese government has only approved 

some dozens of genes for clinic diagnosis – fewer than 3% of those 

in the US. Due to the differences between the yellow and white races, 

China cannot imitate foreign diagnostic standards. With Research on 

the yellow race's genome atlas will provide a more accurate genetic 

standard atlas pool for genetic research and disease treatment. 


The first human genome project was a result of cooperation of 6 

countries, several years’ work, and hundreds of millions of US dollars. 

Now with high-throughput sequencing technology, it only took a few 

months and tens of millions of yuan to complete. The project started 

the research of individual genome and their variations. This is not only 

the first attempt of sequencing individual genome of Asian people, but 

also a diploid sequencing including both genetic information inherited 

from both father and mother. It is clear that this project will greatly 

help the building of approaches for personalized genetic research, especially 

for the Asian race. 



READY FOR PRIME TIME IN THE U.S.? 

An Overview of the Regulatory and Patent Environment for Follow-on Biologics 1 

y. Philip Zhang, J.d., Ph.d. 

About the author: Philip Zhang is 

chief IP counsel at ensemble discovery 

corporation, a biotechnology 

company based in cambridge, massachusetts, 

where he handles all patent 

and other IP matters for the company. 

Prior to joining ensemble, he was Patent 

counsel at Genzyme corporation, 

a major biopharmaceutical company, 

and handled patent matters for 

Genzyme’s drug discovery and development 

efforts. Before joining Genzyme, 

he was in private law practice 

for several years with Testa, hurwitz 

& Thibeault llP, where he advised 

numerous clients on various intellectual 

property matters. dr. Zhang is a 

co-founder and current President of 

chinese american IP law association 

(www.caipla.org). 

dr. Zhang holds a Ph.d. in organic 

chemistry from dartmouth college and 

a J.d. from Vanderbilt university law 

school. he graduated from university 

of science & Technology of china 

with a Bachelor of science degree 

in chemistry. he is a member of the 

massachusetts bar and is registered 

to practice before the u.s. Patent & 

Trademark Office. 


ABSTRACT 

Follow-on biologics or biosimilars present unique regulatory issues that 

await guidance from the U.S. legislature and the FDA. High cost of biological 

drugs, patient safety and protection of biotechnology innovations are 

among the key issues being debated on Capitol Hill and among industry 

advocates alike. In the meantime, Europe has taken the steps of approving 

biosimilar products since 2006. It is likely that the immense political and 

economic pressure will result in legislative and regulatory actions that would 

pave the way for follow-on biologics in the U.S. The regulatory review and 

approval process for follow-on biologics, however, is unlikely to be as simplified 

and streamlined as in the case of conventional generic chemical drugs 

due to the unique safety and efficacy concerns for follow-on biologics. In 

contrast to the Hatch-Waxman Act’s bioequivalence approach, new legislation 

and regulations on follow-on biologics likely would require demonstration 

of clinical safety and efficacy as conditions for market approval. 

摘要 

仿制生物药(Follow-on Biologics),也称相似生物药(Biosimilars),的 

审批程序尚有待美国国会和FDA的新法案和管理条例的颁布。仿制 

生物药的高价格,病人的安全,和对生物技术创新的保护与鼓励是 

目前美国国会辩论的主要争结所在。与此同时,欧盟自2006年以来 

已经批准了几种相似生物药。在美国不断增强的政治和经济压力很 

有可能在不远的将来导致相关法案和管理条例的颁布。但是,介于 

生物药和化学药的巨大区别,仿制生物药的审批要求和程序将和仿 

制化学药的审批要求和程序有明显的不同。现行的亥赤-威克斯曼 

法案(Hatch-Waxman Act)中针对仿制化学药申请和审批的生物等效 

(Bioequivalence)框架将不适用于仿制生物药的申请和审批。针对仿 

制生物药的新法案很有可能要求仿制生物药的申请者通过临床试验 

确证药物的安全性(Safety)和疗效(Efficacy)。 

Key words: follow-on biologics; biosimilar; Hatch-Waxman; ANDA; patent. 

INTRODUCTION 

The past decade has seen mounting economic and political pressure on 

reducing healthcare cost and drug prices in the United States. The U.S. legislature 

and the FDA continue their struggle to define a clear regulatory path 

for follow-on biologics, with drug safety and protection of innovation at the 

center of a persistent debate. This article hopes to provide an overview of 

the regulatory and patent environment for follow-on biologics. 

Biotechnology and Biologics 

The biotechnology industry accomplished its first major milestone in 1982 

when the FDA approved the first genetically engineered drug, Genentech’s 

human insulin produced by genetically engineered bacteria. Still a young 

industry comparing to traditional pharmaceuticals, biotechnology has had

a significant impact on the availability of new and improved 

treatments. More than two hundred new therapies and vaccines 

have been created, targeting cancers, diabetes, HIV/ 

AIDS, autoimmune disorders and rare genetic disorders such 

as Gaucher’s disease. 2 Additionally, more than four hundred 

biotech drugs and vaccines are currently in clinical trials aimed 

at more than 200 diseases. Biologics produced by recombinant 

DNA technology such as insulins, interferons and human 

growth hormones are being used everyday by millions of patients 

throughout the World. The biotech industry has grown 

rapidly. There are now over 1,400 biotechnology companies 

in the U.S. with biotech healthcare revenues at more than $50 

billion. 

Political Environment and Follow-on Biologics 

With the escalating healthcare cost in the U.S., the pressure to 

reduce the cost of prescription drugs and treatments continues 

to mount. The typically much higher price of biological 

drugs has caused politicians and advocates alike to call for 

reform of the FDA regulatory process to allow easier approval 

of cheaper generic biological drugs. While generic chemical 

drugs have been around since the mid-1980s ever since 

Congress enacted the Hatch-Waxman Act, cheaper versions 

of biologics, called “follow-on biologics” or “biosimilar products,” 

have been off-limited to the U.S. consumers partly due 

to the lack of clearly-defined regulatory pathways. 

Biopharmaceuticals generally cost more than chemical drugs. 

For example, biologic drugs for treating rheumatoid arthritis 

and multiple sclerosis cost more than $15,000 per year. 

Table 1 Examples of Brand Chemical and Biological Drugs 

Trends In BIo/PharmaceuTIcal IndusTry | 3-2007 

IP Law 

Higher cost of biologics is due to a variety of factors such as 

lengthy development time and high cost to bring a biological 

drug to market. 3 Biotechnology is still an infant science and 

much risk exists in developing a drug. Patient population also 

has a direct impact on drug prices. Some biologics are approved 

for a small number of patients, making it hard for the 

biotech firm to recover research and development cost and to 

make a profit without a huge price tag. For example, Elaprase, 

a treatment for a rare genetic disease, is used only by about 

250 patients and can cost up to $300,000 a year. 

The political pressure on lowering drug price, however, is generally 

less on innovative drugs that are protected by patents. 

Generally speaking, the political pressure favoring generic 

drugs grows when a drug is off-patent and still maintain its 

price due to the lack of generic competition, with potentially 

anti-trust concerns. 4 Examples include drugs such as insulins 

and certain interferons, some of which are off patent but do 

not face competition of follow-on biologics in the U.S. 

While not yet available in the U.S., follow-on biologics are 

available in many parts of the World. Recently, European 

Union adopted biosimilar regulations, making some follow-on 

biologics available in the EU member countries. 

HISTORY AND STATUS OF ABBREVIATED FDA 

APPROVALS 

Biologics vs. Small Molecule Drugs 

In contrast to traditional pharmaceuticals (referred to as 

Brand Name Active Ingredient Indication Company 

Chemical (“Small Molecule”) Drugs 

Lipitor Atorvastatin calcium High cholesterol and triglycerides Pfizer 

Gleevec Imatinib mesylate Leukemia Novartis 

Claritin Loratadine Allergy Schering-Plough 

Plavix Clopidogrel bisulfate Vascular ischaemic events BMS; Sanofi 

Biological Drugs 

Epogen Epoetin Alfa Anemia Amgen; Roche 

Herceptin Trastuzumab Breast cancer Roche; Genentech 

Erbitux Cetuximab 

Head and Neck and 

Colorectal Cancers 

Merck KGaA; BMS 

Humalog Insulin lispro Diabetes Eli Lily


“drugs” in statutory texts) that are made by synthetic chemistry 

or plant extractions, “biological products” or “biologics” 

are often derived from or made in living cells, organisms, 

plants or animals. Small molecule drugs usually are pure 

chemical substances formulated with excipients. A single or 

small number of chemical structures define the active ingredients. 

Their characterization tends to be straightforward, 

and different products can be easily compared for chemical 

content, purity, safety and efficacy. Biological drugs, on the 

other hand, are composed of much larger and more complex 

macromolecules that are typically composed of molecules of 

varied chemical compositions. 

Due to these differences, traditional pharmaceuticals are 

reviewed by the Center for Drug Evaluation and Research 

(CDER) through New Drug Applications (NDAs) while many 

types of biological drug products (e.g., blood and blood components) 

are reviewed by the Center for Biologics Evaluation 

and Research (CBER) under Biologics License Applications 

(BLAs). Historically, however, some large molecule, nature 

source protein drugs such as insulin, hyaluronidase, menotropins, 

and human growth hormones (hGHs) were approved 

as drugs via NDAs under Federal Food, Drug, and Cosmetic 

Act (the FD&C Act) while other nature source proteins such 

as blood factors are approved as biologics via BLAs under the 

Public Health Service Act (the PSH Act). 5 In early 1990s, the 

FDA moved all recombinant proteins and monoclonal antibodies 

to CBER except hormones such as insulins and hGHs, 

which continued to be regulated by CDER. In 2003, the 

FDA again moved therapeutic products overseen by CBER to 

CDER. As a result, some proteins are currently approved via 

NDA under Section 505 of the FD&C Act while others are 

licensed via BLA under Section 351 of the PHS. 6 

Overview of the Hatch-Waxman Act 

The modern generic approval procedure at the FDA was established 

in 1984 with the enactment of the Drug Price Competition 

and Patent Term Restoration Act, often referred to as 

the Hatch-Waxman Act after the bill’s congressional sponsors, 

Senator Oren Hatch (R-Utah) and Congressman Henry 

Waxman (D-California). The key component of the Hatch- 

Waxman Act as it relates to generic drugs is the establishment 

of the Abbreviated NDA (ANDA) regulatory process which 

allows much streamlined approval processes for generic drugs. 

Before 1984, generic drug sponsors had to submit full NDAs 

which required a complete documentation of safety and efficacy 

of a generic drug. 

The ANDA regulatory pathway is codified in Section 505(j) 

of the FD&C Act. 7 The ANDA pathway allows the generic 

drug sponsor to heavily rely on the safety and efficacy data of 


the reference listed drug. The ANDA sponsors only need to 

demonstrate “bioequivalence” between the generic drug and 

the reference listed drug, thus substantially cutting down the 

time and capital resources needed to bring a generic drug to 

market. 8 In addition, most generic drugs are able to receive 

the “A” interchangeability rating which allows the pharmacy to 

substitute the brand drug with the A-rated generic version. 

As part of the political deal that resulted in the passage of the 

Hatch-Waxman Act, the Act also provides for patent term extension 

and market exclusivities for innovative drugs. A NDA 

holder is entitled to various market exclusivities based on the 

nature of the NDA approval, ranging from five years for new 

chemical entities to three years for supplemental NDAs. In 

addition, the NDA holder can receive up to five years of extended 

(or “restored”) patent protection. The actual length of 

the patent term extension is calculated based on lose of patent 

term due to regulatory reviews at the FDA. 

Patent Challenge under the Hatch-Waxman Act 

The Hatch-Waxman Act further provided a mechanism by 

which a generic drug may be approved before the patent term 

of the brand drug expires. On the one hand, the Act provides 

a generic drug applicant the ability to start patent challenge 

before it places the generic drug on the market and risks patent 

infringement damages. On the other hand, the Act allows 

the NDA and patent holders certain benefits in terms of 

predictable delays of generic approval during patent litigation 

proceedings. 

In particular, the NDA holder is required to list certain types 

of patents that cover the brand drug in “Approved Drug 

Products with Therapeutic Equivalence Evaluations,” often 

referred to as “the Orange Book.” 9 An ANDA applicant is 

required to certify whether it wishes to challenge the listed 

patents and if so, must make a so-called “Paragraph IV 

certification.” 10 The ANDA applicant must notify the NDA 

and patent holders of its intention to challenge a patent and 

provide relevant legal and factual bases for the challenge. If 

the NDA holder files a patent infringement suit against the 

ANDA applicant within 45 days, the FDA approval of the 

ANDA is stayed (i.e., the FDA cannot approve the generic 

application) for 30 months or until the resolution of the law 

suit, whichever comes earlier. If the NDA holder does not file 

patent infringement suit, the FDA may approve the ANDA if 

the FDA is otherwise satisfied with the ANDA. 

To achieve the purpose of increasing drug price competition, 

the Hatch-Waxman Act also provides a unique market incentive 

to the generic drug industry. The first generic applicants 

that successfully challenge an Orange Book-listed patent

enjoy a 180-day generic exclusivity. The FDA cannot approve 

another ANDA on the same reference listed drug until the 

180-day exclusivity has run. During this exclusivity period, the 

generic drug not only can gain a large market share, but also 

can typically charge a much higher price than if other generic 

products are also on the market. 

Impact of the Hatch-Waxman Act 

The Hatch-Waxman Act of 1984 gave birth to the generic 

drug market in the U.S., which has since grown to a size of 

over $20 billion. Today, the largest generic manufactures are 

pharmaceutical giants in their own right, having annual revenues 

in billions of dollars. 

Table 2 Leading Generic Firms in the World 

Company Country 

Teva Israel 

Mylan U.S. 

Sandoz Switzerland 

Apotex Canada 

Ranbaxy India 

SAFETY CONSIDERATIONS FOR FOLLOW-ON 

BIOLOGICS 

Biologics, such as proteins or other large and complex macromolecules 

or living cells, are typically comprised of a number 

of variations in terms of molecular size and structures. They 

are often difficult to purify and susceptible to contamination, 

degradation and loss of activity. The production of biologics 

often presents difficulties not encountered in the manufacture 

of small molecule drugs. While small molecule drugs can be 

copied exactly in terms of their chemical contents, biologics 

manufactured from different cell lines in principle are not 

chemically or structurally identical. Small changes in manufacturing 

protocols sometimes yield substantial modifications in a 

Table 3 First Biosimilar Products in Europe 

IP Law 

biological product’s chemical composition, purity and potency. 

As a result, the manufacturing process places a critical role in 

defining the identity and quality of a biological product. 11 

While the active ingredients of a conventional pharmaceutical 

can be easily identified and measured, currently available 

analytical tools often are unable to fully identify and characterize 

a biological product to such degree that it can be compared 

directly with another product, such as a reference biological 

drug. Therefore, pharmaceutical and biological equivalence 

is difficult to establish, and sometimes cannot be established, 

through chemical analyses as in the case of small molecule 

drugs. As a result, the FDA places heightened oversight on 

manufacturing procedures for biologics than traditional drugs. 

Immunogenicity also presents a serious safety 

concern in the case of biologics. A well-known 

example of immunogenicity occurred several years 

ago when Johnson & Johnson changed the manufacturing 

process for Eprex. The manufacturing 

change was later found to cause certain severe adverse 

reaction in a small number of patients. Other 

safety issues that have been raised include processrelated 

impurities and conformational differences. 

Due to these reasons, it is unlikely that a simple 

“bioequivalence” study can be deemed sufficient, 

as is the case for generic chemical drugs. 12 It is 

generally agreed that a “generic” or “bioequivalent” 

biological product is not scientifically feasible, at least as of today. 

As a result, some in the industry continue to advocate the 

requirement of demonstration of clinical safety and efficacy as 

conditions for market approval of follow-on biologics. 

BIOSIMILARS IN EUROPE 

Follow-on biologics are called similar biological medicinal 

products or “biosimilars” in Europe. The first approval of a 

biosimilar was on April 12, 2006 when the European Medicines 

Agency (EMEA) granted approval to Omnitrope. 13 

EMEA clearly stated that Omnitrope is a biosimilar product 

with Pfizer’s Genotropin (a hGH) as its reference product. 14 

Biosimilar Product Brand Product Biosimilar Sponsor Approval Date 

Omnitrope Pfizer’s Genotropin Sandoz April 12, 2006 

Valtropin Eli Lily’s Humatrope BioPartners May 4, 2006 



In 2003, EU established a regulatory path for biosimilars with 

the adoption of the general regulatory guideline for evaluating 

and approving biosimilars. 15 Additionally, certain scientific 

guidelines have since been issued. 16 Generally speaking, the 

EU’s approach is that of “case-by-case” as EMEA reserves 

the right to set criteria for biosimilars (e.g., what comparability 

data is required) and decides each biosimilar application 

on a case-by-case basis. In many cases, both pre-clinical data 

and clinical efficacy trials are required. And the biosimilar 

manufacturer must characterize, in parallel, both its biosimilar 

product and the reference product and demonstrate, with a 

high degree of certainty, that the quality of the biosimilar is 

comparable to the reference product. Immunogenicity tests 

are often needed as well. The reference product’s molecular 

complexity, unique characteristics, safety and efficacy concerns, 

and manufacturing processes influence the type of tests 

and trials that are required for approval. Recently, EMEA 

issued new guidelines for biosimilars. 17 

In June 2007, EMEA’s Committee for Medicinal Products for 

Human Use (CHMP) recommended approval of three more 

biosimilar products: Binocrit from Sandoz GmbH, Epoetin 

alfa Hexal from Hexal Biotech Forschungs GmbH, and Abseamed 

from Medice Arzneimittel Pütter GmbH for the treatment 

of anemia associated with chronic kidney disease and 

in oncology patients and to reduce blood transfusion requirements 

in oncology patients. 18 All three biosimilar products 

have been shown to be similar to Johnson & Johnson’s Eprex 

(erythropoietin or EPO). In late August of 2007, EMEA 

granted final approval to Sandoz’s biosimilar Epoetin alfa. 19 

REGULATORY PATH FOR FOLLOW-ON BIOLOG- 

ICS IN THE U.S. 

