The following is part 2 of a 3-part series investigating central issues underlying the development of psilocybin-based therapies for depression. Read part 1 here.
A US patent granted for a formulation of synthetic psilocybin used in a therapy for depression has drawn attention to how pharmaceutical companies might claim ownership over forms of long-established psychedelic substances. Chemists and researchers examine why the company that filed the claim chose a specific crystalline structure of psilocybin and how attorneys are challenging the patent.
Compass Pathways, a UK-based mental health care company, announced in January that it had received US Patent 10,519,175 giving the company ownership of a therapy for treatment-resistant depression using a preparation of crystallized synthetic psilocybin. Part 1 of this series examined challenges to this patent from intellectual property attorneys at Kohn & Associates PLLC who filed a petition with the United States Patent and Trademark Office (USPTO) questioning the validity and ethics of its claims.
The patent, titled “Preparations of Psilocybin, Different Polymorphic Forms, Intermediates, Formulations and Their Use,” describes a process for synthesizing and manufacturing a specific dosage form of crystalline psilocybin, called COMP360, which includes microcrystalline cellulose—a refined wood pulp often used in food production—as a tableting agent, to bind the drug in a pill form
An examination of the 21 claims in the Compass patent show that they all depend on a specific composition of crystalline psilocybin described in Claim 1 and referred to as Polymorph A. Polymorphs are materials, organisms, or objects that can assume different forms. To understand the claims in the patent, it’s necessary to learn a bit about crystallography, or the science and properties of crystals.
The structure of Polymorph A is described in the patent by an XRPD (X-ray powder diffraction) diffractogram produced by a process called X-ray crystallography. Similar to a microscope at the atomic level, X-ray crystallography reveals the arrangement of atoms in a crystalline substance through the diffraction pattern that occurs when a beam of X-rays is diffracted or bent by the compound. Crystallography is used by scientists to understand the structure and function of larger molecules and develop new polymers, textiles and pharmaceuticals. Claim 1 of the patent grants Compass ownership over the following therapy and crystalline structure:
“A method of treating drug-resistant depression comprising [sic] orally administering to a subject in need thereof a therapeutically effective amount of an oral dosage form, wherein, the oral dosage form comprises: crystalline psilocybin in the form Polymorph A characterized by peaks in an XRPD diffractogram at 11.5, 12.0, 14.5, 17.5, and 19.7°2θ±0.1°2θ, wherein the crystalline psilocybin has a chemical purity of greater than 97% by HPLC, and no single impurity of greater than 1%; and silicified microcrystalline cellulose.”
In other words, Polymorph A has a specific crystalline structure documented in the XRPD diffractogram and a chemical purity defined by high-performance liquid chromatography (HPLC).
Decades of Research
Psilocybin is a natural substance found primarily in mushrooms of the Psilocybe genus, some of which have been used for centuries by indigenous healers. It was first isolated and synthesized in 1958 by a group of chemists, including Albert Hofmann who first synthesized LSD. While working at Sandoz Laboratories in Switzerland, Hofmann and fellow chemist Franz Troxler, reported a process for synthesizing the psilocybin analog psilacetin in a 1963 patent filing. Since those early investigations, forms of synthetic psilocybin have been examined by researchers throughout the world.
As Compass applied for patents for Polymorph A in the US and Great Britain, attorneys at Kohn & Associates challenged these claims arguing that the company was unfairly attempting to block potential competitors by claiming ownership of prior research. The attorneys contend that the XRPD data and analysis of crystalline psilocybin presented in the Compass patent has already been published.
The Compass patent claims ownership over a formulation that includes a specific crystalline structure of synthetic psilocybin and not the entire molecule. But some worry that Compass could attempt to extend ownership over products based on mushrooms that contain psilocybin or extracts that may include this same crystalline structure.
