Complement in Action: An Analysis of Patent Trends from 1976 Through 2011
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Complement is an essential part of the innate immune response. It interacts with diverse endogenous pathways and contributes to the maintenance of homeostasis, the modulation of adaptive immune responses, and the development of various pathologies. The potential usefulness, in both research and clinical settings, of compounds that detect or modulate complement activity has resulted in thousands of publications on complement-related innovations in fields such as drug discovery, disease diagnosis and treatment, and immunoassays, among others. This study highlights the distribution and publication trends of patents related to the complement system that were granted by the United States Patent and Trademark Office from 1976 to the present day. A comparison to complement-related documents published by the World Intellectual Property Organization is also included. Statistical analyses revealed increasing diversity in complement-related research interests over time. More than half of the patents were found to focus on the discovery of inhibitors; interest in various inhibitor classes exhibited a remarkable transformation from chemical compounds early on to proteins and antibodies in more recent years. Among clinical applications, complement proteins and their modulators have been extensively patented for the diagnosis and treatment of eye diseases (especially age-related macular degeneration), graft rejection, cancer, sepsis, and a variety of other inflammatory and immune diseases. All of the patents discussed in this chapter, as well as those from other databases, are available from our newly constructed complement patent database: www.innateimmunity.us/patent.
KeywordsSystemic Lupus Erythematosus Complement Activity Complement System Complement Component European Patent Office
21.1.1 Complement: A Powerful Network for Immune Surveillance
21.1.2 Complement in Infection and Disease
Because of the essential role of complement in the defense of the host against intruders, decreased activation of the complement system or deficiency in complement components can increase the risk of infection and cause various pathological conditions (Skattum et al. 2011). For example, alcoholic cirrhosis patients with low serum C3 concentrations and decreased hemolytic complement activity have been reported to have an increased risk of infections (Homann et al. 1997). Deficiencies of components of the classical pathway such as C1q, C2, and C4 have been found to be strongly associated with systemic lupus erythematosus (SLE) (Pickering et al. 2000; Pettigrew et al. 2009). On the other hand, uncontrolled, inappropriate, or excessive complement activity can cause damage to host cells and give rise to many diseases ranging from autoimmune to inflammatory pathologies (Markiewski and Lambris 2007; Holers 2003; Ricklin and Lambris 2007; Lambris and Sahu 2001). Indeed, the dual role of complement is illustrated by several pathological conditions. For example, the early increase of complement activation during sepsis may relate to the beneficial opsonization of bacteria. However, complement activation during subsequent phases of sepsis can amplify the initial insult, leading to inflammatory activity, tissue injury, and finally to multiple organ failure and death in many cases (Markiewski et al. 2008a).
Although complement has traditionally been seen as a defense mechanism against pathogens, it has been shown in recent years to also play a role in general immune surveillance, as well as a host of other immune-related functions and inflammatory diseases. Tissue regeneration, lipid metabolism, transplant rejection, age-related macular degeneration (AMD), rheumatoid arthritis, hemodialysis-associated thrombosis, and cancer are just a few of the increasing number of physiological and pathological processes in which complement activity has been implicated (Ricklin et al. 2010). As with pathogen defense, complement can act as both a protective and damaging factor in many of these conditions. For example, complement inhibits tumor growth through antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) (Markiewski and Lambris 2009). However, it has been found that tumors express high amounts of membrane-associated regulators of complement activity (mRCAs) and secrete fluid-phase regulators, which inhibit the activation of complement and contribute to tumor growth (Markiewski and Lambris 2009). In addition, a recent study has shown that complement can promote the progression of tumors in a mouse model of cervical cancer through the generation of C5a in the tumor microenvironment, which enhances the activity of immune-suppressing cells (Markiewski et al. 2008b). Thus, complement activity is critical for certain homeostatic or immune processes, but in some instances, such as over-activation or improper timing or length of activity, it can become detrimental to the overall health of the host.
