The Quest for Secondary Pharmaceuticals: Drug Repurposing/Chiral-Switches Combination Strategy

Abstract

Drug repurposing toward new medical uses and chiral switches are elements of secondary pharmaceuticals. The drug repurposing and chiral-switches strategies have mostly been applied independently in drug discovery. Drug repurposing has peaked in the search for therapeutic treatments of the Coronavirus Disease 2019 pandemic, whereas chiral switches have been overlooked. The current Perspective introduces the drug repurposing/chiral-switches combination strategy, overviewing representative cases of chiral drugs that have undergone this combination: ketamine, flurbiprofen, fenfluramine, and milnacipran. The deuterium-enabled chiral switches of racemic thalidomide analogs, a variation of the repurposing/chiral-switch combination strategy, is also included. Patenting and regulatory-exclusivity considerations of the combination strategy in the discovery of new medical uses are considered. The proposed combination creates a new synergy of its two elements, overcoming arguments against chiral switches, with better prospects for validation of patents and regulatory exclusivities. The combination strategy may be applied to chiral switches to paired enantiomers. Repurposing/chiral-switch drugs may be ‘obvious-to-try’; however, their inventions may be unexpected and their patents nonobvious. Patenting repurposing/chiral-switch combination drugs is not ‘evergreening’, ‘product hopping’, and ‘me-too’. The expected benefits and opportunities of the combined repurposing/chiral-switch strategy vis-à-vis its two elements are superior pharmacological properties, overcoming arguments against patent validities, challenges of chiral-switch patents, reduced expenses, shortened approval procedures, and higher expectations of regulatory exclusivities.

1. Drug Repurposing and Chiral Switches

The U.K. Supreme Court stated in 2018 in the Lyrica (pregabalin) litigation:¹

An important objective of modern pharmaceutical research is the discovery of new medical uses for known molecules [an element of secondary pharmaceuticals, and the essence of repurposing]. This commonly involves expensive research programmes, which will not be rewarded and will therefore not happen unless patent protection is available. Patent protection for second use medical patents is, however, difficult to accommodate within the traditional scheme of patent law.

The following types of claims of such pharmaceutical patents are noted: “Markush claims; selection patents; polymorphs; enantiomers; salts; ethers and esters; compositions; doses; combinations; prodrugs; metabolites; and new medical uses. Patents with claims of this type are sometimes referred to as ‘secondary’ pharmaceutical patents, distinguished from ‘primary’ patents directed toward a novel active ingredient.” ² (See also refs (3−5).) A ‘secondary pharmaceutical patent’ (SPP, see Box 1) is “a patent that protects a range of aspects related to but other than the direct active pharmaceutical ingredient (protected by the primary pharmaceutical patent).”⁵ (See also ref (4).) The strategy of Pharmaceutical Lifecycle Management (LCM) includes secondary pharmaceutical patents, applied by pharmaceutical companies in their attempts to extend exclusivity periods. Drug repurposing and chiral switches are elements (types) of secondary pharmaceuticals. Likewise, drug repurposing patents and chiral-switch patents are elements (types) of secondary pharmaceutical patents. In principle, benefits and opportunities of the combined repurposing/chiral-switch strategy are expected, as compared to each of the elements of repurposing strategy and chiral-switch strategy alone: (i) the superior pharmacological properties (efficacy and/or safety) of the repurposed/chiral-switched drug, (ii) overcoming the arguments against the validities of chiral-switch patents (e.g., obviousness/noninventiveness, anticipation) vis-à-vis challenges of chiral-switch patents (Section 3, vide infra), (iii) reduced expenses in developing the combined repurposing/chiral-switch drug, and (iv) shortened approval procedures and higher expectations of regulatory exclusivities.

Box 1. Definition of Terms.

Biopiracy: the appropriation and commercialization of indigenous technologies without adequate permission, acknowledgment, or compensation

Enantiomer Patent: a patent that claims a single enantiomer of a chiral drug that has been claimed previously in the corresponding basic (broader) patent as a racemate or as a mixture of diastereomers

Evergreening: intellectual property-based evergreening is a business strategy to extend the duration of the effective protection derived or derivable from a portfolio of intellectual property rights in order to increase the appropriability of an innovation or a set of business-related innovations or technologies

Patent Troll: a pejorative term for a company that uses a portfolio of patents not to produce products but solely to collect licensing fees or settlements on patent infringement from other companies

Product Hopping: the process by which a brand, as the patents on an older branded drug are expiring, uses its current dominant market position to switch doctors, pharmacists, and consumers to a newer version of the same (or similar) drug with later-expiring patents

Secondary Pharmaceutical Patent (SPP): a patent that protects a range of aspects related to but other than the direct active pharmaceutical ingredient (protected by the corresponding primary pharmaceutical patent)

Selection Patent: a patent claiming an invention that selects a group of individually novel members from a previously known class, on the basis of superior properties

Teaching Away: a reference may be said to teach away when a person skilled in the art, upon reading the reference, would be discouraged from following the path set out in the reference or would be led in a direction divergent from the path that was taken by the applicant

Unexpected Results: superior results in comparison with the previous art in the context of a nonobviousness (inventive step) assessment of a claimed invention

1.1. Repurposing/Chiral Switches of Chloroquine and Hydroxychloroquine for the COVID-19 Pandemic

The patenting of secondary pharmaceuticals (including chiral switches) is a controversial topic.²⁻⁶ Drug repurposing, an element of secondary pharmaceuticals, peaked in the worldwide search for Coronavirus Disease 2019 (COVID-19) pandemic therapies. Another element of secondary pharmaceuticals is chiral switches, referred to as ‘Enantiomers’ (vide supra) in the 2015 UN Guidelines for Pharmaceutical Patent Examination: Examining Pharmaceutical Patents from a Public Health Perspective.³ On March 28, 2020, the U.S. Food and Drug Administration (FDA) “issued an Emergency Use Authorization (EUA) to allow [the old antimalarial racemic drugs hydroxychloroquine] HCQ sulphate and [chloroquine] CQ phosphate products [...] to be distributed and used for certain hospitalized patients with COVID-19.” ⁷ In April 2020, we and Lentini et al. called for adopting “a variant of the [above-mentioned] repurposing strategy: developing [the more-promising] single enantiomers [(S)-CQ and/or (S)-HCQ] for the treatment of COVID-19.”^7,8 On June 15, 2020, the FDA revoked the EUA for CQ and HCQ and “concluded that it is unlikely that CQ and HCQ may be effective in treating COVID-19” for the authorized U.S. users, pointing out additionally “ongoing reports of serious cardiac adverse events” and other potential serious side effects of these drugs.⁹ Since then, a wealth of evidence has accumulated worldwide on the “lack of efficiency and increased odds of cardiac adverse events” ¹⁰ in using CQ and HCQ for treating hospitalized COVID-19 patients.^10,11 Nevertheless, our ineffective specific call has inspired us to write the present Perspective to introduce the concept of the drug repurposing/chiral-switches combination strategy.

This Perspective’s review of drug repurposing/chiral-switches combination cases is not comprehensive. The combination strategy may be applied within the jurisdiction of a specific drug regulatory authority, even in a scenario in which a drug repurposing or a chiral-switch strategy has previously been applied and approved in another jurisdiction. Furthermore, the review is limited to combination cases thereof in the drug-regulation era, 1938–2022. It does not cover the era prior to U.S. drug regulation, from the 1638 discovery of the Cinchona tree bark (‘Fever Tree’), originally as a remedy to treat fever and since the 1860s for the treatment of malaria,¹²⁻¹⁴ to enacting the U.S. Food, Drug, and Cosmetic Act (FD&C Act) in 1938. The scopes and limitations of each of the drug repurposing and chiral-switches elements considered in the present Perspective are indicated in Section 1.2 and Section 1.3, respectively.

1.2. Drug Repurposing as a Secondary Pharmaceutical Element of the Combination Strategy

“Drug repurposing (also called drug repositioning, reprofiling or re-tasking) is a strategy for identifying new uses for approved or investigational drugs that are outside the scope of the original medical indication.” ¹⁵ This definition emphasizes the regulatory aspects of drug repurposing. The term ‘investigational drug’ is defined as “a substance that has been tested in the laboratory and has been approved by the U.S. Food and Drug Administration (FDA) [and/or by another regulatory authority] for testing in people.” ¹⁶ A previously known clinically relevant drug is not sufficient for drug repurposing in the regulated era. Off-label use of an original drug for a specific indication does not qualify for drug repurposing candidacy. In the pre-regulated era (prior to 1938), sporadic, limited clinical trials are not a sufficient condition for drug repurposing. On the other hand, extensive use of an unofficially recognized original drug is sufficient. Therefore, a substance that had undergone sporadic “clinical trials” not authorized by a state regulatory authority does not qualify for drug repurposing. Since the original definition,¹⁷ the application field of drug repurposing has “been extended to include active substances that failed the clinical phase of their development on account of their toxicity or insufficient efficacy”.¹⁸ The benefits of this strategy are “to move straight to clinical trials for the new indication, bypassing the costly and lengthy discovery and early-stage development research that is needed for [the approval of] completely new drugs.”¹⁹ “Developing new uses for old drugs is much cheaper than de novo drug development.” ²⁰ However, developing a repurposed drug may require a significant amount of high-risk investment, in part owing to legal and regulatory barriers.¹⁹ Furthermore, many instances of drug repurposing still require full clinical trials. “There are still substantial barriers to drug repurposing, but they are not insurmountable, and solutions could help realize the full potential of the strategy.” ¹⁹ Drug repurposing terminology and definitions have been reviewed.^18,21−23 In addition to the definition of drug repurposing offered at the outset of this section, the following couple of examples, selected from the numerous published definitions, are quoted. (i) Drug repositioning, drug repurposing, drug redirecting, and drug reprofiling are “the process of finding new uses outside the scope of the original medical indication for existing drugs” (the original definition).¹⁷ (ii) “The search for new indications for marketed medicines or for compounds that have at least shown an acceptable safety profile in clinical trials.”¹⁹ (iii) “The process of identifying new indications for existing drugs, discontinued, or ‘shelved’ assets and candidates currently under development for other conditions—activities” was referred to as ‘indications discovery’.²⁴

The term ‘indication’ is defined as “a medical condition that a medicine is used for. This can include the treatment, prevention and diagnosis of a disease.” ²⁵ A new indication of a repurposed drug may be related to the same therapeutic category as that of the original drug.

