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Tech Transfer Done Right

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By John S. MacNeil

Samuel Reich and Michael Tolentino were pretty sure they were on to something when they discovered a way to use short interfering RNA to inhibit the expression of VEGF, the protein solely responsible for vision loss associated with age-related macular degeneration and diabetic retinopathy, two leading causes of adult blindness. Reich, a former graduate student at the Scheie Eye Institute of the University of Pennsylvania Medical School, and Tolentino, at the time a faculty researcher and retinal surgeon at Penn, realized that they had stumbled upon an almost ideal system for employing an siRNA reagent as a drug.

“The molecular pathogenesis is ideally suited to an siRNA therapy, [and] the cellular target is easily accessed and post-mitotic in an organ which is not only amenable but best suited by local [drug] administration,” says Reich. “The anatomy of the eye is very much like the physical properties of a cell culture dish, so we can give the drug locally and it gets taken up by the exact cell population we need it to.”

So what did Reich and Tolentino decide to do? Not surprisingly, they convinced Penn’s Center for Technology Transfer to help them patent their discovery. Now, two years later, Reich serves as senior director of research and development for Acuity Pharmaceuticals (Tolentino, who has returned to private practice, serves as an advisor), and this fall the company began human clinical trials to prove the viability of their siRNA therapeutic.

If only all technology transfer opportunities were so straightforward. In the 24 years since Congress passed the Bayh-Dole Act giving universities the right to commercialize the fruits of federally funded research undertaken in their labs, practically every major research institution in the US has established an office for technology transfer. The reasons are fairly clear: to ensure that promising academic research is translated into commercial products that benefit society as a whole, to manage a university’s licensing arrangements and equity stakes in startups, and to encourage and guide their academic researchers through this process.

This last responsibility is particularly important in today’s hyper-charged environment of drug discovery. More than any other scientific discipline, biomedical discoveries are serving as the engine for creating new businesses and markets, and academics — not typically known for their business savvy — need the assistance university tech transfer offices provide them in making sure their work has tangible ramifications in the wider world. As GT has learned, there are many ways a university tech transfer office can help, including: providing assistance with the patent application, helping decide whether to create a startup or license the technology to an already established company, recruiting management to help lead a startup, and lining up investors to contribute venture capital to get a company off the ground.

Setting the Stage

First, a little history. After all, the university tech transfer office as a concept is still relatively new. Some universities, like Stanford and the University of Wisconsin, have had tech transfer operations for more than 30 years; others, like the University of Pennsylvania and Yale, have only made a concerted effort at bridging the gap between academia and industry since the early ’80s (see profile boxes, below and p. 29).

The pivotal event in the world of tech transfer was the passage of the Bayh-Dole Act of 1980. The legislation, sponsored by Senators Birch Bayh of Indiana and Bob Dole of Kansas, was a response to the longstanding policy under which the US government owned all intellectual property generated by federally funded research and in theory licensed it out to businesses. But bureaucratic red tape — and knowing that one’s competitors could license the same technology — put a damper on commercial development. In 1980 the federal government held title to approximately 28,000 patents, but fewer than five percent of these were licensed to industry for development of commercial products.

Bayh-Dole changed all that by giving universities the right to negotiate directly with businesses to license out intellectual property created in their labs. Because universities stood to gain through royalties, many created offices devoted specifically to marketing the commercial potential of their researchers’ work.

In the past 24 years, the field has done nothing but grow. In the early ’90s, the Association of University Technology Managers began surveying its members to gauge that growth — finding that in fiscal year 2002, 7,741 patent applications were filed in the US, up from 2,201 patent applications in 1991. Likewise, universities executed 4,673 licenses and options in 2002, compared with 1,148 in 1991.

First Steps

It makes sense, then, that the number of researchers involved in the process of technology transfer has also steadily increased — especially in the burgeoning area of biotechnology. By and large, academic researchers have handled this expansion in their responsibilities well, but that doesn’t mean it’s always easy. “Some academic researchers are savvy about the process,” says Bryan Renk, a licensing director at the Wisconsin Alumni Research Foundation, “but for others, it’s not their highest priority — and quite frankly, it shouldn’t be.” Part of the job of university tech transfer departments, Renk says, is to teach would-be inventors about the process.

