Author Archives: Hervé Lebret

Global Entrepreneurship 2016 – Part 2: the microeconomic analysis of the Startup Playbook by Sam Altman

After Part1 about the global vision of Entrepreneurship in 2016, here is a “micro” analysis of what entrepreneurship is. I finished reading this report while on a transcontinental flight, where I watched recent movie The Martian with Matt Damon.

Not only is The Martian describing a story very similar to what being a CEO might be – lonely with a life and death situation (at least for the start-up) after each major decision, but that day, I also learnt the death of David Bowie. In that movie, you can listen to Starman… my humble tribute to a great artist.

Again Ycombinator produces an efficient and compelling document about start-ups and entrepreneurship. After Paul Graham’s blog and Sam Altman’s class at Stanford in 2014, here is his Startup Playbook. A short document “for people new to the world of startups. Most of this will not be new to people who have read a lot of what YC partners have written—the goal is to get it into one place.” Altman explains “So all you need is a great idea, a great team, a great product, and great execution. So easy! 😉 A must read which I summarize my way through shorter extracts:

startup_playbook

Friendly advice first
– Make something users love.
– A word of warning about choosing to start a startup: It sucks!
– On the other hand, starting a startup is not in fact very risky to your career.

A great idea (including a great market)
– Something explained clearly and concisely with a fast-growing potential.
– It’s easier to do something new and hard than something derivative and easy.
– The best ideas sound bad but are in fact good.

A great team
– Mediocre teams do not build great companies.
– A great founder characteristics include unstoppability, determination, formidability, and resourcefulness; intelligence and passion.
– Good founders have a number of seemingly contradictory traits such as rigidity and flexibility.

A great product
– A great product is the only way to grow long-term.
– “Do things that don’t scale” has rightfully become a mantra for startups.
– Iterate and adapt as you go.
PS: By the way, “product” includes all interactions a user has with the company. You need to offer great support, great sales interactions, etc.

A great execution
– You have to do it yourself — the fantasy of hiring an “experienced manager” to do all this work is both extremely prevalent and a graveyard for failed companies. You cannot outsource the work to someone else for a long time.
– Growth (as long as it is not “sell dollar bills for 90 cents” growth) solves all problems, and lack of growth is not solvable by anything but growth.
– Extreme internal transparency around metrics (and financials) is a good thing to do.

Focus and intensity
– The best founders are relentlessly focused on their product and growth. They don’t try to do everything—in fact, they say no a lot.
– While great founders don’t do many big projects, they do whatever they do very intensely. Great founders listen to all of the advice and then quickly make their own decisions.

Being a founder & CEO
– The CEO jobs: 1) set the vision and strategy for the company, 2) evangelize the company to everyone, 3) hire and manage the team, especially in areas where you yourself have gaps 4) raise money and make sure the company does not run out of money, and 5) set the execution quality bar.
– As I mentioned at the beginning, it’s an intense job. If you are successful, it will take over your life to a degree you cannot imagine—the company will be on your mind all the time. Extreme focus and extreme intensity means it’s not the best choice for work-life balance. You can have one other big thing—your family, doing lots of triathlons, whatever—but probably not much more than that.
– No first-time founder knows what he or she is doing. To the degree you understand that, and ask for help, you’ll be better off. It’s worth the time investment to learn to become a good leader and manager. The best way to do this is to find a mentor—reading books doesn’t seem to work as well.
Be persistent. A successful startup CEO is not giving up (although you don’t want to be obstinate beyond all reason either—this is another apparent contradiction, and a hard judgment call to make.)
Be optimistic. Although it’s possible that there is a great pessimistic CEO somewhere out in the world, I haven’t met him or her yet.

Additional advice

– Hiring: Don’t do it. Wait!
– Competition: 99% of startups die from suicide, not murder.
– Fundraising: Investors are looking for companies that are going to be really successful. The “really successful” part is important. If an investor believes you have a 100% chance of creating a $10 million company but almost no chance of building a larger company, he/she will still probably not invest. Always explain why you could be a huge success. . Many of the best companies have struggled with this, because the best companies so often look bad at the beginning (and they nearly always look unfashionable.) And remember that anything but “yes” is a “no”.
– Investors: Good investors really do add a lot of value. Bad investors detract a lot. Most investors fall in the middle and neither add nor detract. Great board members are one of the best outside forcing functions for a company.

All this again was extracted from Sam Altman’s Startup Playbook. Thanks to him for a great job! I must also thank one of my students (he will recognize himself) for mentioning that document to me…

Global Entrepreneurship 2016 – Part 1: the Macroeconomics

I just read two great reports about entrepreneurship. The first one is the Global Entrepreneurship Index 2016 (GEI). The second one is the Startup Playbook by Sam Altman (Ycombinator). Whereas the second one is about the micro features of entrepreneurship, the GEI is a worldwide macro-economic analysis. I will cover the Startup Playbook in the part 2 of these series of posts, so let me focus here in the GEI.

Global-Entrepreneurship-Index

What I found really interesting is that compared to the Global Innovation Index (GII) about which I always have doubts – I think it measures more the inputs necessary for innovation than the outputs – I feel much more comfortable with the criteria and results of the GEI. For example, the USA is number one which makes a lot of sense and Switzerland is #8. Switzerland is #1 in the GII which is some kind of a mystery to me. France and Israel are #10 and #21 in the GEI but #20 and #21 in the GII.