21.1.3 Protecting Intellectual Property in Complement Research: An Analysis
The multifaceted role of complement in immune defense and disease makes it an attractive biomarker for diagnostic purposes and an obvious target for intervention by complement therapeutics. Thus, it is not surprising to see research and development in complement diagnostics and therapeutics reflected in a large number of granted patents and an increasing number of new patent applications being filed every year. Here, we investigate and analyze the patent landscape as it applies to complement, focusing on granted patents and applications as published by the United States Patent and Trademark Office (USPTO) and, in part, the World Intellectual Property Organization (WIPO). We highlight the history and emerging trends in patent publications on the complement system in different fields. We performed statistical analyses on (1) the specific complement components being targeted by innovations, (2) the areas in which complement-related patents have been focused, (3) the different complement inhibitor forms developed for experimental and potential therapeutic use, and (4) the clinical areas upon which relevant patents were centered. To further assist researchers in the complement field, a complement patent database has been constructed, and all the documents used in the statistical analyses presented here (from the USPTO and WIPO), as well as those retrieved from the European Patent Office (EPO) and Japanese Patent Office (JPO), are available from the database website:www.innateimmunity.us/patent. Patents stored in the database have full-text links and are classified in terms of target, disease, application, and entity type. An advanced search function is available for finding patents based on specific interests. This database was intended to be thorough; however, there is no way to ensure that all complement-related patent publications are included. Accordingly, this database and the analysis of it as described in this chapter should be taken as reflecting trends only; they are not intended to replace a firsthand search of the USPTO and WIPO databases.
21.2 Study Design and Methodology
It should be noted that in the text and figures here, the term “documents” is used to refer to all records retrieved from a database (both applications and granted patents). When a distinction is required between “applications” and “granted patents,” these specific terms are used (with “US-granted patents” or “US applications” referring to those obtained from the USPTO). The term “publications” is used in a general sense to refer to data currently being discussed (in most cases, US-granted patents).
21.2.2 Data Retrieval and Analysis
To identify complement-related patent data as presented in this study, the databases of the USPTO and the WIPO were searched, retrieving all documents (applications and granted patents) whose title or abstract contained the keyword “complement.” It should be noted that the WIPO searches were confined to publications that were part of the Patent Cooperation Treaty (PCT), which at the time consisted of 144 states. Dates of coverage for the searches were from the earliest dates for which data was available through December 31, 2011. For the USPTO database, the earliest date for records was January 1, 1976, for granted patents and March 15, 2001, for applications (no application records were available prior to this date), while for the WIPO/PCT, which did not distinguish between applications and granted patents, records started on January 1, 1978.
Once all complement-related documents were retrieved, the Python programming language was used to organize and process the resulting enormous amount of data. Documents that were not related to the complement system, as determined by using rules to exclude those containing keywords unrelated to biological systems (e.g., “automobile,” “logic calculator,” etc.), were discarded from the data pool; the remaining documents were individually examined to verify their association with the complement system.
Once patents were verified as relating to the complement system, they were classified into various groups based on target, application, or disease, as presented in the results below.
21.2.3 Patent Database
The complement patent database was created using MySQL. The web interface was implemented using PHP language. The database is running on a Windows 2003 server with IIS6 as the http server. To ensure comprehensive coverage, results were included from not only the USPTO and WIPO/PCT but also the EPO and JPO.
21.3 Results and Discussion
21.3.1 Patent Trends Reflect an Increased Interest in Complement Research
More than 1,000 patent documents related to the complement system have been published by the USPTO and WIPO/PCT since 1976. The publications have followed a general trend of yearly growth (Fig. 21.2a, b, graphs). Specifically, the number of US applications has increased rapidly over the last 10 years, averaging about 48 per year since 2005 (Fig. 21.2a, graph). Compared to US applications, the number of US-granted patents has remained steadier. When analyzed by decade, the average numbers of granted patents in the 1980s, 1990s, and 2000s were 10, 10, and 16, respectively. Interestingly, over the last decade, the only year for which application data are available, the number of granted patents was less than half the number of applications. As is true for the trend in US applications, the number of documents issued by the WIPO/PCT has generally increased over the years (Fig. 21.2b, graph). The distribution patterns of US documents (applications and granted patents) and WIPO documents targeting different complement components were quite similar (Fig. 21.2a, b, pie charts), with C3, C5, C1, factor H (fH), and mRCAs (defined in this study as including MCP/CD46, DAF/CD55, CR1/CD35, and CD59) as the top five targets. Documents targeting these five complement components accounted for more than half of all publications. Correspondingly, the number of documents targeting other complement components was quite low, consisting of only 7% of all publications. Taken together, the data indicate that interest in the complement system has grown dramatically since the 1970s, with a particularly striking increase over the last 20 years. This is not entirely surprising, since there has been a corresponding increase in knowledge about the complement system during this same time period. Also, the perception of complement has shifted from that of an innate immune system that is primarily important for host defense against pathogens to a much more complex and cross-interactive pathway of proteins involved in a multitude of pathological and homeostatic responses (Ricklin et al. 2010). Thus, interest in and innovations related to complement have grown along with this gain in knowledge. It is also worth noting that while the number of complement-related US-granted patents has remained relatively steady during the past two decades, there has been a blossoming of international publications. This growth may reflect not only an increasing presence of complement research outside of the USA but also the general globalization trends leading US researchers to seek patents both at home and abroad; when the number of applications is taken into account, it is obvious that complement-related research remains prolific in the USA.
