Kein Folientitel

1
The spatial innovation biography of a successful
monoclonal antibody
Christian ZellerApril 17, 2007CIRUS Workshop
on Innovation, Institutions, and Path
Dependency,Forum Chriesbach, Eawag, Dübendorf
2
Presentation

1. Theoretical bases and questions
2. The pharma-biotech-complex
3. Antibodies slow breakthrough of a new technology
4. The spatial innovation biography of the drug
5. Conclusions

3
1. Theoretical bases
Industrial organization in the pharmaceutical and
biotech industries
Research
Development
Production
Sales
Universi-ties
Until mid-1970s
Pharma-cies,clinics
Transnational pharmaceuticals
National pharmaceuticals
Pharma-cies,clinics
1980s and 90s
Transnational pharmaceuticals
Universities
Biotech companies
Specialized pharmaceuticals
Contract manufacturing
Contract Research Org.
Pharma-cies, clinics
Transnational pharmaceuticals
Possible tendency
Universities
Specialized pharmaceuticals
Biotech companies
HMOs
Contract manufacturing
Contract Research Org.
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1. Theoretical bases
Question

• How influence the changes of industrial
  organization innovation systems as well as
  research, development and commercialization of
  new technologies and therapeutic active
  substances?

5
1. Theoretical bases
Theoretical framework
Macro-societal and economic context
Mode of regulation
Accumulation regime
Technology generation and evolution?
technological system
Industrial organization in a sector, markets?
sectoral innovation system
Design space
Institutional rules
Actors and organizations
Market conditions, industrial organization
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1. Theoretical bases
Sectoral, national and regional innovatio
systemstechnological systems
Financial system
Knowledge base
Learning process through interaction
Organizations
Inputs
Sectoral innovation system
Demand
Technological system
Companies
Technologies
Individuduals
RegulationInstitutions, rules, coordination,
cultural context
Regional innovation system
Nationalinnovation system
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1. Theoretical bases
More precise questions

• How are organized and structured the flows of
  resources, knowledge and values in a
  technological system? (power relations)

• How institutional changes, particularly at
  intellectual property rights, influence the
  organization and dynamics of innovation systems?

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1. Theoretical bases and questions
2. The pharma-biotech-complex
3. Antibodies slow breakthrough of a new technology
4. The spatial innovation biography of the drug
5. Conclusions

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2. The Pharma-Biotech-Complex
Arenas of innvation and north-atlantic innovation
relations
Quebec / Montreal

Lund/Kopenhagen
Boston

c


a
Oxford / Cambridge
a


a


b
C
New Jersey
Rheinland

A



Bay Area
b

Rhein / Main / Neckar
Paris

München
c





a

b
b

B



Basel
Maryland

b
Research Triangle Park
Big pharma headquarters and most important
Centers of Excellence Big pharma Centers of
Excellence Biotech companies Financial
institutions Research institutes Innovation
arenas and hubs Innovation relations
structured by oligopolistic rivals
A
a
c



a
b


San Diego
Quelle Zeller, Christian (2004) North Atlantic
innovative relations of Swiss pharmaceuticals and
the importance of regional biotech arenas,
Economic Geography 80 (1) S. 83-111
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2. The Pharma-Biotech-Complex
Paul Herrling, Global Head of Research of
Novartis Pharmaceuticals, compared himself with a
piano player. Each biotech firm represents a key
and large pharmaceutical company puts the piano
together.
As a pharma guy who makes therapies I compbine
the keys and I play the music (Interview, March
6, 2001).
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1. Theoretical bases and questions
2. The pharma-biotech-complex
3. Antibodies a slow breakthrough of a new
   technology
4. The spatial innovation biography of the drug
5. Conclusions

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3. Antibodies a slow breakthrough of a new
technology
Technological paths Markets Products
Three key technologies in the 1970s
Recombinant DNA technologies (Arber 1970 Nobel
prize in medicine 1978),Boyer/Cohen 1973 Berg
Nobel prize in chemistry 1980 Monoclonal
Antibodies (Jerne, Milstein/Köhler 1975 Nobel
prize in medcine 1984) Polymerase Chain Reaction
(PCR) (Mullis 1983 Nobel prize in Chemistry 1993)
Multiplication of biotechnologies
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3. Antibodies a slow breakthrough of a new
technology
1975 Monoclonal antibodies from hybridoma cells

• Georges Kohler and Cesar Milstein (1975) in
  Nature
• Monoclonal antibodies are artificially produced
  against a specific antigen.
• Production of monoclonal antibodies with
  hybridoma technique.
• With this technique a group of lymphocytes
  producing all the same antibody protein is
  obtained.
• ? revolutionizing diagnostic medicine.
• ? Medicaments against cancer and infections.

