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Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

Do inventors have moral rights and does morality matter in patent law? Whilst morality provides a normative justification for property as a right having an erga omnes effect, moral rights of the property owner does not exist a priori. In contrast as property right imposes a duty of abstention, morality may justify such duty. As a specie of property right, intellectual property necessarily includes a dimension of morality implied as restriction. Moreover, as intellectual property includes inalienable, personal mental inputs of the creator and inventors into the abstract objects, moral interests of the creators and inventor also justifies the exclusive right. Despite the foundational significance, the moral interests of an inventor based on patent law is scarcely debated. In contrast to perennial discussion on the morality’s restriction of the patent grants and exercise of patent rights, the perception of patent as a moral right is not widely accepted, nor the expression, ‘moral right’ is found in positive patent law. The absence of academic discussion of moral right for inventors begs the question if morality means and should mean different value in patents than copyright, and if indeed there is no ‘moral interests’ that are protected or should be protected for inventors. The chapter aims to answer this by first conceptualizing morality generally in patent law, and then identify areas where it may be expressed as a right in the European Patent Convention (EPC). Finally, the paper explores one concrete aspect in the positive patent law where the moral interest of an inventor is indeed protected. Using the controversial decision on Broad Institute’s European patent application based on gene-editing invention, CRIPSR, as a case study, this paper illustrates how moral right of an inventor exists and how it may be used as a positive right, which may control the use of the invention, although limited in its scope. As the current right is limited in scope, a cautious normative claim calling for extending a moral right based defence to the inventor is made, as it would imbue fairness into the discussion patent law and ameliorate individual inventor’s position in an increasingly corporate owner-centric patent system.

Many pesticides and chemical warfare nerve agents are highly toxic organophosphorus compounds (OPs), which inhibit acetylcholinesterase activity. Human paraoxonase 1 (PON1) has demonstrated significant potential for use as a catalytic bioscavenger capable of hydrolyzing a broad range of OPs. However, there are several limitations to the use of human PON1 as a catalytic bioscavenger, including the relatively difficult purification of PON1 from human plasma and its dependence on the presence of hydrophobic binding partners to maintain stability. Therefore, research efforts to efficiently produce recombinant human PON1 are necessary. In this study, we developed a Drosophila S2 stable cell line expressing recombinant human PON1. The recombinant human PON1 was fused with the human immunoglobulin Fc domain (PON1-hFc) to improve protein stability and purification efficiency. We purified the recombinant human PON1-hFc from the S2 stable cell line and characterized its enzymatic properties for OP hydrolysis. We purified the recombinant human PON1-hFc from the S2 stable cell line and characterized its enzymatic properties for OP hydrolysis compared with those of the recombinant human PON1 derived from E. coli . We observed that the recombinant human PON1-hFc is functionally more stable for OP hydrolyzing activities compared to the recombinant human PON1. The catalytic efficiency of the recombinant PON1-hFc towards diisopropyl fluorophosphate (DFP, 0.26 × 10 6 M −1 min −1 ) and paraoxon hydrolysis (0.015 × 10 6 M −1 min −1 ) was 1.63- and 1.24-fold higher, respectively, than the recombinant human PON1. Thus, we report that the recombinant PON1-hFc exerts hydrolytic activity against paraoxon and DFP.

We derive twenty five basic identities of symmetry in three variables related to higher-order Euler polynomials and alternating power sums. This demonstrates that there are abundant identities of symmetry in three-variable case, in contrast to two-variable case, where there are only a few. These are all new, since there have been results only about identities of symmetry in two variables. The derivations of identities are based on the p-adic integral expression of the generating function for the higher-order Euler polynomials and the quotient of integrals that can be expressed as the exponential generating function for the alternating power sums.

The structural genes of the Pseudomonas maltophilia alk system, which are localized on the OCT plasmid were cloned as a 4.2-kilobase pair Hind III fragment. This fragment contains sequences for alkane hydroxylase gene ( alk B) and rubredoxin reductase gene ( alk A), respectively. The alk B gene encodes a 373-amino acid polypeptide (47.4 kD) that can be expressed at high levels in Pseudomonas and Esherichia coli . The alk BA genes were complemented with alkane hydroxylation in both bacteria. This result shows that alk BA gene is essential for alkane hydroxylation since chromosomal loci have been encoded for other enzymes involved in fatty acid oxidation.