Global-Entrepreneurship-Index-USA-Isr-CH-FR

The 3 As of Entrepreneurship

So how is this measured? The authors define 3 framework conditions entrepreneurship: attitudes, abilities and aspirations.[Pages 26-27 of the document or 49-50 of the pdf]. They also define 14 related pillars [Pages 19-22 of the document or 42-45 of the pdf]

Entrepreneurial attitudes are societies’ attitudes toward entrepreneurship, which we define as a population’s general feelings about recognizing opportunities, knowing entrepreneurs personally, endowing entrepreneurs with high status, accepting the risks associated with business startups, and having the skills to launch a business successfully. The benchmark individuals are those who can recognize valuable business opportunities and have the skills to exploit them; who attach high status to entrepreneurs; who can bear and handle startup risks; who know other entrepreneurs personally (i.e., have a network or role models); and who can generate future entrepreneurial activities.

Moreover, these people can provide the cultural support, financial resources, and networking potential to those who are already entrepreneurs or want to start a business. Entrepreneurial attitudes are important because they express the general feeling of the population toward entrepreneurs and entrepreneurship. Countries need people who can recognize valuable business opportunities, and who perceive that they have the required skills to exploit these opportunities. Moreover, if national attitudes toward entrepreneurship are positive, it will generate cultural support, financial support, and networking benefits for those who want to start businesses.

Entrepreneurial abilities refer to the entrepreneurs’ characteristics and those of their businesses. Different types of entrepreneurial abilities can be distinguished within the realm of new business efforts. Creating businesses may vary by industry sector, the legal form of organization, and demographics—age, education, etc. We define entrepreneurial abilities as startups in the medium- or high-technology sectors that are initiated by educated entrepreneurs, and launched because of someone being motivated by an opportunity in an environment that is not overly competitive. In order to calculate the opportunity startup rate, we use the GEM TEA Opportunity Index. TEA captures new startups not only as the creation of new ventures but also as startups within existing businesses, such as a spinoff or other entrepreneurial effort. Differences in the quality of startups are quantified by the entrepreneur’s education level—that is, if they have a postsecondary education—and the uniqueness of the product or service as measured by the level of competition. Moreover, it is generally maintained that opportunity motivation is a sign of better planning, a more sophisticated strategy, and higher growth expectations than “necessity” motivation in startups.

Entrepreneurial aspiration reflects the quality aspects of startups and new businesses. Some people just hate their employer and want to be their own boss, while others want to create the next Microsoft. Entrepreneurial aspiration is defined as the early-stage entrepreneur’s effort to introduce new products and/or services, develop new production processes, penetrate foreign markets, substantially increase their company’s staff, and finance their business with formal and/or informal venture capital. Product and process innovation, internationalization, and high growth are considered the key characteristics of entrepreneurship. Here we added a finance variable to capture the informal and formal venture capital potential that is vital for innovative startups and high-growth firms.

Each of these three building blocks of entrepreneurship influences the other two. For example, entrepreneurial attitudes influence entrepreneurial abilities and entrepreneurial aspirations, while entrepreneurial aspirations and abilities also influence entrepreneurial attitudes.

GEI-Conditions

The 14 Pillars of Entrepreneurship

The pillars of entrepreneurship are many and complex. While a widely accepted definition of
entrepreneurship is lacking, there is general agreement that the concept has numerous dimensions. […] Considering all of these possibilities and limitations, we define entrepreneurship as “the dynamic, institutionally embedded interaction between entrepreneurial attitudes, entrepreneurial abilities, and entrepreneurial aspirations by individuals, which drives the allocation of resources through the creation and operation of new ventures.”

Entrepreneurial Attitudes Pillars

Pillar 1: Opportunity Perception. This pillar captures the potential “opportunity perception” of a population by considering the size of its country’s domestic market and level of urbanization. Within this pillar is the individual variable, Opportunity Recognition, which measures the percentage of the population that can identify good opportunities to start a business in the area where they live. However, the value of these opportunities also depends on the size of the market. The institutional variable Market Agglomeration consists of two smaller variables: the size of the domestic market (Domestic Market) and urbanization (Urbanization). The Urbanization variable is intended to capture which opportunities have better prospects in developed urban areas than they do in poorer rural areas.

Pillar 2: Startup Skills
. Launching a successful venture requires the potential entrepreneur to have the necessary startup skills. Skill Perception measures the percentage of the population who believe they have adequate startup skills. Most people in developing countries think they have the skills needed to start a business, but their skills usually were acquired through workplace trial and error in relatively simple business activities. In developed countries, business formation, operation, management, etc., requires skills that are acquired through formal education and training. Hence education, especially postsecondary education, plays a vital role in teaching and developing entrepreneurial skills.

Pillar 3: Risk Acceptance. Of the personal entrepreneurial traits, fear of failure is one of the most important obstacles to a startup.

Pillar 4: Networking. Networking combines an entrepreneur’s personal knowledge with their ability to use the Internet for business purposes. This combination serves as a proxy for networking, which is also an important ingredient of successful venture creation and entrepreneurship.

Pillar 5: Cultural Support. This pillar is a combined measure of how a country’s inhabitants view entrepreneurs in terms of status and career choice, and how the level of corruption in that country affects this view.

Entrepreneurial Abilities Pillars

Pillar 6: Opportunity Startup. This is a measure of startups by people who are motivated by opportunity but face regulatory constraints. An entrepreneur’s motivation for starting a business is an important signal of quality. Opportunity entrepreneurs are believed to be better prepared, to have superior skills, and to earn more than what we call necessity entrepreneurs.

Pillar 7: Technology Absorption. In the modern knowledge economy, information and communication technologies (ICT) play a crucial role in economic development. Not all sectors provide the same chances for businesses to survive and or their potential for growth. The Technology Level variable is a measure of the businesses that are in technology sectors.

