A hand holds psilocybin mushrooms under a pink and purple light.
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Psychedelics Patent Claim Raises Questions From Researchers Who Say They Did It First

A recent application from CB Therapeutics on biosynthetic psilocybin is emblematic of the IP concerns around novelty and obviousness the psychedelic field will face.
June 3, 2021, 5:00pm

Two weeks ago, German microbiologist Felix Blei received a barrage of messages, all telling him to look up a patent application filed by CB Therapeutics, a psychedelics company. 

The application, published on May 20, was originally filed on November 15, 2019. (Patent applications are kept secret for 18 months.) First reported by Psilocybin Alpha, the application has claims on organisms genetically modified to produce psilocybin by giving them the genes for enzymes that make the compound naturally in mushrooms. 

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It's a promising approach to make psilocybin in the large quantities needed to do research, or, one day, treat various mental health conditions. In a press release, CB Therapeutics wrote that its application represented a “major breakthrough in the biosynthesis of psilocybin."

But the four enzymes in the patent application were discovered in 2017 when Blei was getting his PhD at the Leibniz Institute for Natural Product Research and Infection Biology. He published a scientific paper on those enzymes with his colleagues Janis Fricke and Dirk Hoffmeister in the German journal Angewandte Chemie International Edition; they wrote in the paper how their findings could be used to produce psilocybin by "using engineered microbial hosts." 

Their research was not cited in the patent application. Yet, if this patent application was granted as is, it could block others—including Blei, who is now the co-founder of Mimosa Therapeutics—from producing psilocybin using host organisms with these enzymes. 

This application is also notable because it involves Christian Angermayer, a funder of the Peter Thiel-backed psychedelics company Compass Pathways and co-founder of the also Thiel-backed Atai Life Sciences, who has publicly written in favor of the value of patents. CB Therapeutics recently closed its first round of funding, which was “filled entirely by re.Mind Capital, a fund that sits within Christian Angermayer’s family office,” reported Psilocybin Alpha. Angermayer joined CB Therapeutics as advisor, and Atai’s chief scientific officer, Srinivas Rao, joined the board of directors. In the press release, CB Therapeutics called Angermayer “the psychedelics kingmaker.”

In response to questions from Motherboard, CB Therapeutics' founder and CEO, Sher Ali Butt, said in a statement, "A comparison of our patent application to the paper identified … readily shows advancements beyond the paper and we look forward to establishing the validity of our invention through the proper process before the United States Patent and Trademark Office. 

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Butt also referred to a post on LinkedIn by Mimosa CEO James Keim, who claimed the patent application overlapped with Blei's work, noting that “Dr. Blei is a Vice President of Mimosa Therapeutics, a competitor of CB Therapeutics.” He said that, "while it is disappointing that Mr. Keim chose to raise unfounded allegations on social media, it is not surprising that he would attempt to mischaracterize our achievements," and that "CB Therapeutics believes in its intellectual property, has invested significant resources to protect its intellectual property, and will defend it as necessary, though both our and Mimosa Therapeutics’ resources would be better spent focusing on delivering the best products to our respective customers."

This patent application, Blei's assertion that it has obvious overlap with his and others' research, and Butt's response that his company's work is original are emblematic of the kinds of IP stumbling blocks the psychedelic community will have to contend with as companies try to get control of and rights to intellectual property relating to the creation, formulations, and genetic material of psychedelic compounds. That's because a vast amount of research and knowledge on psychedelics already exists—both published and unpublished. “Is simply putting work into the public domain sufficient to prevent it from later being patented?” Psilocybin Alpha asked—and it's not a question with an obvious answer yet. 

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Patents are supposed to only be granted on inventions that are both novel and non-obvious, words that have specific meanings under the law. Will companies check to make sure there's no prior art (past work done on that same topic) before filing patent applications, though? If they don't, what steps will be taken, either by a patent office that may be unfamiliar with research in the field or the public? And to what extent will we see broad patent claims become a central strategy in an industry now attracting the likes of Thiel, the co-founder of PayPal who has, in the past, promoted the benefits of monopolies over competition? These, too, aren't questions with obvious answers. (CB Therapeutics' statement did not answer a question from Motherboard about whether or not their Seed A funding from re.Mind Capital was connected to Peter Thiel.) 

Amidst pushback against aggressive psychedelic patent strategies and discussions about what ethical IP might look like in the field, this application, and the challenges that await it, will likely set the stage for how others will respond when it seems like a company is trying to gain ownership over well-trodden aspects of psychedelic therapy and research.

