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Patent Analysis: Lykos Suffers Blow from USPTO As All Patent Claims Stand Finally Rejected

The future direction of MDMA drug developer Lykos Therapeutics is uncertain on many fronts since the FDA rejected its new drug application last Summer. Questions abound, including: What will the outcome of the independent review of its Phase 3 program be? What does the path to resubmission look like? Will the company secure the funding it needs to continue on that path? What might the priorities of those funders look like?

Now, there’s another major question looming over the company: Will it be able to secure any meaningful intellectual property, like patents, to protect its MDMA product?

That is the subject of our latest Patent Analysis, which takes a deep dive into the company’s patent strategy, the USPTO’s apparent dim view of its application, and where it might go from here.

At over 6,000 words it really is a deep dive, which gets quite technical in some areas.

Looking for the TL;DR?

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Written by Noah Smith with support from Editor-at-Large and patent attorney Graham Pechenik of Calyx Law.

Note: We’re making this issue of our Patent Analysis free to read. To receive all of these issues, including regular browsable databases of recent psychedelics-related patent actions, subscribe to Pα+ today. Besides our patent-related content, you will receive our regular Bulletins, exclusive interviews and our independent coverage of the field.

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    Last June we broke the news that, in a notable departure from MAPS’ historical anti-patent stance, the nonprofit’s for-profit spinout Lykos Therapeutics had moved to patent its formulation of MDMA (see Lykos Therapeutics Moved to Patent MDMA In Late 2022, Filing Reveals). The effort appears to be part of the company’s larger commercial endeavour to evolve from its non-profit progenitor into a more conventional (albeit still somewhat non-traditional) pharmaceutical company.

    Last January, a decade or so since its founding, the subsidiary of the non-profit MAPS, MAPS PBC, was officially rebranded as Lykos Therapeutics. Along with the rebrand announcement came news of a $100+ million Series A financing round, providing the company with more of the financial support it needs to bring its MDMA drug candidate to market (see MAPS PBC Closes $100m Series A, Rebrands to Lykos Therapeutics).

    While the investment, led by Helena Special Investments, was a significant break from MAPS’ historic reliance on philanthropic support, the need for such a large injection of funds was not surprising in view of the high costs of drug development and commercialization. Perhaps, then, it was Lykos’ pursuit of non-philanthropic funding that necessitated efforts to establish a stronger moat around its drug candidate in order to make the company more attractive to would-be investors, especially given the ever-increasing level of competition around MDMA and related compounds.

    What’s more, in early August the FDA issued a Complete Response Letter (CRL) to Lykos’ New Drug Application (NDA) and requested an additional Phase 3 study, leaving the company in a very challenging position that will require a fresh injection of capital (see FDA Rejects Lykos Therapeutics’ MDMA-Assisted Therapy For PTSD).

    Shortly thereafter, in a clear effort to conserve its cash runway, Lykos announced an internal “reorganization”, eliminating approximately 75% of its workforce. Then, in October, following a meeting with the FDA, Lykos appeared to confirm that the path forward for its MDMA development program would include an additional Phase 3 trial.

    For now, securing funding for the future development, approval, and roll-out of MDMA is a priority for Lykos, with two competing visions and directions currently being fought over. (See Billionaire Investor Antonio Gracias Plots $100M Lykos Takeover with Doblin’s Backing.)

    The strength and prospects of Lykos’ intellectual property will be a key consideration for the future direction of the company, making now an opportune time to dig a little deeper into Lykos’ patent application…

    Anti-Patent Strategy Leads to Lykos’ Late Filing, Focus on the “Particle Size” of its MDMA

    TL;DR: MAPS’ historic “anti-patent strategy” means Lykos was late to the game in filing patent applications on MDMA, leading it to pursue an arguably shaky strategy: claiming specific particle sizes.

    As we shared in our earlier article, owing to a 1912 patent from the pharmaceutical company Merck and a plethora of prior art, MDMA has long been regarded as “non-patentable.”

    While this reality holds true for MDMA as a compound per se (or as a racemic mixture), in recent years numerous companies have pursued (and some have already obtained) patents on new salts and polymorphs of MDMA, on the R-enantiomer of MDMA, and on non-racemic preparations of MDMA; applications have also been filed on methods of using MDMA, such as for specific indications, or in specific therapeutic protocols. (For more, see Patenting MDMA, its Enantiomers and Mixtures Thereof from our February 2024 Patent Analysis.)

    As noted in our earlier article, Rick Doblin’s 1985 proposal for “A Psychedelic Medicine Pharmaceutical Corporation” asserted that “[alt]hough “MDMA could not be patented, a version of MDMA
could be.” Indeed, Doblin’s proposal stated: “The first research project of the newly formed company would be to explore various possible chemical modifications of the basic MDMA molecule”, in pursuit of “new compounds that could be patented”.

    Above: An interactive table of patent filings covering MDMA and its enantiomers.