Pillar 8: Human Capital. The prevalence of high-quality human capital is vitally important for ventures that are highly innovative and require an educated, experienced, and healthy workforce to continue to grow.

Pillar 9: Competition. Competition is a measure of a business’s product or market uniqueness, combined with the market power of existing businesses and business groups.

Entrepreneurial Aspirations Pillars

Pillar 10: Product Innovation. New products play a crucial role in the economy of all countries. New Product is a measure of a country’s potential to generate new products and to adopt or imitate existing products.

Pillar 11: Process Innovation. Applying and/or creating new technology is another important feature of businesses with high growth potential. New Tech is defined as the percentage of businesses whose principal underlying technology is less than five years old.

Pillar 12: High Growth. This is a combined measure of the percentage of high-growth businesses that intend to employ at least ten people and plan to grow more than 50 percent in five years (Gazelle variable) with business strategy sophistication (Business Strategy variable).

Pillar 13: Internationalization. Internationalization is believed to be a major determinant of growth. A widely applied proxy for internationalization is exporting.

Pillar 14: Risk Capital. The availability of risk finance, particularly equity rather than debt, is an essential precondition for fulfilling entrepreneurial aspirations that are beyond an individual entrepreneur’s personal financial resources.

The reason I really felt synchronized with the authors (congrats to Zoltán J. Ács, László Szerb, Erkko Autio for the great work!) is a final extract from pages 63-64 (86-87 of the pdf): they explain the challenges and related mistakes and describe better approaches.

Unfortunately, although high-growth entrepreneurship and entrepreneurial ecosystems are high on many policy agendas, there is fairly little understanding of how policy can foster them most effectively. Most entrepreneurship policy playbooks remain stuck with old world policy approaches, which focus on identifying and fixing “market failures” and “structural failures.” Such approaches, while effective in addressing well-specified market and structural failures, are hopelessly inadequate to deal with the complexities of entrepreneurial ecosystems.
A classic example of a market failure is the failure of businesses to invest in R&D. Because R&D is a risky and uncertain activity, many firms are tempted to wait, to let others to take the risk, and then quickly copy successful projects. But if everyone thought this way, no one would invest in R&D, and innovative activities would stagnate. Therefore, governments address this market failure by providing subsidies for R&D—in effect, participating in the downside risk while allowing firms to keep the upside returns.
In contrast to subsidizing specific activities, a structural failure policy would seek to build support services and structures that support new firm creation and growth. Examples of structural failure policies include, for example, the creation of science parks and business incubators to shelter and support startup ventures.
Both of these approaches fail to address the complexities of entrepreneurial ecosystems, which are too complex to allow easy identification of specific clean-cut market failures, such as insufficient investment in R&D. The “product” entrepreneurial ecosystems produce is innovative and high-growth new ventures. Creating high-growth new ventures is a far more complex undertaking than starting an R&D project. If we do not see a sufficient number of high-growth new ventures, where exactly is the market failure supposed to reside? The standard approach by governments, which is consistent with market failure thinking, is that there perhaps is not sufficient support funding available to start new, high-growth firms. However, as much as governments have provided subsidies to support new firm creation, the results have not been very encouraging.
Another major problem with both market failure and structural failure approaches is that they are top-down, where the policy maker analyzes, designs, and implements entrepreneurship policy. Top-down, however, is not a feasible approach in entrepreneurial ecosystems that consist of multiple independent stakeholders. In such situations, a policymaker cannot simply command and control, as you have no formal authority over ecosystem stakeholders. Instead, policymakers need to engage the various stakeholders and co-opt them as active participants and contributors to the policy intervention.
[…]
Entrepreneurial ecosystems are fundamentally interaction systems consisting of multiple, co-specialized, yet hierarchically independent stakeholders, many of which may not even know one another. Here, co-specialization means that different stakeholders play different roles—venture capitalists, research institutions, different supporting institutions, new ventures, established businesses, and so on. They offer complementary skills and services, and normally depend on others to accomplish their goals, which implies that team play is needed.
In the above, hierarchical independence means that there are no formal lines of command, unlike, say, within government agencies or industrial corporations. Everyone makes their own independent decisions and optimizes their own performance. Combined with co-specialization, this creates a mutual dependency dilemma: to accomplish your goals you must depend on others, yet you cannot tell others what to do. Cooperation is therefore required. This limits the usability of traditional top-down policies, which are usually implemented through formal chains of command (e.g., a government department designing a policy, which is then implemented by a government agency overseen by the department).
Also of relevance is the notion of interaction systems, which means that the stakeholders of entrepreneurial ecosystems “co-produce” their outputs, such as innovative high-growth new ventures. These outputs are coproduced through a myriad of usually uncoordinated interactions between hierarchically independent yet interdependent stakeholders. This combination of independence and interdependence makes coordination challenging.
In the GEI model, it is the entrepreneurs who drive the entrepreneurial trial-and-error dynamic. This means that entrepreneurs start new businesses to pursue opportunities that they themselves perceive. An entrepreneurial opportunity is simply a chance to make money through a new venture, such as producing and selling goods and services for profit. However, entrepreneurs can never tell in advance whether a given opportunity is real or not: the only way to validate an opportunity is to pursue it. In other words, entrepreneurs need to take risks: they need to access and mobilize resources (human, financial, physical, technological) before they can verify whether or not a profit can be made. This means, then, that not all entrepreneurial efforts will be successful, as some opportunities turn out to be mere mirages. In such cases, the budding entrepreneur will realize sooner or later that they are never going to make a profit, or that they could make more money doing something else. In such cases, the entrepreneur will abandon the current pursuit and do something else instead.
If, however, an entrepreneurial opportunity turns out to be real, the entrepreneurs will make more money pursuing that opportunity than doing something else, and they will continue to exploit it. The net outcome of this entrepreneurial trial-and-error dynamic, therefore, is the allocation of resources to productive uses. In other words, a healthy entrepreneurial dynamic within a given economy will drive total factor productivity, or the difference between inputs and outputs. The greater the total factor productivity, the greater the economy’s capacity to create new wealth.