Current Status in the U.S. 

Although an abbreviated approval procedure does not yet 

exist in the U.S. for follow-on biologics, there are ways one 

can bring an off-patent biologic product to market. Firstly, 

one can always conduct all necessary trials and file a complete, 

unabbreviated NDA or BLA. This route, however, is typically 

commercially impractical because the high cost and lengthy 

development process make it unattractive to generic firms. 

The May 30, 2006 approval by the FDA of Omnitrope 20 

under the FDCA’s 505(b)(2) re-candled the generic industry’s 

hope that a somewhat abbreviated approval procedure does 

exist in the U.S. Section 505(b)(2) provides a sponsor the 

ability to submit a full NDA without having to generate all 

necessary data by itself. Rather, the sponsor can “cite” or incorporate 

certain data available in scientific literature and other 

FDA recognized sources. Previously referred to as a “paper” 


NDA, a 505(b)(2) NDA is typically used by innovative firms 

for approval of slightly modified drugs, such as a drug having 

a different delivery or of a different salt. 

Omnitrope, developed by Sandoz, the generic unit of pharmaceutical 

giant Novartis AG, was filed under 505(b)(2). Initially, 

the FDA refused to grant final approval. Novartis sued the 

FDA in U.S. federal court and, through a court order, successfully 

forced the FDA to act on the application. 21 Although 

the FDA made it clear that the approval of Omnitrope under 

505(b)(2) does not signal the availability of this pathway to follow-on 

biologics, 22 many in the industry believe Omnitrope’s 

approval makes 505(b)(2) a practical, albeit imperfect, procedure 

for follow-on biologics approval in the U.S. 

Legislative Activities 

In June 2007, the U.S. Senate Health, Education, Labor and 

Pensions (HELP) Committee passed the Biologics Price 

Competition and Innovation Act, leading some in the industry 

to speculate the imminent adoption of new laws on followon 

biologics in the U.S. The proposed legislation includes 

provisions for streamlined approval of follow-on biologics 

and was sponsored by key senator from both parties: Senators 

Kennedy (D-Massachusetts), Hatch (R-Utah), Clinton (D-New 

York), Enzi (R-Wyoming) and Schumer (D-New York). 

The Senate bill (S. 1695) 23 provides “a procedure designed 

to help resolve patents in an expedited way, and strong but 

responsible incentives to encourage innovation and the 

development of new therapies.” 24 It amends Section 351 of 

the PSA to provide for an approval pathway that requires the 

demonstration of “biosimilarity” - that there are no clinically 

meaningful differences in safety, purity and potency between 

the follow-on product and the reference drug. The demonstration 

of biosimilarity includes “analytical data, animal testing 

and one or more clinical studies, unless such a requirement 

is determined by the FDA to be unnecessary.” 

As to interchangeability, the bill allows the FDA to FDA to 

approve a biosimilar product as interchangeable. The bill, 

however, requires the sponsor of follow-on biologics to provide 

evidence that the biosimilar product will have “the same 

clinical result as the brand product in any given patient” and 

will present “no additional risk in terms of safety or diminished 

efficacy” if a patient alternates or is switched between 

the brand and biosimilar products. 

Regarding data exclusivity, i.e., the period of time during 

which no follow-on products can be approved, the bill provides 

twelve years of data exclusivity for the brand company, 

much longer than the five year exclusivity available to new

chemical entities. Additionally, as incentive to follow-on product 

manufactures, a one-year exclusivity is provided for the 

first interchangeable follow-on product, comparing to the 180day 

exclusivity for the first generic chemical drug applicant 

that must also have successfully challenged a brand patent. 

The bill also includes provisions on patent dispute resolution 

and challenge. Information exchange is required between 

the biosimilar applicant and the brand company, including 

information on patents covering the brand product and the 

biosimilar’s manufacturing process. This process is intended 

to identify relevant patents and disputed issues on patent . 

validity and infringement. The two parties either agree to a list 

of patents to be litigated first or exchange patent lists if they 

cannot agree on them. The brand company then has 30 days 

to file patent suits against the biosimilar sponsor over the disputed 

patents. Interestingly, the bill provides that if the brand 

company fails to identify a patent, it is forever prevented from 

enforcing it against the biosimilar product. 

One vehicle for the passage of this bill would have been 

through the FDA Amendments Act of 2007, which was going 

through the Senate and the House and includes a variety of 

FDA-related legislations. The FDA Amendments Act was 

passed by both Congress and signed into law by President Bush 

in late September 2007. The provisions on biosimilars that were 

in earlier drafts of the legislation, however, were not included in 

the final enacted version. 25 The most contested issues are the 

length of the data exclusivity period for the brand biologics and 

the review standard for safety and efficacy of follow-on products. 

As such, the highly anticipated FDA regulatory overhaul 

of biosimilar approval procedures must now re-gather political 

momentum and await future legislative action. 

CONCLUSION 

The current political pressure in the U.S. will likely continue 

and may result in legislative and regulatory actions that would 

pave the way for follow-on biologics. The FDA approval 

process for follow-on biologics, however, is unlikely to be 

as simplified and streamlined as in the case of conventional 

generic chemical drugs due to the unique safety and efficacy 

concerns for follow-on biologics. 

References 

1. The content of this article is not to be attributed to the 

author’s current, past or future clients or employers, nor 

should it be viewed or regarded as legal advice to anyone. 

2. Biotechnology Industry Organization (BIO), http://bio. 

org/speeches/pubs/er/statistics.asp. 

IP Law 

3. Some recent studies have questioned the potential savings 

of follow-on biologics. For example, Avalere Health’s 

studies have suggested that government savings from 

follow-on biologics to be only $3.6 billion over the next 

ten years. See, http://www.avalerehealth.net/research/ 

docs/Modeling_Budgetary_Impact_of_FOBs.pdf. 

Congressional Budget Office is also studying the economic 

savings of follow-on biologics, which, if found to be 

insubstantial, could have an impact of the support for 

legislative activities. 

4. Remarks of FTC Commissioner Pamela Jones Harbour’s, 

“The Competitive Implifications of Generic Biologics,” 

June 14, 2007, http://www.ftc.gov/speeches/harbour/ 

070614genbio.pdf, see p.13-14. 

5. http://www.fda.gov/opacom/laws/phsvcact/phsvcact. 

htm. 

6. See, e.g., Statement by Acting Commissioner of Food and 

Drugs Department of Health and Human Services on 

the Law of Biologic Medicine (2004), http://www.hhs. 

gov/asl/testify/t040623.html. 

7. P.L. 84-417, 98 Stat. 1585 (1984). http://www.fda.gov/ 

opacom/laws/fdcact/fdctoc.htm. 

8. In addition to bioequivalence, pharmaceutical equivalence 

of the generic and brand products are required and are 

typically met by the “five sameness” requirements, i.e., 

same active ingredient, label, route of administration, 

dosage form, and strength. 

9. An online version is at http://www.fda.gov/cder/ob/. 

10. There are four categories of patent certification in an 

ANDA. A “Paragraph I” certification is used when there 

are no patents listed in the Orange Book for the drug. A 

“Paragraph II” certification applies when the relevant 

patent has expired. A “Paragraph III” certification applies 

when the ANDA does not seek marketing approval 

until after a listed patent expires. A “Paragraph IV” 

certification is made when the ANDA applicant claims 

that a listed patent is invalid or will not be infringed by 

the manufacture, use, or sale of the generic drug. Thus, 

an ANDA applicant wishing to challenge a listed patent 

must make a Paragraph IV certification. The “paragraph” 

numbers refer to the paragraphs of the relevant statutory 

language in the FD&CA. 

11. Studies have suggested that biosimilar products made by 

certain generic firms are different from Amgen’s Epoetin 

Alfa approved in the U.S. and Europe. 

12. For example, BIO has raised certain safety issues with 

follow-on biologics. See, “http://www.bio.org/healthcare/ 

followonbkg/PatientSafety.asp. 

13. EU’s press release: http://europa.eu/rapid/ 

pressReleasesAction.do?reference=IP/06/ 

511&format=HTML&aged=0&language=EN&guiLangu 

age=en. 



14 European Public Assessment Report: http://www. 

emea.europa.eu/humandocs/PDFs/EPAR/Omnitrope/ 

060706en1.pdf. 

15 http://www.emea.europa.eu/pdfs/human/biosimilar/ 

043704en.pdf. 

16 EMEA scientific guidelines: http://emea.europe.eu/ 

htms/human/biosimilar/biosimilarfin.htm. 

17 EMEA guidelines on biosimilars: http://www.emea. 

europa.eu/pdfs/human/pcwp/7456206en.pdf. http:// 

www.emea.europa.eu/htms/human/humanguidelines/ 

biologicals.htm. 

18 See, http://www.emea.europa.eu/pdfs/human/ 

press/pr/26755607en.pdf. The EC usually follows the 

recommendation of CHMP. 

19 http://hugin.info/134323/R/1150279/220459.pdf. 

20 FDA approval letter, http://www.fda.gov/cder/foi/ 

appletter/2006/021426s000LTR.pdf. 

21 April 10, 2006 decision of the US District Court for the 

District of Columbia. See, http://www.orangebookblog. 

com/files/sandoz_v.%20Leavitt.pdf. The FDA has since 

appealed the decision. 

22 FDA “Omnitrope Questions and Answers,” http://www. 

Introduction 

Founded in 2001, Shanghai-based WuXi PharmaTech is China`s 

leading drug R&D service company. As a research-driven and 

customer-focused company, WuXi PhamaTech offers global 

pharmaceutical and biopharmaceutical companies a diverse, 

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Process Chemistry and 

Manufacturing Services 

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Chemistry Services 


Service Biology 

fda.gov/cder/drug/infopage/somatropin/qa.htm. 

23 http://frwebgate.access.gpo.gov/cgi-bin/getdoc. 

cgi?dbname=110_cong_bills&docid=f:s1695is.txt.pdf. 

24 Senate Committee press release, http://help.senate.gov/ 

Maj_press/2007_06_27_c.pdf. 

25 FDA Amendments Act of 2007 was passed by both 

the U.S. Senate and House of Representatives and was 

signed into law by President Bush on September 27, 

2007. http://frwebgate.access.gpo.gov/cgi-bin/getdoc. 

cgi?dbname=110_cong_bills&docid=f:h3580enr.txt.pdf. 

The Act includes the Prescription Drug User Fee Act, 

the Medical Device User Fee and Modernization Act, the 

Best Pharmaceuticals for Children Act, and the Pediatric 

Research Equity Act. 

Say it in Chinese: 

Follow-on Biologics 仿制生物药 

Biosimilars 相似生物药 

Bioequivalence 生物等效 

Value 

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关于知识产权促进医药创新的政策思考 

周和平 

作者介绍: 周和平,研究员(律 

师、专利代理人资格),中国药科 

大学知识产权管理办公室。1977年 

毕业于南京药学院药学专业,留 

校。2002年被江苏省人民政府知识 

产权联席会议办公室聘为江苏省知 

识产权咨询专家组成员。2005年入 

选国家知识产权战略专家库。 

IP Law 

摘要:为建立创新型国家这一奋斗目标,本文分析创新与知识产权 

的辩证关系,根据我国尤其是医药领域自主创新及其知识产权保护 

的现状,探讨利用知识产权促进创新的政策调整的目的、原则及必 

要性,并对医药领域创新类别及相应政策调整提出若干具体设想。 

知识产权制度不仅要保护现有创新权利人的利益,更要促进全社会 

的创新。因为知识产权制度对创新力强的给予强保护,对创新力弱 

的是弱保护,甚至制约大于保护。所以需要根据我国在不同领域的 

创新能力强弱来设置知识产权政策,使我国创新力量由弱变强,从 

而体现知识产权制度与经济基础的适应及良性的相互作用。这种中 

长期的政策调整应贯穿国家及各行各业的知识产权战略研究中。 

关键词知识产权创新政策医药 

本文根据创新与知识产权的本质及有关特点,初步分析其间之辩证 

关系,根据我国尤其是医药领域的自主创新及其知识产权保护的现 

状,探讨利用知识产权促进创新政策调整的目的、原则及必要性, 

并对医药领域创新类别及相应政策调整提出若干具体设想。 

一、创新的本质及特点 

除体制创新外,创新主要是指科学技术的创新(以下简称“创 

新”)。创新活动的产物是智力劳动成果,亦称为创新成果或创 

新。创新活动的本质是一种个体的智力劳动。科技创新的特点是要 

具备三个必不可少的条件: 

(一)物质基础; 

(二)相关的知识积累; 

