You are currently viewing Psychedelic Bulletin #141: Terran’s 4-OH-DiPT Prodrug Patent App.; Generic Ketamine Appears Effective for TRD; VA/DoD Guideline Reviews Psychedelics

Psychedelic Bulletin #141: Terran’s 4-OH-DiPT Prodrug Patent App.; Generic Ketamine Appears Effective for TRD; VA/DoD Guideline Reviews Psychedelics

This Week:

  • 🔨 Terran Biosciences’ 4-OH-DiPT Prodrug Patent Application: Another Nail in the Coffin for Reunion’s Lead Candidate?
  • 💉 Generic Ketamine Appears Effective for TRD
  • 📄 New VA/DoD PTSD Guideline Reviews Psychedelics
  • 💬 You Say “Psilocybin Treatment”, I Say “Psilocybin-assisted Psychotherapy”
  • 🗳 UC Berkeley Poll Shows Support for Psychedelic Policy Reform in U.S.
  • 💶 EU Committee Asks for Devoted Funding for Psychedelic R&D
  • 📋 New: Ibogaine Patent Tracker

and lots more…

Psychedelic Sector News

Terran Biosciences’ 4-OH-DiPT Prodrug Patent Application: Another Nail in the Coffin for Reunion’s Lead Candidate?

Reporting by Noah Smith1


Here, we explore the latest twist in the battle over 4-OH-DiPT2 prodrug patents as a new player enters the fold: Terran Biosciences.

Recap: Reunion and Mindset’s Competing Claims to 4-OH-DiPT Prodrug

Earlier this year we provided analysis of a lawsuit filed by Reunion Neuroscience (which was formerly part of Field Trip) against its competitor, Mindset Pharma. In its complaint (PDF), Reunion asserted that Mindset had “knowingly copied” its then-recently unveiled lead candidate, RE104, by filing a continuation patent application claiming RE104 “as its invention.”

In doing so Mindset had, by employing a competitive patent strategy, managed to secure a claim to Reunion’s lead candidate, leaving the recently spun-out drug developer, and its development program, at an apparent impasse.

With its development of RE104 in jeopardy, Reunion elected to file suit against Mindset alleging inequitable conduct. However, as Matt Zorn shared in our March analysis of the case, “the claims and legal contentions appear neither to have a basis in existing law nor are justified by a nonfrivolous argument to extend, modify, or reverse existing law.” Reunion’s suit appeared to have been somewhat of a “hail mary” attempt at saving its only real drug candidate.

Reunion had admitted that Mindset’s claim over Reunion’s lead drug candidate had drastically stalled the company’s capacity to raise the funding needed to continue operations (see the aforementioned suit). What’s more is that, in light of Mindset’s claim to RE104, Reunion would likely need to licence the candidate from its competitor in order to move forward free of freedom-to-operate risk.

For a much more detailed discussion of these prior events, please refer to our earlier coverage.

Terran’s Fast Filing on 4-OH-DiPT Prodrug

On Thursday July 13, 2023, a patent application titled Salts and Solid Forms of 4-Hydroxy-N,N-Diisopropyltryptamine Hemi-Glutarate and Hemi-Succinate was published. The PCT, filed by Terran Biosciences, includes claims to solid forms of 4-OH-DiPT hemiglutarate, the very same compound Reunion and Mindset have been competing over.3

The PCT claims the benefit of six provisional applications. Surprisingly, Terran’s first four provisional applications were filed on January 6, 2022, just one week after the broad nature of RE104 was uncovered for the first time following the publication of the company’s patent application on December 30, 2021. That’s an impressive turnaround, especially over the holiday season.

As Graham Pechenik noted in his December 30, 2021 twitter thread—the day Reuion’s patent application published—there was some uncertainty regarding which precise prodrug RE104 referred to, as the company’s published application included both “4-hemiglutarate & 4-hemisuccinate of 4-HO-DiPT”.

Accordingly, Terran’s first four provisionals included prophetic examples describing how to perform a salt and polymorph screen of the two 4-HO-DiPT prodrugs 4-hemiglutarate and 4-hemisuccinate that Pechenik had referenced in his Twitter thread. Solid forms of the prodrugs “having at least one improved property compared to previously known sold forms” were claimed (such properties still to be determined, given no screen had yet been done).