“Typically, a drug repurposing strategy consists of three steps [...]: [(i)] identification of a candidate molecule for a given indication [...]; [(ii)] mechanistic assessment of the drug effect in preclinical models; and [(iii)] evaluation of efficacy in phase II clinical trials.” ¹⁵ Step (i) is the most critical: both computational and experimental approaches are being used synergistically for identifying repurposable drug candidates. “A clinically used drug is virtually never truly selective for a single target [(an exception being, e.g., therapeutic antibodies)] and biological signaling mechanisms are designed to be robust and redundant.” ²⁶ Therefore, a deep screening of both biological receptors and signaling pathways is needed to identify new druggable targets for previously approved drugs.

Repurposed drugs can be promising candidates for emergencies and outbreaks of pandemics. The COVID-19 pandemic has accelerated the drug repurposing strategy worldwide.²⁷ An important repurposing case in point is Paxlovid (nirmatrelvir co-packaged with ritonavir).^28,29 Paxlovid is “nirmatrelvir, a SARS-CoV-2 main protease [...] inhibitor, co-packaged with ritonavir, an HIV-1 protease inhibitor and [cytochrome P3A4 (CYP3A4)] inhibitor.” ²⁸ (Figure 1). Ritonavir is included in Paxlovid “to inhibit the CYP3A4-mediated metabolism of nirmatrelvir and consequently increase nirmatrelvir plasma concentrations to levels anticipated to inhibit SARS-CoV-2 replication.” ²⁸ The FDA issued an Emergency Use Authorization (EUA) for the unapproved product Paxlovid “for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients [...] with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death”.²⁸ The Paxlovid component ritonavir, brand name Norvir, FDA NDA#020659 (oral solution), approved on 01/03/1996, was first “indicated in combination with nucleoside analogues or as monotherapy for the treatment of HIV infection when therapy is warranted.” ³⁰ Thus, the repurposing element has been realized in Paxlovid. On 28/01/2022, the European Commission, at the recommendation of the European Medicine Agency (EMA) Committee for Medicinal Products for Human Use (CHMP), granted “conditional marketing authorization” of Paxlovid containing the two active substances PF-07321332 [(aka nirmatrevir)] and ritonavir co-packaged [...]. This was granted in the interest of public health because the medicine addresses an unmet medical need and the benefit of immediate availability outweighs the risk from less comprehensive data than normally required [...]. Paxlovid is indicated for the treatment of coronavirus disease 2019 (COVID-19) in adults who do not require supplemental oxygen and who are at risk for progressing to severe COVID-19.” ²⁹ A drug repurposing approach to the discovery of new drug indications for COVID-19 has been proposed.³¹

Figure 1.

Chemical structure of Paxlovid containing nirmatrelvir co-packaged with ritonavir.

1.3. Chiral Switches as a Secondary Pharmaceutical Element of the Combination Strategy

Since the mid-1980s, the majority of the new chiral drugs approved worldwide have been single enantiomers.³²⁻³⁵ The strategy of chiral switches has emerged as one of the two principal scenarios in chiral drug development,³²⁻³⁶ along with the de novo development of enantiomerically pure drugs.^32,34,35 “The essential criterion of a chiral switch is a change in the status of chirality.” ^32,37 (vide infra). The most frequent chiral-switch scenario is developing a single enantiomer based on a previously developed racemic drug or on a mixture of chiral diastereomers with stereogenic element(s) (often approved).^37,38 The switch of an existing racemic drug (E_1,2) to one of its enantiomers (E₁ or E₂) was originally termed a ‘racemic switch’.³⁹ This term was replaced by the preferred term ‘chiral switch’.³⁹ The change in the name of the term to ‘chiral switch’ meant also that the switches are not only from racemic mixtures (E_1,2) but also from single enantiomers (E₁) to their paired enantiomers (E₂).³⁹ Hence, the scope of chiral switches is not limited to switches of racemates to single enantiomers. The active ingredients of an approved racemate and its switched single enantiomer, according to the FDA, are not identical (e.g., the chiral switch of omeprazole (Prilosec) to esomeprazole magnesium (Nexium)). The submission code⁴⁰ of an approved switched single enantiomer from an approved racemate is ‘New Active Ingredient’. Chiral switches include also the following other scenarios: (i) A switch of a stereogenic diastereomer to a corresponding stereogenic diastereomer. An overlooked case in point is the chiral switch of the antimalarial drug (−)-quinine (stereodescriptors 1S,3R,4S,8S,9R) to the antiarrhythmic drug (+)-quinidine (stereodescriptors 1S,3R,4S,8R,9S).^37,41,42 Quinine and quinidine are enantiomeric (aka quasi-enantiomeric) at the β-hydroxyamine functionality (C-8 and C-9).^43,44 (ii) A switch of a (+)-enantiomer to its paired (−)-enantiomer (or vice versa), e.g., the switch of a natural steroid to its unnatural ent-steroid.⁴⁵ “Ent-steroids define fertile ground for discovery in biomedical science, boasting complementary three-dimensional structures of potential relevance for targeting biology that is distinct from the nat-series, and retaining the extremely valuable drug-like properties of the parent class.” ⁴⁵ (iii) A switch of a racemate or a single enantiomer to a nonracemic (scalemic)^46,47 mixture of the corresponding enantiomers and vice versa. A case in point is the chiral switches of Benzedrine (racemic amphetamine) and Dexedrine (dextroamphetamine) to the ADHD drug Adderall,^37,48 a ca. 3:1 mixture of dextroamphetamine and levoamphetamine (made up of four salts of amphetamine and dextroamphetamine). A possible switch of Adderall to different mixtures of dextroamphetamine and levoamphetamine should be considered. The “classical” chiral switches of Benzedrine to Cydril (levoamphetamine) are also recalled.⁴⁸

It should be noted that the definition of the term ‘chiral switch’ should apply not only to the currently known cases of chiral switches but also to scenarios that may be discovered in the future. The philosopher John Stuart Mill stated: “The meaning of a term actually in use is not an arbitrary quantity to be fixed, but an unknown quantity to be sought.” ⁴⁹

A chiral switch does not mean that a racemate has previously been marketed. Lipitor (atorvastatin calcium) and Plavix (clopidogrel bisulfate) have “never been marketed as racemate[s], so the switch[es] [in these situations] are operating at the level of the intellectual property.” ⁵⁰

[Note: The racemate of clopidogrel and its enantiomers and salts thereof and methods of treating or inhibiting thrombosis and inhibiting platelet aggregation were claimed in the basic patent US 4,529,596 (dated 16/07/1985). The single (+)-enantiomer clopidogrel bisulfate and its pharmaceutical composition, which comprises an effective platelet aggregation inhibiting amount, were claimed in the enantiomer patent US 4,847,265 (dated 11/07/1989).³⁸ Racemic atorvastatin (3R,5R/3S,5S), its pharmaceutical composition, useful as a hypocholesterolemic agent, and method of inhibiting cholesterol biosynthesis thereof were claimed in the basic patent US 4,681,893 (dated 21/07/1987). The single (+)-(3R,5R)-enantiomer atorvastatin, its pharmaceutical composition for treating hypercholesterolemia, and method of inhibiting cholesterol synthesis thereof were claimed in the enantiomer patent US RE40,667 (dated 17/03/2009) (reissue of patent US 5,273,995, dated 28/12/1993).⁵⁰]

The developments and approvals of racemic drugs remain an option.⁵¹ “The prior success of the chiral switch approach ensures its utility as appropriate substrates present themselves.” ³⁶

‘Enantiomer patent’ (see Box 1), a type of secondary pharmaceutical patent, is an essential constituent of a chiral switch.⁵ The definition of an enantiomer patent is “a patent that claims a single enantiomer of a chiral drug that has been claimed previously in the corresponding basic (broader) patent as a racemate or as a mixture of diastereomers”.⁵²

The FDA and EMA published guidelines for the development of chiral-switch drugs.^53,54 The FDA’s 1992 Guidance Document entitled “Development of New Stereoisomeric Drugs” states, in section IV, ‘Developing a Single Stereoisomer After the Racemate is Studied’, “[...] an abbreviated, appropriate pharmacology/toxicology evaluation could be conducted to allow the existing knowledge of the racemate available to the sponsor to be applied to the pure stereoisomer.” ⁵³ The EMA’s 1993 Guideline entitled “Investigation of Chiral Active Substances” states, in section 5.3, ‘Development of a new single enantiomer from an approved racemate’, “Suitable ‘bridging’ studies should be carried out to link the complete racemate data to the incomplete data on the selected enantiomer. [...] The extent of bridging studies should be defined on a case-by-case basis. [...] A suitable program of ‘bridging’ studies may consist of: an acute toxicity study of the selected enantiomer using the racemate as positive control, a repeated dose study (up to 3 months) in a single most appropriate species and a study for effects on pre- and post-natal development (including maternal function) with the modification of starting treatment at conception, not at implantation, in a single most appropriate species, with the selected enantiomer and with the racemate as a positive control at least one effective dose level.” ⁵⁴ The ‘bridging’ studies would allow efficient fast regulatory approval of chiral switches.³²

It should be noted that the chiral-switch strategy element per se is not necessarily a drug repurposing. In previous cases of chiral switches, most of the applications of the chiral-switch strategy were not drug repurposing.⁶

2. Drug Repurposing/Chiral-Switches Combination Cases

This section provides representative cases of chiral drugs that have undergone a repurposing of medical uses combined with a change in the chirality status. The application of the combination of repurposing and chiral-switches elements is not new. However, it has previously been applied unintentionally, incidentally, case-by-case, not as a designed strategy in the discovery and development of new drugs.

