case study in biotechnology

Global Dimensions of Intellectual Property Rights in Science and Technology (1993)

Chapter: 13 biotechnology case study, 13 biotechnology case study.

GEORGE B. RATHMANN

I want to describe a bit of the history of the biotechnology field to give you a strong sense of the importance of this field, not just in itself but as a prelude to a new technology as it develops over the next century. I then relate that history to some questions that have been raised and finally relate my conclusions with respect to biotechnology to the objectives of the conference.

As rocky as the road for biotechnology was in the United States, what we see coming up on the world scene is much more difficult, much more serious. We desperately need a legal system to solve the problems, and it is our hope that there are ways of dealing with these issues.

The biotech era really dawned when Watson and Crick defined the structure of deoxyribonucleic acid (DNA). As with many world-shattering discoveries, this was simple and concise—a publication of one page outlining the structure of DNA ( Nature, April 25, 1953, p. 737). They also had the vision to say it would affect not only how we looked at deoxyribonucleic acid, but how we looked at life itself and our ability to understand living systems. There would be products, there would be opportunities, and there would be new insights that would be most important. All that was recognized in a one-page article.

As important and earth shaking as that was, from the standpoint of the commercialization of biotechnology, something nearly as important occurred on June 17, 1980, when the Supreme Court ruled that live organisms could be patented. It was well recognized as important at the time, but I think few

people realized how important it was for launching the commercialization of biotechnology.

In that patent, Dr. Ananda Chakrabarty, who was at G.E. at the time, claimed an organism that would digest oil. The invention was never commercialized, but it told the world that this field was going to be important and there were going to be commercial opportunities. An investment in trying to understand the biochemistry of life would pay off in the sense that the intellectual property could be protected. Within four months (October 14, 1980), the biotechnology company Genentech went public and jolted Wall Street with a rise in its stock price from $35 to $71 1/4. So it is clear that as of that date, biotechnology assumed increasing commercial importance.

At that time, in October 1980, I was looking at the opportunity to start a biotech company called Amgen and we were putting out a document that we hoped would raise $15 million. Partly because of Genentech's success, we were able to raise $19 million—with only a scientific advisory board, one employee, and promises for two future hires. So it certainly had a profound effect on whether Amgen would ever be. As a matter of fact, within a year, Amgen, Genetics Institute, Immunex, Genetics Systems, Chiron, and many others companies were formed. Within two years, more than 100 companies were formed as this era was launched.

Now, the Chakrabarty decision made it look simple: life forms were patentable. Genentech, Cetus and many others afterwards launched public offerings, recognizing the commercial potential that biotechnology would lead to new discoveries of valuable intellectual property, which could be protected by patents. In reality, it was not quite that simple and the launchings were not that consistent.

Venture capital funds vacillated quite a bit, although after 1980 there was a very substantial influx of venture capital ( Figure 13-1 ). There were periods when it went down, and periods when it went up. Although these look like gigantic numbers, remember it takes about a quarter of a billion dollars to bring a pharmaceutical product to market. It probably takes more than that to commercialize something important in agriculture, food, or other areas. So this flow of venture capital was actually inadequate to keep it going. Of course, the public made the difference, but it can be seen that this was not exactly a consistent, reliable source of funds, either.

If we smooth everything out, the market value of biotechnology stocks moved dramatically from 1980, when it was literally zero, to 1991, when it was more than $35 billion ( Figure 13-2 ). Those of us in the industry saw some very serious bumps in that curve. In 1987 some biotech companies lost 30-40 percent of the value of the company in a matter of a few days. When you finally smooth everything out, it looks a lot simpler and surer than it felt.

FIGURE 13-1 Venture Capital Disbursements in Biotechnology

Source: Venture Economics and Ernst and Young

Figure 13-3 shows the amount of capital raised through public stock offerings. In 1991, more money was raised in six months than for many years, and as a matter of fact, when the total figures came in for the year they exceeded $4 billion—equal to all the money that had been raised in the previous years since the launching of commercial biotechnology. Of course, the big news is $550 million in initial public offerings. Those are new companies whose survival may mean wonderful improvements to our lives around the world. At the same time they will be facing some of the rocky roads that the earlier companies faced. So we can see that it is not a steady, easy trip.

Product sales in the industry today have reached about $8 billion and are expected to reach $20 billion by the year 2000. That may be a very conservative figure. The drug industry worldwide by that time will be well over $200 billion, and biotechnology is contributing roughly half of the most important products today. By the time the year 2000 comes around, biotechnology-derived products could be even more important. Of course there should be many other parts of the biotech industry that are commercially interesting by that time.

FIGURE 13-2 Market Value of Biotechnology Stocks

FIGURE 13-3 Amount of Capital Raised Through Initial Public Offerings and Other Public Offerings

Source: Paine Webber and Ernst and Young

So we are looking at something of great importance to the economy of the country and to international trade, which is discussed below.

I was asked by the National Research Council to address several questions. The first was, What adjustments in intellectual property rights have been made? Well, of course, the first is the allowance of claims to living organisms. The United States certainly led the way there. It was a very important opportunity that organisms that produced a pharmaceutical material could be claimed in patents. We had something tangible to claim even if the product being produced was already known or already had been defined.

One of the things that has been evolving over the last few years, and certainly in 1987 had a pretty dismal outlook, is referred to as In re Durden . This case implied that just because you have a novel starting material on which you carry out a process to produce another material, the process is not automatically patentable. That case was often interpreted much more severely to mean that unless the process is highly inventive, mere novelty because of novel starting materials does not make it patentable. So it was not possible in 1987 to get claims to the process that was going to produce, for example, in Amgen's case, erythropoietin by using a novel organism.

Because inventors could not claim the process, they had a very serious problem. They could not invoke any rights at all against companies who used their organism overseas, produced the product, and brought it in. They did not have a final product claim; they did not have a process claim; and there was no mechanism for protecting against the direct theft of the organism overseas—copying it, or following the teachings of the patent, and then just shipping the product to the United States.

However, an evolution has occurred since then. Certainly, a lot of process claims have now been granted. There is a bill authored by Congressman Boucher that would give guidance to the Patent Office to make sure it issues those claims. Without those claims, the organism patent is meaningless with respect to overseas competition. What if the overseas country does not issue the organism patent? The organism has only one purpose—to produce the protein, so the inventor is left with no protection against importation. Amazingly enough, the inventor is protected from infringement in the United States by U.S. companies but is unable to stop foreign infringement and U.S. importation. The trade implications are clear.

This has been a very serious problem that is now being addressed. Yet there are still concerns from people who wonder if it is really "fair" to keep foreign companies from bringing their products into the United States. They ask, "Isn't that protectionism?" This a very strange interpretation of fairness. I think these inventions are clearly being copied and misappropriated by foreign companies. Changes may or may not move smoothly, but these issues should be resolved in the next few years, and more and more compa-

nies are availing themselves of the process protection, though some opportunities have been abandoned after In re Durden objections.

There have been great differences in the interpretation of the scope of claims. My initial discussion is limited to the United States because global issues have really only come into play in the least five years. Even in the United States, the scope of claims has been quite a difficult issue with which to deal. The questions stated are, If the claims are too broad, doesn't it mean we are inhibiting the diffusion of technology? If the claims are too narrow, doesn't it mean that the inventor really is disadvantaged? I could say a lot about that, but in actual fact I will cite the record. A Boston court in the United States leaned toward a pretty narrow interpretation of the claims. In a Delaware court, a jury decided that the Genentech case should be very broadly interpreted and cover structures quite different from the ones that were defined in the patent simply because all the rest were straightforward once the patent teachings were available. So these are still issues, but I think we will move toward a pretty clear understanding over the next few years.

The effect on biotechnology advancement has not been smooth even in this country. Patent uncertainty has encouraged second entrants, who then plead that since they made such a significant investment, believing they were not going to be prevented from manufacturing the product, the terms of the claims of the patents should be relaxed. This has certainly been an expensive mistake in many cases.

Major delays in issuance of patents have prevented some innovators from pushing their products as rapidly as they could, because they feared that they might never have coverage and once they proved the success of the product, it could be duplicated relatively readily. I think many of us in the business got a lot of encouragement from the Orphan Drug Act, because that act suggested that we at least could get six years of protection if we were the first to have a product approved for an orphan indication. If we never received adequate patent protection, we still might be able to recoup our investments, which was very comforting. There has been a lot of controversy about the Orphan Drug Act and whether it should serve as a kind of substitute for the Patent Act. Nevertheless, it helped an embryonic biotechnology industry raise money and sustain its early critical momentum.

Finally, patents played a key role in attracting pharmaceutical companies' investments. These were very important for some companies in the early days. Even though the pharmaceutical companies were not the innovators, they certainly helped support many new biotechnology companies and they clearly needed the confidence of patent exclusivity.

As stated in congressional testimony by Dr. P. Roy Vagelos, Chairman of Merck & Co., "To sustain their ability to discover and develop products which form the basis of American competitiveness, U.S. pharmaceutical

companies count on renewed government support ... in strengthening international protection of intellectual property rights." We can illustrate that perhaps even more significantly in the biotech industry.

For example, in 1986 a pharmaceutical product would cost about $94 million and take somewhere between 10 and 20 years before entering the market. Some kind of protection is certainly required before that kind of investment is made. The figure today is $240 million. That number has been challenged by Congress and looked at many ways by the Office of Technology Assessment (OTA); the latest OTA study says that costs may often be that high, although sometimes they may be lower. However, it does not require a lot of arithmetic to figure this out. The pharmaceutical industry in this country alone spends about $10 billion on R&D per year, and about 30 new products—30 new molecular entities—are approved each year. That comes out to be more than $300 million invested for each success.