Indigenous communities have entered the patent debate and opposed ownership of psychedelic plants. According to the Richmond Journal of Law and Technology, lawyers representing a coalition of indigenous groups in the Amazon Basin filed a request in 1999 for a re-examination of a 1986 US patent USPP5751P granted to Loren S. Miller for Banisteriopsis caapi, or what Miller called “Da Vine,” which is one of the key ingredients of ayahuasca. One of the arguments against the patent made by the attorneys is that Banisteriopsis caapi is “well described in the scientific literature and in the ‘traditional knowledge of indigenous peoples throughout Amazon.’” The patent was not overturned and appears to have expired in 2003.
Compass declined to comment for this story, but in an essay on the website of the nonprofit Multidisciplinary Association for Psychedelic Studies (MAPS), Compass Chief Medical Officer and co-founder, Ekaterina Malievskaia, MD, asserts that the company’s intellectual property claims will not “preclude the use of naturally occurring mushrooms, extracts, or any other products created by alternative synthesis and formulation routes.”
Other critics raise concerns about whether polymorphs of well-known substances such as synthetic psilocybin should be claimed as intellectual property. Nicholas Cozzi, Ph.D., a pharmacologist and chemist at the University of Wisconsin School of Medicine and Public Health and the Alexander Shulgin Research Institute, notes that prior to the Compass patent claims, drug developers have been granted patents for polymorphs. Cozzi notes that in the late 1990’s, researchers noticed that some polymorphs of the HIV drug ritonavir were more shelf-stable over time. As a result, the United States Patent and Trademark Office (USPTO) issued a patent for a ritonavir polymorph which set a precedent for establishing intellectual property claims over other polymorphs.
While polymorphs can be patented, some observers, including Cozzi, question why the Compass patent does not explain the specific medicinal benefits of Polymorph A that differ from other forms of psilocybin. Cozzi has produced synthetic psilocybin and created synthesis methods for the Usona Institute, which is developing its own psilocybin therapy to treat major depressive disorder. He notes that a specific polymorph has no unique therapeutic value in itself and has the same action as other crystals of the same substance when dissolved in water or stomach fluids.
“Once it dissolves, there are no clinical differences,” says Cozzi of the Compass polymorph. “But initially the crystal structure might influence the rate at which the compound dissolves and enters the bloodstream. If polymorphs dissolve at different rates, there could be differences in bioavailability.”
As precedents are in place to patent polymorphs, other companies may follow this strategy to establish ownership of psychedelic substances which they claim as novel discoveries. It remains to be seen how well these arguments stand up to challenges.
Patenting a Formulation of Psilocybin
While the Compass patent does not explain the specific medical benefits or unique effects of Polymorph A, one chemist who contributed to the Compass patent, offers an explanation for why certain crystalline forms might be particularly desirable.
Dave Nichols, Ph.D., a professor emeritus of medicinal chemistry and molecular pharmacology at Purdue University, is co-inventor of patent 10,519,175 and advised Compass on aspects of the synthesis. He does not believe that the patented Compass polymorph will block other developers of psilocybin-based therapies or encourage other companies to patent polymorphs of psychedelic substances.
“The strongest patents are based on novel molecules,” says Nichols.
Nichols says he does not know why Compass chose Polymorph A. He agrees with Cozzi that crystalline forms may have different solubilities in gastric fluid, but once dissolved they will act the same.
“A crystal structure of a molecule bound within a receptor may give information about how the molecule acts at the receptor, but the crystal structure of an isolated molecule (i.e. psilocybin itself) will generally not tell anything about how the compound acts,” says Nichols.
Nichols observes, however, that the crystalline form of a molecule is largely relevant to the development of dosage formulations. While he did not address the specific solubility of Polymorph A, Nichols notes that the crystalline structure can impact how easy it is to formulate as a compound, such as capsules or tablets. He says some companies may choose a certain polymorph because it has better formulation properties that could impact the desired rate of dissolution in the gastrointestinal tract. For example, if a pain relief drug has several polymorphic crystalline forms, a company may choose one that has superior solubility in the stomach and therefore offers more rapid pain relief.
Cozzi says while some polymorphs might dissolve more quickly than other crystalline structures and thereby change the kinetics of drug absorption by the body, nobody has tested this with psilocybin. He notes that the patent for Polymorph A appears to be based entirely on a specific formulation of psilocybin that is mixed with microcrystalline cellulose and does not appear to claim ownership of any other substances.
