Biosimilars--global issues, national solutions

Biotechnology derived medicinal products are presently the best characterized biologicals with considerable production and clinical experience, and have revolutionized the treatment of some of the most difficult-to-treat diseases, prolonging and improving the quality of life and patient care. They are also currently one of the fastest growing segments of the pharmaceutical industry market. The critical challenge that the biopharmaceutical industry is facing is the expiry of patents for the first generation of biopharmaceuticals, mainly recombinant DNA derived products, such as interferons, growth hormone and erythropoetin. The question that immediately arose was how should such copies of the originator products be licensed, bearing in mind that they are highly complex biological molecules produced by equally complex biological production processes with their inherent problem of biological variability. Copying biologicals is much more complex than copying small molecules and the critical issue was how to handle the licensing of products if relying in part on data from an innovator product. Since 2004 there has been considerable international consultation on how to deal with biosimilars and biological copy products. This has led to a better understanding of the challenges in the regulatory evaluation of the quality, safety and efficacy of "biosimilars", to the exchange of information between regulators, as well as to the identification of key issues. The aim of this article is to provide a brief overview of the scientific and regulatory challenges faced in developing and evaluating similar biotherapeutic products for global use. It is intended as an introduction to the series of articles in this special issue of Biologicals devoted to similar biotherapeutic products.     

Recent developments in the use of transgenic plants for the production of human therapeutics and biopharmaceuticals

In recent years there has been a dramatic increase in the application of plant biotechnology for the production of a variety of commercially valuable simple and complex biological molecules (biologics) for use in human and animal healthcare. Transgenic whole plants and plant cell culture systems have been developed that have the capacity to economically produce large-scale quantities of antibodies and antibody fragments, antigens and/or vaccine epitopes, metabolic enzymes, hormones, (neuro)peptides and a variety of biologically active complexes and secondary metabolites for direct use as therapeutic agents or diagnostic tools in the medical healthcare industry. As the products of genetically modified plants make their way from concept to commercialization the associated risks and acceptance by the public has been become a focal point. In this paper, we summarize the recent advances made in the use of transgenic plants and plant cell cultures as biological factories for the production of human therapeutics and biopharmaceuticals and discuss the long-term potential of `molecular farming' as a low-cost, efficient method for the production of biological materials with demonstrated utility to the pharmaceutical industry or medical community.     

三种常见品牌护肤品暴露对鲮肝脏SOD和GST活性、GSH含量的影响

研究护肤品暴露对鲮(Cirrhinus molitorella)的毒性效应,为护肤品的安全使用和污染控制提供科学依据。配置不同浓度(0 g·L^-1、0.5 g·L^-1、0.75 g·L^-1、1.00 g·L^-1)的护肤品暴露鲮48h,在暴露时间为0、6 h、12 h、24 h、36 h、48 h时,测定鲮肝脏中超氧化物歧化酶(SOD)活性、谷胱甘肽转移酶(GST)活性、谷肮甘肽过氧化物酶(GSH)含量,观察并记录鲮的死亡情况,计算三种护肤品对鲮的半致死浓度(LC50)。结果表明:三种护肤品的暴露浓度为1.00 g·L^-1时,SOD酶和GST酶活性达到最大;三种酶活性都是随着时间的增加呈现先增后减的变化规律;护肤品B、C暴露48h时,GSH酶被抑制;护肤品A、B、C 48h的LC50分别为807 mg·L^-1、973 mg·L^-1和1147 mg·L^-1。护肤品A、护肤品B和护肤品C的毒性分别为中毒物质,中毒物质和低毒物质,中高价位的护肤品对鲮的伤害相对较小。     

Exopolysaccharides produced by Lactobacillus plantarum: technological properties,biological activity,and potential application in the food industry

Some lactic acid bacteria are capable of producing capsular or extracellular polysaccharides, with desirable technological properties and biological activities. Such polysaccharides produced by lactic acid bacteria are called exopolysaccharides and can be used to alter rheological properties, acting in processes involving viscosity, emulsification, and flocculation, among others. They may also be involved in prebiotic, probiotic, and biological activities, as well as having potential application in the food industry. In this mini-review, the objectives were to present some beneficial properties of exopolysaccharides (EPS) produced by Lactobacillus plantarum that have not been commercially explored. For that, the article focused to summarize revision of current publications within the following topics: (1) rheological properties, (2) prebiotic properties, (3) biological activities, and (4) potential application in the food industry. EPS produced by Lb. plantarum can be used as gelling agent, emulsifier, or stabilizer for food products. The glucan nature of the produced EPS enhances probiotic properties of this LAB species. Lactobacillus plantarum EPS has antioxidant, antibiofilm, and antitumor activities. Finally, there is an improvement in texture of fermented food products where Lb. plantarum is used as starter culture which is related to EPS production in situ. Therefore, EPS produced by Lb. plantarum have important and desirable properties to be explored for several applications, including health and food areas.     

