Antibody-Drug Conjugates: Intellectual Property Considerations
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PERSPECTIVE mAbs 7:6, 989--1009; November/December 2015; © 2015 Taylor & Francis Group, LLC Antibody-drug conjugates: Intellectual property considerations Ulrich Storz* Michalski Huttermann€ Patent Attorneys; Dusseldorf,€ Germany ntibody-drug conjugates are highly to develop and sell new ADCs or protect Acomplex entities that combine an the compounds and technologies from antibody, a linker and a toxin. This com- which they are derived are faced with chal- plexity makes them demanding both lenges when making business decisions. In technically and from a regulatory point addition, the numerous players active in of view, and difficult to deal with in their this field have created a maze of third- patent aspects. This article discusses dif- party IP rights that is difficult to navigate. ferent issues of patent protection and Further, because ADCs combine biotech- freedom to operate with regard to this nology and organic chemistry, IP counsels promising new class of drugs. working in this area need a thorough tech- nical background in both disciplines. This article discusses some of these Introduction aspects in more detail, and discloses IP rights that stand exemplarily for a given Antibody-drug conjugates (ADCs) are technology or concept. It can, however, one of the most promising classes of new not replace a case-specific FTO analysis or drugs, although the idea is not new.1 novelty search. Some of the IP rights dis- ADCs embody the oft-cited concept of cussed herein may not have been granted “magic bullets,” which was described by yet, or they may have already expired or Paul Ehrlich over 100 y ago. As of 2015, been revoked. The latter, which are 3 ADCs have been approved by the marked with an asterisk in the respective US Food and Drug Administration tables, may thus constitute free prior art, (FDA), namely gemtuzumab ozogamacin and, as such, provide a valuable source of (MylotargÒ), ado-trastuzumab emtansine information for competitors. Keywords: ADC, antibody-drug conju- (KadcylaÒ) and brentuximab vedotin gates, antibody, freedom to operate, (AdcetrisÒ). Their characteristics are Freedom to operate immunotoxin, Kadcyla, patent shown in Table 1. More than 40 other The term “Freedom to Operate” refers 2 Abbreviations: FDA, Food and Drug ADCs are in clinical studies today. to a determination that the commerciali- Administration; FTO, Freedom to Oper- ADCs combine an antibody, a linker zation of a product does not infringe ate; IP, Intellectual property; ADC, Anti- and a toxin (often called “payload” or, third-party IP rights, in particular patents. body-Drug Conjugates; EPO, European more martial, “warhead”), and, for that Establishing FTO requires that all compo- Patent Office; USPTO, United States Pat- reason, they are technically demanding to nents of the respective technology, encom- ent And Trademark Office; CDR, Com- develop and pose challenges in passing methods as well as compounds 3 plementarity Determining Region; HC/ manufacturing. They can also raise regu- and intermediates, are analyzed with 4 LC, Heavy Chain/Light Chain; DAR, latory issues. because ADCs can be con- respect to whether they are the subject of Drug-Antibody Ratio; IPR, Inter Partes sidered prodrugs that release their active valid and enforceable third-party IP rights. Review; PTAB, Patent Trial and Appeal compound–the toxin–at the site of action. Because IP rights have a territorial Board While their complexity has been called effect and a restricted lifetime only, an „ 5 *Correspondence to: Ulrich Storz; Email: an invitation to innovation,” ADCs are FTO analysis does not only focus on the [email protected] difficult to deal with in their intellectual technologies as such, but also considers Submitted: 05/28/2015 property (IP) aspects. Both Freedom to where IP rights are in force and when they Operate (FTO), as well as the protection expire. In this context, the estimated time Revised: 08/03/2015 of ADCs and technologies to generate to market of the product that is to be com- Accepted: 08/05/2015 them, are affected by the complexity of mercialized should be weighed against the http://dx.doi.org/10.1080/19420862.2015.1082019 the molecules, and thus those who want lifetime of a given IP right. Further www.tandfonline.com mAbs 989 Table 1. Characteristics of the 3 ADCs approved to date by the US Food and Drug Administration Target also used in conventional Drug Antibody Key IP right mAb Linker Site specific Antibody ADC name target US/EP therapy? Linker cleavable? Toxin conjugation? Ratio Gemtuzumab CD33 US5773001/ no hydrazone yes calicheamicin no Only 50% of the ozogamicin** EP0689845B1* antibody is loaded at all (avg 4 – 6) Trastuzumab HER-2/neu US8337856/ yes SMCC (maleimide) no DM1 (maytansinoid) no 0–8 (avg 3,5) emtansine EP2283867B1 Brentuximab CD30 US7829531/ no maleimidocaproyl yes MMAE (auristatin) no 3–5 vedotin EP2353611B1 