    Unfortunately for Lykos, no patents on any new “version of MDMA” were ever pursued, as MAPS had instead decided to adopt an “anti-patent strategy”. This forbearance in pursuing IP left its competitors with the latitude to lay claim to swaths of the MDMA-related white space. Despite leading one of the earliest psychedelic commercialization efforts, Lykos’ late decision to pursue IP consequently meant the company was limited in what was still available to be patented, and especially limited with regard to any new “version of MDMA”, as a novel form could require extensive new preclinical and clinical studies.

    Nevertheless, drawing on common industry strategies, in December 2022 Lykos filed its first of four provisional patent applications covering its drug candidate and the company’s specific MDMA formulation. Then, in December 2023, claiming priority to these four provisionals, the company filed its first ‘international’ Patent Cooperation Treaty (PCT) application.

    Lykos’ PCT application (which published June 13th as WO2024/123706) contains claims largely focused on MDMA of specific “particle sizes.”1 At its broadest, the application claims a “composition comprising 3,4-methylenedioxymethamphetamine (MDMA), or a pharmaceutically acceptable salt and/or solvate thereof, and one or more pharmaceutically acceptable excipients, wherein the average particle size is from about 50 ”m to about 400 ”m.” 

    Dependent claims are more limited in scope, also containing the particle size limitations but further honing in on specific salts (MDMA hydrochloride), excipients, diluents, dosage forms, and more. The company also, unsurprisingly, includes claims directed towards methods of using the compositions and dosage forms to treat post-traumatic stress disorder (PTSD), the subject of its ill-fated NDA. Interestingly, Lykos also claims its compositions for use in the treatment of eating disorders, which may be suggestive of the company’s original indication expansion plans.

    For more on the specifics of Lykos’ patent applications, including the particle size strategy, read our earlier coverage: Looking Under the Hood of Lykos’ Patent Apps. (June 13, 2024).

    LYKOS USPTO APP

    To What End?

    TL;DR: Lykos pays to fast-track examination of its U.S. patent application, presumably hoped IP would extend its market exclusivity.

    In our earlier article on Lykos’ PCT, we shared that the company had until June 5th and July 5th, 2025 (i.e., 30 and 31 months from the earliest priority date) to enter national and regional phase applications in any of the 157 PCT contracting states. Accordingly, we discussed how it may be many months, or even years, before the company’s resulting national phase applications undergo any substantive examination, sharing that a U.S. application from Lykos may not reach final disposition until some time in 2028.

    However, we noted that Lykos “also could enter national phase early, and could pay to “fast track” its examination in the U.S.” The company in fact committed to this type of aggressive strategy, filing its resulting U.S. patent application (US 18/611,564) as a “bypass continuation” on March 20, 2024, just over three months after its PCT, rather than waiting a full 30 months to file in the U.S. In addition to the company’s swift filing, Lykos filed a Track One request with the USPTO, seeking prioritized examination for its U.S. application.

    The request was granted on June 6, 2024, one week before the company’s PCT published, and it has indeed helped expedite the start of prosecution, which could otherwise take over 20 months from filing to begin. On July 16, 2024, the company received its first office action, a restriction requirement requesting that the company elect a narrowed set of claims to allow the Examiner to more efficiently search and appraise Lykos’ application.

    In early August, Lykos elected to have claims 33-52 of its application searched, which are directed to the company’s pharmaceutical composition (withdrawing from examination its method of treating PTSD claims). Then, on September 6, Lykos received the result of the first substantive examination of its claims: a non-final office action rejecting all claims.

    Between the receipt of its restriction requirement and the most recent final office action (discussed more below) Lykos received a complete response letter (CRL) from the FDA, rejecting its NDA in its current form. While the CRL is not a death blow to the company’s development program, as the company emphasized in an October 2024 statement, it means that Lykos will now be required to conduct an additional Phase 3 clinical trial, pending the outcome of an independent review of its existing program, in order to resubmit the NDA.

    Despite the present lack of patent protection for its drug candidate, should the company eventually see its MDMA HCl drug product approved by the FDA, Lykos would still be sheltered from competition for the duration of the 5-year data exclusivity period afforded by the FDA.

    However, given what would presumably be a slow rollout of an unprecedented treatment modality that includes both a drug and psychotherapy (a sticking point for the FDA Advisory Committee), a relatively short 5-year period of exclusivity (not including any extensions afforded through, for example, Pediatric Exclusivity) may not give the company enough time to recoup the costs of development and commercialization, or generate sufficient profits to reinvest into new indications, drug candidates, and patient support programs
 or to satisfy investors.

    For example, Spravato, launched in the United States in March 2019, has steadily seen its revenue increase year over year. With annualized projections for 2024 resting at just under $1 billion, Spravato is now, after 5 years on the market, nearly reaching ‘blockbuster drug’ status. Unfortunately for Lykos, making MDMA-assisted therapy a commercial success will be even harder than Spravato, given its longer duration of action and much more involved facilitation requirements.