When researchers think they might have developed a patentable invention, the first step, say Renk and other tech transfer officials, is to act immediately to file an invention disclosure form — a procedure mandated under federal law. Most of the time scientists will know if they’ve discovered something new and potentially useful, but Renk says that even if there is some ambiguity it makes sense to file a disclosure anyway.

Mike Snyder, a molecular biologist at Yale University and co-founder of Protometrix, a protein microarray company acquired this spring by Invitrogen, says getting the ball rolling on a patent application is one of the most important lessons he’s learned. “You just can’t file early enough,” he says.

Once an academic researcher files an invention disclosure, the university tech transfer office decides whether to file a patent. In general, this process involves evaluating a technology’s commercial potential, technical merit, patentability, and protectability. “If no one else has discovered what you’ve just discovered — that’s patentability,” says Alan Carr, a senior licensing associate at Yale University. Protectability, he adds, has to do with whether another patent has claims that encompass your discovery.

Assuming a scientist’s discovery passes these tests, the next hurdle is to determine whether the intellectual property warrants founding a new company to license and develop it, or whether it makes more sense to seek out an already existing business as a licensee. Each university will vary slightly in its policies, but in general, says Louis Berneman, the managing director for Penn’s Center for Technology Transfer, “if a technology represents an evolutionary change, then we usually try to license it to an established company.” On the other hand, for the 10 percent of the time that a discovery represents a platform for developing multiple products, the policy is to try to found a new venture.

Often the inventor will have a role in this discussion — especially if the lead researchers want to take an active role in advising or helping manage a startup based on their work. “The inventor has to convince the tech transfer office that the discovery is good enough [to warrant establishing a new venture],” says Reich, the co-founder of Acuity Pharmaceuticals. Seeking out an established company as a licensee has the advantage from the university’s perspective of offering a guaranteed source of royalties, he says, whereas helping launch a startup is riskier.

Down the Road

For the scientist lucky — or brave — enough to want to get involved in a new venture, things continue to become more complicated, and here’s where it’s most important to have a strong relationship with the university office of technology transfer. On one hand, the founders are involved in negotiations with the university to determine their stakes in the new company, and on the other, the researchers need to rely on the tech transfer office to help track down venture capital and managers with experience running startups.

The trickiest part of the negotiations involve the VCs that a startup may need to get off the ground, and here’s where you want the tech transfer office on your side. “We know the people to bring in the money,” says John Maroney, director of the office of technology transfer at Cold Spring Harbor Laboratory. “But it doesn’t just skip right along. Each one of these negotiations is complex and argumentative.” At Cold Spring Harbor, which like many institutions doesn’t invest its own money in startups, the founding researchers typically receive about 30 percent of the royalties from the tech transfer agreement, Maroney adds.

At the same time, academics involved in starting a new venture have to decide how large a role they wish to play in the company. Many universities — Penn is one example — prohibit their researchers from taking an active management or fiduciary interest in a business, so scientists must choose whether to leave their academic appointments and help run the company or stay in academia and serve as an advisor to the firm.

For Sam Reich, who was pursuing a PhD at Penn when he and Tolentino discovered the potential for an siRNA therapeutic against macular degeneration, the choice was tough. “I can’t describe to you how exciting it was to be involved in this work,” he says. The discovery was historic, and everyone in the field was excited about the development, he says. “The academic setting is a tremendous springboard, but ultimately drug development doesn’t take place there. It was important for me to see this process through, and that meant taking it to patients with the disease.” Accordingly, he put his degree on ice and joined the management team at Acuity.

Snyder at Yale wasn’t ready to jump completely into the business world, so for him the internal debate came down to how much time he wished to devote to the fledgling Protometrix as an advisor. As a member of the board of directors, he says he’d have more influence on the company’s business decisions, but he preferred to advise the company strictly on technical issues and scientific strategy. “If you want more control, you should be on the board,” he says, “but in my opinion, it depends on how much time you have.”

Ultimately, however, the desire to get involved in a startup based on one’s academic research should be motivated by the right reasons, say Snyder and Reich. “There’s no guarantee you’ll make money,” Snyder says. “I got involved because I thought it would be fun, and to make the promise of the research a reality — that should be the main motivating factor.”

Yale University Office of Cooperative Research

Director: Jon Soderstrom, PhD

Guiding philosophy: Foster cooperative efforts to translate academic research into products and services for the benefit of society, support of the broader research and education missions of Yale, and, where possible: catalyze local economic development; enhance the reputation of the university; and generate revenue for reinvestment in those missions.