Antigen
Sang
Melanoma cells
B-cells from spleen
Fusion
Hybridoma cells
Selection of hybridoma cells with antibody
activity, culture of selected cell lines (clones)
from positive cell cultures
monoclonal antibodies
Quelle Der kleine LaRoche (2003 15)
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3. Antibodies a slow breakthrough of a new
technology
At the beginning no patents!Then multiplication
of intellectual property monopolies!

• Milstein und Köhler did not try to patent their
  invention!
• Basic technology was freely accessible for
  subsequent scientists.
• Revolution in immunology laboratories.
• Foundation of numerous young companies and
  institutes which wanted to transfer monoclonal
  antibodies into efficient therapies.

Soon, each aspect of their production was
enclosed by patents. Subsequent users are forced
to pay royalties (cf. Zeller 2007).
Institutional change
Currently, about 100 recombinant biotech drugs
are on the market, 21 of them are monoclonal
antibodies.
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3. Antibodies a slow breakthrough of a new
technology
Monoclonal antibodies approved by the FDA
1. Appr. Product Companies Indication Royalties to
6/86 Orthoclone OKT3 Ortho Biotech (JJ) Verhinderung aktuter Abstoßung bei Nierentransplantation -----
12/94 ReoPro Centocor (JJ) Lilly Vorbeugung gegen Verengung der Blutgefäße Celltech
11/97 Rituxan IDEC Pharmaceuticals (Biogen Idec) Genentech Roche CD20-positives B-cell Non-Hodgkin's Lymphom Celltech
12/97 Zenapax Protein Design Labs, Roche Vorbeugung aktuter Abstoßung bei Nierentransplantation Celltech
5/98 Simulect Novartis Vorbeugung akuter Abstoßung bei Nierentransplantation Celltech
6/98 Synagis MedImmune Abbott Laboratories Vorbeugung ernster Erkrankun-gen der unteren Atemwege Protein Design Labs, Celltech, Genentech Centocor
8/98 Remicade Centocor (JJ) Schering-Plough Hemmt Entzündungen, vermeidet Gelenkzerstörung Genentech, Celltech
9/98 Herceptin Genentech Roche Metastatisierender Brustkrebs Protein Design Labs, Celltech
5/00 Mylotarg Wyeth Celltech Group akute myeloische Leukämie Protein Design Labs
5/01 Campath Genzyme (Ilex Onco-logy) Berlex Laboratories (Schering) Chronisch, lympathische Leukämie Cambridge University BTG
First product 11 years after invention of basic
technique.
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3. Antibodies a slow breakthrough of a new
technology
1. Appr. Product Companies Indication Royalties to
2/02 Zevalin IDEC Pharmaceuticals (Biogen Idec) Schering B-cell Non-Hodgkin's Lymphom GSK (Corixa)
12/02 Humira Cambridge Antibody Technology Abbott Laboratories (Knoll/BASF) Moderate bis ernsthafte rheumatoide Arthritis CAT MRC, Scripps und Stratagene (über CAT) Genentech
6/03 Bexxar Corixa (Coulter Pharmaceutical) GlaxoSmithKline CD20-positive non-Hodgkin's lymphoma University of Michigan
6/03 Xolair Genentech Tanox Novartis bis schwerem Asthma Bronchiale Protein Design Labs
10/03 Raptiva Genentech Xoma Serono mittelschwerer bis schwerer Plaque-Psoriasis Protein Design Labs
2/04 Avastin Genentech Darmkrebs Protein Design Labs
2/04 Erbitux ImClone Systems Bristol-Myers Squibb Dickdarmkrebs Genentech
11/04 Tysabri Biogen Idec Elan Multiple Sklerose Protein Design Labs
06/06 Lucentis Genentech altersbedingte Makuladegeneration Protein Design Labs, Xoma
09/06 Vectibix Abgenix (Amgen) fortgeschrittenem Darmkrebs nach erfolgloser Chemotherapie
03/07 Soliris Alexion Pharmaceuticals paroxysmal nocturnal hemoglobinuria Protein Design Labs filed patent infringement
Intellectual property monopolies on each aspect
of production
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3. Antibodies a slow breakthrough of a new
technology