In fact, there are at most only four or five new therapeutic products approved each year that are important and if you divide by that, you arrive at astronomical figures for important new therapeutics. Also, all this investment is required years before you can enter the market and start to get a return. So this certainly fits the pattern of something that requires protection, and patents look like the way to do it.

In 1986 the average development time of a new pharmaceutical product was 10 years. The interesting thing is that biotechnology has compressed that time. Because of the rational design of these products, their remarkable efficiency and safety profile, and the understanding and cooperation of the U.S. Food and Drug Administration, the average development time is about four to seven years today for biotechnology products, which is a big help. However, it is still a long time and a large investment.

So let us review how biotechnology was commercialized. What happened is not particularly logical, not what anyone would have deduced sitting around a table trying to decide what was going to happen. When a biotech company decided it wanted to launch a product, it had to build a company to launch the product. All the different stages and structures had to be built—the vectors and expression systems, purifications, scale-up, manufacturing, clinical testing, regulatory submissions, and marketing. Surprisingly enough, almost all of these things were in place in major pharmaceutical companies, yet almost every single important invention was done by independent biotechnology companies. That is the fact; that is what we have to deal with. How were they able to do all this, why would they be the first to do it, and was it effective? Is it not terribly inefficient to have to create a company for each new product? That is what was done.

Small, start-up biotechnology companies were responsible for many miracle drugs. For example, Amgen developed erythropoietin, and we now know that 10 milligrams per year, one-fiftieth of an aspirin tablet, will

prevent 20 or more transfusions for people that are deficient in erythropoietin—and there are many more. Chiron produced the answer to hepatitis C, which is something that has plagued society and challenged scientists for more than 30 years—a well-defined disease about which nothing could be done. Cetus discovered ways of amplifying genes. Individual inventors, individual small companies, are pioneering and finding important new molecules and insights that are changing the way medicine is practiced today. This was done in a way that perhaps was hardly predictable—small, independent companies got started and did this all on their own—but this is exactly what happened. Sometimes it occurred with the support of large companies, but none of the key innovations and developments throughout the field were made by the large companies.

As I said, it was a fairly rocky road. I think that is important. The fragility of a new technology and the need for immediate action are more critical than making long-range plans to do wonderful things over long periods of time. These companies are fragile and their viability is always in question. Their survival is in jeopardy at all times. Take 1989 as an example. Headlines blared, "Clouds gather over the biotech field." Interestingly enough, firms were stumbling on regulation and patent problems. The patent situation looked very confused at that time. It was very difficult again to get financing, and the feeling was that many companies would go out of business and some did.

If we look at the number of financings, we see what has faced this emerging technology—and will probably apply to every new technology—big financing surges, dry spells, big surges. The dry spell in 1984 and 1985 seemed to last forever. We learned it can take eight quarters before you see another chance to raise money. When 1987 came along, the stock market wilted, and 1988, 1989, and 1990—one after another—were all very bad years. Of course, 1991 salvaged a lot of companies, but those were dangerous times for fragile, embryonic businesses.

So some protection is required. There is no question that patent protection fits the need in terms of the large investment required over a long period of time. The question is always asked, however, whether keeping the inventions secret would work. Well, it doesn't. Once the gene has been described, it is trivial to produce the product. Even if the gene is not described anywhere, once the structure is out, once the product is available even in clinical trials, the structure can be determined and often easily duplicated at a much lower cost. The cost is even lower because the copier only has to copy winners. He does not have to duplicate the losers. The copier avoids the major investments that the innovator had to make.

So international protection becomes the issue today. The problems in obtaining worldwide protection are difficult. There are many countries that do not honor the patent system. Surprisingly, countries that do not have

strong patent systems (e.g., China, India, Argentina, Brazil) are not troublesome to the biotech field, although the pharmaceutical industry has expressed concern. However, international trade competition with countries that purport to have a patent system is a very serious issue.

For example, Japan is a strong competitor. In Japan, patent flooding surrounds innovator's patents. The Japanese patent office grants narrow patents instead of broad ones. I think it is pretty obvious to those in this industry that small companies need broad patents. If you are going to try to compete in the marketplace with giants, you had better know that you have some reasonable protection against obvious duplication or partial duplication. The Japanese system has not produced many biotechnology innovations and has not produced biotechnology companies. Our problems with the Japanese system are narrow patents, sometimes taking 10 or more years to issue, and patent flooding, which surrounds the inventor's contribution and forces him to join up with a large, entrenched Japanese company to survive.

To summarize, developing countries have concerned some industries, but they have not been competitive in biotechnology. Europe has awarded strong patents that afford U.S. innovators reasonable protection. Japan has been a very serious issue. Today we see two companies in Japan enjoying the products of Amgen—two products approaching a billion dollars in sales, at prices two to four times that of the products in this country, guaranteeing high profits. It is very easy to see what is going to happen over the long term. Those companies are going to be able to invade other countries in the field of biotechnology and be very active participants in trade.

The question then is, Can the United States dictate or influence international patent practices? Well, somehow it has to. This sounds unfair to some, but it is equally unfair to have misappropriation of intellectual property.

We know the history of what happened: Japan behind, Japan even, Japan ahead. The outlook is very serious. If we think back about that 20year period around the 1960s when U.S. patents were not being upheld, that may have been why it was easy for the Japanese to move in and take over the territory.

Now, for future challenges: The federal government's patenting of the genome was a hypothetical question until a short time ago. Would this be serious? It has now become a very practical question. The U.S. Patent Office is currently examining the NIH's application for patents on certain gene sequences. In the meantime, the Industrial Biotechnology Association has held discussions with Reid Adler of the National Institutes of Health (NIH), biotech executives and administration officials who are examining this issue. What should the NIH do with respect to all of these gene patents? A good start is to provide a forum between industry, NIH and other inter-

ested parties to see if we can understand whether these patents should be applied for, whether they should be issued, and if issued, how they should be handled.

Finally, can patents be issued faster? The U.S. Patent and Trademark Office's numbers on the average time of application pendency are very strange and not helpful. The Patent Office has always figured out ways to say it is doing things in two years when, in fact, there has not been a useful biotech patent that has taken less than four years, and usually five. If we cannot get meaningful numbers, I don't think the problem can be solved. I think the Patent Office is misleading all of us.

In terms of the conference objectives, I would like to close with these thoughts concerning a few final issues: First, with respect to international perception of the importance of intellectual property rights, the world acknowledges that the United States was the pioneer in biotechnology, and that it was done by risk capital, as well as federal support of R&D, originally. The positive contribution to human welfare is acknowledged worldwide. That does not mean that all the countries in the world want to give strong patent protection for biotechnology, which is a very difficult issue.

Second, with respect to biotechnology patents, in the United States, the road has been rocky but reasonably satisfactory. Worldwide protection will ultimately be critical. It is sad that this did not occur long ago. Because of this lack, we are seeing companies in foreign countries appropriating U.S. technology to get started.

Finally, with respect to conflict resolution, the most precious resource of a budding new industry or budding new technology is time. The solutions have to be time sensitive. Grandiose solutions that involve 60 or 70 countries, and take years and years, will mean that a lot of the companies will fail before the solutions are in place. I think people should be aware of that.

I would remind you of one last thing. This is an industry of small companies. If you look at the profile of public biotechnology companies, only 13 percent have more than 300 employees, and none have more than 2,000 employees. If we look at all biotech companies (publicly and privately held), there are only 3 percent with more than 300 employees. We are dealing with a very, very broad-based, small-company business and my remarks apply as well to my firm, ICOS, which we started within the last year, as well as to the largest biotech companies, which are still relatively small. These are the companies seeking patent protection. Strong protection can hardly ''disadvantage small companies" as some critics suggest.

As technological developments multiply around the globe—even as the patenting of human genes comes under serious discussion—nations, companies, and researchers find themselves in conflict over intellectual property rights (IPRs). Now, an international group of experts presents the first multidisciplinary look at IPRs in an age of explosive growth in science and technology.

This thought-provoking volume offers an update on current international IPR negotiations and includes case studies on software, computer chips, optoelectronics, and biotechnology—areas characterized by high development cost and easy reproducibility. The volume covers these and other issues:

• Modern economic theory as a basis for approaching international IPRs.
• U.S. intellectual property practices versus those in Japan, India, the European Community, and the developing and newly industrializing countries.
• Trends in science and technology and how they affect IPRs.
• Pros and cons of a uniform international IPRs regime versus a system reflecting national differences.

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Case study: How a global leader in biotechnology is advancing science and innovation

This BIOVIA customer is one of the world’s leading biotechnology companies, working to translate new ideas and discoveries into medicines for patients with serious illnesses. The company works to serve patients by transforming the promise of science and biotechnology into therapies that have the power to restore health or save lives. It strives to work collaboratively, and to quickly move scientific breakthroughs from the lab, through the clinic, and to the patient.

Challenge: connecting data silos and streamlining workflows

With nearly 2,000 scientists and twice as many instruments spread across multiple global locations, the customer managed eight electronic notebooks (ELN) systems and laboratory information management systems (LIMS), and faced a seemingly insurmountable task attempting to network and integrate such a large number of disparate systems. It also dealt with the constant risk of transcription errors, because data was manually transferred between systems; sometimes with Excel spreadsheets as the intermediate step. An immense amount of time was spent ensuring the validity and integrity of the data throughout the discovery and development process. Experimental data was further divided between small- and large-molecule divisions, with no way to cross-interrogate the information.

The customer’s challenge was to unify data collection and management across the different phases of early discovery, R&D, and clinical and commercial manufacturing. The scale and complexity of this challenge were enormous, completely changing how data is handled throughout all aspects of their organisation.

If the data identification could be unified, the data becomes smarter and self-aggregating, making it easier to locate and re-use and more meaningful for the scientists.