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Mushrooms produce psilocybin by taking nutrients from the environment and forming them into the precursor compounds for psilocybin. The mushrooms also contain enzymes, encoded for in their DNA, which act on those precursors to make psilocybin. The enzymes, and the exact order in which they are used, are what Blei, Fricke and Hoffmesiter published about in 2017. 

“We found, as the first in the world, the enzymes which are responsible for the production of psilocybin,” Blei said. “It’s really obvious, if you just Google it. You would find our old papers on the first page.” 

When prior art is exactly the same as what another is trying to patent, it’s called “anticipation,” and a company or person is not entitled to the patent. In this case, the patent application references the same enzymes that Blei and his colleagues discovered, and makes claims on a handful of organisms with the genes for those enzymes added to them. By inserting the DNA that makes the enzymes in hosts like yeast or E.Coli, all is needed is a regular diet of glucose and a hospitable environment, and they will produce psilocybin.

This is close to what Blei and Fricke have done before. In the 2017 paper, they genetically altered E. Coli and the fungus Aspergillus niger to make the enzymes. The microbes didn't produce psilocybin themselves, but they made proteins, which then made psilocybin in a test tube. In 2018, Fricke said, he and his colleagues made a "magic" mold by using the enzyme's genes in the fungus, Aspergillus nidulans, to produce psilocybin. 

The validity of CB Therapeutics' patent application will likely rest not on whether their work is "original," but whether its claims are "obvious" or "non-obvious," based on that past work. The way the patent office tries to determine that is by looking at the claims and asking a question: Would this be an obvious thing to do to a skilled person in that field, at the time the patent application was filed? If the answer is yes, then the application is obvious.

There’s a lot of law surrounding this area, explained David Casimir, a lawyer specializing in intellectual property who has a Ph.D. in biochemistry. And the law changed in 2007 because of the Supreme Court case KSR International Co. v. Teleflex Inc

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It used to be more difficult to challenge a patent application as being obvious. That changed with the KSR decision. “The legal concept that this relates to is called 'obvious to try,'” Casimir said. “If something is obvious to try, then it should be obvious. Prior to KSR, it was not permissible to use that type of argument; after KSR the court said it is permissible if the things that one would try are a finite list of predictable options.”

In the biosynthesis of psilocybin, the question is whether it would be on a predictable list of next steps to take, after the discovery of the enzymes, to put them into organisms using genetic modification. A second question is what the organisms are that someone might use for that. If the organisms the CB Therapeutics application contains are on such a predictable list, their claims could be at risk of being obvious, Casimir said. 

Blei said that taking the genes for the enzymes and putting them in host cells would also be an obvious next step for scientists in this field to consider doing. In their original paper, Blei and his co-authors even wrote so: “Our findings set the stage for heterologous production of 1 in a controlled place for pharmaceutical purposes, using engineered microbial hosts, should the re-discovered pharmaceutical value lead to increased demands.” This means that their discovery of the enzymes could lead to using other organisms to produce psilocybin, which is what the patent application is trying to claim. 

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Regarding the host organisms in the application, Fricke said, "In my personal opinion it is absolutely obvious to use these genes to generate psilocybin producing organisms." S. cerevisia, especially, is "THE model organism when it comes to the production of pharmaceutical compounds," Fricke said. "The other fungal species also serve often as model organisms in basic research."

Motherboard asked CB Therapeutics to respond to the assertion that its application might be “obvious” because the list of host organisms, as well as the assertion that process of adding the enzyme DNA to those host organisms is “predictable” and “obvious to try,” but this was not directly addressed in its statement.

This method is at least common enough that there have been other patent applications on it already. A team from the VTT Technical Research Centre of Finland filed a patent application in 2018, which received a written opinion that its claims were obvious based on the paper from Blei, Fricke, and Hoffmeister. The applicants added in new genes into the application, outside of the ones that were published by Blei and his colleagues, and the application then received a preliminary report on patentability. Since that application predates the CB Therapeutics application, it could potentially be used as more prior art against their application, in addition to Blei’s work.

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Another international patent application published this month, for the biosynthesis of psilocybin in E. Coli, was filed between VTT and CB Therapeutics—and it too was found obvious because of VTT in a written opinion. It could be used as prior art against CB Therapeutics, too. 

Blei and his colleagues will be filing a "third-party preissuance submission,” sometimes called just a "third-party submission.” The law states that a third party can submit any information that might be relevant to the consideration of a patent application before the deadline. Patent lawyer Graham Pechenik explained that generally speaking, people submit issues regarding lack of novelty or obviousness. 