基于国际专利数据的真菌黑色素创新发展趋势分析

【背景】黑色素具有抗肿瘤、抗辐射等多种生物活性,在生产和生活中具有巨大的应用潜力,通过真菌生产是获取黑色素的一条重要途径,它与动植物相比具有更短的生产周期和更高的产量,并且易于实现商业应用。【目的】揭示真菌黑色素的生产及应用发展情况和创新趋势,为致力于真菌黑色素产业的科研人员和企业提供参考。【方法】基于Inco Pat科技创新情报平台,通过对全球真菌黑色素相关专利进行检索统计,从专利涉及的菌株、专利技术构成、申请人专利价值等多维度对真菌黑色素相关专利进行深入分析。【结果】真菌黑色素在生产制备领域申请专利数量最多(50.56%),作为化工染料和化妆品原料应用的专利申请数量最少(13.48%),涉及的真菌菌属主要有层孔菌属、短梗霉属、木耳属、纤孔菌属、粒毛盘菌属、灵芝属和曲霉属。目前真菌黑色素专利技术申请的热点领域主要在C12 (微生物发酵、培养基、突变或遗传工程)类和A61 (医学)类,并且在未来一段时间内,C12和A61将继续作为热点技术申请领域。中国申请的真菌黑色素专利数量最多,但拥有的高价值专利比例较低,较国外仍具有一定差距。【结论】我国科研人员需要加强在医药和化工领域核心专利技术的创新应用与海外布局,增强与企业的合作研发和技术转移,以抢占真菌黑色素在这些领域的应用市场,并推动真菌黑色素相关专利向高质量发展。     

Polymorphs and Prodrugs and Salts (Oh My!): An Empirical Analysis of “Secondary” Pharmaceutical Patents

Background

While there has been much discussion by policymakers and stakeholders about the effects of “secondary patents” on the pharmaceutical industry, there is no empirical evidence on their prevalence or determinants. Characterizing the landscape of secondary patents is important in light of recent court decisions in the U.S. that may make them more difficult to obtain, and for developing countries considering restrictions on secondary patents.

Methodology/Principal Findings

We read the claims of the 1304 Orange Book listed patents on all new molecular entities approved in the U.S. between 1988 and 2005, and coded the patents as including chemical compound claims (claims covering the active molecule itself) and/or one of several types of secondary claims. We distinguish between patents with any secondary claims, and those with only secondary claims and no chemical compound claims (“independent” secondary patents).We find that secondary claims are common in the pharmaceutical industry. We also show that independent secondary patents tend to be filed and issued later than chemical compound patents, and are also more likely to be filed after the drug is approved. When present, independent formulation patents add an average of 6.5 years of patent life (95% C.I.: 5.9 to 7.3 years), independent method of use patents add 7.4 years (95% C.I.: 6.4 to 8.4 years), and independent patents on polymorphs, isomers, prodrug, ester, and/or salt claims add 6.3 years (95% C.I.: 5.3 to 7.3 years). We also provide evidence that late-filed independent secondary patents are more common for higher sales drugs.

Conclusions/Significance

Policies and court decisions affecting secondary patenting are likely to have a significant impact on the pharmaceutical industry. Secondary patents provide substantial additional patent life in the pharmaceutical industry, at least nominally. Evidence that they are also more common for best-selling drugs is consistent with accounts of active “life cycle management” or “evergreening” of patent portfolios in the industry.     

Is Patent “Evergreening” Restricting Access to Medicine/Device Combination Products?

Background

Not all new drug products are truly new. Some are the result of marginal innovation and incremental patenting of existing products, but in such a way that confers no major therapeutic improvement. This phenomenon, pejoratively known as “evergreening”, can allow manufacturers to preserve market exclusivity, but without significantly bettering the standard of care. Other studies speculate that evergreening is especially problematic for medicine/device combination products, because patents on the device component may outlast expired patents on the medicine component, and thereby keep competing, possibly less-expensive generic products off the market.

