catalysts Review Biocatalysis as Useful Tool in Asymmetric Synthesis: An Assessment of Recently Granted Patents (2014–2019) Pablo Domínguez de María 1,*, Gonzalo de Gonzalo 2,* and Andrés R. Alcántara 3,* 1 Sustainable Momentum, SL. Av. Ansite 3, 4–6, E-35011 Las Palmas Gran Canaria, Spain 2 Organic Chemistry Departament, University of Sevilla, c/ Profesor García González 2, 41012 Sevilla, Spain 3 Department of Chemistry in Pharmaceutical Sciences, Section of Organic Chemistry (Pharmaceutical Chemistry), Faculty of Pharmacy, Complutense University of Madrid, Plaza de Ramón y Cajal, s/n., E-28040 Madrid, Spain * Correspondence: [email protected] (P.D.d.M.); [email protected] (G.d.G.); [email protected] (A.R.A.); Tel.: +34-60-956-52-37 (P.D.d.M.); +34-95-455-99-97 (G.d.G.); +34-91-394-18-20 (A.R.A.) Received: 6 September 2019; Accepted: 22 September 2019; Published: 25 September 2019 Abstract: The broad interdisciplinary nature of biocatalysis fosters innovation, as different technical fields are interconnected and synergized. A way to depict that innovation is by conducting a survey on patent activities. This paper analyses the intellectual property activities of the last five years (2014–2019) with a specific focus on biocatalysis applied to asymmetric synthesis. Furthermore, to reflect the inventive and innovative steps, only patents that were granted during that period are considered. Patent searches using several keywords (e.g., enzyme names) have been conducted by using several patent engine servers (e.g., Espacenet, SciFinder, Google Patents), with focus on granted patents during the period 2014–2019. Around 200 granted patents have been identified, covering all enzyme types. The inventive pattern focuses on the protection of novel protein sequences, as well as on new substrates. In some other cases, combined processes, multi-step enzymatic reactions, as well as process conditions are the innovative basis. Both industries and academic groups are active in patenting. As a conclusion of this survey, we can assert that biocatalysis is increasingly recognized as a useful tool for asymmetric synthesis and being considered as an innovative option to build IP and protect synthetic routes. Keywords: biocatalysis; asymmetric synthesis; patents; lipases; oxidoreductases; lyases; transaminases 1. Motivation. The Role of Granted Patents as Key Actors in Innovation Biocatalysis is currently recognized as a mature technology for asymmetric synthesis, based on the excellent selectivity (enantio-, chemo, and regio-) that enzymes often display in many chemical processes. The field has experienced a tremendous development when emerging Molecular Biology techniques, used to produce and design enzymes, have been synergized with both process-development concepts (batch to continuous reactors) and medium engineering strategies (non-aqueous media, immobilization, etc.). As a result, biocatalysis can fulfil, in many cases, the demands of modern organic synthesis, which must align a high selectivity and efficiency with sustainability and tight economic figures. As a result, an increasing number of industrial processes have been successfully established, comprising many diverse examples using free enzymes, whole cells, systems biocatalysis, multi-step processes, etc. [1–19]. The abovementioned broad interdisciplinarity profile makes biocatalysis in a fertile landscape for innovation. It is common that researchers of different backgrounds (chemistry, biology, engineering, etc.) Catalysts 2019, 9, 802; doi:10.3390/catal9100802 www.mdpi.com/journal/catalysts Catalysts 2019, 9, 802 2 of 42 Catalysts 2019, 9, x FOR PEER REVIEW 2 of 41 cooperate closely in setting up new enzymatic reactors [20–23]. Overall, each biocatalytic industrial engineering, etc.) cooperate closely in setting up new enzymatic reactors [20–23]. Overall, each reactionbiocatalytic contains industrial highly reaction evolved contains parts, highly which ev areolved not parts, standing which alone, are not but standing that do alone, form but a robustthat processdo form when a robust all of process them when are combined all of them smartly. are combined Some smartly. key concepts Some key for concepts industrial for biocatalysisindustrial maybiocatalysis be: i) designed may be: enzymei) designed variants enzyme with variants improved with selectivity,improved selectivity, high resistance high resistance to chemicals, to thermostability,chemicals, thermostability, etc. [24–30]; etc. ii) bio-based [24–30]; ii) (non-conventional)bio-based (non-conventional) solvents solv usedents as co-solventsused as co-solvents in water, orin as water, biphasic or as systems biphasic [systems31–38]; [31–38]; neoteric neoteric solvents, solvents, such assuch deep as deep eutectic eutectic solvents