Patenting Non-Naturally Occurring Fragrance Compounds

Contact Author Heidi M. Berven, Ph.D., J.D.
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As one of the most popular and expensive oils of the 19th century, violet oil’s compounds could be isolated into three major ionones. It was found that depending on the synthetic route, mixtures of the ionones in different ratios were formed, each of which had unique fragrance profiles.

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A century ago, perfumers practiced their craft behind a cloak of mystery. The components of perfumes were understood to be derived from natural sources, but neither the structures of individual fragrance compounds nor the ratio in which particular fragrance compounds were blended to create perfume compositions was readily discoverable to consumers or competitors.

All has changed with the development of sophisticated analytical techniques such as gas chromatography (GC), Mass Spectrometry (MS) and Nuclear Magnetic Resonance (NMR). Now, using these techniques, it is possible to “reverse engineer” the fragrance compounds in any perfume. Perfume compositions are thus easy targets for counterfeiters and other market interlopers. The counterfeiter need only analyze the branded perfume and obtain the known components to produce the fake product.

To make counterfeiting fragrances more difficult, perfumers have turned to the development of non-naturally occurring fragrance compounds. Non-naturally occurring fragrance compounds are synthesized in a laboratory, and, unlike naturally occurring fragrance compounds, they can be protected by patents. A patent on a non-naturally occurring fragrance compound or composition grants the patent owner a 20-year term to exclusively make, use or sell the fragrance compound or composition, while excluding others from doing the same—meaning counterfeiters can still employ analytical techniques to determine “what’s in the bottle,” but cannot produce counterfeit fragrances without violating the perfumer’s patent.

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There are other justifications for developing non-naturally occurring fragrance compounds. For example, using non-naturally occurring fragrance compounds can dramatically reduce production costs. If the yield of a fragrance compound from its natural source is low, the overall cost will be high. An example is the cost of violet oil, which is discussed below. In some cases, the non-naturally occurring fragrance compounds can be safer than those that are naturally occurring, as some naturally occurring compounds are toxic to animals and people. Finally, non-naturally occurring fragrance compounds may be a solution to a changing environmental landscape. As more and more of the natural landscape is replaced by urban and highly mechanized agricultural landscapes, naturally occurring fragrance compounds, as well as the plants and animals that produce them, are at risk of extinction.

Requirements for Obtaining a Patent

The three major requirements for patentability of an invention are novelty, utility and non-obviousness. According to the noveltyrequirement, an invention must be new; that is, it cannot be something that is found in nature or that has been made previously. According to the utility requirement, an invention must have an identifiable use. Finally, according to the non-obviousness requirement, an invention must have some attribute that would be considered unpredictable, surprising, or unexpected to a skilled person. A previously undisclosed non-naturally occurring fragrance compound would meet the novelty requirement. It would meet the utility requirement simply by having an odor (hopefully a pleasant one). It would also meet the non-obvious requirement if it had a characteristic that could not be predicted by a fragrance chemist or perfumer.

A patent is also required to teach the public how to make and use the invention. A non-naturally occurring fragrance patent should disclose the process for how the desired compounds are made, example compositions containing the compounds, and how the compounds and compositions were tested. A patent’s 20 years of exclusivity is effectively granted in exchange for the invention disclosure, which is considered to be in the public interest.

Designing New Fragrance Compounds

How do chemists approach the problem of making compounds that are not naturally occurring but that may (or may not) possess similar characteristics? The development process follows a general pattern that has been used by chemists for many years. First, someone finds a chemical compound with desirable properties. Then, chemists devise efficient methods for obtaining the compound with high purity from the natural source. Next, they determine the best way to make the compound, first in small quantities the laboratory and then in large quantities in production plants.

Chemists also search for new compounds that have the same desirable properties. One strategy for finding new compounds is to test or “screen” hundreds of thousands of known compounds contained in “chemical libraries” for the desired property. Many chemical companies maintain their own chemical libraries for this purpose. Screening libraries may also be available from third party vendors. Compounds that are flagged during the screening process are then used as chemical “leads” for structural optimization. The chemist will tinker with the structure of the lead compound until discovering an “optimized” chemical analog with the desired property and the best profile for commercial use.

Another discovery strategy is to modify the structure of a naturally occurring compound. Generally speaking, the connectivity of the atoms in a naturally occurring compound can be changed to generate new compounds. New compounds can also be created by adding another atom or group of atoms to the structure of a naturally occurring compound. Computer-based modeling programs can be employed to design these new compounds. Ultimately, however, just because compounds have similar structures does not mean that that will share similar fragrance profiles.

The Search for Non-Naturally Occurring Ionones

The search for non-naturally occurring compounds that are similar in structure or fragrance profile to the ionones illustrates the process of innovation in the fragrance industry.

One of the most expensive raw materials used in perfumes in the 19th century was violet oil. The high cost of violet oil is partially attributed to the low yield of oil from violet flowers. The root of iris flowers (“orris root”) was often used as a substitute for violet oil, since orris root was cheaper and had an odor similar to that of violet oil. The major constituents of violet oil were subsequently identified as compounds called “ionones.” The common ionones are alpha-ionone (woody, violet sweet) and beta-ionone (woody, violet). An additional isomer, gamma-ionone (with a natural violet, soft, floral odor), also exists in nature and is the most scarce. The structures of these compounds are shown in F-1, F-2 and F-3.

