Janssen Biotech

The subsidiary Janssen Biotech, Inc. was founded in Philadelphia in 1979 as Centocor Biotech, Inc., with an initial goal of developing new diagnostic assays using monoclonal antibody technology.

Centocor Biotech

In 1982, Centocor transitioned into a publicly traded company.[12] In the early 1980s, the company moved to Malvern, Pennsylvania.[12] In 1984, Centocor opened an overseas plant in Leiden, the Netherlands.[13]

In 1997, eighteen years after its foundation, Centocor achieved its first year of operating profitability.[14][15] In 1998, Centocor sold its diagnostic division to Fujirebio, Inc.[16]

In 1999, Centocor became a wholly owned subsidiary of Johnson & Johnson.[17]

In 2004, Centocor purchased a new manufacturing plant in St. Louis, Missouri, and is currently opening a new manufacturing facility in County Cork, Ireland. The Dutch plant has been expanded substantially with a $250 million investment in additional production facilities, which were opened in 2006.[citation needed]

In 2007, Centocor broke new ground in advertising by releasing Innerstate, believed to be the first theatrically released documentary film both created and entirely funded by a drug company, to promote Remicade (Infliximab).[18]

Two scientific groups have independently reported complete analyses of the genetic material of the virus that is believed to cause the deadly disease acquired immune deficiency syndrome, or AIDS.

Their success is considered important not only as a powerful aid to understanding the virus and how it causes illness, but also in efforts to develop diagnostic and screening tests and a preventive vaccine against the fatal, incurable disease.

The genetic analyses, known technically as nucleotide sequencing, confirm the growing evidence that two viruses that have been strongly linked to AIDS are actually the same virus. Some experts think this virus may represent a hitherto undefined class.

One of the two versions of AIDS-related virus, known as HTLV-3, was analyzed by scientists of the National Cancer Institute, Harvard University and two industrial laboratories in the United States.

The other version, called LAV, was analyzed by scientists at the Pasteur Institute in Paris.

Data Indicate Same Virus

The two analyses produced closely similar results, giving the strongest proof yet attained that the two viruses are the same. In the light of their analyses, both the American and French groups now agree that they are presumably working with the same virus, a member of a large group known as retroviruses, but that the AIDS virus is markedly different from all other known retroviruses.

''If you understand the sequence,'' said Dr. Robert C. Gallo of the Cancer Institute, ''you understand the genes eventually and we hope that will tell us more precisely how the virus works and therefore give us ideas of how to do something about it.''

Knowing the complete nucleotide sequence of the virus should facilitate growth in the laboratory of key portions of that virus for research, diagnostic and vaccine purposes. The use of portions of the virus for such purposes would be safer than use of specimens of the whole virus because the selected portions would be incapable of causing infection. This is an important consideration in dealing with such a dangerous disease as AIDS.

The analysis has produced some surprises. Dr. Lee Ratner, first author of the American report, said one of the key genes, that for producing the virus's outer envelope, was not where the scientists expected it to be in the overall genetic sequence; that the envelope protein is larger than it is in most other retroviruses and that it appears to be situated partly inside and partly on the outside of the virus coat.

Vital Clue on Infection

The virus's envelope protein is particularly important because its chemistry determines what cells the virus can infect and how the body's immune defenses are likely to react to the virus.

The American analytic work was initiated in the laboratory of Dr. Gallo and Dr. Flossie Wong-Staal of the Cancer Institute, Bethesda, Md. Collaborators included a group at Harvard led by Dr. William Haseltine; and research teams of E. I. du Pont de Nemours & Company, Wilmington, Del., led by Dr. Mark Pearson, and a team directed by Dr. Nancy Chang at Centocor, a biotechnology company, Malvern, Pa.

Authors of the report from France are Dr. Simon Wain-Hobson, Dr. Pierre Sonigo, Dr. Olivier Danos, Dr. Stewart Cole and Dr. Marc Alizon, all of the Pasteur Institute in Paris.

Dr. Haseltine of Harvard's Dana- Farber Cancer Institute said the American group had published the sequence data on two different specimens of HTLV-3 virus and that the two differed by about 1 percent among 9,749 nucleic acid subunits that make up its genetic material together with that of closely related genetic segments adjacent to the genes for the virus itself.

He said the genetic analysis by the French team differed from one of the two published American sequences by only about 1 percent although the French published total of subunits comes to 9,193 because they did not include in their count some of the adjacent genetic material.

Dr. Haseltine said the analyses in both reports showed some significant differences not only between HTLV-3 and most other retroviruses, but also differences between that virus and two others HTLV-2 and HTLV-1 that do not cause AIDS but have been linked to cancers. The American report, he said, also showed some important similarities among the three so-called HTLV viruses.

The report from the group at Pasteur Institute is published in the forthcoming January issue of the journal Cell. The American group's report will be in the Jan 24 issue of Nature.

At least two other research teams, one at Genentech Inc. and the other at the Chiron Corporation, biotechnology companies in California, are believed to be close to success in analyzing the AIDS virus, but they have not yet published their analyses. Chiron expects to publish its results in Science magazine Feb. 1.

As of Jan. 14, a total of 7,857 cases of AIDS have been reported in the United States. Of these, 3,737 patients have already died.

[...] An indication of how well the biotech industry has developed both scientifically and commercially is the recent acquisition by Bristol-Myers Company, a major pharmaceutical house, of [Genetic Systems Corporation], a biotechnology company based in Seattle. The purchase price was $294 million in Bristol-Myers stock.

The next two years ''will be the most exciting for the biotech industry,'' says Parag Saxena, portfolio manager for health-care funds at New York's Citibank. As the industry enters this new phase, the handful of leading independent companies, according to Saxena and other analysts, include [Cetus Corporation], Genentech (of South San Francisco), Biogen (of Cambridge, Mass.) and [Centocor Biotech Inc.] (of Malvern, Pa.).  [...]

Scientists have taken another step toward producing a vaccine against AIDS by showing that only a fragment of protein from the AIDS virus is necessary for developing antibodies against it.

A group of industry, government and university researchers says the protein spurs high levels of antibodies that neutralize the virus in test animals such as goats.

But they said it remained to be proved whether the protein could produce enough neutralizing antibodies in humans to protect them against acquired immune deficiency syndrome.

Even if effective, a practical preventive vaccine is still years away because extensive safety and effectiveness tests would be required before approval, experts say.

However, the researchers said they had shown that this protein could be inexpensively mass-produced in large, pure quantities using genetically altered bacteria. Testing on Chimpanzees

Dr. Robert Gallo of the National Cancer Institute, a co-discoverer of the AIDS virus who is a collaborator on the vaccine research, said he was enthusiastic about the latest findings. ''We are excited by the results to date and have begun the process of testing the experimental vaccine in chimpanzees,'' Dr. Gallo said in a statement.

Chimpanzees are the only known animals other than humans that can get AIDS from the virus. Other test animals, such as goats and rabbits, develop antibodies to the virus but do not get the disease.

''We are hopeful that the results of these tests will give us a better idea whether or not this protein fragment has the potential of producing an immune response capable of protecting against the AIDS virus in humans,'' Dr. Gallo said.

At the time it is inducing antibodies, the whole protein binds with the white blood cells that the AIDS virus seeks, but the segment at issue does not bind with the cells, the experts said. Cell binding may mask other defensive mechanisms that might fight off the virus, they added.

The researchers said in a paper to be published Friday in the journal Science that the the segment of the protein gp120, which coats the AIDS virus, might be a better choice for a vaccine than the whole protein, even though both induce neutralizing antibodies.

How Antibodies Work

Foreign proteins can stimulate a host to produce antibodies against them. These antibodies, also proteins, stick to the foreign substance to inhibit it and serve to guide it to defensive cells that devour it.

The protein fragment work was conducted by Dr. Scott Putney and colleagues of his in the Repligen Corporation, a biotechnology company in Cambridge, Mass. Other researchers involved in the project were at Centocor Inc., a Malvern, Penn., genetic technology company, the Duke University Medical School and the cancer institute.

Dr. Putney said in a telephone interview that the AIDS virus, designated HTLV-3 or LAV, mutates rapidly and that there are many related varieties of it. ''A vaccine would have to protect against multiple, mutant forms of the virus,'' he said.

The protein segment contains regions that are stable and common to all mutations and areas that change to produce variations unique to each one. Dr. Putney said that if the protein area that activates a neutralizing antibody was stable, it alone could be reproduced to make a vaccine to defend against all varieties of the virus.

But if the antibody-producing area was variable, he said researchers would have the harder job of trying to make a vaccine of multiple protein fragments from numerous viruses.

''The gp120 surface protein we're working with has both conserved and variable regions to it, and we're trying to determine where the neutralizing part is located,'' Dr. Putney said.

Biotechnology companies are getting ready to sell a new class of products that will greatly increase the ability of doctors to detect and diagnose cancer, heart ailments and other diseases.

The first of these, known as monoclonal antibody imaging agents, went on sale in some European countries last week. The product, made by Centocor Inc. of Malvern, Pa., detects dead heart tissue, giving physicians a clear picture of the damage after a heart attack.

That product and one from the Neorx Corporation of Seattle for detecting melanoma, a form of skin cancer, are awaiting approval from the Food and Drug Administration to be sold in the United States.

Several other products from Centocor, Neorx and three other biotechnology companies - Cytogen, Hybritech and Immunomedics - are in clinical trials that are expected to be completed in the next year or two. And work is under way in developing agents that can detect other illnesses, from infections to hardening of the arteries and Alzheimer's disease. 

'Great Benefit to Patients'

''I think the concept is very important and it's going to be of great benefit to patients,'' said Steven M. Larson, chief of the nuclear medicine service at Memorial Sloan-Kettering Cancer Center in New York. He said the new tests would be especially useful in finding tumors not detected by other means. ''There's no question they add information,'' he said.

