3D-printing of pharmaceuticals: patent and regulatory challenges

3D-printing of pharmaceuticals: patent and regulatory challenges Additive manufacturing, specifically three-dimensional printing (3DP) has been in use in the manufacture of medical devices for some time, with the FDA recently issuing draft guidance for technical considerations in this regard 1. More recently, however, attention has turned to the use of these techniques in manufacturing pharmaceuticals, in particular pharmaceutical dosage forms 2 including orally administrable dosage forms and drug-loaded implants. In addition to the technical challenges faced by inventors in this field, there are a number of regulatory and legal issues to be addressed. This article explores some possible issues relating to the procurement and enforcement of intellectual property rights, and potentially arising at the interface of 3DP pharmaceuticals with regulation and consumer protection. Patentability The requirements for patentability of inventions involving 3DP are identical to those of any other invention. According to Section 1(1) of the Patents Act 1977 (PA77), a UK patent may be granted only for an invention that is new, involves an inventive step, is capable of industrial application, and which relates to subject-matter in respect of which the grant of a patent is not excluded. There are corresponding requirements under Article 52 of the European Patent Convention (EPC). An invention is new if it does not form part of the state of the art 3. The state of the art is taken to comprise all information that has at any time before the priority date of the invention been made available to the public anywhere in the world by any means 4. However, a prior disclosure is only novelty-destroying if it conveys sufficient information for the invention to be reproduced by the hypothetical skilled person, i.e. if the disclosure is enabling 5. This raises an interesting point for establishing novelty in emerging technologies such as 3DP of pharmaceuticals. As the technology becomes generally more widespread, the enablement requirement for a given disclosure is likely to be reduced as the skilled person becomes more likely to be able to fill in any gaps in the total information content of a disclosure by using their own common general knowledge. Thus, it can be expected to become harder over time to establish novelty of further inventions in this area over a given disclosure. An invention involves an inventive step if it is not obvious to the skilled person over the state of the art 6. Thus, one of the key issues in assessing inventive step is to identify the skilled person in question. When 3DP was first considered for pharmaceuticals, the skilled person would likely have been a pharmaceutical formulation scientist. However, as 3DP becomes more common, the skilled person is more likely to be viewed as a team of people. This could include a 1 Technical Considerations for Additive Manufactured Devices, Draft Guidance for Industry and Food and Drug Administration Staff May 10, 2016, http://www.fda.gov/ucm/groups/fdagov-public/@fdagovmeddev-gen/documents/document/ucm499809.pdf 2 Emergence of 3D Printed Dosage Forms: Opportunities and Challenges, M. A. Alhnan, T. C. Okwuosa, M. Sadia, K-W. Wan, W. Ahmed and B. Arafat, Pharm. Res. DOI 10.1007/s1 1095-016- 1933-1 3 Section 2(1) PA77; Article 54(1) EPC 4 Section 2(2) PA77; Article 54(2) EPC 5 Merrell Dow v Norton [1996] RPC 76 HL 6 Section 3(1) PA1977; Article 56 EPC

formulation scientist, but could also include software engineers and designers who work with 3D-printers routinely as part of their design equipment, and possibly also materials scientists and engineers. As 3DP becomes more widespread, it seems increasingly likely that producing an existing pharmaceutical formulation by means of 3DP where this involves only the application of existing 3DP processes would be considered obvious, particularly where this does not present any difficulties other than those that can be addressed by workshop variations which would be routine for the skilled worker. Thus, as this field of technology advances, inventive step is likely to require overcoming a particular problem or alternatively providing a particular advantage, either through the 3DP process itself or in the printed product, in comparison with existing formulations or conventional manufacturing processes. An invention is capable of industrial application if it can be made or used in any kind of industry, including agriculture 7. 3DP clearly satisfies this requirement. In the UK, subject-matter in relation to which the grant of a patent is excluded is defined as: (a) a method of treatment of the human or animal body by surgery or therapy, or (b) a method of diagnosis practised on the human or animal body 8. 3DP therefore is not excluded subject-matter and, in principle, it is clear that 3DP-related inventions constitute potentially patentable subject-matter in the UK and Europe. Patent Landscape Early 3DP patent applications (barring those relating to the development of 3DP itself) related to its use in the rapid manufacture of components and prototypes. For example, US 5,204,055 in the name of the Massachusetts Institute of Technology (MIT) relates to layers of powder material bound by a liquid binder selectively deposited to produce a layer of bonded powder material. Repetition of the steps produces a layered bonded component. MIT followed this case with WO 95/11007 which related to solid free form methods for making medical devices for controlled release of bioactive agent and implantation, including techniques such as stereolithography (SLA), selective laser sintering (SLS) and fused deposition modelling (FDM). However, by the time they filed WO 03/037607, MIT had moved into compression of a 3DP dosage form to decrease void space and incorporate a greater amount of active agent (still using liquid binder 3DP methods). Cases such as US 2004/0005360 also focussed on the dosage form produced again, using a liquid binder method where a powder bed was bound into core and shell form by liquid droplets controlled by 3DP. More recent patent applications, for example WO 2014/075185 and WO 2015/143553 by the Orthopaedic Innovation Center, Inc. (CA), continue to focus on implants, in these cases implants which are antimicrobial, produced by 3DP methods. However, there have now also been a small number of patent applications published which relate to the direct production of complete pharmaceutical dosage forms by 3DP methods, for example US 2014/0271862, WO 2016/038356 and WO 2017/010938. US 2014/0271862 and WO 2017/010938 contain claims to inter alia the dosage forms and methods for delivering and producing these. In other words, conventional pharmaceuticaltype claims. 7 Section 4(1) PA77; Article 57 EPC 8 Section 4A(1) PA77; Article 53 EPC

