REGULATORY FRAMEWORK AND THE SIGNIFICANCE OF INTELLECTUAL PROPERTY (IP) & SUPPLEMENTARY PROTECTION CERTIFICATE (SPC) IN COMBINATION PRODUCTS

Introduction of Combination Products

Combination products are made up of any pair of auxiliary medicine, device, & biologically active substance. Examples include drug-eluting stents and therapeutic dressings, both of which contain a therapeutic component that performs a secondary role to the primary function of the device. Metered-dose inhaler devices and insulin injecting pens, which act as systems for delivering prefilled medications, are further examples. Due to the presence of a medicinal component, combination products are categorized as class 3 devices under the EU Medical Devices Regulation (MDR).[1] All the rules and regulations essential for monitoring combination products in the EU are established and maintained by the European Commission (EC). They operate together with the EMA and other regulatory bodies to ensure compliance with rules and patient safety.

As these combination products are a promising area in the treatment of many diseases, it is essential to safeguard against potential challenges and issues associated with these products, particularly those involving intellectual property rights. Companies developing combination products may face the risk of infringing existing patents or face challenges during the patent application process if prior art references already disclose similar combinations. At the same time, combination products that gain market recognition and success may become targets for counterfeiters or unauthorized use. Maintaining confidentiality and protecting patents, trademarks, trade secrets, and other forms of IP rights can help prevent infringement and safeguard the reputation and market share of the product. Disclosing sensitive information without appropriate confidentiality agreements or security measures can lead to the loss of valuable intellectual property rights.

Regulatory Framework of Medical Device-Drug Combination (DDC) Products

All medical devices containing products marketed in the EU have to clear a conformity assessment conducted by notified bodies to show that they comply with safety and usability standards. These bodies are autonomous organizations chosen by member states to perform conformity assessments and to examine whether all medical devices comply with applicable EU regulations. Once a medical device has passed a conformity assessment, manufacturers may attach the Conformité Européenne (CE) mark to it. ?

For Integral combination products, the General Safety and Performance requirements (GSPRs) of the EU MDR apply to the device and the marketing approval application must contain a CE certificate for the device. If the device is not CE marked but requires to be certified when marketed individually, the candidate should submit the opinion provided by a notified body on the device's conformity and this requisite is effective since May 26, 2021, under article 117 of Medical Devices Regulation (MDR); a systematic regulation that outlines the standards for developing, producing, and marketing medical devices. [2]

Although they are governed by EU Member States, the EMA is a significant player in regulating the usage of combination products where the medicinal component has the primary therapeutic effect. The entire combination product where the drug accomplishes the primarily targeted action is regulated under EU pharmaceutical legislation (Directive 2001/83/EC or Regulation (EC) No 726/2004).[3]

One of the essential points to consider is the fact that in the European Union, in contrast to the USA, the regulatory structure for both medicinal products and?medical devices does not possess a singular definition of a combination product. Products made in the EU that combine a medical device and a medicine are either regulated as medicinal products or as medical devices, with the primary means of action regulating the authorization pathway.

The EMA published a draft set of guidelines on quality standards for human medicine-specific drug-device combinations in 2019. The guidelines, which address the key facts of the quality requirements, were developed in response to an increase in the number of requests for advice. In July 2021, EMA published final guidance on the quality documentation for combination product manufacturers when submitting the marketing authorization applications (MAA) for drugs containing medical devices. This addresses responsibilities in the Medical Devices Regulation, specifically those under Article 117, and explains the standards outlined in Directive 2001/83/EC.[4]

Regulatory Framework of Drug-Drug Combination Products

??????????? The regulation of drug-drug combination products in the EU falls under the European Medicines Agency (EMA) scope and the centralized marketing authorization procedure. Companies seeking approval for drug-drug combination products must submit a comprehensive regulatory dossier demonstrating the quality, safety, and efficacy of the product.

The regulatory requirements are similar to those for single-entity drugs, including preclinical studies, clinical trials, and data on quality and manufacturing.