2.1. Ketamine to Esketamine and to Arketamine

Ketamine is a racemate. It is “a non-selective, non-competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, an ionotropic glutamate receptor”.⁵⁵ It causes the blockade of the hyperpolarization-activated cyclic nucleotide channels (HCN1) receptors.⁵⁶ The WHO Model List of Essential Medicines has included ketamine since 1985 as a general anesthetic.⁵⁷

Ketamine is classified as a psychedelic substance.⁵⁸ Recreational abuse of ketamine “seems to be an important public health challenge”.⁵⁹ In the U.S., ketamine hydrochloride is on the Drug Enforcement Administration (DEA)’s list of Schedule III controlled substances under the Controlled Substances Act (CSA).⁶⁰ Furthermore, ketamine is designated a “date rape drug” under the U.S. Code Title 21– Food and Drugs §841 Prohibited acts A, section (g).⁶¹

The racemic drug Ketalar, active ingredient ketamine hydrochloride (injection), a non-barbiturate general anesthetic, FDA NDA#016812, was first approved on 19/02/1970 (Table 1).⁵⁵ Indications and uses of Ketalar were as a rapid-acting general anesthetic, administered in solution for either intravenous (IV) infusion or intramuscular (IM) administration. According to the latest approved NDA#016812 SUPPL-51, dated 03/06/2022, Ketalar “is indicated as the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation, for the induction of anesthesia prior to the administration of other general anesthetic agents, and as a supplement to other anesthetic agents.” ⁵⁵ In the United Kingdom, ketamine was first authorized as a general anesthetic on 22/05/1973.

Table 1. FDA New Drug Applications (NDAs) of Repurposing/Chiral-Switches Drugs.

The first chiral switch of racemic ketamine to (S)-(+)-ketamine (esketamine, Table 1) was approved in Germany in 1997, when Ketanest S, active substance esketamine hydrochloride, was introduced in clinical anesthesiology to achieve comparable clinical results of the racemate, but with a 50% reduction of dosage.⁶² Interestingly, the approved indications of Ketanest S included pain relief (analgesia) in emergency medicine, besides general and local anesthesia: this was clearly the first case of drug repurposing/chiral-switch combination of ketamine to esketamine.

On 22/07/2013, esketamine hydrochloride was authorized in the U.K. as an anesthetic (brand name Vesierra). It has been approved as a general anesthetic in 17 countries.⁶³ Notably, esketamine was not approved in the U.S. as an anesthetic agent.

The first case of repurposing/chiral switch of ketamine to (S)-(+)-ketamine in the U.S. resulted in Spravato, FDA NDA#211243, active ingredient esketamine hydrochloride nasal spray, approved on 05/03/2019 (Table 1).⁶³ Spravato is indicated, “in conjunction with an oral antidepressant for the treatment of treatment-resistant depression (TRD) in adults.” ⁶³ It was the first NMDA receptor antagonist to be approved for the treatment of depression in adults. On 31/07/2020, the FDA approved a Spravato new indication (NDA#211243 SUPPL-4) for “depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior.” ⁶³

On 18/12/2019, the EU/EMA granted marketing authorization for “Spravato [(esketamine hydrochloride), nasal spray], in combination with a [selective serotonin-reuptake inhibitor] SSRI or [serotonin and norepinephrine-reuptake inhibitor] SNRI, is indicated for adults with treatment-resistant Major Depressive Disorder [(MDD)]...”.⁶⁴ On 19/05/2021, the EU/EMA approved a further Spravato indication for “adults with a moderate to severe episode of Major Depressive Disorder, as acute short-term treatment, for the rapid reduction of depressive symptoms, which according to clinical judgment constitute a psychiatric emergency.” ⁶⁴ It has previously been shown that the “antidepressant effect of esketamine is mediated via antagonism of N-methyl-d-aspartate (NMDA) receptor” ⁶⁵ and “in terms of NMDA receptor inhibition, esketamine was found to be the most potent as compared to ketamine, arketamine [(vide infra)] or their metabolites. [See also Section 3.1.] [...] Based on published data, esketamine can be considered to be 1.5- to 2.8-fold more potent than ketamine in terms of NMDA receptor inhibition. [...] Patch clamp experiments indicated that esketamine is about 2–3-fold more potent at the NMDA receptor than arketamine.” ⁶⁵ In a two-patients case report of treatment of major depressive disorder, it was concluded that esketamine “might exert similar antidepressant effects as ketamine in drug-resistant depression but may be better tolerated by the patients.” ⁶⁶ The limited significance of a two-patients clinical trial cannot be denied.

A relevant development in the repurposing/chiral switch of ketamine to esketamine regarding the indication Major Depressive Disorder (MDD), though not a head-to-head comparison, is the February 2022 U.S. Department of Veterans Affairs (VA) and U.S. Department of Defense (DoD) approval of a joint clinical practice guideline (CPG) for the management of MDD. Its synopsis, which included a section on ketamine and esketamine, summarized key recommendations.⁶⁷ “One significant change in the 2022 CPG is a new recommendation to suggest ketamine or esketamine as a treatment option in patients who have not responded to several adequate pharmacologic trials. The 2016 guideline recommended against the use of ketamine to treat MDD outside research settings [...]. Ketamine lacks long-term efficacy and safety trials in MDD”.⁶⁷ The synopsis states also that “there is evidence to support longer-term maintenance use of esketamine [...]. Unlike ketamine, esketamine has risk evaluation and mitigation strategy requirements”.⁶⁷ The fact that ketamine has not been approved by the FDA for the MDD indication should not be overlooked.

The paired enantiomer (R)-(−)-ketamine hydrochloride (aka arketamine hydrochloride, Table 1), a glutamate receptor modulator and weaker NMDA receptor antagonist, is currently being developed as a potential treatment for mood disorders such MDD and TRD and for rapid acting antidepressant (RAAD) activity. Phase 1 and Phase 2a studies are suggesting that (R)-ketamine has a “more favorable safety and tolerability profile” ⁶⁸ as an antidepressant than (S)-ketamine. It has recently been argued that “it is unlikely that [NMDA receptor] plays a major role in the antidepressant action of (RS)-ketamine and its enantiomers[...]. However, further study in this field is required.” ⁶⁹

2.2. Flurbiprofen to (S)-Flurbiprofen and to (R)-Flurbiprofen

Flurbiprofen, a non-steroidal anti-inflammatory drug (NSAID), is a 2-arylpropionic acid derivative (profen).⁷⁰ Profens have analgesic, antipyretic, and anti-inflammatory properties.

The racemic drug Ansaid, active ingredient flurbiprofen, FDA NDA#018766, was approved on 31/10/1988 (1987 in the United Kingdom) and discontinued in 2016 (Table 1).⁷¹ The indication of Ansaid was the relief of the signs and symptoms of rheumatoid arthritis and of osteoarthritis treatment.⁷¹ The FDA classified Ansaid not as a New Molecular Entity (NME) but as a New Dosage Form, because the racemic drug Ocufen, active ingredient flurbiprofen sodium, FDA NDA#019404, was approved earlier, on 31/12/1986 (as ophthalmic solution), and classified as a NME.⁷¹ Ocufen was discontinued in 1997. The FDA indication of Ocufen was inhibition of intraoperative miosis.

Stereochemistry affects the profens’ mechanism of action.⁷² Most of the approved profens are racemates.⁷³ Exceptions are the single (S)-(+)-enantiomer naproxen (FDA NDA#017581),⁷⁴ dexibuprofen, and dexketoprofen.³² “The clinical activity of the [profens] is due mainly to their inhibition of prostaglandin-H synthases (PGHS) [by selectively inhibiting COX-1/COX-2 enzymes], an activity that resides in the (S)-enantiomers. (R)-Enantiomers, while contributing little to activity as such [...], undergo chiral inversion of configuration to (S)-enantiomers, the eutomers. The first step in this pathway [...] is the formation of acyl-Coenzyme A (acyl-CoA) conjugates, a reaction catalyzed mainly by long-chain acyl-CoA ligase. This reaction is enantioselective, in that it shows a marked or practically exclusive preference for (R)-profens”;⁷² only the (R)-profenyl-CoA are formed and serve as substrates for epimerization (via the enols), catalyzed by 2-methylacyl-CoA epimerase. The resulting (S)-profenyl-CoA then undergoes hydrolysis catalyzed by acyl-CoA thioesterases to give the PGHS-1 and PGHS-2 inhibitor (S)-profen.⁷²

It has been claimed that “at best, the R-isomers [of profens] function as pro-drugs for the therapeutically active S-forms, [...] [when the racemic drug is administered]. [...] At worst, the R-enantiomers are undesirable impurities in the active drug, and may cause difficulties due to non-stereoselective toxicity [...]. The use of the S-isomers alone could allow the safer and more effective use of this class of drugs.” ^75,76 These claims called for chiral switches to (S)-enantiomers but were “teaching away” ⁵ (see Box 1) from chiral switches to (R)-enantiomers of profens. Clinical trials of (S)-flurbiprofen (Table 1) for knee osteoarthritis and transdermal patch have been recently reported.⁷⁷⁻⁷⁹

Flurbiprofen differs from the other profens: unidirectional bioinversion of (R)-flurbiprofen to (S)-flurbiprofen does not occur in humans.^70,80 This remarkable stereoselectivity is the basis of the repurposing/chiral switch of flurbiprofen to (R)-flurbiprofen, including the method of use patent claiming the use of (R)-flurbiprofen for delaying symptoms of Alzheimer’s disease (AD).⁷⁶

(R)-Flurbiprofen (brand names Flurizan and Tarenflurbil, Table 1) is a potent, selective amyloid-β peptide (Aβ₄₂)-lowering agent. Its phase II clinical trial^81,82 for mild to moderate AD treatment “demonstrated encouraging results on cognitive and functional outcomes among mildly affected patients”.⁸³ However, in a phase III clinical trial, Tarenflurbil failed to show significant improvement in mild AD patients.⁸³ Consequently, Tarenflurbil’s development was discontinued in 2008.

