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Invitrogen Bolsters ‘Click’ Chemistry Patent Portfolio with Harvard License

Invitrogen last week said that it has exclusively licensed from Harvard University cell proliferation assays based on a chemical synthesis technology originally developed by Scripps Research Institute scientists and also licensed by Invitrogen.
Harvard becomes the most recent addition to a list of universities, non-profit research institutes, and government labs from which Invitrogen has licensed variations of the technology. It may also not be the last, as Invitrogen is actively seeking more applications of the biochemical technique, a company official said last week.
“We’re always interested in new and novel applications of the click chemistry,” Vicki Singer, science and technology advisor in the cellular analysis division at Invitrogen, told BTW last week. “It’s an area where we have a large R&D effort, and do plan to support for quite a long time to come.”
The underlying technology, called “click” chemistry, was developed early this decade in the laboratory of Nobel laureate Barry Sharpless, a professor of chemistry at Scripps. At its core, click chemistry describes a set of catalyzation techniques for rapidly synthesizing new compounds via heteroatom links. After the technique was developed, many laboratories became interested in using it in a broad range of biological and chemical applications.
According to Singer, scientists from the former Molecular Probes in Eugene, Ore., were among those interested in the technology due to its potential for developing biological labels.
Singer said that researchers at Molecular Probes, which was acquired by Invitrogen in 2003, “found over time that there are certain biological applications where the label alone is not useful if you can’t connect it to the right biological entity in the most efficient way possible.”
As specifically applied to biological probe chemistry, the click technique made it possible to couple together azide and alkyne moieties to form a covalent bond and create biological dyes that had little to no interference from background signals.
“That’s different than, say, taking an average dye and connecting it through an amine to a protein,” Singer told BTW. “There are lots of things in cells that have amines, so protein-specific labeling is just not possible using most conventional chemistry. That was the first piece of this — to understand [that] this fundamental click chemistry is about connecting two moieties that would never interact with one another in a very specific and efficient manner.”
Molecular Probes, already operating under the Invitrogen umbrella, licensed that technology from Scripps with the intent of building a set of commercial offerings around it. Details of that licensing deal are unclear, though Singer told BTW that the license was non-exclusive and that, as far as she knew, Invitrogen was the only licensee of the method, at least for its application to biological probes.
“Once we knew that we had that kind of chemistry in hand, and we licensed that, then we started thinking about all the things we could do with it and which biological problems are the most difficult right now,” Singer said.

“We are bringing in these other technologies – in some cases it is a method; in others, it might be one of the enzymes involved in one of the processes; or in some cases it might be an improvement on one of the processes.”

Invitrogen began developing its own applications for the click chemistry, as well as licensing variations on the method from laboratories at other non-profit research institutes and governmental labs, all of whom had taken a keen interest in applying Sharpless’ advance to various biological problems, Singer said.
“We are bringing in these other technologies – in some cases it is a method; in others, it might be one of the enzymes involved in one of the processes; or in some cases it might be an improvement on one of the processes,” Singer said.
One particularly hot area is using click chemistry to label subsets of glycoproteins in live cells, extracts, or purified samples. Invitrogen has licensed intellectual property related to this application from the University of California at Berkeley, the National Institutes of Health, and the California Institute of Technology in order to sell its Click-iT kits for glycoprotein profiling.
“These [were] not sponsored research agreements,” Singer said. “The Sharpless technology caught the attention of a lot of scientists very quickly. We knew the kinds of directions we wanted to go in, and so we approached people who were experts in these areas. For several of them, we worked with them from the time we started the work, but it doesn’t mean we sponsored that.”
Nevertheless, Invitrogen has licensed — in some cases exclusively — the technologies developed at each of those schools, the company said.
Invitrogen’s deal with Harvard expores other avenues of biological research. Harvard Medical School researchers Adrian Salic and Tim Mitchison developed a method for detecting cellular proliferation that uses EdU, a modified nucleic acid subunit that is taken up by actively dividing cells and incorporated into newly synthesized DNA.
Singer said that this type of assay typically requires the use of tritiated thymidine, which is dangerous due to its radioactivity, or bromodeoxyuridine (BrdU), which requires that researchers subsequently fix cells, treat them with acid, and then label them with appropriate antibodies — an approach that has “many steps, is time-consuming, and very harsh,” Singer said.
“The nice thing about the click method is that it is very similar: you feed them [5-ethyl-2-deoxyuridine, or EdU], and that is taken up the same way BrdU is, and incorporated into the nascent DNA,” Singer said. “Then you don’t have to use an antibody. You use a very mild fixation, and then directly use the click reagent. It saves time, it saves energy, it’s easier to do, and it’s extremely flexible.”
Combining the click chemistry technology with the methods licensed from Harvard, Invitrogen intends to make assay kits to sell to pharmaceutical companies to test anti-proliferative reagents for treating cancer. Overall, Singer said that Invitrogen’s platforms based on click chemistry should be applicable across a wide range of biological research, from basic laboratory research to primary and secondary screening in drug discovery.
And the company may not be done collecting IP. Singer said that in general, Invitrogen is committed to developing more internal applications for click chemistry as well as seeking out and participating in projects at universities and non-profit research institutions. She added that such entities should feel free to contact Invitrogen if they have an interesting application for the method.

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