As the paradigm of innovation becomes more user oriented and collaborative, to benefit from this changing paradigm, firms need to adjust their intellectual property rights management strategy and devise tools to manage openness. Crucially, firms need to resolve is how to interface the “closed innovation” paradigm required to acquire intellectual property rights in law and to introduce openness in the process of innovation and decentralised innovation process. While the topic of open innovation has produced numerous works especially in the area of business administration and organizational studies, literature on interfacing open innovation with intellectual property law is rare or rather focused on specific subject matters of IP. For example, legal research on open innovation focus on computer, open source software or user generated contents types. This leaves out vast areas of technology uncovered and under researched. Based on literature review and qualitative case studies on a group of Finnish firms, this paper aims to identify tools that are required to manage openness, in response to legal context, and examine to what degree the protection of intellectual property, in particular patent, can be adapted or interfaced with open innovation paradigm. The paper finds that (1) open innovation is dynamic, (2) all commercial open innovation is always managed or controlled, and that (3) actors and modalities of exchanges are heterogeneous and dynamic. Multiple claim holders – as contributors, investors, co-inventors, collaborator call for a governance structure over how their claims can be prioritised. This paper argues that intellectual property law do regulate the question of co-inventor, co-creator, and co-owner but do not regulate how these rights may be coordinated or managed, in what hierarchy. Thus, we argue that to prevent disputes, proactive private ordering is necessary. Furthermore, while open innovation benefits from open exchange in communication, in the absence of clear and certain rules on how such exchange lead to loss of right, “open” communication may not occur. In other words, unless openness is managed implicitly or explicitly, communications that are crucial in open innovation will not occur. Thus we find that openness in innovation is always managed either formally (through formal governance means i.e. contract, explicit firm policy) or informally (through community norms, trust and implicit corporate culture).The paper argues that governance means are best provided by the firms either as a contracts, or general policy over information exchanges, in other words a broader form of contract (Private ordering). As a secondary option, a certain proposals to the patent law revision can also be made through introduction of limitation and exception to the right. This paper has two practical implications. First, in the absence of proper legal safeguard for own collaborative input, the paper advocates contract based governance approach. Reflecting this, open and collaborative innovation requires firms to more actively and strategically involve in the governance of intellectual property. Secondly, as a proposal for patent law reform, the paper may enlighten law and policy makers to explores for a creation of particular defence against the claims of infringement in patent law.

Institutional choice theory seems to provide a refreshing perspective to assess the efficacy of the patent system by bringing a process oriented insights and the costs of participation into the discussion. One variation of this approach is to examine how the current shape of a law or a policy is the result of a particular institutional choice. This can be done by analysing the correlating policy tools of institution and the policy substance that are affected by each institutional choice. As multiple institutions are heavily involved both in the affirmation of the right and in the assertion and enforcement of the right, patent policy and law making is one area of law that benefit from the comparative institutional analysis. Institutional comparison requires identification of the status quo (identification of the current path of decision making and institutional choice). This identification may reveal the direction of changes in law and policy, affected by the institutional choice. In other words, comparison identifies defects in current institutional arrangement. Also comparison of institutions holding peer position may encourage competition among the institutions in a positive way. By identifying path of decision making process and comparing institutional competence and capabilities, institutional comparison may reveal incompetent or inefficient decision making process. Thus institutional comparison helps articulation of new law and policies.In this context, this paper aims to identify the institutions that are involved in the operation of the systems of patent for the purpose of comparative institutional analysis and to flesh out the details of comparative institutional analysis as applied to a system of patent and patent right. Additionally, as an endeavour to identify the correlating legal rules and policy resulting from the institutional choice, this paper follows the debates surrounding the patentable subject matter in US, Japan and Europe.