(三)智力劳动。 

在具备一定物质基础和相关知识背景的前提下,人通过智力劳 

动,迸发智慧火花,量变导致质的飞跃,就产生智力劳动成果,即 

专利法中的创造发明、著作权法中的作品、商标法中的可视性标 

志。 

二、知识产权的本质及若干特点 

“知识产权本质上是一种特定主体所专有的财产权” 1 ,是一种私 

权,其相对应的是公众利益。 

知识产权作为一种私有财产权,权利人会使用各种手段使其获得最 

大程度的保护,以便最大限度地通过市场独占而获利。这就是为什 

么会屡屡出现用专利申请号、外观设计专利甚至于非有效专利去套 

取国家优惠政策现象的根本原因。 

知识产权属于无形财产权范畴。无形财产不象实物,其权利的范 

围、权利的存续期限均有一定的不确定性。“中华人民共和国专利 



法释义” 2 中就明确“专利权作为一种无形的财产权及 

授权情况的复杂性,很难保证每一项被授予的专利权都 

符合法律规定的条件而不在其后被宣告无效”。这种不 

确定性更因涉及人为因素而复杂化。 

三、创新与知识产权之间的辩证关系 

(一)知识产权属于上层建筑。 

知识产权属于上层建筑,上层建筑取决于经济基础,并 

反作用于经济基础。因此,知识产权的保护类型、范 

围、强度及具体措施等,应当与社会发展一定阶段的经 

济基础相适应。 

(二)没有创新就没有知识产权。 

创新是知识产权的保护对象,没有创新就没有知识产权。 

正如没有专利法意义上的发明创造就不可能获得专利权、 

没有著作权法意义上的作品就不能享有著作权一样。 

(三)市场经济环境下,没有知识产权保护难有重大基 

础创新 

创新是人类社会发展的动力。当社会发展到市场经济占 

主导的阶段,知识产权是促进创新的关键。正如郑成思 

先生所强调的“如果不真正保护好知识产权,中国以后 

就难再有‘四大发明’那样的科技创新” 3 。并不是没 

有知识产权保护就没有创新。 

(四)有创新也不一定就能获得知识产权。 

除著作权是自作品完成之日即自动产生以及商业秘密 

外,知识产权中其它权利,几乎都需要依法办理手续、 

经过审批或认定。 

需要办理却没有依法办理相应手续或经过相关程序审批 

或认定,即便是创新,也不一定能够获得知识产权法律 

保护。例如:一项具备新颖性、创造性、实用性的发明 

创造,但发明人没有申请专利,或者申请文件反复修改 

后仍不符合法律要求等等。申请专利、委托高水平的代 

理人、维持专利权、维护专利权等等,也都需要有相应 

的财力支撑。 

(五)知识产权有可能保护的不是创新。 

《中华人民共和国专利法》(以下简称《专利法》)第 

47条第1款规定:“宣告无效的专利权视为自始即不存 

在”。 

专利权作为一种无形的财产权及授权情况的复杂性,很 


难保证每一项被授予的专利权都符合法律规定的条件而 

不在其后被宣告无效,而不具备新颖性、创造性、实用 

性而被无效掉的专利中的技术方案不是真正的创新。 

(六)知识产权保护力度与创新高度成正比。 

知识产权制度是对个体创新活动给予物质回报的一种法 

律保障。知识产权制度对创新力强的给予强保护,对创 

新力弱的给予弱保护,有时甚至是制约大于保护,对不 

具创新力的没有保护只有制约。 

对于一项具体发明创造,就技术方案本身而言,其知识 

产权保护力度与创新高度成正比。例如:工艺改进只能 

获得方法发明专利,全新结构的化合物可以获得物质发 

明专利,而器械的小改动只能获得实用新型专利。实用 

新型专利保护期为10年,发明专利保护期为20年。显而 

易见,发明专利保护力度显著大于实用新型专利,而化 

合物发明专利保护力度又显著大于方法发明专利。 

(七)实施自主知识产权也会受到他人制约 

如果是在别人创新基础上作出的改进发明,即使获得专 

利保护,也是他人基本专利的从属专利,其实施需要得 

到基本专利专利权人的许可,从而受他人制约。 

(八)知识产权在保护权利人创新的同时,亦存在制约 

创新的因素 

知识产权本质上作为一种私权,其在保护权利人的创新 

的同时,亦存在抑制他人创新的因素。为此,法律明确 

规定了限制知识产权条款,如专利权期限、强制许可、 

若干不构成侵权行为的例外,以及著作权法中的合理使 

用等等。 

在有关基因专利的争论中,专家明确指出“基因专利在 

减少低水平重复的同时,也减少同一领域的研究者。据 

2月7日出版的《自然》杂志,1998年提出的与80%- 

85%的血色沉着症发生有关的C282Y和H63D突变测试 

专利,其现在的临床测试许可证的持有者宣布,诊断实 

验室人员要向该公司支付费用以继续使用自己的测试, 

或者向这家公司购买测试试剂盒。虽然许多美国实验室 

在专利授予前就开始了血色沉着症的遗传测试,但大约 

30%的被访实验室因为临床测试服务中的专利问题,而 

不再使用或是不再发展该类遗传测试,这样将会限制技 

术的进一步发展” 4 。 

(九)知识产权制度是在私权与公众利益之间寻求平衡 

如前所述,知识产权是一种私权,其相对应的是公众利 

益。一个蛋糕,中间切一刀,一边多了,另一边肯定就 

要少。

这就是为什么发明专利保护期限为20年,而不是10年或 

40年。因为一般认为20年时间内专利权人通过市场的获 

利已可以补偿其对社会的贡献(包括向社会公开其发明 

内容),过短得不到足够回报,过于长则可能有损公众 

利益。 

保护现有创新权利人的利益与促进全社会的创新既有相 

关性,亦有矛盾性。无论是专利审查还是司法保护都须 

在权利人与公众之间寻求一种利益平衡。显著破坏这种 

平衡,不管偏向哪一边,都会妨碍创新。通过政策调 

整,可以达到相对平衡。任何平衡都是动态的。为此, 

所进行的政策调整不但应有阶段性、连续性,而且应有 

地域及行业差异性的特点。 

(十)知识产权保护是手段,促进创新是目的 

正如已故美国总统林肯所说“专利制度是给智慧之火添 

加利益之油”。 “添油”即专利权人通过市场独占,将 

创新获得最大收益,使权利人愿意(耗费智力)并且有 

能力(物质基础)投入新一轮的创新,以此形成良性循 

环。在 “各尽所能、各取所需”的人类最高文明阶段到 

来之前,没有知识产权保护,创新得不到物质回报,就 

不可能持续进行,最终影响到社会文明的进程和全人类 

的利益。 

但是,知识产权制度不仅仅是为了保护权利人的知识产 

权,还要“鼓励发明创造”(不单是鼓励已有权利人, 

而是所有公民),“促进科学技术进步和创新” 5 。郑 

成思先生在讲解《与贸易有关的知识产权协议》(简称 

Trips协议)第7条时明确提出“知识产权保护本身,并不 

是目的”,知识产权保护的目的“在于促进技术的革 

新、技术的转让与技术传播,以有利于社会及经济福利 

的方式去促进技术知识的生产者与技术知识使用者互 

利,并促进权利与义务的平衡” 6 。 

所以,如果只看到知识产权制度中保护权利人权益的表 

层作用,而忽视其促进全社会创新的深层目的,只注意 

知识产权有促进创新的一面,忽视其抑制创新的一面, 

仅强调保护现有创新权利人的利益,忽视对全社会创新 

的促进,单纯为知识产权保护而知识产权保护,这种对 

知识产权制度片面、机械地理解,会对创新产生负面影 

响,从而影响到知识产权制度的正确施行。 

四、我国自主创新及其知识产权保护的现状 

(一)我国在许多领域原始创新的能力极弱小 

我国在许多领域原始创新的能力极弱小,仅有不同程度 

的集成创新能力和引进消化吸收再创新的能力。 

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(二)我国创新成果受知识产权保护的难度大、力度弱 

我国集成创新和引进消化吸收再创新的成果往往创新力 

度小。 

这些创新力度小的成果,获得知识产权保护的难度大。 

即使获得了知识产权保护,不但保护范围小、保护力度 

弱,而且往往受到他人制约。 

(三)我国医药领域创新成果与专利保护现状 

以医药专利为例,目前医药领域创新成果可分为三大 

类:原始创新药、集成创新和引进消化吸收再创新的 

药,以及工艺改革。 

第一类,原始创新药,其专利权人几乎全为外国制药公 

司。 

第二类,集成创新和引进消化吸收再创新的药,如工艺 

改进的仿制药、新制剂、新用途。这方面创新成果中, 

我国企业占有一席之位。我国医药企业很大部分专利也 

都属于此类。但是,如果化合物专利是外国制药公司所 

有,会直接制约我国企业创新成果的产业化。例如: 

外国制药公司拥有某化合物专利A,而我国制药企业拥 

有该化合物的新合成方法专利B,但专利A仍在有效期 

内,我国制药企业必须得到该外国公司的许可,才能实 

施自己的专利B。 

第三类,已知化合物的工艺改进,如维生素C的工艺改 

进。工艺改革是我国制药企业的长项。 

在2006年举办的“北京国际医药化工知识产权高峰论 

坛”上,专家强调“国内医药化工专利申请还明显存在 

诸多不足;复方及制备方法等下游产品多,保护效力 

弱;中药制药及保健品多;权利要求范围窄且种类及项 

数少”等等 7 。实际上,这些所谓不足反映的正是我国 

现阶段医药领域的创新现状。 

(四)目前我国医药创新企业面临前堵后追的困境 

目前我国医药创新企业正面临前堵后追的困境。 

前面有外国制药企业的新化合物专利阻挡,即便在仿制 

过程中有所创新并获得专利保护,也受制于他人。 

由于我国企业研发成果的创新程度低,专利保护力度 

弱,抵御侵权的难度大。其它企业稍改动,就跳出了专 

利保护范围,随后出现大量低水平重复产品围追初见效 

益的自主创新成果。 



(五)有些规定使我国企业雪上加霜 

以专利为例: 

1、专利申请时,外国制药企业研发全新结构化合物可 

用范围很大的通式表示。而我国发明往往是在已知 

结构基础上修饰的新化合物,其只能用范围很小的 

通式表示;如果修饰位点分散,常因不符合单一性 

被要求分案,专利保护范围更小,有时仅能保护几 

个零星的化合物且被要求分案。而分案又加重了企 

业的经济压力。 

2、财力雄厚的外国制药企业可以制备大量实施例化合 

物,以支持其通式范围很大的权利要求。而我国企 

业因经济原因不能合成大量实施例化合物,审查时 

往往被要求缩小权利要求范围。 

3、专利审查时,全新结构化合物,只要有一定用途和 

效果,就认为具有创造性;而在已知结构基础上修 

饰的新化合物,必须要有预料不到的用途和效果, 

才能被认为具有创造性,而现阶段我国医药领域研 

发的新化合物绝大多数是对已知化合物进行的结构 

修饰,常因创造性缺乏而得不到保护。 

4、新复方、新制剂、以及大量中药复方类新药目前占 

我国医药领域创新的大半壁江山。但这类创新常因 

被认为创造性不够而难以获得保护。 

在审查通知书中常见“所用辅料为药学领域常规辅 

料”一类措辞来否定发明的创造性。实际上,任何 

药物制剂,如真想用于临床,就必须使用药典规定 

的辅料。 

再有,对区别特征的认定是创造性审查的前提与基 

础。当申请人根据对比文件指出审查员没有提及的 

区别特征时,审查员是否应对申请人提出区别特征 

作出评述,还是可以不置可否?《审查指南》对此 

没有明确规定。 

5、新修改的《审查指南(征求意见稿)》将“半开放 

式”删除,会使我国具有较大创新空间的复方、制 

剂,包括大量中药复方的新技术方案,即便获得专 

利,也得不到有效专利保护,从而严重影响医药领 

域创新。 

《审查指南》规定了药物组合物可用三种方式表述:开 

放式、半开放式、封闭式 8 。在用途限定的前提下,真 

正可用开放式限定的药物组合物实际上并不存在。所 

谓“半开放式”,指药物组合物中可以加入一些未指出 

的、但对主要药效没有实质影响的组分。比如,一般中 


药复方,加点大枣或甘草;一般片剂,制颗粒时加点淀 

粉、糊精之类,对药物组合物的基本特性并无实质影 

响。如果不允许用半开放式,一般就只能用封闭式来表 

述药物组合物。此时,稍加一点药效相近的、或者对药 

效无影响的组分,就跳出了用封闭式权利要求限定的专 

利保护范围。 

五、利用知识产权促进创新政策调整的原则、目的 

及必要性 

(一)政策调整的目的 

利用知识产权促进创新政策调整主要目的是:最大限度 

促进我国全面创新。即便我国自主创新成果弱小,也要 

力促其获得知识产权保护,并使权利人能够获得较多回 

报,以便积累实力,逐步由弱变强。每个企业增强,国 

家必定富强。 

(二)政策调整的原则 

政策调整的基本原则是:以促进创新为目的,根据我国 

在不同领域的创新能力的强弱来设计相关知识产权政策。 

利用知识产权促进创新不能搞一刀切、粗放式管理,而 

需要根据我国不同领域的具体情况,区别对待。笔者认 

为:这是在知识产权与创新领域,对温家宝总理政府工 

作报告中 “正确把握宏观调控的方向和力度,注重区别 

对待、分类指导,有针对性地解决经济发展中的突出矛 

盾” 精神的具体贯彻。 

(三)政策调整的必要性 

1、从社会公益角度,需要政策支持市场回报率低或风 

险大的创新 

一方面,我们提倡用市场检验创新成果的价值,由市 

场得利来补偿发明创造者。另一方面,从国家安全 

和人民利益角度,市场行为需要政策引导和调控。 

例如医药领域创新的风险极大,如果没有政策支 

持,罕见病用药、基础研究等就不会有企业投入巨 

资进行研发。 

2、创新能力强者,可通过市场独占获得回报 

知识产权是一种财产权。创新权利人通过知识产权 

法授予的市场独占地位,在市场竞争中获得物质回 

报。这是一种纯粹、个体的市场行为。 

我国创新能力强的项目,可依据市场独占强势地位获 

得利益回报,无须政府再锦上添花。再者国家在政

策财政资助方面僧多粥少,只能将其用在国家最迫 

切需要而我国创新能力又最弱的领域。 

3、政策调整有助于我国创新能力弱的领域走出“恶性 

循环” 

虽然不同领域、不同行业在评判创新能力强弱时的具 

体标准不尽相同,但一般而言,创新能力最弱的领 

域,往往创新难度最大、风险最大。 

我国创新能力最弱的领域,即使有创新,也多半是 

在他人基础上的改进。这类创新往往力度弱小,因 

此不但获得知识产权保护的难度大,而且获得的保 

护范围小,最终通过市场获利也很小。唯有通过政 

策调整才能使我国创新能力弱小领域走出“恶性循 

环”。 

因此,有必要在我国已确立的知识产权法律体系的框 

架内,依据我国具体国情,宏观调控、区别对待, 

通过政策调整,趋利避害,达到利用知识产权促进 

全民创新、建成创新型国家的目标。 

六、医药领域创新分类及相应政策调整的探讨 

首先根据技术难度或创新高度对医药领域的创新成果进 

行分类,对不同类型的创新给予不同类型的政策支持; 

对相同类型的创新,依疗效、毒副作用、环境与资源保 

护这三大指标,选择重点给予政策支持。 

(一)根据技术含量对医药领域创新进行分类 

医药领域的创新类型可按技术含量初步分类如下: 

1、发明专利 > 实用新型专利 > 外观设计专利 

2、化合物发明专利 > 复方发明专利、用途发明专利、 

制剂发明专利、用方法限定的药品专利 > 单纯方法 

发明专利。 

(二)促进医药领域不同类型创新的政策倾向 

1、上述不同的创新类型,给予不同的政策支持。 

2、相同的创新类型,优选考虑疗效、毒副作用、环 

境与资源保护这三大指标,选择政策重点支持的对 

象。 

3、在疗效相同或等同,甚至于略低于现有技术时,毒 

副作用明显降低或减少是创新的显著标志。 

4、在疗效与毒副作用相同或等同的前提下,有利于环 

IP Law 

境保护或资源保护是创新的显著标志。因为环境与 

资源是可持续发展的基础。 

(三)医药领域利用知识产权促进创新的具体措施 

1、化合物专利保护的新药 

具有化合物发明专利的新药,因其高技术、高风险、 

高效益,是各项政策支持的主要对象。在已知结构 

基础上修饰的新化合物,应多方面考虑其创造性。 

具有化合物发明专利的新药应在药品定价、招标采 

购与进入医保方面优先考虑。在具有化合物发明专 

利的新药中,政策优选支持疗效好的品种;在疗效 

相同或等同的新药中,优选支持毒副作用明显降低 

或减少的品种;在疗效与毒副作用相同或等同的前 

提下,优选支持有利于环境或资源保护的品种。 

2、复方发明专利、用途发明专利、制剂发明专利在 

招标采购中给予考虑。但是,招标采购与医保方面 

的政策优惠只应考虑有效保护期内的发明专利。同 

样,对于这类具有发明专利的新药,政策支持疗效 

好的品种;在疗效相同或等同的新药中,政策支持 

毒副作用明显降低或减少的品种;在疗效与毒副作 

用相同或等同的前提下,支持有利于环境或资源保 

护的品种。 

3、方法发明专利,政策只支持二类专利:一是显著有 

利于环境保护的制备方法专利;二是显著有利于资 

源保护的方法专利(主要涉及中药领域)。其余如 

降低成本的制备方法、检测方法专利等,可依靠市 

场竞争获得优势。 

(四)政策调整应贯穿新药研发、专利审查、新药审 

批、生产、销售的全过程 

政策调整是一系统工程,应贯穿新药研发、专利审查、 

新药审批、生产、销售的全过程。例如:新药研发阶段 

的政府基金、资金投入;专利审查阶段对结构修饰新化 

合物、药物组合物的创造性评价;涉及从属专利药品的 

强制许可及强制许可费的调控;销售阶段的药品定价、 

招标采购与进入医保,等等。 

(五)政策调整应增加透明度、建立共享专家库及相应 

管理、监督程序 

各级政府资助、科技部立项、风险基金及药品定价、招 

标采购与进入医保等,均应该透明公开,对不同类型的 

创新给予不同形式、不同侧重点的政策支持,集中财力 

重点支持我国创新能力弱、创新风险大、国计民生迫切 

需要的创新成果的产业化。 



为防止弄虚作假,套取国家优惠政策以获私利,政策调 

整这一系统工程中,每个重要环节须设置知识产权管理 

及监督程序,并按专业领域建立共享知识产权专家库。 

例如:2004年WHO专门成立“知识产权委员会”, 

研究新药研发中不断出现的有关知识产权的问题,并 

定期与相关部门沟通、协调 9 。再如:加拿大卫生部 

设有“专利药品及联络办公室”(Office of Patented 

Medicines and Liaison) 10 。 

另外,专家意见应向社会公布,专家也应受公众监督。 

七、结语 

知识产权制度是保护创新,然其终端目的是激励、促进 

全社会的创新。知识产权制度不仅要保护现有创新权利 

人的利益,更要促进全社会的创新,加快全人类的文明 

进程。国家通过对知识产权的适当保护,达到促进全社 

会创新的目的。适当的知识产权保护是建立创新型国家 

的基础和动力。是否适当要依据具体国情及不同领域的 

相应的发展阶段而定。是否适当的标准在于看其是促进 

了创新还是抑制了创新。十全十美不可能,但依据具体 

情况作相应的政策调整却是可为且必为的。这种中长期 

life sciences 

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This communication is provided as a general informational service to clients and friends 

of Morgan, Lewis & Bockius LLP. It should not be construed as, and does not constitute, 

legal advice on any specific matter, nor does this message create an attorney-client 

relationship. These materials may be considered ATTORNEY ADVERTISING in some 

states. Please note that the prior results discussed in the material do not guarantee 

similar outcomes. The photos in this material are dramatizations. 

