By Kevin Davies
June 27, 2011 | A pair of former advisors to Ion Torrent Systems, the semiconductor sequencing company founded by Jonathan Rothberg that was acquired last year by Life Technologies in a deal potentially worth as much as $725 million, are upset about the licensing deal negotiated with the company by the Stanford University Office of Technology Licensing (OTL), which they say is symptomatic of the mistreatment of academic inventors by their employers.
One of those researchers, Nader Pourmand, received his first annual royalty check in the amount of just $2,300.
“The comparison between $700 million and $2,000 just doesn’t jive very well. It’s another illustration where inventors are being ripped off. We really need inventors. It’s about big money ripping off inventors,” said Stanford University’s Ron Davis, in whose lab the technology in question was developed. “If they [Stanford’s OTL] had told us [the deal], we’d have said, ‘You’re crazy—this is worth much, much more than that. You’re off by two orders of magnitude!’”
Pourmand, now at the University of California Santa Cruz (UCSC), and Davis, a renowned geneticist at Stanford University School of Medicine, were co-authors on an important 2006 paper in the Proceedings of the National Academy of Sciences describing the production of hydrogen ions and electrical detection during DNA synthesis. The corresponding patent (“Charge perturbation detection system for DNA and other molecules”) was submitted prior to publication (incorporating a related patent originally filed in 2000) and eventually published last year (U.S. patent #7,785,785; published August 2010).
“Hydrogen generation [during DNA sequencing] is my patent, my invention,” says Pourmand, who led the work while a postdoc in the Davis lab. “Without this patent, they [Ion Torrent] don’t have freedom to operate. In our papers and license, we clearly show the concept -- the physical property -- of hydrogen release.”
The recently launched Personal Genome Machine from Ion Torrent conducts DNA sequencing on a chip with more than 1 million wells by detecting incremental shifts in pH, produced by the generation of a hydrogen ion (proton) when a nucleotide is incorporated into a DNA strand. Ion Torrent obtained an exclusive license to the Pourmand/Davis technology from Stanford’s OTL before commercial launch, but Pourmand only learned the terms of that deal when he opened his first royalty check—in disbelief.
“Stanford gave away a core technology, exclusively to Ion Torrent, almost for free,” he told Bio-IT World. “I received only $2,300 as inventorship.” Equal shares were received by the two other co-inventors on the patent, Davis and Miloslav Karhanek (a colleague of Pourmand’s at UCSC), although Davis could not immediately confirm the amount because his various licensing fees are lumped together by Stanford. (It is customary in academic licensing deals for one third of the license fee to go to the university, a third to the researchers’ department, and a third to the inventor(s).)
Over a 30-year career, Davis has produced a series of major genetics discoveries (including the concept of human genetic mapping using DNA markers in 1980), technologies and commercial spin-offs. Later this year, he will receive a $500,000 genetics prize from the Gruber Foundation. But for Pourmand, the stakes are particularly high.
“Stanford didn’t negotiate the right deal and it’s having a huge impact on my career. I’m not fighting for [more] money. This is about how American institutes protect inventors’ rights,” says Pourmand. “My purpose [in raising this issue] is how US institutes handle this kind of thing. They should be encouraging inventors to invent.”
Pourmand acknowledged that it was possible the royalty amount could increase in later years, but said that all directly assignable expenses, including patent filing fees, were recovered as a separate fee.
Davis says that Pourmand’s technology, as is frequently the case with technology coming out of academia, was ahead of its time. “He tried to license it to [Applied Biosystems] in the early days and they weren’t interested. I could understand that—why would you want electronic sequencing? We were still worried about capillary sequencing. They [didn’t] have much vision. The problem is, the community catches up, but it still has little allure in Stanford’s eyes.”
Davis says he has raised the issue with Stanford’s OTL, but the problem boils down to “a lack of communication,” he said. “Nader and I were on the SAB at Ion Torrent and they clearly needed this license. It had been failed to be licensed before, so we [told] Ion Torrent, you’ve got to get the license. They wanted the exclusive license. We didn’t have any pushback on that. [Stanford OTL] viewed Nader and me as having a conflict of interest. Well, we are in terms of having any final decision... but that shouldn’t mean that we’re not involved in communication.”
“The real culprit here is the university being absolutely scared to death of conflict of interest and going to great lengths to protect the university,” Davis continued. “As a result, they don’t do their job. The university should be promoting the technologies leaving the university and getting implemented in the public domain so the public can benefit from it. The conflict of interest rules get in the way all the time.”
The director of the Stanford OTL, Kathy Ku, declined to comment specifically on the Ion Torrent case. “We do not talk about terms of license agreements, as you can understand, because they are business confidential,” she said in an email.
Davis says the primary mission of any university OTL is first to expose the technology and second, to make money. “They undervalued it from a legal point of view. They cut us out because of this conflict of interest. I don’t know why we can’t talk to them. The university’s gone overboard.” That said, he believes the problem is not unique to Stanford. “I think it’s totally endemic,” he says.