• Technologies to reduce immunogenicity of
  monoclonal antibodies
• TIS
• technological evolution towards humanization,
  human antibodies
• innovation biography of drugs

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1. Theoretical bases and questions
2. The pharma-biotech-complex
3. Antibodies slow breakthrough of a new technology
4. The spatial innovation biography of the drug
5. Conclusions

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4. The spatial innovation biography of the drug
Sales of Rituxan / MabThera  a blockbuster 
The most successful biotech drug!
Quelle Informationsdienst Biotechnologie
(http//www.i-s-b.org/business/rec_sales.htm)
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4. The spatial innovation biography of the drug
Rituxan / MabThera (Rituximab)
Basic research 1970s
Preclinical RD 1991-93
Clinical devel., clinical trials 1993-1997 1997-?
Manufacturing 1993/1997-
Sales 1997-
Applied research / discovery 1980s




Lee Nadler, Dana Farber, Boston Antigen CD20 1980
IDEC Nabil Hanna, A. Grillo-López Phase
I/II1993-4 Phase II 1994-95 Phase III
1995-96 Phase II 1995-98 Idec, OceansideUp-scalin
g
Milstein/Köhler, Cambridge, Basel Hybridoma,
Antibodies 1975
IDEC Mitchell Reff et.al Engineering of Rituximab
Preclinical (safety, toxicology)
Ronald Levy, Stanford Univ., Palo Alto IDEC, San
Diego 1991
Genentech, Vacaville
G./.F. Stevenson, Univ. Southampton B-cell
lymphoma 1976
IDEC/ Genentech
IDEC, San DiegoOceanside
Genentech U.S. South San Franciso
Roche
Lizenz
Roche EU Basel
Lonza Biologics, Portsmouth, NH
Chugai
Zenyaku Kogyo Japan
Zenyaku Kogyo
Glaxo-Wellcome Patentstreit Columbia
Univ.) Patentstreit
Patent
Lizenz
Collaboration with NCI Extension to further
therapeutic potentials
Lizenzgebühren für Patent
Pharma. Partners Royalty Pharma Schaffhausen
Celltech, GB patent (manuf. Antibodies)
Glaxo-Wellcome (Coulter SmithKline Beecham 1998
Verkaufskooperation Bexxar
Xoma Berkeley AntiCD20 patent
Patent sold 1997
Knowledge flows
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4. The spatial innovation biography of the drug
Lee Nadler, Professor, Senior vice president of
Experimental Medicine, Dana Farber Cancer
Institute, Boston
 I tried to convince many, many, many
pharmaceutical firms between 82 and 84 that pan
B-cell antibodies would run. And they all told
me the same thing. If the drug couldnt make 300
million dollars, they werent interested. So they
rejected antibodies. And to be honest, in those
early days, it was impossible, impossible to get
any of the large pharmaceutical companies
interested in antibodies. (Interview, October
20, 2006)
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4. The spatial innovation biography of the drug
What does us say this example?

• Synthesizing explicit and tacit knowledge ?
  Decisive phases of innovation trajectory
  happen in close social and spatial proximity
• Biotech companies transform basic knowledge of
  universities in marketable knowledge.
• Pharmaceutical companies appropriate knowledge
  and technologies and are responsible for
  commercialization.
• Intellectual property rights can take independent
  properties and be a pure financial asset

Knowledge and proximity
Role and financing of universities
Hierarchies of innovation and production networks
Aspect of increased influence of placement
(financial) capital
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1. Theoretical bases and questions
2. The pharma-biotech-complex
3. Antibodies slow breakthrough of a new technology
4. The spatial innovation biography of the drug
5. Conclusions

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5. Conclusions
Innovation systems

• Innovation systems consist of power hierarchies.
  TNC are on the top of these cascades of power,
  financial flows and governance of innovation
  systems.

• Institutional forms such as the regime of
  intellectual property rights, shape the
  innovation networks.
• Hunting for intellectual property monopolies
  leads to a complex landscape of property rights
  and cascades of royalties.
• ? Strategies for extracting rents

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5. Conclusions
Societal challenges

• Innovation deficit
• Problem of contradicting cycles
• Which demand and which needs?
• Democracy

Challenges for innovation research

• Technological systems and power relations in a
  changed configuration of capitalism!
• Consider financing and institutional changes!