Antibodies, which are produced by the body to fight invaders, are extremely specific in recognizing their target by its shape. In the last 15 years, scientists have developed the ability to mass-produce uniform, or monoclonal, antibodies in mice.

Such antibodies are already used for diagnostic tests performed outside the body, like those on blood samples, but the new products will be used inside the body. The antibodies are linked to a radioactive isotope and injected into the patient. The antibodies flow through the blood and latch onto their targets, like tumors. The patient is then photographed with the gamma-ray detection cameras used in conventional nuclear medicine, and the target sites show up as hot spots of radioactivity.

Eventually, scientists expect such monoclonal antibodies to be used as well to treat disease in so-called magic bullets. An antibody linked to a toxin, for instance, could seek out cancerous cells and deliver the poison, leaving the rest of the body unscathed. But such therapeutic use of antibodies, particularly for cancer, is not likely occur for several years.

Imaging, however, is easier to do than therapy, and the clinical trials required are shorter, allowing those products to come to market sooner.

The imaging products will also be the proving ground for therapeutic products. ''You have to be fairly comfortable that the antibody is identifying the target tumors before you try to treat the tumor,'' said Martin P. Sandler, professor of radiology and director of nuclear medicine at Vanderbilt University Hospital.

For cancer, where most of the attention is focusing, the antibody imaging products have shown the ability to detect tumors that are not detected by other means, like computerized tomography, known as CT scanning, which detects dense areas in the body.

''We can tell they're malignant, while a CAT scan can merely say there's something that's there,'' said Robert T. Maguire, director of clinical investigations for the Cytogen Corporation in Princeton, N.J.

Antibodies can also pick up tumors anywhere in the body, while CT scans usually look at a particular section. ''This is the only agent as a class that can simultaneously evaluate the entire body and all different organ systems,'' said Paul G. Abrams, vice president and medical director for Neorx. There is also some evidence that antibodies can detect smaller tumors than can be found with other methods, Dr. Sandler said. 

Drawbacks of the Products

Still, the products have their drawbacks. Since tumors differ, it is hard to find a single antibody that will target all tumors. Hence, even though antibodies find tumors that CT scans miss, they also miss tumors that CT scans find. That means antibodies are likely to supplement existing approaches, not replace them, doctors say.

In addition, since the antibodies are made by mice, the human body tends to attack them as invaders and build up immunity to them. That could prevent the products from being used over and over again in such procedures as tracking the effectiveness of cancer therapy. Various approaches are being taken to make antibodies more human-like, but they will not be available in the first generation of imaging products.

Another point that could limit the use of the products is more subtle: Just because an imaging product allows something to be seen in the body does not mean it will help the patient. To do that, therapy must be altered on the basis of that information. ''Defining patient benefit and then demonstrating it is very difficult,'' said Peter F. Drake, executive vice president of Vector Securities International Inc. in Deerfield, Ill., an investment firm that specializes in biotechnology companies.

F.D.A. Approval Is Delayed

Mr. Drake said the inability to demonstrate such benefits has delayed the approval of these drugs by the F.D.A. Neorx, for example, submitted its application to market its melanoma imaging agent in November 1987 and has still not received approval.

Company officials and doctors say the products are useful in planning therapy and in preventing needless operations. For instance, if imaging detects that cancer has spread beyond its original site, then trying to remove the original tumor surgically would be futile and a treatment directed at the entire body, like chemotherapy, would be needed. Similarly, if imaging with Centocor's product shows part of the heart to be irreversibly damaged, then an operation to open up the artery feeding that part of the heart could be avoided.

''What this test can do is put patients in the category of high risk or low risk,'' said Jamshid Maddahi, associate professor of medicine at the University of California at Los Angeles and director of nuclear cardiology research at Cedars-Sinai Medical Center. Dr. Maddahi is a member of Centocor's scientific advisory board. Sales Estimates Vary

Depending on the particular form of cancer, imaging products could command sales of as little as $5 million a year or as much as $100 million a year, according to customer and analyst estimates.

The antibody imaging kits are likely to cost from $200 to $400. To that must be added the cost of the isotopes and the doctor's time, meaning total cost to a patient for a monoclonal imaging session might be about $600, roughly comparable to a CT scan.

Centocor has differentiated itself from other companies by concentrating on cardiovascular diseases, which it sees as more feasible. ''Getting the antibody to a clot or the heart is much easier than getting to the center of a solid tumor,'' said Harvey J. Berger, senior vice president of research and development.

Centocor's first product, Myoscint, uses an antibody that detects a protein inside heart cells that is exposed only after the cells die, allowing it to depict damage to the heart after a heart attack. Mr. Drake of Vector Securities estimates that the product will have sales of $65 million annually by 1992. Centocor is also close to finishing clinical trials on Fibriscint, which detects blood clots in the legs. That product could have even larger sales, Centocor officials predict.

Products of Other Companies

Neorx's melanoma agent is likely to have a market of only $5 million to $10 million annually. But the company is finishing clinical trials on imaging agents for two kinds of lung cancer that could present much larger opportunities.

Cytogen is focusing on colorectal cancer, a potentially huge market because CAT scans have particular trouble in the abdominal area. Cytogen expects to file for F.D.A. marketing approval this quarter.

Close on its heels is Hybritech of San Diego, a subsidiary of Eli Lilly & Company. A spokesman said the company is close to completing clinical trials of its imaging agent for colon and breast tumors.

Immunomedics, based in Warren, N.J., is also focusing on colon cancer for its first product but will not finish trials until next year, said David M. Goldenberg, the company's chairman.

Several European companies, including Hoechst of West Germany, are also developing monoclonal imaging products. Superior Technology

The companies all argue that their technology is superior; even those that are behind say they will make up for lost ground. Immunomedics and Neorx use technetium as the radioisotope. Technetium is already commonly used by hospitals, which should ease its acceptance into the market.

Cytogen and Hybritech use indium as the radioisotope, which is somewhat less usual for hospitals to work with but easier to attach to antibodies. Moreover, indium has a longer half life than technetium, meaning the radioactivity lasts longer. While images using technetium have to be taken within a day after the antibody is injected, indium images can be taken several days later, allowing more time for the antibodies to concentrate in the tumor sites. But Cytogen maintains that it can use far lower doses of antibody than its competitors, reducing side effects.

Future products might hold the promise of detecting disease early enough to save lives. Centocor plans to begin clinical trials soon of an antibody for detecting hardening of the arteries, a precursor of heart attacks. Such a test might give people enough warning to allow corrective actions. ''These are ideas that have not been proven, but they are exciting,'' said Dr. Maddahi of U.C.L.A.

The Xoma Corporation, a biotechnology company, received a patent covering a drug for bacterial infections. Xoma immediately filed a lawsuit against Centocor Inc., which is developing a similar drug.

Stuart Weisbrod, biotechnology analyst with Prudential-Bache Securities, said it appeared as if Xoma's patent was broad enough to cover Centocor's product.

Centocor's stock fell $1.625 today, to $29.625 Xoma's stock jumped $2, to $20.75. Both are traded over-the-counter.

Hubert J. P. Schoemaker, the chairman of Centocor, said, ''We believe the patent is invalid, and we believe we did not infringe on it.'' He said that Centocor developed its antibodies in 1982, well before Xoma's work. Xoma, based in Berkeley, Calif., and Centocor, based in Malvern, Pa., are developing drugs to treat gram negative bacterial infections that affect 200,000 to 400,000 people in the United States each year, mostly hospital patients. The infections can lead to a condition called septic shock, which can be fatal.

• A correction was made on April 19, 1990: Thursday, Late Edition - Final
• A brief Company News article in Business Day yesterday about a patent lawsuit by the Xoma Corporation against Centocor Inc. misstated the Centocor stock price in some editions. The stock fell $1.625 a share on Tuesday, to $29.625.

Out to strengthen its pipeline of new drugs, Johnson & Johnson announced yesterday that it would buy Centocor Inc., one of the nation's largest biotechnology companies, for $4.9 billion in stock.

The acquisition is part of a rapidly growing trend among drug makers to snap up biotechnology companies. Last month, Pharmacia & Upjohn said that it would pay $650 million for Sugen Inc., while earlier this year Warner-Lambert bought Agouron Pharmaceuticals for $2.1 billion.

''All of the drug companies are looking to invigorate their research and development efforts through biotech companies,'' said Jack Lamberton, a managing director with HSBC Securities. ''Johnson & Johnson is a leader in biotechnology anyway. It's not a huge leap for them to bring it in house.''

The deal appears to be a part of the Johnson & Johnson strategy to shift more of its focus to high-profit pharmaceuticals.

Even though Johnson & Johnson is one of the world's most diverse health care companies -- making medical devices like heart stents and consumer brands like Band-Aid and Tylenol -- analysts say the company's diversity has caused its earnings gains to lag behind those of some competitors. Johnson & Johnson, which is based in New Brunswick, N.J., surprised analysts on Tuesday by beating second-quarter per-share earnings estimates by 2 cents.

Investors applauded the deal. Shares of Centocor jumped $7.875 each yesterday, to close at $57.375. Johnson & Johnson's stock advanced $1 a share, to $97.4375. The Wall Street Journal reported yesterday that a deal was imminent.

The terms of the accord are complex. Each Centocor's share will be exchanged for a fraction of a Johnson & Johnson share, depending on the value of the acquirer's stock during a 20-day trading period. If Johnson & Johnson's shares trade between $85.71 and $104.76, as expected, Centocor's shareholders will receive $61 in Johnson & Johnson stock for each of their shares.

Johnson & Johnson officials said yesterday that the deal should dilute earnings by 15 cents a diluted share this year and another 5 cents in 2000. Centocor is expected to aid Johnson & Johnson's earnings in 2001, even though company officials declined to say by how much.