21.3.2 Target Analysis Reveals a Shift in the Focus of Complement Patents
21.3.3 Publication Trends Demonstrate Varied Applications of Complement Research and the Expansion of Inhibitor Forms
Despite an overall strong interest in developing complement inhibitors, to date only two complement therapeutics have been approved by the FDA for use in humans (Ricklin and Lambris 2007). One is the purified glycoprotein C1 esterase inhibitor (C1-INH; Cinryze/ViroPharma, Cetor/Sanquin, Berinert/CSL Behring, Lev Pharma), and the other is a C5 antibody (Eculizumab; Soliris/Alexion Pharmaceuticals). Thus, it is not surprising that more and more attention has been paid to proteins and antibodies in recent years. Apart from chemical compounds, proteins, and antibodies, peptides and nucleic acids are the focus of the remaining 7% and 3% of all publications, respectively. Although they represent only a small fraction of all inhibitor-related publications, peptides and nucleic acids have been proposed as experimental therapeutics for several pathologies, and their potential future in disease treatment should not be neglected. For example, the peptidic C3 inhibitor compstatin and its analogs (Lambris and Sahu 2001; Lambris and Katragadda 2011) have been utilized and/or proposed for the treatment of eye disorders (Deschatelets et al. 2007), sepsis (Fung and Mollnes 2007), acute respiratory distress syndrome (ARDS) (Lambris and Ritis 2011), trauma (Francois et al. 2011a), Alzheimer’s disease (Dinu 2007), pain (Woolf et al. 2006), and nerve regeneration (Baas and Ramaglia 2010), as well as other pathophysiological conditions.
21.3.4 Emerging Disease Areas Drive New Patent Applications
In the case of eye disorders, about one-third of granted patents have claimed to use complement components to diagnose these diseases, while the other two-thirds focus on the application of complement inhibitors for the purpose of treatment. The three most common subjects of eye disorder-related patents have been fH, C3, and fB (Fig. 21.5, graph). For example, polymorphisms in the C3, fH, and fB genes have been found to predict the occurrence of AMD (Thakkinstian et al. 2011; Zipfel et al. 2010) and thus have been used as diagnostic markers (Allikmets et al. 2011; Day et al. 2010). In other instances, a factor D antibody was patented as a treatment for complement-associated eye conditions such as AMD and choroidal neovascularization (CNV) (Hass et al. 2011). Eculizumab was patented by Alexion Pharmaceuticals, Inc. as a C5-specific antibody for therapeutic use in various complement-related diseases (Evans et al. 2002; Bell 2008; Wang and Matis 2007; Bell and Rother 2009; Rother et al. 2010) and is currently being evaluated for the treatment of AMD (Ricklin and Lambris 2007; Yehoshua et al. 2012). In addition, virus proteins such as smallpox inhibitor of complement enzymes (SPICE) and vaccinia virus complement control protein (VCP), both of which inhibit C3 activity, have been administered locally to the eye to treat disorders such as macular degeneration and choroidal neovascularization (Francois et al. 2011b).