Importance of Intellectual Property Rights in Combination Products

Inventions that combine several active ingredients, formulations, or technology are given legal protection under intellectual property (IP) rights. These IP rights are essential for the pharmaceutical sector as they promote innovation, grant market exclusivity, safeguard against unauthorized use or imitation and protect the investments made in developing and promoting combination products. There are different types of IP rights which include patents, trademarks, copyrights, and trade secrets. These rights establish legal frameworks to preserve the distinctiveness and commercial worth of combination products while guaranteeing that?innovators benefit from their advancements?in the sector. [5]

Patent rights and their infringements

For combination products, patents are frequently the principal form of IP protection. A patent can be secured for an inventive and non-obvious combination of active chemicals, a distinctive?formulation, a particular delivery method, or a manufacturing procedure. With the help of a patent, the patent holder is given the sole authority to stop unauthorized production, use, sale, or import of the patented combination product.[6]

Over the past generation, medicine has evolved and become more customized, which has had an impact on the medication patent system. The development of combination products has been one significant trend. Combination products have a more difficult, expensive, and complicated path to market than single-ingredient products. Because combination products are more complicated than products with a single active ingredient, patent issues also tend to be more complicated.[7]

Companies developing combination products may face various challenges involving?the risk of infringing on already-issued patents. If a combination product contains a component or technology that is already covered by a valid patent, employing that component without proper authority or licensing may result in a patent infringement claim.[8] Apart from these, the companies sometimes face patent infringement disputes on their combination products with other companies. The infringement of European patents can be evidenced in the case Edwards Lifesciences LLC v. Boston Scientific Scimed, Inc. In the legal battle between Edwards Lifesciences LLC and Boston Scientific Scimed, Inc., a transcatheter heart valve (THV) system was at issue. The defendant ("Boston") owns two European patents that claim inventions called "Repositionable heart valve." The claimant ("Edward") requested the cancellation of Boston's EP (UK) 2 749 254 ("254") and EP (UK) 2 926 766 ("766") patents. However, the defendant, on the other hand, filed a counterclaim, claiming infringement by the claimant and other organizations in the same group. As a result, the claimant and three other organizations, all of which belonged to the same group, were named as defendants in the supplementary claim. Hence,?even though this was nominally a claim for cancellation with a counterclaim for infringement, the trial proceeded considering that Boston was the claimant in an infringement case against Edwards. Edwards' Sapien 3 THV is the claimed infringement product involved in this dispute. The court was assigned to assess the reasons and arguments presented by both parties and render a decision on the matter. [9]

About case specifics, the key element of the invention in 254 was that the THV's skirt "bunched up" to form a seal. While, in 766, The THV's seal was made?by a sac or sacs wrapped around the frame's outside.[10] Boston argued that the seal could take either or both forms, whereas Edwards contended that they are incompatible with one another. The court determined that one of the defendant's two European patents for a heart valve was not valid, but the other one was valid and violated by the claimant's "Sapien 3" valve. Both parties were allowed to appeal the judgment. The defendant requested a permanent injunction prohibiting the claimant and its affiliated firms from promoting the "Sapien 3." Normally, an injunction would be granted to a patentee who proved at trial that their patent was legitimate and being violated, but in this case, the public interest was more important, so a final injunction was disallowed. For a specific group of patients, the Sapien 3 was the only suitable heart valve, and if it weren't available, the patients' lives would be in danger. It would be a tragic conclusion, not only for the patient but also for his family and other people if one person dies?because of an injunction issued in the current case. The simplest and most proper course of action, though, was to award the injunction as usual while staying it awaiting the outcome of the appeal. [11]

As part of a settlement to put an end to lengthy patent disputes between the two medical device manufacturers, Edwards Lifesciences Corp. agreed to pay rival Boston Scientific Corp. $180 million. Later, all the pending cases or appeals in the court and patent offices were dismissed. Analysts considered the agreement to be a "win-win" for all parties, with one pointing out that it might also be advantageous for the sector as a whole. As part of the agreement, the companies promised not to pursue patent litigation for transcatheter aortic valves, specific mitral valve repair tools, and left atrial appendage closure devices.[12]

In these types of patent infringement disputes, companies may incline to show more interest in a settlement among them, rather than extending the disputes which may lead to pending litigation and the possibility of a decline in both companies' growth.