The company’s initial four prophetic provisionals, which were filed presumably in order to secure the earliest priority date possible, were followed by two further provisionals. This time the company included data that it had generated in advance of the June 30, 2022 filing date (having now done the salt and polymorph screen).

Based on the scope of Terran’s later provisionals, at this point the company refined its focus to cover only solid forms of 4-OH-DiPT hemiglutarate hydrochloride (HCl). This narrowed focus suggests that between filing its first and follow-on provisionals, Terran had determined the prodrug that was of particular interest to Field Trip/Reunion. Indeed, in a January 2022 press release, Field Trip disclosed: “The preferred prodrug, FT-104, comprises the endogenous, natural compound glutaric acid as a hemi-ester. As such, FT-104 has been given a common name, Isoprocin Glutarate, for simplicity.”

Indeed, despite claiming priority back to all six provisionals, Terran’s ultimate PCT only included claims covering 4-OH-DiPT hemiglutarate HCl.


The PCT includes a broad generic claim to “a solid form of 4-OH-DiPT hemi-glutarate hydrochloride”, a generic claim to the solid form “wherein the solid form is crystalline”, and several specific claims to the crystalline polymorph (as well as a pharmaceutical composition claim, and a number of method of use claims).

Terran’s generic “solid form” claim was found to lack novelty, in view of the disclosure in Field Trip’s patent application of a solid “white ‘cake.’” Terran’s generic  “crystalline” form claim was found novel, but to lack an inventive step, since even though Field Trip’s solid white “cake” was an amorphous form (and not crystalline), “it would have been obvious to one of skill in the art to crystallize the solid product.”

However, in the written opinion, Terran’s specific claim to its defined crystalline polymorph was found to satisfy the requirements for novelty, inventive step, and industrial applicability. This specific polymorph claim can now be pursued under the Patent Prosecution Highway (PPH), which typically leads to swift allowance in most countries (in the U.S., often in as little as six months).

If granted, Terran’s newly-published patent application would add a wrinkle of complexity to an already complicated intellectual property contest.

Wiggle Room for Reunion and Mindset?

In spite of Terran’s new patent application, both Mindset and Reunion maintain their claims to 4-OH-DiPT hemiglutarate (aka RE104) given their earlier priority dates.

Nonetheless, Terran—through its recently-published patent application—looks to be in a position to obtain claims that would block both from using this specific crystalline polymorph of the drug, and that would make it more challenging to obtain further claims on other crystalline forms of 4-OH-DiPT hemiglutarate.

While Terran’s efforts have thus limited the latitude of both Reunion and Mindset over the prodrug, should Terran (or any other party) wish to eventually pursue development of 4-OH-DiPT hemiglutarate HCl, it would still need to licence rights to the drug itself from both Mindset and Reunion (as each separately have compound claims covering the drug). However, there is no clear indication that Terran has a near-term intention of developing any of the compounds contained within its growing psychedelics patent portfolio.

CaaMTech Gets Scooped Too?

It doesn’t stop there, though. Private psychedelic drug discovery company CaaMTech has also publicised its foray into 4-OH-DiPT prodrugs. In September 2022, the company announced that it had synthesised and characterised “two novel prodrugs of 4-HO-DiPT”.

In the associated press release, CaaMTech were keen to point out how Field Trip/Reunion’s RE104 patent application described the solid form of its prodrug of 4-OH-DiPT as “an amorphous ‘white cake’”, with “[n]o crystalline material [..] reported, leaving questions about the identity of the compound in view of widespread ambiguity amidst different crystalline forms of structurally related tryptamines.”

One can only assume that CaaMTech filed a patent application prior to publicising these explorations. One might further presume that CaaMTech, a drug discovery company that appears to have little ambition for in-house clinical development, might have hoped to license these prodrugs to a drug developer like Reunion.

However, since no such CaaMTech patent application has yet published, it is possible that Terran might have scooped CaaMTech, too (although one might question whether the prophetic disclosure of a polymorph screen is sufficient to hold a priority date for claims to a specific polymorph—and thus CaaMTech could still have priority).

