Focus on life sciences

Protecting deuterated drugs

With companies paying substantial sums for marketing rights over deuterated drugs, Michael Furrow and Erin Austin examine critical patent strategies and considerations

euterium (2H) is a nonradioactive profile. Additionally, benefits in terms of investigating DRX-065, a deuterium-stabilised isotope of hydrogen that half-life of the active ingredient may be version of the (R)-enantiomer of the diabetes contains a neutron in addition to counterbalanced by undesirable increases in drug Actos (pioglitazone), for the treatment of hydrogen’s proton and electron. the half-life of certain deuterated metabolites. nonalcoholic steatohepatitis, a liver condition. Deuterium can covalently Pharmaceutical companies have shown Dbind to other atoms in the same manner as Industry investment in interest not only in deuterated versions of hydrogen. Because deuterium and hydrogen deuterated drugs approved drugs, but also in incorporating are essentially the same size, a deuterated Scientists began incorporating deuterium deuterium into their discovery programmes. compound and its hydrogen-containing into potential drugs over 50 years ago,1 and In 2017, Merck KGaA paid Vertex $230m up (proteo) counterpart may bind similarly to a enthusiasm about using deuterium to modify front (with a promise of royalties on future sales) biological target, such as a protein relevant to pharmacological properties waxed and waned for M9831, a deuterated inhibitor of DNA- treating disease. However, deuterium is heavier over the subsequent decades. In the 1970s dependent protein kinase with the potential than hydrogen and can form stronger bonds and 1980s, Merck advanced the deuterated to enhance certain cancer treatments, that with carbon. These differences can give rise to antibiotic fludalanine into the clinic, but resulted from Vertex’s efforts to improve the differences in pharmacological properties. development ultimately stopped due to metabolism of a leading candidate in one of For example, where a drug’s primary toxicity resulting from a metabolite. its R&D programmes. route of metabolism involves the breaking of More recently, several deuterated drugs The amount of recent investment in this carbon-hydrogen bonds (eg, by the oxidative have advanced clinically and companies area evidences the potential for deuterated cytochrome P-450 enzymes of the liver), have started paying substantial sums for drugs to provide new and improved replacing the relevant hydrogen atom(s) with marketing rights. In 2012, Celgene paid $42m treatments for patients, and to be an important deuterium may slow metabolism. A longer for rights to Deuteria’s deuterium-enriched consideration in drug life cycle management. half-life may permit a reduced dose amount analog of Celgene’s anti-cancer drug Revlimid or dosing frequency, or may help to decrease (lenalidomide). In 2015, Teva acquired Auspex Proof of principle: Austedo unwanted side effects caused by metabolites. and its then-clinical candidate Austedo In April 2017, the US Food & Drug As another example, replacing carbon- (deutetrabenazine, discussed further below) Administration (FDA) approved the hydrogen bonds with carbon-deuterium bonds for $3.5bn. Concert Pharmaceuticals, a first deuterated drug, Teva’s Austedo may also slow undesirable epimerisation (the company focused on deuterium chemistry, (deutetrabenazine).2 Deutetrabenazine is a interconversion of enantiomers of a chiral has partnered or sold several deuterated selectively deuterated version of , drug). drugs, including Avanir’s AVP-786 (d6- the active ingredient in Xenazine, a drug Whether deuteration has any meaningful ), which is in Phase III approved in 2008 for treating chorea beneficial effect, however, depends on the clinical trials for the treatment of agitation in associated with Huntington’s disease. compound and its use. For example, reduction Alzheimer’s disease, and VX-561 (a deuterated Compared to tetrabenazine, deutetrabenazine of one metabolic pathway may lead to a version of Vertex’s Kalydeco (ivacaftor)), which provides deuterated active metabolites with compensatory increase in metabolism at a is part of a combination treatment in Phase II longer half-lives, and it may be dosed less different site (metabolic switching). Further, trials for cystic fibrosis. Otsuka acquired Avanir frequently. even where a compound’s metabolism involves for $3.5bn in 2014, and Vertex paid $160m Austedo’s approval is interesting for breaking a C-H bond, that cleavage may not for VX-561 in 2017, with an additional $90m reasons beyond showing that a deuterated be a rate-limiting step, and inhibiting it may in milestones possible. Another company drug can receive FDA approval. It was based not affect the compound’s pharmacokinetic focused on deuterium chemistry, DeuteRx is on a 505(b)(2) application, meaning that,