Materials and Methods

We focused on four common conditions that are often treated by medicine/device product combinations: asthma and chronic obstructive pulmonary disease (COPD), diabetes, and severe allergic reactions. The patent data for a sample of such products (n = 49) for treating these conditions was extracted from the United States Food and Drug Administration’s Orange Book. Additional patent-related data (abstracts, claims, etc) were retrieved using LexisNexis TotalPatent. Comparisons were then made between each product’s device patents and medicine patents.

Results

Unexpired device patents exist for 90 percent of the 49 medicine/device product combinations studied, and were the only sort of unexpired patent for 14 products. Overall, 55 percent of the 235 patents found by our study were device patents. Comparing the last-to-expire device patent to that of the last-to-expire active ingredient patent, the median additional years of patent protection afforded by device patents was 4.7 years (range: 1.3–15.2 years).

Conclusion

Incremental, patentable innovation in devices to extend the overall patent protection of medicine/device product combinations is very common. Whether this constitutes “evergreening” depends on whether these incremental innovations and the years of extra patent protection they confer are proportionately matched by therapeutic improvements in the standard of care, which is highly debatable.     

Marine Natural Products: The Important Resource of Biological Insecticide

Due to the unique environmental conditions and vast territory, marine habitat breeds more abundant biological resources than terrestrial environment. Massive marine biological species provide valuable resources for obtaining a large number of natural products with diverse structure and excellent activity. In recent years, new breakthroughs have been made in the application of marine natural products in drug development. In addition, the use of marine natural products to develop insecticides and other pesticide products has also been widely concerned. Targeting marine plants, animals, and microorganisms, we have collected information on marine natural products with insecticidal activity for nearly decade, including alkaloids, terpenes, flavonoids and phenols fatty acids, peptides, and proteins, et al. In addition, some active crude extracts are also included. This review describes the insecticidal activities of marine natural products and their broad applications for future research in agriculture and health.     

A patent landscape on application of microorganisms in construction industry

Construction biotechnology includes research and development of construction materials and processes that make use of various microbes. The present technology landscape gives a perspective on how microbes have been used in construction industry as cement and concrete additives by analyzing patents filed in this technology arena. All patents related to the technology of interest published globally to date have been reviewed. The earliest patent filing in this technology domain was recorded in the year 1958 and the patenting activity reached its peak around mid to late 1990s. The early technology was mainly focused on microbial polysaccharides and other metabolic products as additives. Year 2002 onwards, biomineralization has taken precedence over the other technologies with consistent patent filings indicating a shift in innovation focus. Japan has been the global leader with highest number of patents filed on application of microbes in construction industry. Southeast University, China has topped the patent assignee list with maximum number of filings followed by Kajima Corp. and Shin-Etsu Chemical Co., Ltd. Most patent applications have claimed microbe based bio-products. Construction-related microbial technologies are mainly based on activity of different microorganisms such as urease-producing, acidogenic, halophilic, alkaliphilic, nitrate and iron-reducing bacteria. Sporosarcina pasteurii has been the most widely used microbe for biomineralization.     

Biosimilars advancements: Moving on to the future

Many patents for the first biologicals derived from recombinant technology and, more recently, monoclonal antibodies (mAbs) are expiring. Naturally, biosimilars are becoming an increasingly important area of interest for the pharmaceutical industry worldwide, not only for emergent countries that need to import biologic products. This review shows the evolution of biosimilar development regarding regulatory, manufacturing bioprocess, comparability, and marketing. The regulatory landscape is evolving globally, whereas analytical structure and functional analyses provide the foundation of a biosimilar development program. The challenges to develop and demonstrate biosimilarity should overcome the inherent differences in the bioprocess manufacturing and physicochemical and biological characterization of a biosimilar compared to several lots of the reference product. The implementation of approaches, such as Quality by Design (QbD), will provide products with defined specifications in relation to quality, purity, safety, and efficacy that were not possible when the reference product was developed. Actually, the need to prove comparability to the reference product by the biosimilar industry has increased the knowledge about the product and the production‐process associated by the use of powerful analytical tools. The technological challenges to make copies of biologic products while attending regulatory and market demands are expected to help innovation in the direction of attaining more productive manufacturing processes. © 2015 American Institute of Chemical Engineers Biotechnol. Prog., 31:1139–1149, 2015     