    In the absence of any further protection, a company reaching the end of its FDA-afforded exclusivity period would experience immediate downward pressure on profits from generic erosion, just as the drug was reaching the most profitable stage in its lifecycle.

    There is consequently a clear financial incentive for maintaining market exclusivity. In fact, every day that the period sheltering a billion dollar drug from competition is extended could earn a company an additional $2.7 million dollars in revenue. It is unsurprising, then, with stakes so high, that a company such as Lykos would want to fend off competitors for as long as it conceivably could, and one common means of extending exclusivity is through the use of pharmaceutical patents.

    Strength of the Patent

    TL;DR: Lykos narrows its claims, which could provide latitude for competitors to avoid infringing any eventually-issued patents by bringing an MDMA product to market with different particle sizes or as a different salt.

    Owing in part to the long-held anti-patent stance at MAPS, Lykos—relative to its competitors—is quite late to file for protection of its lead (and sole) drug candidate. Combined with MDMA’s crowded prior art landscape, the company, like others vying for MDMA-related patents, was surely limited in its ability to acquire broad exclusory IP, such as composition of matter patents. One might therefore question what value any patents resulting from Lykos’ application could have.

    Following the expiration of any regulatory exclusivity, might a resulting patent be strong enough to help the company ward off generic competition? In other words, might a competitor simply be able to work around a Lykos patent?

    Because claim scope can (and generally does) change during examination, it is difficult to fully appraise the strength of any eventually issued patents (should they be allowed). Nevertheless, as we shared in our earlier article, some industry experts have regarded particle size patents as a form of IP that “may be easily circumvented.”

    However, depending on the scope of any granted Lykos claims, the company could conceivably prevent would-be competitors from marketing generic MDMA.

    For an Abbreviated New Drug Application (ANDA) to be approved, a company must demonstrate that its generic product is bioequivalent to the name-brand drug on the market. The generic drugs are, accordingly, “expected to have [the] same clinical effect and safety profile when administered to patients under the conditions of use specified in the labeling” (Wang, 2022).

    To this end, 21 C.F.R. § 320.23(b) provides that a generic will be considered bioequivalent if its “rate and extent of absorption do not show a significant difference when administered at the same molar dose of the active moiety under similar experimental conditions, either single dose or multiple dose.”

    Depending on the breadth of any eventually allowed claims, a generic competitor may find it needs to infringe Lykos’ patent in order to develop a formulation that meets these legal standards for bioequivalence.

    Particle Sizes

    For example, if Lykos’ PCT claims in their broadest present form were to be allowed, any competitor seeking to develop a bioequivalent formulation would be precluded from marketing a composition containing MDMA “or a pharmaceutically acceptable salt and/or solvate thereof, and one or more pharmaceutically acceptable excipients, wherein the average particle size is from about 50 ”m to about 400 ”m.”

    The competitor would therefore be forced to develop a composition with an average particle size outside of this range to avoid infringing these claims. However, given the impact of particle size on drug bioavailability (see e.g., Mok, 2024), there is no guarantee that such a composition would be bioequivalent. Consequently, in its broadest theoretical form, a patent from Lykos may be able to provide the company with the exclusivity needed to prevent generic entry for the duration of its term.

    However, with the resulting U.S. application now published, it is clear that Lykos has made considerable amendments to its claim set, cancelling its original 32 claims and including a number of further narrowing limitations in the newly-presented 30, likely in an effort to overcome obviousness hurdles such as those identified in the Written Opinion (WO) of the International Searching Authority (ISA) received by the company for its PCT.

    In the WO, Lykos’ first three claims (the only three for which an opinion was provided)—which claim particle size ranges in ranges of about 50 ”m to 400 ”m, 75 ”m to 200 ”m, and 100 ”m to 200 ”m—were each found to be obvious over Awakn Life Science’s application published as WO2022/150525, MDMA in the Treatment of Alcohol Use Disorder2.

    While Awakn did not specifically claim a composition with limitations on average particle size, the Examiner stated that, in view of Awakn’s disclosure, “it would have been obvious to one of ordinary skill in the art to change the particle size through routine experimentation”.

    In support of this view, the Examiner cited paragraph 201 of Awakn’s application, which states that, “In preparing a formulation, it may be necessary to mill the active agent [e.g., MDMA] to provide the appropriate particle size prior to combining with the other ingredients. If an active agent is substantially insoluble, it ordinarily is milled to a particle size of less than about 200 mesh.”

    Notably, in the case between Cephalon and Mylan mentioned in footnote 1 (see Hayes, 2011), Cephalon’s patents, with claims directed towards compositions with particle size limitations, were found to be obvious. Like the reasoning included by the Examiner in the Lykos WO, modifications made to particle sizes were deemed to be a part of routine investigation aimed at improving drug bioavailability.