Closing Thoughts

To be clear: the dust is yet to settle here. We still await the verdict from patent examiners as well as information about the disclosure and priority dates of potential patent applications from CaaMTech, for example. The ‘fog of war’ surrounding 4-OH-DiPT prodrug intellectual property rights will continue to lift in the coming months.

However, even in lieu of this further information it’s clear that Terran’s IP strategy is going to cause headaches for parties that genuinely wish to develop drugs like 4-OH-DiPT, like Reunion and perhaps Mindset. What’s also clear is that it has the potential to add some drag to the apparent strategies of other IP-focused drug discovery outfits like CaaMTech.

It’s also evident that this is another blow to Reunion, further complicating any path forward for its lead candidate.

Perhaps the thing we know with most certainty, however, is that Terran must be paying their patent attorneys well—they filed a provisional in under a week when this author was enjoying the winter break with family, friends, and lots of food.

It’s also worth noting that this doesn’t seem like an isolated case on Terran’s part. Rather, it looks like it could be a core part of their strategy. We’ll have more on this in the coming weeks.

Generic Ketamine Appears Effective for TRD

An Australian study found that subcutaneous racemic ketamine was “efficacious and safe in treating [treatment-resistant depression] over a 4-week treatment period.” Interestingly, this trial used racemic ketamine, which is generic and cheap; especially when compared to Janssen’s Spravato esketamine product.

The authors were sure to note that, “adequately dosed racemic ketamine was shown to have superior antidepressant efficacy to an active control drug, with the proportional increase in remission comparing favourably to that of studies of intranasal esketamine tested against a non-active placebo.”

Might this study prompt a rigorous head-to-head trial of Spravato vs. bog-standard ketamine?

New VA/DoD PTSD Guideline Reviews Psychedelics

In June, the U.S. Department of Veterans Affairs (VA) and Department of Defense (DoD) released their latest clinical practice guideline for management of PTSD and acute stress disorder.

The guideline reviews the clinical evidence based in order to form clinical practice recommendations. Two of these recommendations substantially concern psychedelic therapies.

Recommendation 17 concerns psychedelic therapies broadly, stating that there “is insufficient evidence to recommend for or against psilocybin, ayahuasca, dimethyltryptamine, ibogaine or lysergic acid diethylamide for the treatment of PTSD.” This should be unsurprising, given the fact that none of these drugs are approved for this indication (or for any indication).

There is one psychedelic therapy that’s close to a potential approval for PTSD, though: MDMA-assisted therapy. As such, this is the subject of a dedicated recommendation (#23).

The VA/DoD guideline discusses the typical MDMA-AT protocol, as seen in MAPS’ late-stage trials, before recognising that “differences in the adequacy of blinding could have potentially biassed outcomes.” It further notes that MAPS’ trials “included few Veterans and no active duty Service members, limiting generalizability to VA and DoD population of interest.” For these reasons, among others, the Work Group deemed the quality of evidence to be “low”.

In terms of the feasibility of delivering MDMA-AT within the VA, the guideline does not have an optimistic tenor. “It would be challenging to implement MDMA-assisted psychotherapy in current VA and DoD health care systems”, the guideline states. “The treatment protocol requires a high investment of resources”, it continues, noting that the allocation of staff to MDMA-AT “could have negative impacts on access for other patients”.

The final verdict: “There is insufficient evidence to recommend for or against [MDMA-]assisted psychotherapy for the treatment of PTSD.”

While it’s not entirely unsurprising that the guideline reaches this conclusion, given the fact that MDMA-AT remains investigational, some might be concerned by the less-than-optimistic tone regarding resource allocation. Many hoped the VA would embrace MDMA-AT.

You Say “Psilocybin Treatment”, I Say “Psilocybin-assisted Psychotherapy”

A Commentary piece published in The American Journal of Psychiatry asks, “Must Psilocybin Always “Assist Psychotherapy”? It’s written by COMPASS Pathways CMO Guy Goodwin and co-founder and Chief Innovation Officer Ekaterina Malievskaia, as well as Greg Fonzo and Charles Nemeroff. The company also press released the paper.

The article purportedly aims to promote a re-examination of “common assumptions about the term ‘psychedelic-assisted psychotherapy’ and the role of psychotherapy when evaluating psilocybin treatment.”

