Deuterated drugs: unexpectedly nonobvious?

• Author: Buteau, Kristen C.

1. Introduction

   The pharmaceutical industry depends heavily on the market exclusivity afforded by patent protection to recoup research and development costs associated with FDA-approval of new drugs. (1) Of particular importance to the validity of pharmaceutical patents is the obviousness requirement codified in 35 U.S.C. [section] 103. (2) Although nonobviousness is a requirement of all issued patents, pharmaceutical patents are especially susceptible to an obviousness challenge because the natural progression of science necessarily builds upon past discoveries and requires considerable experimentation through trial and error, thereby potentially rendering the invention obvious-to-try. (3) The Federal Circuit (and its predecessor, the Court of Customs and Patent Appeals, or "CCPA") has therefore tailored the obviousness requirement to the unique challenges inherent in the chemical arts by outlining ways in which an applicant may overcome an obviousness challenge. (4)

   The pharmaceutical industry utilizes patent law to protect a variety of discoveries, including: compositions of matter, (5) manufacturing processes, (6) new uses or formulations of previously protected compositions of matter, (7) and biological mechanisms of action. (8) Patents on chemical compositions of matter, new salt forms, and new formulations are the most vulnerable to obviousness challenges because the subject matter may be substantially similar to the prior art. (9) Structural similarity between the prior art and a claimed compound is not usually a chance occurrence. (10) As such, pharmaceutical applicants and patentees must be prepared to offer evidence of nonobviousness, either contained in or ancillary to the application. (11)

2. Pharmaceutical Arts Background

   1. Drug Metabolism

      A pharmaceutical drug participates in two general categories of interactions within the body. The pharmacodynamic effect of a drug describes the interaction between the drug and its biological target, most often a receptor. (12) This interaction occurs through the drug's pharmacophore or groups on the molecule which directly interact with the target receptor. (13) In addition to the effect of the drug on its biological receptor, the drug is also susceptible to biological processes, called pharmacokinetics, which are designed to eliminate the foreign agent from the body. (14) Rational approaches to drug design target these processes within the body to improve drug-receptor interaction (pharmacodynamics) and achieve an improved metabolic profile (pharmacokinetics). (15) Because a strong interaction between the drug and its receptor is meaningless if the drug is metabolized so rapidly that it never reaches its target, many drug discovery programs seek to attenuate the pharmacokinetic properties of a drug candidate early in the development process. (16)

      Drug metabolism causes pharmacological deactivation of a drug by modifying its structure so that it is no longer capable of interacting with its biological receptor and is more readily excreted from the body. (17) Metabolism of a drug often generates products which have different biological activities and may be responsible for toxic or carcinogenic side effects. (18) Additionally, rapid metabolism decreases the drug's half-life and concentration in the bloodstream, thereby reducing its efficacy. (19) Because metabolism studies are essential to the evaluation of drug safety and efficacy, the FDA requires an understanding of the metabolic pathways in both humans and animals prior to regulatory approval. (20) As our understanding of metabolic processes improves, pharmaceutical companies increasingly exploit metabolites in an effort to control the down-stream effects of their drugs through a technique called metabolism-induced drug design. (21)

   2. Deuterium and Kinetic Isotope Effects

      Isotopes are atoms which have nearly identical properties but which have different masses due to changes in the number of neutrons in their nuclei. (22) One of the most widely used isotopes in the pharmaceutical industry is deuterium, an isotope of hydrogen with a nucleus comprising one neutron and one proton. (23) Because deuteriu and hydrogen exhibit nearly identical physical properties, deuterium substitution is the smallest structural change that can be made on a molecule. (24) Thus, a parent compound and its deuterated counterpart have nearly identical physiochemical properties. (25) The substantial similarity between a deuterated and parent compound, also called the protio version, is exploited in drug discovery programs through isotopic labeling techniques (26) to identify and quantify metabolites in an effort to understand metabolism-mediated toxicities. (27)

