Following our article on the role and challenges for the IP system in the world of 3D printing (or additive manufacturing), we are now going to focus on the specific field of 3D bioprinting. While many of the fundamental principles of conventional 3D printing apply to 3D bioprinting, such as the use of a CAD file to provide information to the 3D printer that forms the articles, due to the materials used and their potential applications, an additional set of issues must now be considered.
Bioprinting falls within an emerging yet significant application of 3D printing in the field of MedTech, encompassing aspects of biomaterials as well as medical devices. While 3D printing has solidified its place in the production of prostheses and biomedical devices, more recent developments have identified materials that, upon printing, afford tissue-like structures that can mimic natural products. These new “bioinks” can be used to make functional organs and tissue structures and may include tissues, cells and other biomolecules (e.g., growth factors) that are printed to create scaffold-free cell-based structures. Bioinks can also include biocompatible materials that, upon printing, form scaffold-like structures within which the cells propagate. These biocompatible materials include hydrogels having specific properties that allow them to be extruded at temperatures required for maintaining living cells while undergoing gelation during printing to form the scaffold.
The use of 3D bioprinting to produce biodegradable structures and implantable medical devices has the potential to reduce the costs and improve the treatment options available for a range of medical conditions. Examples of applications include skin grafts for the treatment of burns, as well as synthetic tissues for use in in vitro drug testing[1]. One goal would be to 3D print entire organs suitable for implantation[2].
With any new technology, there is a need for robust IP protection to provide security and encourage investment. Patents are an obvious choice in this instance, as they can provide protection for the “bioink” compositions, the processes and equipment used in printing itself, as well as the end products (or products obtained by the specific 3D bioprinting process, protected using so-called “product-by-process” claims). Reflecting the development in this field is the increasing number of filed and granted patent applications, as shown in Figures 1 and 2. With the number of applications increasing consistently since 2015, we might expect this trend to continue into the next decade. Companies filing in this area include Sichuan Revotek Co. Ltd, BICO (of whom CELLINK are a subsidiary), T&R Biofab, Medtronic, 3D Systems, Inc., and Ricoh Company.
While these technologies present myriad opportunities, they can also present challenges for the IP system, both in terms of how to effectively protect new inventions (via patents, designs, copyright etc.), and how to enforce the rights against third parties. General challenges relating to enforcement of IP rights in 3D printing technology have been previously discussed in our related article. In addition to these general issues, inventions relating to 3D bioprinting present several specific challenges.
Bioinks and 3D Printed Biological Tissue
Exciting scientific developments have been taking place in the field of materials science, particularly with regard to biomaterials for medical devices and their application in 3D printing. Biologically active inks can be used to control and direct cell behaviour, and can therefore be used in the manufacture of complex tissue structures for regenerative medicine. Claims directed to bioinks, and the resulting 3D printed tissue structures, must satisfy the standard patentability criteria of novelty, inventive step, and being capable of industrial application. Although many bioink components, particularly biocompatible scaffold-forming materials, are known in the art, innovation may lie in the combination of these well-known components with living cells. Composition claims can therefore be crafted so as to satisfy the requirements of patentability. For example, a particular combination of hydrogels may provide unexpected improvements in a cell-containing composition, such as a reduction in shear force experienced by cells during printing, the provision of nutrients to cells post-printing, or the enhancement of the mechanical properties of the resulting tissue.
Moreover, while 3D printed bone implants have been around for some time, challenges exist in implementing the technology for soft tissues, for example in vascularisation and innervation of the biological tissue. Companies are continuing to advance in this area with 3D bioprinting being developed for use in human organ printing[3]. The bioinks in this case may include living cells or tissue in addition to the scaffold-forming materials, or as a standalone composition. As the technology emerges, it may be necessary to consider whether and to what extent it is possible to protect these natural materials, particularly if it becomes possible to 3D print bioinks comprising cells and natural materials alone. Cell-based bioinks and the resulting 3D bioprinted tissue structures would likely qualify as patentable subject-matter at the EPO; materials found in nature are, at least in principle, patentable under Article 5(2) of the Biotech Directive (incorporated into Rule 29(2) EPC), which confirms that “an element isolated from the human body or otherwise produced by means of a technical process, including the sequence or partial sequence of a gene, may constitute a patentable invention, even if the structure of that element is identical to that of a natural element.” It is notable that the approach in Europe is more patentee-friendly than in the US, where human organisms and products of nature are typically ineligible for patent protection.
Of particular importance in the field of soft-tissue engineering are stem cells, due to their ability to differentiate into the desired cell type. 3D bioprinting processes can be used to control the outcome of stem cell differentiation[4]. The protection of bioinks comprising stem cells would need further consideration, since in Europe, Article 53(a) EPC and Rule 28(1)(c) EPC prohibit claims to the use of human embryos (and thus human embryonic stem cells (hESCs)) for industrial or commercial purposes under grounds of morality. However, the EPO Guidelines for Examination allow protection for certain types of hESCs, such as those derived from parthenogenetically activated human oocytes.