The Challenges of Creating a Start-up

January is the month where we publish our start-up statistics at EPFL and when the media contact us to discuss the matter. I had the opportunity to share my views with Danny Baumann, from the AGEFI, and I have the feeling he gave a very good account of our exchange. Here it is:

Agefi

The EPF Lausanne has been creating, during the last ten years, on average fifteen start-ups per year. Hervé Lebret lists a few leads to follow.

DANNY BAUMANN

The numbers fell the day before yesterday (L’Agefi, January 6): Researchers at the Federal Institutes of Technology in Lausanne and Zurich have created 43 companies in 2015, including 18 in Lausanne. The Innovation Park of EPFL is growing year after year, with as a proof the 700 jobs created since its launch in 1991. Fintech, biotech, medtech are in the mouth of everyone, but how to successfully create and above all to perpetuate a start -up in the world in constant evolution that we know? There is obviously no quick fix, as explained by Hervé Lebret, innovation specialist and teacher at the EPFL.

The success of a start-up depends on countless parameters. These elements must be as the perfect alignment of planets for that success to occur. Random factors, such as chance, are part of this process. The EPFL provides financial support, eight and ten grants per year, the Innogrants. Launched in 2005 with the support of Lombard Odier, these Innogrants consist of a maximum of 100,000 francs in salary. This does not in any way guarantee the success of a start-up but is a great launching pad.

Hervé Lebret lists a few leads to follow. For starters, the overall vision is essential. Having an international goal rather than local. The future of a start-up must immediately be anticipated: it indeed reaches its maturity after five to seven years. “From that moment, either it is acquired by giants such as Google or Apple or it continues to develop via the equity markets. It rarely stays at the stage of SMEs with 20-30 employees”, adds Hervé Lebret. According to him, 90% to 99% of these young companies disappear within ten years.

Another major aspect: not being cautious about the market. “An entrepreneur with a start-up should keep in mind that his company should be constantly growing,” he continues. Being ambitious and trust your potential investors, in order to raise funds, even at the cost of losing some of her company’s control. A must for growth. On average, 100 million Swiss francs are invested annually from private funds in EPFL start-ups. But how to find investors? The award race is a great way to advertise its product. The first two years are rather of survival; it is at this point that the various awards are essential. “The prize is good, but after two years or so, do not forget to pass in growth mode,” he expressed. Many make the mistake of losing sight of the overall objective and thus remain too small in the market while the company development is vital.

A good recruitment is a major asset in the success. Then comes the question of wages to be paid. The newly recruited employees must be aware that the remuneration will be lower than in a large company. The stock options can be a good alternative to compensate for the difference in pay. Still remains the problem of the taxation of stock options which are still seen as an income even if they are paper only. It should be possible to find an agreement on a special status of “start-up” in the law. The issue has been debated for several years.

Other elements are still important for an entrepreneur such as flexibility, creating a dense network, or having mentors, and, this sounds obvious, have a passion for his product.

Macroeconomic factors also make their entrance. To name one, but essential, mainly in Switzerland, migration. Out of the 90 Innogrants distributed by EPFL since 2005, 75% of them have ended up in the hands of foreign entrepreneurs. And it’s not a matter of discrimination. Switzerland needs foreign brains. A long political debate.

For EPFL, creating start-ups, and related jobs, is a major asset. Not so much from a financial standpoint but rather for the image. Economically, revenues come from licenses granted (they receive dividends or royalties in exchange) to the various entities or from the sale of the start-ups, about 1% of the transaction value. [You may check again How much Equity Universities take in Start-ups from IP Licensing?] The image is much more noticeable. Getting the message of constant innovation, to the eyes of the world, is a vital point for EPFL and the country.

The case study of an ambitious start-up at EPFL.

L.E.S.S. Founders - Tissot and Rivier
Yann Tissot and Simon Rivier, co-fouders of L.E.S.S.

The young company L.E.S.S. (Light Efficient Systems) is the perfect example of a fast growing EPFL start-up. The optical fiber of the company helps in generating a new light system that does not leave indifferent the automotive or computer manufacturers. Yann Tissot, co-founder and CEO, received an EPFL Innogrant in 2011. With this investment, the start-up was founded in June 2012. From that time, ambition and passion of the young entrepreneur made the difference. Travelling around the world to make his product known and running the award race such as the Entrepreneurship Prize of the WA de Vigier Foundation, the Strategis Prize competition or the prize for second best Swiss start-up in 2014 [then the best one in 2015!]. Awards that enabled it to survive and to find investors. In April 2015, it raised a vital three million concluded with VI Partners, supervised by Alain Nicod, as well as from various business angels.
Today L.E.S.S. has nine employees and was close to reach one million in sales last year. The estimated income for 2016 will be of the order of several million francs. – (DB)

The business of Biotech – Part 4: Licensing

The business of biotech is very unique as my previous posts illustrated. Companies go public without any revenue or product; they are often times very small firms in part because they are science-based mostly with a lot of collaborations with universities. Finally, an interesting feature is the biotech is a licensing business. Start-ups seldom produce and sell drugs but license their intellectual property (IP) to large pharmaceuticals companies. They also themselves license IP from universities, where the early inventions are made and protected through patent applications.