Solution: a holistic lab environment with BIOVIA ONE Lab

The customer aimed to build a flexible and interconnected system, tie different systems and components together, and make them collaborative. This holistic approach would remove complexity and streamline scientists’ daily workflows. Inspiration was drawn from the Internet of Things (IoT), where individual objects can self-identify based on well-defined parameters and a common language.  By properly parameterising and standardising experimental, instrumental, and process properties in the ONE Lab solution, new laboratory processes are easily created, as if working with building blocks. Scientists can perform these tasks without the need for a software developer. This way of thinking extends throughout the system in multiple applications.

When a new experiment is initiated, most parameters are pre-populated based on the chosen experiment, minimising data input by the scientist. The customer employs a comprehensive Data Lake to store and index all experimental results and metadata. ONE Lab feeds the Data Lake, along with other systems, and maintains a contextualised index of interconnected information. The system manages every piece of equipment, and each piece of data and metadata can now be accurately searched. As part of the ONE Lab solution, BIOVIA also helps the customer manage the delivery of results to scientists, delivering email notifications but not data; thus, the data is not divested from the system to an inbox.

To implement an admittedly ambitious project with such a large scope, the customer and BIOVIA worked to segment the project into smaller, more easily accomplished tasks and committed to the rapid release of further software iterations. An agile framework was adopted, which allows for flexibility in long-term goals, but also relies on clearly defining the goals for each software iteration.

Results: increased workflow efficiency, better data quality, and improved decision-making

With the majority of data entry and transcription now done automatically, the customer no longer needs to expend the same effort validating the integrity of their experimental data. Additionally, scientists no longer need multiple electronic systems to input and manage data throughout their experiments. The customer defined their data taxonomy based on the requirements for FDA submissions, meaning that the appropriate data is naturally aggregated together, saving time in submission preparations. However, the data itself is also smarter – a sample in the system identifies what processes it has already undergone, and what the appropriate next steps are. Scientists can find previous related results, including those which would have previously been hidden as ‘dark data’, resulting in a 60% increase in scientific and engineering analysis efficiency.

By consolidating the legacy LIMS and ELNs into a single deployment of BIOVIA ONE Lab, the customer was able to greatly increase the efficiency of its procedure development organisation. The project capacity increased from 30 to nearly 100 over the course of two years, with no increase in headcount. The efficiencies gained with ONE Lab resulted in more than $50m savings in operating expenses.

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A new portfolio model for biotech

Until recently, biotech companies tended to be founded with a focus on a single technology or biological pathway. An early exemplar of this was Genentech, founded in 1976 on the promise of recombinant DNA to generate proteins relevant for human health. 1 Sally Smith Hughes, Genentech: The Beginnings of Biotech , Chicago, IL: University of Chicago Press, 2011. Proof of concept came with the production of the hormone somatostatin in 1977, and the company made its synthetic insulin breakthrough in 1978, alleviating the need to harvest the protein from animal pancreases.

Over the past five years, however, an innovative business model has emerged for biotech. In it, a portfolio manager controls a set of companies spanning multiple technologies and disease areas. Instead of focusing on a single technology or in the traditional way, the portfolio manager uses a distinctive form of expertise—such as in fundraising, investment, venture creation, R&D, manufacturing, commercial management, leadership, and broad credibility—to start a suite of subsidiaries, each dedicated to an individual drug program.

That portfolio model is being pioneered by companies such as BridgeBio and Roivant Sciences. Each has a central management team with a distinctive skill set and a diversified portfolio of programs covering different therapeutic areas, indications, and technologies. The portfolio managers not only make investment decisions but also play critical roles in managing the portfolio companies, with varying levels of direct control over decision making in them. Similar portfolio models have been adopted by other companies, including Biohaven Pharmaceuticals, ElevateBio, Gossamer Bio, Nimbus Therapeutics, and PureTech. As of August 2020, such companies had raised approximately $6 billion in capital and had an estimated public- and private-market valuation of approximately $20 billion (Exhibit 1).

A number of venture-capital investors, such as Atlas Venture and Flagship Pioneering, share some similarities with the portfolio model for biotech because they engage in venture creation and early-stage-company management and may sometimes have some direct control. While there are both advantages and disadvantages to employing a portfolio model, the approach is gaining in use and reshaping the R&D landscape for biotech.

What are the advantages of the portfolio model?

In the traditional biotech-investment model, investors bet on a company’s technology or understanding of a disease. That can be a risky bet, with roughly one in 20 preclinical-stage biotech assets making it to launch. 2 Joseph A. DiMasi, Henry G. Grabowski, and Ronald W. Hansen, “Innovation in the pharmaceutical industry: New estimates of R&D costs,” Journal of Health Economics , May 2016, Volume 47, pp. 20–33, sciencedirect.com. In the portfolio model, investors put capital behind a central management team that offers a distinctive edge and harnesses its expertise to pursue many different bets. Investors can leave their capital invested in a management team over the long term. Individual entities within a portfolio may reach an IPO or be sold off, but the portfolio-management team continues.

The new model can also allow a portfolio manager to raise capital from a broader group of investors, such as those that seek exposure to early-stage biotech, lack the technical-due-diligence capabilities or risk appetite for individual bets, and wish to diversify their risk. Investors that believe in the success of an individual subsidiary can sometimes follow up with direct investments at a later stage. Investors without biotech or life-science expertise can also rely on the portfolio manager’s expertise, saving themselves the time of performing due diligence on each new play executed by the portfolio manager.

Companies within a portfolio each focus on a narrow program, often a single drug. Whereas large companies have multiple assets in development at any one time, each company in a portfolio can be dedicated to a single asset or small family of assets. With a team focused exclusively on one program that determines the success or failure of the whole business, governance and resource allocation are simplified. Asset valuation may be more accurate, too, since investors valuing early-stage companies tend to focus on the lead asset, with the rest of the pipeline sometimes being unfairly discounted.

The single-asset focus of individual portfolio companies also gives the portfolio managers flexibility in capital financing. Portfolio managers can raise funds centrally through private markets or IPOs. The same options are available for individual companies. Portfolio managers with Wall Street or venture-capital expertise have been particularly creative in their financing strategies.

The portfolio model is also highly attractive to employees. Portfolio companies have successfully recruited top biomedical personnel who sometimes have little previous experience into their executive roles because the resources and expertise of the portfolio managers’ central teams can complement the new executives’ deep biomedical expertise. Portfolio managers have also attracted a growing number of skilled professionals from Wall Street, consulting firms, and even the biopharma industry. The roles available to people with those backgrounds are attractive in responsibility, learning opportunities, and compensation.

A single-asset company structure creates clear financial incentives for employees because performance-related pay is directly tied to one program. Such a structure seems to appeal to senior talent seeking greater financial benefits with less bureaucratic complexity than they might see at a large pharma company. It also appeals to junior talent looking for start-up experience with some financial upside but less risk than in an independent venture. If a company should fail, its employees may be able to pursue other options in the portfolio.

Portfolios also offer flexibility in resourcing when general and administrative functions are managed centrally and a portfolio-management team can tap into relevant expertise. For example, a central team could bring in biopharma veterans from an operations or commercialization team to support subsidiaries in making critical decisions at inflection points. More broadly, the portfolio model allows early-stage R&D platforms to access scaled-up capabilities and resources such as procurement functions, lab software subscriptions, and leasing.

Finally, there is some emerging evidence that the portfolio model is an effective R&D machine. In 2020, BridgeBio reported more than 20 disclosed programs in its pipeline, more than ten investigational-new-drug applications submitted since 2015, 16 ongoing clinical trials, and two product launches expected in 2021. 3 R&D Day , BridgeBio, September 29, 2020, investor.bridgebio.com.

What are the disadvantages of the portfolio model?

Any portfolio could accumulate risk and give rise to systemic failure. Diversifying based on a central team’s strength is a challenge. A portfolio manager in cell-therapy manufacturing, say, would need to place bets across a range of manufacturing methods, cell types, indications, and locations. Even then, the potential for a portfolio-wide failure would remain. That is true of any specialism—especially, perhaps, those focused on a biology or disease hypothesis. For instance, a portfolio based on the amyloid hypothesis for Alzheimer’s disease would have failed.

Portfolios may also create inefficiencies by sustaining programs that should fail. Portfolio managers have more cash on hand than an individual biotech would, though not necessarily on a per-asset basis. That allows managers to fund programs for longer than may be prudent. Diligence and discipline in resource allocation are needed to prevent such waste. Similarly, too many maturing clinical programs can rapidly expand the capital needs of a portfolio, creating an urgent need for private or public fundraising.

Another potential downside is that, with a central portfolio-management team and distributed asset-leadership teams, decision-making clarity can suffer. Portfolio managers need to be clear as to where their CEOs’ autonomy begins and ends, who controls the allocation of centrally held resources, and how disputes should be resolved.

Finally, centralizing critical functions has both advantages and disadvantages. Centralized functions can bring economies of scope and scale and foster an environment centered on customer needs. That enables capability developers to focus on creating value and opens up a rich testing ground for refining and improving offerings, as seen in projects such as Roivant Science’s Datavant and VantAI. On the downside, a company has to compete for time and resources with other companies in the portfolio and may not get the service it needs from central functions. Moreover, some internal high-need use cases may be given lower priority than larger use cases for external customers. As portfolio managers work to create efficient core functions, they may also shortchange functions, such as pharmacovigilance and quality, that tend to mature in later-stage biotech companies.

What is driving the growth of portfolio-model use in biotech?

A traditional biopharma-innovation model is based on a specific technology, a biological insight, or both (for example, using exon-skipping technology to treat Duchenne muscular dystrophy). By contrast, the portfolio model in biotech is based on more abstract propositions, such as neglected monogenic diseases, abandoned drug arbitrage, expertise in developing and manufacturing cell therapies, and excellence in business development. Raising capital to pursue options like those requires a portfolio structure.