“My understanding is that this particular composition is the central aspect on which the patent is based,” says Cozzi.
Does the Compass Patent Claim Ownership Over Synthesis?
Within the Compass patent is a description of how to crystallize synthetic psilocybin. This part of the patent’s language has raised questions about whether the company intends to claim ownership over the synthesis process that it describes. As this process is already well-established in scientific literature, some believe that it would be difficult for Compass to claim that it is their intellectual property.
According to Nichols, anyone looking to patent a polymorph is required to provide a specific detailed description of how a particular polymorph is obtained. Producing different polymorphs of a particular compound usually involves describing changes in crystallization solvents, temperature, cooling or heating durations. Descriptions of synthesis and general synthetic approaches provide patent inspectors with relevant background as to what the inventors were thinking. Nichols notes that the Compass patent must demonstrate the exact conditions that would reproducibly lead to Polymorph A from batch to batch— a process which scientists call “reducing the art to practice.”
According to Nichols, the clearest rationale for ownership made by Compass is presented in Column 3 of the patent, which describes methods of synthesizing large amounts of crystalline psilocybin.
“Evidently, when using different methods of manufacture, different polymorphic forms of psilocybin were obtained,” says Nichols. “Thus, the inventors identified reaction and crystallization conditions that would reproducibly lead to only one of the possible isomorphic forms.”
While large-scale synthesis is listed in the patent objectives, the crystallization process and the chemical route to synthesize psilocybin has been published before. Lawyers challenging the Compass patent argue in their petition to the USPTO that this information is in the public domain and cannot be patented.
Researcher Matthew Baggott, former director of data science and engineering at the biotechnology corporation Genentech, says a patent on a method of manufacturing psilocybin potentially creates barriers for other companies interested in synthesizing psilocybin.
“With a patent on a manufacturing process,” says Baggott. “Compass can make it expensive and difficult for another company to produce psilocybin.”
Baggott notes that patents last 20 years, which is much longer than the five years of data and marketing exclusivity that the FDA might grant for a drug that has shown to be safe and effective in clinical trials. The synthesis of the psilocybin used in the Compass patent involves six chemical reactions. Three of the key tryptamine-forming reactions come from a synthesis method first published in 1954, known as Speeter-Anthony. The other three reactions have also been published. All are central features of modern psilocybin synthesis.
Cozzi observes that the process of synthesis outlined in the Compass patent is well-known in the scientific literature.
“The synthetic route described in patent 10,519,175 is not new or innovative,” says Cozzi. “The chemistry is well-known and has been used to create hundreds or maybe thousands of various tryptamines, including psilocybin, over the past 60 years or so.”
The solvent used in the crystallization of psilocybin can also influence the shape of the crystals. Cozzi says that Hofmann used both water and methanol to crystallize synthetic psilocybin. Some molecules like psilocybin will crystallize in different ways depending on how the solution is heated to a specific temperature.
While the Compass patent describes optimizing an existing water recrystallization method to achieve a 97% purity for Polymorph A, the patent’s claim of ownership over a new method of “controlled crystallization” is under question.
The Compass patent does not explain how its method is different from prior crystallization methods. The process described in the patent appears to make only small changes in how long the water-based recrystallization remains at room temperature and when cooled.
“There are obvious tweaks that you can make, but I don’t know if they are patentable,” says Cozzi.
Usona has developed a new five-step synthesis of psilocybin for multigram quantities which it published online in January and did not patent.
Longer term, synthesis may play less of a role for companies like Compass in establishing exclusive ownership. These claims may focus on patenting the pairing of a polymorph with a mental health treatment.
“What they are trying to do is patent the use of this polymorph formulation, according to the patent ‘for use in medicine, particularly, but not exclusively for the treatment of treatment-resistant depression,’” says Cozzi.
Continued scrutiny of Compass’ possible patent claims over psilocybin synthesis, and its pairing of synthetic psilocybin with a therapy protocol, may serve as a warning to other companies in the psychedelic space that their patent applications may be closely examined.