One of the best-guarded secrets is the terms of such licenses. I have already published articles about the licensing conditions by universities to start-ups. See for example:
– June 2010: University licensing to start-ups – https://www.startup-book.com/2010/06/15/university-licensing-to-start-ups-part-2/
– November 2013: How much Equity Universities take in Start-ups from IP Licensing? – https://www.startup-book.com/2013/11/05/how-much-equity-universities-take-in-start-ups-from-ip-licensing/
– June 2015: Should universities get rich with their spin-offs? – https://www.startup-book.com/2015/06/09/should-universities-get-rich-with-their-spin-offs/

So I’d like to revisit the topic for biotech companies. In terms of equity, there is not much difference; you can read again the table below. But there is an additional term that I’ve seen less often in other fields. Royalties on sale are very much accepted because Genentech (part 3) and Amgen (part 1) defined the industry rules.

Uni-licenses-startups-2015

Again let me quote my previous articles:“[…] negotiated an agreement between Genentech and City of Hope that gave Genentech exclusive ownership of any and all patents based on the work and paid the medical center a 2 percent royalty on sales of products arising from the research.” [Page 57]

“For an upfront licensing fee of $500,000, Lilly got what it wanted: exclusive worldwide rights to manufacture and market human insulin using Genentech’s technology. Genentech was to receive 6 percent royalties and City of Hope 2 percent royalties on product sales.” [Page 94] Perkins believed that the 8 percent royalty rate was unusually high, at a time when royalties on pharmaceutical products were along the lines of 3 or 4 percent. “It was kind of exorbitant royalty, but we agreed anyway – Lilly was anxious to be first (with human insulin). […]The big company – small company template that Genentech and Lilly promulgated in molecular biology would become a prominent organizational form in a coming biotechnology industry.[Page 97]

“Memorial Sloan-Kettering had filed a weak patent, not knowing what it actually had. Therefore, said my general counsel, Amgen was legally free to process on its own, without paying a royalty to MSKCC. That didn’t seem ethical to me; without Sloan-Kettering, we wouldn’t have stumbled across filgrastim (Neupogen’s generic name). We negotiated a license with a modest royalty.” [Pages 143-44]

Another interesting source of information is KUL (Katholieke Universiteit Leuven) in Belgium and its spin-offs Thormbogenetics and Tibotec. KUL has a long history of licensing with its R&D arm (LRD) founded in 1972. Here are examples of licenses.

KUL-LRD-Licensing

One particular example is the Genentech-Thromobogenetics-KUL relationships with license terms as follows:
Genentech-LRD-Thrombogenetics

as well as royalties
Genentech-LRD-Thrombogenetics-payments

All this comes from http://www.seii.org/seii/documents_seii/archives/colloques/2012-10-12_5_TG%20NV%20from%20lab%20to%20company-COLLEN.pdf

So what is a fair deal? I do not know. If you check the footnotes in the table above, you can see again a 2-4 % royalty range. So let me finish with a text I found many years ago:
– A raw idea is worth virtually nothing, due to an astronomical risk factor
– A patent pending with a strong business plan may be worth 1 %
– An issued patent may be worth 2 %
– A patent with a prototype, such as a pharmaceutical with pre-clinical testing may be worth 2-3 %
– A pharmaceutical with clinical trials may be worth 3-4 %
– A proven drug with FDA approval may be worth 5-7 %
– A drug with market share, such as one pharma. distributing through another, may be worth 8-10%
Ref: Royalty Rates for Licensing Intellectual Property by Russell Parr

The business of biotech – Part 3: Genentech

I should have begun with Genentech this series of posts about Biotech (see part 1: Amgen or part 2 about more general stats). Genentech was not the first biotech start-up, it was Cetus, but Genentech was really the one which launched and defined this industry. All this really began with the Cohen Boyer collaboration. Genentech would have loved to get an exclusive license on their patent about recombinant DNA, but the universities could not agree for business as well as political reasons. Genentech was an unknown little start-up and genetic engineering a very sensitive topic at the time. Swanson had tried even to offer shares to Stanford and UCSF (the equivalent of 5% of the existing shares at the time).

Please note I already wrote about Genentech here in Bob Swanson & Herbert Boyer: Genentech. But this new post follows my reading of Genentech – The Beginnings of Biotech by Sally Smith Hughes.

Genentech-the_beginnings_of_biotech

Chronology
– November 1972 – Meeting of Cohen and Boyer at aconference in Hawaii
– March 1973: First joint lab. experiments
– November 1973: Scientific publication
– November 4, 1974: Patent filing
– May 1975: Cohen becomes an advisor for Cetus
– January 1976: Meeting between Swanson and Boyer
– April 7, 1976: Genentech foundation
– August 1878: first insulin produced
– Q2 1979: 4 research projects with Hoffmann – La Roche (interferon), Monsanto (animal growth hormone), Institut Mérieux (hepatitis B vaccine) and an internal one (thymosin).
– July 1979: first human growth hormone
– October 1982: FDA approval of Genentech insulin produced
– October 1985: FDA approval of human growth hormone

I have to admit I had never heard of the Bancroft Library’s website (http://bancroft.berkeley.edu/ROHO/projects/biosci) for the Program in Bioscience and Biotechnology Studies, “which centerpiece is a continually expanding oral history collection on bioscience and biotechnology [with ] in-depth, fully searchable interviews with basic biological scientists from numerous disciplines; with scientists, executives, attorneys, and others from the biotechnology industry.”