的政策调整规划贯穿于国家及各行各业的知识产权研究 

战略中,任重而道远。 

参考文献: 

1. 郑成思:《WTO知识产权协议逐条讲解》,中国方 

正出版社2001年第1版,第3页。 

2. 中华人民共和国专利法释义第四十七条,全国文化 

信息资源共享工程www.ndcnc.gov.cn 

3. “两会”媒体关注教育,www.hainan.gov.cn 

4. 周和平:《关于基因专利的争论》,载《中国新药 

杂志》2004年第13卷1期,第5页 

5. 参见:《中华人民共和国专利法》第1条。 

6. 郑成思:《WTO知识产权协议逐条讲解》,中国方 

正出版社2001年第1版,第42页。 

7. 刘仁:《国知局专家解读医药化工知识产权问 

题》,载《中国知识产权报》2006-5-10 

8. 《审查指南》,知识产权出版社2001年版,第二部分 

第十章,2-156页 

9. www.un.org /chinese/News/fullstorynews 

10. The Food and Drug Regulations-http://laws.justice.gc.ca/ 

en/f-27/c.r.c.-c.870/text.html-2004-08-31 

www.morganlewis.com 

Morgan, Lewis & Bockius LLP • 1701 Market Street • Philadelphia, PA 19103-2921 • Tel: 215.963.5000

2006年我国中药资源研究与学科建设进展 

段金廒 1 吕洁丽 2,1 宿树兰 1 周荣汉 2 

(1 南京中医药大学江苏南京,210046;2 中国药科大学江苏南京,210009) 

作者介绍: 段金廒教授目前担任南京 

中医药大学科技副校长兼中医药研究 

院院长、江苏省方剂研究重点实验室 

主任及中国药科大学兼职教授。段 

金廒教授从事中医药学领域科学研 

究、教学等工作27年余,主要研究方 

向包括:1. 方剂(复方)效应物质基 

础与配伍规律;2. 中药资源化学与活 

性物质的寻找。并同时担任中华中 

医药学会理事、国家科技部中国高新 

技术产业促进会理事、江苏省中医药 

现代化领导小组副组长、全国天然药 

物资源专业委员会主任委员等;被聘 

为《中国实验方剂学》杂志副主委、 

《中药材》杂志副主委、《药学研究 

与临床》杂志副主委、《世界科学技 

术-中医药现代化》杂志编委、《中 

国药科大学学报》编委、《中国天 

然药物》编委、《Asian Traditional 

Medicine》编委等。主编和副主编科 

技专著2部;发表科技论文百余篇; 

培养硕、博士研究生30余人。 

DRUG DISCOVERY AND DEVELOPMENT 

摘要: 通过检索我国学者2006年在国内外发表的中药资源研究相关 

文献,综述了我国中药资源研究与学科建设进展。本文重点介绍了 

中药资源调查、中药资源生产、资源综合开发利用、中药及天然药 

物资源化学、植物化学分类学与亲缘学、中药资源学科建设等方面 

的进展。 

中药资源是自然资源的一部分,人类在漫长的生活实践和生产实践 

中利用自然资源,发现并累积了利用植物、动物和矿物防病治病的 

知识,并逐渐形成体系,著成多部本草学。随着社会对中药资源的 

需求量的增加,使得中药材原料供求矛盾突出。中药资源的可持续 

利用与发展是中药资源科学发展的关键及核心问题。如何实现中药 

资源的可持续利用和发展,是中药和天然药物资源科学工作者的任 

务。2006年,我国中药及天然药物资源研究在资源调查、资源生产 

及质量评价、新技术的应用、资源化学及分类、资源开发利用、中 

药资源学科建设等方面取得了显著进展。 

1 中药资源的调查与研究 

1.1 中药资源种类、数量及地理分布的调查研究 

中药资源调查研究是充分开发利用中药资源的前提,主要包括药用 

植、动物种类、蕴藏量、资源更新的调查。 

药用植物资源调查徐淑珍等[1]对我国菝葜属药用植物的种类、分 

布、生态环境和蕴藏量进行调查,整理出270份标本,已鉴定菝葜属 

16个种和2个变种,其中3个为新记录品种;获取13个省份菝葜属植 

物的分布特征、生长环境及其蕴藏量的信息。徐文芬等[2]通过野外 

调查、标本采集及分类学研究,明确了《贵州中药资源》收载的贵 

阳市菊科药用植物的种类、拉丁学名、地理分布等。贵阳市分布新 

记录1种,产地县分布首次记载7种,贵州省药用新资源7种,贵阳 

市药用新资源14种,《贵州中药资源》记载的有7种贵阳市未见分 

布,2种贵州不产,17种为拉丁异名;确认贵阳市现有菊科药用植物 

130种6变种。经调查鉴定 [3] ,重庆獐牙菜属药用植物有9种,其中西 

南獐牙菜、北方獐牙菜为重庆分布新记录。 

王业桥等 [4] 对海南药用植物的种类、数量、分布、生境以及开发、 

利用现状进行分析,针对海南药用植物保护和利用中存在的问题进 

行了探讨,提出海南今后发展植物药产业的建议和措施。三峡库区 

有药用植物1129 种,隶属于603 属,174 科。根茎类药用植物占 

42.1% [5] 。经调研四川省攀枝花市中药资源全市共有植物药1300余 

种,动物药300余种,矿物药30余种, 常用药约300余种。其中优质高 

效多产动植物药有菌灵芝、川续断、首乌、山药、川牛膝、核桃、 

高山胆草、重楼、白花蛇舌草、苏铁、穿山甲等,且具有川滇两地 

特色 [6] 。广东省江门市锦江源自然保护区内共有维管植物232种, 

370属,1179种,拥有国家重点保护野生植物15科19种,珍稀濒危植 



物15科17种。其中药用植物527种,用材植物216种,观 

赏植物198中,油脂植物132种,蜜源植物63种,纤维植 

物85种 [7] 。 

整理出甘肃秦艽组植物6种1变种 [8] ;六盘山区分布有秦 

艽Gentiana macrophylla、小秦艽G. dahurica 和麻花秦艽G. 

straminea 3 种 [9] 。广西青蒿资源进行调查研究 [10] 发现全 

区40余个县市均有青蒿资源的分布, 为中国青蒿生产地的 

主要省份,2005 年广西种植青蒿约670公顷,靖西县达 

340公顷,且该地的青蒿提取物青蒿素含量可达1.2%。 

药用动物、海洋生物资源调查 2002-2004年陕西家 

养林麝资源实地考察结果表明 [11] :截止到2004年8月 

底,陕西家养林麝存栏量约800余只,主要集中在宝 

鸡、安康和汉中,约占全省家养林麝资源80%以上。 

嵊山岛礁生物资源以及邻近海域的微藻资源调查 [12] , 

共发现121种潮间带生物,其中有28种海洋药用生物, 

包括红条毛肤石鳖(Acanthochiton rubrolineatus) 、马 

粪海胆(Hemicentiotus pulcherrimus) 、海萝(Gloiopeltis 

furcata)等,嵊山岛丰富的海绵资源具有筛选天然活性 

物质的潜力。嵊山岛邻近海域的产毒藻类包括产麻痹 

性贝毒( PSP)的链状亚历山大藻(Alexandrium catenatum 

) 、塔玛亚历山大藻(Alexandrium tam arens),产腹泻 

性贝毒(DSP)的倒卵形鳍藻(Dinophysis forti) 、具尾鳍 

藻(D. caudata);产记忆缺失性贝毒(ASP)的尖刺拟菱 

形藻( Pseudonitzschia pungens) 、多列拟菱形藻( P. m 

ultiseries)和多纹拟菱形藻( P. multistriata);产神经性 

贝毒(NSP)的短凯伦藻(Kerina breve)以及红色裸甲藻 

(Gymnodinium sangium ) 、米氏凯伦藻( Kerinamik imoto) 

