Plecanatide versus Linaclotide : Impending Patent Disaster for the Synergy Partner
Gary Jacob, CEO, Synergy Pharmaceuticals, notes that the lead investigational drug, plecanatide, has a composition of matter patent that is strong but narrow and not the weaker use patents that linaclotide (Linzess) carries. The US patent issued to Synergy covers the plecanatide sequence of amino acids for use as a guanylyl cycalse agonist. It is a composition of matter patent. However, in reality, the patent has positioned plecanatide precariously. Analysts note that with the Synergy-Ironwood use patent dispute being settled, the last hurdle for finding a partner has been cleared. Not exactly, the composition of matter patent may be what is keeping partners away. The patent remains the main risk that cannot be mitigated.
First, some background on drug patent challenges. Large pharma have been bitten by patent disputes, especially those filed by generic drug companies. At these companies, the lawsuits are the substitute for the normal discovery portfolio. The challengers include off-shore generic drug companies such as Reddy Labs, Apotex and Ranbaxy and want to be research based pharmaceutical companies like Teva and Forest Labs. The argument used most often is obviousness. Next is inequitable conduct. Another charge made is “fraud”. This has made large pharma wary about keeping their discovery process cleaner and the need to present experimental data in patents without cherry-picking to support the utility claim. The Lipitor Patent Fraud filed by Ranbaxy against Pfizer was one such case with all three words being invoked without basis. The case was settled in overwhelmingly favor of Pfizer without the possibility for an appeal by the pirate. Companies like Pfizer, Bristol Myers Squibb, Sanofi and Novartis, who have been bitten by such charges, are very careful. I expect them to be equally careful when doing due diligence on investigational drugs that they want to in-license. So, how does all this apply to plecanatide ? The plecanatide patent challenger may use all three words while filing a lawsuit. If there is success with finding plecanatide sequence in nature, the charges may stick and the patent for plecanatide will be invalidated. Here is more.
Plecanatide is a version of uroguanylin with just one mutated amino acid, third from the N-terminal end (US 7,041,786 that issued in 2006, filed 2002). In the patent, molecular modeling is described as being was used for short listing peptide sequences with a length of 13 to 16 amino acids to minimize or eliminate inter-conversion of the biologically active Confomer A and inactive Conformer, B. In the case of uroguanylin, these conformers may be isolated by HPLC (rare indeed). The aspect of inter-conversion is more complicated and better studied experimentally. The usual alanine scanning method was used by other researchers (in 2005) to show that the C-terminal end plays a role in the inter-conversion rate and it depends on temperature. Guanylin that lacks a residue after the cysteine at the C-terminus shows one HPLC peak at physiologic temperature and two peaks at lower temperature. In contrast, uroguanylin that has a leucine after the penultimate cysteine shows two peaks at physiologic temperature. An uroguanylin mutant that lacks a C-terminal leucine works like guanylin and guanylin mutant with an additional leucine at the C-terminus works like uroguanylin. Both guanylin and uroguanylin have glycine prior to the C-terminal end cysteine, mutating the glycine to an amino acid with a larger side chain (versus hydrogen) greatly reduces the inter-conversion rate. These changes are non-obvious and have utility. However, C-terminal end changes were not used by Synergy in the patent, N-terminal end changes were used to generate plecanatide. After short-listing through modeling, the patent notes that the peptides were the checked experimentally for proteolytic and temperature stability. Sequence ID 20, SP 304 aka guanilib aka plecanatide, is the only sequence claimed as novel (synthetic) with utility (more stable to pH and more active). Other sequences appear in the equivalent EP patent but not granted in the US patent. Meeting novel with utility attributes for the discovery allowed the US patent to be issued for plecanatide. The USPO is expected to have made an effort to determine if the mutation that generated plecanatide is present in nature, we presume none existed till the time the patent was granted (2006). The Europeans have taken longer considering that the EP patent issued in 2009 after being filed in 2002. So, one may assume that as of 2009, the plecanatide sequence has not been reported to be found in nature. However, should the novel part or utility parts disappear in future, the patent will do likewise. Pirates have considerable expertise in digging-up dirt, it is part of their discovery effort.