Venture creation is maturing as managers and investors build portfolios and the supply of talent grows. The new generation of flexible junior operators and investors makes for ideal employees for a portfolio manager. Such workers have the right training to dedicate time to a subsidiary, float it within a portfolio, and support an investing team.

Many early-stage biotech companies are keen to retain control and keep as much value for themselves as possible, rather than ceding ground to pharma companies. They represent growing shares of innovation and originators launching their own drugs (Exhibit 2).

A portfolio manager with access to pooled capital offers asset developers an alternative to the pharma-company route. When a portfolio manager acquires or seeds a new company, that company will likely have access to a larger pool of capital, which provides the originator with financing options outside pharma-company acquisition and IPO. Even so, pharma companies are likely to offer high premiums for strategic acquisitions, as well as compelling liquidity options, for biotech shareholders. Competition for assets looks likely to increase as portfolio managers enter the field. At the end of the day, portfolio managers will be also looking for liquidity, but with their ability to hold assets longer, they may give originators the option of holding their stakes deeper into development.

In spite of the downturn associated with the COVID-19 crisis, pharma companies still have significant capital at their disposal: the top ten companies have a near-record $116 billion in cash on hand (Exhibit 3). Meanwhile, venture-capital investors continue to invest at scale, spending $16.6 billion in 2019 across 866 pharma and biotech deals. 4 Venture Monitor: Q4 2019 , joint report by National Venture Capital Association and PitchBook Data, January 27, 2020, pitchbook.com. Private-equity investors have entered life sciences too. 5 Henny Sender, “How private equity overcame its fear of dabbling in drugs,” Financial Times , July 7, 2019, ft.com. All in all, plenty of investment dollars are available for biotech companies at various stages of development.

Innovative asset classes are in high demand, as seen in a number of large gene-therapy acquisitions in the past few years. AveXis was bought by Novartis for $8.7 billion, Spark Therapeutics by F. Hoffmann-La Roche for $4.8 billion, Audentes Therapeutics by Astellas Pharma for $3.0 billion, and Nightstar Therapeutics by Biogen for $0.8 billion. 6 “Astellas completes acquisition of Audentes Therapeutics,” Astellas Pharma, January 16, 2020, astellas.com; “Biogen completes acquisition of Nightstar Therapeutics for approximately $800 million,” Biogen, June 7, 2019, investors.biogen.com; “Spark Therapeutics enters into definitive merger agreement with Roche,” Spark Therapeutics, February 25, 2019, sparktx.com. Those deals were not only large, they also commanded high premiums. Both Audentes Therapeutics and Spark Therapeutics were acquired at a more than 100 percent premium over the previous day’s close. 7 Angus Liu, “The top 10 largest biopharma M&A deals in 2019,” FiercePharma, January 6, 2020, fiercepharma.com.

How could the portfolio model disrupt R&D in biotech?

The impact of using the portfolio model will differ for biotech companies, pharma companies, pharma-service providers, and investors.

For biotech companies, the portfolio model represents an alternative to an acquisition or IPO. Companies have traditionally funded maturing pipelines through a combination of public investment and industry partnerships. Portfolio models—with their access to leading talent from discovery to launch, shared services, and subsidiary-level focus on individual assets—may be able to shepherd a program all the way to commercialization without a pharma-company partner. Partnerships can still be pursued but primarily to reduce a portfolio manager’s risk exposure to an asset, rather than to satisfy a need for expertise or capital.

For pharma companies, the portfolio model represents a two-pronged threat. It could increase competition not only for innovative assets, as mentioned previously, but also for talent. As a preemptive move, pharma companies could emulate portfolio managers by introducing equity-based incentive structures for their own internal-asset teams to reward winners for the success of their programs. This would be similar to an internal version of the earnout or licensing models that pharma companies use for external partnerships. We see some early evidence of that change emerging—for example, when Bayer acquired BlueRock Therapeutics, Bayer left the cell therapy company operating as an independent company. 8 “Bayer acquires BlueRock Therapeutics to build leading position in cell therapy,” Bayer, August 8, 2019, media.bayer.com.

Competition among pharma-service providers could increase as central functions are externalized. Companies such as Datavant and VantAI, as well as those with a central manufacturing capability, such as ElevateBio, are emerging as important forces in the pharma-services landscape. In this way, a new wave of vendors could emerge to compete with existing contract research organizations, contract development-and-manufacturing organizations, and data and analytics specialists.

For investors, the portfolio model offers three benefits. First, the stability provided by portfolio-management teams may appeal to investors with long horizons, such as pension funds and sovereign wealth funds, that are seeking attractive ways to invest in a traditionally risky asset class. Second, the portfolio model expands the options for biotech investment beyond those offered by an asset- or platform-based approach, allowing investors to support otherwise unattainable areas, such as abandoned asset arbitrage. And third, those two benefits may attract new classes of investors that see exciting opportunities in an industry they have not previously considered investing in.

The portfolio model has emerged as an innovative solution to biotech financing and operations—and a way for a strong central team to maximize its impact. While portfolio managers have experienced some clinical-trial setbacks over the past few years, the world will learn more about the long-term success of the model in the next few years, with pipelines developing and regulatory and commercial success being tested. As companies mature and clinical-trial data flow in, the industry will be able to judge how well the portfolio model performs compared with others. If the signs are positive, changes in the dynamics of biotech investments and operations are likely to accelerate.

Joachim Bleys is a partner in McKinsey’s New York office, where Jonathan Coravos is a consultant and David Quigley is a senior partner; Edd Fleming is a senior partner in the Silicon Valley office.

The authors wish to thank Asli Aksu, Minyoung Kim, Angela McDonald, Joey Merrill, and Sheeba Soin for their contributions to this article.

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Epistemic Beliefs and Conceptual Understanding in Biotechnology: A Case Study

• Published: 27 November 2010
• Volume 42 , pages 353–371, ( 2012 )

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• Carina M. Rebello 1 ,
• Marcelle A. Siegel 1 , 2 ,
• Stephen B. Witzig 1 ,
• Sharyn K. Freyermuth 2 &
• Bruce A. McClure 2  

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The purpose of this investigation was to explore students’ epistemic beliefs and conceptual understanding of biotechnology. Epistemic beliefs can influence reasoning, how individuals evaluate information, and informed decision making abilities. These skills are important for an informed citizenry that will participate in debates regarding areas in science such as biotechnology. We report on an in-depth case study analysis of three undergraduate, non-science majors in a biotechnology course designed for non-biochemistry majors. We selected participants who performed above average and below average on the first in-class exam. Data from multiple sources—interviews, exams, and a concept instrument—were used to construct (a) individual profiles and (b) a cross-case analysis of our participants’ conceptual development and epistemic beliefs from two different theoretical perspectives—Women’s Ways of Knowing and the Reflective Judgment Model. Two independent trained researchers coded all case records independently for both theoretical perspectives, with resultant initial Cohen’s kappa values above .715 (substantial agreement), and then reached consensus on the codes. Results indicate that a student with more sophisticated epistemology demonstrated greater conceptual understandings at the end of the course than a student with less sophisticated epistemology, even though the latter performed higher initially. Also a student with a less sophisticated epistemology and low initial conceptual performance does not demonstrate gains in their overall conceptual understanding. Results suggest the need for instructional interventions fostering epistemological development of learners in order to facilitate their conceptual growth.

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Acknowledgements

We thank Brandon Messner and Shirley Kowalewski for their research assistance. This material is based on work supported by the National Science Foundation under Grant No. 0837021. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation (NSF).

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Rebello, C.M., Siegel, M.A., Witzig, S.B. et al. Epistemic Beliefs and Conceptual Understanding in Biotechnology: A Case Study. Res Sci Educ 42 , 353–371 (2012). https://doi.org/10.1007/s11165-010-9201-6

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5 Case Studies

• Introduction

Each of the following cases involves an important research tool in molecular biology, and each was chosen to illustrate a form of protection of intellectual property and a pattern of development involving both the public and the private sector. For each case, we present background material and a summary of the discussion that raised issues peculiar to the case.

The ideal strategies for the handling of intellectual property in molecular biology are not always immediately obvious, as these case studies illustrate. For most, final decisions have not been made about how access to these research tools will be controlled. Such decisions might be modified in response to both scientific and legal developments.

• Recombinant DNA: A Patented Research Tool, Nonexclusively Licensed With Low Fees

The Cohen-Boyer technology for recombinant DNA, often cited as the most-successful patent in university licensing, is actually three patents. One is a process patent for making molecular chimeras and two are product patents—one for proteins produced using recombinant prokaryote DNA and another for proteins from recombinant eukaryote DNA. Recombinant DNA, arguably the defining technique of modern molecular biology, is the founding technology of the biotechnology industry (Beardsley 1994). In 1976, Genentech became the first company to be based on this new technology and the first of the wave of biotechnology companies, which in fifteen years has grown from one to over 2000.

The first patent application was filed by Stanford University in November 1974 in the midst of much soul-searching on the part of the scientific community. Stanley Cohen and Herbert Boyer, who developed the technique together at Stanford and the University of California, San Francisco (UCSF), respectively, were initially hesitant to file the patent (Beardsley 1994). Several years of discussion involving the National Institutes of Health (NIH) and Congress followed. By 1978, NIH decided to support the patenting of recombinant DNA inventions by universities; in December 1980, the process patent for making molecular chimeras was issued. The product patent for prokaryotic DNA was issued in 1984. The patents were jointly awarded to Stanford and UCSF and shared with Herbert Boyer and Stanley Cohen. The first licensee signed agreements with Stanford on December 15, 1981. As of February 13, 1995, licensing agreements had generated $139 million in royalties, which have shown an exponential increase in value since their beginning. In 1990–1995 alone, the licensing fees earned $102 million.