、环状异甲藻(Heterocapsa circularisquama)等能产生生理 

活性物质的藻类,其中嵊山岛邻近海域产石房蛤毒素和 

神经毒素的有毒藻类可能具有药用开发价值。 

1.2 新技术、新方法在中药资源调研中的应用 

地理信息系统( Geographic Information System,GIS) 、遥 

感(Remote Sensing,RS)和全球定位系统(Global Positioning 

System,GPS)三大空间科学技术(简称“3S”技术),为中 

药资源研究如资源的调查、监测、中药资源的宏观分析 

和管理提供了新方法 [13] 。赵润怀等 [14] 运用《中药材产地 

适宜性分析地理信息系统》( TCMGIS - I),分析了附子 

的全国适宜产地,结果表明四川江油县等为附子的传统 

产区外,全国共有四川、陕西、贵州、湖南、湖北、甘 

肃、云南、广西、江西、安徽等10个省区的336个县市为 

附子适宜产区,适宜产区面积总和为294057169km 2 。附 

子的次适宜产区和适宜产区面积大致相等。附子适宜区 

分析结果覆盖了第3次全国中药资源普查记载的95%以上 

的区域,同时还分析预测出贵州、江西等普查没有记载 

的区域,同时也验证了TCMGIS-Ⅰ系统的科学性和可靠 

性。孙成忠等 [15] 进一步阐述了地理信息系统GIS的功能以 


及在中药资源信息化建设中的作用,同时对中药资源信 

息化建设过程中有关GIS的关键问题提出合理化建议。孙 

宇章等 [16] 通过对中药资源调查的现状及调查中存在问题 

的分析,阐述遥感的概念、特点及其在中药资源调查中 

应用的优势,列举了遥感在国内外资源调查中的实例, 

提出遥感应用于资源调查的思路和方法,指出遥感在中 

药上的应用必将成为中药研究的一个热点。 

中药资源可持续利用是中药产业健康发展的关键和核 

心,国内许多学者致力于此项研究,探索中药资源可持 

续发展的有效模式。陈世林等 [17] 率先在青藏高原山地实 

施川贝母野生抚育,突破了传统药材人工种植的模式, 

在中国对濒危药材建立规模的野生抚育体系。川贝母野 

生抚育地是在其原有生态环境条件下,主要在海拔约 

4000米的高山灌丛和高山草甸,建立川贝母野生抚育推 

广体系,产生了重要的社会生态效益和经济效益。川贝 

母野生抚育在其特有分布的群落类型中进行,其抚育技 

术突出了川贝母生物学特性及群落等产地适宜性。通过 

测定川贝母分布的群落样地的相对优势度,应用Bray- 

Curtis 距离系数以计算机进行聚类分析等数值分类方法 

划分川贝母分布的群落类型。成都恩威集团建立2500余 

亩川贝母的种源基地,修建了网围栏,对采集的川贝母 

种子进行后熟和低温处理,并进行了中小规模的试种试 

验,为以后种子的生理研究及种子繁育技术研究打下了 

基础。中药品种70%-80%来源于野生资源,因此,中药 

材野生抚育可发展成一种新兴的中药生态产业模式。 

黄明进等 [18] 从地理条件、气候环境、人类活动等方面阐 

明了中药资源储量形成和积累的自然、社会条件;从中 

药材本身的物种遗传、所处的生态环境和人类活动对环 

境的污染,滥用农药造成农药残留超限以及重金属超标等 

方面,阐明了中药资源质量形成的内外因素。从而为合 

理开发、应用中药材,实现中药资源的可持续发展提供 

参考。 

对伞形科野生药用植物资源因药用和食用种类多而被重 

视,皖南山区有伞形科野生药用植物28种2变种1变型, 

多数种类开发利用不够;对皖南山区该科野生药用植物 

资源的现状进行了分析, 对永续利用提出了建议 [19] 。陈 

仕江等 [20] 分析了我国的冬虫夏草及其资源概况以及国内 

外冬虫夏草人工培殖研究进展,提出冬虫夏草资源可持 

续利用的对策与建议。分析中药资源的应用现状、提出 

促进中药资源可持续发展的措施 [21] 。 

2中药资源生产现状 

2.1 中药材规范化生产(GAP)基地建设 

1997年起在国家食品监督管理局的主持和重视下,在相 

关管理部门和全国天然药物资源学会的大力支持下,经

过几年来若干次会议讨论,发布出台了《中药材生产 

管理规范》(GAP),迄今已通过国家GAP认证的品种 

已达140多个。据有关资料报道,目前全国已建成的中 

药材生产基地600多个,中药材生产专业场1.3万个,中 

药材专业户达34万个,中药材种植面积600万亩,产量 

35万吨,年生产总值约160亿元。 

GAP实施两年有余,但中药材基地建设上缺乏技术依托 

和专门人才,优质优价的政策环境尚未形成等,仍然制 

约着GAP产业的健康发展。浙江省中药材行业针对存在 

的问题,提出了产业发展目标及实施中药材良种工程、 

加强标准化体系建设、提高药农组织化程度、加快先进 

技术开发与应用、加大产品开发力度、建立现代中药先 

进制药产业链等对策。在国家科技部“中药现代化研究 

与产业化开发”重点项目资金的支持和引导下,全国中 

药规范化种植基地发展迅速,发挥了良好的示范带动作 

用,促进了中药产业化的发展 [22] 。“十一五”国家科技 

部支撑计划项目“中药资源可持续利用与产业共性技术 

研究”的启动和推进必将使中药资源事业的健康发展起 

到重要支撑。 

2.2 优良种质选育研究 

优良的药用生物资源种质是产生优质丰产药材的根本因 

素。从现有种质资源中用形态描述和分子标记分析相结 

合的方法,进行遗传多样性评价,构建出含有野生种、 

农家种和主要改良种的核心种质,并进行有效的保护是 

中药材栽培可持续发展的基础。同时,根据药用植物有 

效成分生物合成的分子机理,发掘一批重要的有效成分 

调控基因,也可为今后用基因工程等生物技术开发利用 

中药资源打下基础。杜娟等 [23] 选择全国10个主要产地 

的野生或栽培半夏为材料,采用扩增酶切片段多态性 

AFLP方法研究,绘制的系统进化树不同种源之间遗传 

关系的远近与其总生物碱含量差异趋势一致。为半夏及 

其他中药材道地性研究、种质资源鉴定、亲缘关系研 

究、品种选育和引种栽培提供分子水平生物学依据。马 

小军等 [24] 采用加权打分法定量评价半夏种质资源,收集 

到7个省(市)的9个主产区栽培或野生种质,在田间进行完 

全随机种植实验,根据半夏特点选相应关键指标。探讨了 

人工诱变技术在药用植物育种中的发展方向及前景 [25] 。 

3 中药资源的综合开发利用与保护更新 

3.1 中药资源的综合开发利用研究 

我国在药用植物资源开发利用方面已取得可喜成果。以 

四大南药——砂仁、益智、槟榔、巴戟天为主的热带药 

用植物标准化、规范化开发已取得进展。用现代科学手 

段和方法研究热带植物药,从热带植物天然产物中寻找 

新的活性成分,是发展创新天然药物的有效途径 [26] 。按 


照我国行政区划对六大区(华北、东东、华东、中南、西 

南和西北) 的中药资源开发利用研究的现状进行综述 [27] 。 

储蓉等 [28] 通过调查贵州裸子药用植物种类、分布、现状 

及用途,为开发利用提供依据。采用野外调查、引种保 

存、资料收集、分析、市场调研等方法,指出贵州裸子 

药用植物种类较多,具有良好的开发应用效果,应走可 

持续发展模式。 

3.2 中药资源的保护与管理 

长期以来,由于对合理开发利用中药资源的认识不足, 

致使有些药用种类过度采收,资源受到不同程度的破 

坏,一些种类出现衰退甚至濒临灭绝;有些物种的优良 

种质正面临消失和解体。因此,加强中药资源保护和管 

理已势在必行。同时,引起国家及相关部门的高度重 

视。我国科技工作者一直在进行着很有意义的研究与探 

索,闫志峰 [29] 等针对我国中药资源保护和可持续利用目 

标,开展动态监测和系统评价研究,提出了构建我国濒 

危中药资源系统评价保护体系的思路和系统评价内容、 

评价方法及相关评价指标。李西林等 [30] 分析了我国濒危 

药用动植物资源的现状及造成生物物种灭绝的原因,列 

举国际、国内颁布的濒危物种保护公约与名录,以及我 

国对药用动植物的保护条例,探讨了中药资源保护和管 

理的意义与对策。通过对药用濒危野生动物的界定和我 

国药用濒危野生动物繁育利用的调查、调查方法、分析 

方法、繁育利用技术和管理模式的研究,使产业化的发 

展模式和管理政策科学化、标准化 [31] 。 

陈静等 [32] 分析了我国野生药材资源现状、中药材管 

理、保护、利用的立法现状及以现存问题,提出关于野 

生药材资源的可持续利用原则必然要求以综合的长远的 

观点对药材资源进行开发利用,其立法亟待解决的首要 

问题是制定专门的野生药材资源保护法律,对其资源保 

护及综合性开发进行法律规定。提出药用植物资源管理 

系统的功能 [33] ,以鸡血藤为例从药用植物资源管理系统 

在鸡血藤中生产应用的结果显示出,该系统能有效地管 

理中药材的生产。药用植物资源管理系统既可用于监测 

药用植物资源状况,又可指导人们的生产活动,达到可持 

续利用的目的,为解决药用植物资源保护、开发和可持 

续利用的矛盾提供了很好的决策。提出基于3S (GPS、 

GIS、RS) 技术的中药资源信息化管理 [34] ,是提升和改 

造传统中药研发、生产、销售等供应链的前提条件,可 

以帮助中药资源管理的需求者获得相应的中药信息和管 

理决策支持,进而对我国中药自然资源进行合理有效地 

利用和管理,实现中药产业的可持续性发展。 

3.3中药新品种、新药源的发现 

对于濒危物种开展替代资源研究,是中药资源有效保护 

的重要方面,在进行保护生物学研究的同时,开展以优 



南 

京 

高 

新 

南京•高新 

P h 

a 

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m 

a 

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y 

請聯繫我們,告訴我們您的想法和需求 

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人文南京創意高新 

An innovative area in a civlized city 

南京高新技術產業開發區於1988年創建,是全國首批國家級高 

新區,地處中國東部沿海長江三角洲中心,位於史稱“六朝古都 

、十朝都會”的古城南京江北地區的中心位置。東南瀕長江,西 

接被稱為城市綠肺的國家級旅遊度假區珍珠泉公園和國家級森林 

公園老山風景區,北靠龍王山風景區,是江蘇省環境優秀園區, 

生態環境得天獨厚,極其優美。目前1700多家企業在高新區註 

冊,其中外商投資企業320家,產業涉及電子資訊、軟體、生物 

醫藥、新型材料、汽車製造、軌道交通車輛製造等領域。 

生物醫藥園是南京高新區建區以來一直重點發展的園區,區內現 

有南京歐加農制藥有限公司、南京康海藥業有限公司、愛斯醫藥 

科技(南京)有限公司、南京靖龍醫藥技術有限公司、南京川博 

生物技術有限公司等近六十家生物醫藥生產及研發外包骨幹企業 

,產品涉及化學合成、生物合成、基因醫藥、醫療器械、天然保 

Nanjing Hi-Tech Zone

南 

京 

高 

新 

健品等領域。區內的“國家遺傳工程小鼠資源庫”是國家科技部“十 

五”科技攻關專案,是國際知名、國內唯一的小鼠基因庫;生物醫藥 

研發公共服務平臺---南京高新生物醫藥研究所,總面積超過2500平 

方米,目前已建成:化學分析中心、生物分析測試中心、生化試劑中 

心、化學合成中心,並有大量公共研究儀器設備可供使用;再加上高 

新區內生物工程與醫藥園內的13000平方米專業醫藥孵化器平臺和 

中國南京留學人員創業園的政策支持,這四大生物醫藥研發的綜合服 

務平臺作為南京高新區的生物醫藥研發外包基地的基礎支撐平臺,將 

把南京高新區的生物醫藥研發外包基地打造成具有世界一流水平的“ 

藥穀”。 

為對接全球醫藥企業,打造全國一流“藥谷”,南京高新區已正式啟 

動了占地5.25平方公里的南京高新區生物醫藥園新區建設,為生物 

醫藥產業的發展拓展空間。新園區將以培育優勢產品為特色,以引進 

研發企業為突破,構建以生物醫藥研發、製造為一體的醫藥產業基地 

。 

請聯繫我們,告訴我們您的想法和需求 

電話:86 25 66982666-6118,86 13913943244 

電郵:njnhz@163.com 網址:www.njnhz.com.cn 

Sci-tech Park 

高新生物醫藥外包產業基地 

Nanjing Hi-Tech Zone 



质栽培品替代野生植物,以资源丰富的物种取代濒危物 

种,以再生性强的部分(如枝、叶)取代再生性弱的部 

分(如根及根茎)等研究,是确保中药资源可持续发展 

的重要途径和措施。索风梅等 [35] 分析当前濒危中药替代 

资源的研究现状及存在问题,并对我国今后替代品研究 

方向及策略提出了建议和展望。谭仁祥 [36] 从兼具材料稀 

有性、结构新颖性、功能独特性和药源可供性四种特性 

出发,对海洋微生物可作为新天然药物的重要资源进行 

了剖析,并对海洋微生物的关键共性问题进行了探讨。 

从本草、功效、化学成分、机制等方面将常用马兜铃药 

用植物与《中国药典》规定的已有替代药材进行比较, 

探讨其可行性 [37] 。药用植物内生真菌能够产生许多结构 

新颖的活性次级代谢产物,已成为发现新天然活性物质 

的重要源泉 [38] 。Rongmin Yu et al. [39] 采用HPLC- 

DAD指纹图谱技术对人工蛹虫草进行研究,对人工新药 

源的质量进行评价。 

利用组织培养、细胞培养等现代生物技术生产中药资源 

或其药用次生代谢产物越来越受到重视。林丛发等 [40] 采 

用组织培养技术进行铁皮石斛(Dendrobium officinale 

Kimura et Migo)及其类原球茎增殖培养的改良、组培 

苗的移栽进行了研究。李永丽等 [41]综述了近年来细胞培 

养生产药用次生代谢物的研究进展。为保护自然资源做 

出了有益探索。 

4 中药及天然药物资源化学研究 

4.1 中药及天然药物资源有用物质的动态积累及变化 

规律研究 

4.1.1 植物次生代谢产物的生物合成、基因调控及生 

态环境的影响研究 

黄酮类化合物合成过程受到苯丙氨酸解氨酶(PAL)、 

茶尔酮合成酶(CHS)、茶尔酮异构酶(CHI)、黄烷 

酮醇还原酶(DFR)、异黄酮合成酶(IFS)等系列酶 

的调控,而这些酶的活性及其分子合成水平又受到光 

照、水分、矿物质等环境因素的影响。通过黄酮类化合 

物合成途径及其关键酶的分析,明确环境因子影响黄酮 

合成及其分子机制 [42] 。植物甾醇和三萜类皂苷是在生物 

合成过程中有许多关键酶,如鲨烯合成酶(SS) 、鲨烯氧 

化酶(SE) 、氧化鲨烯环化酶(OSCs) 和糖基转移酶(GT) 

等。综述这些关键酶在催化机理、基因克隆与表达调控 

方面的研究进展,并简要探讨了通过这些关键酶的代谢 

工程研究来增产植物甾醇和三萜类皂苷的广阔前景 [43] 。 

药用生物的次生代谢产物,包括生物碱、萜类、酚类、 

甙类等,在植物的生理调节、自身保护、生存竞争、协 

调与环境关系等生命活动方面均起着重要作用。各种生 


态环境因素包括光、温度、土壤、空气以及生物因素均 

影响到药用植物的次生代谢过程。对药用植物次生代谢 

成分与生态环境因素的关系进行研究有利于揭示药用植 

物药用有效成分地域性差异的原因,可为药用植物的育 

种、栽培提供理论依据 [44] 。有对基因调控技术提高药用 

植物细胞有效成分产量的研究进行综述 [45] 。 

4.1.2 不同产地、不同采收期药用生物体内代谢产物 

动态积累及变化规律研究 

运用固相萃取预处理、HPLC - ELSD等方法建立了不同 

产地连钱草中三萜酸类、黄酮类成分的分析方法,评价 

了不同产地连钱草中多类型、多指标药效物质成分及其 

质量 [46] 。采用多变量分析(multivariate data analysis) 

方法 [47] 对53个不同产地的蛇床子样品中11种香豆素成分 

进行分析,采用PCA法进行分析归类,揭示该类成分在 

不同产地蛇床子中的分布具有一定规律性。采用酸性染 

料比色法与两相滴定法 [48] 对不同产地、不同采收期平贝 

母中总生物碱的积累进行研究。 

采用HPLC指纹图谱技术 [49] 对中国当归属及其伞形科植 

物药材进行研究。采用HPLC-ELSD法 [50] 同时测定了通 

光藤Marsdenia tenacissima中7种多氧孕烷苷类化合物。 

采用高效液相色谱法(HPLC) [51] 对分布于我国11个省份 

的红花药材(共36份样品)进行色谱分离,对不同种质红 

花药材进行聚类分析,并对其相似度进行分析。 

采用HPLC-MS法 [52] 对当归及伞形科相关药用植物中藁本 

内酯成分进行定量分析。采用紫外-可见分光光度法 [53] 测 

定不同采收时间苏薄荷中总黄酮的含量,采用HPLC法考 

察黄酮苷元(香叶木素)和黄酮苷(蒙花苷)的动态变化;采 

用GC法 [54] 考察苏薄荷挥发性成分的动态积累变化。 

研究了不同生长期连翘果实干物质及叶和果实中有效成 

分的积累规律 [55] 。分析了不同生长发育期北细辛中挥 

发油的形成和积累,采用GC-MS法测定北细辛根中不 

同样品的挥发油含量,并对其进行主成分分析,确定了 

北细辛的最佳采收期 [56] 。采用HPLC分析不同时期采收 

的桑叶药材中芦丁及绿原酸的含量 [57] ,桑叶最佳采收 

期应为10月下旬经初霜后,这符合桑叶药用须经霜的传 

统要求。研究了蓝花桔梗和白花桔梗中总皂苷的动态积 

累 [58] 。 

对湖北两个天麻GAP ( good agricultural practice)基地不 

同品种的天麻进行了天麻素含量的动态检测和生态条件 

及产量的考察 [59] 。采用紫外分光光度法 [60] 对野马追生 

长过程中总黄酮含量的变化规律进行研究。利用分子生 

物学技术中随机扩增多态性DNA(RAPD) 技术和HPLC技 

术 [61] 对不同农家类型的巴戟天进行内在质量的分析。

4.2 植物化学分类学及亲缘学研究 

植物化学分类学以植物化学成分为依据,对药用植物加 

以分类,研究各植物类群间的亲缘关系探讨植物界演化 

规律;同时更好地引导开发和利用植物资源,如药物新 

品种、新原料和新资源的发现等。 

彭勇等 [62] 研究了毛茛科Ranunculaceae扁果草亚科 

Isopyroideae药用植物亲缘学,对扁果草亚科植物形态、 

化学成分、药理作用及其疗效研究数据进行归纳分析, 

综合研究该亚科各属的形态、化学成分,并结合以往系 

统分类结果,对该亚科内各属系统发育和亲缘关系进行 

探讨。肖培根等 [63] 对中国乌头属植物药用亲缘学进行 

研究,发现牛扁亚属subgen. Lycoctonum是以牛扁碱和 

C18-二萜生物碱为主的类群,由于其毒性中等,因而是 

寻找镇痛、抗炎等新药的一个对象。从二萜生物碱化学 

成分来看,露蕊乌头亚属subgen. Gymnaconitum并不显 

得最为进化,对其分类位置尚难作出最后的结论。并对 

乌头亚属subgen. Aconitum亚属下系之间的化学分类表 

现出的特征进行分析研究,指出各乌头系的毒性差异及 

其开发利用价值。 

5 中药资源学科发展现状 

5.1 中药资源科学研究进展 

随着中药产业的发展,中医药行业的发展越来越受到国 

家科技部、国家中医药局、国家生物技术中心以及各级 

相关部门的重视,相关科研项目资助力度有逐年上升趋 

势。2006年新发布的中医药创新发展规划纲要中明确提 

出“加快构建中药农业技术体系”,开展中药材规范化 

生产技术、绿色无公害技术、中药材质量系统评价、珍 

稀濒危品种保护、繁育和替代品等研究。在资源调查基 

础上建立中药材种质库、基因库、化学样品库等。 

2006年启动实施的国家“十一五”科技支撑计划项 

目“中药资源可持续利用及产业共性技术研究”,分 

为八个课题。主要研究内容包括:1、生物技术与中药 

材优良品种选育研究;2、道地药材适宜生产区的区划 

及生态适宜性研究;3、有效恢复中药材生产立地条件 

与土壤生态环境修复技术研究;4、种子贮存、栽培生 

产、商品流通等环节的病虫害防治技术研究;5、药材 

采收、初加工、贮藏过程中共性技术研究;6、中药饮 

片炮制技术和相关设备研究;7、中药制药过程与设备 

工程化共性技术研究;8、现代制剂技术在中药制剂中 

应用的适宜性研究。该项目的启动实施必将大力推进中 

药资源事业的快速发展。 


5.2 中药资源学科建设 

中药资源学作为一门以生物学为基础的多学科交叉学科, 

涉及生物分类学、生理生态学、地理学、生物化学、天然 

产物化学和中药学等学科。其目的是研究药用植、动物自 

身生长发育规律及其繁衍与生长所依赖的生态环境,以及 

在研究其资源分布规律的基础上,运用经济效益的优化技 

术,合理安排中药资源采收、加工和综合利用等,使社会 

效益、经济效益及生态效益三者协调发展,为人类医疗事 

业及中药产业提供质优量足的中药原料。 

学科体系:中药资源科学的分支学科主要包括中药资源 

化学、植物化学分类学、中药资源生态学、中药资源地 

理学、中药资源管理学、中药资源法学等。 

研究任务:中药资源学作为一门新兴学科在许多方面都 

有长足发展,但在理论和实践上有待充实和提高。基本 

任务是:(1)中药资源科学基础理论和方法学研究; 

(2)中药资源调查,蕴藏量的调查和测算,重要药用 

动植物、珍稀濒危药用植物资源保护、天然更新和人工 

更新研究,药物资源定位观测研究等;(3)重要生物 

资源生态环境、地理分布和活性成分、原料产量间的关 

系,药物资源带动生产区划研究等;(4)医药工业原 

料的综合利用和开发;(5)重要药用植物化学成分积 

累动态、生物合成及增产因子研究;(6)紧缺药材、 

进口药材代替品和类效品以及新资源寻找与开发;( 

7)防治重要疾病药物新品种、新资源寻找和开发;( 

8)运用现代科学技术(离体保护、细胞工程、基因工 

程等)进行种质资源保护研究。 

发展趋势:1、中药资源可持续发展与利用的系统性研 

究 (1)、优良种质资源保存与优良品种选育研究;( 

2)、濒危、珍稀品种的抚育更新与繁育技术研究;( 

3)、道地药材适宜生产区的区划及生态适宜性研究; 

(4)、大宗品种的资源综合利用研究;(5)、稀缺、 

贵重中药材的生物工程技术应用性研究;(6)、新资 

源、替代资源的系统研究。 

2、中药生产过程中共性关键技术系统性研究 (1)、有 

效恢复中药材生产立地条件与土壤微生态环境修复技术 

研究;(2)、种子贮存、栽培生产、药材贮藏、流通 

各环节的病虫害防治技术研究;(3)、药材适宜采收 

期、初加工技术、贮藏期质量控制技术研究。 

教材建设:1993年中国药科大学周荣汉教授主编的《中 

药资源学》教材由中国医药科技出版社正式出版发行, 

这是我国第一部中药资源学专著,对该学科的发展和相 

关学科人才培养发挥了重要作用。 


在中药资源普查工作的基础上,我国相继出版了若干具 

有代表性的大型著作,如《中国中药资源志要》、《中 

国中药区划》等,系统地记载了我国中药资源状况。之 

后,有些学者就资源学科研究内容编纂出版了一批有影 

响力的著作和专论,为学科建设及科学研究做出了重要 

贡献。近年来出版的具有代表性的著作如下:《中药 

资源科学百科全书》(上、下册)、《植物化学分类 

学》、《中药资源可持续利用导论》、《中药材规范化 

种植(养殖)技术指南》等,供从事中药领域研究的科 

研、教学人员很有价值的参考书籍。其中2005年出版的 

由周荣汉、段金廒主编的《植物化学分类学》一书荣获 

2006年度华东地区优秀科技图书一等奖。 

5.3中药资源人才培养现状 

5.3.1 高等院校相关专业设置情况 

随着社会和市场对中药及中药资源人才的需求,各高校相 

继设置中药学、中药资源学、中药资源与开发等专业,以 

适应我国及世界范围内对中药领域人才的需求。同时,注 

重高层次人才的培养,如设置中药学、生药学及中药资源 

学专业的硕士点、博士点,为中医药事业的发展输送或贮 

备高层次、高水平人才资源。目前,我国主要高等院校中 

药资源相关专业设置及培养人才概况如下: 

(1)开设“中药资源与开发”本科专业的院校: 

2个药科大学(中国药科大学、沈阳药科大学);12个 

中医药类院校(南京中医药大学、广州中医药大学(新 

增)、黑龙江中医药大学、山东中医药大学、北京中医 

药大学(中药专业新增中药资源与开发方向)、成都中 

医药大学、湖南中医药大学(新增)、广西中医学院、 

云南中医学院、安徽中医学院、江西中医学院、湖北中 

医学院);9个农(林)类大学(安徽农业大学生命科 

学学院、江西农业大学、吉林农业大学(中药学专业中 

药资源方向)、山西农业大学(新增)、山东农业大 

学、南京农业大学、湖南农业大学、河北农业大学(专 

科)、吉林农业科技学院(中药科学系)、浙江林学院 

(中药资源));其他院校(广东药学院、浙江工业大 

学、新疆医科大学、黑龙江林业职业技术学院、山西生 

物应用职业技术学院、黑龙江农业经济职业学院、广西 

卫生管理干部学院等)。 

(2)开设“中药资源”相关专业、方向硕士点、博士 

点的院校 

开设中药资源学专业硕士点的学校中国药科大学、沈 

阳药科大学、西北大学 

开设中(生)药学专业设有中药资源研究方向硕士点 


的高校浙江中医药大学、甘肃中医学院、广西中医学 

院、贵阳中医学院、南京中医药大学、浙江大学、华中 

科技大学、江苏大学、四川大学、南京农业大学等。 

开设“中药资源学、中药学、生药学”博士点的高校 

沈阳药科大学、浙江中医药大学、长春中医学院、新疆 

医科大学、四川大学等。 

5.3.2人才队伍状况及培养目标 

目前,中医药高等院校包括综合性大学的药学专业已累 

计超过300所,每年培育的专业技术人才已逾万人,每 

年培育的硕士、博士人才超过千人。相对而言,中药资 

源研究人才队伍缺乏系统性、整体性,人才流失严重。 

各大院校培养的中药资源人才往往转向药剂学、药理 

学、化学等领域,基层单位的情况则更为严峻,与中药 

资源相应的研究室和部门几乎形同虚设。国家如果对资 

源的调查研究仍不进行大规模投入,由于中药资源短缺 

和资源研究人才短缺造成的中药现代化发展瓶颈问题将 

会日益突出。 

中药资源人才培养应适应中药资源基础与应用研究、中 

药现代化与中药产业化发展的需要,如培养“GAP种植 

基地基地建设”的专业人才、管理人才等;培养“资源 

保护与更新”的专业技术人才、管理人才等。 

6 结语 

综上表明,2006年中药资源学科在国家科技管理和行业 

管理部门的高度重视、投入和引导下,在本领域科、 

教、产、商及政府各环节的共同努力下取得了丰硕成 

果。中药资源作为国家战略资源和储备物资,即满足了 

日益增长的人口健康保障需求,产生了巨大的社会效 

益;又满足了国内外制药工业、食物补充剂、保健品、 

化妆品等产业链的原料药需求,产生了巨大的经济效 

益;随着中药材栽培品种和面积的不断扩展,有效地调 

整了药材主产区的农村产业结构和增加了农民收入,同 

时又使自然药用生物资源的种群数量和蕴藏量得到有效 

保护和更新,产生了巨大的社会、经济和生态效益。 

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Label-Free Optical Biosensors in Drug Discovery 

ye Fang 

About the author: dr. ye Fang is 

currently a research manager at 

corning Incorporated. Prior to corn- 

ing, he was a postdoc at Johns hop- 

kins university school of medicine 

from 996 to 2000, and at univer- 

sity of Vermont from 995 to 996. 

he received his Bs in chemistry 

from hubei university, and his ms 

in physical chemistry from Wuhan 

university, and his Phd in Biophysi- 

cal chemistry from the Institute 

of chemistry, chinese academy of 

sciences. he has published over 80 

papers. his areas of research inter- 

est include biophysics, systems cell 

biology, protein microarrays, and op- 

tical biosensors. ye can be reached 

by email at fangy2@corning.com. 


