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Home > Nanotechnology Columns > Magda Carvalho PhD, JD > Patenting a Novel Industrial Method for Hydroxyapatite Nanoparticles.

Magda Carvalho
Patent Attorney
Patent Law at M. Carvalho

Co-author Dr. Jose Carlos Lopes, Chairman.
Novelty and nonobviousness are two legal requirements to be met for an innovation to be patentable. These requirements are required to ensure that not just any innovation is patentable. Nanosized Hydroxyapatite is in great demand due to its medical use. It is an area where possibilities of novel methods are not exhausted yet. An example of these novel possibilities being given legal effect is a patent granted for a novel method of producing Hydroxyapatite nanoparticles. The invention tries to match natural Hydroxyapatite. This is a significant development for biopharma which is seeking ways to more effectively incorporate Hydroxyapatite into a wide range of biomedical uses.

December 6th, 2008

Patenting a Novel Industrial Method for Hydroxyapatite Nanoparticles.

This column discusses patentability issues regarding a new method for producing nanosized Hydroxyapatite. Producing Hydroxyapatite is, in and of itself, not novel. At least prior to the latest invention discussed below, the then-current state of the art was problematic. There were problems with purity, implementation of the methods, consistent reproducibility, and costs of production. Accordingly, there was a need to develop a more simplified and cheaper method that produced nanosized Hydroxyapatite with a higher purity profile. The new method discussed here overcomes the disadvantages and the final Hydroxyapatite nanoparticles are more natural.(1)

Hydroxyapatite is a mineral, a calcium phosphate form, and one of few materials with medical uses. It is the main mineral component of both the human bone and the tooth enamel; it gives bone and teeth their rigidity. For biomedical uses, the nanosized Hydroxyapatite is better than the micro species. Hydroxyapatite is used in bone graft for bone replacement, growth and repair. It is also used in biocements and coating of metallic implants; chromatography (separation of proteins and DNA); supplements; cosmetics (it diminishes wrinkles); toothpaste; drug delivery (binds numerous biological molecules); cancer treatments.

This column previously discussed both patent requirements: 35 U.S.C. 103 and 35 U.S.C. 102. The novelty requirement is set out in Section 102, which states that an invention is novel if it is not part of the state-of-art. There are two main issues under Section 102. One is a statutory bar that deals with timing issues. The other is anticipation which is concerned with newness. The law recognizes three types of novelty: physical difference, new combination, and new use. However, novelty is not enough. Section 103 requires that the differences over the prior art must also be "unobvious" to an artisan. Several factors are taken into account in deciding whether an invention is or is not obvious. Examples of factors that show an objective evidence of nonobviousness are commercial success, long-felt but unsolved needs and failure of others.

State-of-Art and Quality of Mixing.

Producing Hydroxyapatite with nanosized particles involves the interaction of calcium ions with phosphate ions in a stoichiometric ratio. A mixing process (such as diffusion, mechanical stirring) is applied and it is here that the chemical reactions occur. Thus, the quality of the mixing process affects the properties of the nanoparticles. For Hydroxyapatite, the ratio between calcium and phosphate ions is crucial because certain values create a deficient form. At the state-of-art preceding these patents, the mixing process was not that efficient. As a consequence, the material produced by each batch at the industrial scale had different crystal properties (size, morphology, crystallinity and size distribution).

One way to produce Hydroxyapatite nanoparticles, and the most common, is the wet chemical reaction. This reaction involves temperatures below 100 C and the process uses different routes such as chemical precipitation. Chemical precipitation is normally conducted in stirred reactors. However, the resulting product requires further processing which adds to the cost. An inherent problem of stirred reactors is that they provide a good macromixing quality but not a good micromixing quality due to the formation of stagnation zones at the smallest scales of the mixing vortices. For Hydroxyapatite, applying the wet chemical method in a stirred tank was troublesome related to the calcium phosphate stoichiometry and the process reproducibility in terms of some properties. The invention described below overcomes these disadvantages by providing a method that controls the mixing at the molecular level, the scale where the reactions occur.

The Invention.

The invention provides for a method of wet chemical production of Hydroxyapatite nanoparticles by using a Network Mixer. (2) The advantages of the invention lie on the simplicity of the reactor, continuous production, micromixing, control of the reaction, reproducibility and low cost. The method has been commercially proven as Hydroxyapatite nanoparticles have been thus produced and, the nanocrystals were needle-like in the size of 10 x 70 nm.

Network Mixers were geometrically designed to promote the convective mixture mechanism. In nature, convection is a micromixing process; it is the movement of molecules within fluids. Therefore, promoting the intervention of convection provided an efficient and natural process of micromixing. Examination of the reactor shows that the inventors configured a device consisting of a network of cells. Each cell possesses a chamber with connecting channels. Each chamber is a zone of complete mixing and the channels of complete segregation. Some channels allow the injection of the reactants at different times in a particularized chamber, thus solving a fault of the prior art regarding the lack of control of the reaction. Other channels serve to promote the occurrence of convective mixing mechanism by being positioned obliquely in relation to the direction of the flow into the cell; an element not presented in the prior art. In the prior art the mixing mechanism was by diffusion (random Brownian motion of individual particles in the fluid) or mechanical stirring. Thus, the invention overcomes several disadvantages of the prior art.

Production of Hydroxyapatite simply requires solutions made of calcium, phosphorous, alkaline (to adjust PH), and, optionally, one solvent. These solutions are fed into different streams of the reactor. The maximum nanoparticles aggregates size is 10 microns.

In summary, novelty requirements were satisfied: there is a new physical device operationally different. In the state-of-art, the reactor's interior geometry (a) limited the mixing of fluids by diffusion, (b) possessed pseudo-chambers (intersections) or plates and (3) the channels allowed introduction of a reagent only after a precedent mixture was completed. The invention is also determined to be nonobvious as the new embodiments confer advantages and solve a long-felt need.

(1) This commercially desirable development is what the two European patents "Network Mixer and related mixing process" (PCT WO 2003/077508 A1) and "Production method for calcium phosphate nano-particles with high purity and their use" (PCT WO 2008/007992 A2) are all about. Currently, there are also U.S. patent applications pending for both patents.
(2) The unique available commercial version is the NETmix technology (registered Portuguese brand).
(3) Caveat: This writer is representing the inventor in the United States.

Dr. Jose Carlos Lopes can be reached at:
Fluidinova, Engenharia de Fluidos, SA
TECMAIA, Rua Eng. Frederico Ulrich, 2650
Moreira da Maia, 4470-605 Maia, Portugal
Tel: (+351) 229 408 265
Fax: (+351) 229 408 266

Please send your comments to Magda Carvalho at

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