While some analysts said that Johnson & Johnson might have overpaid for Centocor, few disputed the benefits of the deal. Analysts have chided Johnson & Johnson for its weak pipeline of new drugs, a problem that Centocor should quickly remedy.

Analysts said yesterday that Johnson & Johnson and Centocor shared several key development areas, including cardiovascular and gastrointestinal products. With the acquisition, Johnson & Johnson will get Centocor's anti-clotting drug Reopro -- with half of the profits going to Eli Lilly -- and Remicade, a treatment for Crohn's disease.

Reopro and Remicade should prosper under Johnson & Johnson's management. Analysts noted yesterday that Reopro is used in half of all stent procedures. Since Johnson & Johnson is a major stent maker, the company could easily add to Reopro sales by peddling it to its stent buyers. Centocor is also waiting on approval from the Food and Drug Administration to market Remicade as a treatment for rheumatoid arthritis, a market that is expanding rapidly.

''Strategically, Johnson & Johnson's deal is a very good move,'' said Sergio Traversa, an analyst with Mehta Partners. ''Johnson & Johnson will leave Centocor alone so that it will function as an independent subsidiary. That's good, because there are a lot of synergies here.''

Vical Inc. said Tuesday that Centocor Inc. expanded an option and license agreement to use Vical's naked DNA technology to develop DNA vaccines for cancer.

The expansion of the agreement, first established in 1998, will provide an undisclosed up-front payment to Vical, and it could lead to milestone payments and royalties, said Alan Engbring, director of investor relations for San Diego-based Vical. Centocor is a Johnson & Johnson company.

"They have expanded the agreement beyond what the original agreement called for, but the specifics we have agreed not to discuss," Engbring said. "They have not named any targets."

There is no defined endpoint to the agreement.

"It is an ongoing relationship," Engbring said.

The naked DNA technology is a gene delivery technology, and it involves the direct injection of plasma DNA, he said.

"When you're using it for cancer vaccines, you would use a tumor-specific antigen and deliver the gene that encodes for that antigen, which triggers an immune response against the cancer," he said.

However, the technology can be used in infectious disease to deliver therapeutic proteins, or antigen proteins, he said.

Vical has agreements with other companies that are developing therapeutic and vaccine product candidates for infectious diseases and metabolic disorders. The companies with which Vical has existing agreements include Merck & Co. Inc., of Whitehouse Station, N.J., which is developing a vaccine to combat HIV, among other efforts; Aventis Pasteur, of Lyon, France, for a tumor-associated antigen therapeutic vaccine; and Aventis Pharma AG, of Frankfurt, Germany, for a cardiovascular therapeutic vaccine.

Internally, Vical has the immunotherapy Allovectin-7 in Phase II and Phase III studies in patients with metastatic melanoma and in Phase II studies in patients with head and neck cancer. Allovectin-7, which is injected directly into tumors, is a DNA/lipid complex containing the human gene encoding HLA-B7, which is seen infrequently in the human population, the company said.

"Allovectin has completed the Phase III study, and we are now collecting data from that study and expect to have completely adjudicated results in the second half of the year," Engbring said. "At that point, we will decide whether the data are sufficient to support a [biologics license application]."

Another immunotherapy, Leuvectin, is in Phase II studies in prostate cancer. The company said Leuvectin uses a lipid-DNA complex to stimulate an immune response against cancer cells.

Engbring said Vical would have "information about the future of that program in the second half of this year."

In April 2001, Vical ended a Phase II study of Leuvectin in metastatic kidney cancer after failing to achieve the desired results with 37 patients in what was planned to be an 80-patient trial. (See BioWorld Today, April 23, 2001.)

Vical's stock (NASDAQ:VICL) fell 3 cents Tuesday to close at $5.60.

(Chapter 37)  Biotech-Pharma Collaboration—  A Strategic Tool: Case Study of Centocor

Lara V. Marks, D.Phil Oxon, FRSB

Honorary Research Associate, Department of Science and Technology Studies, University College London and Managing editor of www.whatisbiotechnology.org, London, United Kingdom

Chapter Outline

• The Birth of Centocor 553
• The Collaborative Journey Begins 555
• Finance: “GRAB as Many Cookies as You Can” 557
• Expanding Its Market Potential 558
• Therapeutics 559
• Centocor Goes It Alone 560
• “Centocorpse”: Centocor in Crisis 562
• Collaboration—A Means of Rescue 563
• Centocor Becomes Profitable 564
• Conclusion 565
• Acknowledgments 565
• References 565

The estimated value of alliances signed between pharmaceutical and biotechnology companies was $160 billion per annum in 2011.1 Underlying the vast sums being paid out for alliances is the fact that such collaboration is a lifeline for pharmaceutical companies scouting for new products to fill their dwindling portfolios in the face of expiring patents and rising generic competition. It is also vital to biotechnology companies seeking to raise funds for their research and development (R&D) and establishing a footprint on the market.

Since their inception, biotechnology companies have depended on partnerships for their survival and growth. This chapter looks at the pivotal role alliances played in the foundation and growth of Centocor, one of America’s pioneering monoclonal antibody (mAb) companies. Set up in 1979, 3 years after Genentech, the world’s first dedicated biotechnology company, Centocor was among the first handful of biotechnology companies started in the 1970s. Within 5 years of its founding, Centocor had become a highly competitive and profitable diagnostics company based on mAbs. As this chapter shows, much of this success rested on the collaborations its founders secured with research institutes and larger health-care companies. Through skillful networking, Centocor’s executives secured the scientific and technological expertise, products, capital, and market distribution necessary to mature from a small start-up company to a major player in the global diagnostic market. In 1992, however, Centocor faced imminent collapse, brought on in part by its executives’ decision to go it alone in the development and marketing of the company’s first therapeutic. What saved the company from extinction and allowed it to subsequently succeed in therapeutics was a reversion to its strategy of collaboration 2.

The Birth of Centocor

In May 1979, [Dr. Hilary Koprowski (born 1916)], a Polish virologist, immunologist, and director of the Wistar Institute3, entered a partnership with Michael Wall, an MIT-educated electrical engineer and founder of several electronics, computer, and biological start-up companies, to establish a new biotechnology company.4 Calling the company Centocor, Koprowski and Wall aimed to create, develop, and market diagnostics and therapeutics based on mAbs. mAbs were new to the scientific and commercial world, having been devised by Ce´sar Milstein and Georges Ko¨hler at the Laboratory of Molecular Biology, Cambridge in 1975. Derived from natural antibodies (proteins produced by the immune system that are designed to attach to and inactivate foreign particles, or antigens), mAbs were produced as a result of the fusion of myeloma cells with antibodies taken from the spleen of previously immunized animals 5.

Providing for the first time a long-lasting and standardized form of antibodies that could be used for various medical applications, mAbs were quickly adopted by various academic and commercial laboratories globally. This included Koprowski and his team at the Wistar Institute. Using cells sent by Milstein, Koprowski, and his colleagues began to develop mAbs against the influenza virus and malignant cancer tumors.6 Funded by government grants, this research formed the basis for patent applications in 1978. Granted in 1979 and 1980, these patents were the first-ever patents for mAbs.7 In 1978 Koprowski offered to license the patents to Boehringer-Ingelheim for $500,000 annually over 10 years. The pharmaceutical company, however, had dragged out negotiations for 6 or 8 months before saying no on the basis that they saw no future for mAb products 8.

Frustrated by his experience with Boehringer- Ingelheim and other companies, Koprowski realized that the only way forward would be to establish a separate company. He decided to do this in partnership with Wall. At the time that Wall and Koprowski started discussing their plans for a company, Wall was getting itchy feet for a change of scenery, having just sold Flow Laboratories, a company he had set up to produce and sell cell cultures and related products. Wall had various business schemes in mind, including growing orchids. His idea of founding a company based on flowers, however, soon dissipated on talking to Koprowski. What captured Wall’s attention was the fact that Koprowski believed he could have in hand a mAb diagnostic very quickly. This was named 19-9, a mAb developed at the Wistar Institute that Koprowski saw as having potential as a diagnostic for pancreatic cancer 9.

Setting up an office in downtown Philadelphia in May 1979, Wall started to build Centocor’s executive team as the company chairman with scientific support from Koprowski and the Wistar Institute. One of the first to join the executive team was Ted Allen. Allen’s background was ideal for Centocor as he had been a marketing manager at Corning Medical, a Boston-based division of Corning Glass Works. More importantly, he came from a company that had begun to establish a strong portfolio of diagnostic immunoassays. Such diagnostics were rapidly replacing the more traditional chemical-based tests that had dominated the diagnostics market since the 1940s 10.

With Allen on board, Centocor soon attracted the interest of another Corning employee who would prove pivotal in moving the company forward. This was Hubert Schoemaker, one of Allen’s former Corning colleagues who had been instrumental in building up Corning’s pioneering portfolio of diagnostics. Schoemaker was a biochemist by training and had completed a doctorate at MIT within a department at the cutting edge of biotechnology research. One of the factors determining Schoemaker’s decision to join the Centocor start-up was his desire to find a way to improve people’s lives. His inspiration came from the profound disabilities of his daughter, who was born with lissencephaly, a rare brain malformation causing severe mental disability and motor dysfunction. Schoemaker joined Centocor initially in an unofficial capacity, helping with research and planning while continuing to work at Corning. In early 1980, however, he began officially, taking over the position of chief executive officer in the wake of a sudden departure by Allen.11 (See Fig. 37.1.)

Within months of joining Centocor’s team, Schoemaker had sourced another individual who soon became vital to the company’s operation. This was Vincent Zurawski. He joined Centocor in August 1979 as the company’s first Chief Scientific Officer. Zurawski came well equipped for the post. A chemist by training, he had been a pioneer in mAb production at Harvard Medical School and Massachusetts General Hospital (MGH), where he had held a postdoctoral research fellowship.

