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Sequenom, Stanford Stake IP Claims for Sequencing-Based Prenatal Test Methods

NEW YORK (GenomeWeb News) – A new paper by researchers at Sequenom and the Chinese University of Hong Kong is confirming the feasibility of using high-throughput sequencing of fetal and maternal DNA in a mother’s blood as part of a non-invasive prenatal test for Down syndrome. But with it come new questions over intellectual property related to the test.
 
In a paper that’s scheduled to appear online this week in the Proceedings of the National Academy of Sciences, Chinese University of Hong Kong researcher Dennis Lo led a team of investigators who demonstrated that they could use massively parallel DNA sequencing to detect Down syndrome from cell-free fetal DNA in pregnant women’s blood. The researchers pinpointed more than a dozen Down syndrome pregnancies — regardless of whether the women had previously undergone invasive testing.
 
The publication is the latest in a string of papers covering the development of prenatal genetic tests that do not rely on the use of invasive procedures such as chorionic villi sampling or amniocentesis, which carry a small miscarriage risk.
 
But it is not the first to report on the use of genomic sequencing of maternal blood samples for prenatal Down syndrome diagnosis. This October, a team of researchers from Stanford University led by Stephen Quake published a paper in PNAS demonstrating that they could detect fetal Down syndrome and other trisomies by sequencing fetal and maternal DNA in a mother’s blood sample and assessing the relative amount of sequence from each chromosome.
 
The intellectual property landscape surrounding the technologies is uncertain given that both teams have claimed patents related to the techniques described in their respective papers.
 
Seven authors on the Lo-led paper have reportedly filed patent applications related to the detection of fetal nucleic acids in maternal blood using non-invasive techniques. Sequenom said earlier today that it has recently licensed exclusive rights to the massively parallel genomic DNA sequencing test used in the Lo-led study.
 
Meanwhile, Quake and co-author Christina Fan, also at Stanford, filed for a patent related to the technology used in their own paper. “I think everything in this [new Sequenom] paper is covered by my patent,” Quake told GenomeWeb Daily News.
 
Earlier today, Fluidigm announced that it has secured co-exclusive licenses to the Stanford researchers’ approach for assessing fetal genetic characteristics from fetal DNA in maternal blood using digital PCR and high-throughput sequencing. The licenses reportedly cover the use of fetal genetic screening by digital analysis, non-invasive fetal aneuploidy diagnosis by sequencing, and digital PCR-enabled prenatal diagnosis.
 
Quake, who is a co-founder of Fluidigm and chair of its scientific advisory board, said that Fluidigm and a prenatal diagnostic company that did not yet wish to be identified had obtained co-exclusive licenses to the IP.
 
Fluidigm spokesman Howard High told GenomeWeb Daily News that the company took the opportunity to secure rights to an important piece of intellectual property as part of its ongoing effort to make sure that its customers have access to important research tools.
 
He said he believes the whole area of non-invasive prenatal research has the potential to benefit families worldwide. But High emphasized that Fluidigm’s current focus is on providing tools to those involved in various kinds of research. “We’re a company right now that services researchers,” he said. “We’re not a diagnostic company as such.”
 
Meanwhile, Charles Cantor, Sequenom’s CSO and co-author on this week’s PNAS paper, told GenomeWeb Daily News that Sequenom’s patents, based on Lo’s research over the past decade or so, “cover the application of circulating fetal RNA and DNA for the purposes of non-invasive prenatal testing regardless of the platform used.”
 
In their October publication, Quake and his team used Illumina Genome Analyzers to sequence DNA from the blood of 18 pregnant women. They found that they could detect fetal chromosomal abnormalities, including trisomy 21, trisomy 13, and trisomy 18, in a mother’s blood as early as 12 to 14 weeks into pregnancy.
 
For the latest paper, Lo, Cantor and their colleagues took their own crack at genomic sequence-based prenatal testing. While Cantor said that the “principle is pretty much the same” as that used in the Quake paper, he noted that “the protocols are different.”
 
After determining that they could indeed detect and sequence fetal DNA from maternal blood samples in pregnancies involving both male and female fetuses, Lo and his team tested the approach specifically for trisomy 21, assessing blood samples from 28 pregnant women — 14 carrying Down syndrome fetuses and 14 carrying euploid fetuses.
 
They obtained blood samples from each of the women during their first or second trimester, did massively parallel sequencing with an Illumina Genome Analyzer and aligned the sequences using the ELAND software package to determine the chromosomal origin of each sequence. The team then counted the number of reads from each chromosome and looked for over-representation of chromosome 21, indicating trisomy 21.
 
Lo and his team detected all of the trisomy 21 pregnancies regardless of whether the mother had already undergone an invasive procedure such as amniocentesis. These results were independently confirmed by karyoptyping.
 
The major difference between the papers, according to Sequenom, is that the latest research establishes the effectiveness of a non-invasive, massively parallel genomic sequencing test before any invasive procedures, such as amniocentesis. In contrast, the Stanford paper relied on blood samples taken from women who had undergone such procedures relatively recently — which Cantor said may have artificially increased the level of circulating fetal nucleic acids in the women’s blood.
 
“I think that’s a lot of sleight of hand,” Quake said. He argued that the amount of cell-free fetal DNA he and his team found in maternal blood was not substantially higher than that reported in other papers. “There’s no significant variation.”
 
The teams also disagree about the diagnostic role for sequencing-based prenatal tests. Although Cantor said the method works very well and is a “wonderful academic achievement,” he said it is still too expensive to use diagnostically.
 
According to Lo and his co-authors, the cost of sequencing reagents was $700 per sample with an output of 16 samples per week per Illumina instrument. Though both cost and sequencing time are expected to decrease, Cantor said the sequencing-based tests are as much as three years behind non-invasive tests currently being evaluated in a clinical setting.
 
Sequenom is currently testing its SEQureDx test, which uses Sequenom’s mass spectrometry platform to diagnose trisomy 21 from fetal RNA in maternal blood. If clinical trials are successful, the company plans to commercialize that test next June. The SEQureDx approach is currently several orders of magnitude cheaper than sequencing-based testing, according to Cantor.
 
The company recently announced that Brown University researchers are starting a 16-month, 10,000 person study of SEQureDx technology for detecting Down syndrome in the first trimester of pregnancy. And Cantor anticipates at least two large clinical trials of the SEQureDx platform, one in which Sequenom researchers are not involved and another, an in-house study, that will help the company get its CLIA lab up to speed.
 
For his part, Cantor speculated that the massively parallel genomic sequencing test could eventually complement more cost-efficient tests such as SEQureDx. For example, he said, sequencing may eventually be used to assess the roughly five to seven percent of cases that are inconclusive following SEQureDx testing.
 
Quake disagrees. Sequencing is the clear way to do non-invasive prenatal testing, he argued. “I think this will become the diagnostic.” He claimed existing noninvasive Down syndrome tests are not very informative and provide variable results depending on the ethnicity of those taking the test.
 
A clinical study on the sequencing-based method for prenatal diagnosis is ongoing at Stanford University, Quake added. It involves several hundred patients and researchers plan to expand the scope of the study. For example, Quake said they plan to compare Helicos BioSciences' sequencing technology with the Illumina platforms already being used.
 
Quake, a co-founder of Helicos, said the goal is to begin testing Helicos' Heliscope for prenatal diagnostics within the next month or so.
 
But while Quake believes sequencing-based, non-invasive tests will be used diagnostically within three years, Cantor predicted it will take longer. Between now and then, Cantor said, “There will be time to sort out the patent issues, if there are any.”

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