There are not many weeks, not to say days when you cannot read something new about CRISPR. I have to admit I do not know much about it given my total incompetence in health related matters. But when I heard there was a battle around intellectual property between universities (see Bitter fight over CRISPR patent heats up for example) and that start-ups were already entering the field, to the point that one was already public and another one filing to be, my interest was aroused… So I had a look at 3 of the more visible companies, and you know what… I could build their cap. tables… here they are:

– Editas Medicine

– Intellia Therapeutics

– Crispr Therapeutics

What is worth noticing, at least for me? They are young companies (less than 3 years old. they have raised a lot of money, at least $50M. They have very reputable investors: Polaris, Third Rock & Flagship for Editas; Atlas & Orbimed for Intellia; and Versant, NEA, Abingworth & SROne for Crispr Therapeutics. the founders are alreday quite diluted as they all less own than 15% as a group in each. Additional comments welcome!

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.

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.

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

as well as royalties

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

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).

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.

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.

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 …

I do not know much about biotechnology (my background is IT). Though a start-up is a start-up, I always had the feeling that biotech was a different world. You often read that it easily takes ten years to develop a drug, so that biotech start-ups do not have any sales from products for even longer (with revenue coming only from R&D deals with big pharma). You also hear about going public through an IPO far before your product is on the market, something unusual in the IT world (except during the Internet bubble). Finally the financing needs from VCs seem to be much larger than in IT.

I have already written articles about this topic and you can find them under the tag biotech but I plan to write soon three new posts on the topic, related to recent readings and analysis:
– this post deals with my reading of Science Lessons – What the Business of Biotech Taught Me About Management by Gordon Binder, former CEO of Amgen & Philip Bashe.

– I will then give an update of cap. tables with 350+ companies. I will focus then on biotech firms.
– Finally, I should read soon another book, Genentech – the Beginnings of Biotech by Sally Smith Hughes. Hopefully it will be as good as Science Lessons. (And here is my synthesis, Part 3: Genentech.)

The Business of Biotech

Amgen is probably the biggest biotech firm today (with a market cap. around $100B in 2015). “The company debuted on Nasdaq stock exchange on June 17, 1983. Considering that Amgen didn’t have any products at the time, going public seemed premature to some observers. And it was; an IPO wasn’t in the original timetable at all. But our other sources of capital had shriveled up like foliage during Southern California’s dry season, leaving an initial public offering our only option.” [Page 6]

Amgen’s secret weapon

From the beginning, Amgen was a magnet for gifted, innovative men and women. How does an organization attract outstanding employees? […] Certainly we offered attractive salaries and benefits, and the stock options made available to every Amgen employee no doubt induced some folks to stay who otherwise might have sought opportunities elsewhere. As numerous studies have established, however, pay and perks aren’t what foster long-term employee loyalty. It’s something more profound, something that speaks to the very soul of a company. […] Because a company’s culture emerges from its values, we interviewed hundreds of staff members in all areas of Amgen to learn which values they believed constituted the core of that culture. Today it seems that every company under the sun (or under a cloud) has a values statement. Some are written by the CEO, and others are concocted by the public relations or human resource department. Sometimes they’re written by consultants who don’t even work there. More often than not, the statement doesn’t truly reflect the organizations values; it’s either a wish list of what the company aspires to be or a PR tool for impressing customers, suppliers, and investors. [Page 9]

As Amgen grew exponentially, we constantly wrestled with the same quandary that confronts most flourishing companies at some point: how to remain nimble when you’re no longer a small start-up. You do it by decentralizing power, of course, but also by establishing an entrepreneurial culture that embraces change and encourages innovation. For that to happen, management must empower its people and then support them 100 percent, because staffers do not offer ideas freely if they secretly believe they will be hung out to dry should their promising project flop. In an industry such as biotechnology, failures abound. Had Amgen not lived its principle “Employees must have the freedom to make mistakes,” we would not have survived. [Page 14]

Amgen’s financings

Amgen was incorporated on April 8, 1980. Then Bowes the cofounder and 1st investor “coaxed six venture-capitalist into putting up roughly $81,000 apiece in seed money.” [Page 18] George Rathmann became the CEO and only employee in the company. When the company needed a serious series A funding, Rathmann was convinced it needed much more than the typical $1M first round and looked for $15M. No VC would have agreed, so he convinced first corporations. Abbott invested $5M (which would be worth $700M in 1990). Tosco added $3.5M. And New Court (managed by Rothschild) would then invest $3M. The Series closed with $19.4M on January 23, 1981. Then the IPO brought $42M in 1983, but this was only another beginning as more public financings would follow: $35M in 1986 for the “secondary” and $120M for a third financing the next year.

Here is the cap. table of Amgen at IPO:

Though biotech start-ups have longer horizons that IT firms, the intensity of activities is very similar. Binder shows examples such as Amgen’s IPO (chapter 2), the discovery of EPO (chapter 4) and its FDA approval (chapter 5). There is however a major difference. Biotech is about science and research. “It’s fair to say that at many companies, if not most, sales and marketing dominate corporate strategizing; the scientific or creative end may be behind the wheel, but ultimately the sales-and-marketing people commandeer the road map, barking out directions from the passenger seat. Not so in the field of biotechnology and certainly not at Amgen where even the company’s location was chosen to attract first rate scientists. Our headquarters sat more or less equidistant to the three principal research centers in southern California: the University of California at Los Angeles (UCLA), the University of California at Santa Barbara (UCSB), and the California Institute of Technology (CalTech), in Pasadena”. [Pages 57-58]

Amgen’s partners

“Success is the ability to survive your mistakes.” George Rathman

Chapter 6 (Partnerships Made in Heaven – and That Other Place) is a must read. Binder explains how critical good and bad partners may be and again this is linked to values and ethics. Binder claims that managers are much more careful when they hire someone than when they sign a partnership.

“Our search for a corporate partner started at home. Much to our shock, not a single U.S. pharmaceutical firm showed interest. […] Abbott Laboratories, one of Amgen’s original investors, had the opportunity to be involved in the Epogen project. CEO and Chairman Bob Schoellhorn turned it down. He’d been influenced by Abbott’s chief chemist, who apparently didn’t think much of drugs based on large proteins. As we would discover, that bias was not unique to Abbott; in fact it dominated traditional pharma. One company’s representative informed us that his bosses were passing on Epogen because the opportunity was too small; their market research department predicted sales would never eclipse $50 million per year (For the record, the drug generates $10 billion in annual revenue. Some market research!).” [Page 126]

Their first partner would be Kirin, the Japanese beer company with which trust, transparency and little paper work helped in building a great partnership. This was not the case with Johnson & Johnson. “To this day, contempt for Amgen’s former partner runs so deep that many employees proudly proclaim their homes to be 100 percent “J&J free.” Considering that Johnson & Johnson and its many businesses sell more than one thousand products, from Band-Aids to Tylenol, that’s no small feat.” [Page 133]

Amgen also has academic partners: “Memorial Sloan-Kettering possessed a mixture of about two hundred proteins. But it didn’t have the technology to separate them. Amgen did. […Amgen] discovered the human gene that produces G-CSF, located on chromosome 17. Once isolated, the gene was cloned using the same process as for human EPO. 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]

Finally for now, here is Amgen growth curve – revenues & profits. When a biotech start-up is successful, the numbers are impressive…