The Collaborative Journey Begins

The founders decided to focus their resources initially on diagnostics, predicting $17 million in revenues by 1984,12 with therapeutics as their long-term goal. Diagnostics were easier to develop and could win regulatory approval more easily than therapeutics, thereby enabling faster revenue growth.13 In addition to developing diagnostic products, they aimed to supply antibodies on contract to other companies for using their proprietary diagnostic kits 14.

Entering the diagnostics sector was ambitious. The $2 billion diagnostics market was highly competitive, dominated at that time by health-care giants such as Abbott Laboratories, F. Hoffman-La Roche, and Warner Lambert who had developed tests that could only be analyzed through their own proprietary instruments. In 1979 two companies were already offering mAbs on a commercial basis: Sera Lab, a British company (with which Ce´sar Milstein was involved) and Hybritech, a San Diego startup founded in 1978 by Ivor Royston, a professor at the University of California San Diego and his research assistant Howard Birndorf. Both of these companies were marketing mAbs as reagents to researchers and exploring their use as diagnostics.15 The competitive landscape, however, quickly changed. By 1983 more than 150 companies, including large pharmaceutical companies, had mAbbased diagnostic programs, and 23 such diagnostics were being marketed and another 100 were in the pipeline 16.

From the start, Wall and Koprowski saw collaboration as key to their business model. The very name “Centocor” was derived from the words (1) “cento” that describes (in Latin) an old garment made of hundreds of patches of material or a literary or musical composition made up of parts of other works, and (2) “cor(e)” as in the center.17 Centocor’s collaborative philosophy was unusual for the time. In 1979 most start-up biotechnology companies were trying to do everything internally from the discovery process through development. Centocor’s founders believed, however, that rather than depending solely on in-house research they should use internal skills to identify and fund prominent external researchers and laboratories working in areas where the company wanted to develop and where there was an appropriate license for the technology.18 As Wall told Forbes magazine in May 1985, “You can have a garage full of Ph.D.s working on a project and nine times out of ten some guy across the street is going to come up with the discovery that beats them all” 19.

Central to Centocor’s policy of collaboration was Wall and Schoemaker’s remarkable ability to network.20 By being well-connected and plugged into the academic world, Wall and Schoemaker realized they stood a better chance of finding promising products at a relatively early stage when they were not unduly expensive.21 As Schoemaker later recalled, “We realized it was a lot cheaper to roam academe and pay a royalty back for what we developed than start our own research facilities. Collaboration was the best way to be competitive” 22.

One of Centocor’s strongest academic collaborations was with the Wistar Institute, fueled in part by Koprowski’s connection with the company. In 1979 Centocor signed three licensing deals with the institute for rights to four approved and pending patents for diagnostic and therapeutic purposes. Centocor paid $25,000 upfront and agreed to make royalty payments of 4% 6% for any resulting products 23.

Centocor’s alliance with the Wistar was helped by the fact that the latter had its own charter and board. This allowed greater flexibility for an academic company collaboration than otherwise was normally possible in the late 1970s. Although the pioneering academic company relationship between Centocor and the Wistar raised some concern about conflict of interest for one Wistar board member, this was soon overcome24. The relationship set an important precedent for the partnerships Centocorentered thereafter 25.

Centocor, like other biotechnology companies, was helped enormously by passing of the Bayh Dole Act in late 1980, which established for the first-time uniform guidelines for the patenting and commercialization of government-funded academic research.26 Between 1985 and 1990 Centocor’s partnerships with research institutions grew from 15 to more than 80 worldwide, many involving license and license-option agreements.27 These collaborations were vital to Centocor’s business, providing materials for some of its early products.28 Crucially, it allowed the company to keep its costs to a minimum while increasing sales: between 1984 and 1990 Centocor’s R&D budget remained at the same level while its sales increased fivefold 29.

In addition to partnering with research institutions to fill its product pipeline, Centocor pursued marketing alliances. Facing a highly competitive environment, Wall and Schoemaker realized they could strengthen the company’s market position by having licensing agreements with companies that had well-established market positions and distribution channels. This would eliminate the time and expense of establishing Centocor’s own distribution mechanism and facilitate faster entry to the market 30.

Centocor’s team deliberately secured agreements with key diagnostic companies, whereby the companies would buy and sell Centocor’s antibodies in completed test kits and separate antibodies to be used in their own proprietary machines.31 All of Centocor’s diagnostic tests were designed to be compatible with existing diagnostic systems that allowed for both the testing and analysis of results, such as those marketed by Abbott and Roche, and used by the majority of clinical laboratories.32 This arrangement not only helped Centocor gain a broad market penetration but also allowed it to leverage its technical strength without threatening competitors.33 As David Holveck, who headed up Centocor’s diagnostics department from 1983, stated, “Because of the marketing strategy of networking with all of the major suppliers, we insulated ourselves from competition because we were the suppliers of the reagents, and they were looking for ways of adding tests to their instrumentation” 34. In 1983 61% of Centocor’s product sales were being sold by major distributors. Two years later, this had increased to 74%.35 (See Fig. 37.2.)

An important catalyst in Centocor’s early success was its swift winning of regulatory approval for two diagnostic tests: one for gastrointestinal cancer (using an antibody licensed from the Wistar) and the other for hepatitis B (developed by Zurawski and licensed from MGH). Both the tests had reached the market by 1983. The approval of the hepatitis test was significant as it was the first mAbbased test approved for this disease by the Food and Drug Administration (FDA). Centocor’s hepatitis B test was in high demand because from the early 1970s many countries, including the United States, required the screening of blood intended for blood transfusion. Some idea of how popular the test was can be seen from the fact that between April and December 1983 Centocor sold 600,000 of its hepatitis tests.

Between 1983 and 1986, Centocor introduced another three tests to the market: one for diagnosing ovarian cancer (licensed from the Dana Farber Cancer Institute), the first diagnostic tool available for the disease; a test for breast cancer (licensed from Scripps Clinic and Research Foundation); and another for colorectal cancer (licensed from the Wistar) [1]. All three tests are still used in clinical practice today. In addition to these diagnostics, Centocor also put into the market the first diagnostic test for multidrug resistance, a major problem for cancer patients. By 1990, Centocor had captured more than a quarter of the world’s market for antibody-based tests for cancer 36.

Between 1979 and 1985, Centocor’s team built up a profitable business with revenues of just under $50 million. It was highly lucrative because most of the bottomline revenue came from royalties.37 By 1987 Centocor was one of the very few mAb companies with earnings 38.

Finance: “GRAB as Many Cookies as You Can”

Just as fundamental as partnering was to Centocor’s early success was Wall and Schoemaker’s ability to find capital. What helped this process was the fact that soon after setting up the company, Wall, using his previous reputation in the business world, persuaded Tony Evnin, a senior partner in Venrock Associates, a venture capital firm, to become one of the company’s directors. This was important as Venrock had a history of investment in the diagnostics and therapeutic sector. Venrock subsequently became the first major investor in Centocor, providing $300,000. This would just be the start of raising funds. Between 1979 and 1981 Centocor raised approximately $7 million through private placement of its stocks.39 The Centocor executives raised further cash from public offerings in 1983, 1986, 1990, and 1991, the last raising $100 million 40.

Wall and Schoemaker also secured funds through R&D limited partnerships. First used by the Delorean Car Company in 1975, R&D partnerships allowed companies to raise capital from private individual investors for specific research projects off the balance sheet, providing investors with tax benefits and potentially higher returns than equity investments.41 In 1982 Genentech was the first biotechnology company to use the mechanism to develop human growth hormone and gamma interferon drugs.42 Centocor was one of the most successful and aggressive users of R&D limited partnerships within the biotechnology industry, establishing at least four such partnerships between 1984 and 1987 43.

Central to Centocor’s fundraising was Schoemaker’s philosophy that it should not be driven by the company’s business plan. He believed that even if Centocor had a lot of money on the balance sheet, more money should be raised whenever the opportunity arose. As he explained, “In Centocor’s early days, Bill Hambrecht of Hambrecht and Quist advised me: ‘When the cookie jar comes around, grab as many cookies as you can because you’ll never know when it comes around again’. He also advised me to discard all of the traditional business evaluations such as cash flow, price/earnings, etc. in deciding when and how much money to raise. He told me that each week he had five CEOs in his office who had insufficient capital and that he had never had a CEO come to him and tell him he had too much money” 44.

Expanding Its Market Potential

While initially funneling resources into blood-based diagnostics, Wall and Schoemaker quickly looked for ways to expand into the therapeutics sector. Therapeutics posed greater uncertainties than diagnostics. Much of the commercial attention in the nascent biotechnology therapeutics industry was focused on using recombinant DNA technology for the production of drugs for which there were existing therapeutic models and markets.45 Therapy based on mAbs was a novel idea and remained uncharted territory.

Using mAbs for therapeutic purposes presented considerable new challenges. Unlike the blood-based diagnostics that Centocor had heretofore been developing, which involved the deployment of mAbs in tests on blood removed from the human body, therapeutics required the administration of mAbs directly into the human body. mAb drugs therefore posed greater safety concerns. Therapeutics also required far greater quantities of mAbs than needed for diagnostics, posing new manufacturing and quality-control challenges 46.

In order to gain experience in the therapeutic sector, Centocor devised a strategy to initially develop mAbs as contrast agents for diagnostic-imaging procedures. While not therapies in themselves, the use of mAbs as imaging agents tested the safety of mAbs for potential therapies and provided useful aids for the evaluation and therapeutic treatment of a patient. In 1985 Centocor established an in vivo diagnostic-imaging unit and began to develop three products directed toward imaging diseases such as cancer and conditions of the cardiovascular system. The market for mAb-imaging diagnostic products was expected to be between five and ten times larger than that of blood-based diagnostics. 47 Within the field of cancer alone, imaging diagnostics were expected in 1985 to grow by 200% each year, reaching $200 million by 1988. The market size for cardiac imaging was also projected to increase from $70 to $130 million between 1985 and 1988 48.