Recent startups: Protometrix, Agilix, TurboWorx

Unique aspects: Established in 1982, the Yale Office of Cooperative Research is making a concerted effort to encourage the growth of high-tech businesses in the New Haven area. In addition, OCR says it also tries to consider attributes of a technology’s potential other than just return on investment. “Discoveries with high potential to improve the health or prosperity of the global community will be vigorously pursued irrespective of monetary gain to Yale,” OCR says on its website.

Selected available technologies:

“Developing new anti-fungal compounds and other therapeutics with genomic insertion collections”

A unique collection of yeast strains designed for discovering anti-fungal compounds and therapeutic modulators of eukaryotic cellular functions (such as immunomodulators, antiproliferatives, differentiation therapies), these strains contain large numbers of defined mutations that tag yeast genes with reporter constructs and proteins with epitopes. Yale is using this system to create 30,000 defined mutations throughout the yeast genome and is initiating a similar approach for human and mouse cells.

“Novel and rapid method allows large numbers of insertional mutants to be rapidly and efficiently identified from pools of spontaneous or randomly generated insertions”

The invention provides a highly efficient method for selecting and identifying insertional mutants. A non-selective amplification is used to isolate many insertion events from a population of individuals comprising insertion mutations. Specific insertion events can then be identified from the population by the use of gene-specific probes or primers. Data may be obtained regarding the function and phenotypic effects of a particular gene, which can then be used to create novel biotech products.

“Simple system to insert transposon randomly into target DNA in vitro for gene identification/gene function research”

An in vitro system for Tn552 transposase-catalyzed concerted transposition. This transposase efficiently catalyzes concerted insertions into an added target DNA using substrate DNA with processed ends. The insertions obtained in vitro show all the hallmarks of normal transposition (i.e., duplicated target site) and are randomly targeted.

University of Pennsylvania Center for Technology Transfer

Director: Louis Berneman, EdD

Guiding philosophy: To convert Penn’s research capacity into commercial activity and contribute to the public good, promote regional economic growth, reward and retain faculty, forge ties to industry and investors, and generate license income to fund Penn’s core academic mission

Approach to startups versus licensing: If the technology represents an evolutionary change, then we usually license the IP to an established company, Berneman says. But if the technology represents a disruptive platform that could lead to multiple products — an event that occurs about one time out of 10 — the Center for Technology Transfer at Penn will start a new venture, lobby VCs for money, and recruit management to establish a startup.

On faculty conflict of interest: “None of us wants to see faculty doing development work for a company,” Berneman says. Penn, he adds, prohibits faculty from taking a fiduciary or direct management role in university spinoffs.

Recent startups: Acuity Pharmaceuticals, BIOSoftware Systems

Unique aspects: “Penn was actually the last of the major research universities to start a tech transfer program — and we’re paying a bad price for that now because these kinds of activities take a long time to incubate,” Berneman says.

Selected available technologies:

Live Genomics

The technology employs a technique similar to ELISA, in which one uses an array of detector molecules to determine the presence or absence of protein targets at concentrations as low as 1 in 100 trillion.

Micro RNA

Analagous to siRNA, but via a separate mechanism, this microRNA technology is broadly suited for disease treatment. It’s based on pioneering work that identified necessary key factors for producing a microRNA capable of specifically targeting genes.

Transposagen

A novel random mutagenesis system for use in rats that employs an L1 transposon. Used thus far to create knockouts in mice, the transposon system involves no chemical or radiation mutagenesis and creates gene mutations randomly within the genome. The mutagenesis occurs at the level of germ line cells, generating offspring that stably inherit the transgenes.

Stanford University Office of Technology Licensing

Director: Katherine Ku

Guiding philosophy: “In general, the university is supposed to make its knowledge known, and it’s supposed to teach people,” says Hans Wiesendanger, a senior associate in the Stanford Office of Technology Licensing who has responsibility for biotechnology and medical devices. “It’s an extension of [the university’s] role in creating mechanisms for the general good. University technology can also lead to industrial uses, but not if it’s not promoted.”

On faculty conflict of interest: “If university scientists begin slanting their research toward applied science, the quality of their research diminishes, as does the reputation of the university,” says Wiesendanger. “Stanford has been a leader in technology transfer for the last 30 years, and our reputation certainly hasn’t gone down,” he says.