2.3. Fenfluramine to Dexfenfluramine to Levofenfluramine and Back to Racemic Fenfluramine

Fenfluramine, a serotonergic drug and a CF₃-substituted amphetamine, “was first introduced in France in 1963 and used initially as an antidepressant and later as an appetite suppressant.” ⁸⁴ The racemic drugs Pondimin (tablets) and Ponderex (capsules), active ingredient fenfluramine hydrochloride, FDA NDA#016618, were approved on 14/06/1973 for short-term treatment of obesity (Table 1).⁸⁵

The single-enantiomer (S)-(+)-fenfluramine (dexfenfluramine) was first developed/marketed in France.³² In the United States, the single-enantiomer serotonergic drug Redux, active ingredient dexfenfluramine hydrochloride, FDA NDA#020344, was approved on 29/04/1996 (Table 1).⁸⁶ Redux was indicated for long-term treatment of obesity, with a caveat³² that its “safety beyond 1 year of use had not been established in clinical trials.” ⁸⁷

Fen-phen was the combination drug of fenfluramine and the achiral phentermine (Ionamin, FDA NDA#011613, approved on 04/05/1959), indicated for short-term treatment of obesity. The FDA did not approve fen-phen (including the dexfenfluramine–phentermine combination).³² Fenfluramine and dexfenfluramine products, including fen-phen, which were prescribed as appetite suppressants, became very popular worldwide in 1996–1997. They were voluntarily withdrawn from worldwide markets in late 1990s (FDA, September 1997), following “new evidence that the products were associated with valvular heart disease.” ⁸⁵ A causal link between fenfluramine and primary pulmonary hypertension was suggested.^84,87 The FDA determined on 29/09/2015 that “Pondimin and Ponderex were withdrawn from sale for reasons of safety or effectiveness.” ⁸⁵ The Agency previously withdrew approval of Redux effective 30/01/2007 and recommended withdrawal of the marketing authorization for fenfluramine and dexfenfluramine products effective 09/09/1999.

The fenfluramine renaissance occurred with the approval on 25/06/2020 of Fintepla, active ingredient fenfluramine hydrochloride (racemate), FDA NDA#212102 (Table 1).⁸⁸ Fintepla is indicated for the treatment of seizures associated with Dravet syndrome (DS) in patients 2 years of age and older.^89,90 “Dravet syndrome (DS) is a severe form of childhood epilepsy that is characterized by early onset of refractory seizures of multiple types, frequent episodes of status epilepticus, and developmental arrest or regression.” ⁸⁸ Fintepla received EU/EMA market authorization on 18/12/2020, designated ‘orphan medicine’ (EMEA/H/C/003933), “indicated for the treatment of seizures associated with Dravet syndrome as an add-on therapy to other anti-epileptic medicines for patients 2 years of age and older.” ⁹¹

One reason fenfluramine could be repurposed is the lower dose for treating DS. The EMA CHMP Assessment Report on Fintepla noted that DS patients are exposed to 2–4-fold lower doses of Fintepla.⁹¹ Odi et al. noted that “Although it is often stated that fenfluramine is used at ‘low-doses’ in patients with epilepsy [...], the highest recommended dose (0.7 mg/kg/day) in children with epilepsy weighing 37 kg or less is actually similar or even higher than the median mg/kg dose associated in the past with cardiac valvulopathy in adults who used fenfluramine as an appetite suppressant.” ⁸⁴

The choice to develop the racemate (±)-fenfluramine for the DS indication was driven by the efficacy in its isolated clinical studies.⁹¹ “The paucity of accessible information on the comparative antiseizure activity of the enantiomers of fenfluramine and norfenfluramine” ⁸⁴ was noted. An exceptional study on a zebrafish mutant model of DS showed that the efficacy profiles of (+)- and (−)-fenfluramine (levofenfluramine, Table 1) in comparison to that of (±)-fenfluramine suggest an additive effect and that the antiseizure activity of (+)-fenfluramine is more efficacious than that of (−)-fenfluramine.⁹² “However, the two enantiomers were equally effective in suppressing brain epileptiform discharges.” ⁸⁴ Therefore, in the event that the preliminary findings on the zebrafish model “are confirmed and extended to other seizure/epilepsy models, there would be an incentive for a chiral switch from racemic-fenfluramine to l-fenfluramine, which could minimize the risk of cardiovascular toxicity and reduce the incidence of adverse effects such as loss of appetite and weight loss.” ⁸⁴ “If [l-fenfluramine] is found to have a significant independent antiseizure impact, a chiral switch with developing this single enantiomer can be a safer treatment option.” ⁹³

The fenfluramine repurposing/chiral-switch case illustrates an adaptation of the chiral switch of racemate to single enantiomer, unapproved drug combinations, tragic fiasco, drug withdrawals worldwide of racemate and single enantiomer, and a score of years later a repurposing renaissance, resulting in an orphan drug for treatment of an epilepsy syndrome. Unfortunately, so far, the renaissance skipped the chiral-switch opportunity. Nevertheless, the opportunity for using a single enantiomer is still being evaluated. Future options for repurposing/chiral switch of fenfluramine may be based on low doses that would neutralize the risk of cardiovascular damage.

2.4. Milnacipran to Levomilnacipran

Milnacipran is a serotonin and norepinephrine-reuptake inhibitor (SNRI).⁹⁴ Its dual inhibition on both monoamine systems made milnacipran superior in efficacy as an antidepressant compared to typical SSRI drugs. Milnacipran was “first approved for the treatment of major depressive episodes in France in December 1996.” ⁹⁵ “It has since been approved and marketed [as an antidepressant] in multiple countries”,⁹⁴ but not in the U.S.

The fact that milnacipran has not been approved by the FDA for the treatment of MDD rendered the application of the repurposing/chiral-switch combination strategy to milnacipran, within the jurisdiction of the FDA, the U.S. drug regulatory authority. This application of the combined strategy could not have been possible in jurisdictions where the repurposing of milnacipran for the MDD indication has been approved, e.g., in France.

The cis-racemic (±)-[(1R(S),2S(R)] drug Savella, active ingredient milnacipran hydrochloride, FDA NDA#022256 (tablets), was approved on 14/01/2009 and designated a New Molecular Entity (NME, Table 1).⁹⁴ The indications and uses of Savella were for the management of fibromyalgia in adults, a syndrome that causes chronic musculoskeletal pain. Savella was not approved for use in pediatric patients.

On 08/04/2010, EMA announced its refusal of marketing authorization of Milnacipran Pierre Fabre Medicament intended for treatment of fibromyalgia in adults. The refusal followed the recommendation of its Committee for Medicinal Products for Human Use (CHMP).⁹⁶ The grounds for refusal included “a lack of robust evidence of efficacy [...], insufficient demonstration of maintenance of effect [... and] the safety profile, whilst well characterized, is not considered to be outweighed by the benefits”.⁹⁶ The opposing decisions of the EMA and FDA are noted.

On 25/07/2013, FDA approved the single (1S,2R)-(−)-enantiomer drug Fetzima, active ingredient levomilnacipran hydrochloride, FDA NDA#204168 (capsules), the first chiral-switch drug granted NCE* status and conferred 5-year exclusivity (Section 3.2.1, vide infra). Fetzima (Table 1) was indicated for the treatment of MDD⁹⁷ but not approved for the management of fibromyalgia. Notably, levomilnacipran-based medicines are not authorized in the EU in adults for the treatment of depressive disorders.⁹⁸ On April 17, 2015, the Paediatric Committee of EMA refused a product specific waiver for levomilnacipran for the treatment of stroke.⁹⁸

The FDA approval history in the milnacipran case exemplifies the application of drug repurposing in combination with chiral switch, from the cis-[(1R(S),2S(R)] racemic drug indicated for fibromyalgia to the single 1S,2R)-(−)-enantiomer indicated for MDD.

2.5. Deuterium-Enabled Chiral Switches of Thalidomide Analogs

A twist of the drug repurposing/chiral-switch combination strategy introduced the element of the deuterium-enabled chiral switches and applied it to thalidomide analogs.

The myth that the thalidomide tragedy, a landmark in drug regulation, could have been avoided by a chiral switch of the teratogenic racemic drug to (R)-(+)-thalidomide, the non-teratogenic “good” thalidomide, is an urban legend.^47,99,100 A recent quotation highlighting the myth appears in the Nobel Committee for Chemistry 2021 Popular Science Background paper: “A catastrophic example of this was the thalidomide scandal in the 1960s, in which one mirror image of the thalidomide pharmaceutical caused serious deformities in thousands of developing human embryos,” ¹⁰¹ and in news media (e.g., ref (102)). Both thalidomide enantiomers (Figure 2) have been shown to racemize rapidly in vivo, each one undergoing chiral inversions.^{47,99,100,103} This aspect gave rise to the controversial “thalidomide paradox”.¹⁰⁴ A hypothesis to explain the paradox through the in vivo “self-disproportionation of the [thalidomide] enantiomers” has been advanced.¹⁰⁴

Figure 2.

Chemical structures of the enantiomer pairs of thalidomide and of deuterium-enriched thalidomide analogs.