In this regard, it is worth commenting on science behind the lesser cousin, Linzess. The patent is actually far more solid, Synergy settled the use patent issue in favor or Ironwood. Linaclotide is a leucine to tyrosine mutated and truncated version of the heat stable E Coli toxin, ST. Due to the additional intra-molecular cysteine disulfide bonding, linaclotide is locked in the active Conformation A and cannot interconvert. For these reasons, linaclotide becomes a super-agonist of the guanylate cyclase C receptor (plecanatide is less potent). Linaclotide has a wider range for pH optimum working throughout the whole intestine versus only the duodenum for plecanatide. This improves linaclotide efficacy (numerically 10% more than plecanatide) but with an increased side effect of diarrhea (numerically 10% more than plecanatide). Note we are not treating IBS-D (with diarrhea) here as Linzess would be a real problem here. So, Linzess is more efficacious at relieving symptoms of IBS-C (with constipation) and CIC but that comes with increased diarrhea. The oral dose for linaclotide is 0.3 mg per day versus 3 mg per day for plecanatide. Gary Jacob notes that plecanatide has a composition of matter patent but the lesser cousin, linaclotide, has only broad use claims. I have taken Jacob’s comment on linaclotide patent at face value considering that Synergy has licensed Ironwood use patent for guanylyl cyclase agonists for treating GI disease for a single digit royalty payment paid to Ironwood. Synergy and Ironwood have agreed not to muddy-up waters anymore (Synergy versus Mark Currie and Ironwood). This type of dispute may bring-up more dirt for the pirates to feed on. The L to Y mutation to make linaclotide is expected to happen more readily in microbes (E Coli). Hence, wisely the synthetic sequence claim for linaclotide was not resorted to and a composition of matter patent has not issued for linaclotide but use patents have. The use patent for linaclotide may be what saves Linzess.
Note that the sequence for plecanatide is all natural (l) amino acids. This leaves the patent vulnerable to a missense SNP for the codon at amino-acid 99 of the full sequence for uroguanylin. A switch for aspartate (GAT, GAC) to glutamate (GAA, GAG) by a single nucleotide change will result in a potentially improved uroguanylin (Darwinian) to be formed by post-processing with the affected individuals showing lower IBS incidence. However, now the plecanatide sequence becomes natural and the patent issued to Synergy ceases to be valid. Plecanatide is not covered by a use patent unlike linaclotide and hence, plecantide loses all patent protection.
The potential partner that has not turned-up since 2009 though Gary Jacob has made efforts to bring a partner (to fund trials). Is the real issue bothering potential partners linked to the plecanatide composition matter patent being dependent on a SNP not being found in future ? The large pharma partner should have realized this part during due diligence. These days, almost no large pharma will introduce a claim of a one amino acid mutation with a natural amino acid on a natural peptide to obtain a composition of matter patent as Synergy has done for plecanatide. In fact, USPO now requires two changes of significance to a small molecule fast-follower patent to a drug discovered by the competing innovator pharma for granting a composition of matter patent. For SP-333, Synergy has added unnatural d-amino acids as the first and last amino acids of plecanatide. The novelty claim may be given due to the unnatural amino acids as there is zero likelihood for this sequence being present in nature. But then obviousness steps in as such d-amino acids are not present in humans. To counter this, a significant (unexpected) utility claim over plecanatide is needed and the stability and potency claims are likely to be brought forward. SP-333 is being developed for ulcerative colitis, the original indication for plecanatide (then guanilib).
If Synergy had the foresight to recognize the potentially serious patent liability of the single amino acid mutation they have made in plecantide, things may have been different. All that was needed was needed was a d-amino acids. They did this but too late in SP-333 by adding d-amino acids at the start and end. As far as the plecanatide patent challenge goes, the pirates may behave differently. Instead of invoking the usual three words without basis, they may use science to break the Synergy plecanatide patent. The pirates may genotype people (or our near cousins) with highly improved digestive system health, cardiac and kidney function (lower blood pressure) to see if they carry the required SNP for the aspartate to glutamate mutation in the C-terminal region of GUCA2B. Alternatively, one may screen urine of these individuals to see if plecanatide is present, may be along with uroguanylin if the individuals are hereterozygous. If plecanatide is shown to occur in nature, disaster strikes Synergy. Now the pirate gangs step in to devour what is left of Synergy/Partner.
In the meantime, Mark Currie waits patiently to have the last laugh on Gary Jacob’s claim of plecanatide being Best-in-Class guanylyl cyclase agonist for IBS-C and CIC.