Given the technological developments needed to support the advancement of 3D bioprinting, protection for the scaffolds, implants or full-scale organs “obtained by” 3D printing (product-by-process claims) as well as for the products per se is conceivable. Regardless of whether a product or product-by-process claim is utilised, the products themselves must be novel. 3D bioprinting may give rise to structures with controlled porosity, permeability, or mechanical properties, as well as bespoke arrangements of cells and scaffold materials, or highly mature biological functions, such that structural and/or functional features may be used to distinguish over, e.g., natural tissues or organs.
Medical Use Claims
It is entirely feasible that the innovation of a bioink or a 3D bioprinted article lies in its medical use, that is, it provides a therapeutic effect. Protecting known bioinks or 3D printed biomaterials may therefore be achieved via Article 54(5) EPC, which states that claims to the use of a known “substance or composition” may be patentable provided that the use is not known in the art. However, this raises the question of whether the bioink or printed material would be considered a “substance or composition”.
Under the EPO’s Guidelines for Examination, a material qualifies under this provision provided that it is the active agent or ingredient in a specific medical use and if the therapeutic effect can be ascribed to its chemical properties. In practice, this means that 3D printed materials which aid in the regeneration of tissues by virtue merely of its porous or permeable structure, for example, would be considered a device rather than a substance or composition, and thus not covered by the provisions of Article 54(5) EPC. In contrast, if a 3D printed material produces a regenerative effect on tissue that could be attributed to its chemical properties (e.g., biomolecules, chemical entities, etc.), it would be considered as a “substance or composition” in the sense of Article 54(5) EPC. The wide range of applicable materials that could be used in 3D bioprinting gives rise to a high degree of flexibility and versatility in producing therapeutic products, which should not be overlooked when seeking to obtain patent protection.
3D Bioprinting Methods
Claims to conventional 3D printing processes, for example, to the 3D printing of a new prosthesis, will rarely be excluded from patentability under the EPC. However, as companies continue to advance this technology, particularly in the field of organ-level regenerative medicine, it can be envisaged that in situ bioprinting will evolve. These systems eliminate the artificial environment need for printing, e.g., in a sterile lab setting using a bioreactor, such that the human body behaves as the bioreactor. Moreover, in situ bioprinting could overcome problems associated with 3D bioprinting using bioreactors, including reducing the risk of contamination or breakage that can occur when handling and implanting the products. Several different approaches to in situ bioprinting have already been developed and patent applications are starting to be filed. While claims to new equipment and/or bioinks used in in situ bioprinting would be eligible for patentability, applicants should be aware of the potential exclusions that may apply in this setting, in particular, Article 53(c) EPC which prohibits claims to methods of treatment of the human or animal body by surgery or therapy. Thus, while a claim to a method of 3D bioprinting a skin graft may be patentable, skin regeneration which takes place directly onto a patient may fall foul of this exclusion.
Applicants should consider the EPO’s criteria for assessing Article 53(c), wherein a method is excluded if, when carried out, “maintaining the life and health of the subject is important and which comprises and encompasses an invasive step representing a substantial physical intervention on the body which requires medical expertise to be carried out and which entails a substantial health risk even when carried out with required professional care and expertise” (G1/07). Whether or not a claim to an in situ bioprinting method is excluded under these provisions will typically be assessed on a case-by-case basis, taking into account the relative risk to the patient and the necessity for a surgeon to perform the procedure. Relevant EPO Case Law in this regard held that a process involving the removal and subsequent return of blood to patient was excluded under Article 53(c) EPC,[5] as it required “professional medical expertise”.
Accordingly, while in situ bioprinting has the potential to play a key role in organ formation and regeneration, careful consideration should be given when drafting to cover related methods where the manufacture takes place in the human body. Claims may need to be adapted to focus on, e.g., the method of operating the device or the device itself, as well as any specific bioinks that are used in such processes.
Summary
3D bioprinting is an emerging field with great potential for improving the treatment options for a range of conditions. The technology can be used to produce new materials and therapies through the printing of bioinks comprising cells and biomolecules, with or without scaffold-forming materials. Applicants in this area will want to protect the bioinks themselves and the 3D printed products that result, as well as the equipment and associated methods of use. While claims to methods of bioprinting as well as to biomaterials used in methods of treatment may be patentable, applicants should be aware to avoid any exclusions. If you would like to discuss these issues in more detail, please let us know.
[1] Active players in this area include T&R Biofab, CELLINK (in partnership with AstraZeneca), and Prellis (in partnership with Sanofi), who develop 3D printed organoids for this purpose.
[2] Companies pursing this goal include CELLINK, 3D Systems, Medtronic, United Therapeutics, Ricoh, and Organovo
[3] Volumetric Biotechnologies and 3D Systems 3D printing platform for human organ printing (3D Systems Announces Acquisition of Volumetric Biotechnologies | 3D Systems)
[4] 3D bioprinting using stem cells (nature.com)
[5] T1695/07, which applies G1/07.