For example, the authors argue that the intense subjective experience on psilocybin is “largely incompatible with simultaneous evidence-based psychotherapy”. As such, they follow, it is ‘psychological support’ that is an essential element of psilocybin therapy, as opposed to psychotherapy.

The authors acknowledge that the case might be different for MDMA-AT, given that the drug leads to “notably increased empathy and sociability”. However, they’re keen to point out that the “significant active interaction between patient and therapist” in MAPS’ protocol “raises multiple concerns about whether the drug effect per se is distinguishable” and “has inevitably raised ethical concerns because of the vulnerable state of the patient”.

Why might the use of the terms ‘psilocybin-assisted therapy’ or ‘psychedelic-assisted therapy’ move the authors to pen this article? Well, for the most part these authors are drug developers (as in the case of the two COMPASS C-suite members) or researchers that advise or consult with drug developers (as in the case of Fonzo and Nemeroff): i.e., they have their drug development hats on.

COMPASS is gunning for FDA approval, but FDA’s remit doesn’t conventionally extend to psychotherapy. What’s more, FDA expects to see a submission that’s formed of ‘adequate and well-controlled’ studies. Given the much-discussed difficulties of expectancy effects and blinding challenges in psychedelic studies, it’s in COMPASS’ interest to present as if they are able to disaggregate or isolate the pharmacological effect as much as possible.

We wrote about this broad topic in further detail as part of our 2022 Year in Review in the context of research on the importance of therapeutic alliance in psychedelic therapy outcomes:

COMPASS appears to be pitching [a] lack of relationship between therapeutic alliance and outcomes as a benefit, given that less emphasis on the therapy element (which is even described as “a safety measure”, in the poster) allows them to make the case that the drug is driving efficacy.

Contrast this pursuit of standardised, low-variance psychological support with the types of therapy seen in MAPS’ trials of MDMA-AT for PTSD, which provides a great deal of latitude. Beyond differing philosophies among trial sponsors, might it be the case that aspects like the quality of therapeutic alliance and the flexibility with which a therapist can operate are more important for certain drug-assisted therapies than others? Given the effects of an entactogen like MDMA, it may not be surprising if patients undergoing MDMA-assisted therapy might benefit from a more ‘involved’ facilitator or therapist; versus, say, a patient undergoing psilocybin therapy, which might be more introspective and as such the therapist could adopt a less involved approach. It’s also possible that the importance of therapeutic alliance might differ between conditions, as alluded to above.

While 2022 was a productive year for this research topic, there’s still a dearth of data. Given that we only have two post hoc analyses of controlled studies, which produced conflicting results, the causal effect of therapeutic alliance on patient outcomes–if any–remains unclear. Nevertheless, ongoing research and discussions, such as those highlighted above, will undoubtedly shed more light on this topic.

The present Commentary piece ruffled some feathers, as predicted by our Medical Advisor Michael Haichin. “Rush for the [conflict of interest] $ection on this one”, said psychedelic researcher Eduardo Schenberg.

ZI Mannheim researcher Moritz Spangemacher, meanwhile, suggested it was somewhat rich for the authors to highlight safety issues with MDMA-AT, given that the commentary was written by “the study team with the most [serious adverse events] in psychedelic research”.

“Whether you agree with these points or not, it raises a lot of important questions”, said researcher Matt Wall on Twitter.

Featured Psychedelic Jobs

Browse more roles and get more job posts to your inbox by signing up for alerts here. Make an account to join our free talent pool, too.

Miscellaneous News

UC Berkeley Poll Shows Support for Psychedelic Policy Reform in U.S.

The inaugural national poll from UC Berkeley’s Center for the Science of Psychedelics (BCSP) demonstrates significant support for psychedelic policy reforms across the United States, with 69% of voters polled endorsing at least two flavours of policy reform.

Despite this propitious context for reforms the poll suggests that some negative or equivocal perceptions of psychedelics persist. A majority of voters do not perceive psychedelics as “good for society”, while 69% said that they’re not “something for people like me”; an interesting result when considered alongside the fact that the same percentage of respondents endorsed some reforms.

