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Gene Patents Decision: Everybody Wins

Last week’s Supreme Court decision to invalidate patents on human genes was a win for patients, independent researchers, and even the wider biotech industry.

By | June 18, 2013

DNA purificationWIKIMEDIA, MIKE MITCHELL FOR THE NATIONAL CANCER INSTITUTEIt’s been nearly a week since the US Supreme Court invalidated Myriad Genetics’ patents on the BRCA1 and BRCA2 genes, and the response from bioethicists, patient advocates, and the research community has been nearly uniformly positive.

“VICTORY! Supreme Court decides: Our genes belong to us, not companies,” declared the American Civil Liberties Union (ACLU), who with the Public Patent Foundation filed the suit.

Mary-Claire King, the pioneer who first established the genetic basis of familial breast cancer and pinpointed the BRCA1 gene in 1990, told the New Scientist two days following the ruling, “I am delighted. This is a fabulous result for patients, physicians, scientists, and common sense.”

The Court’s unanimous decision in Association for Molecular Pathology v. Myriad Genetics, Inc., held that, “A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated.” Specifically, that invalidates some (but not all) patent claims held by Salt Lake City firm Myriad Genetics, which has held a near-monopoly on BRCA1 and 2 testing through its Sanger sequencing-based BRACAnalysis test. But more generally, the ruling invalidates all such claims on natural human gene sequences, some 4,000 of which have been patented.

Without question, that finding is a victory for women, who now can get a second opinion before making the drastic decision (as Angelina Jolie recently did) to undergo prophylactic mastectomy or ovariectomy in light of negative test results. It’s a victory for healthcare consumers in general, who can anticipate lower cost diagnostics and more competition in the genetic marketplace. And it is a win for researchers, who can pursue their studies unfettered by the threat of litigation.

According to a post-ruling analysis by Lori Andrews, director of the Institute for Science, Law and Technology at the IIT Chicago-Kent College of Law, “prior to the Supreme Court’s decision, 53 percent of genetics labs had stopped doing research due to concerns about gene patents. Forty-nine percent of American Society of Human Genetics members had to limit their research due to gene patents.”

In her analysis, Andrews wrote that the Myriad decision was good news for the pharmaceutical and biotech industries, enabling drug companies to tailor drugs to different patient populations and diagnostics developers to design new tests without paying royalty fees. And indeed, the decision prompted immediate movement in the genetic diagnostics marketplace. Ambry Genetics, GeneDx, and DNATraits all announced Thursday the availability of competing BRCA tests. DNATraits priced its offering at $995. Ambry’s BRCA1/2 tests costs approximately $2,200, according to the company’s marketing director, Humberto Huerta.

Ambry also is incorporating the gene into panel assays, such as the $3,300 BRCAPlus, which uses next-generation DNA sequencing to test for BRCA1 BRCA2, and four other breast cancer-associated genes. GeneDx said it would be launching a 27-gene panel for breast and ovarian cancer, including BRCA1/2, on or after August 1. King recently developed a 40-gene panel called BROCA, which also includes BRCA1/2. The test, she told New Scientist, “has been used for months, but until today we had to mask BRCA1 and BRCA2. The Supreme Court ruling removes the illogical situation of being able to test all genes but having to mask some.”

Even Myriad is getting in on the act; in May, the company announced plans to phase out its BRACAnalysis test in favor of “25 clinically actionable genes” for a range of tumors including breast, colon, ovarian, and pancreatic.

But on another level, the practical impact of the ruling may be relatively minor, said Hank Greely, director of Stanford’s Center for Law and the Biosciences. Of the thousands of genes covered by patents, relatively few were actively enforced as Myriad Genetics’ were, he told The Scientist.

“The cystic fibrosis gene is patented,” Greely noted, but “did you ever hear someone complain about cystic fibrosis gene patents?”

Furthermore, as Greely told the National Geographic Daily News, many gene patents are set to expire in the next few years, and in any event it’s not clear whether new testing methods such as whole-genome and whole-exome sequencing—which are replacing the single-gene Sanger sequencing approach Myriad Genetics uses—would have actually violated the company’s patents in the first place.

The Court did uphold Myriad’s patents on the BRCA gene cDNA sequences. But Andrews notes that the Court did not preclude those patents being challenged for other reasons, especially “nonobviousness.”

“If you can’t patent the whole sequence, then it’s perfectly obvious to take out the noncoding regions,” Andrews told The Scientist. “Those patents are going to fall on the nonobvious test in a second.”

Academic diagnostics labs welcomed the news. Wayne Grody, director of the Molecular Diagnostics Laboratories at the University of California Los Angeles Medical Center, who worked with ACLU lawyers in drafting their arguments in the case, calls the decision “a victory for the team I was on, and more locally for our DNA diagnostics lab and all my peers.”