The ionones are present in plants as mixtures with other compounds. Isolating ionones from plants is not a trivial undertaking, and the separation of one ionone from another remains challenging even today. The difficulty in isolating the natural ionones spurred the development of synthetic routes that could be performed in a laboratory and even on an industrial scale. Each synthetic route produced mixtures of the ionones in different ratios, and chemists discovered that each mixture had a unique fragrance profile.

During the last century’s search for non-naturally occurring ionones, a number of commercially important fragrance compounds were identified. One such compound is isoraldeine, which is commercially available as Isoraldeine Cetone Alpha (Givaudan) and Iralia (Firmenich). The structural similarity between isoraldeine and the ionones is emphasized using bold lines in F-4. Isoraldeine is readily prepared from commercially available starting materials.

Non-Naturally Occurring Ionone Patents

Given the commercial success of compounds such as isoraldeine, chemists continue today to pursue the discovery and development of non-naturally occurring ionones for the fragrance industry. Several patents that claim non-naturally occurring ionones are described below. Each of the below listed patents illustrate a “truism” about the structure and fragrance of non-naturally occurring compounds as compared to naturally occurring compounds.

1. Structural similarity is not a necessary requirement for a non-naturally occurring compound to have the same ionone fragrance profile.

In U.S. Patent No. 9,517,992, owned by Givaudan, the inventors sought to develop a more plentiful and cheaper substitute for Orris Absolute, the essential oil of orris root. The inventors noted that the essential oil of orris may be the most expensive perfumery raw material still in use. The components of the oil were found to include alpha irone (F-5), beta irone (F-6), and gamma irone (F-7)—compounds that have very similar structures and fragrance profiles to the ionones depicted above.

Preparing alpha irone, beta irone and gamma irone selectively via an industrial process rather than by extraction is not feasible and would not provide a cost savings. The inventors found that the acyclic compounds shown below had “characteristic orris facets.” Although the compounds are not cyclic like the ionones or irones described above, they possess many common atoms, represented by the bolded bonds in F-8 and F-9.

In particular, (3E,5E)-5-tert-butylocta-3,5-dien-2-one (F-8) was found to possess “a typical orris, irone, sweet-violet odor with carrot-like and woody-leathery undertones.”

2. The fragrance profile of a non-naturally occurring fragrance compound that is structurally similar to a natural occurring fragrance compound cannot always be predicted.

In U.S. Patent No. 8,911,716, owned by Firmenich, the inventors discovered several compounds that looked like ionones or irones but that had a saffron odor, as opposed to the woody/violet odor of the naturally occurring compounds (see F-10 and F-11).

3. The ratio of fragrance compounds present in a natural mixture can affect the fragrance profile of the mixture. The same is true for mixtures of non-naturally occurring fragrance compounds.

In U.S. Patent No. 9,453,182, owned by International Flavors and Fragrances, mixtures of compounds II (see F-12) and III (see F-13) present a spectrum of fragrance profiles. The inventors found that mixtures containing compound II and III with a weight ratio of about 4:1 or lower had desirable fragrance profiles (“fresh, green aldehydic”), while mixtures containing compound II and III with a weight ratio of above 4:1 possessed off-notes that rendered the mixtures unsuitable for fragrance use.

4. Chemists can modify chemical compounds by adding a “protecting” group. The resulting compounds may have favorable fragrance profiles.

Protecting groups are used to protect a part of a molecule that is susceptible to degradation. For example, the fragrance compounds in U.S. Patent 9,453,182 (above) contain an aldehyde functional group. Aldehydes are generally known to be susceptible to air oxidation and can degrade. Chemists protect aldehydes by converting them to acetals. Acetals are not susceptible to air oxidation, and can be converted back to aldehydes under certain reaction conditions.

The acetal functional group can also be found in fragrance compounds. The non-naturally occurring fragrance compounds claimed in U.S. Patent No. 8,236,749, owned by Firmenich, contain an acetal functional group. The structure of the corresponding aldehyde is provided for comparison in F-14. The acetals have distinct fragrance profiles, ranging from woody to earthy to camphoraceous to minty.

5. Other derivatives of non-naturally occurring compounds may have favorable fragrance profiles.

As noted previously, aldehydes are susceptible to oxidation—they can degrade to form carboxylic acids. Carboxylic acids can be converted to other compounds called “carboxylic acid derivatives.” Carboxylic acid derivatives, such as some esters or nitriles, may also have favorable fragrance profiles (see F-15). This finding is illustrated by U.S. Patent No. 8,183,194, owned by Firmenich. The compounds were found to have a violet and/or woody odor.

Conclusion

Fragrance producers stand to benefit by discovering, making and patenting non-naturally occurring fragrance compounds. Unique and safe non-naturally occurring fragrance compounds and compositions are being patented because of their ongoing potential value to fragrance producers in the face of increasing consumer demand and pressure from counterfeiters.

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F-1 through F-3

F-1 through F-3

F-4.

F-4

F-5 through F-7

F-4 through F-7

F-8 & F-9

F-8 & F-9

F-10 & F-11

F-10 & F-11

F-12 & F-13

F-12 & F-13

F-14

F-14

F-15

F-15

Author Bio

Heidi M. Berven, Ph.D., J.D.

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