A potential patent and licensing mess involving Penn State and Oncoceutics may be brewing. Research findings by innocent bystander Scripps Research Institute on potential anti-tumor activity of the TIC10 molecule is at the center of Penn State/Oncoceutic’s woes.
Sometime before April 2011, Oncoceutics founder Dr. Wafik El-Deiry began testing a compound named “TIC10” for anticancer activity. “TIC10” is short for “Trail Inducing Compound 10”. Dr. El-Deiry’s work expounded on findings that TIC10 (also known as “ONC201”)was able to kill cancer cells by stimulating production of a tumor suppressor protein, “TRAIL” (short for ‘TNF-related apoptosis-inducing ligand’).
TIC10 itself is not a recent discovery. C.H. Boehringer Sohn disclosed TIC10, along with 43 other compounds, in German Publication 2150062 (German App. No. DE19712150062, published in 1973), which covered anti-seizure therapeutics. Later, the National Cancer Institute (“NCI”) placed TIC10 in its public ‘Diversity Set II’ database. Researchers use the database to find compounds with interesting bioactivities. The listed structure of TIC10 in the NCI database matches the structure disclosed in Boehringer’s now-expired patent.
Dr. El-Deiry’s group assumed that they had been working with a TIC10 molecule that was identical in structure to the TIC10 structure disclosed in the Boehringer patent. At the time, that would have made sense to El-Deiry’s group since their molecule matched (via mass spectrometry) the structure of the TIC10 molecule listed in the NIC database.
However, at the time, it appears that neither Oncoceutics, nor the other researchers studying TIC10, had actually determined the structure of the TIC10 molecule that they were studying. Rather, they had matched their molecule to that in the NIC database and assumed that the structure listed in the Boehringer patent/NCI database was correct and complete. The recipe in the Boehringer patent did in fact yield a bioactive molecule, as did obtaining the molecule from NCI. But the patent and database described a molecule with a three-ring linear structure. And in reality, there was a bit of a twist on that.
Dr. Kim D. Janda, post-doc Jonathan Lockner, grad student Nicholas Jacob and their colleagues at the Scripps Research Institute discovered the discrepancy while they were trying to use TIC10 in their own research on a anti-cancer combination therapy (Scripps’ May 19, 2014 press release is here). When Dr. Janda’s group tried to make the molecule based on its structural description rather than using the Boehringer recipe, the resulting molecule was not bioactive. But when Dr. Janda’s group used the molecule obtained from NCI it was bioactive. To resolve the discrepancy, Dr. Janda’s group analyzed the NCI TIC10 and found that its actual structure did not match the listed structure. Rather than having a three-ring linear structure, bio-active TIC10 had two fused rings with the third ring being at an angle to the other two. For an interesting (even to us non-chemists) explanation of the chemistry behind the mis-assigned structure, see Derek Lowe’s (of In the Pipeline) article, here.
At the time of his discovery on TIC10, Dr. El-Deiry was at Penn State, which obtained a patent on TIC10 to treat brain cancer (U.S. Patent No. 8,673,923). Penn State then licensed the ‘923 patent to Oncoceutics. According to reports, Dr. Janda and Scripps have filed their own patent application on TIC10, which discloses the correct structure for the bioactive version of the TIC10 molecule.
As Derek Lowe correctly notes, the ‘923 patent may encounter more than a few problems, notwithstanding Oncoceutic’s claim that the structure of TIC10 is “not relevant” to the underlying invention (see C&EN May 26 article citing Lee Schalop, Oncoceutic’s CBO, here). While we don’t fully know Onoceutic’s reasoning, it may be referring to the fact that the bioactive TIC10 molecule itself is not patentable. Clearly, though, we’re guessing that Oncoceutic is a savvy potential litigant and knows of the risk that the ‘923 patent could be found non-compliant with the written description requirement of the Patent Act, among other potential issues. At this point, no one can predict what will happen to the ‘923 patent. Its true that molecules and compounds can be characterized in many different ways, e.g. via HPLC, spectrometry etc. Hypothetically speaking, its also possible to describe a compound as the result of bringing together particular starting materials within a particular process and set of parameters. For example, perhaps if Oncoceutics, in its patent claims, had recited a method using a molecule obtained by using the Boehringer recipe, the claims would have a better chance. But that’s not what the ‘923 patent claims appear to recite.
The ‘923 patent contains only 1 independent claim, which recites a method to treat a brain cancer patient using a particular formula. And, from Dr. Janda/Scripp’s work, that formula appears to describe a molecule that might not work for the purpose intended in claim 1 of the ‘923 patent.
According to a companion article in the upcoming issue of C&En (by Stu Borman, C&En June 9, 2014, article here), Dr. Janda believes that the TIC10 structure mischaracterization (and others, see here) stems from the pharma industry’s layoffs in their medicinal chemistry divisions. As reported by C&En, Dr. Janda says that “[n]ow we see how ditching the chemistry can really bite you in the ass.”