    It appears that this view is also shared by at least one of Lykos’ competitors. When asked about his general impressions of the Lykos application last summer, PharmAla CEO Nick Kadysh shared with Psychedelic Alpha that, “Generally speaking, I think the patent has some obvious(ness) issues, pun intended. I’m not an IP expert, but generally, I think particle-size patents are relatively weak, and subject to both difficulties in patent granting and subsequent post-patent challenges. Per Lykos’ patent application, their manufacturing process typically creates 90% of their MDMA particles in the range of 800-1600 microns, so they had to create a process to reduce their particle size (which they patented). PharmAla’s manufacturing process already yields a majority of MDMA particles less than 250 microns in size, so we didn’t have the same problem.”

    It is important to note that the WO is a preliminary and non-binding assessment of the PCT claims and national phase Examiners conduct their own independent assessments of the patentability of Lykos’ claims. However, the WO can nonetheless provide the company with insight into how subsequent Examiners (such as the company’s assigned U.S. Examiner) might appraise Lykos’ claims.

    In view of the WO, given that modifications made to particle sizes for drug formulations were, (and have previously been) considered to be a part of “routine experimentation”, Lykos was surely aware of the struggle it would face in securing allowable claims to the broad ranges claimed in its PCT. Lykos, in its U.S. application, accordingly amended the claims it presented for examination to evidently focus more closely on the optimal average particle size arrived at for its formulation and to align more with its supporting data.

    The company’s early set of amended claims featured a number of narrower limitations. For example, the first outstanding claim, claim 33, included limitations related to dose amount (about 34 mg or 50 mg), the solid form of the API (MDMA HCl “on a free base basis”), average particle size (50 to 610 microns), a particle size range limit (less than 400 microns), and distribution of particle size in the composition (Dv90 of less than 420 microns). 

    Any move to more narrowly limit claims may eventually come at a cost. Here, for example, were Lykos’ ultimately granted claims limited to very narrow ranges and parameters of particle sizes, a generic competitor could, in theory, more easily circumvent Lykos’ patent, while maintaining an acceptable degree of bioequivalence (see, e.g., Chow, 2014).

    However, as discussed further below, that a generic drug product should ultimately be found not to infringe would not be the end of the story, since even a narrower patent could be listed in the FDA Orange Book, and—as long as Lykos could bring reasonably supported, even if ultimately losing, infringement claims—the company would still be afforded an additional (and automatic) 30 months of exclusivity while its infringement allegations are heard by a court.

    While this may not provide the exclusivity period of a stronger patent (which would not expire until, at the earliest, December 4, 2043), it would still afford another 30 months. But, as also discussed below, even losing claims may not be able to be brought against some ANDA or 505(b)(2) applicants.

    Salts & Solvates

    In addition to claiming broad particle size ranges, in its PCT, Lykos also generically claimed compositions comprising MDMA “or a pharmaceutically acceptable salt and/or solvate thereof.” While the company’s later dependent claims specify the hydrochloride salt of its MDMA drug product, Lykos’ broader claims included no such limitations.

    Accordingly, if the company were to have such broad claims allowed, they may be able to wield them in a manner that could also exclude competitors from advancing new solid forms of MDMA.

    As we’ve discussed in previous issues (see Psychedelic Patent Analysis: February 2024), one such competitor is Terran Biosciences, which has positioned itself to take advantage of Lykos’ limited IP moat. The company has developed and patented its own salt forms of MDMA (e.g., MDMA hemifumarate) that it intends to seek approval for immediately following the expiration of any FDA-afforded data exclusivity using the 505(b)(2) pathway, according to public comments made by its executives.

    However, like the particle size amendments discussed above, Lykos has also narrowed the claims in its U.S. application to cover only the hydrochloride salt form of its drug product.

    Should any future allowed claims continue to be limited to its hydrochloride salt form, a competitor advancing an alternative salt form through the 505(b)(2) pathway would presumably not face the same infringement concerns that a generic competitor seeking approval through the ANDA pathway might.

    After all, while 505(b)(2) applicants are expected to establish a bridge between their alternative product and the listed drug, they may leverage the pathway to seek approval for a product with changes made to the active ingredient, such as a new salt form (Ball & Alenci, 2015). Two such examples are Dr Reddy’s Laboratories’ Amvaz and Noven Therapeutics’ Pexeva, which were both new salt forms of existing reference products previously approved under the 505(b)(2) pathway (Prasad et al., 2014).

    In an August 2024 statement to Psychedelic Alpha, Terran Biosciences CEO Sam Clark shared that the company does not believe such a patent would stand in the way of their competitive aims. “Terran is committed to bringing accessible and affordable treatments to patients as quickly and efficiently as possible”, he said, adding that the company “plan[s] to utilize our novel patented form of MDMA and the 505(b)(2) pathway to accomplish this and do not believe the Lykos patents would prevent us from this goal.”

