What happens when patents do not reward R&D?
Zachary Silbersher
One of the common refrains from the pro-patent drug chorus is that patents are necessary to protect and incentivize expensive research and development by pharmaceutical companies. While that may be true in some cases, there are examples where it is clearly not. One current example includes deuterated analogs for ruxolitinib. One company researched which deuterated analogs among thousands of possibilities might be useful, whereas a different company cornered the market on all deuterated analogs based upon two sentences in patent disclosure years ago. Guess who wins.
Deuterated Ruxolitinib
The successful clinical development of a molecule requires not only selectivity and potency, but also acceptable pharmacokinetic properties. One method for improving a drug’s pharmacokinetic properties, without decreasing its selectivity or potency, is through deuteration. Deuteration involves substituting one or more deuterium atoms for hydrogen atoms within a given molecule.
Deuterium is an isotope of hydrogen, and because it is nearly identical to hydrogen, deuterium substitution can have negligible impact on a molecule’s selectivity or potency. Yet, because the carbon-deuterium bond is significantly stronger than the carbon-hydrogen bond, more energy is required to break it. This can reduce the rate of metabolism of the deuterated molecule, which can—in some, but not all cases—improve the molecule’s pharmacokinetic properties. Whether that will happen, however, is often unpredictable for many reasons. For instance, whether cleavage of the carbon-deuterium bond is a rate-limiting step in the catalytic cycle is important. Whether a deuterated analog leads to metabolic switching is also important. There are many other reasons.
Ruxolitinib is a drug sold by Incyte that has been approved for treating certain fatal cancer conditions, including myelofibrosis, a rare bone marrow/blood cancer. Despite its efficacy, the drug’s side-effects are equally serious—including anemia, thrombocytopenia, neutropenia and lowered hemoglobin. The severity of these side-effects is generally tolerable for cancer patients given that their condition is potentially fatal.
Ruxolitnib has been shown, however, to be useful for treating less-fatal conditions, such as alopecia. Yet, patients suffering from alopecia are unlikely to tolerate the severe side-effects associated with ruxolitinib. Concert Pharmaceuticals has researched using ruxolitinib to treat certain forms of alopecia, and purportedly discovered that a deuterated analog of ruxolitinib can be efficacious without the attendant side-effects associated with non-deuterated ruxolitinib.
Ruxolitinib’s toxicities are understood to be dose-dependent, which suggests that increasing the dosage also increases the risk and severity of its side-effects. That, in turn, suggests that slowing the molecule’s metabolism could increase the patient’s exposure to the drug from the same dosage, and therefore, exacerbate its side-effects.
Yet, ruxolitinib’s mechanism of action for treating certain cancer conditions (inhibition of the Janus Kinase mediated EPO signaling pathway) is different from the one for treating alopecia conditions (interferon gamma pathway). Ruxolitinib’s toxicities, however, stem from the same mechanistic pathway for treating cancer conditions. Because of this, Concert Pharmaceuticals claims to have discovered that a lower dosage of ruxolitinib may be efficacious against alopecia, while not exacerbating the toxicities associated with treating cancer conditions.
Concert Pharma’s development of a deuterated analog of ruxolitinib for alopecia
Concert developed a deuterated analog of ruxolitinib that it claims exhibited surprising properties. In particular, although Concert’s deuterated analog of ruxolitinib does, in fact, decrease the molecule’s metabolic rate, Concert claims that the drug nevertheless exhibits a flatter pharmacokinetic curve. This means that Concert’s deuterated ruxolitinib purportedly spends a longer time within the body, but at a lower maximum plasma concentration, which delivers sufficient exposure to treat alopecia without exacerbating the severe side-effects associated with cancer patients taking ruxolitinib.
So, what does all of this have to do with patents? Concert acquired a patent that covers different deuterated ruxolitinib analogs, namely, U.S. Patent No. 9,249,149. Importantly, deuteration of a molecule such as ruxolitinib can yield thousands of different versions. Put simply, ruxolitinib has many different hydrogen atoms, and deuteration can include substitution of one or more in different combinations. Part of Concert’s research included isolating specific deuterated analogs that are likely to have favorable pharmacokinetic properties for the treatment of alopecia conditions. This in itself was the result of considerable research and development.
Incyte’s patents on deuterated ruxolitinib
So far so good, right? Well, not so much. Incyte, which sells ruxolitinib for different conditions, has entered a collaborative agreement with Eli Lilly to use versions of ruxolitinib also for the treatment of alopecia conditions. To that end, in June 2022, Eli Lilly launched Olumiant® (baricitinib), which is a cousin molecule to ruxolitinib, but not a deuterated analog of ruxolitinib.