The invention of new research and business practices over a very short period

Swanson was captivated: “This idea [of genetic engineering] is absolutely fantastic; it is revolutionary; it will change the world; it’s the most important thing I have ever heard.” [… But Swanson was nearly alone.] “Cetus was not alone in its hesitation regarding the industrial application of recombinant DNA technology. Pharmaceutical and chemical corporations, conservative institutions at heart, also had reservations.” [Page 32] “Whatever practical applications I could see for recombinant DNA… were five to ten years away, and, therefore, there was no rush to get started, from a scientific point of view.” [Page 32] “I always maintain” Boyer reminisced, “that the best attribute we had was our naïveté… I think if we had known about all the problems we were going to encounter, we would have thought twice about starting… Naïveté was the extra added ingredient in biotechnology.” [Page 36]

The book shows the importance of scientific collaborations. Not just Boyer at UCSF but for example with a hospital in Los Angeles. A license was signed with City of Hope Hospital with a 2% royalty on sales on products based on the licensed technology. “[…] negotiated an agreement between Genentech and City of Hope that gave Genentech exclusive ownership of any and all patents based on the work and paid the medical center a 2 percent royalty on sales of products arising from the research.” [Page 57]

Even if in 2000, City of Hope had received $285M in royalties, it was not happy with the outcome. After many trials, the California Supreme Court in 2008 awarded another $300M to City of Hope. So the book shows that these collaborations gave also much legal litigation. [Page 58]

In a few years, Genentech could synthesize somatostatin, insulin, human growth hormone and interferon. It is fascinating to read how intense, uncertain, stressful these years were for Swanson, Perkins, Boyer and the small group of Genentech employees and academic partners (Goeddel, Kleid, Heyneker, Seeburg, Riggs, Itakura, Crea), in part because of the emerging competition from other start-ups (Biogen, Chiron) and academic labs (Harvard, UCSF).

“On August 25, 1978 – four days after Goeddel’s insulin chain-joining feat – the two parties signed a multimillion-dollar, twenty-year research and development agreement. For an upfront licensing fee of $500,000, Lilly got what it wanted: exclusive worldwide rights to manufacture and market human insulin using Genentech’s technology. Genentech was to receive 6 percent royalties and City of Hope 2 percent royalties on product sales.” [Page 94] They managed to negotiate a contractual condition limiting Lilly’s use of Genentech’s engineered bacteria to the manufacture of recombinant insulin alone. The technology would remain Genentech’s property, or so they expected. As it turned out, the contract, and that clause in particular, became a basis for a prolonged litigation. In 1990, the courts awarded Genentech over $150 million in a decision determining that Lilly had violated the 1978 contract by using a component of Genentech’s insulin technology in making its own human growth hormone product. [Page 95] Perkins believed that the 8 percent royalty rate was unusually high, at a time when royalties on pharmaceutical products were along the lines of 3 or 4 percent. “It was kind of exorbitant royalty, but we agreed anyway – Lilly was anxious to be first (with human insulin)” […]The big company – small company template that Genentech and Lilly promulgated in molecular biology would become a prominent organizational form in a coming biotechnology industry. [Page 97]

The invention of a new culture

Young as Swanson was, he kept everyone focused on product-oriented research. He continued to have scant tolerance for spending time, effort, and money on research not tied directly to producing marketable products. “We were interested in making something usable that you could turn into a drug, inject in humans, take to clinical trials.” A few year before his premature death, Swanson remarked, “I think one of the things I did best in those days was to keep us very focused on making a product.“ His goal-directed management style differed markedly from that of Genentech’s close competitors. [Page 129]

But at the same time Boyer would guarantee a high quality research level by encouraging employees to write the best possible scientific articles. This guaranteed the reputation of Genentech in the academic world.

A culture was taking shape at Genentech that had no exact counterpart in industry or academia. The high-tech firms in Silicon Valley and along Route 128 in Massachusetts shared its emphasis on innovation, fast-moving research, and intellectual property creation and protection. But the electronics and computer industries, and every other industrial sector for that matter, lacked the close, significant, and sustained ties with university research that Genentech drew upon from the start and that continue to define the biotechnology industry of today. Virtually every element in the company’s research endeavor – from its scientists to its intellectual and technological foundations – had originated in decade upon decade of accumulated basic-science knowledge generated in academic labs. […] At Boyer’s insistence, the scientists were encouraged to publish and engage in the wide community of science. [Page 131]

But academic values had to accommodate corporate realities: at Swanson’s insistence, research was to lead to strong patents, marketable products, and profit. Genentech’s culture was in short a hybrid of academic values brought in line with commercial objectives and practices. [Page 132]

Swanson was the supportive but insistent slave driver, urging on employees beyond their perceived limits: “Bob wanted everything. He would say, If you don’t have more things on your plate than you can accomplish, then you’re not trying hard enough. He wanted you to have a large enough list that you couldn’t possibly get everything done, and yet he wanted you to try.” […] Fledging start-ups pitted against pharmaceutical giants could compete mainly by being more innovative, aggressive, and fleet of foot. Early Genentech had those attributes in spades. Swanson expected – demanded – a lot of everyone. His attitude was as Roberto Crea recalled: “Go get it; be there first; we have to beat everybody else… We were small, undercapitalized, and relatively unknown to the world. We had to perform better than anybody else to gain legitimacy in the new industry. Once we did, we wanted to maintain leadership.” […] As Perkins said “Bob would never be accused of lacking a sense of urgency. “ […] Even Ullrich, despite European discomfort with raucous American behavior, admitted to being seduced by Genentech’s unswervingly committed, can-do culture. [Page 133]