Grody’s lab was licensed by Myriad to perform limited BRCA gene testing. Where Myriad sequenced the entirety of the BRCA loci, Grody’s lab was authorized to detect just three specific mutations associated with breast cancer among Ashkenazi Jews. The charge for that test was $400, Grody says, including a royalty payment, compared to $3000 or so for the full sequence test performed by Myriad Genetics.

Grody said his lab will continue offering that test, but will now supplement it with a handful of additional tests, probing genes for neurologic and muscular diseases, congenital deafness in infants, and leukemia, several of which were precluded by patents owned by Athena Diagnostics.

Farid Chehab, director of the Molecular Diagnostics Laboratory at the University of California, San Francisco, also used to test for the Ashkenazi mutations using a “reverse dot blot” assay, but stopped “two or three years ago” due to a lack of interest. Today, he said, he plans to offer an exome-sequencing service instead.

Exome sequencing, Chehab explained, costs about $1,200—on par with BRCA1/2 testing alone—but produces orders of magnitude more information. “You can blind yourself to everything else but BRCA1 and 2, concentrate on them on the bioinformatic level,” he said. “And then, if the doctor wants additional information, we can look at other genes, too.”

Arupa Ganguly, laboratory director of the University of Pennsylvania’s Genetic Testing Laboratory, received a cease-and-desist letter from Myriad Genetics for BRCA testing in 1999. Fourteen years later, she said, the Supreme Court decision is “big victory in terms of principle.”

Still, though her lab is now technically free to offer BRCA screening, Ganguly said she hasn’t yet decided if it will. For one thing, there’s the growing commercial competition. But also, she noted, in the years since she last tested for BRCA mutations, Myriad has likely tested tens or even hundreds of thousands of samples, compiling a database of variants and their clinical significance, data she and others would not be able to access.

“It’s a very big handicap,” she said.

Greely, though, said he doubts the handicap will prove all that practically significant. For one thing, many of those variants are well documented, and labs can always refer patients with novel variants to Myriad anyway. Also, a new initiative called Free the Data!, launched following the Supreme Court’s decision, seeks to nullify Myriad’s advantage by building a public database of BRCA1 variants using patient-submitted genetic data.

“Last Thursday was a happy day for people who might want BRCA1 or 2 testing done in the next few years, and their doctors,” Greely said. “Whether the consequences are much broader than that is unclear.”

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June 19, 2013

Unfortunately, the case is more about the politics of healthcare and will hurt investment in the short term because of short-sightedness. The implications of Myriad however impact far more than genes and healthcare.  This is more about money - not wanting to pay appropriate licensing fees to patent owners in order to start their own LDT as funding of university research dries up. 

Many of the gene patents and applications have lapsed or have gone abandoned. The claims at issue were written according to USPTO format set up by the USPTO Utility Guidelines in 2001. The claims were intended to capture the degeneracy of the DNA code. In other words, more than one DNA can code the same protein. Most of these types of claims were NOT intended to encompass the gene. The gene, outside of the body, is too large and unstable to be capable of manipulation and scientific study. The gene as a whole therefore has little commercial value. So you have to get the gene down to the size (no introns or non coding sequences) where you can manipulate it. What was claimed of the genes was the open reading frames or exons. For BRCA1 and BRCA2 that ranged from 5-11% of the gene that was being claimed. Unfortunately, the courts did not do claim construction to determine eligibility. They don’t have to do any claim construction to make a 101 eligibility determination. They never determined what IT was and whether IT was elibile or NOT. Otherwise that would have been evident from the specificaiton and the prosecution history. How can you determine elibility on anything if you don’t know what the THING is? To take 110000 bases and get it down to the portion of the gene coding for the actual protein, given all the splice products that took many labs filled with many post docs and grad students many years is inventive. What was claimed is not found in nature. And without the patent initiative of the 1990′s and 2000 and human genome project we wouldn’t know what we know today.

Oh and if you think patents raise the cost of things, there are few patent protections in Africa for AIDS drugs and Cooke-Degan of Duke University has shown that there is no discernable correlation between a patent on a diagnostic test and its cost. Cost of diagnostics deals with insurance reimbursement, and access to the professionals performing the test, and lots of other things, but not patents.

Avatar of: kristindewey

kristindewey

Posts: 4

June 19, 2013

I partially disagree with Mercedes Meyer. This decision was really about the ability for one company to monopolize a expensive test. This test done by Myriad is around the $3500 range, and unless you had insurance that paid for it or were granted a free (no cost to patient) test either by Myriad or private foundations, you paid for it out of pocket. With the recent ability to map a person's genome inexpensively (see The Scientist articles from the past 2-3 months), inevitably the BRCA1/BRCA2 genes would be detected along with whatever else that person's genome held. In the past Scientist articles it was even stated that it would be cheaper to do the whole genome to detect more than one faulty gene than to target on just one faulty gene/disease.