In their reports to investors, Centocor’s executives predicted the company’s imaging diagnostics would swiftly be on the market within a couple of years of their first testing.49 What they hoped to do was capitalize on the mAbs, it was already deploying in the development of its in vitro blood tests. To this end, early on the team looked into developing CA 19-9 as a tool for imaging gastrointestinal cancers and CA-125 for imaging ovarian cancer.50 Progress, however, was slow and not as straightforward as anticipated. One of the problems was that while the mAbs proved good imaging agents, they took a long time to clear from the body which delayed the reading of the images and thus obtaining the diagnostic results 51.

Centocor’s difficulties in utilizing mAbs for imaging diagnostics were not unique. Indeed, many other companies would struggle to reach the market with such products, and their overall worldwide sales would remain small. In 1998, for example, the worldwide sales of diagnostic-imaging products using mAbs were worth $10 million. The sales revenue would grow over the coming years, but would continue to be small, estimated to be $15 million in revenue in 2005. Such figures were well below the projected figures Centocor, and others had forecast back in the 1980s. Back in 1987 one financial analyst had forecast the annual sales for Centocor’s cardiovascular imaging tests could reach between $300 and $400 million [2].

Despite the slow progress, in August 1989, Centocor won European approval for its first imaging product called Myoscint. Licensed originally from MGH, Myoscint could locate and estimate the amount of dead heart tissue from a heart attack. The product was first marketed in France, Germany, Italy, Spain, and the United Kingdom and then in America from 199652. Overall the product did not take off in a significant way. By the time the product reached the market, other methods had appeared that proved less invasive for the patient and more accurate in terms of the data they provided. In the end, Myoscint proved more useful for detecting heart transplant rejection and myocarditis (inflammation of the heart muscle). It was used for these purposes off-label in Europe, where those performing heart transplants found it an invaluable tool 53.

Therapeutics

While the experience with imaging diagnostics proved disappointing, it gave the Centocor team some expertise in the development of mAbs for use directly in humans. This was invaluable in going forward in the creation of mAb-based medicines. Importantly, it provided a starting point in terms of what was needed for the R&D for a therapeutic as well as learning the ropes for clinical trials and manufacturing. Going, forward with therapeutics, however, was by its nature a much bigger risk for the company. Nothing could fully prepare Centocor’s executives, then more familiar with the business model for developing diagnostics, with what would be needed for the development of mAbs as drugs. Moreover, they had little to go on from the nascent biotechnology therapeutics industry. At the time, companies in this sector had more expertise in using the new recombinant DNA technique to develop drugs in disease areas for which there were already wellestablished treatment protocols and market systems. By contrast, few knew which disease areas mAbs could be successfully used therapeutically or which market they would be able to penetrate.

Early on, Wall and Schoemaker recognized that the time and cost required to bring therapeutic products to market exposed their newly emerging company to unacceptable financial risks, which could divert resources and hinder innovation. In order to minimize the risk and gain financial, scientific, and technical resources as well as credibility, they therefore devised a strategy to generate relationships with leading companies. By 1983 Centocor had established collaborations with two companies for this purpose: the American chemicals company FMC Corporation and the Swiss-based pharmaceutical company F. Hoffmann-La Roche 54.

Centocor’s alliance with FMC began in 1980 with FMC agreeing to contribute a total of $12.4 million. Split 50/50 and managed by a committee with a representative from each company, each partner had the option to purchase all of the other’s interest in the joint venture.55 One of the aims of the collaboration was to find a way to produce mAbs from cell lines more closely resembling human antibodies. This was particularly important if Centocor was to gain leadership in the mAb therapeutics field. Most of the early mAbs developed from the time of Ko¨hler and Milstein were derived from mouse cells. These mAbs had certain drawbacks: a short half-life, poor recognition by receptors in the human body, necessitated administration in high doses, and had greater potential to cause life-threatening allergic reactions and viral safety problems. For Centocor, human antibodies not only promised greater safety and efficacy for therapeutic products but also provided a competitive advantage in securing investment.56 In 1986 Centocor gained exclusive rights to the human antibody technology developed through the venture. In return, FMC received 1.35 million shares of Centocor’s stock.57 The only other biotechnology company that had managed to develop human antibodies by then was Cetus 58.

Centocor Goes It Alone

In 1986 Wall and Schoemaker decided that while they would continue to develop therapeutic products through joint ventures, the profits generated from the highly successful blood test business and contract revenue from technology licensing, and selected product marketing arrangements could be used to build Centocor into a major pharmaceutical company. Their ambition was for the company to be as big as Merck, by the year 2000.59 Transforming Centocor into a globally integrated pharmaceutical company was not an unusual goal for the time. Other executives from leading biotechnology companies were pursuing the same vision with some success. In 1985 Genentech launched Protropin to treat growth hormone deficiency in children. It was the first recombinant pharmaceutical product to be manufactured and marketed by a biotechnology company without the help of a partner 60.

By 1988 Centocor’s research group had identified 30 new entities for possible drug development and had 12 Investigational New Drug Applications filed with the US FDA, many of which were mAbs, and had clinically evaluated 10 products.61 While many of Centocor’s competitors at this time were focusing on deploying mAbs for cancer treatment and Centocor had its own cancer program, 62 Centocor’s preferred lead candidate was an antibody-targeting septic shock, a deadly disease usually acquired in hospitals and traditionally treated, ineffectively, with antibiotics. By 1986 Centocor had two human antibodies, one developed in-house through their collaboration with FMC, and one licensed in from the University of California San Diego, known as HA-1A 63.

At least, a third of septic shock cases are caused by Gram-negative bacteria, a class of bacteria that possesses a unique outer membrane that hinders cell penetration by antibiotics and other drugs. During the 1980s, Gramnegative sepsis was the third leading cause of death in the United States, with over 100,000 people dying from the condition each year, accounting for up to $10 billion in health-care expenditures annually. Wall and Schoemaker believed that should Centocor develop a drug to combat a critical medical problem, they would have a major blockbuster. The estimated market for products to treat septic shock in 1990 was more than $300 million 64.

In order to maximize the potential of HA-1A, trade named Centoxin, Wall and Schoemaker, in part encouraged by their Wall Street advisors, decided that rather than selling the rights to the drug to another company they would develop and market Centoxin internally. This they believed would give them greater control over the product and larger revenues.65 As Tony Evnin, one of Centocor’s first investors and directors, explained, “At that point in time it seemed like such an important product and it was a product in a new area. We wanted the ability to keep it all to ourselves. Perhaps we were a bit greedy, but it seemed like it was something that, by bringing in . . . additional talent [from the pharmaceutical industry], we could take on ourselves” 66 (Fig. 37.3).

One of the reasons the Centocor executives decided to develop and market Centoxin internally was that it would help build the necessary infrastructure for becoming an integrated pharmaceutical company.67 This, however, required major upscaling of the company’s manufacturing capabilities and marketing that involved large sums of cash. At least, $150 million was needed to get Centoxin to market. Between 1986 and 1992, Centocor went through nine different equity, debt, and off-balance sheet financings, netting more than $500 million. By 1992 $450 million had been spent on clinical trials, building a sales force of 275 people (200 in the United States and 75 in Europe) and two new factories—one in Holland and one in the United States 68.

Heeding advice from Wall Street, the management team was also restructured to bring on board skills in pharmaceutical development, regulation, and marketing by the hiring of staff from large pharmaceutical companies. In December 1987 James Wavle, the former president of Parke-Davis, Warner Lambert’s pharmaceutical unit, became Centocor’s president and chief operating officer. Working alongside Schoemaker, who retained his position as chief executive officer and replaced Wall as chairman, Wavle took on the responsibility for turning Centocor into a globally integrated pharmaceutical company [3]. The recruitment of pharmaceutical executives had a major impact on the culture within Centocor, bringing in new management styles, more aggressive marketing, and a higher cash burn 69.

Confidence was high that Centoxin would succeed. Such optimism was not unfounded. In February 1991 a leading American journal ran an article indicating Centoxin reduced Gram-negative sepsis by 39%. For those who went into septic shock, the drug reduced mortality by 47%.70 The same month the United States Army administered the drug to soldiers fighting in the first Gulf War.71 A month later the European drug regulatory body approved Centoxin for the treatment of Gram-negative sepsis. Six months later, in September 1991, a FDA panel advised approval of Centoxin to treat septic shock.72 Centocor’s sales were predicted to soon be in excess of $1 billion. On this basis, Schoemaker believed Centocor would have more than 50% of the share of the antibody pharmaceuticals market in Europe, the United States, and Japan by 2000 73.

“Centocorpse”: Centocor in Crisis

The good news, however, did not last. In late October 1991 an American federal court ruled that Centocor’s patent for Centoxin infringed on one held by Xoma Corporation, a competitor biotechnology company based in California developing a similar drug for septic shock in partnership with the pharmaceutical company Pfizer Inc.74 Centocor’s executives were unsure how they should handle the matter. This was the first major case of litigation they had experienced. Initially, Schoemaker wanted to settle, but Wavle persuaded him to fight based on the belief that a settlement could result in cross-licensing and thereby a loss in revenues. The hope was Centocor might strike as lucky as the biotechnology company Amgen in its patent dispute with Genetics Institute.75 In retrospect, Schoemaker believed the decision to fight Xoma was one his biggest strategic errors.76 Losing the patent battle to Xoma, the litigation cost Centocor dearly in terms of time and money. It also publicly aired questions about the design of Centoxin’s trials and the data analysis 77.