Patent Infringement by Generic Drugs Manufacturers

??????????? Patent infringement by generic drug manufacturers is a significant concern in the pharmaceutical industry, including for combination products. When a patent holder has obtained patent protection for a combination product, they have exclusive rights to the invention, including the right to prevent others from making, using, or selling the patented combination product without permission. However, generic drug manufacturers may attempt to bring generic versions of the combination product to market before the expiration of the patent, which can lead to patent infringement disputes.

Before launching a generic version of a combination product, generic drug manufacturers typically need to seek regulatory approval, such as an Abbreviated New Drug Application (ANDA) in the United States or Marketing Authorization in the European Union.[13] In these applications, the generic manufacturer may need to address the patents held by the innovator company and provide certifications regarding the patent status. However, in some cases, the generic manufacturers may market their generic combination product before the expiry of the SPC of the innovator leading to patent infringement. A legal dispute may arise if a generic drug manufacturer is accused of patent infringement by the patent holder of a combination product. In this scenario, the patent holder must assert their patent rights and provide evidence that the generic product infringes on their patent claims. The generic manufacturer may defend itself by challenging the validity or enforceability of the patent, or by arguing that their product does not infringe on the patent claims. One such patent infringement can be seen in Novartis AG v. Actavis UK Ltd.[14] A combination product?with two active ingredients was the focus of the Novartis Case, for which?Novartis AG (Plaintiff) obtained the SPC (Supplementary Protection Certificate). One of the active components covered by patent EP (UK) 0 443 983, which expired on February 12, 2011, was valsartan. Based on the patent and the 16 October 1996 marketing approval for Diovan, a medication with valsartan as its only active ingredient, Novartis was given an SPC for that active ingredient on 22 August 1997. Co-Diovan, a medication combining valsartan and another active ingredient, the diuretic hydrochlorothiazide, which also lowers blood pressure, is marketed and sold by Novartis.[15] However, Novartis did not submit an SPC application in the UK for the use of valsartan and hydrochlorothiazide together. After the patent EP (UK) 0 443 983 expired, Actavis (Defendant) declared its desire to market a generic medication containing valsartan and hydrochlorothiazide. Actavis was then sued by Novartis in the referring court for allegedly violating Novartis' rights under the SPC it has for the drug valsartan by marketing a similar pharmaceutical. Actavis, however, essentially countered stating that the SPC owned by Novartis exclusively covers valsartan as the single active component. As a result, the defendant argues that the rights of the owner of that SPC would not be violated if a pharmaceutical product was marketed that contained valsartan in combination with another active ingredient. As a final judgment, the Court of Justice of the European Union (CJEU) ruled that Novartis' SPC for the combination product was valid and infringed by Actavis' generic product. The CJEU stated that an SPC may be granted for a combination product when the active ingredients have not been previously authorized in the same combination. It concluded that Novartis' SPC was valid because the combination of active ingredients in their product met the criteria for SPC protection.[16]

Without strong?patent protection, bringing a combination product into the market could not be beneficial in the end. In order to fulfill the need for improved patent protection for medications that required regulatory approval to be introduced to the market, Supplementary Protection Certificates (SPCs) were developed in Europe. With strong patent protection, the patent holder can prevent others from manufacturing, selling, or using the same or similar combination of products without permission.

Supplementary Protection Certificate (SPC)

??????????? SPC is one of the crucial forms of intellectual property which are intended to compensate for the time it takes to obtain regulatory approval and bring the product to market. SPC regulation is amended by the “manufacturing waiver” Regulation (EU) 2019/933 of the European Parliament on July 01, 2019.[17] It is a type of patent term extension for approved medicinal products that is based on the product that is the subject of marketing authorization and is protected by a relevant patent that is in force. To be granted an SPC, a medicinal product must be covered by a?basic patent in force?and have marketing authorization to be placed on the market as a medicinal product. The product cannot be the subject of another SPC, and the MA must be the "first" MA associated with the product.[18]