Broadly speaking, inventions in the UK are defined and claimed as products or processes. However, certain fields of technology tend to use particular claim types, for example medical use claims, which have a specific format. In contrast to the more conventional claims of US 2014/0271862 and WO 2017/010938, a recently published international (PCT) patent application by the University of Central Lancashire, WO 2016/038356, illustrates the broader range of claim types and aspects that could be usefully be claimed for 3DP-related pharmaceutical inventions. Among other things, this application claims a solid dosage form printing apparatus 9, a method of printing a solid dosage form 10, a solid dosage form obtainable by the method 11, a method of preparing a printing filament 12, the printing filament itself and a filament spool 13, a computer for operating the apparatus 14, and a computer-implemented method of operating the apparatus 15. The variety of claim types that are potentially available in respect of the different aspects of 3DP processes and products provide proprietors with a number of tools for protecting their position, and these are discussed below, although it should be noted that these approaches are as yet untested in the courts. Infringement The possible advent of truly personalised medicine gives rise to a number of questions and issues in relation to infringement, both direct infringement and indirect or contributory infringement. It is important to remember that patents provide a negative right, i.e. the right to stop unauthorised working of the invention. In essence, UK patent law provides that making, importing, disposing of, offering for disposal, keeping or using a patented product in the UK constitutes infringement, where these acts are committed without the consent of the patent proprietor. Likewise, in relation to a patented process, using the process constitutes infringement, while making, importing, disposing of, offering for disposal, or keeping the direct product of the patented process in the UK also constitute infringing acts. These are direct infringements. Indirect or contributory infringements essentially consist of supplying or offering to supply in the UK, to a person not entitled to work the invention, and without the consent of the proprietor, any means relating to an essential element of the invention, for putting the invention into effect, when it is known or is obvious to a reasonable person in the circumstances, that those means are suitable for putting, and are intended to put, the invention into effect in the UK. Since this discussion relates primarily to pharmaceutical products, it is relevant to note that in the UK, pharmacists currently benefit from the protection of an exemption to infringement. Under s.60(5)(c) PA77 the extemporaneous preparation in a pharmacy of a medicine for an individual in accordance with a prescription given by a registered medical or dental practitioner, or dealing with a medicine so prepared, are acts which are deemed not to constitute patent infringement. 9 WO 2016/038356, claims 1-19 10 WO 2016/038356, claims 20-24 11 WO 2016/038356, claim 25 12 WO 2016/038356, claims 26-27 13 WO 2016/038356, claims 29-31 14 WO 2016/038356, claim 32 15 WO 2106/038356, claim 33

