Although the RNAi intellectual property landscape has long been a muddy one, a spate of activity at the US Patent and Trademark Office has begun to give greater clarity to the situation.
However, questions remain about how and if companies with newly issued patents will handle licensing activities. Further complicating the matter is the Supreme Court's recent decision in the Merck KGaA vs. Integra LifeSciences case, which essentially gave drug developers the freedom to use other's patented technology to develop new medicines.
This week, Alnylam announced that it has received a notice of allowance for a patent application in its Tuschl-2 patent family about one week after it made a similar announcement about another Tuschl-2 application (see RNAi News, 1/19/2006). Meanwhile, rival Sirna Therapeutics said this week it has been granted a US patent covering chemical synthesis and manufacturing of RNAs.
Alnylam's latest notice of allowance is for US patent application No. 20040259248, entitled "RNA Interference-Mediating Small RNA Molecules." According to the company, it covers the preparation of a dsRNA formed from two RNA strands between 19 and 25 nucleotides long, and having one or more 3' overhangs on the ends of the double-stranded molecule.
"Things become clearer because you actually have a ruling from the governmental authority that decides whether a patent is valid or not. At least you now know what claims are owned by" a patent holder.
"The claims cover siRNAs for mediating cleavage of an mRNA in mammalian cells, and therefore cover siRNAs with the [aforementioned] structural elements that are directed toward any and all target genes expressed in mammalian cells," Alnylam said. The company noted that it expects the patent to be issued within about three months.
The Sirna patent, No. 6,989,442, is entitled "Deprotection and Purification of Oligonucleotides and Their Derivatives." According to the company, it covers a process for synthesis, deprotection, and purification of nucleic acids with one or more ribonucleotides.
"This process is critical for the efficient synthesis of RNA at high yields and high purity, and is applicable to both small- and large-scale production of oligonucleotides such as siRNAs," the company said.
With these and other patents granted, or nearing issuance, the RNAi IP scene is slowly coming into perspective, according to Richard Warburg, a partner in the IP department at the law firm of Foley & Lardner.
"Things become clearer because you actually have a ruling from the governmental authority that decides whether a patent is valid or not," Warburg told RNAi News this week. "At least you now know what claims are owned by [a patent holder]. You can look and see what they had to do to get those claims … so with a careful analysis you can actually see what the metes and bounds of that [intellectual] property are."
However, questions then arise over how companies will react to the patents that is, whether the holder will offer licenses to its IP at reasonable terms, and whether those that may need the IP will pursue licensing deals or seek ways to sidestep the patents.
Alnylam has had in place for several years a program, termed InterfeRx, under which it out-licenses its IP to other companies. Earlier this month, the company said it expects to grant five new licenses to its IP during 2006, bringing to 22 the total number of such deals the company has inked since 2003 (see RNAi News, 1/12/2006).
Already, Alnylam counts several RNAi drug developers as licensees under the program, including Benitec, Isis Pharmaceuticals, and Nastech. Alnylam is currently in a quiet period following its recent public stock offering, and company officials were not available for comment, a company spokeswoman told RNAi News.
Sirna has remained fairly quiet about its out-licensing activities, although it has publicly stated that it is willing to grant licenses to the Tuschl-1 IP it controls pursuant to a deal with the IP's owner, the University of Massachusetts (see RNAi News, 9/12/2003). It is unclear whether Sirna has granted any licenses for either the Tuschl-1 IP or any other patents and applications it owns.
Sirna officials did not answer a request for comment.
After Merck vs. Integra, "it doesn't matter how good a patent is out there; you can still be carrying on and doing the work you need to do within the United States … knowing that you're exempt from infringement of the patent."
Not all IP holders have been willing to negotiate with potential licensees, however. In April 2004, Benitec initiated patent-infringement lawsuits against three companies alleged to have infringed its US patent No. 6,573,099 (see RNAi News, 4/2/2004). While two of those sued, GenScript and Ambion, took licenses to settle the disputes, Nucleonics chose to fight.
Although the lawsuit against Nucleonics was dismissed, the claims in Benitec's patent have been rejected by the USPTO based on a re-examination of the IP conducted at Nucleonics request (see RNAi News, 9/9/2005). Benitec has said it will appeal the USPTO decision.
Additionally, an Alnylam European patent is being opposed by several companies alleging that its claims are not supported by sufficient data (see RNAi News, 1/16/2004 and 1/14/2005).
Merck vs. Integra
Regardless of who ends up controlling what IP, the rules of the game were drastically changed after the Supreme Court handed down its ruling in Merck vs. Integra last June.
In the case, Integra sued Merck for infringing a number of its patents in the course of drug discovery. Though Integra offered to license its patented compounds to Merck, the drug giant declined to take them, asserting that its use of the technology covered by the patents was protected by a statutory patent exemption: 35 U.S.C. 271 (e)(1).
While a court originally ruled in Integra's favor, the US Supreme Court handed down a decision on the case finding for Merck, essentially giving drug companies significant leeway in ignoring other companies' patented compounds during the course of early-stage research.
"The Merck/Integra case says [that] if you are performing work on a potential drug, which you'll need to get approval on to sell in the United States, then that work is exempt from patent infringement," Warburg said. "Then it doesn't matter how good a patent is out there; you can still be carrying on and doing the work you need to do within the United States … knowing that you're exempt from infringement of the patent."
Warburg also pointed out that the average timeline for a drug's development is about 10 years. Since a US patent's life is 20 years from the time it is filed with the USPTO, he said, a drug developer may not need to take a license to a particular patent at all.
"Let's say a patent is going to expire about the time [a company] is going to get [its] approval from the FDA, [then the developer] can basically … ignore it," Warburg noted.
That said, he pointed out that some of the patents that "issue now may be relatively narrow patents, and broader patents can issue in the future. There's nothing to stop people from going back to the patent office and saying, [for example,] 'You gave me all chlorines, now I'm going to ask you for all of the other halogens as well."
Doug Macron ([email protected])