Disputes related to SPC

In EU nations, the granting of SPCs for products that contain a combination of active substances has been a contentious issue and poses several difficulties for applicants, particularly for combination products containing more than one active component where no clearly defined law can be seen.?However, a recent ruling by the Court of Justice of the European Union (CJEU) on SPCs for a product made up of a combination of pharmaceutically active substances (C-121/17 - Teva UK Ltd & Others v. Gilead Sciences Inc. / Truvada?)?demonstrates that there is now a more defined line of law about how to regulate and?protect such innovations. [19]

In the Teva case, the Court of Justice of the European Union (CJEU) issued a ruling on July 25, 2018, that addressed the interpretation of Supplementary Protection Certificates (SPCs) and the question of whether a combination product is "protected by a basic patent".[20] The case concerned Gilead's (Defendant) request for an SPC for the combination drug Truvada, which has two active components used to treat HIV (Tenofovir disoproxil and Emtricitabine). The defendant had received a European patent for a pharmaceutical composition intended to treat viral infections in both humans and animals. However, the substance Emtricitabine was not mentioned in the patent. Subsequently, an SPC was granted to the defendant for a substance known as a " Composition containing both Tenofovir disoproxil, optionally in the form of a pharmaceutically acceptable salt, hydrate, tautomer or solvate, together with Emtricitabine".[21] A generic drug firm named Teva (Claimant) and other generic companies disputed the SPC's granting, claiming that the combination product?was not "protected by a basic patent" under Article 3(a) of the?SPC Regulation.[22]?

The CJEU judged that even if the precise mix of active ingredients is not specifically indicated in the patent claims, a combination product can still be deemed "protected by a basic patent" and be eligible for an SPC. The key factor to be considered is how closely the product relates to the invention covered by the basic patent and whether it satisfies the requirements for patentability, such as novelty and inventive step.[23] Even if the particular combination of active ingredients is not expressly described in the claims, the court ruled that the protection provided by an SPC must correspond to the invention described in the basic patent.

In addition, the CJEU made it clear that the phrase "specified in the wording of the claims" should not be taken literally, but rather as requiring a clear and direct connection between the combination of active ingredients and the invention described in the basic patent.[24] This clarification aids in enabling the likelihood of obtaining SPCs for combination products that satisfy the prerequisites for patentability and fit within the scope of the innovation covered by the basic patent as well as broader patent protection. Likewise, a similar important interpretation of the SPC regulation is provided by CJEU in Medeva BV v. Comptroller General of Patents, Designs and Trademarks. The case involved the interpretation of the requirements for obtaining a Supplementary Protection Certificate (SPC) under the SPC Regulation (EC) No 469/2009.[25] The dispute in the case centered around the question of whether an SPC could be granted for a combination of active ingredients if only one of the active ingredients was specifically mentioned in the claims of the basic patent.[26]

On November 24, 2011, the CJEU issued a ruling in the case of Medeva (C-322/10) regarding the requirements required to obtain an SPC. The ruling made it clear that an SPC can only be given for an active ingredient or combination of active ingredients that are mentioned in the claims section of the basic patent and must have been the focus of a valid marketing authorization prior to being marketed as a medicinal product. The court emphasized the need for clarity and detail in the patent claims in order to establish the level of protection and eligibility for an SPC.[27]

All these rulings or judgments provide a clear interpretation of SPC regulation in terms of combination products. As these combination products are a promising area in the treatment of many diseases.? A co-therapy approach where patients are dosed with more than one active substance, either as separate dosages or within a single dosage form in order to treat certain diseases, is now a growing area for the development of new medicines. In some instances where the combination products that gain market recognition and success may become targets for counterfeiters or unauthorized use. Protecting trademarks, trade dress, and other forms of IP can help prevent infringement and safeguard the reputation and market share of the product.

Overall, SPCs play a crucial role in the pharmaceutical industry, particularly for combination products. They incentivize innovation, protect intellectual property, extend market exclusivity, and provide commercial advantages, ultimately contributing to the development of new therapies and improved patient care.