Racemic thalidomide was marketed in Europe since 1957 for the treatment of insomnia and morning sickness in pregnancy. “The link between thalidomide administration and an epidemic of congenital malformations (phocomelia and other organ defects) occurring in Europe was recognized in 1961 and the drug was withdrawn from marketing.” ¹⁰⁵ Repurposing of thalidomide led on 16/07/1998 to the FDA approval of Thalomid, active ingredient thalidomide, FDA NDA#020785, ironically, yet legally designated NME, NCE, and ‘orphan drug’, “indicated for the acute treatment of the cutaneous manifestation of moderate to severe erythema nodosum leprosum (ENL),” ¹⁰⁵ under highly restricted distribution program (STEPS).¹⁰⁵ Further repurposing resulted in FDA approval of Thalomid, active ingredient thalidomide in combination with dexamethasone on 25/05/2006, FDA NDA#021430. “Thalomid (thalidomide) in combination with dexamethasone is indicated for the treatment of patients with newly diagnosed multiple myeloma. Thalidomide [only] is indicated for the acute treatment of the cutaneous manifestations of moderate to severe ENL. Thalidomide is [also] indicated as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence.” ¹⁰⁶

EU/EMA approved Thalidomide Pharmion (later renamed Thalidomide Celgene, now Thalidomide BMS), active substance thalidomide, EMEA/H/C/000823, on 16/04/2008, “in combination with melphalan and prednisone is indicated as first line treatment of patients with untreated multiple myeloma [...]”.¹⁰⁷

Application of the direct chiral-switch strategy to (±)-thalidomide in order to remove the teratogenic (S)-(−)-enantiomer is not feasible, due to its in vivo racemization. DeWitt et al. have overcome this difficulty, which occurs particularly in molecules with hydrogen-containing chirality centers prone to enolization, by inventing the deuterium-enabled chiral-switch strategy (DECS), which may inhibit racemization, yet according to the inventors, it retains the pharmacological characteristics of the parent racemate.^108,109 Deuterium can stabilize hydrogen-containing chirality centers through the deuterium kinetic isotope effect, “thereby reducing the incidence of stereoisomerization[/enantiomerization] both in vitro and in vivo.” ¹⁰⁹

The DECS strategy was applied to the thalidomide analog Revlimid, active ingredient lenalidomide (Figure 2), FDA NDA#021880, approved on 27/12/2005, NME.¹¹⁰ The racemic drug Revlimid, an immunomodulatory agent with anti-angiogenic properties, is “indicated for the treatment of patients with transfusion-dependent anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.” ¹¹⁰ Indications and uses of Revlimid NDA#021880 SUPPL-65, approved on 24/05/2022, “are multiple myeloma [in combination with dexamethasone], myelodysplastic syndromes, mantle cell lymphoma, follicular lymphoma [in combination with a rituximab product], and marginal zone lymphoma [in combination with a rituximab product].” ¹¹⁰

U.S. Patent 8,288,414 B2 claims (inter alia) deuterium-enriched lenalidomide (Figure 2) and its method for treating chemotherapy-induced nausea and vomiting.¹¹¹ U.S. Patent 8,669,276 B2 claims the method of use of deuterium-enriched lenalidomide for treating multiple myeloma.¹¹² DeWitt’s affidavit, filed during the prosecution of patent application 12/196,672 that resulted in the approval of 8,288,414 B2 (see also ref (108), ref 53 therein), included the following conclusion pertaining to deuterium-enriched lenalidomide enantiomers: “A. Deuterium enantiomers of lenalidomide are more stable than protonated enantiomers [...]. B. Deuterated (S)-lenalidomide is significantly more potent than deuterated (R)-lenalidomide [...]. C. Deuterated (S)-lenalidomide is 30–40% more potent toward TNVα and IL-10 than protonated (S)-lenalidomide. D. Deuterated (S)-lenalidomide reduces exposure to the (R)-enantiomer 5x compared to protonated (S)-lenalidomide in rats.” ¹¹³ DeWitt demonstrated in her affidavit that ‘unexpected results’ (see Box 1) rebutted any possible prima facie case of obviousness. Although it had been argued that previous publications indicated that “one is motivated to prepare deuterated versions of drugs to obtain a version with better pharmaceutical properties” ¹¹⁴ (US Patent Application 12/196,672, USPTO Prosecution, 28-07-2011, Non-Final Rejection), the approval of US Patents 8,288,414 B2 and 8,669,276 B2 indicated cases of ‘unexpected results’ winning over ‘obvious-to-try’ (Section 3.1, vide infra).⁵ The deuterated S-enantiomer of lenalidomide DP-053 (formerly CTP-221, Figure 2) was shown to be “greatly stabilized to epimerization and results in a more desirable pharmacokinetic profile than racemic lenalidomide”¹¹⁵ (see also ref (108), ref 56 therein). Notably, the emphasis in the deuterium-enriched lenalidomide enantiomers’ invention and development was on the chiral switch and not on repurposing.

The deuterium-enabled chiral-switch strategy was applied by DeWitt et al. to the thalidomide analog avadomide (CC-122, Figure 2), 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, which has been under investigation “in human clinical trials for hematological cancers and solid tumors.” ¹⁰⁸ “Replacing the exchangeable hydrogen at the chiral center with deuterium allowed stabilization of individual enantiomers of lenalidomide and avadomide. [...] In vivo, deuteration at the chiral center did not affect the pharmacokinetics of the individual enantiomers [...]. Distinct pharmacological effects between deuterium-stabilized enantiomers were demonstrated as [...] [the (S)-(−)-enantiomer of the deuterated avadomide] is a 20-fold more potent inhibitor [of TNF-α production] than the corresponding deuterated (+)-enantiomer,” as compared with the corresponding 10-fold of deuterated (S)-lenalidomide versus deuterated (R)-lenalidomide. “In vivo, [the deuterium-(−)-enantiomer] was antitumorigenic while the deuterated (+)-enantiomer showed limited antitumorigenic activity and perhaps even some tumorigenic properties.” ¹⁰⁹ Differentiation of anti-inflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs has been revealed.¹⁰⁸

The deuterium-enriched (S)-(−)-enantiomer of avadomide SP-3164 (formerly DRX-164, Figure 2) is currently being developed as a targeted protein degrader that induces selective elimination of cancer-causing proteins and (similarly to avadomide) “as a potential treatment for hematological cancers and solid tumors”.¹¹⁶

The application of the strategy of drug repurposing in combination with deuterium-enabled chiral switches is illustrated in European Patent EP 2,943,201 B2.¹¹⁷ The patent claimed (inter alia) the deuterium-enriched compound (−)-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-(3-²H)-piperidine-2,6-dione, the (−)-enantiomer of deuterated avadomide, and its methods of “use in treating disorders selected from the group consisting of an immune disorder and an inflammatory disorder. Its claimed abundance of deuterium is at least 95%.” ¹¹⁷ The validity of the patent was contested in the Opposition Department (OD) of the European Patent Office (EPO). The OD confirmed the validity of the patent, determining that it was novel and nonobvious (in view of the deuterium-enriched lenalidomide).¹¹⁸ According to the OD, the effects associated with the replacement of hydrogen by deuterium are unpredictable and highly variable; in vitro deuterium/hydrogen exchanges and enantiomerization are not always predictive of in vivo effects. The OD concluded that in vivo effects are the complex results of the interplay of various phenomena leading to a final result which may largely vary depending on even small chemical modifications.

In addition to thalidomide analogs, the strategy of deuterium-enabled chiral switches of racemic drugs is currently being applied to other chiral drugs, e.g., pioglitazone, prasugrel, bupropion, and donepezil.¹¹⁹ In particular, clinical development of deuterated R-pioglitazone (PXL065) for the treatment of nonalcoholic steatohepatitis (NASH) is ongoing (phase 2; NCT04321343), and deuterated S-bupropion (NTY-184) proved to be a more potent and targeted drug in preclinical studies for CNS disorders relative to racemic bupropion.

The application of the strategy of deuterium-enabled/enriched chiral switches of racemic drugs and drug candidates with hydrogen-containing chirality centers in combination with repurposing creates new opportunities for drug discovery and development. The outcome may prove to be beneficial, beyond a superposition of its two elements. This statement is expected to be relevant, particularly with respect to the defense of drug repurposing/chiral-switches combination patents claiming deuterium-enabled chiral switches and gaining for these drugs FDA and EMA NCE* and NAS designations conferring regulatory exclusivities (Section 3.2, vide infra).

3. Patentability and Regulatory Exclusivities Considerations

3.1. Patentability Considerations of Drug Repurposing/Chiral-Switches Combination Drugs

3.1.1. General Considerations

Patents and regulatory data exclusivity are intellectual property (IP) instruments which protect drugs from competition. Attempts to overcome the legal and regulatory barriers to drug repurposing, an element of secondary pharmaceuticals, have recently been highlighted.¹⁹ Secondary pharmaceutical patent (SPP, see Box 1) (Section 1, vide supra), essential to Pharmaceutical Lifecycle Management (LCM),¹²⁰ includes new medical-use (aka method of treatment, MOT) patents²⁰ and chiral-switch patents (e.g., typically enantiomer patents³⁸). The doctrine of SPP is controversial.^3,5,121,122 The distinction between primary and secondary pharmaceutical patents is absent in patent laws worldwide.⁴ The attempts to invalidate all enantiomer patents and new medical-use patents may not be relevant to these elements. This is an advantage of patents claiming drugs developed by the repurposing/chiral-switch combination strategy. Another advantageous scenario in this strategy (following a racemic drug repurposing/chiral switch to one of the respective enantiomers) is a new repurposing/chiral switch to the paired enantiomer. Furthermore, “repurposed drugs are typically only patentable using method of treatment (MOT) claims (e.g., ‘a method of treating disease X, comprising administering a therapeutically effective amount of drug Y’) [...] [whereas] composition of matter claims (e.g., ‘a composition, comprising drug Y’)” ¹²³ of repurposed/chiral-switch drugs may be patentable. It has been advocated that “an innovator should not enjoy an exclusive market and supra-competitive pricing for innovations that stem in some fashion from a separate innovation for which it already enjoyed a 20-year patent term. Or, at least, a drug innovator should not.” ¹²⁴ However, this argument is not valid for patents claiming repurposing/chiral-switch combination drugs. Patenting such drugs is not IP-based evergreening. ‘Evergreening’ was defined as follows:¹²⁵

...the business strategy to extend the duration of the effective protection derived or derivable from a portfolio of [Intellectual Property Rights] in order to increase the appropriability of an innovation or a set of business related innovations or technologies.

