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Thermo Fisher Scientific Charts Digital PCR Expansion After Combinati Acquisition

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NEW YORK – Having recently acquired private digital PCR instrument developer Combinati for an undisclosed amount, Thermo Fisher Scientific plans to expand into the research and clinical markets with a microfluidics-based digital PCR platform called the Absolute Q.

Mark Smedley, Thermo's president of genetic sciences, noted that he expects the Combinati technology to drive a bigger focus for Thermo on digital PCR in the future.

"We think it is a pretty innovative digital PCR technology," he said. While Thermo Fisher Scientific has a sizable qPCR business, "we've had a relatively small entry into digital PCR, so we were interested in expanding that," Smedley said.

Thermo began initial conversations and advising of the Combinati team in 2018, in a semiformal collaboration. Scientists at Thermo did some of the alpha testing of a prototype instrument and provided feedback, Smedley said, and also beta tested the next iteration of the system.

"We really liked what we saw, and thought that was the point to go ahead with an acquisition," he said, but declined to disclose the terms of the deal, which closed in September.

Paul Hung, Combinati's CEO, said that his team sought out Thermo's consult because the company is a market leader and could advise it on making its patented technology into a scalable product.

Hung said the Combinati system is "fundamentally different" from existing dPCR tech.

The Combinati instrument, now dubbed the QuantStudio Absolute Q Digital PCR System, uses microfluidic array plates that allow all of the steps of digital PCR to be performed in a single instrument with no manual transfer steps required.

The system sequesters PCR reactions into 20,000 dead-ended microchambers with a single, five-minute hands-on step. It also produces results on a timescale approximating standard qPCR, with digitization, thermal cycling, and data collection typically performed in approximately 90 minutes.

The system also boasts four optical channels and less than 5 percent dead volume, so that 95 percent of the input sample is analyzed per reaction. It can process as many as 16 samples per array plate, or as few as four.

Overall, the Absolute Q continues what Smedley said is a trend across the industry — to develop the simplest workflows possible, with consistent scientific results, and offering fast turnaround times at low costs.

"With 'faster, better, cheaper,' the usual joke is you can pick any two — we thought with Combinati we could get all three," Smedley said, adding, "We discovered during testing that it delivered on that expectation, so we moved forward."

Hung said working with Thermo allowed relatively small Combinati to be able to consult with a team that knows how to scale up and distribute technologies broadly and globally.

The injection molding of the plates in particular enables cost benefits at scale, Hung said, and unlike other partition-based platforms, the system has no moving parts, which also helps keep manufacturing costs down.

As a tool in the research market, users can create their own Absolute Q workflows, and as a solution in applied markets, Thermo would develop validated workflows. The plan now is to start off focusing on the tools market and develop applied solutions over time, Smedley said.

However, he added, "We fully intend for this to be a product available in the clinical setting."

Hung noted that the team has already developed "whole-product solutions" in the research-use tools space, including quality control for biopharma and an AAV assay kit for gene therapy development. It has also launched an RUO SARS-CoV-2 assay and a wastewater monitoring solution.

In addition, the team has developed a suite of liquid biopsy and oncology assays and is also focusing on developing a broader viral epidemiology strategy. "The common denominator here is digital PCR used in what we call molecular monitoring," Hung said.

An example of a potential clinical application for the system comes from a recent peer-reviewed publication describing its use.

The Combinati digital technology was deployed by researchers at Stanford University to detect miniscule levels of SARS-CoV-2 viral RNA in the blood of infected people, also called RNAemia.

In a study published in Clinical Infectious Diseases, the researchers found that RNAemia in SARS-CoV-2 predicts more severe disease. Importantly, among COVID-positive patients in the study, only approximately 1 percent had detectable SARS-CoV-2 RNA in their plasma using qPCR, while 23 percent had viral RNA detected using the Absolute Q.

Samuel Yang, a professor of emergency medicine specializing in infectious disease at Stanford and corresponding author on the study, said in an email that given the clinical application of its research, the team wanted to use a digital PCR system with a simple workflow that could in turn enable "easy clinical adoption."

Yang and his colleagues were also intrigued by the Absolute Q's rapid turnaround, which could make testing "suitable for the acute-care timescale," he said, as well as the fact that array-based partition schemes have minimal dead-volume which could improve detection sensitivity. The team did not directly compare the Absolute Q system to any other digital PCR systems, however.

The dPCR space

Thermo currently markets a digital PCR system originally acquired from Applied Biosystems called the QuantStudio 3D. The system processes reactions on sealed chips using multiple instruments, and Smedley said it has a core of dedicated customers that the firm intends to continue to support.

But, "Over time, given the relative capabilities between the QuantStudio 3D and the Absolute Q, I would imagine most of our customers will migrate pretty quickly," he added.

The QuantStudio 3D is also Thermo's smallest business segment within qPCR and has not been a focus in the last few years, Smedley said.

On the other hand, "We think Absolute Q will become one of our larger [instrument platform businesses] on par with the QuantStudios 3, 5, 7, and 12," he said. "That describes a little of the ambition that we have for it."

Thermo also sees many potential customers, including a significant opportunity among customers who aren't yet using digital approaches.

There are a handful of other digital PCR systems currently on the market, but Hung and Smedley said the Absolute Q is differentiated from these competitors.

Both the QX suite of digital PCR systems from Bio-Rad Laboratories and the Continuum system from newcomer Dropworks use oil emulsion as the mechanism to create droplets. The Naica system from Stilla Technologies uses a hybrid approach it calls crystal digital PCR which combines microchambers and droplets, while the Qiagen QIAcuity system also uses microwells.

The Bio-Rad and Stilla systems also utilize multiple instruments, while Dropworks and Qiagen use a single instrument.

Bio-Rad and Stilla recently settled a lawsuit over IP, while a Bio-Rad lawsuit against Dropworks is ongoing.

Although IP infringement is always a concern, Smedley said, "we have a lot our own IP, and we wouldn't intentionally infringe upon on any other company — we are big supporters of the right to patent and benefit from those patents so you can reinvest in innovation."

Thermo's due diligence has suggested "the likelihood of infringement is very low," Smedley said, adding, "That was part of our basis for moving forward" on the acquisition.

The Absolute Q system was officially launched in September, and Hung said it will be priced "to encourage rapid adoption" of the technology, though declined to provide specifics.

Thermo also debuted the system in its booth at the American Association for Clinical Chemistry annual meeting. Hung said the system was displayed along with Thermo's qPCR offerings and that the team got more than 50 leads in a few days of the conference.

"People were excited by how easy it is [to use]; it is exactly like a RT-qPCR instrument, with very intuitive software, a very easy to use workflow, and also a similar time-to-answer," Hung emphasized. The team now expects to demonstrate the system on the global conference circuit going forward.

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