This case has three key elements. First, the technology was inexpensive and easy to use; from a purely technical standpoint, there were only minimal impediments to widespread dissemination. Second, there were no alternative technologies. Third, the technology was critical and of broad importance to research in molecular biology.

The technology was developed in universities through publicly funded research. The strategy used to protect the value of the intellectual property was to make licenses inexpensive and attach minimal riders. The tremendous volume of sales made the patent very lucrative. Every molecular biologist uses this technology. However, not all inventions are as universally critical. Only a few university patents in the life sciences, such as warfarin and Vitamin D, have been even nearly as profitable as the Cohen-Boyer patent. Clearly, had this technology not been so pivotal for molecular biology or had an equally useful technology been available, the licenses would not have been sold so widely and the decision to license the technology might have met with more resistance.

The Cohen-Boyer patent is considered by many to be the classic model of technology transfer envisaged by supporters of the Bayh-Dole Act, which was intended to stimulate transfer of university-developed technology into the commercial sector. Ironically, it presents a different model of technology than that presumed by advocates of the Bayh-Dole act (for discussion, see chapter 3 ). Lita Nelsen, director of the Technology Licensing Office at the Massachusetts Institute of Technology (MIT), noted that the premise of the Bayh-Dole Act is that exclusivity is used to induce development and that universities should protect their intellectual property because without that protection, if everybody owns it, nobody invests in it. ''The most-successful patent in university licensing, in the entire history of university licensing, is the Cohen-Boyer pattern which is just the reverse. It is a nonexclusive license. It provides no incentive, just a small tax in the form of royalties on the exploitation of the technology.''

The biotechnology boom that followed the widespread dissemination of recombinant DNA techniques transformed the way universities manage intellectual property. It also fundamentally changed the financial environment and culture of biological research.

Nelsen described two ways in which this patent was so successful in fostering the aims of the Bayh-Dole Act. First, it got the attention of biologists by showing the advantages of protecting intellectual property. Stanford earned respectability for the venture by involving NIH and discussing in a public forum how this technology could be disseminated in a way that would not impede research. Second, it got the attention of university chancellors. They began to see that licensing, patenting, and technology transfer might have some financial benefits for the university. Nelsen commented that "that went a little too far. Everybody was waiting for $100 million per year out of their technology transfer offices. Most of them did not get it, and most of them are never going to get it." In the meantime, technology transfer managers developed more experience and became professionalized. They began to learn how to decide what to patent, how to market technology, and how to close deals at reasonable prices and with reasonable expectations. And industry learned how to negotiate licenses with universities.

Nelsen concluded that the whole biotechnology industry came out of the Cohen-Boyer patent, not only because Cohen-Boyer developed gene splicing, but because universities learned how to do biotechnology and early technology licensing—even if the first example was paradoxical.

The decision to negotiate nonexclusive, rather than exclusive, licenses was critical to the industry. If the technology had been licensed exclusively to one company and the entire recombinant DNA industry had been controlled by one company, the industry might never have developed. Alternatively, major pharmaceutical firms might have been motivated to commit their resources to challenging the validity of the patent.

Nelsen noted that at most major universities, it has become standard in industry-sponsored research agreements that the university will retain ownership of any resulting patents but almost without exception will grant the sponsor a first option to an exclusive license. With the increase in university-industry partnerships this applies to more research than in past years. Moreover, the Bayh-Dole Act encourages universities to grant exclusive licenses to companies even if the research was publically sponsored. But as the next case study shows, even when a company holds exclusive rights to a fundamental technology, it might choose to disseminate the technology broadly.

• PCR and TAQ Polymerase: A Patented Research Tool for Which Licensing Arrangements Were Controversial

Polymerase chain reaction (PCR) technology presents an interesting counterpoint to the Cohen-Boyer technology. Both are widely used innovations seen by many as critical for research in molecular biology. However, the licensing strategies for the two technologies have been quite different, and they were developed in different contexts.

PCR allows the specific and rapid amplification of targeted DNA or RNA sequences. Taq polymerase is the heat-stable DNA polymerase enzyme used in the amplification. PCR technology has had a profound impact on basic research not only because it makes many research tasks more efficient, in time and direct cost, but also because it has made feasible some experimental approaches that were not possible before the development of PCR. PCR allows the previously impossible analysis of genes in biological samples, such as assays of gene expression in individual cells, in specimens from ancient organisms, or in minute quantities of blood in forensic analysis.

In less than a decade, PCR has become a standard technique in almost every molecular biology laboratory, and its versatility as a research tool continues to expand. In 1989, Science chose Taq polymerase for its first "Molecule of The Year" award. Kary Mullis was the primary inventor of PCR, which he did when he worked at the Cetus Corporation. He won a Nobel Prize for his contributions merely 8 years after the first paper was published in 1985, which attests to its immediate and widely recognized impact. Tom Caskey, senior vice-president for research at Merck Research Laboratories and past-president of the Human Genome Organization, attributes much of the success of the Human Genome Project to PCR: "The fact is that, if we did not have free access to PCR as a research tool, the genome project really would be undoable. . . Rather than bragging about being ahead, we would be apologizing about being behind."

Whereas recombinant DNA technology resulted from a collaboration between university researchers whose immediate goal was to insert foreign genes into bacteria to study basic processes of gene replication, PCR was invented in a corporate environment with a specific application in mind—to improve diagnostics for human genetics. No one anticipated that it would so quickly become such a critical tool with such broad utility for basic research.

Molecular biology underwent considerable change during the decade between the development of recombinant DNA and PCR technologies (Blumenthal and others, 1986). The biotechnology industry emerged, laws governing intellectual property changed, there was a substantial increase in university-industry-government alliances, and university patenting in the life sciences increased tenfold (Blumenthal and others 1986, Henderson and others). There was virtually no controversy over whether such an important research tool should be patented and no quarrel with the principle of charging licensing fees to researchers. The controversy has been primarily over the amount of the royalty fees.

Cetus Corporation sold the PCR patent to Hoffman-LaRoche for $300 million in 1991. In setting the licensing terms for research use of PCR, Roche found itself in a very different position from Stanford with respect to the Cohen-Boyer patent. First, it was a business, selling products for use in the technology. That made it possible to provide rights to use the technology with the purchase of the products, rather than under direct license agreements, such as Stanford's. This product-license policy was instituted by Cetus, the original owner of the PCR patents. An initial proposal to the scientific community by the president of Cetus for reach-through royalties—royalties on second-generation products derived through use of PCR—was met with strong criticism. Ellen Daniell, director of licensing at Roche Molecular Systems, noted that the dismay caused by the proposal has continued to influence the scientific community's impression of Roche's policy.

Roche's licensing fees have met with cries of foul play from some scientists who claim that public welfare is jeopardized by Roche's goals. Nevertheless, most scientists recognize that Roche has the right to make business decisions about licensing its patents. The fact that Roche had paid Cetus $300 million for the portfolio of PCR patents led some observers to think that Roche intended to recoup its investment through licensing revenues, a point that Daniell disputed. She pointed out that Roche's business is the sale of products and that licensing revenues are far less than what would be needed to recoup the $300 million over a time period that would be relevant from a business viewpoint. Daniell listed Roche's three primary objectives in licensing technology:

• Expand and encourage the use of the technology.
• Derive financial return from use of the technology by others.
• Preserve the value of the intellectual property and the patents that were issued on it.

Roche has established different categories of licenses related to PCR, depending on the application and the users. They include research applications, such as the Human Genome Project, the discovery of new genes, and studies of gene expression; diagnostic applications, such as human in vitro diagnostics and the detection of disease-linked mutations; the production of large quantities of DNA; and the most extensive PCR licensing program, human diagnostic testing services. Licenses in the last-named category are very broad; there are no upfront fees or annual minimum royalties, and the licensees have options to obtain reagents outside Roche.

Discussion about access to PCR technology centered on the costs of Taq polymerase, rather than on the distribution of intellectual property rights. Tom Caskey's view was that "the company has behaved fantastically" with regard to allowing access to PCR technology for research purposes. Bernard Poiesz, professor of medicine at the State University of New York in Syracuse and director of the Central New York Regional Oncology Center, agreed that he knew of no other company that had done as well as Roche in making material available for research purposes. But he also argued that the price of Taq polymerase is too high and has slowed the progress of PCR products from the research laboratory to the marketplace. Poiesz stated that the diagnostic service licenses "are some of the highest royalty rates I have personally experienced." He cited the example of highly sensitive diagnostic tests for HIV RNA, which he said are too expensive for widespread use, largely because of the licensing fees charged by Roche. 1 Caskey felt that Roche should have expanded the market by licensing more companies to sell PCR-based diagnostic products and profited from the expansion of the market, rather than from the semiexclusivity that it has maintained.

Nor are all university researchers satisfied with their access to Taq polymerase. Ron Sederoff commented that—in contrast to the human genomics field, in which funding levels are much higher than for other fields of molecular biology—many academic researchers do not find easy access to the technology. Several workshop participants noted that the high cost Taq polymerase made many experiments impossible for them.

What is the effect of the Cetus-Roche licensing policy on small companies? Tom Gallegos, intellectual property counsel for Oncorpharm, a small biotechnology company, stated that most small companies cannot afford the fees charged by Roche. He noted that the entry fee for a company that wants to sell PCR-based products for certain fields other than diagnostics ranges from $100,000 to $500,000, with a royalty rate of 15%. By comparison, a company pays about $10,000 per year and a royalty fee of 0.5–10% for the Cohen-Boyer license. The effect is an inhibition of the development of PCR-related research tools, with consequent reductions or delays in the total royalty stream and possibly litigation.