全球虾青素研究专利计量分析

由于虾青素具有极高的应用价值,近几十年来,虾青素的应用研究取得了很大的进展。本文以Derwent Innovations Index(DII)数据库为统计分析源,检索并分析了数据库中关于虾青素的所有专利产出,利用Thomson Data Analyzer(TDA)分析工具和Thomson Inovation分析平台进行数据挖掘。通过对专利申请趋势、高产机构、核心技术、专利布局、热点技术领域等方面的计量分析,揭示了全球虾青素技术的发展现状,探索我国发展虾青素技术面临的机遇与挑战。虾青素的应用集中在鱼类饲料的添加剂和疾病治疗两个领域。日本、美国和中国为排名前三的优先权受理国,日本公司的申请数量占主导地位,从专利布局看,杜邦和东曹公司几乎全部集中在发酵或使用酶的方法合成目标化合物或组合物或从外消旋混合物中分离旋光异构体和微生物或酶其组合物这两个领域,而排名靠前的日本公司的研究领域主要集中在医用、牙科用或梳妆用的配制品、食品、食料或非酒精饮料制备或加工处理以及化合物或药物制剂的特定治疗活性三个领域。     

Phycobiliproteins as a commodity: trends in applied research,patents and commercialization

Phycobiliproteins are a group of colored proteins commonly present in cyanobacteria and red algae possessing a spectrum of applications. They are extensively commercialized for fluorescent applications in clinical and immunological analysis. They are also used as a colorant, and their therapeutic value has also been categorically demonstrated. However, a comprehensive knowledge and technological base for augmenting their commercial utilities is lacking. Hence, this work is focused towards this objective by means of analyzing global patents and commercial activities with application oriented research. Strategic mining of patents was performed from global patent databases resulting in the identification of 297 patents on phycobiliproteins. The majority of the patents are from USA, Japan and Europe. Patents are grouped into fluorescent applications, general applications and production aspects of phycobiliproteins and the features of each group are discussed. Commercial and applied research activities are compared in parallel. It revealed that US patents are mostly related to fluorescent applications while Japanese are on the production, purification and application for therapeutic and diagnostic purposes. Fluorescent applications are well represented in research, patents and commercial sectors. Biomedical properties documented in research and patents are not ventured commercially. Several novel applications are reported only in patents. The paper further pinpoints the plethora of techniques used for cell breakage and for extraction and purification of phycobiliproteins. The analysis identifies the lacuna and suggests means for improvements in the application and production of phycobiliproteins.     

Total biosynthesis of antitumor nonribosomal peptides in Escherichia coli

Nonribosomal peptides (NRPs) are a class of microbial secondary metabolites that have a wide variety of medicinally important biological activities, such as antibiotic (vancomycin), immunosuppressive (cyclosporin A), antiviral (luzopeptin A) and antitumor (echinomycin and triostin A) activities. However, many microbes are not amenable to cultivation and require time-consuming empirical optimization of incubation conditions for mass production of desired secondary metabolites for clinical and commercial use. Therefore, a fast, simple system for heterologous production of natural products is much desired. Here we show the first example of the de novo total biosynthesis of biologically active forms of heterologous NRPs in Escherichia coli. Our system can serve not only as an effective and flexible platform for large-scale preparation of natural products from simple carbon and nitrogen sources, but also as a general tool for detailed characterizations and rapid engineering of biosynthetic pathways for microbial syntheses of novel compounds and their analogs.     

Detection of small bioactive peptides from Atlantic herring (Clupea harengus L.)

Recent research has shown that fish residual materials contain a range of components with interesting biological activity. Therefore, there is a great potential in the marine bioprocess industry to utilize these by-products as starting material for generating more valuable products. The aim of the present study was to search for bioactive peptides (in particular small natural bioactive peptides with molecular weight lower than 10 kDa) in Atlantic herring (Clupea harengus L.) by-products such as skin and more general residual materials. By such means a range of peptides with claimed interesting biological activities was found. Herein the activity of the detected bioactive peptides and strategies for isolating peptide fragments containing the bioactive motif is discussed. Identification of bioactive peptides in crude peptide/protein sources (skin and residual materials) was performed directly using a combination of mass spectrometry (Orbitrap), bioinformatics and database search. This method was a good angle of approach in order to map the potential in new species and species that have been very little studied.     