In transplantation medicine, complement activity is known to critically contribute to inflammation and the accommodation or rejection of transplanted tissue (Asgari et al. 2010; Hughes and Cohney 2011). Complement inhibitors have been utilized in transplant recipients through various means to reduce the occurrence of adverse events against transplanted tissues, with mRCAs and C3 (or C3 convertases) being the most common points of intervention (Fig. 21.5, graph). Cells in transplanted tissues have been modified to express mRCAs, or organs have been perfused with membrane-targeted forms of recombinant RCAs in order to suppress complement activation and reduce the chances of complement attack on the tissue (Zhu 2007; Sims and Bothwell 1996; Smith et al. 2010, 2011). Transgenic animals expressing mRCAs have been produced for xenotransplantations (Diamond et al. 2000), and chimeric vaccinia virus proteins against C3b and C4b have been developed to prevent rejection by transplant recipients and improve the function of donor organs and tissues (Rosengard et al. 2000).
Complement and its modulators, especially mRCAs, C3, and C1, have been widely used in the diagnosis and treatment of cancer (Fig. 21.5, graph). One patented method for treating cancer has been the administration of an effective amount of a Coxsackie A-group virus, which recognizes and kills abnormal cells that express the mRCA DAF (Shafren 2008). C3b antibodies, alone or as conjugates with other antibodies, have been used to treat cancer through their binding to C3b on the surface of cancer cells (Taylor et al. 2003). Yet another patent describes analyzing patients’ C1qA gene sequence as a means of predicting their response to CD20 antibody therapy (Racila and Weiner 2007).
Inhibitors against C3 and C5 have also been patented for the treatment of sepsis (Fig. 21.5, graph). An immunoadsorber with immobilized antibodies against C3a and/or C5a was developed for blood treatment in sepsis therapy (Heinrich et al. 2005) since excess activity of these anaphylatoxins can contribute to poor outcome in this disease (Bosmann and Ward 2012). Furthermore, complement and its modulators have been used in the diagnosis and treatment of arthritis, diabetes, SLE, ischemia, atherosclerosis, spinal cord and neuronal injury, and other diseases. For example, antibodies that inhibit the cleavage of C5 to C5a and C5b have been used to treat arthritis and prevent excessive downstream complement activation (Wang and Matis 2007). A C3 precursor biopolymer detected through the use of mass spectrometry has been utilized as a biomarker for type II diabetes (Jackowski and Marshall 2006). Finally, the levels of C4d and/or C3d on the surface of T lymphocytes, B lymphocytes, or monocytes in blood samples have been used to diagnose SLE (Ahearn et al. 2009). These are just a few examples of the many disease-related applications of complement that have been patented in the USA, yet they impressively illustrate the large diversity and creativity of complement-related patents, as well as their potential impact on both biomedical research and public health.
21.4 Conclusions and Outlook
The complement system has long been known to be important for host defense against invading pathogens. This alone would make it an attractive target for potential therapeutic applications to enhance the immune response and fight infections. However, studies over the past few decades have revealed an increasing role for complement in a large variety of both pathological and homeostatic processes (Ricklin et al. 2010). In many instances, complement can be beneficial in one respect but becomes harmful to the host in another, namely, when its activity is not properly regulated. Thus, the appeal of targeting complement in an attempt to control its activation and effects has only grown as its many functions and cross-interactions with other biological systems have been increasingly revealed. Further increasing the attractiveness of targeting the complement system is the fact that this system consists of over 50 proteins, which for the most part act in a hierarchical pathway, with the later steps heavily dependent on actions that occur upstream. This situation presents a multitude of potential targets for managing complement activity. Even so, the regulation of complement has not been the only goal of the many innovations patented over the past four decades. Just as important has been the development of assays to detect complement activity, which have aided both experimental research and diagnostic practices. As a result of these new ideas and discoveries, interest in the complement system has continued to grow in the USA and around the world. In addition, the ability to manipulate the production and activity of many complement factors has led to the development of potentially life-saving diagnostic and therapeutic tools. Thus, it seems that the observed trend toward a constantly increasing wealth of complement-related innovations will continue well into the future.
J.D.L. holds several patents about the development and clinical application of complement inhibitors, including compstatin. He has previously served as a member on the Scientific Advisory Board of Potentia Pharmaceuticals and is the founder of Amyndas Biopharmaceutics, which perform clinical development of compstatin analogs for various indications.
The authors wish to thank Deborah McClellan for editorial assistance. This work was supported by National Institutes of Health grants AI030040, AI068730, AI071028, AI072106, AI097805, GM097747, DE021685, and EY020633.
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