      Kinetic isotope effects are the observed changes in the rate of reaction that occur when deuterium is substituted for hydrogen. (28) Deuterium isotope effects result from the greater energy required to break a covalent bond to deuterium versus a covalent bond to hydrogen, and are expressed as a ratio of the rate of reaction for the protio molecule ([k.sub.H]) over the rate of reaction for the deuterated molecule ([k.sub.D]). (29) Deuterium isotope effects occur because of the significant mass difference between hydrogen and deuterium. (30) The C-D bond is ten times stronger than the C-H bond, making it more resistant to chemical or enzymatic cleavage. (31) If the cleavage of a C-H bond is implicated in the rate-determining step of a metabolic pathway, an overall decrease in metabolism will be observed when hydrogen is substituted with deuterium. (32) Therefore, the reduction in metabolism attributable to deuterium substitution extends the desired effects of a drug while retarding its undesirable effects. (33)

      There are numerous examples of deuterium's effect on the metabolism of biologically active molecules. The anesthetic chloroform (CH[Cl.sub.3]) is metabolized in vivo to phosgene, a highly reactive alkylating agent. (34) Deuteration of chloroform to deuterochloroform (CD[Cl.sub.3]) decreases its metabolic rate, thereby reducing liver and lung toxicity in rats by five to seventy percent over chloroform. (35) Conversely, 1,2-dibromoethane (Br[CH.sub.2][CH.sub.2]Br) is itself a DNA alkylating species, and the tetradeuterated species Br[CD.sub.2][CD.sub.2]Br is indeed metabolized more slowly than the protio version. (36) However, the deuterated species actually causes more DNA damage than its protio counterpart because reduced metabolism prolongs the existence of the reactive species in the body. (37) Similarly, the anticonvulsive diazepam requires metabolic oxidation to its active form, oxepam, and deuteration therefore inhibits the anticonvulsive activity observed from administration of diazepam by preventing the production of the pharmaceutically active species. (38)

      Although the deuterium isotope has been extensively used as a tool to identify metabolites and metabolic pathways, (39) it has not yet been incorporated into a clinical candidate. (40) one of the challenges of incorporating deuterium into a drug is the possibility of deuterium/hydrogen exchange within the physiological environment, eviscerating the effect of the compound. (41) Further, when deuterium retards metabolism at one site, a phenomenon called "metabolic switching" or "metabolic shunting" can occur where the suppression of one metabolic pathway promotes metabolism at another site. (42) For a deuterated clinical candidate to be successful, it must address the problems of biochemical deuterium exchange and metabolic switching. The "ideal starting point" in developing a deuterated drug, also referred to as an isotopolog, is to selectively deuterate a drug in clinical development which has a known metabolic profile. (43) Deuterated drugs of interest are those whose pharmacological or metabolic profiles differ from their protonated versions. (44)

      Incorporating deuterium into novel compounds in an effort to mediate metabolism is a strategy which may find success in traditional drug design and development. Recently, two small pharmaceutical companies, CoNCERT Pharmaceuticals, Inc. in Lexington, MA and Auspex Pharmaceuticals in Vista, CA, have initiated drug development programs targeting deuterated analogs of prior art small molecules in an effort to improve their safety and efficacy by altering their metabolic profiles. (45) The issue of whether a deuterated analog of a prior art compound is obvious has not yet been presented to the courts. This Note surveys the courts' approaches to other obviousness challenges in the chemical arts in an attempt to discern how they will address the deuteration of known compounds in an obviousness inquiry. As outlined below, unexpected differences between the prior art and the deuterated compounds may be the determining factor in assessing whether such compounds are obvious in light of the prior art.

3. Obviousness Jurisprudence Under Graham (46) and KSR (47)

   The obviousness requirement of 35 U.S.C. [section] 103 ensures that patent monopolies are only granted in exchange for disclosure of the invention. Thus, knowledge which is already in the public domain is not adequate consideration for a patent monopoly. (48) The seminal case on obviousness jurisprudence is Graham v. John Deere Co. in which the Supreme Court outlined four factual determinations necessary to the ultimate decision of obviousness. (49) The scope and content of the prior art are determined, the differences between the prior art and the claimed invention are ascertained, and the level of ordinary skill in the pertinent art is resolved. (50) Secondary considerations, such as evidence of commercial success, long-felt but u resolved needs, and failure of others are additional indicia of nonobviousness and are therefore also relevant to the inquiry. (51) Recently, the Supreme Court has further held in KSR v. Teleflex that the combination of known elements is likely to be obvious when it yields no...