Policy matters in the discussion of intellectual property law. On a most superficial level, law differs from policy in the sense that law is neutral and objective, while policy subjectively guides the actions of the societal members. Subjectivity of a policy highlights the need to make the process of policy making neutral, so that the outcome is socially desirable. Law, on the other hand, is an incorporation of the most important core of the public policy. It is obvious that in this sense, objective law and subjective policy are closely connected and interlinked. As in any study of law, the study of intellectual property law need to incorporate this interplay of objective and subjective aspects of law and policy, and an academic research need to constantly question beyond the neutral surface of the law and legal change, and positive interpretation and description of law, to identify the subjective aspects of intellectual property law. In this context, this paper reviews some of the law and policy questions in the development of patentable subject matter rules in Europe, Japan and the US and aim to identify the prevailing policy, in the swing of changes.

Complex questions seem to arise as validly granted computer program and Internet related patents are used and enforced. Enforcement of computer program and Internet patents raises several interesting points that shed lights on how the doctrines surrounding patent infringement is structured. As computer programs are highly accumulative, and incremental, even when used in a non-Internet context, computer program patents increases possibility of partial or incomplete infringement. In today's globalized economy, modular production of computer program products often involve cross border production, utilizing lower production costs. On the other hand, the concept of patent right, based on national patent law, is based on the idea that the effect of right is territorial, and its infringement often by a singular and complete action. In this context, this paper discusses how the computer program patent challenges this model of single infringer, within one territory with one complete action of infringement. In the context of globalised economy, this paper comparatively reviews some of the theories of infringements in the patent laws of Japan, the US and in Europe, that aim to bridge the patchwork patent infringement doctrines to regulate these fragmented activities.

Technical standards that facilitate interoperability are believed to be crucial in the growth and development of the network and computer industry. In a modular and globalized economy, it is believed that the development of compatibility standards benefit from being widely accessible. On the other hand, as intellectual property is based on the idea of exclusion and creates incentives for the right holder to arbitrarily discriminate the access to the protected information, it seems to be inherently incompatible with the efficient development of public, non-discriminatory and well-understood compatibility standards. Literature studying standardization invariably discuss this problem from various angles. However the relationship of standardization and intellectual property from the point of law has only been started to be of concern, as some of the more onerous business practices, such as hold-up or industry standard capture problem began to surface, in a anticipatory standardization. Most of these comments focus on the strategic use and abuse of intellectual property prior to, during and after the setting of the standards, either by an organisation or by a dominant firm, suggesting solutions mainly from contractual, or antitrust or competition law perspective. This paper argues that intellectual property law based solution should accompany these, with the example of patent law, and attempts to identify the aspects of patent law where the solutions to these problems could be based on. This is because often patent law includes specific tools of regulating uses beyond the grants of patents. As the problems are caused by some of expansionary shifts in the doctrines within patent law discipline, it is possible to devise the solution within the discipline of patent law. In sum, standards and standardization should be a concern for patent law.

This paper analyses the evolution of the institution of patent by examining the normative meaning of business method patents. A business method is defined as a process of converting abstract data to useful information, to be applied in business activities. A business method patent is a patent whose claims are directed to a business method, regardless of the claim format. In recent years, the patenting of business methods in the US, Japan and in Europe has generated a global claim of controversy. Business method patenting is often seen as an example of subject matter expansion, by which process the institution of patent accommodates challenges brought forth by the increased quantity of potential subject matter. As the subject matter expansion begs the question of what is the proper boundary of the patent law, this paper attempts to answer this question by examining relevant statutes and cases, the administrative examination guidelines of the patent offices, and the claims of business method patents issued in Japan, the US and Europe. Specifically, the thesis questions (1) whether business method patenting signifies something more than a mere accretion of a subject matter, and is a reconfiguration of patent eligible subject matter; and (2) whether this can be justified with the instrumentalism. The paper suggests that to include business methods as a patent-eligible subject matter, courts and patent offices in the US, Japan and Europe have commonly redefined the meaning of invention of technology, from the context of physical instantiation, i.e., physical transformation, to the level of conceptual instantiation, i.e., useful information. Although they are varying in their extensiveness, as a result, the practical definitions of patent-eligible subject matter in all three regions, understood from the issued patents, court decisions and examination guidelines, reflects this change. This thesis argues that this could signify the reconfiguration of patent-eligible subject matter.