Disputes and infringements related to other IP rights:

??????????? Other than patent rights, various types of intellectual property (IP) rights can come into play in the context of combination products. They include trademarks, copyrights, trade secrets, and Regulatory Data Exclusivity. Trademarks protect brand names, logos, or symbols associated with a combination product. They distinguish the product from others in the market and help consumers identify and differentiate it. Trademarks provide exclusive rights to use the mark and prevent others from using similar marks that may cause confusion. Any unauthorized use or imitation of a registered trademark concerning a combination product without the permission of the trademark owner results in Trademark Infringement. It occurs as a result of the use of similar trademarks, Counterfeit combination products and when the product is falsely endorsed or affiliated with the innovator.[28]

??????????? Copyrights protect original creative works, such as software, user interfaces, packaging designs, or product documentation associated with a combination product. Copyrights grant the creator exclusive rights to reproduce, distribute, display, or modify the copyrighted material. Infringement of copyrights occurs when any violation or unauthorized use, reproduction, distribution, or creation of derivative works based on copyrighted material without the permission of the copyright owner. Copyright infringement in combination products can result in legal consequences, including civil lawsuits, injunctions, damages, and the requirement to cease using the infringing copyrighted material. Registering, monitoring, and implementing certain guidelines and contracts are some of the strategies which aid in preventing copyright and trademark infringements.

Trade secrets encompass confidential business information that provides a competitive advantage. In the context of combination products, trade secrets can include proprietary formulations, manufacturing processes, or undisclosed components that give the product its unique characteristics. Trade secrets are protected by maintaining their secrecy and implementing appropriate measures to prevent unauthorized disclosure or use.

Conclusion

Combination products?are gaining significant demand in the pharmaceutical sector because of their potential for improved treatment outcomes and patient convenience. The convergence of drugs, medical devices, and biologics provides novel therapeutic choices and meets complex medical requirements.??????? The future development of combination products is expected to witness continued growth and advancements as new technologies emerge, regulatory frameworks evolve, and healthcare needs evolve. In this landscape, intellectual property (IP) rights play a crucial role in protecting combination products.

Innovators can protect their ideas, brands, creative works, and private information using intellectual property rights. IP rights?also encourage and incentivize innovation by providing a framework for researchers, developers, and manufacturers to recuperate and profit from their creations. This fosters an environment that is suitable for the development of novel and ground-breaking combination products. Intellectual property rights enable inventors to license their innovations, collaborate with other industry players, and form strategic alliances thereby?promoting knowledge exchange, technology transfer, and resource pooling, facilitating the development and marketing of innovative combination products.

In conclusion, the demand for combination products is rising, driven by the potential for improved patient outcomes. The future development of combination products holds great promise as new technologies emerge. The significance of preserving intellectual property rights, however, cannot be emphasized.

References:

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[2] Ema. (2023, May 3). Medical devices. European Medicines Agency. https://www.ema.europa.eu/en/human-regulatory/overview/medical-devices

[3] Ema. (2023b, May 3). Medical devices. European Medicines Agency. https://www.ema.europa.eu/en/human-regulatory/overview/medical-devices.

[4] Nasto, B., & Sutch, J. (2021, June 2). An overview of drug-device combination products in the EU. https://compliancenavigator.bsigroup.com/en/medicaldeviceblog/an-overview-of-drug-device-combination-products-in-the-eu/

[5] Trademark, patent, or copyright. United States Patent and Trademark Office - An Agency of the Department of Commerce. (2023, February 6). https://www.uspto.gov/trademarks/basics/trademark-patent-copyright.

[6] DrugPatentWatch. (2018, June 5). Patents for combination products: Challenges and opportunities – drugpatentwatch - make better decisions. DrugPatentWatch. https://www.drugpatentwatch.com/blog/patents-combination-products-challenges-opportunities/

[7] DrugPatentWatch. (2018, June 5). Patents for combination products: Challenges and opportunities – drugpatentwatch - make better decisions. DrugPatentWatch. https://www.drugpatentwatch.com/blog/patents-combination-products-challenges-opportunities/.

[8] DrugPatentWatch. (2018, June 5). Patents for combination products: Challenges and opportunities – drugpatentwatch - make better decisions. DrugPatentWatch. https://www.drugpatentwatch.com/blog/patents-combination-products-challenges-opportunities/.