Once a person or group files their third-party submission, it goes into the patent application’s file history for the patent examiner to consider, but it’s still between the applicant and the patent office. It can be an added expense: it costs $180 to file a third-party submission, not including lawyer fees, which can cost $5,000 to $10,000. 

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One way that companies with a lot of resources may be able to get around this is by filing “Track One,” or paying more to have their application expedited and giving third parties less time to file a submission. (Compass Pathways' most recent granted patent was filed Track One.) 

"I am totally aware that the field of psychotropic drugs for therapy purposes is booming right now and also quite competitive, so I was not surprised," Fricke said. "But honestly, I was disappointed and sad that our knowledge should now only be used by one company to generate profits. Especially when they use our work and try to label it as theirs." 

So why file a patent application like this one, with so much potential prior art? 

As Casimir told Motherboard in the past, it’s not uncommon for patent applicants to file broad claims, even if they know they are not patentable. Once an applicant sees how the patent office responds, they can respond with more focused or narrower claims, potentially getting a claim that slipped by. 

As Motherboard previously reported, this is one reason why a group of patent lawyers and scientists recently launched a prior art database called Porta Sophia. If you type “biosynthesis” into Porta Sophia, Blei’s paper is one of the first results. 

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Casimir said while he hopes that innovators will use Porta Sophia to determine if what they're claiming is new or not—but even if they don't, Porta Sophia can still be of use to others, like the patent office. “[They] will have easy access to the relevant prior art and ideally identify that prior art and stop the patent applications from issuing,” Casimir said. 

Porta Sophia serves another role too, which is that it provides the general public and any interested parties easy access to this information so that they can either challenge a patent application by making third party submissions, or challenging patents after they're issued. 

“One of the ideas with Porta Sophia is it will make the community aware of it, they’ll talk about it in social media and elsewhere, and then the company will become aware of it before the patent application goes through the process,” Casimir said. 

That kind of peer pressure has legal ramifications. Once a group that’s applying for a patent becomes aware of prior art, it has an obligation to tell the patent examiners about it: This is called “duty of candor,” though this only applies in the United States. 

This rule says that a patent applicant and anyone associated with the patent application, including attorneys, have an obligation to turn over relevant prior art to the patent office during the review process. If they don’t do that and the patent is granted, if the patent is later challenged in court and it can be shown that the patent owner was aware of any prior art, it’s called “inequitable conduct.” 

“Inequitable conduct is essentially a type of fraud that says you committed fraud on the patent office,” Casimir said. The punishment would be up to a judge, but usually is that the patent becomes unenforceable. This means that community outreach—speaking out against patents that appear non-novel or obvious—actually does make an impact, because it can invoke "duty of candor."

Motherboard asked if CB Therapeutics was aware of the duty of candor. In his statement, Butt said, "Our patent application is based on our own, homegrown invention. CB Therapeutics has retained experienced patent prosecution counsel to protect its invention, has complied with all requirements of the patent statute in filing its patent application, and will continue to abide by all laws and regulations, including the duty of candor, in prosecuting its patent."

Porta Sophia is set up to mirror existing and potential patent applications. Casimir and his collaborators have identified every published or talked about patent application in psychedelics, identified prior art relevant to them, and curated the search on the site so that a user can quickly see the most important overlaps. The Porta Sophia team is now working on identifying obscure prior art that's just not detectable elsewhere, through archivists around the world who have materials that are not so easy to find on Google. 

Blei said that seeing another company trying to patent his work goes against his original intent in publishing findings for everyone to see, and use. “In the past, we had the decision if we wanted to publish it or patent it,” Blei said. “And we decided to publish, not patent. And that was for a reason—so everyone could access it. That was a big goal of mine."

It's a place where patents, ironically, could help. As psychedelic companies, investors, and enthusiasts search for ways to ethically deal with the realities of IP, if someone has the resources to file a patent, they could do so and dedicate the technology to the public domain. That would block any future party from trying to file a patent on the same thing and leave it out in the world for anyone to use. It's just one potential intriguing solution in the search for ethical ways to both secure IP, and maintain what Blei said he wanted—for anyone to have access to his discovery. 

"I thought it would be really cool if everyone could work with these enzymes, put it in hosts and produce, on a big scale, psilocybin for therapeutic usages," Blei said. "If they are going to patent it in this way, then nobody could do it. And that's totally against what we wanted to achieve." 


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