## 8 Clinical Trials and Patents  
The wide chemical diversity of natural compounds has led them to be considered the fourth generation of ABC transporter inhibitors. As we have shown, natural products have demonstrated great potential to overcome MDR both in vitro and in vivo, but most of them need to be tested in clinical trials. Several clinical studies have been carried out involving the treatment of advanced cancer patients with natural products, such as curcumin [114], resveratrol [25], tetrandrine [22], and flavonoids [18]. Although they did not focus specifically on the effect on MDR, previous in vitro and in vivo evidence supports their results in terms of combating tumor resistance. However, studies of multidrug tumor resistance in patients undergoing such clinical trials are needed to test the ability of natural products to reverse it. On the other hand, although much remains to be done in terms of the clinical translation of natural compounds to overcome MDR, the development of these products is continuously expanding, as evidenced by the publication of a large number of related patents in recent years. In this sense, although products obtained directly from nature are not patentable, they can be patented when, in order to be used as medicine or food, these natural products require a specific manipulation or treatment, or when a new activity or utility can be associated with them. In the last ten years, numerous patents related to natural products and their activity in reversing MDR have been developed (Table 3). Most of the currently active patents are of Chinese origin, and they are related to natural compounds and plants of traditional Chinese medicine, as described by the inventors [PERSON] and [PERSON] (CN102908405A) [115]. Some of the patents on the list focus on protecting the extraction method used to obtain a functional extract. For example, [PERSON] et al. are the inventors of multiple patents where extracts derived from diverse plants (_Trichosanthes kirilowii_ Maxim, _Dicatmunus dasycarpus_ [PERSON], and _Morus aliba_ L.) are described as MDR inhibitors (KR20120124151A; KR20120124142A; KR101283562B1; WO2021187905A1) [116; 117; 118; 119]. Other reasons for the development of these patents are, on the one hand, to provide a new use for natural products, as in the case of salvianolic acid A (CN103690519A) [120] and ergotamine (CN110327337A) [121], and, on the other hand, to facilitate compound isolation and preparation, as in the examples of dicoumarol (CN112121043A) [122], Salpha-epoxylantolactone from Compositae methanol extract (CN110051663A) [123], the new skeleton cyclic lipopeptide from the neem plant family (CN111689923A) [124], and terpenoids isolated from kansui tuber (CN112479889A) [125], from _Hypericum monogynum_ L. (CN113149820A) [126], and from _Euplorbia soria_ (CN107827752A) [125]. Derivatives of another _Euplorbia_ species have also been patented for the preparation of antitumor drugs (CN107164421A) [127]. \begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Patent No.** & **Inventors** & **Title** & **Natural Compound,** & **Year** & **Reference** \\ \hline CN102908405A & [PERSON]. [PERSON] and [PERSON] & Traditional Chinese medicine composition of reversing tumor multi-drug resistance (MDR) and preparation method thereof & Traditional Chinese medicine composition & 2013 & [115] \\ KR20120124151A & [PERSON]. [PERSON] et al. & Composition for inhibition of MDR containing an extract of _Morus alba_ L. & Extract of _Morus alba_ L. & 2012 & [116] \\ KR20120124142A & [PERSON] et al. & Composition for inhibition of MDR containing an extract of _Dicatmunus dasycarpus_ [PERSON]. & Extract of _Dicatmunus dasycarpus_ [PERSON]. & 2012 & [117] \\ \hline \hline \end{tabular}
\end{table} 
Table 3: Patents published in the last 10 years related to the use of natural products in overcoming MDR. In addition, the good experimental results have made the application of nanoformulations loaded with natural products against MDR also patentable.