Sidney Winter, professor of economics at the Wharton School of Business, suggested that in asking whether the price of some technology is too expensive, one should consider "compared with what?" Compared with licensing and royalty fees for Cohen-Boyer, PCR might seem excessive. If one imagines that the cost of the PCR patent were financed by a tax on the annual US health-care expenditure which was about $1 trillion in 1995 (Source: Congressional Budget Office), that tax would be roughly equal to 0.03% and might be a price worth paying for the advances made possible by PCR technology.

During the workshop, several people distinguished between research tools that are commercial products and tools that have little market value but are important tools for discovery. In the case of PCR, the research tool is both a commercial product and a discovery tool. As such, it raises questions. Are the PCR patents an example of valuable property that would have been widely disseminated in the absence of patent rights? Is PCR an example of a technology that has been more fully developed because of the existence of patent rights? Daniell stated that Roche has added considerable value to the technology, in part through the mechanism of patent rights. There was vigorous discussion and disagreement as to whether the licensing fees justify the value added by Roche.

• Protein and DNA Sequencing Instruments: Research Tools to Which Strong Patent Protection Promoted Broad Access

This case study was selected because it provides a clear example of how patent protection promoted the development and dissemination of research tools. By most standards, this would be considered a successful transfer of technology. The possibility of automated, highly sensitive DNA and protein sequencers was developed in the public sector by Leroy Hood's group at California Institute of Technology (Cal Tech). However, it was only with the help of substantial private investment that these research tools were widely disseminated.

The ability to synthesize and sequence proteins and DNA revolutionized molecular biology; automating these tasks promised to consolidate the revolution. Indeed much of the achievement of the Human Genome Project is attributable to the development of automated sequencing instruments, which greatly reduced the time and cost needed to sequence DNA. Because the effects of genes depend on the proteins that they encode, protein sequencing has been a key step in deciphering gene function. Until automated sequencing instruments were widely available, only a few laboratories had access to this technology.

The prototypes for these instruments were developed in Hood's laboratory during the years 1970–1986. Over a period of six or seven years, the team of scientists assembled by Hood increased the sensitivity of protein sequencing instruments by a factor of about 100. That transformed a difficult and uncertain task into one that could be reliably accomplished with the minute quantities of purified proteins that so often limited the scope of the analysis. Hood's laboratory was the first to sequence lymphokines, platelet-derived growth factor, and interferons. After those successes, he was approached by many scientists who asked why the technology could not be made available to the whole research community. Since the middle 1990s, the technology has become widely available.

The broad availability of sequencing technology is due, in no small part, to Hood's perseverance in the face of widespread skepticism. His 1980 manuscript that described, for the first time, automated DNA sequencing was delayed by the journal Nature on the grounds that this technology sounded like "idle speculation." Hood wrote three or four proposals to NIH and the National Science Foundation but was unable to obtain funding for his instrumentation work. The bulk of the support for this technology came from the private sector, and even then companies were reluctant to invest in developing the sequencing instrumentation. He approached nineteen companies, all of which declined to support the development of the sequencers. Eventually, he obtained funding from Applied Biosystems (ABI), but even this support required difficult negotiations between Cal Tech and ABI. ABI insisted on, and received, an exclusive license. As Hood told it, the argument that convinced Cal Tech to support the arrangement was that "if the scientific community wants these instruments, it is our moral obligation to make them commercially available."

At the time of this workshop, ABI had sold more than 3,000 DNA sequencers and more than 1,000 protein sequencers worldwide (although some elements of the technology, such as peptide synthesis, were not protected by patents, most of the instrumentation was patented by ABI). Sequencing facilities that serve multiple investigators are now standard features at research universities. That is not to say that licensing of this technology has been without controversy. Cal Tech licensed the technology to ABI with the stipulation that ABI would sublicense it under what Cal Tech considered reasonable terms. A number of companies have argued that ABI's terms are not reasonable. As with PCR, the situation is complicated in that the primary licensee claims that its license fees reflect what it needs to charge to earn a reasonable return on its investment in developing the technology.

ABI is clearly the leader in the world market for DNA sequencers. But other companies, such as Pharmacia and LI-COR, have important market shares. LI-COR has established a niche in the market with its infrared fluorescence DNA sequencer; infrared light has low background fluorescence, which allows for the development of more robust, solid-state instrumentation than is possible with other DNA sequencing technology. LI-COR is typical of many small biotechnology companies in its reliance on its patent portfolio. Harry Osterman, director of molecular biology at LI-COR, noted that "DNA sequencing is more than just an instrument, it is a system. To make a viable product, all the disparate pieces need to be integrated. That makes for a challenging intellectual property and licensing exercise, unless you have the internal funds to do everything. You require instrumentation, software, chemistry, and microbiology." Patent protection allows a small company to negotiate cross-licenses, which are critical in systems technologies, such as sequencing instrumentation. It can provide an opportunity that a small company would not otherwise have to compete in a market.

One might argue that patent protection served both the large company (ABI) and the small company (LI-COR) in bringing their sequencing technology to the market. In the case of ABI, patent protection afforded them the opportunity to develop a complex system of technology in an orderly and efficient manner, as proposed by the prospect development theory presented by Richard Nelson in chapter 3 . In the case of LI-COR, patent protection of sequencing systems enabled it to negotiate the cross-licenses needed to develop its product fully. In both cases, private support has driven the development and dissemination of a research tool. The public and private sectors seem to have gained equally.

• Research Tools in Drug Discovery: Intellectual Property Protection for Complex Biological Systems

Research tools in drug discovery present an example of the difficulties in protecting intellectual property when technologies involve complex biological systems that lack discrete borders. The information is often broad and refers to general categories of matter, such as a class of neural receptors, rather than finite entities, such as the human genome, or specific techniques, such as PCR or recombinant DNA techniques. Controversies have emerged over broad patents, which some see as stifling research on and development of useful drugs and others see as critical to the translation of research knowledge into useful products. The focus of the discussion in the workshop was the tension between the dependence of small biotechnology companies on patents and the difficulties created when research on complex biological systems is restricted by a thicket of patents on individual components of the systems.

When research on a complex system—for example, receptor biology or immunology—requires obtaining multiple licenses on individual components of the system, the potential for paying substantial royalty fees on any useful application derived from that product can be daunting. "Royalty stacking" can swamp the development costs of some therapies to the point where development is not economically feasible. That is a problem particularly in gene therapy, where the most promising advances now are related to rare genetic diseases that present small markets.

Bennett Shapiro, vice-president for worldwide basic research at Merck Research Laboratories, argued that the central issue is not about patenting, but about access, about encouraging the progress of biomedical research. Problems can arise when access to related components of biological systems is blocked. For example, schizophrenia is often treated with compounds that suppress dopaminergic neurotransmission. Many such compounds, for example haloperidol, act nonspecificially and suppress the entire family of dopamine receptors. People who take those compounds for schizophrenia often develop other disorders some of which resemble Parkinson's disease, another disease involving the dopamine system. A rational approach to discovery of improved schizophrenia drugs would be to target specific dopamine receptors. But if different companies hold patents on different receptors, the first step on the path to an important and much needed therapeutic advance can be blocked.

Shapiro commented that when only one company starts along the path of discovering a particular type of drug, its chance of discovering it is very low. Merck supports only a tiny fraction of total biomedical research, and it benefits enormously from research going on elsewhere in the world. It is in Merck's interest to share the results of its research with the understanding that they can be even more useful if placed in the pool of worldwide research resources.

It is interesting to compare that perspective on drug discovery with the early history of radio and television, other examples of complex systems of which many components were patented individually. In chapter 3 , Richard Nelson noted that it was not until cross-licensing practices became widespread in the early development of radio and television that important advances that enabled broad access to the technology took place. When the intellectual property was sequestered in the hands of a few companies, the entire electronics industry remained sluggish. Of course, the progress of the industry overall must be balanced by the financial needs of individual companies. Shapiro noted that Merck has felt the need to become more energetic about patenting than it was years ago. For example, carrageenan footpad assays were used to develop non-steroidal anti-inflammatory drugs. The assays were in the public domain, and many companies used them to develop new drugs. Today, Merck would patent such an assay and use its patent position to trade with other companies for access to other research tools.

James Wilson, director of the Institute for Human Gene Therapy at the University of Pennsylvania, described his experience with the different ways in which patents on research tools are used. One is to block others from using the tools—to protect one's proprietary use—which he did not see as economical. Genetic therapy patents might not generate enough financial return to offset the investment costs. Wilson also suggested that genetic therapy patent files are only going to waste money in lawsuits brought against those patents. Second is to generate revenues for universities to support their infrastructures, although, as Lita Nelsen noted, most universities are not likely to earn much from patent revenues. The third is to barter so as to continue development without creating an economic disadvantage.

Like previous panelists, Larry Respess of Ligand Pharmaceuticals, argued that the chances of survival of a small biotechnology company would be slight without patents. He noted that the biotechnology industry is composed of small companies that have grown through venture capital and public offerings and that finance research through equity, not product revenues. The goal is to develop products and then evolve into an independent company.

Wilson also pointed to a dramatic increase over the last two to three years in the difficulty in transferring material between universities. Nelsen emphasized that university technology transfer managers are still learning. And many decisions of the US Patent and Trademark Office (PTO) are controversial and under close scrutiny by those charged with managing intellectual property.

In commenting that "it is hard to know what the proprietary landscape is going to be, but it will be complex, whatever it is," Wilson summarized many of the workshop participants' comments.