‘Evergreening’ (see Box 1) is controversial. Patent laws worldwide do not refer to ‘evergreening’—it is just a social idea.⁵ The goal of proving the validities of drug repurposing/chiral-switch patents, including novelty and nonobviousness, becomes within reach. The U.S. Supreme Court held in the seminal KSR judgment that “the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” ¹²⁶ However, the results of the combination of repurposing and chiral-switches elements may be unpredictable/unexpected and thus nonobvious. ‘Unexpected results’ (see Box 1) are superior results in comparison with the previous art in the context of a nonobviousness (inventive step) assessment of a claimed invention.⁵

‘Enantiomer patents’ (see Box 1) have been obvious to try since the 1980s. “One of the matters which it may be appropriate to take into account is whether it was obvious to try a particular route to an improved product or process. There may be no certainty of success but the skilled person might nevertheless assess the prospects of success as being sufficient to warrant a trial. In some circumstances this may be sufficient to render an invention obvious. On the other hand, there are areas of technology such as pharmaceuticals and biotechnology which are heavily dependent on research, and where workers are faced with many possible avenues to explore but have little idea if any one of them will prove fruitful. Nevertheless, they do pursue them in the hope that they will find new and useful products. They plainly would not carry out this work if the prospects of success were so low as not to make them worthwhile. But denial of patent protection in all such cases would act as a significant deterrent to research”.¹²⁷ “When the description in an enantiomer patent includes superior pharmacological and/or pharmaceutical properties of the claimed single enantiomer, versus the racemate (efficacy, and/or reduced toxicity and/or solubility and other pharmaceutical properties), well above the expected ratio of 2:1, ‘unexpected results’ wins [over ‘obvious-to-try’], so that inventiveness/nonobviousness is established.” ⁵ Drug repurposing/chiral-switches combination patents would be in accord with this scenario: inventions that are obvious-to-try nevertheless may be nonobvious.

The present Perspective reinforces the defense of patents of drug repurposing/chiral-switches combination, elements of secondary pharmaceutical patents.

3.1.2. The Spravato Patents

The Spravato (esketamine, see Section 2.1) U.S. Patents 10,869,844 B2¹²⁸ and 10,098,854 B2,¹²⁹ entitled “Methods for the Treatment of Depression” (vide infra), offer an opportunity to evaluate the patentability of drug repurposing/chiral-switch combination drugs.

3.1.2.1. Challenging the Esketamine TRD Patents

Very recently (February 2022), the patents for esketamine (including Spravato) have been under attack, along with patents on psychedelics.¹³⁰ The authors Marks and Cohen (M&C) attacked these secondary pharmaceutical patents (and the tactics of their assignees/proprietors), using pejorative terms such as ‘evergreening’,^5,125 ‘product hopping’,^5,131 ‘promoting biopiracy’,¹³² ‘patent trolling’,¹³³ ‘unwarranted’, and ‘me-too drugs’^5,130,134 (see Box 1).

M&C’s allegations challenging the validities of esketamine patents claiming treatment-resistant depression (TRD) usage, specifically U.S. Patent 10,869,844 B2 (footnote 86 of ref (130)), were primarily based on the following arguments: “The discovery that ketamine could be prescribed off-label to manage treatment-resistant depression was an important breakthrough.” ¹³⁰ The esketamine TRD patents were issued despite longstanding off-label use of the racemic mixture ketamine for treating depression. M&C stated that “Spravato has failed to show a meaningful benefit over generic ketamine,” ¹³⁰ referring in their footnote 89 to ref (135). Furthermore, they stated, “One meta-analysis even concluded that intravenously administered racemic ketamine [...] appears to be more effective than intranasal esketamine for addressing treatment-resistant depression,” ¹³⁰ referring in their footnote 90 to ref (136). “The case for granting a patent right is less appealing when there is an existing synthetic variant or naturally occurring version of a substance.” ¹³⁰ Although M&C admit that “esketamine is not identical to generic ketamine formulations,” they argue that “characterizing it, or its intranasal administration, as a novel invention is a stretch.” ¹³⁰ The authors M&C call for “tightening up U.S. patent law requirements for novelty and nonobviousness. For instance, Congress, courts, and the [U.S. Patent and Trademark Office] could follow the example set by the Canadian court [ruling that Spravato was not an ‘innovative drug’, which confers data protection exclusivity (Section 3.2, vide infra)] and declare that salts, enantiomers, and other subtle variations on existing inventions are not innovative drugs because they lack inventiveness. Though the Canadian court’s decision dealt with data exclusivity, the same logic can be applied to patents.” ¹³⁰

3.1.2.2. Attempts to Overcome the Challenges of the Esketamine TRD Patents

We attempt here to refute M&C’s arguments¹³⁰ challenging the validities of the esketamine TRD patents.

(i) The “off-label” use of the ketamine argument:

“Unapproved use of an approved drug is often called ‘off-label’ use. This term can mean that the drug is used for a disease or medical condition that it is not approved to treat [...], given in a different way [...], given in a different dose [...]”.¹³⁷ The FDA issued in February 2022 an alert of “potential risks associated with compounded ketamine nasal spray”. “Compounded drugs are not FDA-approved, which means FDA has not evaluated their safety, effectiveness, or quality prior to marketing. Therefore, compounded drugs should only be used in patients whose medical needs cannot be met by an FDA-approved drug.” “Ketamine is not FDA-approved for the treatment of any psychiatric disorder.” ¹³⁸ The FDA emphasized that it has not determined that ketamine is safe and effective for the unapproved uses. The FDA was well aware of the extensive off-label use of ketamine. The FDA alert was issued in spite of its general approach toward unapproved use of approved drugs “off-label”,¹³⁷ and of the extensive off-label use of ketamine. The FDA’s timely alert definitely discourages the off-label usage of ketamine, bearing in mind its highlighting by M&C. Off-label drug usage in phase 2 and phase 3 clinical trials results has been scrutinized by drug regulators, ipso facto, during evaluations of New Drug Applications (NDAs). However, so far, the reported off-label clinical trials of ketamine for psychiatric disorders have not been part of an NDA to a drug regulator.

(ii) The TRD U.S. patents of esketamine and ketamine:

The TRD esketamine U.S. Patents 10,869,844 B2 (priority date 15/09/2014)¹²⁸ and 10,098,854 B2 (priority date 13/08/2014),¹²⁹ both assigned to Janssen Pharmaceutica NV, illustrate a repurposing/chiral-switch combination patenting. Claims 1–3 of the 10,869,844 B2 patent read: “1. A method of treating major depressive disorder in a human patient in need thereof, comprising intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino) cyclohexanone [esketamine] in an induction dosage to the patient in an amount in the range of from about 56 mg to about 84 mg in an induction phase [...]. 2. The method of claim 1, wherein the induction dosage is about 56 mg or about 84 mg. 3. The method of claim 2, wherein the patient exhibits suicidal ideation or behaviour.”¹²⁸ Thus, the patent highlights “more preferably, the depression is treatment-resistant depression”.¹²⁸ The description includes the results of clinical trials of esketamine and of ketamine, indicating certain superior aspects of esketamine versus ketamine. “[The description also includes] genetically testing (or genotyping) a patient suffering from depression to determine its Val66Met rs6265 polymorphism in the brain-derived neurotropic factor [(BDNF)] gene (i.e., to determine if the patient is a Val/Val homozygote, a Val/Met heterozygote or a Met/Met homozygote) [...]. The effect of Val66Met rs6265 polymorphism in BDNF gene on clinical response to esketamine and ketamine was investigated through a retrospective analysis of the above clinical trials.” ¹²⁸ The patent is subject to a terminal disclaimer overcoming obvious-type double-patenting challenge, including the abandoned US Patent Application 2013/0236573 A1, referred to by M&C (footnote 83 of ref (130)). A terminal disclaimer is a statement in which “a patentee owning the whole or any sectional interest in a patent may disclaim any complete claim or claims in a patent. In like manner any patentee may disclaim or dedicate to the public the entire term, or any terminal part of the term, of the patent granted”.¹³⁹ In the U.S., “The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the ‘right to exclude’ granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). [...] A timely filed terminal disclaimer [...] may be used to overcome an actual or provisional rejection based on nonstatutory double patenting [...]”.¹⁴⁰ During the prosecution of US Patent 10,869,844 B2, certain of its claims were “rejected under the doctrine of obviousness-type double patenting being unpatentable over [certain] claims of pending reference applications and patents [(e.g., US Patent 10,098,854)]”.¹⁴⁰ An approved terminal disclaimer obviated the double patenting rejection. Thus, “the patent was subject to a terminal disclaimer”.¹⁴⁰

Claims 1 and 2 of the TRD esketamine 10,098,854 B2 patent read: “1. A method for treatment of depression comprising Step A) obtaining a biological sample comprising genetic material from a patient suffering from depression; Step B) detecting the patients genotype at rs4306882 by performing a genotyping assay on the genetic material from Step A; Step C) detecting a G allele at the polymorphic site of rs4306882 in the patients genetic material; and Step D) administering esketamine intranasally at a dosage of about 28 mg to about 32 mg, one to three times per week for up to about 8 weeks to said patient. 2. The method as in claim 1, wherein the depression is treatment-resistant depression (TRD).” ¹²⁹ Interestingly, the application of this “genotype-dosing” regiment patent originally claimed the administration of both ketamine and esketamine. However, during the patent prosecution, ketamine was dropped from the claims.