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Focus on life sciences

although Teva conducted clinical and other one or more hydrogen atoms are replaced by formation. The PTAB also found that the effect studies for Austedo, it relied in part on data deuterium.”5 of deuteration was not predictable because for the reference listed drug Xenazine to gain To support a narrow claim to a specific of potential alternative rate-limiting steps in approval. Austedo was also granted five- deuterated compound or small genus of ’s metabolism and the possibility year new chemical entity (NCE) exclusivity deuterated compounds, more targeted of metabolic switching. It credited evidence and seven-year orphan drug exclusivity.3 language may be warranted. submitted by the patent owner showing that When deciding Austedo’s entitlement to Accordingly, practitioners involved in deuterium substitution could actually increase those exclusivities, the FDA determined application drafting for discovery programmes metabolism (eg, as observed for certain that deutetrabenazine is not the same drug should consider specifically disclosing – by deuterated derivatives) or have no as tetrabenazine based on the agency’s chemical name or structure – and exemplifying effect (eg, as observed for certain phentermine chemical structure-centric interpretation of any deuterated derivatives of interest. derivatives), and that deuteration reducing in the term “active moiety”. Thus, Austedo’s Practitioners involved in due diligence vitro metabolism might not translate into approval shows how a deuterated version of analyses for potential acquisitions, or in superior in vivo potency or pharmacokinetic a previously approved drug can benefit from portfolio analyses for life-cycle development properties (eg, as observed with a deuterated reliance on the proteo drug’s data for approval planning, should be aware of IP issues derivative). Further, the PTAB held yet also receive regulatory exclusivities for new surrounding deuterated compounds. A full that D-9 venlafaxine would not have been drugs. picture of the patent landscape around a “obvious to try” given that venlafaxine had key compound will involve any patents or 27 hydrogen atoms that might be replaced Patent strategies and applications related to deuterated analogs, with deuterium, resulting in over 100 million considerations which can signal potential future competition possible deuterated derivatives. Given the potential, and newly highlighted or present an opportunity to invest in IP that importance of deuterated compounds to drug protects a drug with potential advantages over Footnotes R&D, patent practitioners should be aware existing proteo treatments. 1. B Belleau et al, ‘Effect of deuterium substitution of certain considerations when prosecuting Given the recent approval of the first in sympathomimetic amines on adrenergic patent applications for a discovery programme, deuterated drug, case law has not yet responses’, 133, Science 102 (1961). evaluating a patent portfolio for potential developed in the courts from suits between 2. Charles Schmidt, ‘First deuterated drug acquisition or life-cycle management, or branded and generic companies. However, approved’, 35, Nature Biotechnology 493 assessing the merits of post-grant or litigation PTAB decisions rendered thus far in inter (2017). challenges. partes review (IPR) proceedings suggest that 3. Memorandum from the CDER Exclusivity For those drafting patent applications nonobviousness arguments of the same Board to the Office of Orphan Drug Products for discovery programmes that are not types that succeed for proteo NCEs can also Designation and CDER’s Division of Neurology already zeroed in on a particular deuterated be useful for defending the patentability Products in the Office of Drug Evaluation I (31 compound or motif, consideration should be of deuterated compounds. For example, in July 2015). given to whether and how to support claims Incyte v Concert (the deuterated ruxolitinib IPR 4. IPR2017-01256, Paper No 9 (19 Oct 2017). to deuterated compounds. In Incyte Corp noted above), the PTAB rejected the argument 5. PGR2017-00034, Paper No 9 (11 Jan 2018). v Concert Pharmaceuticals, Inc,4 the Patent that a person of ordinary skill (POSA) would 6. IPR2017-01256, Paper No 9 at 17. Trial and Appeal Board (PTAB) held that a have selected ruxolitinib as a lead compound 7. Id at 17-18. disclosure of a genus encompassing ruxolitinib, based on the Jakafi label’s teaching that it 8. IPR2015-01313, Paper No 25 (19 Dec 2015). the active ingredient in Incyte’s Jakafi, and was FDA-approved, stating that it was not 9. Id at 9-10. general language about “all isotopes of convinced a POSA would select ruxolitinib 10. Id at 13-21. atoms occurring in the intermediates or final over any other compound with known clinical compounds” was not so limited that it could efficacy.6 Further, even if ruxolitinib were a be treated as equivalent to a description lead compound, the PTAB found a lack of of each embraced species. Although that motivation to modify it with deuterium, eg, the case involved an unsuccessful anticipation petitioner had not shown ruxolitinib had toxic challenge to Concert’s patent claims to certain metabolites, that it was not well-tolerated, or Authors deuterated analogs of ruxolitinib under 35 USC that it had poor bioavailability.7 section 102, it is instructive when considering As another example, in Neptune Generics, the breadth that such language supports as LLC v Auspex Pharmaceuticals, Inc, the PTAB far as written description under section 112 is declined to institute IPR for a patent claiming concerned when applied to a particular genus D-9 venlafaxine, a deuterated analog of or species. That is, depending on the number the active ingredient in the antidepressant of potential isotopes implicated, boilerplate Effexor.8 The petitioner argued that D-9 language including “isotopes” may support venlafaxine was obvious because venlafaxine only a genus of all isotopes. was known to be metabolised to an active As an example, a specification disclosing O-desmethyl metabolite (ODV) and two Michael Furrow is a partner and Erin ruxolitinib and “all isotopes of atoms” occurring inactive desmethyl metabolites, and it Austin is an associate in the New York in compounds of the invention (including, but was known that deuteration could reduce office of Fitzpatrick, Cella, Harper & not limited to, deuterium isotopes), and stating metabolism.9 The PTAB disagreed.10 It held Scinto. Both former chemists, they represent innovators across the that synthetic methods for incorporating that, because ODV was a desired active life sciences in all aspects of patent radio-isotopes were well-known, was found metabolite, a POSA would not have had a acquisition and enforcement. to support a claim to ruxolitinib “wherein reason to modify venlafaxine to reduce ODV

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