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Harvard 'Co-Exclusively' Licenses Microscopy Technology to Imaging Rivals Leica and Zeiss

Harvard University has “co-exclusively” licensed a label-free microscopy technology based on vibrational spectroscopy to European microscope manufacturers Leica Microsystems and Carl Zeiss Microimaging, according to Harvard’s Office of Technology Development.
The agreement is unique in that it involves licensing IP to two direct competitors, which increases the likelihood that Harvard’s technology gets a strong start in the market. The deal made for tricky, but “not impossible” negotiations, according to Harvard OTD officials, but in the long run may speed the commercialization of the technology for multiple applications.
The technology, called frequency modulation coherent anti-stokes Raman scattering, or FM-CARS, enables researchers to rapidly image biological specimens without perturbing them by producing contrast based on the intrinsic vibration of molecules.
Harvard’s OTD disclosed the agreements along with Leica and Zeiss in separate statements in the last two weeks of May. Leica said that it would use FM CARS in its confocal microscopes, while Zeiss said that it would use the technology in both its confocal and multiphoton microscopes.
Specific financial details of the agreements were not disclosed. However, Alan Gordon, director of business development for the Harvard OTD’s division of engineering and applied science, said that the deals followed a general licensing structure. Such an arrangement would require the companies to pay Harvard an upfront fee, a “minimum annual commitment,” and an ongoing royalty of an undisclosed percent of net product sales that would be credited to the minimum commitment.
Xiaoliang Sunney Xie, a professor of chemistry and chemical biology at Harvard who invented the technology, will receive a percentage of future product royalties commensurate with Harvard’s royalty-sharing policy for faculty inventors, which is posted on the OTD’s website.
FM-CARS microscopy uses laser beams of different frequencies to coherently “excite” the vibration frequencies of specific chemical bonds, and detects the new “anti-Stokes” frequency emitted from these bonds.
By scanning over an entire sample, users of the technique can map the concentration of a molecule of interest throughout a sample. If near-IR wavelengths are implemented, the technique can image relatively deep under the surface of biological tissue.
Xie first invented the underlying CARS technology while he was a researcher at Pacific Northwest National Laboratory and, along with two other inventors, was awarded US Patent No. 6,108,081 entitled “Nonlinear vibrational microscopy.” The Battelle Memorial Institute, which manages technology commercialization for PNNL and other US government-sponsored laboratories, owns the rights to this IP, which is available for licensing.
FM-CARS improves on the original technology by making it more sensitive, Xie said. Harvard and Xie have filed for several patents in both the US and Europe related to variations on the original CARS technique and, more recently, related to FM-CARS. All of the US patents are still under review by the US Patent and Trademark Office.
‘Piece of the Action’
Leica and Zeiss are among the companies that already had a non-exclusive license to some of the CARS-related IP, but the latest agreement is related only to FM-CARS and is exclusively licensed to Leica and Zeiss. It is unclear whether Leica or Zeiss would need to take a license to the PNNL patent. Calls to both companies were not returned in time for this publication.
According to Xie, the companies became familiar with the technology after representatives attended Harvard’s third-annual CARS microscopy workshop last July, which Harvard and Xie hold with the aim of popularizing the technique.
“Zeiss and Leica came to the workshop, liked [the technology], and both wanted to have a piece of the action,” Xie said. “So we started negotiations and it happened very rapidly.”
Gordon told BTW that negotiating a co-exclusive deal with two companies – especially when those two companies are direct competitors – is atypical.
“Both expressed interest, and we had to weigh that and make some decisions,” Gordon said. “We just ended up having an open conversation with both, independently. Our primary focus as a university is to ensure that things get out there for the public good … and we felt that if we were able to get both of them to agree to the co-exclusive nature of the license, then that was the best way to ensure that this got out there.
“Up front, it wasn’t initially an easy thing to do,” Gordon added. “There were definitely some issues to resolve and work through, but we were able to do that.”
Gordon declined to discuss some of the specific issues that Harvard needed to work through with Leica and Zeiss. However, he told BTW that they revolved “around the things you might anticipate” when more than one company is licensing a technology, and are not all that different from the issues that universities face when negotiating a non-exclusive license for a technology.
“You want to encourage a company to invest in this and bring it forward and know that they’re going to have some period of time to take advantage of the market that they’re going to create,” he said. “That’s the conversation we needed to have with both companies, to make them both comfortable with their ability to still invest in the technology.”

“Our primary focus as a university is to ensure that things get out there for the public good … and we felt that if we were able to get both of them to agree to the co-exclusive nature of the license, then that was the best way to ensure that this got out there.”

One interesting aspect of the deal is that it may ensure that the technology is commercialized at a rate and in a way that is amenable to Harvard. Diligence requirements are a common aspect of university technology licensing deals, and if a company is not doing enough to commercialize a particular technology, then schools often retain the right to seek another suitor.
In this case, there are only so many large microscopy manufacturers in the world, and two of them are now going to attempt to bring the FM-CARS technology to market. Because of the unique nature of the deal, it did “change the parameters” of what Harvard would typically negotiate with a single company, Gordon said.
The deal could serve as a model for other tech-transfer offices seeking to commercialize their technologies as broadly as possible.
“We thought it was interesting to let people know that we were open to co-exclusivity, and the companies were open to it,” Gordon said. “It’s not impossible. If we help more people do deals like this, that’s great. People can argue either way about whether you have to do a deal exclusively or not, but neither company would have done a straight non-exclusive license. But the co-exclusive, they were OK with.”
Part of Leica and Zeiss’ reasoning may be that the microscopy technique has multiple potential applications and, according to Xie, is just at the cusp of a growth curve.
“Only in recent years has the field exploded with many applications – biomedical, chemical, and research,” Xie said. In 2006, he said, more than 60 peer-reviewed papers were published on CARS microscopy, of which the Harvard group contributed only two.
Both Xie and Gordon told BTW that one of the most promising initial applications will be for personal care product companies that want to assess how products such as skin cream and suntan lotion are absorbed and distributed on the skin. This concept can extend to topically applied pharmaceuticals, as well.
“We’ve spoken with companies in all those spaces that are interested in the technology and who, I think, over time are going to buy microscopes from [Leica and Zeiss] to do these types of studies in their own labs,” Gordon said. “Of course, we’re a few years from that point.”
Even further down the road is the possibility of using the technique to help guide endoscopy procedures or neurosurgery, for instance. In this case, the technique may allow doctors to rapidly and accurately determine the borders between diseased and healthy tissues. Diagnostic applications are also a possibility.
“There is a growing interest, and this is before commercial products have become available,” Xie said. “As soon as commercial products get into people’s hands, I expect there to be many more applications.”

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