The TRD esketamine 10,869,844 B2 and 10,098,854 B2 patents were preceded by the TRD ketamine US Patent 8,785,500 B2 (priority date 13/12/2007), entitled “Intranasal Administration of Ketamine to Treat Depression”,¹⁴¹ assigned to Ichan School of Medicine at Mount Sinai (NY), Yale University and NIH. In contrast to US Patents 10,869,844 B2 and 10,098,854 B2, this ketamine patent is a case of drug repurposing, without the chiral-switch element. The ketamine patent describes “methods and compositions for the treatment of ‘treatment-resistant major depression’, [which refers to] the depression experienced by any subject who has not previously responded to two adequate antidepressant trials.” ¹⁴¹ Claim 1 of the TRD ketamine US Patent 8,785,500 B2 reads: “A method of treating depression comprising intranasally administering a patient who suffers from said depression and who has not responded to at least two adequate antidepressant treatments a composition comprising ketamine [...]”.¹⁴¹ Remarkably, the U.S. Patents and Trademark Office determined on 10/03/2022 that the claims of the ketamine TRD US Patent 8,785,500 B2¹⁴¹ “cover the method of using the drug product known by the trademark SPRAVATO^® (esketamine hydrochloride)” ¹⁴² and that this patent is eligible for a term extension of a period of 605 days.¹⁴² Thus, this ketamine patent term extension (PTE) was based on the periods of the clinical trials and regulatory review of Spravato (FDA NDA#211243). The ketamine patent was followed by US Patent 9,592,207 B2 (priority date 22/03/2006) claiming, among other methods of use claims: “1. A method of treating depression comprising intranasally administration of a dose of ketamine effective to alleviate depression to a patient afflicted with depression that has not responded to at least two adequate antidepressant treatments. 7. The method of claim 1 wherein the depression comprises major depressive disorder.” ¹⁴³

(iii) Marks and Cohen’s recorded references:(135,136)

Contrary to M&C’s claim, the McIntyre article¹³⁵ points out aspects of superior TRD use of esketamine versus ketamine, stating (see BOX 2 in ref (135)) that “there is insufficient evidence for oral, subcutaneous, or intramuscular ketamine in TRD [and] intranasal esketamine demonstrates efficacy, safety, and tolerability for up to 1 year in adults with TRD.” ¹³⁵ The Bahji article¹³⁶ emphasizes the fundamental limitations of the authors’ M&C review, stating, e.g., that “the results of the trials may not represent the real-world efficacy of ketamine.” “When appraising the relative efficacy of racemic ketamine to intranasal esketamine, one must also consider the timepoint [...]. While racemic ketamine has demonstrated significant short-term benefits in several clinical studies, the long-term benefits remain insufficiently explored, and this may be a contributor to the current lack of FDA approval for racemic ketamine.” ¹³⁶

(iv) Evergreening, me-too drugs, product hopping, and biopiracy:

The allegation of a generalized concern about ‘evergreening’ (see Box 1) is unjustified. The Supreme Court of Canada held in the chiral-switch drug Plavix (clopidogrel bisulfate) enantiomer patent case that “evergreening is a legitimate concern and, depending on the circumstances, strategies that attempt to extend the time limit of exclusivity of a patent may be contrary to the objectives of the Patent Act.” ¹⁴⁴ However, the Court noted that “a generalized concern about evergreening is not a justification for an attack on the doctrine of selection patents” ¹⁴⁴ (including enantiomer patents). The Court stated that “selection patents encourage improvements over the subject matter of the original genus patent because selection does something better than or different from what was claimed in the genus patent.” ¹⁴⁴ In the Plavix patent CA 1,336,777 case, the main question was whether the patent was a selection patent according to the selection patents doctrine. Second, whether the patent was considered evergreening—whether a “concern about evergreening is a justification for an attack on the doctrine of selection patents.” ¹⁴⁴ The Court held that “the Plavix patent was a valid selection patent. The genus [basic] patent (CA 1,194,875) claimed all derivatives of a general formula as well as the two enantiomers and the racemic mixture. It is a broad claim for a class or a genus. The claim in the ‘777 patent is specific. It claimed only the dextro-rotatory isomer [(+)-enantiomer] of the racemate. This is a typical selection patent. [...] Since the ‘875 [basic] patent did not teach the special advantages, the invention of the ‘777 patent [the enantiomer patent] was not disclosed and was therefore not anticipated.” ¹⁴⁴ Furthermore, Spravato (esketamine hydrochloride) is not a ‘me-too drug’,¹³⁴ because ketamine has not been approved for TRD usage and is not on the market for this purpose. Me-too drugs were defined as “substances that pharmaceutical companies claim are novel and nonobvious inventions to obtain a new patent despite there being little or no structural or functional differences between existing drugs and the subject matter claimed in the new patent”¹³⁰ (footnote 41 in ref (130)).

The term ‘product hopping’ (see Box 1) is not applicable to the esketamine TRD patents. In fact, according to M&C, ‘product hopping’ is “the process of subtly modifying an existing product and patenting the result”.¹³⁰ ‘Product hopping’ has recently been defined as “the process by which a brand, as the patents on an older branded drug are expiring, uses its current dominant market position to switch doctors, pharmacists, and consumers to a newer version of the same (or similar) drug with later-expiring patents”.¹³¹

‘Biopiracy’ (see Box 1) is defined as “the appropriation and commercialization of indigenous technologies without adequate permission, acknowledgement, or compensation”.¹³⁰ “Biopiracy occurs when bioprospecting is used to appropriate knowledge and biodiversity resources to gain exclusive use through intellectual property rights (IPRs) without benefits for indigenous populations.” ¹³² Likewise, ‘biopiracy’ is not applicable to the esketamine TRD patents.

3.1.3. Corollary

It will be intriguing to pursue whether the chiral-switch element in combination with the repurposing element in the Spravato esketamine patent will be sufficient to overcome a judicial challenge based on lack of novelty and nonobviousness, in view of the TRD ketamine patent. The prospective decisions in the litigations concerning the validities of the esketamine TRD patents will serve as precedents for the patentability of repurposing/chiral-switch drugs.

3.2. Regulatory Exclusivities Considerations for Drug Repurposing/Chiral-Switches Combination Drugs

Regulatory exclusivities of approved chiral-switch new drugs vary in regulatory jurisdictions worldwide. Such variations may affect new drugs developed by the strategy of drug repurposing/chiral-switches combination.

3.2.1. U.S. FDA New Active Ingredient (NCE*) Exclusivity

U.S. Congress’ newly enacted Public Law 117-9 (2021), an act to amend the FD&C Act with respect to the scope of new chemical entity (NCE) exclusivity, confers exclusivity based on a drug’s ‘active moiety’, not on its ‘active ingredient’ ¹⁴⁵ (see also ref (146)). A single enantiomer drug of a racemic mixture that was previously approved contains an active moiety that had previously been approved. Therefore, it is not considered a NCE, and thus is not eligible for 5-year regulatory exclusivity and an FDA NDA Classification Code Type 1 – New Molecular Entity (NME).⁴⁰

Subsection 505(u) of the U.S. FD&C Act entitled “Certain Drugs Containing Single Enantiomers” (codified in 21 U.S. Code § 355(u), amended)^145,147 states, “[...] if an application is submitted [...] for a non-racemic drug containing as an active moiety [...] a single enantiomer that is contained in a racemic drug approved in another application [...], the applicant may, in the application for such non-racemic drug, elect to have the single enantiomer not be considered the same active moiety as that contained in the approved racemic drug [...]”.¹⁴⁷ Thus, the applicant may elect to claim, under certain strict conditions, the MAPP NDA classification code Type 2 – New Active Ingredient,⁴⁰ which confers 5-years NCE* exclusivity.

NCE* is an exclusivity abbreviation defined in the FDA “Orange Book” 42nd Edition, 2022, p. 1550, as “NCE* New Chemical Entity (An Enantiomer of Previously Approved Racemic Mixture. See Section 505(u) Of the Federal Food and Drug Cosmetic Act).” ¹⁴⁸ The conditions include (inter alia) “(A) (i) the single enantiomer has not been previously approved except in the approved racemic drug; and (ii) the application [...] for such non-racemic drug—(I) includes full reports of new clinical investigations (other than bioavailability studies) [...]; (II) does not rely on any clinical investigations that are part of an application [...] for approval of the approved racemic drug; and (B) the application [...] for such non-racemic drug is not submitted for approval of a condition of use—(i) in a therapeutic category in which the approved racemic drug has been approved; or (ii) for which any other enantiomer of the racemic drug has been approved. [...] The Secretary shall not approve such non-racemic drug for any condition of use in the therapeutic category in which the racemic drug has been approved.” ¹⁴⁷ According to the FD&C Act §505(u), an NCE*-designated qualified chiral switch is eligible for 5-year market exclusivity, similarly to NCE-designated approved NDAs. The above conditions are pertinent to an NDA of a repurposed/chiral switch to a single enantiomer.

3.2.2. EU/EMA New Active Substance (NAS) Exclusivity

“A new chemical, biological or radiopharmaceutical active substance includes: a chemical, biological or radiopharmaceutical substance not previously authorised in a medicinal product for human use in the European Union; an isomer, mixture of isomers, a complex or derivative or salt of a chemical substance previously authorised in a medicinal product for human use in the European Union but differing significantly in properties with regard to safety and/or efficacy from that chemical substance previously authorized [...].” ¹⁴⁹

8+2+1 exclusivity (data (8 years), market protection (2 years), and market protection for new indications (1 year)) is granted to a new global marketing authorized drug.¹⁰³ An EMA-approved repurposed/chiral-switch drug has a better prospect of being designated a NAS than a chiral-switch drug.