I applaud the judge's decision to rule in favor of the patients because this is more of a win to patients than to the healthcare industry. Isn't that what healthcare really should be about??

Avatar of: Eric J. Murphy

Eric J. Murphy

Posts: 10

June 19, 2013

The myopism here is being focused on only human health.  However, biotech isn't just focused on treating and/or detecting human diseaes.  Many biotech companies, large and small, are also focused on using biotech in an agriculture setting to improve crop performance.  This includes using biotech to change input traits, e.g. RoundUp Ready, but also output traits such as increasing vitamin A content of plants or increasing oil yield of an oil seed crop.  However, there is a large push to make "fish oil" in crops, recognizing that a sustainable source is needed.  The latter requires insertion of genes into the plant, many of which are patented.  So, how will this decision impact agricultural oriented biotechnology companies, including all of the small ones, is a big questioin mark. 

 

Avatar of: David Spencer

David Spencer

Posts: 1

June 21, 2013

I would say much of what Mercedes Meyer has written here is simply off base or blatantly wrong, confused and confusing. Some of the statements, like "The gene, outside of the body, is too large and unstable to be capable of manipulation and scientific study." just make no sense whatsoever and are totally misguided and wrong.

First of all, of patents are not issued by courts but (at least in the US) by the USPTO, and if you have studied the patents issued in the last 20 or 30 years in what you would call the general fields of biotechnology, molecular biology, genetics, medical science, etc. you will see how inept they have been at issuing patents. Patents by their very definition are issued for inventions and to inventors. To me the elation resulting from this recent SCOTUS decision (which first of all should have been unnecessary or at least issued decades ago) is tempered by the justices' clear and continuing ignorance of the subject of cDNA (in which they couldn't even figure out what the "c" stood for). Humans did not "invent" cDNAs. They have been around at least as long as retroviruses and continue to be generated by multiplying retroviruses (including HIV) to generate more viral genomes. The enzymes needed to make the cDNA from the RNA genomes, the reverse transcriptases, are encoded on all retrovirus genomes and are what are essential to anyone in a lab wishing to synthesize cDNAs. The comment "To take 110000 bases and get it down to the portion of the gene coding for the actual protein, given all the splice products that took many labs filled with many post docs and grad students many years is inventive." is just baffling and ludricrous. Every mammalian cell with genes that have introns performs intron splicing to their mRNAs and the whole point of experimentally generating cDNAs using RT is to capture the actual information content from intron-containing genes by allowing the cell to do the hard work first (i.e., transcribe the mRNA and eliminate the introns). If you have read any patents one of the charming phrases routinely still used is "to those skilled in the art", which is written to describe information or techniques and methodologies that anyone trained and experienced in that particular field already knows and therefore cannot be patented. I am sure at this moment there are talented undergraduates generating cDNAs in research labs; the enzymes are readily available, and the methodologies for generating cDNAs are decades old. I would also suggest that even the most able of science undergraduates are not yet "skilled in the art" and yet they can generate cDNAs. As to the comment "And without the patent initiative of the 1990′s and 2000 and human genome project we wouldn’t know what we know today." I guess I could only respond "Say what?". You cannot be familiar with at least how the class of patents we are discussing here (BRCA1 and 2) usually arise. With BRCA1, Mark Skolnick's NIH-funded research group at the University of Utah refined to a precise level the location of the BRCA1 gene on chromosome 17, where earlier work in a different lab had already narrowed down the location fairly well. Skolnick was a co-founder of Myriad, I believe in 1991. The patent was applied for in late 1994, revised in 1995 (with the US government now a co-assignee, an interesting tale in itself) and issued in early 1998. Mary-Claire King had originally discovered the BRCA1 gene and I guess foolishly never imagined that she should patent it (and get rich because of it). The human genome had two initiatives, one the corporate one by Craig Venter's Celera corp and the other the international non-commercial joint one. Venter may have hoped (I don't really know) to patent the whole human genome had he been successful and clearly the first to do so, but even his sequencing project ended up depending on the public consortium data to fill in gaps.

The comment  related to patents and costs of drugs for AIDS or malaria patients in third-world countries is also curious. The complaint has always been that big pharma has been traditionally focussed solely on profit such that providing drugs to the poor (in say Africa) is too expensive and patent protection and licensing costs have precluded supplying critical drugs in other ways at prices the poor can afford.

To me your post rings too much of an apologist for the pharmaceutical industry, and an uninformed apologist at that.

 

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