Changes in Biotechnology Strategies

Respess discussed how R & D strategies for biotechnology have changed over the last twenty years. The biotechnology industry was born in about 1975 by Genentech, and most of the companies that followed Genentech pursued a similar strategy. Their objective was to produce and sell therapeutically-active large protein molecules, which was made possible by the availability of the Cohen-Boyer technology. The strategy was to discover and try to patent a gene for such a protein; it was hoped that the gene could be used to express abundant quantities of the protein. Some of the early examples are insulin, growth hormone, erythropoietin, and the interferons.

The advantages of that approach were that everyone knew that the products would be useful and that recombinant techniques were efficient for production, compared with earlier techniques of extraction from cadavers and tissue. Another advantage—albeit not from a scientific viewpoint—is that it is easy to sell to the investment community; it was a simple, easily understood model. Respess described the raising of capital in the early days of biotechnology as "unbelievable. You could found a company and, within a relatively short time, go public and raise many millions of dollars." However, those days are now past, in part because of the intrinsic limitation of large protein molecules: they are expensive to produce and to deliver to patients (they must be delivered by injection). The drug targets that are easy to identify have already been exploited.

A newer biopharmaceutical strategy emerged—not to discover large proteins or other large-molecule drugs, but to find other therapeutically active small molecules. These are the traditional targets of pharmaceutical research, but a biopharmaceutical company uses modern biotechnology and insights from molecular biology to get to the ultimate target product more quickly and efficiently. This approach has several advantages. The drugs are conventional and can typically be given orally, as well as by injection; they are relatively easy to manufacture; and the Food and Drug Administration is very familiar with such drugs, which makes it easier to get a new drug approved. The problem from a small company's perspective, however, is that it takes a very expensive infrastructure. Ultimately, synthesizing small molecules means making many molecules, and medicinal chemistry is very expensive. You have a tool, but you do not have any products in hand.

• Expressed-Sequence Tags (ESTs): Three Models for Disseminating Unpatented Research Tools

An expressed-sequence tag (EST) is part of a sequence from a cDNA clone that corresponds to an mRNA (Adams and others 1991). It can be used to identify an expressed gene and as a sequence-tagged site marker to locate that gene on a physical map of the genome. In 1991 and 1992, NIH filed patent applications for 6,800 ESTs and for the rapid sequencing method developed by Craig Venter, who was a scientist at NIH. The PTO rejected NIH's application and when Harold Varmus became director of NIH, he decided not to appeal. But controversy caused by the initial patent application continued. In 1992, Venter left NIH to form The Institute for Genome Research (TIGR), a nonprofit company, and William Haseltine joined the newly established private company, Human Genome Sciences (HGS), a for-profit company that initially provided almost all of TIGR's funding. The focus of the controversy then moved from the public to the private sector, and it changed from an issue about patenting research tools to an issue of access to unpatented research tools. Like many other research tools, ESTs fill different roles and some of the controversy has involved disputes of the relative importance of ESTs for uses other than research.

Two factors have contributed to the controversy over intellectual property issues in this particular setting. First is the perception that some of the participants have been staking out intellectual property claims that extend beyond their actual achievements to include discoveries yet to be made by others. There is no question that ESTs constitute a powerful research tool. Questions about the patenting of ESTs have focused on the criteria of utility. ESTs are of limited value without substantial and nonobvious development. Initially a public institution, NIH, proposed to patent discoveries that both scientists and some representatives of industry felt belonged in the public domain. More recently a private institution, Merck, has assumed the quasigovernment task of sponsoring a university-based effort to place information into the public domain. While other private companies have provided funds for public sector research, such as in the Sandoz-Scripps agreement, these efforts have not been with the expressed purpose of putting information into the public domain.

This is a particularly interesting case study, in part because it began as a controversy over patents—over what could be patented, what should be patented and what would be the effect of patenting. It has evolved into a controversy over the dissemination of unpatented information and the terms on which that information will be made available.

Different firms have taken different approaches to the dissemination of these unpatented research tools, thus providing a natural experiment with which to study three models for disseminating the same sort of information. The models all arose in the private sector, and we can assume that although each firm adopted a different strategy, they had the same ultimate goal of maximizing the value that they could obtain from the information. Merck has put the information in the public domain, Human Genome Sciences (HGS) initially adopted an exclusive-licensing model, and Incyte adopted a broad licensing approach of offering nonexclusive licenses to its database to as many firms as would sign up. Putting information in the public domain limits opportunities to exploit it as a trade secret by controlling access to it. Patents, or the patent applications of private database owners, potentially limit the ability to use the information that is in the public domain if any patent rights are ultimately obtained.

• HGS. The strategy of HGS has been to form a major partnership with the pharmaceutical firm SmithKline Beecham (SKB) 2 , with which it agreed to provide a three year exclusive license to its EST database. SKB has sublicensed its rights to a major Japanese pharmaceutical company, Takeda Chemical, Ltd., and HGS also has 200 restricted-licensing arrangements with university researchers. The TIGR database contains a limited portion of the data created by HGS and all of the data created by TIGR before April 1, 1994 which is when TIGR stopped work on human cDNAs. TIGR provides two levels of access to its EST databases. At the first level, an investigator is allowed access to sequences that are owned by HGS that overlap or are identical with sequences already in the public domain and for which public databases are available. At the second level, investigators are allowed access to about 70,000 sequences that are not listed in the publicly available databases (Genbank or the European databases). To obtain the second level, an investigator must agree to disclose any invention that is made at any time after access is gained. Furthermore, HGS or the Institute for Genome Research (TIGR) must be allowed at least six months to negotiate a licensing agreement. 3 The public does not have access to the much larger HGS cDNA database.
• Merck. Merck is interested in using the information from ESTs for furthering its research efforts. The Merck Gene Index was established to fill a public-access gap and was developed in partnership with established genome centers. Sequencing is carried out at Washington University, and the data are handled at the Los Alamos Laboratories. The international databases are a direct source of the information. A biotechnology company has taken all the clones into its distribution system and will freely distribute its materials. Other institutions, such as TIGR and Genethon, have entered sequences into this public database.
• Incyte. Incyte's strategy has been to offer nonexclusive licenses to its database. As of the time of the workshop, six companies (Pfizer, Upjohn, Novo Nordisk, Hoechst, Abbott Laboratories, and Johnson & Johnson) have contributed in the aggregate, around $100 million, exclusive of contingency payments and royalty payments for access to this database. Even as the Merck data continue to be placed in the public domain, Incyte continues to sign up new subscribers; there seems to be continuing value for the subscribing firms to obtain access to one of the private databases. This strategy is interesting not only for what it says about the nonexclusive-licensing strategy but because this is the most current information as to the relative values of the private databases versus the public-domain database.

The Informational Value of ESTs Is Rudimentary

None of the participants disputed the value of ESTs as research information, but several commented on the rudimentary nature of the information. Having an EST in hand does not guarantee a practical strategy for obtaining the identity of the gene of which the EST is but a fragment. Furthermore, if the gene identified is unknown, there remains substantial investment in understanding its function. It has been successfully accomplished in many cases, and many specific strategies have been developed over the years for approaching this task. Nonetheless, it remains fraught with uncertainty. In 1995 the Human Genome Organization (HUGO) issued a statement on ''Patenting of DNA sequences'' arguing that the nature of sequence information is so rudimentary that to limit access to it is to impede development of medical advances.

Several uses have been suggested for genes and gene fragments to claim utility requirement for patent protections. They include the use of genes or gene fragments for categorizing, mapping, tissue typing, forensic identification, antibody production, or locating gene regions associated with genetic disease. However, each of those suggested uses may not be carried out without considerable further effort and additional biological information that is not inherent in the sequence alone. Many of the workshop participants concurred with the HUGO statement that without databases to provide further information, the informational value of ESTs themselves is very limited.

William Haseltine, CEO of HGS, noted that patent applications filed by HGS for ESTs involve considerably more than simply identification of the gene fragments and involve information about the stage of development and tissue type in which those genes are expressed. He further commented that the importance of the EST database is not simply that the fragments are identified, but that the database itself provides a high level of information.

The Value of ESTs Could Be Reduced by Limiting Access

Many of the workshop participants echoed the HUGO statement of concern that "the patenting of partial and uncharacterized cDNA sequences will reward those who make routine discoveries but penalize those who determine biological function or application. Such an outcome would impede the development of diagnostics and therapeutics." Both Harold Varmus and Gerald Rubin suggested that some researchers are likely to be discouraged from working on patented ESTs for fear that the patent holders would lay claim to their future discoveries, particularly discoveries about gene function, which are clearly of far greater biological utility than the identification of anonymous fragments and are more likely to have useful applications for human health.

Several previous reports have stated that research-tool claims should not be so broad as to block the discoveries outside of the patent (House of Commons Science and Technology Committee 1995, National Academies Policy Advisory Group 1995). No one at the workshop argued otherwise.

Fragile X syndrome, which is the most-common form of mental retardation, provides an example of how ESTs can contribute to human disease. The name refers to the fact that the X chromosome is easily broken. Caskey described how he, Steve Warren, and Ed Benustra used an EST to discover that the genetic defect involves multiple repeats of the nucleotide triple CGG. They went on to characterize the gene, and that provided the information necessary to develop what is now the most widely used diagnostic test for fragile X syndrome. When they made their discovery, the sequence information on the gene involved gave no information on function. It was investigators like Bob Nussbaum, and Dreyfus, at Philadelphia, who went on to identify the gene's function.

Caskey suggested that if speculative claims were permitted among a certain set of ESTs the rights of investigation to discover that gene would be denied.

James Sikella cited the example of the HIV patent, which is jointly held by the US and French governments. The patent has not been tightly restricted for investigational use. At the time of its filing, its sequence and functions were not described. Many discoveries about HIV have evolved from that sequence information, and Sikella noted that it would have been a disservice to the public if the sequence information had not been available as a general research tool.