solvents (DES) (DES) [ 39[39––44]; iii)44] whole-cells ; iii) whole-cells[45–48 [45–48],], immobilization immobilization [49 –[49–56],56], continuous continuous processes, processes, etc. [12,23,57,58]; [12,23,57,58]; and and iv) iv) metricsmetrics [59 [59–62],–62], high high productivities productivities to to assure assure anan industrially-soundindustrially-sound reaction. reaction. ToTo obtain obtain deeper deeper insights insights into into these these expectedexpected innovations,innovations, this this paper paper discloses discloses a apatent patent survey survey relatedrelated to biocatalysisto biocatalysis applied applied to asymmetric to asymmetric synthesis. synthesis. Although Although this genre this of studiesgenre of is (surprisingly)studies is rather(surprisingly) scarce in the rather open scarce literature in the [8 open,63,64 literature], we believe [8,63,64], that the we approach believe that may the nicely approach reflect may the nicely modern trendsreflect in the the modern field, provided trends in by the academic field, provided and industrial by academic groups, and industrial and comprising groups, di andfferent comprising enzymes anddifferent chemical enzymes processes. and chemical Importantly, processes. to further Importan refinetly, theto further innovation refine assessment,the innovation the assessment, focus of the studythe isfocus put of solely the study on those is put patents solely thaton those have patent been granteds that have over been the granted last five over years the (2014–June last five years 2019). Remarkably,(2014–June granted 2019). Remarkably, patents may granted provide patents further may proofs provide on the further necessary proofs steps on the of necessary novelty, innovation, steps of andnovelty, resolution innovation, of industrial and resolution problems, of industrial as demanded problems, for intellectual as demanded property for intellectual (IP) rights. property To simplify (IP) rights. To simplify the reading of the article, the granted patents are discussed by enzyme types, the reading of the article, the granted patents are discussed by enzyme types, covering several relevant covering several relevant case studies. Moreover, the focus of the article is strictly scientific, and no case studies. Moreover, the focus of the article is strictly scientific, and no information regarding information regarding the countries in which the invention is granted, nor whether or not patent fees the countries in which the invention is granted, nor whether or not patent fees are being satisfied, are being satisfied, is provided. It must be noted, however, that readers can easily retrieve that is provided. It must be noted, however, that readers can easily retrieve that information from the patent information from the patent servers, by simply tracking the patent number provided in the servers,references. by simply To follow tracking a consistency the patent with number publication provided rules, in thethe references.years denoted To followin the references a consistency are the with publicationpublication rules, years; the in years all cases, denoted the ineffective the references dates of are those the granted publication patents years; mentioned in all cases, in this the article effective datesare ofincluded those grantedbetween patents2014–2019, mentioned and it can in be this retriev articleed from are included patent servers between as well. 2014–2019, According and to itthe can besurvey, retrieved around from 200 patent patents servers related as to well. biocatalysis According have tobeen the successfully survey, around granted 200 within patents the relatedlast five to biocatalysisyears, as shown have been in Figure successfully 1. granted within the last five years, as shown in Figure1. Figure 1. Patents granted in 2014–2019 employing the most usual types of enzymes, according to Figure 1. Patents granted in 2014–2019 employing the most usual types of enzymes, according to severalseveral patent patent engine engine servers servers (e.g., (e.g., Espacenet, Espacenet, SciFinder,SciFinder, GoogleGoogle Patents). Notably,Notably, examples examples for for all all enzyme enzyme typestypes havehave beenbeen found, for for asymmetric asymmetric synthesis synthesis purposes, purposes, andand the the main main strategies strategies to to achieve achieve patentabilitypatentability are either the the protection protection of of known known enzymes enzymes and and variantsvariants with with di differentfferent sequences sequences (covering up up to to so someme homology), homology), or the or theuse useof novel of novel substrates substrates for forthe the intended intended reactions, reactions, or or a acombination combination of of both both approaches. approaches.