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Expiring Patents, Uptick in Biotech Spending Could Spur qPCR-Based Dx, Tool Development

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By Ben Butkus

MILLBRAE, Calif. – The combination of recently expired or soon-to-expire patents in the qPCR space, combined with recent increased financial stability in the biotech tools market, could help spur a proliferation of new PCR-based diagnostics and research tools in coming months, an expert in biotechnology patenting said at a scientific meeting held here this week.

Despite this, there are still a few important "follow-on" PCR patents whose terms don't expire for several more years, and which researchers and companies must work around when developing new PCR-based diagnostics, assays, and tools.

Vern Norviel, a partner specializing in IP counseling and patents at the law firm of Wilson Sonsini Goodrich & Rosati, made his comments as part of an expert panel convened to discuss the expiration of key PCR patents at Intelligent Enterprise Solutions and TATAA Biocenter's US qPCR Symposium, held here this week.

The qPCR field has "an exciting future because of the IP situation," said panel moderator Mikael Kubista, chairman of TATAA Biocenter, before yielding the floor to Norviel, who provided an overview of the current state of the biotech and qPCR markets, followed by a summary of key qPCR patents that have either recently expired or that are anticipated to expire in the near future.

Norviel pointed out that recent M&A and investment activity – such as Pacific Biosciences' recent IPO, Illumina's acquisition of Helixis, and Life Tech's acquisition of Ion Torrent – signified that there is likely to be a flood of innovation and new products in the biotech tool market.

Until the past few years, however, the qPCR arena was largely devoid of such heavy innovation and product development, primarily due to a "patent blockade" that existed in the form of large companies controlling multiple important patents.

Norviel highlighted patents that are no longer valid due to either expiration or challenges. These include original PCR patents on which PCR pioneer Kary Mullis was named as the inventor; and original Taq polymerase patents such as the recombinant polymerase patents invented by David Gelfand.

Norviel also said that so-called "fast PCR" patents expire "in a few months;" as do basic 5' nuclease patents. However, he added that there is still "one vexing" 5' nuclease patent that isn't set to expire until 2015, though he did not provide further detail.

One of the more interesting situations in the field surrounds the so-called Higuchi patents, Norviel said, "which cover the idea, I believe, although some people differ, of the use of an intercalating dye in an assay, which is obviously a fairly basic idea."

Half of the Higuchi patents are owned by Life Technologies (originally by its Applied Biosystems business) and half are owned by Roche. In addition, he noted that the Applied Biosystems patents have "had a number of problems" in the US Patent and Trademark Office, including a re-examination procedure that resulted in a rejection of some patents based on the "double patent" concept that prevents entities from filing a patent within six months of having filed a patent covering the same invention (PCR Insider, 12/3/2009).

This in and of itself is "not usually a big deal," Norviel said, because an entity can pledge to forfeit the additional few months of patent term that the overlapping patent would confer. However, if a patent holder decides to do this, the patent can’t be owned by more than one entity, which could be a problem with the Applied Biosystems-Roche patents.

"This creates a particularly vexing problem for ABI and Roche," Norviel said. "Even though it’s the ABI patents that are in this mess right now, there is a very negative aspect to the Roche method patents that, by implication, they probably would be considered invalid, in my opinion, for the same reasons that the device patent would be invalid. And there is this problem that seems to be unfixable, which is that now the ABI patents could be found invalid because they're not owned by the same party. And that seems like it would be difficult to fix at this stage in the game."

After basic PCR patents, Norviel highlighted a few follow-up patents related to qPCR that have a few years of life left. These include Gelfand patents related to adding buffers to qPCR reactions, which expire in 2017; hot-start polymerase patents, which expire in 2016; and SYBR Green patents, owned by Roche and Idaho Technologies, which expire in 2016.

Many of these patents can be worked around with new inventions, or by companies recommending the use of specific reagents with specific platforms in order to avoid patent infringement, Norviel said. "However, that does create "a division, or schism, between diagnostics and research. So yes, all these reagents are available, but many of them are available for research only, and not diagnostics," and are owned by different industry players.

As an example, Norviel said that this situation is akin to an automobile manufacturer such as Ford, who "could patent a truck but specify that you couldn't use it to deliver fruit." Similarly, certain PCR patents, such as those covering SYBR Green, allow scientists to use the dye in research applications, but not diagnostic applications, and vice-versa.

One conference attendee asked Norviel for clarification regarding whether it was OK at this point to develop diagnostics using reagents covered by patents that are currently expiring.

"The expired ones are fine, so that leaves you with only the [patents] that are expiring in the 2015 or 2016 timeframe," such as SYBR Green, Norviel said. "And people are in fact [developing diagnostics] using expiring patents, and it does take a bit of lawyering around the edges to make sure you can do that, and use the right reagents or get the licenses that are still necessary."

However, "between the fact that there is some money free now, and there are some paths that the patent terms have opened … it's kind of a whole new world; there's no question about it," Norviel said.

Lastly, Norviel noted a final layer to the PCR IP landscape: digital PCR, which "is where you really need to talk to lawyers, because everyone thinks they invented it, including Kary Mullis."

Others claiming to have a possible stake in the digital PCR arena include Life Technologies (via Cytonix); the UK's Medical Research Council; Bert Vogelstein at Johns Hopkins University; Roche; the University of California; and Caliper, Norviel said.

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