Legal Challenges to Polymorph A
Attorneys from the firm Kohn & Associates are actively challenging US patent 10,519,175 and Compass’ patent applications in Great Britain. They argue that the company is attempting to claim ownership of earlier research on psilocybin conducted by Hofmann, Sandoz, and others.
Cozzi says patent 10,519,175 hinges on the crystalline structure described in the XRPD diffractogram. He points out that there are not an infinite number of polymorphs available for crystalline versions of psilocybin, and perhaps only one or two. Cozzi notes that the XRPD data and analysis of crystalline psilocybin used in the Compass patent has already been documented by another researcher. He points to a 1975 paper by V.A. Folen, published in the Journal of Forensic Science titled, “X-Ray Powder Diffraction Data for Some Drugs, Excipients, and Adulterants in Illicit Samples.”
Cozzi notes that Folen’s research has already been cited by the attorneys challenging the Compass patent.
“It appears that the XRPD data that defines Polymorph A is identical to data previously published by Folen in 1975 ,” says Cozzi. “Even if we don’t know whether Folen generated his data from psilocybin obtained from Hofmann, the data was nevertheless put into the public domain in 1975. This suggests that Polymorph A is not a unique, previously unknown substance, but rather it is the same form as psilocybin that has been available for decades.”
Baggott notes that one of the overarching problems with scientific investigations of psychedelics is that sanctioned clinical research was blocked by overly risk averse regulators for decades, while the war on drugs simultaneously ensured that unsanctioned psychedelic innovations remained secretive. While federal opposition to Schedule 1 research in humans ended in the early 1990s, some psychedelic substances and synthesis methods developed outside of the patent system. The Folen data was published and accessible, but some of this knowledge is documented in hard-to-locate sources, such as rare publications focused on underground psychedelic use.
Baggott says that because some research on psilocybin took place so long ago, it may also be more difficult for patent offices in some countries to understand what part of a patent application is truly new. The European Patent Office (EPO) did point to prior patents filed in the early 1960’s by Sandoz and Hofmann, as well as the work of other researchers, when it rejected Compass’ 2018 patent application in Great Britain for its psilocybin-based therapy.
Even if the XRPD data cited in the Compass patent is located by patent examiners and analyzed, Compass may argue that it has exclusive ownership because it was the first to file a patent claim. Some psilocybin-based materials may also include mixtures of naturally-occurring polymorphs. It is unclear whether other developers of therapies or medicines, whose products include the crystalline form of psilocybin in Polymorph A, are vulnerable to possible legal action from Compass for patent infringement.
While it remains to be seen how the Compass patent disputes will play out over time, Nichols, co-inventor of the patent, is not concerned that patent 10,519,175 will impede others who seek to create therapies using synthetic psilocybin. Nichols says other entities could base their therapy protocols on dosage forms which are not crystalline. He also remains skeptical that many companies or researchers working with psychedelic substances will attempt to patent polymorphs.
“I don’t believe that will be a widespread practice because a patent on a molecule itself is stronger,” says Nichols. “And, of course, psilocybin the molecule can’t per se be patented.”
Baggott observes that a number of companies entering the psychedelic industry are applying for patents that contain mixtures of psychedelics or a blend of other psychoactive substances such as psilocybin derivatives with cannabinoids or with immunosuppressant drugs. While it’s possible that such substances could include the Polymorph A crystalline structure, Baggott believes the Compass patent might not be as valuable as some think. He observes that psychedelics containing the active tryptamine chemical structure, of which psilocybin is only one, are fungible—meaning that a different substance may work as well as psilocybin for a given mental health condition.
“A company would still have to spend a few hundred million to show that their molecule is also safe and effective. But that is not a lot of money in pharma, considering the size of the market,” says Baggott. “As psilocybin nears approval for depression, you will see many other groups applying for patents involving other psychedelic tryptamines.”
Top image: Nicholas Cozzi, Ph.D., a pharmacologist and chemist at the University of Wisconsin School of Medicine and Public Health and the Alexander Shulgin Research Institute. Photo by Paul Daley.