Abstract 

Label-free optical biosensors have migrated from a tool solely for 

biomolecular interaction analysis to a universal platform for both 

biochemical and cell-based assays. Together with recent advancement in 

instruments for high througphput screening, the newly discovered ability of 

optical biosensors for assaying living cells will accelerate wide adoption of 

label-free biosensors in drug discovery processes. 

Introduction 

The pharmaceutical industry is constantly looking for new tools, techniques 

and practices to increase the productivity of R&D and improve the 

quality of the innovative medicines they produce. In the recent years, high 

throughput screening (HTS) systems that quickly screen massive numbers 

of compounds have become essential in drug discovery processes. However, 

significant limitations persist in most HTS platforms which utilize labels 

or cell engineering to study an interaction, a pathway or a cellular activity. 

Labels or cell engineering can, in some cases, interfere with the detection, 

the molecular interaction, or the cell biology of target receptors, thus 

resulting in false positives [1] . Importantly, most cell-based assays that are 

biased on a single pathway or activity can also lead to false negatives, given 

that many ligands often exhibit collateral efficacies in activating different 

signaling pathways through a single receptor [2] . To address these limitations, 

solutions-providers have developed label-free techniques, including optical 

biosensors and electrical biosensors. 

Biosensor 

In the past several decades, many types of biosensors have been developed. 

Although there is difference in operating principle (e.g., heat, light, impedance), 

all biosensors consists of three components – a biological component, 

a detector element, and a transducer associated with both components 

(Fig. 1). The biological 

component is generally a 

bioreceptor (e.g., protein, 

nucleic acids, or lipids) 

immobilized on, or a living 

system (e.g., cells, or tissues) 

contacted with, the surface 

of the transducer [3] . The 

interaction between a compound 

and bioreceptors or 

living systems can produce a 

change in physical contents 

of the transducers. Such 

changes can be detected and 

used to directly quantify the 

transducer 

Analyte 

Detector system 

bioreceptor 

Figure 1 The operating principle of 

biosensors.

inding of the compound, or to determine the compoundinduced 

alterations of cells (Fig. 2). Based on the transducer 

used, they are often named as calorimetric, acoustic, electrical, 

magnetic, and optical biosensors. Table 1 summarizes the 

major players in label-free biosensors. 

Optical biosensor 

Optical biosensor is the most important class of biosensors 

[1, 4] . Most of these biosensors exploit evanescent waves to 

characterize molecular interactions, or compound-induced 

response of living cells, at or near the sensor surface [3, 5] . The 

evanescent-wave is an electromagnetic field, created by the 

total internal reflection of light at a solution-surface interface, 

which typically extends a short distance (~hundreds of nanometers) 

into the solution with a characteristic depth, termed as 

penetration depth or sensing volume. Common to all optical 

biosensors is that they measure changes in local refractive 

index at or very near the sensor surface, although commercial 

systems differ greatly in operating principle, throughput, 

sample delivery process, and applications. 

1. Surface Plasmon Resonance (SPR) systems 

SPR relies on a prism to direct a wedge of polarized light, 

covering a range of incident angles, into a planar glass substrate 

having a gold thin film to excite surface plasmons. The resonant 

angle at which a minimal in intensity of reflected light occurs 

is a function of the refractive index of the solution close to 

the gold layer on the opposing face of the sensor surface [5] . 

Coupled with microfluidics which introduces an analyte as 

well as separates unbound and bound molecules, the biosensor 

becomes a powerful biophysical tool for biomolecular interaction 

analysis – quantitatively characterizing how biomolecular 

complexes form and dissociate apart over time. 

a 

E C M 

b 

iec 


cell 

B ro a d b a n d lig h t R e fle c te d lig h t 

itc (transcellular current) 

Electric 

pulse 

D e te c ta b le D M R 

W a v e g u id e 

g la s s 

iec (extracellular current) 

G o ld e le c tro d e 

s u b s tra te 

Figure 2 Principles of two types of biosensors for living 

cell sensing. (a) A RWG biosensor for monitoring ligandinduced 

dynamic mass redistribution in living cells. Cells 

are anchored to the sensor surface through interaction with 

the extracellular matrix (ECM). (b) An electric biosensor 

for monitoring the ionic environment surrounding the 

biosensor and the cells. Cells are cultured on the surface 

of a biosensor having an array of gold microelectrodes. 

Both flows of extracellular (iec) and transcellular (itc) 

current are measured, and a low AC voltage at variable 

frequencies is applied to the cell layer. 

Table 1 Biosensor technologies, manufacturers, instruments, throughput, and website information. 

Technology Manufacturer Instrument Throughput Website 

SPR 

RWG 

Biacore 

GWC Technologies 

BioRad 

Corning Inc 

SRU Biosystems 

A100, T100, S51, FLEXChip 

SPRimager®II 

ProteOn 

Epic® 

BIND 

Low/medium 

Medium 

low 

High 

High 

www.biacore.com 

www.gwctechnologies.com 

www.bio-rad.com 

www.corning.com 

www.srubiosystems.com 

Resonant mirror Thermo IAsys Low www.thermo.com 

Interferometry ForteBio Octet System Medium www.fortebio.com 

Electrical biosensor 

Acea Biosciences 

Applied BioPhysics 

MDS Sciex 

RT-CES 

ECIS 

CellKey 

Medium 

Low 

Medium 

www.aceabio.com 

www.biophysics.com 

www.mdssciex.com 



SPR-based systems were first commercialized in the 1990s by 

a Swedish company Biacore, who still dominates the labelfree 

biosensor market today. Biacore offers a series of SPRbased 

systems, including A100, S51, T100 and 3000, that are 

tailored for profiling the specificity, affinity and kinetics of 

protein interactions. These systems differ in how the sample 

is delivered and processed, and in throughput. Details related 

to these systems can be found from the manufacture’s website 

(http://www.biacore.com). However, Biacore systems suffer 

from low throughput. To increase throughput, Biacore 

recently introduced automated systems such as Biacore 3000, 

and multiplexing system FLEXChip. Although these automated 

systems are configured such that they are readily accept 

samples directly from 96well microplates, these systems have 

relative low to medium throughput because limited channels 

are available for sample analysis, and measurements have to be 

done in series. 

2. Resonant waveguide grating (RWG) systems 

RWG biosensor utilizes the resonant coupling of light into a 

waveguide by means of a diffraction grating. A polarized light, 

covering a range of incident wavelengths, is used to illuminate 

the waveguide; light at specific wavelengths 

is coupled into and propagate along the 

waveguide. The resonant wavelength at 

which a maximum incoupling efficiency is 

achieved is a function of the local refractive 

1 . 0 

index at or near the sensor surface 0 . 0 

PAR 1 

- 1 . 0 

PKC 

[3, 6] . 

For HTS as well as cell-based assays, RWG 

biosensor is advantageous – this type of 

biosensor with appropriate designs allows 

lights at nominally normal incident angle 

to illuminate the biosensor. This is a very 

important design parameter for illuminating 

large numbers of biosensors simultaneously 

– the prerequisite for HTS which 

directly assay samples in the Society for 

Biomolecular Sciences (SBS; http://www. 

sbsonline.org) standard microtiter plates, 

such as 384well microplates. 

Epic® system, commercialized by Corning 

Inc. in 2006, is the first system that is tailored 

for both biochemical- and cell-based assays 

[3, 7-14] . The Epic® system consists of a 

RWG detector, an external liquid handling 

accessory and a scheduler, such that it can 

process large numbers of microplates using 

end-point measurements for HTS, or using 

kinetic measurements for high information 


content screening. Epic® 384well biosensor microplates 

follow the standard SBS footprint. For biochemical assays, 

the microplate surfaces are modified readily such that they 

enable covalent coupling of proteins. For cell-based assays, 

the microplate surfaces are tissue culture compatible for both 

adherent and weakly adherent cells. 

The SRU BIND system is also centered on RWG 

biosensors. It comprises of SBS-standard 96, 384, and 1536well 

microplates and a selection of two types of detection 

instruments. The BIND Reader contains eight parallel 

detection heads, and reads a 96-well plate in 15 seconds. The 

system has a small footprint for compatibility with robotic 

plate handling systems or single-user operation. The system is 

dedicated for bio-affinity measurement, including cell adhesion 

to proteins immobilized on the surfaces [15] . 

3. Interferometry systems 

Interferometry biosensor uses a spectrometer to capture 

interference patterns in the reflected light from the biosensor 

interface. When biological molecules bind to the biosensor 

surface, its thickness increases, and the binding can be 

a 

3 . 0 

b c 

2 . 0 

thrombin 

epinephrine 

0 6 0 0 12 0 0 1 80 0 2 40 0 3 0 00 3 6 0 0 

PLC 

Tim e ( s e c ) 

DAG 

IP3 P-DMR 

G q 

Ca2 + 2 + , Ca 

N -DMR 

1 . 0 

0 . 5 

0 . 0 

- 0 . 5 

- 1 . 0 

2AR 

AC 

cAMP 

0 6 0 0 12 0 0 18 0 0 24 0 0 3 00 0 3 60 0 

Tim e ( s e c ) 

G s 

1 . 5 

1 . 0 

0 . 5 

0 . 0 

- 0 . 5 

LPA 1 

Lysophosphatidic acid 

AC 

cAMP 

G i 

0 6 0 0 1 2 0 0 1 8 0 0 2 4 0 0 3 0 0 0 3 6 0 0 

T im e ( s e c ) 

Figure 3 Broad applicability of optical biosensor for GPCR screens. (a) 

Gq-signaling and its DMR signal (protease activated receptor subtype 1 in 

Chinese hamster ovary cells, 10 unit/ml thrombin). (b) Gs-signaling and 

its DMR signal (β2-adrenergic receptors in A431 cells, 2nM epinephrine). 

(c) Gi-signaling and its DMR signal (lysophophatidic acid (LPA) 

receptors in A431, 100nM LPA). The broken arrows indicate the time 

when an agonist solution is introduced. Data was generated using Epic® 

angular interrogation system. 1 unit equals to 100 pm shift in resonant 

wavelength. Figure was reproduced with permission from Ref. 12.

monitored by analyzing changes in the interference pattern 

at the spectrometer. This type of biosensor does not need 

microfluidics to separate bound and unbound molecules 

in order to study the kinetics of protein interactions, 

since unbound molecules and medium do not change the 

interference pattern. In 2006, ForteBio released the Octet 

system, based on BioLayer Interferometry [1] . The biosensor 

surface is coated with a biocompatible matrix that can interact 

with molecules from a surrounding solution. This system 

is applicable to 96well microplates, and only devoted for 

biomolecular interaction analysis. 

Optical biosensors in drug discovery 

Drug discovery involves the identification, optimization, 

characterization, screening, and assays of drug candidates for 

therapeutic efficacy. The ability of examining living cells is 

increasingly important for the success of drug discovery and 

development. Although more complex and less specific than 

biomolecular interaction analysis, cell-based assays show superior 

ability to facilitate the measurements of mode of action, 

pathway activation, toxicity, and phenotypic responses of cells 

induced by drug compounds. Optical biosensors were solely 

used for biomolecular interaction analysis [1, 4, 5] , and had little 

use in cell-based assays until we recently demonstrated that 

optical biosensors are very useful for probing cell signaling in 

both high throughput and high information content fashions 

[3, 7-14] . High throughput and cell-based assays are the two most 

unmet needs of label-free biosensors. Figure 3 shows the optical 

signals of three classes of endogenous G protein-coupled 

receptors (GPCRs) in living cells. 

1. Systems cell biology 

Optical biosensors can track in real time a ligand-induced 

dynamic mass redistribution (DMR) signal in native cells or 

cell systems, without the need of any labels or manipulations 

of cells [3] . The DMR signal represents an integrated and 

physiologically relevant cellular response [7] , and is an 

approximately global representation of cell signaling and 

physiology of a compound acting on cells [8-13] . Given its 

ability of multiplexing and quantitative system-response 

profiles, biosensor cell assays are well-suited for systems cell 

biology study. In combination with chemical biology approach 

that directly uses chemicals for intervention of specific cell 

signaling components, we have applied optical biosensors to 

study the systems cell biology of epidermal growth factor 

receptor [8] , bradykinin B2 receptor [7,9] and β2 adrenergic 

receptor [10] , all endogenously expressed in A431 human 

epidermoid carcinoma cells. 


2. Systems cell pharmacology 

A compound or drug candidate often has off-target effects, 

such as toxic to cells. Most cell assays rely on the measurements 

of ligand-induced biological responses linked to a single 

signaling pathway. Thus, multiple types of assays are required 

to assess the compound’s off-target effects. Since biosensor 

cell assays do not require prior knowledge of cell signaling and 

are applicable to wide classes of targets and cell signaling [7-14] , 

a single biosensor assay can be used to study the systems cell 

pharmacology of a drug candidate acting on cells. 

3. High throughput screening 

Assaying a large numbers of samples is essential for drug discovery 

– a process to “fish” out druggable hits from a library 

of millions of compounds. Optical biosensor cell assays hold 

great potentials in HTS. Unlike conventional assays that often 

lead to potential false negatives due to the pathway biased 

nature, as well as high false positives due to labels or cell engineering, 

optical biosensor offers a non-invasive and manipulation-free 

alternative to assay endogenous cellular targets such 

as GPCRs in native cells. 

Epic® system is the first biosensor system that has been applied 

for HTS using both immobilized proteins and living cells 

[14]. An internal study using Sigma LOPAC (Library of Pharmaceutically 

Active Compounds) and Epic® cell-based assays 

for endogenous β2-adrenergic receptors in A431 showed that 

Epic® system is able to screen compounds in HTS end-point 

mode (~5min per plate), the assay is robust with a Z’ of 

greater than 0.7, and leads to high quality of data with a hit 

rate of ~2.6%. 

4. Hit selection and optimization 

The process of transforming hits into high-content lead series 

is a crucial step in drug discovery. Both optical biosensor 

biochemical and cell-based assays can find many applications 

during this hit selection and optimization step. Label-free 

cell assays can be used for orthogonal testing and secondary 

screening, whereas label-free biochemical assays can be used 

assess how the compound binds to the target, and to identify 

promiscuous inhibitors. 

Conclusion 

The drug discovery process has been constantly evolving from 

affinity- and targeted-based screens to systems biology- or 

biological or clinical activity-based screens. The advent of 

optical biosensors, particularly high throughput instruments 



and cell-based assays, will accelerate acceptance of optical 

biosensors in many points at many stages of the drug 

discovery process, for which both high information content 

and high throughput are important. 

Reference: 

1. Cooper, M. A. Optical biosensors: where next and how 

soon. Drug Discov. Today 2006, 11, 1061-1067. 

2. Kenakin, T. New concepts in drug discovery: collateral 

efficacy and permissive antagonism. Nat. Rev. Drug 

Discov. 2005, 4, 919-927. 

3. Fang, Y. Label-free cell-based assays with optical 

biosensors in drug discovery. Assays and Drug 

development Technologies 2006, 4, 583-595. 

4. Rich, R. L.; Myszka, D. G. Higher-throughput, label-free, 

real-time molecular interaction analysis. Anal. Biochem. 

2007, 361, 1-6. 

5. Cooper, M. A. Optical biosensors in drug discovery. Nat. 

Rev. Drug Discov. 2002, 1, 515-528. 

6. Tiefenthaler, K.; Lukosz, W. Sensitivity of grating 

couplers as integrated-optical chemical sensors. J. Opt. 

Soc. Am. B 1989, 6, 209-220. 

7. Fang, Y.; Ferrie, A.M.; Fontaine, N.H.; Mauro, J.; 

Balakrishnan, J. Resonant waveguide grating biosensor for 

living cell sensing. Biophys. J. 2006, 91, 1925-1940. 

8. Fang, Y.; Ferrie, A. M.; Fontaine, N. H.; Yuen, P. K. 

Characteristics of dynamic mass redistribution of EGF 

receptor signaling in living cells measured with label free 

optical biosensors. Anal. Chem. 2005, 77, 5720-5725. 

9. Fang, Y.; Li, G.; Peng, J. Optical biosensor provides 

insights for bradykinin B2 receptor signaling in A431 

cells. FEBS Lett. 2005, 579, 6365-6374. 

10. Fang, Y.; Ferrie, A. M.; Lahiri, J. Systems biology and 

pharmacology of β2 adrenergic receptors in A431. 2007, 

In Trends in Signal Transduction Research, Meyers, J.N., 

ed., Nova Science Publishers Inc.: New York, pp. 145- 

171. 

11. Fang, Y.; Ferrie, A. M.; Li, G.; Fontaine, N. H. Cellular 

functions of cholesterol probed with optical biosensors. 

Biochim. Biophys. Acta 2006, 1763, 254-261. 

12. Fang, Y.; Li, G.; Ferrie, A. M. Non-invasive optical biosensor 

for assaying endogenous G protein-coupled receptors 

in adherent cells. J. Pharmacol. Toxicol. Methods 2007, 

55, 314-322. 

13. Fang, Y.; Ferrie, A.M. Optical biosensor differentiates 

signaling of endogenous PAR1 and PAR2 in A431 cells. 

BMC Cell Biol. 2007, 8, 24. 


14. Li, G.; Ferrie, A.M.; Fang, Y. Label-free profiling of endogenous 

G protein-coupled receptors using a cell-based 

high throughput screening technology. J. Assoc. Lab. 

Automat., 2006, 11, 181-187. 

15. Cunningham B.T.; Li, P.; Schulz, S.; Lin, B.; Baird, C.; 

Gerstenmaier, J.; Genick, C.; Wang, F.; Fine, E.; Laing, L. 