An assessment of emerging molecular farming activities based on patent analysis (2002∼2006)

The products of Plant Molecular Farming are recombinant proteins or their metabolic products. In this study, patent data was employed to assess industrial trend in the research and innovation process of Plant Molecular Farming within national and international context. The US Patent and Trade Organization (USPTO), the European Patent Office (EPO) issued a total of 585 patents covering Plant Molecular Farming from 2002 through 2006. By nationality, US inventors predominated as recipients of PMF patents, followed by Germany, Denmark, and Japan. The PMF patents were catagorized in five major areas of research namely pharmaceutical and nutraceuticals with 170 patents (31%) and plant expression tools and methods for alternative production systems with 169 patents (29%) were the dominating patent applications, followed by 102 patent claims associated with antibodies (17%), 71 patents of industrial molecules (12%), 48 patents of vaccines (8%), and finally 18 patents related to post-translational protein glycosylation (3%). The greatest proportion of patentees was of US origin (52%), and PMF associated patenting activities at the USPTO and EPO were dominated with 67% by private organizations. Disclaimer: The views expressed in this study do not necessarily reflect those of the European Commission.     

Biological activities and potential cosmeceutical applications of bioactive components from brown seaweeds: a review

Seaweeds are the primary producers of all aquatic ecosystems. Chemical constituents isolated from diverse classes of seaweeds exert a wide range of nutritional, functional and biological activities. Unique metabolites of seaweeds possess specific biological properties that make them potential ingredients of many industrial applications such as functional foods, pharmaceuticals and cosmeceuticals. Cosmeceuticals of natural origin are becoming more popular than synthetic cosmetics. Hence, the investigation of new seaweeds derived functional components, a different source of natural products, has proven to be a promising area of cosmeceutical studies. Brown seaweeds also produce a range of active components including unique secondary metabolites such as phlorotannins and many of which have specific biological activities that give possibilities for their economic utilization. Brown seaweeds derived active compounds have been shown various functional properties including, antioxidant, antiwrinkling, whitening, antiinflammatory and antiallergy. It is well-known that these kind of biological effects are closely associated with cosmeceutical preparations. This communication reviews the current knowledge on brown seaweeds derived metabolites with various biological activities and the potential use as cosmeceutical ingredients. It is hoped that the reviewed literature on multifunctional properties of brown seaweeds will improve access to the seaweed based natural products specially the ability to incorporate these functional properties in cosmeceutical applications.     

Preparation, properties and biological applications of water soluble chitin oligosaccharides from marine organisms

Chitin oligosaccharides (COSs) can be isolated from various natural resources, which have widely been used in biological active supplements (BAS) for the benefit of humankind. Several technological approaches for the preparation of COSs such as enzymatic, chemical, acid-catalysts hydrolysis, microwave radiation, membrane bioreactor methods have been developed and among them, membrane bioreactor, bioconversion and continuous mass production technologies are reported to be excellent. Compounds isolated from natural products have made a drastic impact on the pharmaceutical industry and especially, water-soluble chitin oligosaccharides have shown greater clinical activity, which have been demonstrated in various cell lines of disease significance. The activities of these COSs were being investigated in different patients, animals and even plants as a broad phase clinical trial program. In the present article, we have discussed the COSs preparation by different methods through comprehensive diffraction procedures along with the merits and demerits given in detail. In addition, a summary of recent work describing the synthesis and biological activities of water-soluble COSs has been presented here.     

Environmental impact of adjuvants in crop protection

The overall performance of chemical and biological plant protection products is enhanced by the use of adjuvants in the formulation (formulation adjuvants) or in the spray tank (spray adjuvants). Both types of adjuvants aim to stabilize the formulation, to improve the efficiency of the active ingredients and to reduce application and environmental risks. As an important part of the formulation, both quantitatively and qualitatively, the environmental impact and toxicology of adjuvants can not always be considered as inert. However, little is known of their impact as part of plant protection products compared with the active substances. Therefore an experimental framework is needed as a tool for a consistent environmental legislation.     

High-performance liquid chromatographic–electrospray ionization mass spectrometric analyses for the integration of natural products with modern high-throughput screening

Within the pharmaceutical industry, significant resources have been applied to the identification of new drug compound leads through the use of high-throughput screening (HTS). To meet the demand for rapid analytical characterization of biologically active samples identified by HTS, the technique of high-performance liquid chromatography–electrospray ionization mass spectrometry (HPLC–ESI-MS) has been utilized, and the application of this technique specifically for the integration of natural product sample mixtures into modern HTS is reviewed. The high resolution provided by reversed-phase HPLC coupled with the gentle and relatively universal ionization facilitated by the electrospray process has had significant impact upon a variety of procedures associated with the HTS of natural products, including extract sample diversity evaluation, dereplication, structure elucidation, preparative isolation, and affinity-based biological activity evaluation.