Introduction.
A belief that the U.S. government holds a patent for medical marijuana is a yet another example of scientific imprecision that obfuscates the national debate on the uses of marijuana as medicine. Advocates for marijuana as medicine, including the journalist Dr. Sanjay Gupta, refer to U.S Patent No. 6,630,507 as evidence of government hypocrisy on marijuana. “the United States already holds a patent on medical marijuana for that very purpose… How can the government deny the benefits of medical marijuana even as it holds a patent for those very same benefits?” The patent in question, “Cannabinoids as Antioxidants and Neuroprotectants” is assigned to the U.S. government (HHS) on behalf of three inventors serving at that time at the National Institutes of Health: Aidan J. Hampson, Julius Axelrod (a Nobel laureate) and Maurizio Grimaldi. The issued patent was published Oct 7 2003, with a priority date of 1998.
A primer on patent claims. Claims are the heart of a patent. Patents protect inventions listed in the patent claims. If a substance is not listed in the claims, the patent does not protect the substance. Claims define the limits of precisely what the patent covers and protects. The patent holder has the right to exclude others from making, using or selling those things which are described by the claims. The claims define, in technical terms, the extent, the scope, of the protection conferred by a patent.
The US government does not hold a patent for marijuana as a medicine. This U.S. patent makes a number of claims but marijuana and THC are not among them. It clearly distinguishes unprocessed botanical marijuana from individual cannabinoids. It specifically rejects marijuana or THC as claims. Instead the patent claims uniquely designed novel cannabinoids not found in nature, or cannabidiol made by the marijuana plant, or endocannabinoids made by the brain. It specifically rejects marijuana and the most abundant plant cannabinoid THC because of their psychoactivity and psychotoxicity. The claims in this patent focus on non-psychoactive cannabinoids synthesized in laboratories or by the brain that act at different targets (receptors) than marijuana or THC. The claims are for specific neuroprotective and antioxidant actions, which are distinct from the majority of reasons currently stated for using marijuana.
Even though the marijuana plant contains some chemicals that may be useful for treating illnesses or symptoms or as leads for chemical modification, the plant itself is psychoactive and the effects of its 750 chemicals, including some 104 different cannabinoids remain largely unknown. The inventors of this U.S. government patent did not patent medicinal uses of whole plant marijuana, nor its most prominent cannabinoid, THC, because they explicitly chose to avoid their undesirable, unacceptable psychoactive effects based on actions at cannabinoid receptors. Instead, the patent claims focus on specific cannabinoids, the majority of which are designed by medicinal chemists and are not found in the marijuana plant. The inventors discovered that certain cannabinoids have neuroprotective and antioxidant properties and antagonize specific glutamate receptor subtypes (neurotoxicity), without activating cannabinoid receptors (psychoactivity), as does the (2) marijuana plant or THC therein. The claim that the U.S. government has a patent on marijuana as a medicine is untenable.
Patent Claims in U.S. Patent No. #6,630,507. Patents protect inventions listed in the patent claims. If a substance is not listed in the claims, the patent does not cover the substance. This patent focuses on individual cannabinoids, mostly synthetic cannabinoids designed and created in laboratories. The claims do not mention marijuana nor are most of the claims based on cannabinoids found in the marijuana plant. Marijuana cannot be used interchangeably with the term cannabinoid (see The Folly of Extrapolation). A few claims include endocannabinoids made by the brain and CBD of the marijuana plant. Even these cannabinoids are not addictive, psychoactive, or intoxicating, in contrast to marijuana and the cannabinoid THC of the marijuana plant which are psychotoxic.
The following outline more specifically the reasons why it is erroneous to conclude that the United States government has patented “medical marijuana” (#6,630,507).
1. Marijuana is not a claim of this invention. The inventions/claims in this patent do not include marijuana (medical or otherwise), and do not mention marijuana in the abstract, which summarizes key concepts of what is claimed and why. The invention refers to single cannabinoids designed by medicinal chemists, including synthetic analogs of cannabidiol (CBD). With the exception of CBD, the cannabinoids claimed are synthetic or derivatives from the brain and not produced by, or have been discovered in the marijuana plant.
2. The claims of this invention are unique, single cannabinoids, not a mixture of 104 cannabinoids or 650 other chemicals found in the marijuana plant. The chemical claims in this patent are single, unique cannabinoids, each of which is to be assessed alone in biological tests – in marked contrast to marijuana, a complex mixture of over 750 chemicals that include 104 known cannabinoids, terpenoids, small molecules like ammonia and hydrogen cyanide and heavy metals. The chemical composition of marijuana is quite similar to that of tobacco, except that it instead of nicotine, it contains cannabinoids (1). If this had been a marijuana patent, it would, by necessity, claim a complex mixture of at least 750 chemicals.