New exit strategies

Initially Kleiner thought Genentech would be acquired by a major pharma company. It was just a question of when. He approached Johnson and Johnson and “floated the idea of a purchase price of $80 million. The offer fell flat. Fred Middleton [Genentech’s VP of finance], present at the negotiations, speculated that J&J didn’t have “a clue about what to do with this [recombinant DNA] technology – certainly didn’t know what it was worth. They couldn’t fit it in a Band-Aid mold”. J&J executives were unsure how to value Genentech, there being no standard for comparison or history of earnings.” [Page 140]

Perkins and Swanson made one more attempt to sell Genentech. Late in 1979, Perkins, Swanson, Kiley and Middleton boarded a plane for Indianapolis to meet with Eli Lilly’s CEO and others in top management. Perkins suggested a selling price of $100 million. Middleton’s view is that Lilly was hamstrung by a conservative “not invented here” mentality, an opinion supported by the drug firm’s reputation for relying primarily on internal research and only reluctantly on outside contracts. The company’s technology was too novel, too experimental, too unconventional for a conservative pharmaceutical industry to adopt whole-heartedly. [Page 141]

When Genentech successfully developed interferon, a new opportunity happened. Interferon had been discovered in 1957 and thought to prevent virus infection. In November 1978, Swanson signed a confidential letter of intent with Hoffmann – La Roche and a formal agreement in January 1980. They were also lucky: “Heyneker and a colleague attended a scientific meeting in which the speaker – to everyone’s astonishment given the field’s intense competitiveness – projected a slide of a partial sequence of fibroblast interferon. They telephoned the information to Goeddel, who instantly relay the sequence order to Crea. […] Crea started to construct the required probes. […] Goeddel constructed a “library” of thousands upon thousands of bacterial cells, seeking ones with interferon gene. Using the partial sequence Pestka retrieved, Goeddel cloned full-length DNA sequences for both fibroblast and leukocyte interferon. […] In June 1980, after filing patent protection, Genentech announced the production in collaboration with Roche.” [Page 145] Genentech could consider going public and after another fight between Perkins and Swanson, Genentech decided to do so. Perkins had seen that the year 1980 was perfect for financing biotech companies through a public offering but Swanson saw the challenges this would mean for a young company with nearly no revenue or product.

New role models

The 1980-81 period would see the creation of a fleet of entrepreneurial biology-based companies – Amgen, Chiron, Calgene, Molecular Genetics, Integrated Genetics, and firms of a lesser note – all inspired by Genentech’s example of a new organizational model for biological and pharmaceutical research. Before the IPO window closed in 1983, eleven biotech companies in addition to Genentech and Cetus, had gone public*. […] But not only institutions were transformed. Genentech’s IPO transformed Herb Boyer, the small-town guy of blue-collar origins, into molecular biology’s first industrial multimillionaire. For admiring scientists laboring at meager academic salaries in relative obscurity, he became a conspicuous inspiration for their own research might be reoriented and their reputation enhanced. If unassuming Herb – just a guy from Pittsburgh, as a colleague observed – could found a successful company with all the rewards and renown that entailed, why couldn’t they? [Page 161]

*: According to one source, the companies staging IPO were Genetic Systems, Ribi Immunochem, Genome Therapeutics, Centocor, Bio-Technology General, California Biotechnology, Immunex, Amgen, Biogen, Chiron, and Immunomedics. (Robbins-Roth, From Alchemy To Ipo: The Business Of Biotechnology)

Following these three posts, I might write a fourth one about academic licenses in the biotechnology if and when I find some time…

When Entrepreneurship Meets Street Art

From time to time, I post articles not related to start-ups and entrepreneurship, but to other topics such as Street Art for example. Now comes the opportunity to join both thanks to Banksy. Indeed I can even relate both to migrants (who are a critical component of entrepreneurship). Banksy recently created the following Street Art work:

jobs_02-932x525

648x415_uvre-banksy-pres-jungle-calais

Banksy explained: “We’re often led to believe migration is a drain on the country’s resources, but Steve Jobs was the son of a Syrian migrant. Apple is the world’s most profitable company, it pays over $7 billion a year in taxes—and it only exists because they allowed in a young man from Homs.” Do I need to add about the importance of migrants in high-tech entrepreneurship? If yes, just read again AnnaLee Saxenian, Migration, Silicon Valley, and Entrepreneurship.

The business of biotech – Part 2

After a short analysis of Amgen through the book by Gordon Binder – Science Lessons – here’s a more statistical description of the world of biotech. I am considering a third part about Genentech as a conclusion of this group. For several years, I have been manually building the capitalization tables of start-ups in general thanks to their IPO documents. They probably contain errors as the exercise requires attention and accuracy, but I imagine that these errors are averaged. I have today more than 350 cases, which are published on Slideshare.

At the end of this document, I have added some synthetic data from which I extract the following. Remember that my sampling is done as I find new companies, so it is not totally random or statistically neutral …

Biotechnology represents a significant part of my data, I will return to this later. VC fundraising is not more important than in other areas, which may seem surprising but it is because a biotech start-up goes public in term of maturity well before the start-ups of other fields. Besides their sales level ($11M on average) is much lower than the others ($114M for the average of all). Also they count 71 employees against 521 for the full set. The Amgen example illustrated that an IPO in fact more a complementary VC round than a market validation. However the first round is much bigger, probably because of the resources required for the initial proof of concept. The (profits and) losses are similar to other areas (excluding software and internet).