Adding to the company’s woes, from late 1991, some medical practitioners began to question the potentially high price of Centoxin (between $3000 and $4000 for each patient) and the degree to which they could predict which patients would most benefit from the drug.78 By early 1992 initial European sales of the drug were also far below expectations. More pessimistic news was to follow when, on February 20, 1992, the FDA requested additional information about Centoxin. Triggering shock in the financial community, the tidings sent Centocor’s shares tumbling 19% or $8.125 a share, closing at $33.125 a share. Only 2 weeks before, the stock had traded at $50 a share. The slide in Centocor’s share represented a $675 million drop in its market value 79.

Despite the negative publicity, Schoemaker believed the problems could be resolved. Three months later, however, on a public holiday in April, he received a telephone call at home from David Kessler, head of the FDA, indicating that Centoxin would not be approved because of insufficient evidence to establish its efficacy and the necessity of more trials before it could be reconsidered for approval.80 For Schoemaker, usually a great optimist, this news was “the worst thing that could have happened.” The devastation was great for everyone in the company 81.

Hitting media headlines on April 15, 1992, the news stunned investors. Nicknamed “Centocorpse” by Wall Street, Centocor’s stock dropped 41% in 1 day.82 In the week that followed, disgruntled investors filed six lawsuits against Centocor’s executives alleging violation of federal securities laws and called for damages.83 Shareholders had seen $1.5 billion of Centocor’s market capitalization disappear, its stock rate having fallen from a high of $60 to just $6.84 Sensitive to the calamities of one of its leading companies, the biotechnology industry suffered its own financial aftershock 85.

Collaboration—A Means of Rescue

The FDA’s decision had not killed Centoxin, but Centocor desperately needed time and money to save the drug, develop its other products, and survive. With the future of the company at stake, Schoemaker and Wall immediately crafted a rescue strategy. To stop the company’s cash burn they rapidly laid off hundreds of people, primarily the sales representatives hired for Centoxin’s launch. Within a short period the company’s employee base had shrunk by a quarter. The company’s management team was also reshuffled: Wavle and other recent recruits from the pharmaceutical industry departed.

Crucial to the company’s financial survival was also Schoemaker and Wall’s reversion to collaboration. The income generated from the diagnostics division, which was bringing in millions of dollars, was insufficient to keep the company afloat and they could not rely on the investment community with the fall in Centocor’s stock.86 Within days of the FDA’s announcement, Wall and Schoemaker plunged into a frenzy of partnership and fundraising efforts with a number of pharmaceutical companies, including SmithKline Beecham and Eli Lilly.87 Schoemaker’s dynamism and optimism were major factors in driving this forward 88.

What Wall and Schoemaker had on their side were some other promising products in Centocor’s pipeline plus the fact that half the industry wanted to obtain Centoxin despite its problems. J.P Garnier, who headed SmithKline Beecham at the time, recalled, “We tried to convince Hubert [Schoemaker] to do a deal with us, and Centoxin turned into a bidding contest between several companies. . .. I remember a phone call coming in over the weekend saying, ‘It’s going to cost you $100 million in an upfront payment to get Centoxin now’. Now, it doesn’t sound impressive, but it was the equivalent of saying a billion today. A $100 million was unheard of. Nobody had ever paid this kind of upfront money.” As Garnier explained, “Hubert was a terrific salesman. He whipped up this asset into something that got to be very appealing. He packaged Centoxin very effectively and before you knew it, the bride looked sensational. Everybody was influenced by his sincere belief in the drug and what it could do” 89.

In July 1992 Centocor finalized a licensing agreement with Eli Lilly. Under the agreement, Centocor received $100 million upfront from Eli Lilly, an unprecedented large payment for the time. Half of this amount went toward Eli Lilly purchasing 2 million shares in Centocor, thereby giving it a 5% stake in the company. The other half went toward providing the much needed cash to continue developing and seeking clearance for Centoxin. In the event that Centoxin failed, Eli Lilly agreed to pay a further $25 million toward the development of ReoPro, a cardiovascular drug that Centocor was currently developing clinically 90.

The alliance was strategically useful for Centocor not only because of the capital Eli Lilly was to provide, but also because they had a significant presence in the antibiotics field and a strong understanding of the United States infectious disease market crucial for the further development of Centoxin. Eli Lilly was also more receptive to biotechnology than many other pharmaceutical companies, having partnered with Genentech to launch the first genetically engineered insulin and having acquired Hybritech, Centocor’s main competitor in mAb diagnostics in 1986.91 For Eli Lilly the alliance gave them a chance to enhance their knowledge in the application of mAbs for infectious disease therapeutics and access to Centocor’s European sales team, thereby opening up a new avenue for selling Lilly products 92.

In the following months, Eli Lilly and Centocor worked closely together, overseen by product committees established at both companies, on a new trial for Centoxin, launched in June 1992.93 Despite Eli Lilly’s support, in January 1993, Centoxin’s development was abandoned because interim trial data indicated unexpected high mortality. The poor results were attributed to a flawed trial design. Centoxin proved effective in treating septic shock stemming from Gram-negative bacteria, but this accounts for only about a third of patients who present with sepsis. No diagnostic tool existed, however, to detect which of the patients presenting in the trials had Gram-negative sepsis. In the absence of a diagnostic tool, Centocor’s clinical team had insufficient data to convince the FDA of the drug’s efficacy 94.

Centocor Becomes Profitable

Despite the setback with Centoxin, by early 1993, Centocor was financially turning a corner. Its cash burn rate had fallen from $50 to $30 million between the first and last quarter of 1992. Part of this had been achieved through layoffs, but it had also been helped by the reversion back to collaboration.95 Good results were also beginning to be reported for other products in Centocor’s pipeline.

Some of the most cheering news was the positive data Centocor’s clinical team was getting from the cardiovascular drug ReoPro. Licensed from the State University of New York, Stony Brook, in 1986, much of the early development and testing of ReoPro had been undertaken by Centocor with funds raised from a R&D-limited partnership set up in 1987.96 By 1992 when Centocor signed its alliance with Eli Lilly, ReoPro was in Phase III clinical trials and Centocor had plans to file for FDA and European regulatory approval the following year 97.

In early 1993 when the first results from the drug’s trial emerged positive, it was clear Centocor not only possessed a marketable drug, but its future was now secure.98 Submitted for approval in 1993, ReoPro took just 10 months to be approved by the European regulatory authorities and 12 months by the FDA. These approvals came through in December 1994. ReoPro’s approval marked a key milestone for Centocor and placed mAbs firmly on the therapeutic map, showing for the first time they could be used for acute conditions. The drug was the second mAb to win approval as a therapeutic, the first having been approved in 1986 by Johnson & Johnson’s Orthoclone OKT3 (used to prevent kidney transplant rejections).99 The first therapeutic product ever to receive simultaneous the United States and European approval, ReoPro was the only new biotechnology product sanctioned in 1994. In December 1995 the drug’s marketing potential was further boosted when clinical trials showed it was effective for unstable angina, broadening its potential market to more than 1 million patients 100.

Centocor’s partnership with Eli Lilly was crucial to the development of ReoPro. While Centocor had undertaken and internally financed much of its early development and clinical trials, the alliance provided the time to do further necessary work 101. Under the alliance agreement, Eli Lilly exercised its right to market the drug in the United States and most of Western Europe. ReoPro rapidly became a success, with worldwide sales of $23 million in its first year, 1995. By 1999 worldwide sales had increased to $447.3 million. Four years later, the drug was being investigated for noncardiac indications, including sickle-cell anemia and cancer 102.

Following ReoPro’s success, Centocor’s team soon had another major breakthrough with a drug called Remicade. The drug, based on an antibody called cA2, originated from a collaborative R&D agreement established in January 1984 between Centocor and the laboratory of Jan Vilcek, a scientist based at the New York University School of Medicine.103 Initially, Centocor’s researchers investigated cA2 in-house alongside Centoxin to combat sepsis, but clinical studies showed it more promising for treating autoimmune disorders. In 1998 Centocor won FDA approval for Remicade, to treat Crohn’s disease. A year later, Remicade was approved for rheumatoid arthritis. By 2007 the drug had received approval in 88 countries for 15 inflammatory disease indications and was being used to treat over 1 million patients worldwide, commanding 23% of the arthritis drug market. In 2006 Remicade generated the US $3.77 billion in worldwide sales. It would rise to $8 billion in 2010, making it the third medicine in history to top $8 billion in annual sales, and the best-selling biological medicine in the world for that year [4]. The approval of Remicade marked a significant point in the development of mAbs as therapeutics, showing for the first time that mAbs could be deployed for chronic conditions.

The approval of ReoPro and then Remicade signaled how far Centocor had come from its humble beginnings as a company specializing in mAb diagnostics. By 1999, 20 years after its founding, Centocor had raised $1.5 billion and brought to market ten products 104. Despite this success, Schoemaker and David Holveck, Centocor’s chief executive officer from September 1992, realized their company could no longer remain independent if it was to go forward as a serious player. The cash they had secured was insufficient for maintaining and growing the company’s R&D program and expanding the company’s manufacturing and marketing capabilities. They also recognized that having become so successful, the company could be subject to a take-over bid. In order to prevent a hostile bid, in 1998 they began to assess the company’s value and identify possible partners.105 A year later Holveck and Schoemaker secured a deal for $5.2 billion from Johnson & Johnson. Making Centocor a subsidiary of Johnson & Johnson, the deal allowed Centocor to continue to operate independently while benefiting from the large company’s infrastructure, financial resources, and credibility. Within 3 years of the deal, Centocor more than doubled its work force from 1200 people to 2800 worldwide, and more than tripled the number of new drug candidates entering late-stage testing, many in disease areas Centocor had not explored before, including diabetes, organ transplant rejection, and asthma [5].

