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USPTO Preliminarily Rejects Two ‘Key’ Terminator Patents Licensed by Solexa

This article has been updated from a previous version to clarify the fact that Richard Warburg's comments referred to the patent reexamination process in general, and not to the specific case regarding Solexa.
The US Patent and Trademark Office in late February preliminarily rejected all claims in two patents licensed by Solexa relating to 3’-protected reversible terminator chemistry after a law firm asked it to reexamine them, In Sequence has learned.
Solexa, which was acquired by Illumina in January, licensed a number of related patents, including the two under reexamination, in 2005 to bolster its intellectual property in the area of reversible terminators, which it uses in the sequencing chemistry for its Genome Analyzer. The company in the past has called the patents “key IP acquisitions.”
The prior-art ruling, which might still be reversed, could potentially affect a number of commercial and academic groups developing sequencing-by-synthesis technologies that involve 3’-protected reversible terminators.
However, in a patent reexamination process like this, the patents remain intact and enforceable until the patent holder has explored all avenues to appeal. “It doesn’t in any way mean that the patentee will lose his patents,” Richard Warburg, an IP lawyer and partner at Foley & Lardner, who is not involved in this case and spoke about the reexamination process in general, told In Sequence this week. “This is not a good sign for the patentee … but it’s certainly not their death knoll.”
Court documents do not reveal the identity of the third party that hired the law firm, Edwards Angell Palmer & Dodge in Ft. Lauderdale, Fla., to ask the USPTO to re-examine the IP last August. The attorney representing the party said his client asked him not to comment on the case.
The patents are No. 5,763,594, entitled “3’ protected nucleotides for enzyme catalyzed template-independent creation of phosphodiester bonds,” issued in June 1998, and No. 6,232,465, entitled “Compositions for enzyme catalyzed template-independent creation of phosphodiester bonds using protected nucleotides,” issued in May 2001. Both cover various kinds of nucleoside-5’-triphosphates where the 3’-OH group is protected by a removable blocking group.
They are part of a group of six related patents held by inventors Andrew Hiatt and Floyd Rose of California. Solexa licensed five of the patents, including the two being re-examined, from Hiatt and Rose in the second quarter of 2005.
In a press release announcing the licensing agreement, Solexa said the patents predate the company’s own work in the area of reversible terminators and cover a broad range of chemical structures that can be used for reversible termination.
“The acquisition of these key early patents … highlights Solexa’s strategy to identify and acquire key intellectual property to complement its internal IP development in this field,” the statement reads.
In the same press release, Solexa said the USPTO had allowed key claims of a separate patent application Solexa filed that covers the use of reversibly labeled terminators in sequencing-by-synthesis, in particular the simultaneous removal of the 3’-blocks and nucleotide labels. Solexa said that invention “provides the advantage of significantly shorter reaction times.”
The patent office’s initial rejection of the claims in the two Hiatt and Rose patents does not necessarily mean the patents will eventually be invalidated, or even narrowed.
According to Foley & Lardner’s Warburg, the patent holder in a case like this now has a chance to respond to the rejection and convince the USPTO that the invention is in fact patentable. “It really is a negotiation process where you need to explain some of the technology” to the patent examiner, Warburg said.
If the patent office issues a final rejection of the claims in a case like this, the patentee can respond another time, and, after that, go to the USPTO’s board of appeals. If the board rules against the patent holder, the final step is to take the case to the federal circuit, according to Warburg.
Warburg said the outcome of a case like this, at least within the patent office, will probably be known within six to 12 months. In the meantime, the patents remain intact and enforceable, “but it’s very likely that any lawsuit on that patent would be stayed pending the outcome” of the re-examination request, Warburg said.
He explained there may be two reasons why a party that requests re-examination does not include all related patents: The others might be irrelevant from a commercial point of view, or the party could not cite prior art for them.
An Illumina spokesperson declined to comment.
Related Research
Besides the Hiatt and Rose IP, other patents cover 3’-protected reversible terminators in the US, and other researcher are working on technologies that involve their use.

“It doesn’t in any way mean that the patentee will lose his patents. This is not a good sign for the patentee … but it’s certainly not their death knoll.”

For example, US patent No. 5,302,509, “Method for sequencing polynucleotides,” also involves the use of fluorescently labeled 3'-blocked nucleotide triphosphates. That patent, by Peter Cheeseman, was granted in April 1994 and assigned to Beckman Instruments.
In addition, Jingyue Ju, a professor of chemical engineering at Columbia University and head of DNA sequencing and chemical biology at the Columbia Genome Center, has developed reversible terminator nucleotides that have a cleavable blocking group at the 3’ end. He licensed his technology to a startup company, Intelligent Bio-Systems, last year (see In Sequence’s sister publication, GenomeWeb News, 12/12/2006). Ju holds a number of US patents, including No. 6,664,079, a sequencing method paper, which was granted in 2003 and includes the use of nucleotide analogs with a cleavable chemical group at the 3’ end. Ju declined to comment on the reexamination because he is not familiar with the case.
And Steven Benner, a group leader at the Foundation for Molecular Evolution in Gainesville, Fla., has been developing Taq DNA polymerases that catalyze the template-directed addition of nucleoside triphosphates carrying large fluorescent groups attached to their 3'-ends, according to an abstract from his National Human Genome Research Institute grant. Benner did not respond to requests for comment by deadline.
Some researchers believe the challenge of the Hiatt and Rose patents, if successful, will be important. “I think that this will have a significant effect on the intellectual property field,” said Mike Metzker, who has been developing his own reversible terminators for sequencing. “Looking at the patents, they are very broad, claiming lots of different functional groups at the 3’ end.”
Metzker leads a research group at Baylor College of Medicine’s Human Genome Sequencing Center and is the co-founder of LaserGen, a company that is developing his sequencing technology commercially.
He said he believes the patents under review do not cover his own reversible terminators, since his have a blocking group attached to the base rather than at the 3’ end.

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