1 Moir et al, A Comparison of Mainstream and Sidestream Marijuana and Tobacco Cigarette Smoke Produced under Two Machine Smoking Conditions. Chem. Res. Toxicol., 2008, 21 (2), pp 494–502
3. A primary objective of the patent is to develop individual cannabinoids that are free of psychoactive or psychotoxic effects and that are substantially non-toxic even at very high doses. The inventors specifically focus on developing single cannabinoids without actions at cannabinoid receptors. This precludes marijuana or THC. Marijuana would not qualify as a claim, and is not claimed because it is psychoactive, psychotoxic at high doses, is a complex mixture that acts primarily at cannabinoid receptors. THC, the most prominent cannabinoid in the marijuana plant is also excluded and not claimed, for the same reasons that
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marijuana is avoided. It is psychoactive and psychotoxic and acts at cannabinoid receptors. The patent defines the term “psychoactivity” to mean “cannabinoid receptor mediated psychoactivity.” “Such effects include euphoria, lightheadedness, reduced motor coordination, and memory impairment.” Unprocessed marijuana and THC mediate psychoactivity via cannabinoid receptors.
4. The majority of the newly designed compounds in the claims not produced by the marijuana plant and may have effects distinctly different from, or may be medicinally advantageous compared with cannabinoids made by whole plant marijuana. The patent covers and assesses unique, synthesized cannabinoids, the majority not found in the marijuana plant. It focuses on newly designed dibenzopyran cannabinoids and newly designed analogs of CBD, as previous studies have indicated that cannabidiol is not psychotoxic or psychoactive or acts at cannabinoid receptors.
5. The patent states that the “cannabinoid may be a cannabinoid other than THC” (the main cannabinoid in marijuana), and excludes “other potent cannabinoid receptor agonists”. This exclusion eliminates any potent cannabinoid receptor agonist that has a cannabinoid receptor potency of 50 nM or less (or even as weak as 190 nM or 250 nM or less). The cannabinoid receptor (CB1) is the mediator of psychoactive effects of marijuana and THC.2 THC potency is higher (25 nM) than the stated cut-off potency and is excluded for this reason. Marijuana is not mentioned and if it were, it would be excluded because it contains psychoactive THC (25 nM) and other cannabinoids with high cannabinoid receptor potency. The patent states: “THC (tetrahydrocannabinol) is another of the cannabinoids that has been shown to be neuroprotective in cell cultures, but this protection was believed to be mediated by interaction at the cannabinoid receptor, and so would be accompanied by undesired psychotropic side effects.” There are no claims of isolating cannabinoids from marijuana or assessing marijuana or THC.
2 Huestis MA, Gorelick DA, Heishman SJ, Preston KL, Nelson RA, Moolchan ET, Frank RA. Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arch Gen Psychiatry. 2001 Apr; 58(4): 322-8.
6. The neuroprotective and antioxidant actions of listed cannabinoids in the claims are based on actions independent of cannabinoid receptors. De facto, marijuana and THC are excluded. The results presented in the patent “therefore surprisingly demonstrate that cannabinoids can have useful therapeutic effects that are not mediated by cannabinoid receptors, and therefore are not necessarily accompanied by psychoactive side effects. The inventors further state, “the therapeutic potential of nonpsychoactive cannabinoids is particularly promising, because of the absence of psychotoxicity, and the ability to administer higher doses than with psychotropic cannabinoids, such as THC.”
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7. Most of the cannabinoids claimed in this patent are not made by, or found in the marijuana plant. 14 claims describe a number of newly designed cannabinoids that can be synthesized in a medicinal laboratory. CBD is claimed, but many of the CBD analogs claimed are novel and not found in the marijuana plant. Separate, unique individual cannabinoids designed and created de novo represent the majority of the patent claims.
The Folly of Extrapolation. The inventors appreciated the pursuit of individual cannabinoids regardless of their origins (plant, synthetic, brain) and not whole plant marijuana. They rejected cannabinoids acting at cannabinoid receptors, the major target of marijuana and THC, to avoid psychoactive and psychotoxic effects. Thus extrapolating the claims of this patent to include whole plant marijuana or even THC is folly. The patent also avoids extrapolating from whole plant marijuana to individual isolated cannabinoids for the same reasons. The patent also recognizes that individual cannabinoids may engender markedly different effects via different brain targets, and eschews extrapolating from one unique cannabinoid to another. For this reason, it outlines biological testing templates designed to assess the therapeutic potential of individual cannabinoids. Currently, about 104 different cannabinoids have been identified in the marijuana plant, which in smoked or ingested form, may be delivered as an ensemble to the brain or body. These include THC that acts at cannabinoid receptors (precluding its development), its active metabolite, and others that may or may not produce similar or opposing pharmacological effects.