Label-free assays on the BIND system. J. Biomol. Screening 

2004, 9, 481-490. 


Label-free 无标记 

Biosensors 生物检测器 

High Throughput Screeen 高通量筛选 

Biomolecule 生物活性分子 

Cell-based Assay 细胞测试


Development of Hepatitis B Therapeutic Vaccine 

lizhen he 

About the author: dr. lizhen he 

is an associate director at r & d 

division in celldex Therapeutics, 

a vaccine company focusing on 

anti-cancer and anti-virus treat- 

ment. dr. he joined medarex in 

200 and moved to celldex with 

its spinning-off in 2005. dr. he 

received her medical degrees from 

Fujian medical university, and did 

her post-doctoral trainings in royal 

Free hospital school of medicine, 

london and memorial sloan-Ketter- 

ing cancer center, new york. 


Abstract 

Hepatitis B virus (HBV) infection is a severe global public health problem. 

The administration of prophylactic vaccine has dramatically lowered the 

incidence of HBV infection, but it is ineffective to those already infected. 

Current anti-viral nucleotide/nucleoside analogues are effective in suppressing 

HBV replication but in most cases fail to clear the virus. HBV mutations 

resulting in resistance to these drugs and the disease recurrence may be 

inevitable in a large proportion of hepatitis B patients. The combination of 

anti-viral drugs with immunotherapies renders the promise of controlling 

and eventually resolving the infection. In this review, different approaches 

in the development of HBV therapeutic vaccines, including selection and 

formulation of antigens and adjuvants, are summarized. The difficulties and 

challenges in the manipulation of immune responses in chronic HBV-infected 

patients are also discussed. 

乙肝病毒感染是一严重的全球性公众卫生问题。注射预防性乙肝疫 

苗大大减低了乙肝病毒感染的发病率, 但是对于已感染人群却无 

效。目前使用的抗病毒核酸类药可以有效地抑制乙肝病毒的福祉, 

但在多数情况下并不能完全清除病毒。同时由病毒异变所造成的抗 

药性和大部分乙肝病人疾病的复发也是不可避免的。因而,联合使 

用抗病毒药和免疫治疗将使得控制疾病以至最终治愈疾病成为可 

能。 

Introduction 

According to WHO report in 2001, 350 million people are chronically 

infected with hepatitis B virus (HBV) worldwide, and the infection is responsible 

for 1 million deaths each year. Typically, chronic hepatitis and its 

complications, i.e., liver cirrhosis and hepatocellular carcinoma, are the death 

causes of HBV infection. 

Since the success of prophylactic vaccines against HBV infection in 1982, 

it has been introduced into childhood immunization services and high 

risk individuals in many countries and the incidence of HBV infection has 

dropped significantly in these countries. The HBV vaccines currently used 

in immunization are HBV surface antigen (HBsAg)-based and their protective 

efficacy is mediated by neutralizing antibodies against HBsAg (HBsAb), 

which block HBV from entering hepatocytes. Around 90% of healthy 

normal individuals, including infants, respond to prophylactic HBV vaccines 

and develop protective levels of HBsAb. However, these vaccines are 

ineffective at treatment in already infected HBV carriers or hepatitis patients. 

On one hand, it is difficult to induce immune responses in infected individuals 

whose immune system is apparently tolerant to HBV; on the other hand, 

HBsAb can not access to and impact on HBV that live and replicate inside 

of hepatocytes.

Much effort and progress has been made in the development of 

antiviral drugs. Alpha-interferon (IFNα) was the first approved 

therapy for chronic hepatitis B. IFNα, combining antiviral and 

immunostimulant properties, results in a sustained suppression 

of HBV replication in only one third of patients [1] , and the 

adverse events are a drawback for its application. Subsequently, 

thenucleoside/nucleotide analogues, such as Lamivudine, 

Adefovir, Entecavir and Telbivudine, were delivered to clinics 

one after another. These are effective in leading to a rapid inhibition 

of HBV replication as well as frequent improvement 

of the necroinflammatory activity of liver diseases and lesser 

extent of fibrosis [2, 3] . Nevertheless, short-term treatment 

with antiviral analogues leads to a frequent relapse of HBV 

replication and long-term treatment may result in virological 

breakthrough related to the selection of resistant viral variants. 

It is evident that clearance of HBV from a chronic carrier by 

these antiviral drugs is an unachievable goal. The limitations 

of all these antiviral therapies in HBV carriers and hepatitis 

patients indicate that development of a more potent therapeutic 

regimen is greatly needed for chronic HBV infection. Vaccines 

designed to elicit significant host immunity to the virus, 

in combination with these therapeutic nucleoside analogues, 

render the promise to effectively control the Hepatitis B virus 

(HBV) infection and its complications. 

Rationale for immunotherapy in chronic HBVinfection 

HBV is a non-cytopathic virus. The host anti-HBV immune 

response is a double-edged sword in HBV infection. While it 

eliminates HBV from bloodstream and hepatocytes, it causes 

liver injury. It is not completely understood why some HBV 

infected individual exhibit self-limited hepatitis and clear the 

virus, whereas the others are unable to do so and become 

chronic HBV carriers or chronic hepatitis patients. Circumstantial 

evidences suggest that the age and the immune status 

at the time of infection are the key factors in this regard. The 

majority of adulthood HBV infection manifests a clinically 

non-symptomatic or mild acute hepatitis and result in virus 

clearance and lifelong protective immunity, which is characterized 

by vigorous polyclonal and multispecific antibody and T 

cell response. On the contrary, up to 90% of HBV infection 

derived from perinatal transmission or during early childhood 

results in chronic infection, exhibiting a weak, transient, 

narrowly focused and antigenically-restricted HBV-specific 

immune response [4, 5] . The small proportion (5-10%) of HBV 

infected adults who become chronic HBV carriers is often 

linked to their suppressed immune status, such as receiving 

chemotherapy, organ transplantation or HIV infection. 

Both type 1 CD4+ helper T lymphocytes (Th1) and CD8+ 

cytolytic T lymphocytes (CTL) that are HBV specific contrib- 


ute to effective control of HBV. Th1 cells exert their effect 

through the secretion of multiple cytokines, which mediate antiviral 

activities directly and promote CTL response. HBV-sensitized 

CTL are capable of recognizing and destroying HBV 

infected hepatocytes. The association of hepatocyte destruction 

with the HBV clearance has been a critical concern in the 

clinical development of immunotherapy against chronic HBV 

infection if a potent HBV-specific CTL response is elicited. In 

fact, both Th1 and CTL contribute to the immunopathogenesis 

of HBV infection [6, 7] . Intrahepatic infiltration of HBVnon-specific 

inflammatory cells, i.e., macrophages, neutrophils, 

NK cells and activated bystander lymphocytes, also contribute 

to the pathogenesis of liver injury. The most important finding 

to support the concept of HBV therapeutic vaccine is 

that clearance of the HBV from infected hapatocytes probably 

does not require massive lysis of hepatocytes, but could 

be largely mediated by antiviral cytokines that are secreted by 

cells of the innate and adaptive immune systems. In particular, 

type 1 and 2 interferon (IFNα, β, γ) and tumor necrosis factor 

alpha (TNFα) have demonstrated the ability to trigger several 

pathways leading to inhibition of viral replication without the 

direct destruction of infected cells in chimpanzee infection 

model and HBV transgenic mice model [8-10] . In the case of 

acute HBV infection in humans, kinetic analysis indicated that 

all or the majority of hepatocytes become infected during an 

acute hepatitis course [11] . Amazingly, these patients are able 

to recover completely without severe liver flare while vigorous 

Th1 and CTL responses to HBV are readily detectable. 

Therefore, manipulation to disassociate immune-mediated 

HBV clearance from destruction of hepatocytes is potentially 

achievable with HBV therapeutic vaccines. 

Clinical development of HBV therapeutic vaccines 

The objective of HBV therapeutic vaccine is to break immunological 

tolerance in chronic carriers and elicit potent 

immune responses leading to the resolution of infection with 

minimized hepatocyte damage. Based on the observation in 

patients and chimpanzees that have completely recovered 

from acute infection, the desired immune response profile 

should include activation of CD4+ T cells with Th1 bias to 

secrete anti-viral cytokines and promote CD8+ T cell activity 

and CD8+ T cells that clear virus through cytolytic (CTL) and 

non-cytolytic (anti-viral cytokines) activities. Many efforts have 

been made by academic, industry and clinicians to develop 

HBV vaccines possessing the desired properties and delivering 

clinical efficacy. Below is a summary of these efforts with 

a focus on on-going clinical programs. Some of the descriptions 

may be quoted from institutional website or conference 

presentations. 



Protein-based vaccines 

Current prophylactic HBV vaccines comprise recombinant 

protein HBsAg and alum as adjuvant, aiming to induce 

antibody responses. Many attempts, including increasing the 

vaccine doses or frequencies, addition of preS2/S1 antigens, 

and changes in the format of recombinant protein, have been 

made to render this vaccine effective in the treatment of HBV 

chronic infection. Decrease in HBV DNA, normalization of 

serum alanine transaminase level (ALT) and seroconversion to 

anti-HBe have been observed in varying small proportion of 

hepatitis B patients or carriers who were recruited to clinical 

studies, but complete elimination of HBV DNA and seroconversion 

of HBsAg to anti-HBsAb have not been achieved [12] . 

Most of these investigations did not go far beyond pilot 

studies or phase I trials. The most advanced on-going study 

is led by Prof. Wen and conducted by Fudan-Yueda Bio-tech 

Co. in Shanghai, China. Their approach is taking advantage 

of immune response enhancement properties of antigen-antibody 

immune complex by mixing prophylactic HBV vaccine 

with human HBV immunoglobulin as therapeutic vaccine. 

Preclinical data generated in mouse models, including HBsAg-expressing 

transgenic mice, showed the induction of 

HBsAb, and IFNγ-secreting CTL [13-15] . Healthy volunteers 

administrated with the HBsAg-HBsAb immune complex in 

combination with alum developed HBsAb without severe 

adverse events. Clinical trial phase IIa and IIb in HBV carriers 

or hepatitis patients have been completed, but to our knowledge, 

no data has been released so far. Along the same line is 

Virexx’s Chimigen, a recombinant chimeric molecule fusing 

HBsAg to xenotypic IgG Fc, which facilitates binding of Chimigen 

vaccine to Fc receptors. In addition, the high mannose 

glycosylation of Chimigen due to its production process is 

expected to be recognized by macrophage mannose receptor 

(MMR). Both Fc receptors and MMR are predominantly expressed 

on antigen-presenting cells (APC), capable of mediating 

the internalization of bound antigens for efficient processing 

and presentation to T cells. It is of interest to explore if 

the promotion of delivering HBsAg to APC results in potent 

anti-HBV immunity in chronic infected patients. 

HBV core protein has been an attractive antigen (HBcAg) in 

HBV therapeutic vaccine development. Unlike the secreted 

HBsAg and HBeAg, HBV core particles are isolated from host 

immune system, and thus highly immunogenic. However, HBeAg 

may function as a T cell tolerogen and regulate the immune 

response to HBcAg due to the homology. In general, HBcAgspecific 

T cell responses are vigorous in infected adults that 

have complete and spontaneous recovery, and are much weaker 

in chronic carriers. The importance of HBcAg-reactive T-cells 

in viral clearance was further emphasized by the association of 

adoptive transfer of HBcAg-reactive T-cells via bone marrow 

transplantation with the resolution of chronic HBV infection 

in recipients, as evidenced that CD4+ T reactivity to HBV core 

was common in donors and corresponding recipients while 

none reacted to S, pre-S1 or pre-S2 antigen, and the frequency 

of core-specific CD4+ and CD8+ T cells in recipients was 


several-fold higher than those specific for surface antigen [16] . 

Celldex Therapeutic is developing an HBV vaccine that is a 

viral-like particle (VLP) comprising 240 modified HBcAg protein 

subunits co-administered with a strong Th1-promoting adjuvant, 

a synthetic lipid A mimetic that acts via Toll-like receptor (TLR) 

4. The proprietary modifications to the HBcAg subunit have 

improved the purity and stability of the VLP, allowing the 

establishment of a robust vaccine manufacturing processes and 

the production of clinical grade VLP material. Immunological 

studies in mice have documented that 10-25µg HBcAg VLP 

with the adjuvant promotes Th1-type CD4+ and CD8+ T cell 

response profile. These responses increased further following 

booster injections a few weeks apart. Studies with peripheral 

blood immune cells from chronic HBV carriers were able to 

show T cell stimulation by the modified HBcAg VLP, indicating 

that the antigen is also appropriately processed and presented to 

human T cells. Based on these data, Celldex is planning to enter 

clinical development in the near future. 

Peptide-based vaccines 

Using modern immunological techniques, several CD4+ 

and CD8+ T cell epitopes have been identified from HBV 

proteins, including core, surface, polymerase and X protein 

[17-22] . One well-established example is the core antigen 18- 

27 peptide, which is immunodominant and subdominant in 

different supertype of HLA-A2 molecules, and could induce 

HBV-specific CTL response in patients with different HLA- 

A2 subtypes. Furthermore, this peptide was also found to 

stimulate HLA class II restricted T-cell response. T cells specific 

to this epitope are widely measured with high frequency 

in most patients with acute self-limited HBV infection 

[17, 18, 23, 

24] . Therefore, it represents the main component of peptidebased 

therapeutic vaccines. A mimetic oligopeptides comprising 

HBcAg18-27 linked to the universal T helper sequence of 

tetanus toxoid (TT830-843) and the PreS2 18-24 B-epitope 

was designed and shown to mediate the induction of CTLmediated 

cytotoxicity in human peripheral blood mononuclear 

cells (PBMCs) from healthy donors and chronic hepatitis B 

patients in vitro and HLA-A2 transgenic mice in vivo [21, 25] . 

Based on these findings, a therapeutic vaccine in the format of 

liposome-oligopeptides has been delivered to clinical development 

by Chongqing Jiachen Biotech Co. with a Phase II trial 

on-going in China. There are no clinical data reported yet. 

Nevertheless, earlier studies with similar lipopeptide vaccines 

showed high immunogenicity in healthy volunteers but comparatively 

weak CTL responses in chronically infected HBV 

patients [26-28] . 

DNA-based vaccines 

DNA vaccine approach utilizes plasmid or modified virus to 

carry and deliver the encoding sequence of antigen, which is 

then synthesized in the vaccination recipients. By virtue of the 

sustained in vivo antigen synthesis and the inherent immunostimulatory 

properties, DNA vaccines appear to induce strong 

and long-lasting humoral (antibodies) and cell-mediated (T-

help, other cytokine functions and cytotoxic T-cells) immune responses 

in animals. Data generated from mouse models showed 

preferential CTL responses elicited by HBV DNA vaccines and 

HBsAg clearance in HBsAg-transgenic mice [29, 30] . However, 

similar results have neither been reproduced in HBV transgenic 

mice [31] , nor achieved yet in humans and non-human 

primates. Oxxon Pharmaccines entered phase II trials with 

its H1-8 HBV therapeutic vaccine, containing 2 doses of 

DNA plasmid primes and two modified vaccinia virus Ankara 

(MVA) boosts, both vectors expressing the same HBV surface 

antigen. The phase IIa study concluded that this novel diseasespecific 

therapeutic vaccine was well tolerated and appeared 

capable of inducing HBeAg seroconversion (4/21, 19%) 

and reducing the HBV viral load in HBeAg seroconverters. 

Meanwhile, PowderMed designed a plasmid DNA (ppdpSC18) 

expressing both HBcAg and HBsAg antigens and is carrying 

out a phase I trial in Hong Kong, Singapore, Taiwan and USA. 

Dendritic cell-based vaccines 

Antigen-pulsed dendritic cells (DCs) have been investigated 

as a vaccine platform to enhance the antigen-specific immunity, 

in particular, in the treatment of patients with cancers. 

Bone marrow-derived DCs pulsed with HBs28-39 peptide or 

recombinant preS2/S particles were used to immunize HBV 

transgenic mice in an attempt to break tolerance to HBsAg 

at the B and T cell levels. The study revealed that while DNA 

vaccination only stimulated an Ab response, infusion of 

activated DCs derived from transgenic or nontransgenic mice 

stimulated a splenic CTL response in all three transgenic lines 

immunized. The CTL precursor frequencies are comparable 

to those in nontransgenic mice, indicating that DC function is 

normal, and HBsAg-specific CTLs are present in HBV transgenic 

mice. However, in spite of the HBsAg-specific CTLs 

response, none of the transgenic mice developed hepatitis or 

displayed suppressed HBV RNA expression or HBV DNA 

replication, implying that the CTLs induced in HBV transgenic 

mice by the DCs vaccination are insufficient in numbers, 

too brief in duration and impaired in functions [31] . A single 

injection of HBsAg-pulsed DCs in normal volunteers either 

sharply increased the serum levels of anti-HBsAg titers in 

HBsAb-positive volunteers or induced anti-HBsAg titers in 

HBsAb-negative normal volunteers with no adverse effects 

documented during a period of 12 months observation [32] . It 

remains to be established if DC-based vaccines are capable of 

eliciting efficient anti-viral immunity in HBV infected individuals. 

Technically, DC-based vaccine is a costly and technically 

challenging approach, and thus the full scale clinical feasibility 

is unclear, considering that chronic HBV infection is most 

significant in developing countries. 