Recent startups: Stanford licensed technology and received equity in 17 companies during the 2002-2003 fiscal year, including Acumen Medical, Molecular Nanosystems, Poetic Genetics, and Avocel.

Unique aspects: Founded in 1970, Stanford’s Office of Technology Licensing is one of the more established university efforts dedicated to matching academic research with commercial applications. One of the office’s early successes involved the patenting of technology developed by Stanley Cohen of Stanford and Herbert Boyer for working with recombinant DNA. In 1981, Stanford began offering non-exclusive licenses to the technology, and by the end of that fiscal year the technology had earned Stanford $1.4 million — more than all other technologies licensed by OTL combined. In fiscal year 2002-2003, Stanford received $45.4 million in gross royalties.

Selected available technologies:

Genscan

Genscan is a program designed to predict complete gene structures in genomic DNA sequences based on a strictly probabilistic model of gene structure/compositional properties. This includes coding exons, introns, promoter and poly-adenylation signals. Genscan is capable of predicting partial genes as well as complete genes and can predict the occurrence of multiple genes in a single sequence, on either or both DNA strands.

SAM

SAM, or Significance Analysis of Microarrays, is a statistical technique for finding significant genes in a set of microarray experiments. It uses repeated permutations of the data — including gene expression measurements and clinical or biological parameters — to determine if the expression of any genes is significantly correlated to the clinical parameter.

Microarray platform

This invention is a novel platform for generating microarrays of DNA and other biological molecules, based on the ability to create high-density arrays (~10,000 features per mm2) of magnetic beads. A prototype chip with ~100,000 features has been fabricated and tested with commercially available functionalized magnetic beads.

Cold Spring Harbor Laboratory Office of Technology Transfer

Director: John Maroney, JD

Guiding philosophy: The Office of Technology Transfer seeks to protect and license intellectual property and to obtain industrial research funding in keeping with the lab’s educational mission.

Recent startups: Genetica, Orion Genomics, Genomica (now part of Exelixis)

Unique aspects: The CSHL Office of Technology Transfer currently manages 76 patented technologies and 127 non-patented technologies, and has 66 pending patent applications from the US Patent and Trademark Office covering inventions and discoveries by CSHL investigators.

Selected technologies available:

In Vivo High-Throughput Selection of Effective RNAi Probes

These are plasmid and retroviral vectors that efficiently and cost-effectively probe gene function through targeted RNAi induction. The ability to generate RNAi-inducing clones that individually target specific genes in the human genome will permit rapid, cost-efficient, loss-of-function genetic screens and rapid tests for genetic interactions to be performed in mammalian cells.

Exon-finding Program Available for Four Different Genomes

MZEF is software that provides a new method for predicting internal coding exons in genomic DNA sequences. This program allows users to predict putative internal protein coding exons, adjust prior probability, and output alternative overlapping exons. MZEF is based on a prediction algorithm using the quadratic discriminant function for multivariate statistical pattern recognition.

First-exon and Promoter Finding Program for Mammalian Genomes

FirstEF is software to enable solving the most difficult problem in gene finding: the identification of promoters and first exons in the human genome. The software employs a set of quadratic discriminant functions that recognize such features as CpG islands, promoter regions, and first donor sites. To overcome the obstacles of the low signal-to-noise ratio and the heterogeneous nature of the data, the software employs both a decision tree and multiple modeling approaches.

University of California, San Diego Technology Transfer and Intellectual Property Services

Director: Alan Paau, MBA, PhD

Guiding philosophy: In addition to the usual reasons for tech transfer, UCSD is concerned with leveraging its research results to create a stimulus to the local economy, says Alan Paau, director of Technology Transfer and Intellectual Property Services at UCSD.

Approach to startups versus licensing: “Most of the time, universities launch startup companies for one or both of two reasons: one is because the technology is too early for any existing company that is not devoted to further R&D,” says Paau. A lot of universities launch startup companies with the hope of incubating and letting the technology mature before it is taken over by a company with more expertise in marketing and sales. Another reason is when the university believes the technology is a “platform technology,” where if you develop expertise in this technology, it can result in many different products, Paau adds.