BiotechDataFeatures

Now a small digression about the founders and the sharing of equity. They are much older (45 years) than average (38 years) and only come close the founders of medtech start-up. Probably because of the specific domain (length of academic curriculum and difficulties in inventing without a long experience). Another consequence of the dynamics of the field (including the uncertainties), the founders retain less equity at the IPO and investors get a larger share.

BiotechDataFeatures2

I now return to the biotech industry through its geography first and its timeline later. One known fact – the importance of the Boston area and the East Coast of the USA in general – and perhaps a surprise – the just as great importance of Silicon Valley and California more generally. It is often believed that the Boston area is the site of biotechnology, which is true with respect to other areas, but the West Coast is just as creative and entrepreneurial.

Cap_Tables_Fields_vs_Georaphy

Finally it would be wrong to believe that the Internet has removed biotech. The periods here represent the years of creation of the startups. Biotech is the main field (over one third) since the 2000’s whereas they accounted for less than a quarter before. Again remember that my sample is not statistically validated …

Cap_Tables_Fields_vs_Period

Cap_Tables_Fields_vs_Period_percent

Elon Musk and the Secret Sauce of Entrepreneurship (according to Tim Urban)

A student of mine (thanks 🙂 ) just sent me a link to amazingly great blog articles about Elon Musk. I had never of heard of the author, Tim Urban, and his blog Wait But Why but I will certainly follow his work from now on.

Tim Urban has written four articles about “the world’s most remarkable living entrepreneur.”
Part 1: Elon Musk: The World’s Raddest Man.
Part 2: How Tesla Will Change the World.
Part 3: How (and Why) SpaceX Will Colonize Mars.
Part 4: The Chef and the Cook: Musk’s Secret Sauce.
These 4 posts represent hundreds of pages if you print them. No kidding. I’ve read part 4 and it was a real (positive) shock. Tim Urban explains Musk’s entrepreneurial strengths. I just give some extracts but if must read it all (if you find the time).

“I think generally people’s thinking process is too bound by convention or analogy to prior experiences. It’s rare that people try to think of something on a first principles basis. They’ll say, “We’ll do that because it’s always been done that way.” Or they’ll not do it because “Well, nobody’s ever done that, so it must not be good.” But that’s just a ridiculous way to think. You have to build up the reasoning from the ground up —“from the first principles” is the phrase that’s used in physics. You look at the fundamentals and construct your reasoning from that, and then you see if you have a conclusion that works or doesn’t work, and it may or may not be different from what people have done in the past.” […] Musk is an impressive chef for sure, but what makes him such an extreme standout isn’t that he’s impressive — it’s that most of us aren’t chefs at all. […] “When I was a little kid, I was really scared of the dark. But then I came to understand, dark just means the absence of photons in the visible wavelength—400 to 700 nanometers. Then I thought, well it’s really silly to be afraid of a lack of photons. Then I wasn’t afraid of the dark anymore after that.” That’s just a kid chef assessing the actual facts of a situation and deciding that his fear was misplaced. As an adult, Musk said this: “Sometimes people fear starting a company too much. Really, what’s the worst that could go wrong? You’re not gonna starve to death, you’re not gonna die of exposure—what’s the worst that could go wrong?” Same quote, right? […] That’s Elon Musk’s secret sauce. Which is why the real story here isn’t Musk. It’s us. […] People believe thinking outside the box takes intelligence and creativity, but it’s mostly about independence. When you simply ignore the box and build your reasoning from scratch, whether you’re brilliant or not, you end up with a unique conclusion—one that may or may not fall within the box.

sjobs

Then Tim Urban quotes Steve Jobs from his famous speech at Stanford in 2005 (I think): “When you grow up, you tend to get told the world is the way it is and your life is just to live your life inside the world. Try not to bash into the walls too much. Try to have a nice family life, have fun, save a little money. That’s a very limited life. Life can be much broader once you discover one simple fact. And that is: Everything around you that you call life was made up by people that were no smarter than you. And you can change it, you can influence it, you can build your own things that other people can use. Once you learn that, you’ll never be the same again.”

Reich_Listen_little_man

And all this reminds me about an essay I mentioned in the conclusion of my book, an essay by Wilhelm Reich, the great psychoanalyst, who he wrote in 1945: “Listen, Little Man”. A small essay by the number of pages, a big one in the impact it creates. “I want to tell you something, Little Man; you lost the meaning of what is best inside yourself. You strangled it. You kill it wherever you find it inside others, inside your children, inside your wife, inside your husband, inside your father and inside your mother. You are little and you want to remain little.” The Little Man, it’s you, it’s me. The Little Man is afraid, he only dreams of normality; it is inside all of us. We hide under the umbrella of authority and do not see our freedom anymore. Nothing comes without effort, without risk, without failure sometimes. “You look for happiness, but you prefer security, even at the cost of your spinal cord, even at the cost of your life”.

Tim Urban is absolutely right and you need to read his piece about dogma and tribes. He made me think again of my readings of the great French philosopher Cynthia Fleury and how we need to balance the individuals and the groups and why democracy is a fragile jewel of societies…

PS: I totally forgot to mention a video that a colleague of mine (thanks to her now 🙂 ) mentioned a few days ago. BY one of these nice coincidences of life, it is precisely one of the arguments of Tim Urban about why some people are “cooks” (followers or incremental innovators) and others “chefs” (disruptive innovators). Enjoy!