Some reasons to avoid extrapolation from whole plant marijuana to cannabinoids:
a. To avoid confusing terminology of marijuana and cannabinoids;
b. The composition, bioavailability, pharmacokinetics and pharmacodynamics of botanical marijuana differs from extracts or purified individual cannabinoids;
c. The bioavailability of active cannabinoids in marijuana, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), cannot be predicted because differences in smoking or vapor inhalationor ingestible products vary between users and types of delivery systems. In contrast, a fixed oral dose of a cannabinoid can be quantified in plasma or whole blood samples, yielding relatively predictable results;
d. To avoid extrapolating to marijuana, conclusions drawn from efficacy of purified cannabinoid or newly designed cannabinoids of known doses, and delivered by common routes used for medications. Marijuana is used predominantly by smoking, inhalation from water pipes or vaporizing, a rapid form of brain delivery considered a route of administration with higher addiction potential;
e. To avoid extrapolation and appropriation of safety data generated from isolated or newly synthesized and medically approved cannabinoids (with known doses) to whole plant marijuana, for which there are no guidelines for doses.
f. To avoid extrapolating from marijuana and THC to novel cannabinoids that may have different medicinal properties and sites of action.
Examples of why modern medicinal chemistry, biology and drug development focus on isolated or synthesized compounds for drug discovery and not on whole plants. Examples of why extrapolating evidence from one unique cannabinoid to another cannabinoid if folly. 5
THC and CBD (cannabidiol) research has shown that these cannabinoids in the marijuana plant have opposite effects in the brain.
a. THC is intoxicating, psychoactive and addictive, can induce psychosis, anxiety, memory impairment and in some cases seizures.
b. THC principal targets are cannabinoid receptors, which the patent clearly states is not a desired biological target.
c. CBD is neither psychoactive nor addictive, does not impair memory, and may alleviate psychosis, anxiety and seizure activity, even antagonizing these THC-induced adverse effects.
d. CBD has very weak activity at cannabinoid receptors (affinity greater than 1,000 nM) and apparently acts on different brain receptors than THC.
e. From the perspective of medicinal properties, it is illogical to deliver two chemicals to the brain which produce opposite effects.
f. In peripheral organs, there are examples of CB2 receptors having beneficial functions in specific organs whereas CB1 receptors may be associated with disease processes. Yet THC targets both receptors with similar potency.
Conclusion. Dr. Gupta and others who allege that the U.S. government is hypocritical because it holds a marijuana patent while simultaneously classifying marijuana in the most restrictive Schedule I category, use the term marijuana inaccurately and indiscriminately to refer to the patented cannabinoids, the vast majority of which don’t exist in the marijuana plant. They disregard the primary focus of this patent, individual and novel cannabinoids created in chemical laboratories. The patent claims are restricted to individual cannabinoids and their structures, regardless of origin: chemically synthesized in a laboratory, made by brain, or CBD made by the marijuana plant. The patent recognizes the complexity, unpredictability and undesirability of marijuana or THC, as both activate undesirable targets (cannabinoid receptors) and display undesirable psychoactive and psychotoxic effects. As marijuana contains over a hundred cannabinoids that may act synergistically, antagonistically, the patent recognizes the value of pursuing individual cannabinoids with their knowable biological targets, beneficial or adverse effects.
The claim that the U.S. government has patented medical marijuana is analogous to claiming that a patent on medicinal amphetamine or digoxin or quinine sulphate or oxycodone, or lidocaine is the same as a patent on Ma Huang, or foxglove, or cinchona bark, or opium poppies, or coca bushes. By this reductio ad absurdum, garden centers marketing foxglove or poppy plants for decorative purposes, Whole Foods marketing cinchona bark as a source for creating tonic water, chemical companies that sell digitonin (an isolate from the digitalis plant) to dissolve lipids in water, would violate patents that protect medicinal preparations of chemically modified drugs whose lead structures are of plant origins. The extrapolation of this patent to a marijuana patent is as irrational as claiming that coca bushes and lidocaine (a cocaine derivative) are one and the same.
Source: Bertha Madras in a letter to Drugwatch International Feb. 2016