[9] Edwards Lifesciences LLC v. Boston Scientific Scimed, Inc., WL 00817012, Case No: HC-2015-004574, [2017] EWHC 405 (Pat).

[10] Edwards Lifesciences LLC v. Boston Scientific Scimed, Inc., WL 01339063, Case No: HC-2015-004574, [2017] EWHC 755 (Pat).

[11] Edwards Lifesciences LLC v. Boston Scientific Scimed, Inc., WL 01339063, Case No: HC-2015-004574, [2017] EWHC 755 (Pat).

[12] Mishra, M. (2019, January 15). Edward Lifesciences Pays Boston Scientific $180 million to end patent row. Reuters. https://www.reuters.com/article/us-boston-edwards-lifesci-litigation-idUSKCN1P91DJ.

[13] Bercu, L. (n.d.). Overview of generic drug-device combination products. https://accessiblemeds.org/sites/default/files/2019-11/Lisa_Bercu_GRxBiosims2019.pdf

[14] Novartis AG v Actavis UK Ltd, Case C-442/11, 62011CO0442, European Court Reports 2012 page 00000.

[15] Novartis AG v Actavis UK Ltd, Case C-442/11, 62011CO0442, European Court Reports 2012 page 00000.

[16] Novartis AG v Actavis UK Ltd, Case C-442/11, 62011CO0442, European Court Reports 2012 page 00000.

[17] Slavík, J., Cardoso, A. M., & blogger, K. P. (2022, October 17). Analysing the use of the SPC waiver provisions and its reach outside the EU. Kluwer Patent Blog. https://patentblog.kluweriplaw.com/2022/10/17/analysing-the-use-of-the-spc-waiver-provisions-and-its-reach-outside-the-eu/.

[18] SPCs and combination medicinal products: A cautionary tale. Kilburn & Strode. (2020, November 5). https://www.kilburnstrode.com/knowledge/european-ip/spcs-and-combination-medicinal-products.

[19] SPCs and combination medicinal products: A cautionary tale. Kilburn & Strode. (2020, November 5). https://www.kilburnstrode.com/knowledge/european-ip/spcs-and-combination-medicinal-products.

[20] Pears, M., & Beevers, J. (n.d.). SPCs for combination products. Potter Clarkson. https://www.potterclarkson.com/insights/spcs-for-combination-products-a-combination-of-requirements/

[21] Intellectual Property Office, Concept House, Cardiff Road, Newport, NP10 8QQ. [email protected]. (2014, September 29). Intellectual property office - patents RSPC. Intellectual Property Office - Patents RSPC. https://www.ipo.gov.uk/p-find-spc/p-find-spc-byspc-results.htm?number=SPC%2FGB05%2F041

[22] Teva UK Ltd v. Gilead Sciences Inc, WL 11807, [2017] EWHC 13 (Pat).

[23] Wallis, R. (2020, January 20). SPCs and combination products. Greaves Brewster. https://greavesbrewster.co.uk/spcs-and-combination-products/

[24] Denison, K. (2020, May 14). Royalty pharma: CJEU ANSWERS SPC questions – and raises new ones. Mathys & Squire LLP. https://www.mathys-squire.com/insights-and-events/news/royalty-pharma-cjeu-answers-spc-questions-and-raises-new-ones/.

[25] REGULATION (EC) No 469/2009 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 6 May 2009 concerning the supplementary protection certificate for medicinal products. (2009, June 16). https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2009:152:0001:0010:en:PDF.

[26] Medeva BV v. Comptroller General of Patents, Designs and Trade Marks, Case C?322/10, https://curia.europa.eu/juris/document/document.jsf?docid=115209&mode=req&pageIndex=1&dir=&occ=first&part=1&text=&doclang=EN&cid=22086923.

[27] Duncan, G. (2022, February 1). SPCs on combination products - is it specified? D Young & Co. https://www.dyoung.com/en/knowledgebank/articles/spccombination.

[28] About trademark infringement. United States Patent and Trademark Office - An Agency of the Department of Commerce. (2022, October 25). https://www.uspto.gov/page/about-trademark-infringement