Other formats of vaccines 

Emergent BioSolutions’ vaccine candidate uses their 

proprietary spi-VEC® oral delivery system to deliver hepatitis 

B core antigen to the human immune system. Spi-VEC 

is based on live attenuated typhoid vaccine and employs 


recombinant technology to insert the gene for hepatitis 

B core into the live attenuated Salmonella bacteria. The 

bacteria produce the antigen once inside the patient. After the 

completion of Phase I clinical trial in the United Kingdom 

in 30 healthy adult volunteers, a Phase II clinical trial in 45 

participants chronically infected with hepatitis B has been 

initiated. The primary purpose of this trial is to evaluate the 

safety and tolerability of six monthly doses of the vaccine 

candidate. The secondary purpose is to investigate whether the 

vaccine candidate can reduce the hepatitis B viral DNA load, 

a recognized surrogate endpoint for treatment of hepatitis B 

using current therapeutics. 

Combination of immunotherapy with antiviral 

drugs 

It is reasonable to combine immunotherapy with antiviral 

chemical drugs. Anti-HBV nucleoside/nucleotide analogues 

quickly inhibit HBV replication resulting in a reduced HBV 

load in circulation and liver. The low virus load environment 

may allow potent anti-viral immunity to be triggered by therapeutic 

vaccines and thus to exert its efficacy in virus clearance 

at absence of massive hepatocyte lysis. Furthermore, the antiviral 

immunity may compensate the short-lasting anti-HBV activities 

of nucleoside/nucleotide analogues and keep infection 

under surveillance. Significant higher negative conversion rate 

of HBV DNA and seroconversion from HBeAg to HBeAb 

were reported in chronic hepatitis patients received Lamivudine 

plus prophylactic HBV vaccine vs Lamivudine monotherapy 

[33] . An on-going phase III study is on-going in Senegalesa, 

sponsored by French National Agency for Research on AIDS 

and Viral Hepatitis and collaborated by GlaxoSmithKline. 

The objective of this study is to compare the combination of 

Lamivudine with the prophylactic HBV vaccine Engerix B to 

Lamivudine alone for any long-term benefit. 

Challenges in the development of HBV therapeutic 

vaccine 

The basic difference between a therapeutic vaccine and a 

prophylactic vaccine for HBV are: neutralizing antibody 

recognizing HBV surface antigen is enough for protection in 

healthy subjects, but potent CD4 and CD8 T cell responses 

in addition to antibody titers are required for HBV clearance. 

Therefore, understanding how to elicit effective T cell responses 

in tolerated chronic HBV carriers without the accompanying 

of dramatic hepatocyte lysis has been the real challenge 

in the development of HBV therapeutic vaccine. Many 

efforts have been made in antigen selection, format design and 

adjuvants formulation. However, all these crucial issues must 

be addressed in HBV infected subjects due to the distinct state 

of immunotolerance and immunopathogenesis in hepatitis 

patients and HBV carriers. Clinical data generated on healthy 

volunteers can not reflect the efficacy and adverse events 

which may appear in hepatitis patients and HBV carriers. The 

lack of suitable animal model that can be infected by HBV 



and mimic the pathogenesis of human hepatitis is a major 

hurdle in the development of HBV therapeutic vaccines. 

Chimpanzee was the only animal being used to create HBV 

infection model for decades. Besides the high cost, a major 

drawback of using the chimpanzee model is that the HBV infection 

in this animal resembles an acute hepatitis course and 

can be resolved spontaneously. The Asian tree shrew (Tupaia 

belangeri), a non-rodent, primate-like small animal, has recently 

been proposed as another HBV infection model. Human 

HBV hepatitis and HBV-related hepatocellular carcinoma have 

been successfully established in the tree shrew [34, 35] . It will be 

worthwhile to investigate the value of using this model in the 

development of HBV therapeutic vaccines. Taking advantage 

of genetic approaches, several lines of HBV transgenic mice 

have been engineered. These express HBV component proteins 

or even assemble HBV virus in hepatocytes in vivo. They 

are suitable models to study the immunotolerance but may not 

truly reflect the immunopathogenesis, because their hepatocytes 

are not infected by HBV and no inflammatory reaction 

is observed in the liver. The transgenic mice are thus very 

helpful subject for the exploration of the potency of vaccine 

candidates and the capability of breaking tolerance but help 

less in prediction of liver damages caused by the vaccination. 

Concerns for the risk of severe liver damage caused by immunization 

with a potent vaccine in HBV chronically infected 

patients have slowed clinical development. 

With the progress on immunology, the indispensable role of 

adjuvant in directing and magnifying immunity has been well 

recognized. Administration of well-defined antigen alone 

normally triggers T cells tolerance. Converting naïve T cells 

to effectors requires the interaction with fully activated APCs. 

Discovering and identifying new adjuvants to effectively activate 

APCs is crucial in the development of vaccines to combat 

cancers or viral infections where robust Th1-biased and CTL 

cell responses are required. More specifically in the case of 

HBV therapeutic vaccine, adjuvants should be able to direct 

the induction of viral inhibiting cytokine profile, but keep 

cytolytic activities under control. 

Alum is the most widely used adjuvant in humans. It is also 

the adjuvant in current commercially available HBV prophylactic 

vaccines. Alum predominantly helps antibody responses 

and does little for the induction of cell-mediated responses. 

Hence, it is not a suitable adjuvant for HBV therapeutic vaccines. 

A variety of molecules have been identified possessing 

adjuvant properties, capable of activating certain subset of 

APC and directing different types of immune responses. One 

good example among them is the toll-like receptor (TLR) 

agonists. Unlike alum, various TLR agonists induce different 

cytokine secretion profile by APC and thus different patterns 

of T cell responses. Furthermore, TLR agonists inhibit HBV 

virus replication in the liver of HBV transgenic mice in an 

IFNα/β-dependent manner [36] . It has been reported that 

TLR agonists, such as CpG or poly I:C, significantly boost 


the preventive effect of current HBsAg-based prophylactic 

vaccine [37] . Combining TLR9 agonist, an immune stimulation 

sequence (ISS), with HBV surface antigen, Dynavax’s prophylactic 

vaccine HEPLISAV in phase III trial showed 100% 

protection. It is superior to conventional vaccines not only in 

healthy young adults to whom only two immunizations over 

a one-month period is enough to achieve protective HBV antibody, 

but more importantly, in old people who traditionally 

respond poorly to current vaccines. A therapeutic vaccine is 

in clinical development based on the same formulation using 

both surface and core antigens. 

Conclusion 

A combined effect of anti-viral treatments and HBV-specific 

immune reconstitution is a potential cure of HBV infection. 

Although many attempts have been made in the development 

of HBV therapeutic vaccines, robust cell-mediated anti-viral 

immunity has not been achieved in chronic infected patients. It 

is critical to employ less tolerogenic HBV component proteins 

as antigens and select adjuvants that are able to direct Th1biased 

anti-HBV immune responses in these subjects. With 

the advance in understanding of the mechanism of persistent 

HBV infection and the recognition of effective anti-viral 

immunity, the availability of suitable animal models and the 

emerging of novel adjuvant candidates, it is possible to work 

out new ways in designing and developing effective anti-HBV 

vaccines. 

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Immunotherapy 免疫治疗 

Prophylactic vaccine 预防性疫苗 



2007国际生物经济大会26日在天津滨海新区举行 

“The 2007 International Conference 

for Bio-economy" was held on June 26 

in Binhai New District, Tianjin. Ms. 

Chen Zhili, State Councilor(国务委员陈至 

立), attended the opening ceremony and 

delivered a speech. Wan Gang (科技部长万 

钢), Minister of Science and Technology, 

Zhang Gaoli, secretary of Tianjing Municipal 

Committee, Dai Xianglong, mayor of 

Tianjing and the leadership of the relevant 

ministries attended the conference. Former 

minister of the Ministry of Science and 

Technology and president of the conference, 

Xu Guanhua (前科技部长徐冠华), the 

1981 Nobel laureate, Weisaier, National Academy Member of United States, William 

Rutter and the famous Chinese biologist, Wang Xiaodong, has made excellent 

reports. From 25 countries and regions, more than 2,000 scientists, and entrepreneurs 

attended the conference. 

At the opening ceremony, State Councilor Ms. Chen ZhiLi said that China has 

already set the goal to develop biotechnology and biological industry in the relevant 

national development plan; arranged three special 

science and technology projects important to the state, 

“Cultivation of new variety of transgenic biological 

product”, “Major new drug discovery and manufacture”, 

and “Prevention of AIDS hepatitis and other major 

infectious diseases”; deployed a set of projects for biotechnology 

research and problem solving. 

She indicated China will initially form the political and 

legal system to benefit development of biological indus- 

46 Trends In BIo/PharmaceuTIcal IndusTry | 3-2007

try, systems for technology innovation, technology 

standardization, biological safety guarantee, industrial 

organizing, and professional service; to realize 

the goals of significantly improving the capability 

of innovation independently in biotechnology, 

optimizing and upgrading the industrial structure, 

rapid expansion of the industrial scale. 

Chen ZhiLi emphasized that China will further improve 

the policy and measure in tax, finance, projecting 

intellectual property to encourage technology innovation in enterprises; create 

the policy and environment beneficial to development of biotechnology and biological 

industry; significantly increase government investment in biotechnology research, 

encourage and attract investment in biotechnology R&D and biological industry from 

corporations and the society; strengthen and expand international interaction and collaboration 

in biology field. 

Ten different sub-conference sessions were held, including 1) Policy Forum, 2) Life 

Science, 3) Bioagriculture, 4) Biomedicine, 5) Chinese Medicine and System Biology, 

6) Industrial and Environmental Biotechnology, 7) Bioenergy, 8) Bioresource and 

Biodiversity, 9) Chemical Drugs and Drug Safety, 10) Biobusiness Forum. 

This conference was sponsored/organized by 14 PRC State Ministries/Bureaus and 

international organizations, including PRC Ministry of Science and Technology, 

Tianjing Municipal Government, United Nations Development Program, World 

Health Organization, European Commission, etc (see details below in 

Chinese). This conference will be held biannually in the future. 

Numerous new technologies and the scientific achievements in the 

biotechnology field have been presented in this conference. 

Conference Reports 



Job Market 

Consultant, VP Director of QA 

Location: 

US & China 

Company: 

Rim Tech Ltd. 

Duty: 

Rim Tech, one of the fastest growing biopharmaceutical companies 

in China focused on developing, manufacturing and 

marketing biologic therapeutics. We are looking for a VP level 

consultant as QA DIRECTOR/MANAGER with strong leadership 

in manufacturing, validation, stability testing, auditing, 

on both pre-commercial and commercial products. Analytical 

method validation, raw material assessment and laboratory 

equipment calibration and maintenance with FDA, cGMP's 

compliance. Duties and Responsibilities: Oversee the overall 

quality management system and implement a cGMP system 

with FDA compliance -Directly supervise all QA activities for 

biopharma manufacturing, including: QA Review and Release; 

QA Components Inspection; Document Control; Consumer 

Affairs; Internal Auditing; cGMP Training, Investigations 

and deviations. -Report to senior management, develop and 

execute department’s strategy and planning. We offer a stimulating 

working environment, a high level of professional and 

intellectual challenge, and attractive salaries and comprehensive 

benefits package depending on qualifications 

Requirement: 

At least 10 years of experience in GMP (FDA or EMEA) 

compliance. -Demonstrated record of FDA or EMEA inspection 

and audit experience, preferably in biopharmaceutical 

manufacturing sites, with strong knowledge of ICH, cGMP 

and EU regulatory guidance required. -Strong ability of managing, 

coordinating, and planning; Proactive, highly energetic 

team leaders -Chinese-English bilinguals helpful (not required) 

-MS or BS and at least 10 years of pharmaceutical QA experience 

in US biopharma companies 

Contact: 

Please send your resume, inquiries and recommendations to 

Billy2k94703@yahoo.com. Please write QA Director in the 

subject line. 


Director, Chemistry 

Location: 

China 

Company: 

LEAD Therapeutics 

Duty: 

LEAD Therapeutics is a new chemistry-driven drug discovery 

company, founded to combine western drug discovery 

experience with the emerging capabilities in China. Funded 

by leading venture capital firms, LEAD is now recruiting the 

Chinese management team. The Director of Chemistry will 

manage medicinal chemistry projects conducted at contract 

research organizations and company laboratories based in 

Shanghai, China. The Director will work with a US-based 

management team to plan projects and then be responsible for 

day-to-day management and execution of the plans in Chinese 

laboratories. 

Requirement: 

Requirements for this position are a PhD with strong training 

in synthetic chemistry, plus at least five years medicinal 

chemistry experience at a pharmaceutical or biotechnology 

company. This experience must include demonstrated contributions 

to drug discovery projects, and responsibility at 

the project leader or director level. Important experience in 

addition to medicinal chemistry will include interaction with 

biologists, hiring and motivating people, and management of 

contract research organizations. Fluency in English and Chinese 

is required. Compensation will include competitive salary, 

benefits, relocation, Shanghai living allowance, and equity. 

Interested chemists should send a CV, including education and 

employment history, description of work experience, publications, 

and patents, to jobs@leadtherapeutics.com or LEAD 

Therapeutics, Human Resources, 999 Bayhill Drive, Suite 130, 

San Bruno, CA 94966. 

Contact: 

jobs@leadtherapeutics.com or LEAD Therapeutics, Human 

Resources, 999 Bayhill Drive, Suite 130, San Bruno, CA 94966.

Senior Scientist Epigenetics 

Location: 

Singapore 

Company: 

Eli Lilly Singapore/LSCDD 

Duty: 

For more than 130 years, Lilly has been dedicated to meeting 

the health care needs of people in the United States and 

around the world. We address these needs primarily by developing 

innovative medicines, investing a higher percentage of 

our sales in research and development than any other major 

pharmaceutical company. The Lilly Singapore Centre for Drug 

Discovery (LSCDD) was founded in November 2002, as Lilly 

Systems Biology. Since its establishment, the facility has shown 

leadership in the use of cutting-edge pharmaceutical research 

technologies to discover new medicines more productively. A 

significant expansion is underway to add additional capabilities 

in the areas of drug discovery research. The Senior Scientist, 

Epigenetics will play a key role in helping LSCDD deliver 

upon portfolio milestones. In this role, you will contribute 

as an independent research scientist in addition to providing 

scientific leadership for a team focused to Epigenetics as 

it relates to drug development in cancer and diabetes. Key 

Objectives/Deliverables Provide scientific leadership focused 

on epigenetics across the Drug Discovery Research organization 

Provide scientific and drug hunting leadership, mentoring 

and professional development for associate scientists within 

an Epigenetics team Provide cutting edge integration of new 

areas of biology associated with epigenetic regulation, e.g. 

miRNA, stem cells Identify and validate targets and pathways 

involved in epigenetic regulation Apply modern cell and 

molecular biology technologies to epigenetic drug discovery 

Collaborate with Systems Biology and Computational scientists 

to identify new therapeutic targets Utilize in vivo modeling 

to establish linkage between biological targets and a disease 

phenotype Design relevant primary and secondary assays 

for compound screening Establish and leverage internal and 

external networks to accelerate drug discovery and development 

efforts Participate in the creation of a Fully Integrated 

Pharmaceutical Network (FIPNET) Oversee recruiting and 

staffing activities 

Requirement: 

Minimum of 7 years of experience; with a minimum of 3 

years pharmaceutical or biotechnology industry experience 

or academic track record in epigenetic research Expertise in 

pathways relevant to chromatin modification Expertise in 

technologies to analyze epigenetic modifications (histone/ 

DNA modifications, CHIP-on-chip analysis) Familiarity with 

Molecular and cell biology scientist 

Location: 

Bay Area 

Company: 

Optivia Biotechnology 

Job Market 

Duty: 

Job Description: We are looking for a highly experienced 

and motivated Ph.D. level scientist to drive development 

and implementation of in vitro drug transport assays for the 

purpose of designing a platform of drug screening and profiling, 

as well as to ascertain a mechanistic understanding of the 

transport properties of drug candidates. Key responsibilities 

include: To clone a variety of drug transporter proteins, and 

to develop, conduct and interpret a diverse array of in vitro 

based drug transport studies including, epithelial cell culture, 

transport kinetics, relevant cell based assays, drug concentration 

analysis, protein concentration determinations, and other 

specialized studies. Experience in drug transporter research 

and assay development is highly desirable but not required. 

Fluent Chinese speaking and being able to travel to China 

occasionally are also desirable. Candidate should have a strong 

background in molecular and cell biology, particularly in gene 

cloning, cell culture and cell-based assay development. 

Requirement: 

Minimum requirements: Candidates should have more than 2 

years relevant postgraduate experience. Excellent collaboration 

and communication skills, both written and oral, strong experimental 

and problem solving skills, as well as a track record 

of strong initiative and follow-through are required. Education: 

Candidates shall have a Ph.D. or an equivalent degree in 

Molecular and Cell Biology, Pharmacology, Pharmaceutical 

Sciences, Chemistry, Biochemistry or a related Biological Science. 

Contact: 

Dr. Y. Huang, Tel: (510)488-3653 Fax: (510)783-4288 email: 

career@rationalbio.com 

epigenetic enzyme classes (HDAC, HAT, methyltransferase 

and demethylase) Familiarity with adult stem cells/cancer stem 

cells and their epigenetic regulation 

Contact: 

Lilly Singapore Centre for Drug Discovery Pte Ltd 1 Science Park 

Road #04-01 The Capricorn, Singapore Science Park II Singapore 

117528 www.lscdd.lilly.com.sg Phone: +65-6416-6300 Fax: 

+65-6416-6311 


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Job 07-0080_OneShotKin_AdDev_FINAL.i1 #: 00-0000 • Publication: ___________________ 1 • Trim: ______” x ______” • Run Date: 00/00/00 

5/2/07 3:06:44 PM

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