Ex Ion Men
It turns out Pourmand and Davis also have a gripe with Ion Torrent. The two men resigned as members of the firm’s scientific advisory board (SAB). “They haven’t acknowledged [our discovery],” says Pourmand. “For me and my co-inventors, it’s about getting proper acknowledgement. Right now, Ion Torrent nowhere acknowledges where the technology came from.”
That issue may in part be why a collaborative study between Davis and Pourmand and Ion Torrent scientists has been shelved, at least for the time being.
“When we joined Ion Torrent, we said we’d work on a lot of the technologies we understood,” Davis recalled. “We both bought instruments to work out protocols, reagent concentrations, etc. to make it work better. We worked on how to get the wells filled with more efficiency and even base-calling software. We were just opening our books to them. It’s in our interest to see this [technology] get out there.”
In exchange, Davis says there was a verbal agreement that the team would publish their results. “We want to be first to publish. That was our price,” said Davis. “The problem has been that the lawyers got in and said everything we’ve done is proprietary. They’d probably sue me if I tell you. It’s unbelievable what they’ve declared as proprietary... I think they had two sentences not lined out in the paper [and those were] referring to some past work. We’ve tried to say that’s ridiculous. I said, ‘You can’t act like that and have me help you.’ Maybe there was something in the paper they were scared to have released?”
A Life Technologies spokesperson said he had no direct knowledge of the manuscript and could not comment.
Pourmand said that “from the get go,” he and Davis “helped develop technology and increase the read length as consultants and SAB members. Now, we want to claim credit. We felt we couldn’t work with them. For some reasons, they are blocking… We had an agreement, but they do not sign off. In that manuscript, we claim the technology of H+ [generation] is our invention. It has been in dispute for quite a while.”
Davis said Rothberg is “has never mentioned” the Stanford license, “nor has anyone else [at Ion Torrent] mentioned it. Second, he claimed he didn’t even know about it. Now, there’s a patent issued. A patent search would have picked it up. I think he’d like to be viewed as the inventor. We discovered it a decade before him. I independently discovered it.”
Life Technologies’ only official comment on the matter stated: “Life Technologies has a substantial international intellectual property estate comprising of more than 100 patents and patent applications for the protection of the Ion Torrent sequencing technology and platform.”
In a briefing with Bio-IT World six months ago, Rothberg was insistent that recognition be paid to three studies that he said provided the critical technological foundation to Ion Torrent’s semiconductor sequencing technology. He said that two papers—a 1992 publication in PNAS by a Japanese group and a Spanish paper from 1999 “never get any credit.”
“I want credit to go to the inventor of the ISFET [Ion-sensitive Field Effect Resistor], the group that first realized you could monitor [DNA] polymerization, and the group that realized you could put it on CMOS [complementary metal-oxide semiconductor],” he said. “We had the idea of putting it on arrays and made the first large working arrays—but the fact you could put ISFET on CMOS gave us the idea. Many people are saying they invented that.”
In 1970, Piet Bergveld, emeritus professor at the University of Twente in the Netherlands, invented a new type of transistor. “Normally the gate on the transistor is wired to a circuit and controls the flow of electrons across the transistor. In 1970, Bergveld pulled the wire off, made a reference electrode and put a fluid above the transistor, inventing the ISFET.” Rothberg said there have been around 800 publications that used the ISFET transistor as a sensor for various biological and chemical sensing applications.
In 1992, a Japanese group published a report using an ISFET to detect polymerization via a solid-state pH machine. “Most low-cost pH machines use an ISFET instead of a glass electrode,” said Rothberg. “[The Japanese group] took an ISFET and dipped it into a container undergoing [polymerase chain reaction (PCR)]. They showed that they could see a pH change as a result of the PCR reaction in 1992.”
Rothberg said he was familiar with ISFETs when he began thinking about Ion Torrent, wanting to apply them in a massively parallel array. His initial goal wasn’t for DNA sequencing but (inspired by his son Noah) to make a broadly applicable biology sensor for brain imaging and other applications.
The third paper was published by a Spanish team. “I found a critical paper—‘ISFET using standard CMOS’—published in 1999 from a Spanish group,” he continued. “That really was the key for me to form a company around this technology. I knew there was a technology that could sense ions [from 1970] and it could be put in CMOS—it’s like a magical word. It’s the technology that gave us all our modern electronics—it allows the microprocessors to give us personal computing, and it’s what allows the imager to become digital photography. It gave us the third leg of the stool. CMOS gave us computing and digital imaging. Now it could give us DNA sequencing in a direct portal between chemical and biological worlds.”
“No-one has ever really sequenced a genome. That’s what we did, by bringing that together, taking the CMOS. We solved a bunch of technical challenges, and realized we could sequence on it.”
Pourmand acknowledges the significance of those reports, but argues, “None of those papers talks about H+ generation and H+ release for DNA sequencing. Tons of other papers show you can detect molecular interactions on an electronic device. If [ours] is not a true technology behind the Ion Torrent platform, why license exclusively?”