    With Lykos now likely to be required to complete an additional Phase 3 trial, competitors that have been positioning themselves to commercialize generic MDMA may now need to wait for the better part of a decade before seeing their candidates on the market owing to the sum of Lykos’ added drug development time and the company’s minimum potential exclusivity period.

    In view of the FDA’s decision, Terran further shared with Psychedelic Alpha in August that it is “evaluating multiple paths forward (including 505(b)(2) and 505(b)(1)) for our own novel patent-protected form of MDMA, and remain excited about the opportunity to develop cost-effective and accessible therapies for the millions of patients suffering from PTSD and other mental health disorders.”

    New Examinations, New Dilemmas

    TL;DR: Examination of Lykos’ U.S. application presents new challenges for the company: Examiner rejects all claims, finds the company’s counter arguments unpersuasive.

    First Office Action

    On September 6, 2024, the results of the first substantive examination of Lykos’ U.S. application (US 18/611,564) posted. The Non-Final Office Action (NFOA) introduced a number of new challenges for Lykos, not least because it was from an Examiner with notably high standards (her “difficulty ranking” according to one widely-used platform is “Extremely Hard”—in the 94th percentile, with only a 23% chance of getting an issued patent after three years of prosecution).

    First, through the course of examining Lykos’ claims, the Examiner found that none of the company’s four provisional applications “provide adequate support or enablement 
 for one or more claims of this application.” Specifically, the Examiner took aim at the upper limit of the average particle size range in the company’s claims.

    Lykos, in claim 33, included an upper limit for its average MDMA particle size of 610 ”m. However, the Examiner asserted that “such a value for the average particle size was not disclosed in any of” Lykos’ provisional applications. Consequently, the Examiner found that Lykos could not claim the benefit of the priority dates of its provisional applications. Instead, the company’s effective filing date (and now the priority date for its claims) was found to be December 4, 2023, the day Lykos’ PCT was filed.

    Such a finding meant that Lykos could have had to contend with another year’s worth of prior art, and any relevant “intervening” disclosures published before December 4, 2023, but after its provisionals, could be used to argue against the patentability of the company’s claims.

    Though, for some of the company’s claims, third party prior art was not even required for the Examiner to issue a rejection. Instead, the contents of Lykos’ own specification, or in this case what was not included, was sufficient for the Examiner to reject claims 41-52 for failing to comply with the written description requirements.

    Each of dependent claims 41 through 52 were directed to compositions with pharmacokinetic limitations (e.g., Cmax, Tmax, and area under the curve). However, the Examiner found that Lykos’ “specification does not even provide general guidelines as to a structure-function relationship between the pharmaceutical composition and the resultant pharmacokinetic parameters.”

    The claims were therefore found to not be supported by a specification that contains “a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art 
 to make and use the same”, and were rejected accordingly. 

    Unfortunately for the company, the Examiner’s initial rejection of Lykos’ amended U.S. claims was not limited only to claims 41-52. As we discussed above, while a PCT Examiner’s WO is a preliminary and non-binding assessment, it is often instructive for an applicant as it can point to how an Examiner may treat their claims during national prosecution.

    For Lykos this appears to have been especially true, with their assigned Examiner citing the same piece of prior art referenced in the WO, the Awakn PCT (WO2022/150525), this time in a rejection of all of the company’s presented claims.

    Awakn’s application was used by the Examiner both alone and in combination with other references to find all of Lykos’ claims obvious. As aforementioned, Awakn’s application discloses compositions of MDMA and mentions the necessity of  “provid[ing] the appropriate particle size” in “preparing a formulation”.

    In Awakn’s application, the company states that certain active agents can be “ordinarily milled to a particle size less than about 200 mesh”, which, as Lykos’ Examiner explained, “corresponds to openings of about 89 microns 
 or about 74 microns.”

    While Awakn did not provide any working examples for compositions of MDMA with particular average particle sizes or ranges, the Examiner found that it would have nevertheless been obvious for one of skill in the art “to mill the MDMA active agent to an appropriate particle size such as less than 200 Mesh” and that in doing so, arrive at a particle size that falls within the range claimed by Lykos.

    This overlap in particle size ranges is, according to the Examiner, “prima facie obvious absent evidence as to the criticality or unexpected properties of the claimed particle size and/or particle size distribution.” In the absence of such evidence, Lykos’ claims were all rejected.

    It appeared then that Lykos needed to show that their particle sizes are demonstrably—and unexpectedly—better than those disclosed in the prior art (e.g., Awakn’s <200 mesh / <~74 micron), or otherwise find a way to carve out specific ranges (or add other limitations) that it can convince the notoriously difficult Examiner are not obvious.

    ‘Final’ Office Action

    After receiving its non-final rejection, Lykos was given until December 6, 2024 to respond to the Examiner with its counter arguments in order to maintain Track One status. One day before that response deadline, Lykos replied to the September 6th office action by further amending its claims and submitting supporting arguments.