Would pharmacists activities remain inside the scope of the existing exemption, even if their extemporaneous preparation or dealing with a medicine involved 3DP, in other words actions equating to manufacture of a pharmaceutical dosage formulation? In Generics v Warner-Lambert 16 there is an indication that if doctors or pharmacists were involved in manufacturing the medicaments in question this could be contributory infringement of a Swiss-type claim in the sense of providing a means essential to putting the invention into effect. However, medical use claims are no longer acceptable in the Swiss-type format, and the scope of the new medical use claim type, substance X for treatment of disease Y, has not been tested. Moreover, pending applications relating to 3DP dosage forms do not generally appear to include medical use claims or Swiss-type claims and these may not be appropriate where the invention relates to the method of manufacture or improved properties of the product itself rather than its use in treating a certain condition. This begs the question: if a patented product or the direct product of a patented process is only made in situ by pharmacists, then who could infringe such a patent? Who can a Patentee sue for unauthorised use of its process, or for performing other acts that would normally infringe, in relation to its product? The exemption for pharmacists appears to mean that they would not be vulnerable to patent infringement actions where their actions relate to preparation of prescriptions. Nonetheless, 3DP processes developed to offer more general benefits such as faster production, reduced wastage or lower costs, or, for example, which allow manufacturers to offer a wider range of dosages without compromising on cost-efficiency, could be attractive to mainstream pharmaceutical manufacturers and generics companies. Such manufacturers would not benefit from the exemption that keeps pharmacists from infringing when performing activities associated with filling prescriptions. Besides process claims there are a number of other claim types that could be useful in protecting different aspects of 3DP technology. For example, apparatus claims might catch infringing manufacturers, importers and distributors of hardware either of the apparatus as a whole or individual elements where these are means essential to working the apparatus and the necessary knowledge or expectation of knowledge is present with regard to intent to work the invention. The same applies to other hardware product claims. As with the methods of manufacture themselves, claims to the use of 3DP in manufacture of a pharmaceutical formulation could be problematic to enforce, with regard to the question of who is the infringer if this is a pharmacist then they are most likely exempted in the UK, although non-pharmacist manufacturers would not benefit from this exemption. Manufacturers could also fall foul of medical use claims and/or claims to methods of drug delivery, where they are manufacturing an essential element of that method, as well as methods of manufacturing a formulation or its starting materials such as filaments (where these are essential elements). Process claims, product claims and intermediate product claims could also encompass as infringers the suppliers of 3DP apparatus, or specialised starting materials or intermediates, where these are means essential for putting the invention into effect. Although, in Nestec v 16 Generics (UK) Ltd (t/a Mylan) v Warner-Lambert Company LLC [2015] EWHC 2548 (Pat)

Dualit 17, where the claimed invention was a system consisting of a coffee machine and a capsule adapted for use in that machine, it was held (with reference to earlier cases 18 ) that owners of the relevant coffee machine do not make the claimed system when they purchase capsules for use in said machine. Following this approach would suggest that sale of e.g. replacement filaments or spools would be unlikely to infringe 3DP apparatus claims. Exhaustion of Rights It is worth considering whether the sale of 3DP apparatus in an EU state and license to manufacture would equate to consent to put the pharmaceutical products on the market in that state and therefore exhaust the proprietor s right to stop import of that product into any other EU state. However, it is well-established by case law that in this context, consent must be expressly given. At present, owners of IP rights such as patents and trade marks can use customs provisions as part of their enforcement strategy, arranging for the seizure of suspected infringing imports. However, the mobility of 3DP systems may mean unlicensed third parties are more likely to produce infringing products locally, rather than exporting/importing, which would reduce the usefulness of the current customs provisions as part of an overall enforcement strategy. Regulatory Issues It remains to be seen how regulators and drug approval bodies such as the FDA will deal with 3DP pharmaceuticals. As 3DP hardware becomes more widespread, and opens up the possibility of production of pharmaceutical dosage forms by a wider variety of manufacturers and on a much smaller scale, it seems likely that regulatory approval requirements may ultimately pertain to all aspects of 3DP i.e. not only the products themselves but the hardware, software, CAD files, intermediate products and component materials needed to make an approved pharmaceutical product. The need for regulation in this area could drive innovation and/or could lead to a de facto global industry standard in 3DP hardware, software, processes, components etc., as has been seen in the mobile phone industry (e.g. GSM vs. CDMA). We have now seen the first FDA approved 3D-printed drug 19, SPRITAM, but there is no guarantee that its approval will facilitate approval for producers of the next 3DP drugs. It also remains to be seen whether there are implications for packaging and labelling requirements when pharmaceuticals are produced in situ on demand, in small quantities, rather than being produced in volume by a relatively small number of licensed and regulated manufacturers. Conclusion In addition to the technical challenges faced by inventors in this field, there are a number of regulatory and legal issues which are likely to develop as 3DP becomes more widespread, in particular regarding not only the procurement and enforcement of intellectual property rights, but also potentially arising at the interface of 3DP pharmaceuticals with regulation and consumer protection. 17 Nestec SA & Ors v Dualit Ltd & Ors [2013] EWHC 923 (Pat) 18 Schütz (UK) Ltd v Werit UK Ltd [2013] UKSC 16 and United Wire Ltd v Screen Repair Services (Scotland) Ltd ([2001] RPC 24) 19 US 2014/0271862 A1

In the meantime, applicants and their representatives would be well advised to consider including in new applications as wide a range of claim types as can be justified on the basis of their invention, with a view to protecting the various aspects against infringement. This article was submitted for publication in Pharmaceutical Patent Analyst on 19 April 2017 and the final version was published online on 11 July 2017: https://www.futurescience.com/doi/full/10.4155/ppa-2017-0017