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Xolair (Omalizumab)
Grundlagen-forschung 1970s
Präklinische FE 1991-93
Klinische Entw. 1994-2004
Produktion 2003-
Verkauf 2003-
Angewandte Forschung / Wirkstoff-findung 1980s




PDL Fremont
John Hopkins University Baltimore Texas
University Houston Tse Wen Chang
Ciba / Novartis Basel Phase II 1996 Phase III
1999-2003 Up-scaling
Patentstreit 199?-2003
Royalities
Milstein/Köhler, Cambridge, Basel Hybridoma,
Antibodies
Genentech USA
Tanox Houston TNX-901
Royalities
Tanox Houston TNX-901 Phase I Phase II
Genentech, Vacaville
Tanox Tse Wen Chang Houston Engineering of
Anti-IgE1989
Tanox Houston
Entdeckung IgE 1968
Royalities
Novartis Huningue
Patent-streit 1993-2003
Novartis except USA
Genentech verhindert Entwicklung von TNX-901
gegen Erdnussallergie
Genentech South San Franciso Phase I/II1994 Phase
II 1994-98 Phase III 1999-2003 Up-scaling
Genentech Houston Engineering of Anti-IgE1989
28
Tamiflu (Oseltamivir) und Relenza (Zanamivir)
Grundlagen-forschung 1980s
Präklinische FE 1994-96
Klinische Entw. 1996-99
Produktion 1999-
Verkauf 1999-
Angewandte Forschung / Wirkstoff-findung 1990s-199
5




China Natural Shikimiacid from Sternanis plant
Gilead Sciences
DSM GrenzachIntermediate Product (Shikimiacid)
EinlizenzierungSep. 1996
Lizenzgebühren
Gilead SciencesFoster City GS 4071 GS4104
Gilead Sciences Nobert Bischoffberger Foster
City GS 4071
Roche Boulder Basel Tamilfu
Roche Welwyn GS4104
Roche
?
CIpla India
Patent Streitigkeiten?
Öffentlich zugängliches Wissen
Monash University Parkville, Aus 1983 mechanism
of virus
Vietnam
Indonesia
Kooperation
GlaxoSmithkline Relenza
Biota Australia GG167
Glaxo GG167
GlaxoSmithKline Relenza
GlaxoWellcome GG167
Lizenzgebühren
Biota
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4. The spatial innovation biography of the drug
Combined basic and applied technologies in the
innovation path of rituximab
Monoclonal antibodies with hybridoma cells Köhler
Milstein Cambridge 1975
Discovery of CD20, creation of an Anti-CD20
monoclonal antiibody Lee Nadler, Boston 1980
Chimerization of murine antibodies Morrison, et.
Al. New York, Palo Alto, Mountain View 1984
Rituximab Chimerization of murine
anti-CD20 Mitchell Reff San Diego
drug target malignant B-cell displays marker
protein G F. Stevenson Southampton 1975?
Anti-Idiotype monoclonal antibodies Ron Levy,
Palo Alto 1981/82
CHO cell line Larry Chasin New York
Manufacturing method based on CHO cell line
expression vector Mitchell Reff San Diego
Expression vector Kline French Lab.,
Philadelphia
Technology to make recombinant DNA Berg, Boyer,
Cohen 1972
Polymerase Chain Reaction (tool) Mullis et
al. Emeryville 1984
tool
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Geographie des Medikaments
Zentrale Arbeitsschritte in der FE von
Therapeutika
Klinische Studien
Phase IV Marketing Entwicklungevtl.
neueIndikationen
Phase I Sicherheit gesunde Freiwillige
Phase III Vergleichstudien mit Standard-therap.
Phase II Wirkung bei Patienten
Zulassungsprüfung
Wirkstoff-findung
Präklinische Entwicklung
gt 4 Jahre
1.5 Jahre
6 Jahre
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1. Theoretical bases
Concentrated financial capital increasingly
influences innovation systems
Power of concentrated placement capital
Institutional changes

• Pension funds, investment funds, venture capital
  funds
• Liquid stock markets, Shareholder value-driven
  Corporate Governance
• Competitive regime shaped by TNCs

• New organizational forms and extension of
  financial markets
• Intellectual property rights
• Changed role of publicly funded research