spacer, valine– (cathepsin) citrulline linker, and PABC spacer *expired; **product voluntarily withdrawn from the market in 2010. considerations should focus on potential linker. The existing IP landscape thus times in biologics are slightly longer than research exemptions as well as on ques- appears more complicated than for naked those reported for small molecular drugs.8 tions of exhaustion, or process patents antibodies, with overlapping patent estates Because of the higher complexity and that might extend their protection on assigned to different owners. Navigating the higher regulatory burden, it can be products obtained therewith. These non- this landscape can become a laborious assumed that, generally, these figures will ADC specific regulations are subject to challenge, and again requires a thorough be even higher in ADCs. A meaningful large variations between different jurisdic- understanding of the technical back- patent strategy is thus indispensable to tions, and thus are outside the scope of ground, including biotechnology and ensure that these investments can be recu- this article. organic chemistry, and the filing strategies perated over at least a given period of If, in the course of an FTO analysis, IP used by competitors. time. ADC-related embodiments that can rights that are likely to be infringed by the Further, inventors often believe that, become subject of patent protection will commercialization of a given product are once a patent has been granted on a given also be discussed in the following. detected, one should consider whether or invention, FTO would be automatically not they are valid and enforceable. If not, warranted. This thinking relies on a mis- The antibody component respective countermeasures should be con- conception. The truth is that even if a pat- An antibody as such can be subject of sidered, like invalidity opinions, opposi- ent has been awarded on a structurally third-party patents. This may encompass tions, nullity actions, or post grant review/ improved second-generation antibody, it 4 categories: 1) patents that protect any inter partes review. can still be the subject of earlier third- kind of antibody binding a particular tar- As an alternative, in-licensing of the party patents protecting the starting anti- get, which at the filing date was novel respective IP rights could be a solution. body, if these are still in force. In the fol- (and specified by the applicant in a suffi- This approach is frequently used in cases lowing sections, the methods and cient way as to enable skilled persons to where the patent protected technology is compounds that are relevant in an ADC make an antibody thereagainst); 2) patents an enabling technology, or refers only to a FTO analysis will be briefly addressed. that protect all antibodies against a given part of the molecule, like a linker. These epitope of such target (if binding said epi- technologies have often been developed by Active IP strategies tope has unprecedented effect); 3) patents technology companies who use out-licens- ADCs do also offer new possibilities to that protect all antibodies against a given ing as their business model. Large bio- obtain patent protection. ADCs can, in target that have a particular functionality pharmaceutical companies are generally some way, be considered as an advance- (e.g., minimum affinity, inhibition of a less inclined to grant a license, in particu- ment of conventional therapeutic antibod- given effect); or 4) patents that protect a lar on a compound-related patent, because ies, and, according to a general principle, specific antibody (either defined by the they seek exclusivity rather than royalties. each bit of advancement can be made sub- respective expressor cell, or by a particular For ADCs, an FTO analysis encom- ject of a patent application. sequence, e.g., of the CDRs, the variable passes all components, i.e., the antibody, According to a study performed at domains or the HC/LC sequences). the toxin and the linker. Numerous play- Tufts University in 2007, the estimated It needs to be added, in this context, ers have already staked their claims, and average costs of developing a new biologic that new targets for ADC therapy are hard many patents and patent applications refer was 1.2 billion USD.6 This figure has to find,9 thus making patents of categories to a combination of 2 of the components, been adjusted upwards in 2014 to even 1 and 2 less frequent nowadays. Further, very often a combination of a toxin and a 2.6 billion USD.7 Further, development it appears that the US Patent and 990 mAbs Volume 7 Issue 6 Trademark Office (USPTO) and the established, and in which markets. The The use of an approved naked antibody European Patent Office (EPO) have same applies in cases where the target of for making an ADC has its merits. For become more critical toward patents of the planned ADC is the subject of third- example, it may appear useless to category 3 because a functional claim fea- party patents.