The Human Genome Is Finite

As of this workshop, some 27,000–5,000 human genes were represented in the database. Humans are estimated to have about 80,000–100,000 genes, so that represents about one-fourth to almost half of the total. Tom Caskey predicted that as the database begins to be flooded with sequence information, there will be a higher stringency on patents and patent claims will be directed more toward functional aspects of the genes, rather than being primarily descriptive.

Caskey also described how the usefulness of the gene index has improved with the addition of more sequences. When the general location of a disease gene is known from genetic mapping, limited sequencing is an important strategy for finding the gene. By sampling the critical region, the small bits of sequences can be used to search for homologies in the gene sequence database. In this way, a previously sequenced gene or gene fragment can be identified as being located in a critical region. Such a gene is then a prime suspect for more detailed studies in those individuals carrying the disease. Initially, the success rate for this technique of finding disease genes in positionally cloned regions was only about 40%. As the size of the gene database increases, so does the success rate. This is, therefore, becoming a fast and facile method for identifying a disease gene in a critical region identified by genetic mapping.

Sikella suggested that the success of the Human Genome Project may be measured, in part, by how the knowledge that it generates benefits society. He emphasized the importance of making these benefits available in a cost-effective way.

The Advent of DNA Sequencing Presents Important Questions about Patentability

Leon Rosenberg commented that "although the debate seems to have cooled a bit, the issues surely have not been resolved." Tom Caskey of Merck and William Haseltine of HGS both commented that they have no quarrel with the current criteria for patents, but they express different views as how those criteria should be interpreted. Since the workshop, HGS has received patents on a number of ESTs with broader claims of utility than the initial EST patent applications filed by NIH in 1974. Whether this will influence the debate over ESTs is an open question. Caskey noted that after one has an EST, identifying the full length sequence cDNA is the obvious next step. And yet this rarely leads to precise knowledge of that gene's function. He predicted that the complete cDNA sequences might become the 1997 version of ESTs—that is, research tools which many people do not believe meets the full potential criteria of novelty, nonobviousness, and utility. Rosenberg suggested that "the biomedical research community has not yet truly grappled with the possibility that a large number of genes could be controlled by the rights of a relatively small number of parties who could not possibly hope to fully exploit their potential value." He suggested that if research tools are not made available to the scientific community and others, we will have to confront this issue directly, whether that requires changes in patent law or other equally drastic directions.

• Adams MD, Kelley JM, Gocayne JD, Dubnick M, Polymeropoulos MH, Xiao H, Merril CR, Wu A, Olde B, Moreno RF, Kerlavage AR, McCombie WR, Venter JC. 1991. Complementary DNA sequencing: expressed sequence tags and human genome project . Science 252(5013): 1651–1656. [ PubMed : 2047873 ]
• Beardsley T. 1994. Big time biology . Sci Amer. November: 90–97. [ PubMed : 7997867 ]
• House of Commons Science and Technology Committee. 1995. Human genetics: the science and its consequences , Vol.1. London, UK: House of Commons;
• National Academies Policy Advisory Group. 1995. Intellectual property and the academic community . London: The Royal Society. 65p.

Royalty rates refer to a charge based on the revenues earned by the licensee and are different from the up-front fees and annual minimum royalties referred to earlier. As a member of a not-for-profit institution, Poiesz was offered the choice between a 9% or 12% royalty rate, with the lower rate available to those who agreed to use Roche-manufactured DNA polymerase for their testing.

Takeda Chemical, Ltd., the largest Japanese pharmaceutical firm, is another partner. Since the workshop, HGS has directly licensed three other companies: Schering-Plough, Merck KGAA (a German company, not affiliated with US Merck), and Synthelabo (a French company).

After April 1, 1997, all of the original EST sequences in the HGS-TIGR databases completed by April 1994 will be publicly available with no restrictions.

• Cite this Page National Research Council (US). Intellectual Property Rights and the Dissemination of Research Tools in Molecular Biology: Summary of a Workshop Held at the National Academy of Sciences, February 15–16, 1996. Washington (DC): National Academies Press (US); 1997. 5, Case Studies.
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Field Evaluation of Transgenic Squash Containing Single or Multiple Virus Coat Protein Gene Constructs for Resistance to Cucumber Mosaic Virus, Watermelon Mosaic Virus 2, and Zucchini Yellow Mosaic Virus

• David M. Tricoll
• Kim J. Carney
• Hector D. Quemada

Resistance of Transgenic Hybrid Squash ZW-20 Expressing the Coat Protein Genes of Zucchini Yellow Mosaic Virus and Watermelon Mosaic Virus 2 to Mixed Infections by Both Potyviruses

• Dennis Gonsalves

Mammalian Cell Expression of Single–Chain Fv (sFv) Antibody Proteins and Their C–terminal Fusions with Interleukin–2 and Other Effector Domains

• Haimanti Dorai
• John E. McCartney
• Hermann Oppermann

Purification and Characterization of Microbially Expressed Neomycin Phosphotransferase II (NPTII) Protein and its Equivalence to the Plant Expressed Protein

• Roy L. Fuchs
• Robert A. Heeren
• Sharon A. Berberich

Safety Assessment of the Neomycin Phosphotransferase II (NPTII) Protein

• Joel E. Ream

Recombinant Human Thyroid Stimulating Hormone: Development of a Biotechnology Product for Detection of Metastatic Lesions of Thyroid Carcinoma

• Edward S. Cole
• Bruce M. Pratt

Production and Functional Characterization of a Recombinant Fragment of Von Willebrand Factor (vWF): An Antagonist to Platelet Receptor Gp Ib

• Christopher Prior
• Valeria Chu
• Michael Hrinda

Production of Human Interleukin-3 Using Industrial Microorganisms

• Rob W. van Leen
• Janny G. Bakhuis
• Gerard Wagemaker

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Case Study of the Biotechnology Industry in Medicine

Experimental Study Design: Research, Types of Design, Methods and Advantages

How to write a Manuscript: Components and Structure of Manuscript writing

Medical case report writing summarizes significant scientific findings that were overlooked or undetected in clinical trials. This can include an uncommon or unusual clinical condition, a previously unreported or undiagnosed disease, unique medication side effects or treatment response, and novel imaging modalities or diagnostic tests used to aid in disease identification. In general, a case report should be concise and focused, with the abstract, introduction, case description, and discussion serving as the primary components.

Case reports that are preciously prepared and examined with precaution play an essential part in the growth of medical case report writing knowledge and design and approach.

Five potential contributions to the defence of case report publication include:

• A new disease has been identified and described.
• Rare manifestations of a known disease are recognized.
• The discovery of a disease’s mechanisms
• Detection of harmful or favourable drug side effects (and other treatments)
• Medical auditing and education

Case Report Guidelines

CARE (Case Report) guidelines for systematic reporting of case reports were produced utilizing a consensus-based procedure. To write a solid case report, you must explain why and how a particular finding is noteworthy in the existing body of knowledge. Clinical case report writing practitioners can meet the need for transparency, clarity, and completeness of case reports by following the 13-item checklist. As a result, CARE guidelines have been endorsed by some biomedical journals. The checklist’s main components are the title, keywords, abstract, introduction, patient information, clinical case report findings, timeline, diagnostic assessment, therapeutic interventions, follow-up and outcomes, discussion, patient perspective, and informed consent.

Stages in Writing a Case Report:

Introduction.

Content should be concise, with no more than three paragraphs:

• Explain the case report.
• Include background details as well as relevant definitions.
• Describe the patient’s situation.

Patient’s Case Presentation

Ascertain that the patient’s case presentation has sufficient information for the reader to determine the case’s validity:

• Patient demographics (age, gender, height, weight, and so on)—avoid using patient identifiers (date of birth, initials).
• The patient’s grievances.
• Before admission, the patient’s current ailment and medical case report /family/social/medication history are.
• The name of each drug, as well as its strength, dose form, route, and administration dates.
• Completed diagnostic procedures that are relevant to and support the case, as well as their key findings.
• Histopathology, roentgenograms, electrocardiograms, skin symptoms, or anatomy photographs
• Consent from the patient and conformity to the institution’s policies.

The abstract should be no more than 350 words long. Abbreviations should be used sparingly, and references should not be cited in the abstract. The following sections must be included in the abstract:

Background: Why should the case be reported, and what makes it unique

Case presentation: A brief explanation of the patient’s clinical and demographic details, the diagnosis, interventions, and outcomes are included.

Conclusions: A brief review of the case report’s clinical study report significance or prospective implications.

Three to ten keywords that represent the article’s core material.

The context of the case report or study, its goals, and an overview of the current literature should be explained in the Background section.

Case Presentation

This part should include a description of the patient’s relevant demographic information, medical case report history, symptoms and signs, therapy or intervention, outcomes, and any other pertinent information.

Conclusions and Discussion

This section should go over the relevant existing literature and express the main conclusions, along with an explanation of their relevance or significance to the field.

List of abbreviations

If abbreviations are used in the text, they should be defined, and a list of abbreviations should be provided.

Declarations

Under the category ‘Declarations,’ all papers must include the following sections:

• Consent to participate and ethics approval
• Consent to be published.
• Data and supplies are readily available.
• There are competing interests.
• Contributions of the authors
• Acknowledgements.
• Information about the authors (optional).

Details on the information to be included in these sections can be found below.

Please include the headline and add Not applicable for any sections that are not relevant to your manuscript.

About Pubrica

Pubrica has a lot of experience writing a detailed clinical case report that includes a patient’s symptoms, signs, diagnosis, therapy, and follow-up. Case reports are a significant, timely, and relevant study design in advancing medical case report writing and scientific knowledge, particularly in uncommon diseases. Case studies demonstrate the decision-making process, allowing other doctors to apply lateral thinking to their problems. Case studies should serve as informative examples for those who may face similar issues.

pubrica-academy

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