Conclusion

This case study of Centocor is illustrative of the important role collaboration has played in the building up of the biotechnology industry. A key lesson from Centocor is how important R&D partnerships can be to a young company just beginning to create a portfolio, and how critical alliances with established companies can be to breaking into a competitive market place. Nearing bankruptcy when straying away from collaboration, the story of Centocor is a salutary reminder of the risks for newly emerging companies of going it alone. The experiences of Centocor’s executives with collaboration and the attempts to go it alone, however, are not universal in the biotechnology industry. Plenty of collaborations between biotechnology companies and large pharmaceutical companies have failed in the past and continue to do so to this day. Amgen, a biotechnology company founded just 1 year after Centocor, landed up in a costly court case over its patents and experienced huge financial losses as a result of the marketing partnership it formed in 1985 with Johnson & Johnson for its first drug erythropoietin, a treatment for anemia 106. The company had more success when it decided to develop and market its second drug Neupogen, a treatment for neutropenia, independently.107 The contrast between Centocor and Amgen shows how idiosyncratic the risks and outcomes can be for biotechnology companies when deciding to collaborate or go it alone. This is highly influenced by the personalities involved, market conditions, scientific and technical developments, and the cultural fit between organizations.

Acknowledgments

The author would like to thank Anne Faulkner Schoemaker for allowing generous access to Hubert Schoemaker’s personal files and reading earlier drafts of this paper. Grateful thanks also go to Stelios Papadopoulos, Alison Kraft, and David Holveck for providing insightful comments on initial drafts of the paper. Much appreciation also goes to all the people who agreed to be interviewed for the research that led to this chapter which was supported by the Chemical Heritage Foundation.

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• 2020-biotechnology-entrepreneurship-lara-marks-phil-oxon-chapter-37-img-2

• FIGURE 37.2 Centocor headquarters in Malvern, Pennsylvania.

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• 1. This figure is based on figures of over 800 deals signed in 2011, each of which was worth approximately $200 million. It is based on data from the EvaluatePharma Deals Database.
• 2. Research for this chapter is based on Centocor’s company papers and the personal papers of Hubert Schoemaker (hereafter HS-PP) kindly provided by his widow Anne Faulkner Schoemaker and on oral interviews with Centocor’s employees undertaken by the author in collaboration with the Chemical Heritage Foundation which houses the interview transcripts. The author conducted all interviews listed below except where specified. Interview transcripts are kept at the Chemical Heritage Foundation.
• 3. For Koprowski’s biography see Vaughan R. Listen to the music: the life of Hilary Koprowski. Springer; 2000.
• 4. HS-PP: Centocor, Centocor Oncogene Research Partners LP, June 9, 1984.
• 5. For the early development of monoclonal antibodies see Marks L. A healthtech revolution: the story of Ce´sar Milstein and the making of monoclonal antibodies, ,www.whatisbiotechnology.org..
• 6. Vaughan, Listen to the music, 174 177.
• 7. Koprowski H, Croce C. Method of producing tumor antibodies, U.S. Patent 4,172,124 (filed April 28, 1978, issued October 23, 1979); Koprowski H, Gerhard W, Croce C. Method of producing antibodies, U.S. Patent 4,196,265 (filed June 15, 1977, issued April 1, 1980).
• 8. Vaughan, Listen to the music, 179.
• 9. Centocor, Centocor Oncogene Research Partners LP, June 9, 1984, HS-PP; Interview with Hilary Koprowski by author and Ted Everson (July 13, 2006), transcript, 16 17; Interview with David Holveck by Lara Marks and Ted Everson (July 14, 2006).
• 10. Wall MA, Allen EC. Investment prospectus: medical diagnostic business, HS-PP, n.d., p. 34 35.
• 11. For a detailed biography of Schoemaker go to his profile on ,www.whatisbiotechnology.org/people/Schoemaker.. 
• 12. Wall and Allen, Investment prospectus, 30.
• 13. Interview with Tony Evnin, Venrock Associates partner and Centocor director (1981 1999) by author and Ted Everson (September 14, 2006).
• 14. Wall and Allen, Investment prospectus, 6.
• 15. Wall and Allen, Investment prospectus, 28 and 31; Author Unknown, A medical marvel goes to market, 56; Author Unknown, Biotechnologists are ready to market another trick, 87; Author Unknown, Smart bombs of biology, 59. For a history of Sera-Labs see Marks, A healthtech revolution; and Marks LV. The “Lock and Key” of medicine: monoclonal antibodies and the transformation of healthcare. Yale University Press; forthcoming [chapter 7].
• 16. Author Unknown, A medical marvel goes to market, 56; Hamilton MM, Competition feverish in health field: immunodiagnostics in infancy, The Washington Post, Sunday Final Edition, October 30, 1983, G1.
• 17. Vaughan, Listen to the music, 179; interview with Koprowski. See also interview with Michael Dougherty by author and Ted Everson (January 23, 2007), transcript. Dougherty was Centocor’s assistant controller, treasurer, chief financial officer and senior vice president (1983 1993).
• 18. Interview with Evnin; HS-PP: Rothschild LF, et al. Centocor Inc: prospectus for public offering, July 22, 1983, 21; Teitelman R. Searching for serendipity: Centocor Combs University Labs for Technology, Forbes, May 6, 1985, 80.
• 19. Teitelman R. Searching for serendipity: Centocor Combs University Labs for Technology. Forbes; 1985, p. 80 81.
• 20. Interview with former NCI researcher and Centocor collaborator Robert Gallo (July 11, 2006). See also interview with Sarah Cabot, Centocor’s technology licensing director (1986 1990), by Jennifer Dionisio (November 7, 2007).
• 21. Interviews with Evnin and Anne Faulkner Schoemaker (July 10, 2006). See also HS-PP: Centocor, Annual Report, 1983, 6. Hereafter all Centocor’s Annual Reports (A/R). The A/Rs are contained in HS-PP.
• 22. Schoemaker cited in Vaughan, Listen to the music, 186; and interview with Faulkner Schoemaker.
• 23. HS-PP: Rothschild LF, et al. Centocor Inc: prospectus for public offering, December 14, 1982, 19 and 25. Stanley Cohen and Herbert Boyer faced similar hostility to the commercialization and patenting of their technology and founding of Genentech (see Smith Hughes S. Making dollars out of DNA: the first major patent in biotechnology and the commercialization of molecular biology, 1974 1980. ISIS 2001;92:541 575, 551).
• 24. Vaughan, Listen to the music, 182 186.
• 25. Interview with Gallo; Schoemaker, cited in Vaughan, Listen to the music, 186.
• 26. Before the Bayh-Dole Act, universities wishing to obtain a patent arising from federally funded research required permission from federal authorities to do so. See Hughes, Making dollars out of DNA, 551.
• 27. Centocor, A/R (1985), 5 and Rothschild, Centocor Inc. (1983), 22; Momich B. Building something significant at Centocor. Pennsylvania Technology, Second Quarter, 1990, p. 25 31.
• 28. Interview with Koprowski. Interview with Zurawski by Ted Everson, (January 4, 2007).
• 29. Dickinson S. Biotech’s Centocor jockeys for position in drug field. The Scientist 1990;4:1 5.
• 30. Wall and Allen, Investment prospectus, 6.
• 31. Interview with Holveck by author and Ted Everson (July 14, 2006). Holveck was Centocor’s head of diagnostics from 1983 and Centocor’s chief executive officer from 1992.
• 32. Rothschild, Centocor Inc. (1982), 15; Rothschild, Centocor Inc. (1983); Centocor, A/Rs (1983), 2 and (1985), 15; Correspondence between author and David Holveck, November 2007; Interview with Holveck.
• 33. By 1983 the company had formed a number of marketing and manufacturing partnerships with key companies for distribution of the test in different parts in the world. This included Warner-Lambert to cover the USA, Toray/Fujizoki for Japan, and Byk-Mallinckroft for Europe. Centocor, A/Rs (1983), 2, 14, 18 and (1985), 15.
• 34. Interview with Holveck by Sally Smith Hughes (1998, 1999), transcript, 43, Regional Oral History Office, Bancroft Library.
• 35. Centocor, A/R (1985), 27.
• 36. Interview with Zurawski; Author Unknown, TWST names award winners biotechnology, The Wall Street Transcript, 97/11 (December 14, 1987)
• HS-PP: Centocor, A/R (1990), 14.
• 37. HS-PP: H. Schoemaker, Wharton Talk, April 17, 2000 and interview with Holveck.
• 38. Bylinsky G. Coming: star wars medicine. Fortune; April 27, 1987.
• 39. Centocor, A/R (1982).
• 40. Rothschild, Centocor Inc. (1982) and (1983); HS-PP: Paine Webber, Centocor, Common Stock, December 13, 1985, 7; Centocor, A/R (1986), (1987), 2, and (1990), 3.
• 41. Interviews by author and Ted Everson with PaineWebber investment bankers Stephen Evans-Freke (September 14, 2006) and Stephen Webster (July 13, 2006), and by author with Bruce Peacock, Centocor’s chief financial officer 1981 1992 (July 10, 2006). See also Schiff L, Murray F. Biotechnology financing dilemmas and the role of special purpose entities. Nat Biotechnol 2004;22:271 277.
• 42. Interview with Fred A. Middleton, by G.E. Bugos (2001), transcript, Regional Oral History Office, Bancroft Library.
• 43. Interviews with Evans-Freke and Webster. See also HS-PP: Centocor, Centocor Oncogene Research Partners LP; PaineWebber, Centocor Common Stock, 22; PaineWebber, Tocor II and Centocor Prospectus, January 21, 1992, 5; Centocor, A/Rs (1985 1988) and (1989), 31.
• 44. Bill Hambrecht, cofounder of Hambrecht and Quist in 1968, an investment bank specializing in emerging high-growth technology companies, was one of Genentech’s early investors. See Interview with Middleton, 28. Schoemaker, Wharton Talk.
• 45. For more on the development of recombinant insulin see Hall S. Invisible frontiers: the race to synthesize a human gene. Oxford: Oxford University Press; 1987.
• 46. Interview with Centocor’s vice president of pharmaceutical development (1988 1993) Renato Fuchs (July 1, 2008). See also Bylinsky, Coming: star wars medicine.
• 47. Bylinsky, Coming: star wars medicine.
• 48. Centocor, A/R (1985), 11.
• 49. Centocor, Investment prospectus, December 14, 1982, 17; Centocor, A/R (1983), 2.
• 50. Centocor, A/R (1983), 2.
• 51. Interview with Fuchs; Interview with Jeffrey Mattis by Lara Marks. Mattis was Centocor’s vice president of pharmaceutical development (1979 1998) (February 22, 2007). Notes.
• 52. PaineWebber, Centocor Common Stock (1985), 4, 6, 34; PaineWebber, Tocor II; Centocor, Annual Report (1990), 7; Centocor SEC filing Form 10-K for the year ending, December 31, 1995; Pollack, The Next Wave of Diagnostics. Interviews with David Holveck by author and Everson (July 14, 2006 and September 9, 2009), Harlan Weisman (November 30, 2006) and Mattis. Harlan Weisman was Centocor’s president of R&D and team leader for ReoPro development (1990 1999).
• 53. Centocor, A/R (1988), 4 and (1990), 7; Interview with Mattis; Interviews with Fuchs, notes and with Stelios Papadopolous (October 19, 2006). Papadopolous was an investment banker with Paine Webber (1987 2000). Centocor’s Myoscint imaging agent backed in USA, The Pharmaletter, February 5, 1996, ,http://www.thepharmaletter.com/file/25880/centocors-myoscint-imaging-agent-backed-in-usa.html..
• 54. Centocor, A/R (1983), 6.
• 55. Centocor, A/Rs (1983), 18, 28, and (1985), 2; Rothschild, Centocor Inc. (1983), 47.
• 56. Interview with Evans-FrekeCentocor, A/R (1986).
• 57. Centocor, A/R (1986), 3.
• 58. Bylinsky, Coming: star wars medicine.
• 59. Centocor, A/Rs (1986), 17 and (1988), 5; Dickinson, Biotech’s Centocor jockeys for position, 2.
• 60. Interview with Middleton. Interview with Fuchs.
• 61. Centocor, A/R (1988), 2 and 12.
• 62. Interview with Richard McCloskey (January 19, 2007). McClosky was Centocor’s vice president of clinical research and medical research (1990 1997).
• 63. Centocor, A/R (1985), 29. Interviews with Denise McGinn (September 12, 2006), Zurawski and Fuchs. McGinn was Centocor’s development project manager (1983 1999).
• 64. Momich, Building something significant at Centocor, 26 28.