Recent licensees: Aurora Biosciences (now part of Vertex Pharmaceuticals), Genomatica, Genomics Institute of the Novartis Research Foundation, Sequenom

Selected technologies available:

Transcriptional Silencing of Genes by Directed Methylation with Introduced RNA

UCSD scientists have developed methylation-promoting RNA that targets specific promoters within mammalian genomic DNA resulting in transcriptional gene silencing, a phenomenon not previously demonstrated in mammalian cells. This invention may provide the key to therapeutics for targeting known tumor initiation and/or proliferation genes; viral promoters; gene screening, or to assess the contribution of individual genes on traits of interest.

Biomarkers for Prostate Cancer, and Method for Diagnosis and Prognosis of Disease by in Silico Dissection

This involves methods and software algorithms for diagnosing and prognosing diseases or conditions by determining gene expression levels by cell type without having to physically separate the cell types. Using this in silico dissection method, the researchers have identified a set of biomarkers for diagnosing prostate cancer, as well as a set of biomarkers for predicting early relapse in prostate cancer.

Combinatorial Transcription Control

This includes strategies and methods for exertion of combinatorial control on gene expression by integrating multiple transcription signals directly in the regulatory region without the need for additional genes and their expressions. This could be used, for example, to detect specific gene expression patterns associated with hazardous, defective, degenerative, enhancing, or regenerative factors in organisms ranging from bacteria to humans.

Wisconsin Alumni Research Foundation (University of Wisconsin-Madison)

Director: Carl Gulbrandsen

Guiding philosophy: To support scientific research at the University of Wisconsin-Madison by moving inventions arising from the university’s laboratories to the marketplace for the benefit of the university, the inventors, and society.

On faculty participation: “Some academic researchers are savvy about the process,” says Bryan Renk, a licensing director at the Wisconsin Alumni Research Foundation, “but for others, it’s not their highest priority — and quite frankly, it shouldn’t be. Their top priorities should be to publish and educate undergraduate and graduate students.” Sometimes publishing one’s work is the best option, he adds, because without a market for the technology, it’s not worth patenting it.

Recent startups: NimbleGen Systems, OpGen, Cambria Biosciences, Third Wave Technologies

Unique aspects: Founded in 1925 to manage a University of Wisconsin-Madison discovery that eventually eliminated the childhood disease rickets. In fiscal year 2003-2004, WARF processed more than 400 invention disclosures made by university faculty and staff, filed 270 U.S. patent applications on UW-Madison technology, obtained nearly 90 issued US patents, gave $46.6 million to UW-Madison to support research, signed 190 new license and option agreements, and took equity in four new UW-Madison spin-off companies.

Selected technologies available:

New Methods for Generating Knockout Rodents

This technique involves subjecting a rat strain to mutagenesis with an agent such as N-ethyl-N-nitrosourea. The rats are then bred and their progeny genetically screened through a yeast-based truncation assay for functional mutations in the targeted gene.

Horizontally-configured Surface Plasmon Resonance (SPR) System

An improved SPR imaging device designed to be more compact and easily adjusted, the instrument allows for horizontal mounting of the sample, as well as horizontal placement of the light source and camera on either side of the instrument. In addition, the optical assembly incorporates four simple, planar mirrors for easy manual control of the angle of incidence of light.

Input Feature and Kernel Selection for Support Vector Machine Classification

Support vector machines (SVMs) are powerful tools for classifying data that are often used in data mining operations. To enhance the performance of an SVM classifier, the set of support vectors defining the separating surface should be made as small as possible. This invention provides a selection technique using a fast Newton method to produce a reduced set of input features for linear SVM classifiers or a reduced set of kernel functions for non-linear SVM classifiers.

The Scan

Two J&J Doses

Johnson & Johnson says two doses of its SARS-CoV-2 vaccine provides increased protection against symptomatic COVID-19, CNN reports.

Pfizer-BioNTech Vaccine Response in Kids

The Pfizer-BioNTech SARS-CoV-2 vaccine in a lower-dose format appears to generate an immune response among children, according to the Washington Post.

Chicken Changes to Prevent Disease

The Guardian writes that researchers are looking at gene editing chickens to help prevent future pandemics.

PNAS Papers on Siberian Dog Ancestry, Insect Reproduction, Hippocampal Neurogenesis

In PNAS this week: ancestry and admixture among Siberian dogs, hormone role in fruit fly reproduction, and more.