Support for psychedelic policy reforms varies by type. For example, while 61% of respondents support regulated therapeutic use of the drugs, only 49% would support decriminalisation.

Discussing the survey, journalist and author Michael Pollan said that “nuanced debate in media, policy reforms, and public education programs will be most effective when informed by data-driven insights rather than assumption and conducted in thoughtful response to the hopes, fears, and perceptions held by different communities across the US.”

BCSP Executive Director Imran Khan, meanwhile, noted that the results also show that “some communities are being left out of an important public conversation”.

The results are worth diving into. You can find a summary from BCSP as well as a video briefing from Khan, Pollan and project lead Taylor West.

In the same week as these results were published, the city of Berkeley effectively decriminalised a number of psychedelics. Read more via Berkeleyside and SF Chronicle. (LSD didn’t make it into the final resolution—see our December 2022 reporting for info on the original version.)

EU Committee Asks for Devoted Funding for Psychedelic Research and Development

The Psychedelic Access and Research European Alliance (PAREA) reports that the European Economic and Social Committee (EESC) has adopted an opinion on Measures to Improve Mental Health that includes the following recommendation on psychedelic research:

“Regarding psychedelic therapies, which are emerging as a new class of groundbreaking treatments for conditions like severe depression, PTSD and alcohol use disorder, more research is needed in a controlled therapeutical [sic] setting. The EESC recognises the potential of these treatments and asks for devoted funding for promoting research, development and eventual commercialisation of them.”

Misc. Media Coverage

Independent: ‘A really wild coalition’: Republican Dan Crenshaw teams up with AOC on psychedelics in military treatment

STAT: As psychedelics near approval, there’s no consensus on how they work

STAT: How the political right came to back psychedelics to treat trauma

CNN: Australia ushers in a new era of psychedelic medicine

New Scientist: Do psychedelics treat chronic pain or is it the placebo effect?

WaPo: AOC, Dan Crenshaw and the mellow struggle for psychedelic drug access

The Times: Psychedelics by David Nutt review — are mushrooms medical magic?

Ecstatic Integration: Who pays the piper: Psychedelic media companies and the hype cycle

Independent: Joe Biden is ‘very open-minded’ about psychedelics, his brother Frank claims

LA Times: FDA widens door to research on psychedelics like ketamine, LSD for treatment of PTSD, depression. (Editor’s note: the door isn’t getting wider as a result of this draft guidance; just more well-defined.)

LA Times: Created in California: How Dr. Bronner’s became the soap for every subculture

Newsweek: I’m Giving $100 Million to Psychedelics Research:  

New: Ibogaine Patent Tracker

Our latest resource is now available to explore: the Ibogaine Patent Tracker. Here, Calyx Law has pulls together all of the ibogaine-related patents and published patent applications that were filed in the U.S. or that later may be filed in the U.S. and become a U.S. patent (as discussed in further detail here). 

Event: Cannabis & Psychedelics Investment Summit

Kahner Global’s 2023 Cannabis & Psychedelics Investment Summit will take place in New York City on November 16, 2023.

Those interested in attending can learn more and request an invitation via the website.

Editor’s note: In our reporting above, we originally wrote the following:

However, there is no clear indication that Terran has a near-term intention of developing any of the compounds contained within its growing patent portfolio.

We have since updated this sentence to clarify that the author was referring to the company’s psychedelics patent portfolio.

Weekly Bulletins

Join our newsletter to have our Weekly Bulletin delivered to your inbox every Friday evening. We summarise the week’s most important developments and share our Weekend Reading suggestions.

Live Updates

Join us on Twitter for the latest news and analysis.

Other Channels

You can also find us on LinkedIn, Instagram, and Facebook.

  1. With thanks to our Editor-at-Large, Graham Pechenik, for review.
  2. 4-OH-DiPT and 4-HO-DiPT are used interchangeably.
  3. Solid compounds, such as RE104, can exist in different crystalline forms that are referred to as polymorphs. Polymorphs differ “due to the arrangements of molecules within the unit cells of the crystalline lattice of each crystal form” (Anderson, 2012). In drug development, one important activity early on in the discovery process is the identification of an optimal and patentable solid form of a drug candidate, as varying forms, despite being the same compound, can exhibit very different stability, pharmacokinetics, and more.