• 65. Interview with Bernard Schaffer. Schaffer is a Philadelphia-based market analyst.
• 66. Interview with Evnin.
• 67. Interview with Fuchs.
• 68. Winslow, Centocor’s new drug clears FDA panel; Dickinson, Biotech’s Centocor jockeys for position in drug field; and Longman R. The lessons of Centocor, in vivo: the business and medicine report, May 1992, p. 24.
• 69. Interviews with Holveck, Peacock, and Cabot. Joint interview with Sandra Faragalli, Patty Durachko, and Ray Heslip (September 12, 2006). All three were long-time employees of Centocor, working in the administrative, finance, warehouse, and shipping sections. Interview with Centocor’s vice president of diagnostics operations (1985 1998), Paul Touhey by author and Ted Everson (September 15, 2006).
• 70. Ziegler EJ, Fisher CJ, Sprung CL, et al. Treatment of Gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebo-controlled trial. The HA-1A Sepsis Study Group. N Engl J Med 1991;324(7):429 436.
• 71. Author Unknown, Blasting Bacteria; Author Unknown, Centocor, Inc.
• 72. Usdin S, Wall Street vents frustration at Centocor, BioWorld Today, February 20, 1992, 1; Shaw D, FDA, Wall Street bring bad tidings to Centocor, The Philadelphia Inquirer, 1992, B11; Author Unknown, FDA Snag and Loss Hurt Centocor Stock; Valeriano LL, Centocor stock slides on news of drug snag, Wall St J, 1992; Newman A, Pettit D, Biotech Stock Lead Index 0.64% lower; Centocor plunges on worry over drug, Wall St J, 1992.
• 73. Author Unknown, Centocor, Inc.
• 74. Patent disputes were common in the industry and could be devastating for the companies concerned. See, for example, the case of CellPro which became bankrupt after failing to win a patent dispute as described in Bar-Shalom A, Cook-Deegan R. Patents and innovation in cancer: lessons from CellPro. Millbank Q 2002;80(4):637 676.
• 75. Interviews with Centocor’s attorney (1987 1999), George Hobbs (September 30, 2006); Papadopoulos; and chief executive officer of Cephalon, Frank Baldino by author and Ted Everson (July 14, 2006). Amgen and Genetics Institute’s patent dispute started in 1988 and ended in May 1993 with the Genetics Institute paying Amgen $15.9 million. Amgen SEC filing: Form: 10-Q, 8/10/1994.
• 76. Interviews with Faulkner Schoemaker, and Schaffer.
• 77. Interviews with Holveck and Papadopoulos. Centocor, A/R (1991), 38 and 39; Valeriano, Centocor stock slides on news of drug snag; Fisher LM. Centocor and Xoma settle patent fight. The New York Times; July 30, 1992.
• 78. Hinds CJ. Monoclonal antibodies in sepsis and septic shock. Br Med J 1992;304:132 133. Interviews with Peacock, Holveck, and Papadopoulos.
• 79. Usdin, Wall Street vents frustration at Centocor; Shaw, FDA, Wall Street bring bad tidings to Centocor; Author Unknown, FDA snag and loss hurt Centocor stock; Valeriano, Centocor stock slides on news of drug snag; Newman and Pettit, Biotech stock lead index 0.64% lower; Longman, The lessons of Centocor, 25.
• 80. Interview with Schaffer.
• 81. Interviews with Faulkner Schoemaker, Holveck (by author and Everson), Faragalli, Durachko, and Heslip.
• 82. Shaw, Centocor absorbs new blows. See also interview with Papadopoulos.
• 83. Author Unknown. FDA: Centoxin data insufficient. In: 74E, Shaw D, editor. Centocor absorbs new blows. The Philadelphia Inquirer. Interview with Holveck.
• 84. Schoemaker, Wharton Talk; Longman, The lessons of Centocor, 23; interview with Holveck.
• 85. Usdin, Wall Street vents frustration at Centocor, 1; Longman, The lessons of Centocor, 27.
• 86. Interview with Touhey.
• 87. HS-PP: Centocor, CenTropics, 1/4 (Fall 1992), 1.
• 88. Interview with Papadopoulos.
• 89. Interview with J.P Garnier by Ted Everson (July 12, 2006).
• 90. Author Unknown, Lilly to acquire marketing rights to Centocor drug, Centocor, Centropics.
• 91. Author Unknown, Lilly to acquire marketing rights to Centocor drug, Centocor, Centropics.
• 92. Interview with Fuchs; Centocor, CenTropics, 1.
• 93. Centocor, CenTropics, 2 4.
• 94. Interviews with Holveck. Papadopoulos. Interview with Michael Melore by Ted Everson. Melore was Centocor’s head of human resources  (1990 1999).
• 95. Centocor, A/R (1992), 7.
• 96. Centocor, A/Rs (1987 1988).
• 97. Centocor, A/R (1992), 4.
• 98. Interview with McGinn.
• 99. Bylinsky, Coming: star wars medicine; Centocor, A/R (1994), 2 and 4; Cochlovius B, Braunagel M, Welschof M, Therapeutic antibodies, American Chemical Society: Modern Drug Discovery, October 2003; Farrell C, Barnathan E, Weisman HF. The evolution of ReoPro clinical development. In: Dembowsky K, Stadler P, editors. Novel therapeutic proteins: selected case studies. Weinheim: Wiley-VCH Verlag GmbH; 2003,  p. 323 346.
• 100. New York Times (December 22, 1995).
• 101. Interview with Holveck.
• 102. Interview with Holveck.
• 103. Interview with Jan Vilcek (July 12, 2006). Vilcek is a microbiology professor at New York University School of Medicine.
• 104. Schoemaker, Wharton Talk.
• 105. Interview with Holveck; Knox A. He is building on his success. The Philadelphia Inquirer; May 7, 2000.
• 106. Moscho1 A, Leiter J. Perfect partnering, Nat Biotechnol, Supplement to Vol. 19, July, 2001, BE21 BE22. For more on Amgen’s development and marketing of Epogen see Goozner M. The $800 million pill: the truth behind the cost of new drugs. Berkeley, CA: University of California Press; 2004, p. 13 34.
• 107. Interview with Papadopoulos.

References

• [1] HS-PP: Centocor Press Release. Centocor receives FDA panel recommendation to Approve Ovarian Cancer Test, November 3, 1986; Thompson L. New test for ovarian cancer detects residual cells in the blood, The Washington Post, June 16, 1987.

• [2] BCC Research. Antibodies for therapeutic and diagnostic imaging applications. In: Report BIO016D, February 2000; BCC Research. Dynamic antibody industry. In: Report BIO016F, August 2005; Wolf R. Centocor makes a deal on product marketing, The Inquirer, December 7, 1987.

• [3] Author Unknown. Centocor Inc. Chief Hubert Schoemaker Adds Chairman’s Post.

• [4] Wiki Analysis. Arthritis drug market, ,http://www.wikinvest.com/wiki/Arthritis_Drug_Market#_note-13.; PharmaLive. Top 500 Prescription Medicine, Special Report, October 2011.

• [5] George J. Centocor now bigger than ever. Philadelphia Bus J August 16, 2002?.