    In response to the issues of support by its provisional applications and the corresponding priority date challenges discussed above, Lykos amended its claimed size range to be an “average size particle size of 50 ”m to 400 ”m.” Unlike the company’s earlier claimed upper limit of 610 ”m, Lykos claimed that this newly amended range was supported by a December 5, 2022 provisional application.

    Lykos then turned its attention to Awakn’s WO’ 525, the primary piece of prior art relied on by the Examiner to support the finding that all earlier claims were obvious. Lykos argued that the prophetic examples included in Awakn’s PCT are “completely silent” with respect to the particular HCl form of MDMA and the particle size limitations found in the company’s claims.

    Consequently, the company argued that the “general statements” found in the Awakn PCT “provide no meaningful guidance to the skilled artisan regarding selection of a specific particle size for MDMA freebase or MDMA HCl,” nor any “reasonable expectation” that selecting other parameters for the salt form and particle size—such as the “specific parameters recited in the pending claims”—“would provide a safe and effective formulation of MDMA”.

    Citing case law, Lykos pointed to the array of dosage amounts including “every possible dosage value from 1 mg to 200 mg” disclosed in Awakn’s PCT to argue the obviousness rejection should be overcome on the basis that the amounts disclosed by Awakn embrace “nearly every conceivable safe amount of MDMA that a dosage form of MDMA can reasonably include.” Accordingly, Lykos held that such a broad disclosure could not “teach or lead a person 
 to any particular dosage amount.”

    In other words, the encompassing breadth of the embodied amounts were said to not provide any specific guidance or teaching to arrive at the amounts Lykos claimed. This lack of specificity, according to Lykos, undermines the finding that the claimed dosages were obvious.

    Instead, the company, with reference to various prior MDMA studies, claimed that “the dosage amounts recited in the claims were discovered through extensive experimentation and careful selection to provide modular dosing to treat various disorders, e.g., PTSD and eating disorders”. This line of reasoning was used to support the argument that, even in view of the disclosures in Awakn’s PCT, one skilled in the art “could not have predicted the effect of the claimed dosage amounts
 for treating disorders such as PTSD.”

    While the amendments made by Lykos did allow the company to once again claim the benefit of its earliest December 2022 priority date for claims 33 through 44, the arguments put forward in response to the Examiner’s non-final rejection were not as fruitful. On December 19 2024, Lykos was mailed a final rejection in which the Examiner found all of Lykos’ arguments to be “unpersuasive”. As a consequence, all earlier obviousness rejections were maintained.

    The Examiner found that just because Awakn’s prophetic examples did not specify the use of MDMA HCl in the specific claimed “about 34 or about 50 mg of [MDMA] on a free base basis” amounts does not make Lykos’ claims non-obvious, “when the entirety of the contents of the applied prior art and the knowledge of one of ordinary skill in the art is taken into account”. The Examiner observed that the dose amount of an active ingredient “is a parameter that would be routinely optimized” and that Awakn “provides a range of possible values to begin the optimization process and [Lykos’] claimed amounts lie squarely within [Awakn’s] disclosed range”.

    Unfortunately for Lykos, the Examiner was therefore not persuaded by the company’s assertion that the “dosage amounts claimed were discovered through extensive experimentation and careful selection.” Instead, the Examiner held that there was a “lack of evidence showing the criticality of the claimed parameters”, supporting a finding of obviousness.

    Were Lykos to provide comparative evidence showing an unexpected or surprising difference over the prior art—for example, through a “comparison with other dosage forms with different amounts of MDMA free base,” or with MDMA “in a different form (e.g., free base versus HCl salt) or particle size”—Lykos may be able to demonstrate that its claimed formulations are non-obvious. In the absence of such comparative evidence, Lykos’ claimed dose amounts and particle sizes are found by the Examiner to be variations of “parameters that would be routinely optimized” for a known therapeutic molecule, and consequently, obvious in view of the prior art.

    What’s Next?

    TL;DR: A look at the potential path ahead for Lykos, which could include narrowing its claims, presenting new legal arguments, and demonstrating with evidence that its claimed MDMA composition is surprisingly superior to prior art MDMA compositions.

    Fortunately for Lykos, the final rejection mailed on December 19, 2024 is not necessarily the end of the road for its IP pursuits. The company has until the March 19, 2025 deadline (which can be extended for a fee until June 19, 2025) to decide its next steps.

    Lykos may elect to file a request for continued examination (RCE), allowing it to once again make amendments or arguments in an attempt to overcome the rejections maintained by the Examiner. Alternatively, Lykos may elect to abandon its US 18/611,564 application in favor of a continuation application with a new set of refined claims, or a continuation-in-part (CIP) that includes new subject matter. Lykos also could choose to appeal the Examiner’s decision to a panel of administrative judges at the Patent Trial and Appeals Board (PTAB).