Meanwhile, Incyte also acquired a patent covering deuterated analogs for ruxolitinib. Incyte’s patent, U.S. Patent No. 9,662,335, is extremely broad. Rather than disclosing specific deuterated ruxolitinib compounds that have been tested for their pharmacokinetic properties, much like the patent owned by Concert, Incyte’s ‘335 patent instead very generally claims every possible deuterated analog of ruxolitinib. In particular, the patent claims recite ruxolitinib, “wherein one or more hydrogen atoms are replaced by deuterium.”
That means that, even though there may be thousands of different permutations of deuterated ruxolitinib, some with advantageous pharmacokinetic properties, others without, Incyte managed to corner the market on all deuterated ruxolitinib compounds. And it did so without disclosing any research in its patent application.
How did it accomplish this? By disclosing just a few sentences in its patent application for ruxolitinib that stated, “Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.” (See ‘335 patent, col. 32, lines 60-64). In fact, despite having a patent that covers every single permutation of deuterium-substituted ruxolitinib, Incyte’s patent only uses the word “deuterium” twice.
The threat to Concert’s R&D from Incyte’s patents
The consequences of this are real. Based upon its collaborative arrangement with Eli Lilly, it is very possible that Incyte has licensed its ‘335 patent to Eli Lilly, and done so on an exclusive basis. Although Eli Lilly’s baricitinib drug is not itself a deuterated analog of ruxolitinib, and therefore, Eli Lilly is not likely itself practicing the ‘335 patent, baricitinib will still most likely be a competing drug to Concert’s drug. That means that, if Eli Lilly is an exclusive licensee of the ‘335 patent, it may be able to sue Concert for infringement of the ‘335 patent and seek injunctive relief.
In other words, even though Incyte’s broad patent discloses no research and development related to deuterating ruxolitinib, its patent may be able to kick off the market one of the few companies that did perform this research.
So, what does this all mean? It means that Incyte’s real genius was to see, years ago, that deuterated analogs of certain Janus Kinase inhibitors might one day be clinically developed. In a patent application filed in 2006, which covered ruxolitinib, but otherwise had nothing to do with the science of deuteration, Incyte had the foresight to drop a couple of sentences that said, essentially, “for ruxolitinib, you can replace the hydrogen atoms with their isotopes, such as deuterium.”
That patent application resulted in U.S. Patent No. 7,598,257, which covers ruxolitinib. Incyte kept that patent application alive for several years, filing a series of follow-on applications based on the same disclosure. In 2015, Concert filed its patent application for its deuterated analogs of ruxolitinib, which was the result of considerable research, and which resulted in the ‘149 patent. A year later—in other words, after Concert disclosed its own research in its own patent application—Incyte filed its patent application that generally covered every possible deuterated analog of ruxolitinib. That application claimed priority back to 2006, and relied upon those two sentences that said, essentially, for ruxolitinib, you can replace the hydrogen atoms with deuterium.
Now, because of those two or three sentences in a patent application drafted in 2006, Incyte has cornered the market on all deuterated analogs of ruxolitinib, and Concert Pharmaceuticals—which purportedly conducted actual research isolating the deuterated ruxolitinib analogs that actually work—could have its drug stalled for another three or four years.
Incyte’s ‘257 patent is not just a minor distraction for a company such as Concert Pharmaceuticals. Rather, it is a direct threat. In 2017, Incyte commenced a proceeding at the Patent Office to invalidate Concert’s ‘149 patent. (See IPR2017-01256). One of the primary prior art reference relied upon by Incyte was its ‘257 patent. In other words, despite conducting considerable research and development to isolate the most favorable deuterated analogs of ruxolitinib, Incyte is trying to take-away the rewards of that hard work from Concert. And Incyte is doing so not based on its own extensive research-and-development, but rather based upon a fortuitous sentence dropped into a patent application.
Incyte succeeded in its invalidity challenge. Concert’s ‘149 patent has been invalidated. An appeal of that decision is pending, and is likely to hear oral argument within the next few months.
What is the takeaway here?
This story offers a glimpse into how manipulation of the patent process can allocate the rewards for hard work to the wrong party. Concert’s extensive R&D may be derailed based on a competitor’s clever and fortuitous patenting tactics.
An important point to observe from this tale is that a patent application does not require testing. In other words, scribbling a few sentences of an idea is, in some circumstances, enough to get a patent. And it may be enough to deprive someone who subsequently put in the hard work of a patent. You don’t necessarily need testing and data to prove anything to be rewarded a patent for that idea. This problem can be particularly acute within the pharmaceutical space where the purported “unpredictable” nature of the science means that most ideas must be tested for efficacy and safety before they can be therapeutic.
If the consequence patenting without testing is to deprive patent protection from those that subsequently put in the time, money and resources to isolate the best possible embodiment, then the patenting system is not working. And then the most common refrain that patents are necessary in all cases to protect valuable R&D becomes a lot less true.
This is a problem with several solutions. Strengthening the role that written description plays during the examination process is a start. Highlighting for Examiners that claims unsupported by any data, even if technically supported by disclosures within the specification, should be afforded increased examination rigor, is another start.