The “Reflection paper on the chemical structure and properties criteria to be considered for the evaluation of new active substance (NAS) status of chemical substances” ¹⁵⁰ of the EMA Committee for Medicinal Products for Human Use (CHMP) states, for ‘Isomers’ (Section 2.1) (understood as enantiomers), “[...] In the case one enantiomer is applied for where the other enantiomer is the active substance in a previously authorised medicinal product for human use within the European Union it has to be assessed whether they differ significantly with respect to safety and/or efficacy properties.” And for ‘Mixture of Isomers’ (Section 2.2): “Where a previously authorised medicinal product for human use in the European Union includes a racemate and a new application for only one of the two enantiomers of the racemate is submitted, this enantiomer would have been a substantial part (50 %) of the racemate and would therefore be considered as the same active substance as the racemic mixture, unless the applicant provides evidence that the two substances differ significantly in properties with regard to safety and/or efficacy.” ¹⁵⁰ The designation of NAS confers periods of protection (data and market exclusivity) according to the 8+2+1 rule.^150,151

3.2.3. Canada’s ‘Innovative Drug’ Exclusivity

The U.S. regulatory exclusivity designation ‘new chemical entity’ (NCE) has been replaced in Canada by the designation ‘innovative drug’. According to the Canadian Food and Drugs Act and the Food and Drug Regulations (FDR), the decision on approvals of drugs is governed by the Canadian Minister of Health.^152,153 Accordingly, data protection will be provided to ‘innovative drugs’, defined as follows: “Innovative drug means a drug that contains a medicinal ingredient not previously approved in a drug by the Minister and that is not a variation of a previously approved medicinal ingredient such as a salt, ester, enantiomer, solvate or polymorph.” ¹⁵³ In Canada, the data protection does not include exclusivity of 8 years and 6 years of denial filing.

A case in point is the designations of the new drug Spravato (active ingredient esketamine hydrochloride, see Section 2.2). Spravato was not designated a NAS by the EMA and was not designated an ‘innovative drug’ in Canada. The Federal Court of Appeal (FCA) of Canada has recently upheld earlier decisions that data protection should not be granted to “an enantiomer of a previously approved medicinal ingredient”.¹⁵⁴ Hence, Spravato was not eligible for data protection pursuant to the Data Protection Regulations on the basis that its medicinal ingredient esketamine hydrochloride was an enantiomer of ketamine hydrochloride—a previously approved medicinal ingredient.¹⁵⁴ The FCA relied on its 2014 relevant enantiomer dexlansoprazole (Dexilant) judgment, in which the FCA’s majority decision “held that salts, esters, enantiomers, solvates and polymorphs of previously approved medicinal ingredients are variations of those ingredients, and, as such, do not fall within the definition of ‘innovative drug’ ” ¹⁵⁴ (see also ref (155)). The request that “the scope of data protection be expanded to include product variations that have different safety and efficacy profiles from the original product, such as metabolites, enantiomers, salts and esters” ¹⁵⁴ was rejected. The minority dissent reasoned that “a drug that contains an enantiomer of a previously approved medicinal ingredient is not automatically excluded from data protection under [FDR]. The listed substances in the definition of ‘innovative drug’ were simply examples of substances that may be ‘variations’, depending on the circumstances surrounding the data that had to be submitted in order to obtain regulatory approval.” ¹⁵⁴

3.2.4. Australia’s Data Exclusivity of New Products Containing ‘Active Components’

The Australian Therapeutic Goods Legislation Amendment Act 1998 inserted a “new Section 25A into the Therapeutic Goods Act 1989 (Act). Section 25A created a data exclusivity regime for new products containing ‘active components’ by establishing ‘protected information’.” ^156,157 “Information is protected information if: (a) the information was given to the Secretary in relation to an application to register therapeutic goods (the new goods) consisting of, or containing, an active component; and (b) the information is about the active component and is not available to the public; and (c) when the application to register the new goods was lodged: (i) no other therapeutic goods consisting of, or containing, that active component were included in the Register; and (ii) no such therapeutic goods had been included in the Register at any time before then; and (d) the new goods became registered on or after the commencement of this subsection [...].” ¹⁵⁷ It provides the following definition: “an active component [...] is a substance that is, or one of the substances that together are, primarily responsible for the biological or other effect identifying the goods as therapeutic goods.” ¹⁵⁷ The data protection scheme means a prohibition for 5 years of using ‘protected information’ for the evaluation of therapeutic goods for registration. Thus, the period of data exclusivity is 5 years.¹⁵⁷ The Federal Court of Australia decided in the Lexapro (escitalopram oxalate, a chiral-switch drug) case that Lexapro’s respective racemate “Cipramil was goods ‘consisting of, or containing’ for the purposes of para (c) of s 25A(2), escitalopram, the active component of Lexapro”.¹⁵⁸ The Court found that “Cipramil contains two active components ((S)-citalopram and (R)- citalopram)”.¹⁵⁸ Hence, escitalopram is the active component both of Lexapro and of Cipramil.¹⁵⁸ While (+)-citalopram can be accepted to be a new chemical entity as against the racemate, this did not answer the statutory question whether Cipramil “contains” the former. ‘New chemical entity’ is defined in the Therapeutic Goods Regulations 1990 (TG Regulations), Schedule 9, as follows: “(a) a chemical, biological or radiopharmaceutical substance that has not previously been included in the Register; or (b) an isomer, mixture of isomers, complex of, derivative of or salt of, a registered chemical substance that, having previously been included in the Register, differs from the registered substance in having different safety or efficacy properties [...].” ¹⁵⁹ The Court rejected the submission that the term ‘active component’ in Section 25A should be interpreted synonymously with the term ‘new chemical entity’, noting that the term ‘new chemical entity’ is not used in Section 25A or elsewhere in the TG Act.¹⁵⁹ “The references to ‘new chemical entity’ that were introduced into the TG Regulations (by the Therapeutic Goods Amendment Regulations 2002 (SI No 2/2002)) after Section 25A was introduced into the TG Act, were all irrelevant to the question of the proper construction of the TG Act.” ¹⁵⁹ The Court concluded that the requirements of Section 25A(2) were not met, so that data exclusivity could not be applied to the chiral-switch drug Lexapro.¹⁵⁹

3.2.5. Corollary

Consider the new-drug designations of the drug repurposing/chiral-switch drug Spravato, active ingredient esketamine hydrochloride, conferred by the various worldwide regulatory authorities. They are not uniform:

According to the U.S. FDA, Spravato was designated “NCE* New Chemical Entity (an enantiomer of a previously approved racemic mixture [...])”,¹⁴⁸ with 5-year exclusivity, expiration 05/03/2024 (Orange Book, 42nd Edition, 2022, p. 1351).¹⁴⁸

According to the EU/EMA, Spravato was not designated a New Active Substance (NAS), which may have conferred 8+2+1 data exclusivity and market protection. This “negative” application was probably due to the fact that, starting in 1997 in Germany, Spravato’s active ingredient “esketamine has been approved and marketed overseas as a general anesthetic in 17 countries, including much of Europe (including the United Kingdom and Scandinavia) and Brazil.” ¹⁶⁰

For Canadian authorities, Spravato was not designated ‘innovative drug’ conferring data protection exclusivity.¹⁵⁴

In Australia, although Spravato is considered a new chemical entity for Australian regulatory purposes,¹⁶¹ following the Lexapro precedent,¹⁵⁸ the requirements of Section 25A(2) of the TG Act would not have been met, so that data exclusivity could not be applied to this repurposing/chiral-switch combination drug.

We submit that in the future, the drug repurposing element combined with the chiral-switch element in new such drugs, which “provides evidence that the [two substances differ] significantly in properties with regard to safety and/or efficacy”,¹⁵⁰ may overcome the legal barriers and convince the regulatory authorities and the courts to grant new-drug designations and consequently eligibility for regulatory exclusivities.

4. Conclusions

Drug repurposing and chiral switches are elements of the secondary pharmaceuticals strategy. The COVID-19 pandemic and modern advances in drug discovery and development have accelerated drug repurposing. Our Perspective calls for the systematic application of the drug repurposing/chiral-switches combination strategy. The outcome may prove to be beneficial, beyond a superposition of its two elements. The combined strategy is not new. However, it has previously been applied unintentionally, not as a designed strategy. The Perspective illustrates previous cases, highlighting the ketamine to esketamine. It has not escaped our minds that the chiral-switch strategy per se is controversial.^5,6,122 However, the repurposing/chiral-switch combination strategy may overcome the arguments (e.g., obviousness) against chiral-switch patents. Moreover, following the past chiral switches, it encourages the application of the repurposing/chiral switches to the paired enantiomers. From the patentability point of view, patents claiming repurposing/chiral-switch combination drugs may represent a “sharp sword” rather than a “toothless tiger”.¹²¹ They are not ‘evergreening’ and ‘product hopping’. There are promising prospects of FDA- and EMA-approved repurposed/chiral-switch drugs being designated NCE* and NAS, conferring regulatory exclusivities, as compared to chiral-switch drugs only.^145,147,149 The deuterium-enabled chiral switches of thalidomide analogs^108,109 are considered a variation of the repurposing/chiral-switch combination strategy. Although repurposed/chiral-switch drugs may be ‘obvious-to-try’, their inventions may be unexpected and their patents nonobvious.

The drug repurposing/chiral-switch combination strategy is an opportunity for enriching the arsenal of secondary pharmaceuticals, in particular for rare diseases, beyond the advantages of the two elements. It creates some new synergy of these elements. Rare diseases share with the COVID-19 pandemic a huge medical and emergency need. Of the ∼7000 known rare diseases, approximately 95% have no approved treatment.^162,163 A case in point is the incentive to develop a chiral switch of Fintepla (fenfluramine hydrochloride) for the treatment of Dravet syndrome (Section 2.3, vide supra).

The expected benefits and opportunities of the combined repurposing/chiral-switch strategy vis-à-vis its two elements include superior pharmacological properties, strengthening validities of patents, overcoming challenges of chiral-switch patents, reduced expenses, shortened approval procedures, and higher expectations of regulatory exclusivities. The present Perspective is a call for a comprehensive search for worldwide-approved racemic drugs that will serve as potential substrates for repurposing/chiral switches and for the application of the combined strategy to chiral switches of the paired enantiomers.

The authors declare no competing financial interest.