    Irrespective of the course of action chosen by the company, in order to overcome the obviousness hurdles before it, it is evident that Lykos will need some compelling combination of narrowing limitations, legal arguments, and likely experimental evidence, such as demonstrating through supporting comparative data why its claimed dose amounts or particles sizes are surprisingly superior to those disclosed in the prior art (e.g., Awakn’s exemplary dose amounts of 62.5 mg and 125 mg, and particle sizes of <200 mesh / <~74 micron).

    Given that the company’s existing working examples include samples with particle sizes that fall within Awakn’s range, supporting its claims by way of comparative tests could require Lykos to generate new data. This could entail producing, or at the very least milling, more MDMA for the experiments. With the deadline to reply fast approaching, it’s not clear whether Lykos could obtain comparative data on such a tight timeline, at least for inclusion in the upcoming response.

    Lykos could potentially also amend their claims to try to more substantially work around the prior art cited by the Examiner. However, by doing so, Lykos might compromise the value of its patent by providing a generic competitor with documented and arguably non-infringing amounts or ranges to manufacture (assuming bioequivalence), as any portion of a range narrowed to avoid prior art could be found “disclaimed” and outside the enforceable scope of the claims. Further, there is no guarantee that amendments alone would be sufficient to satisfy the Examiner that Lykos’ claims are non-obvious.

    Instead, as mentioned, Lykos will likely need to argue that its claimed MDMA composition has some (evidenced) unexpected or surprising advantages. But these arguments could have wider implications beyond just determining the patentability of their claims: Even if Lykos can produce the necessary data to support an argument for the unexpected effects of its range, it will need to be mindful not to contradict the information it already provided to the FDA.

    A 2022 review from S. Sean Tu describes challenges that arise from applicants who present conflicting information to the FDA and USPTO, writing: “On one hand, an applicant might make statements to the FDA that a particular element of the invention was known and well established to avoid safety and efficacy questions. On the other hand, that same applicant might make statements to the USPTO about that same element arguing that the element was unexpected and novel to avoid an obviousness rejection, which would prevent patenting.”

    While we can’t say with certainty what sizes and ranges of particles Lykos uses in its drug product, or if that product does in fact contain particles difficult to distinguish from those described in Awakn’s application, it may be a challenge for Lykos to argue that its product is differentiated (e.g., possesses unexpected properties) without suggesting to the FDA that previously submitted data, such as provided in its Chemistry, Manufacturing, and Controls (CMC), may need to be revisited.

    What Value Remains?

    TL;DR: Even if any eventually-issued patent is too weak to ultimately block competitors from marketing generic MDMA, Lykos might still benefit from a 30 month stay via Orange Book listing.

    Should a Lykos patent not preclude a competitor from advancing and marketing an alternative salt or particle size of MDMA, what value might the patent have? Assuming Lykos addresses the deficiencies identified by the FDA in its CRL, eventually earns approval for midomafetamine, and is successful in acquiring patent protection for its drug candidate, the company would be required to list the patent in the FDA’s Orange Book.

    Subsequently, any generic (ANDA) or 505(b)(2) applicant seeking to market a competing product during the patent term would be required to submit a “Paragraph IV Certification.” This certification would affirm Lykos’ patent “is invalid or will not be infringed by the manufacture, use, or sale of” the applicant’s MDMA product (21 U.S.C. § 355(b)(2)(A)(iv)). Notice would then be sent to the patentee/NDA holder (Lykos), at which point Lykos could commence an infringement suit.

    Electing to commence a suit triggers an automatic stay of FDA approval for the ANDA or 505(b)(2) application for either 30 months or until a period of 7.5 years from the drug’s original approval date. In effect, the stay enables a patent holder to extend their exclusivity until the stay expires. The stay can be terminated early if a court issues a final decision finding the patent invalid, unenforceable, or not infringed—a potential concern for Lykos, for instance if they are forced to very narrowly amend their claims to win allowance, and leave a clear non-infringement position that could be decided on summary judgment.

    Nevertheless, as discussed above, each additional day a company preserves its market share can yield a substantial financial gain. As such, at a minimum, the value of a Lykos patent, and the incentive for it, can presumably be traced to its ability to enable the company to lengthen its period of exclusivity by way of the FDA stay.

    Now, in the absence of approval from the FDA, the value of any future patents from the company may be severely diminished. However, should Lykos elect to rectify the deficiencies identified by the FDA in its CRL, the company would require another cash injection from investors. Such a commitment may be more appealing to parties keen on seeing a return on their investment now that the company has an, albeit difficult, path to extending any eventual period of exclusivity, and its revenue therefrom—especially when that additional period of exclusivity could come right at the point when the market for Lykos’ MDMA has reached maturity and significant revenue is starting to roll in.

    A Lykos representative told Psychedelic Alpha: “This most recent USPTO office action is another step in the application process and a common result at this stage. As is normal practice, we are thoroughly reviewing the examiner’s comments and intend to respond to the office action in the near future. We remain confident in the strength of the application.”

    Pα: The United States Patent and Trademark Office (USPTO) has dealt a substantial blow to Lykos’ hopes of realising meaningful patent protection for its sole and lead candidate, MDMA-assisted therapy (or, ‘midomafetamine capsules’) for PTSD.

    Last year, a USPTO Examiner doubled down on criticisms presented in an earlier written opinion, citing an Awakn Life Sciences PCT publication—both alone and in combination with other prior art—as reason to reject all of Lykos’ claims as obvious.

    What’s more, the MDMA drug developer’s attempt to rebuke the sweeping rejection with its own counterarguments fell flat, with USPTO finding all arguments unpersuasive and maintaining its rejections of all claims in the application, according to a final rejection mailed by the office in December 2024.

    To move forward, it appears Lykos must either narrow its claims substantially or provide evidence that its claimed composition has unexpected properties—or both. The latter would likely require further studies, a challenging task and one that could risk ruffling feathers at the FDA: If Lykos tries to demonstrate to the patent examiner that its claimed MDMA composition has unexpected properties compared to previously known compositions of MDMA, it could raise a question of whether the data provided to the FDA is representative of the composition presented to the Patent Office, such as relating to the Chemistry, Manufacturing, and Controls (CMC) package.

    Should Lykos instead seek to narrow its claims, for example by tightly defining the recited particle size limitations, it could present would-be generic competitors with a strong non-infringement argument, such as by providing clear parameter boundaries for particle sizes to work around. In doing so, generic entrants could see a green light to bring a product to market by staying outside of those boundaries, assuming their resulting products could be found bioequivalent to Lykos’.

    Even if Lykos is successful in securing a patent with narrowed claims, and/or in demonstrating that its claimed composition has surprising properties or effects, competitors like Terran Biosciences might still be able to bring other salt forms, like MDMA hemifumarate, to market during the patent’s term, which in stating that they “do not believe the Lykos patents would prevent us from this goal” they have already made clear.

    It’s a challenging situation for Lykos, which is in the midst of securing funding following its August FDA rejection, the current independent review of its Phase 3 program, and the prospect of conducting another Phase 3 study in order to resubmit its NDA years down the line.

    While some of the Office’s skewering might be down to an unlucky assignment to one of the strictest Examiners in the Technology Center, that is only one of the many uphill battles Lykos must fight to win granted patents on its MDMA. Indeed, the entire basis of Lykos’ patent strategy—claiming certain particle sizes—may have simply been a shaky plan from the start, perhaps in large part due to its late decision to pursue patent protection, after MAPS’ long adherence to an anti-patent strategy instead.

    Given that billionaire investor and Elon Musk associate Antonio Gracias appears to have teamed up with Rick Doblin in a bid to take control of Lykos, this latest patent-related flop might only add fuel to their proposal, which apparently aims to take the company back towards its ‘public benefit’ roots and away from a more conventional pharma strategy.

    We now await Lykos’ next move, and whether it can present sufficiently compelling evidence or arguments to win allowance of any valuable claims. ∎

    Key Terms

    Patent applications are generally published 18 months after filing, meaning they’re something of a lagging indicator.

    PCT stands for ‘Patent Cooperation Treaty’, and refers to a process by which patents ultimately can be sought in a broad swathe of 157 countries (beyond the country in which the original priority application was filed, often a U.S. provisional application) with one ‘international’ PCT patent application.

    ‘Claims’ are a central part of a patent (application); by establishing the ‘metes and bounds’ of the invention, they define the exclusive right.

    ‘The tracker’ refers to Psychedelic Alpha’s in-house database of psychedelics-related patents, curated by Calyx Law. At present, this tracker can be accessed through molecule-themed views.

    Allowance and grants: If the U.S. Patent and Trademark Office (USPTO) intends to grant a patent, it will issue a Notice of Allowance. As such, an allowance foreshadows a grant (when the patent is ultimately published, and becomes enforceable).

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    1. At the time Lykos’ PCT was published, the claim language was unclear whether the average particle size limitations apply only to the MDMA within the pharmaceutical composition, or to the composition as a whole, and embodiments for both “the particle size of the MDMA” and “the particle size of the composition” are described in the application. Similarly ambiguous claim construction led to a legal dispute in the United Kingdom between the pharmaceutical companies Cephalon and Mylan over modafinil patents claiming varying particle size ranges (see Hayes, 2011). In that case, the courts ruled in favor of Mylan’s interpretation that the particle size limitations applied to the active pharmaceutical ingredient (API) and not to the composition as a whole. However, this ambiguity appears to be removed in Lykos’ sister U.S. application, published last August (US 18/611,564). In its U.S. application, the ambiguity no longer appears, as the U.S. claims specify that the particle size limitations apply to the MDMA API in its formulation, and not to the composition as a whole.
    2. For full disclosure, Psychedelic Alpha editor-at-large Graham Pechenik acted as Awakn’s agent for the PCT application, and currently is attorney-of-record for its related U.S. application.