激素治疗市场以9.8%的复合增速自2004年的63亿美元成长为2008年的91亿美元。 增长主要来自于主导产品Casodex, Zoladex, Aromasin, Femara 和 Arimidex的销售增长。

        The FDA may not approve an ANDA for a generic product until any applicable period of non-patent exclusivity for the reference-listed drug has expired. The Federal Food, Drug, and Cosmetic Act, or FDCA, provides a period of five years of non-patent exclusivity for a new drug containing a new chemical entity, or NCE. Specifically, in cases where such exclusivity has been granted, an ANDA may not be filed with the FDA until the expiration of five years unless the submission is accompanied by a Paragraph IV certification that a patent covering the reference-listed drug is either invalid or will not be infringed by the generic product, in which case the applicant may submit its application four years following approval of the reference-listed drug. It is unclear whether the FDA will treat the active ingredients in our product candidates as NCEs and, therefore, afford them five years of NCE data exclusivity if they are approved. If any product we develop does not receive five years of NCE exclusivity, the FDA may approve generic versions of such product three years after its date of approval, subject to the requirement that the ANDA applicant certifies to any patents listed for our products in the Orange Book. Three year exclusivity is given to a drug if the NDA includes reports of one or more new clinical investigations, other than bioavailability or bioequivalence studies, that were conducted by or for the applicant and are essential to the approval of the NDA. Manufacturers may seek to launch these generic products following the expiration of the applicable marketing exclusivity period, even if we still have patent protection for our product.

        Filing, prosecuting, enforcing and defending patents on our product candidates in all countries throughout the world would be prohibitively expensive, and our intellectual property rights in some countries outside the U.S. can be less extensive than those in the U.S. The requirements for patentability may differ in certain countries, particularly in developing countries; thus, even in countries where we do pursue patent protection, there can be no assurance that any patents will issue with claims that cover our products.

Yang, J. & Liu, Y. Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis. The American journal of pathology. 159, 1465–1475 (2001).

These consolidated financial statements are the responsibility of the Company’s management. Our responsibility is to express an opinion on the Company’s financial statements based on our audits. We are a public accounting firm registered with the Public Company Accounting Oversight Board (United States) (PCAOB) and are required to be independent with respect to the Company in accordance with the U.S. federal securities laws and the applicable rules and regulations of the Securities and Exchange Commission and the PCAOB.

Majmundar, A. J., Wong, W. J. & Simon, M. C. Hypoxia-inducible factors and the response to hypoxic stress. Mol. Cell 40, 294–309 (2010).

There are opinions that glycine uptake influences the precipitation rate of aspirin.https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-2005-870853 Translation: “Salicylic acids are coupled to glycine by peptides and as salicyluric acid renally eliminated. The precipitation rate ( rate at which a substance is removed from the body) at higher concentrations of aspirin is dependent on the amount of available glycine. One can suppose, that the uptake of glycine helps to lower the concentration of aspirin. Comparing examinations about effects and side effects should therefore orient themselves on the blood concentration and not the dosis uptake.”

Brightman Almagor Zohar & Co., Member of Deloitte Touche Tohmatsu Limited, an independent registered public accounting firm, served as our independent public accountants for the fiscal years ended December 31, 2018 and 2017, for which audited financial statements appear in this annual report.

(a) Cd38+/+ or Cd38−/− NK cells stimulated with B16F10 tumor cells. The percentage of conjugation formation at indicated time was analyzed by flow cytometry. Data are mean ± SEM of three independent experiments. (b) Cd38−/− NK cells were inhibited tumor-triggered translocation of perforin and granzyme B towards immunological synapses. Cd38+/+ or Cd38−/− NK cells were stimulated with B16F10 cells at 1:1 ratio at 37°C for 20 min, and then stained with perforin or granzyme B. The dashed line indicates the immunological synapse. (Scale bar, 5 μm). All images were representative of at least three independent experiments. (c) Degranulation of Cd38+/+ or Cd38−/− NK cells upon stimulation with B16F10 cells for 2 h at 37°C. Shown is a representative of three independent experiments. (d and e) Ca2+ signals in Cd38+/+ or Cd38−/− NK cells upon stimulation with B16F10 cells. NK cells were loaded with Fluo-4 AM for 40 min at 37°C and Ca2+ levels in NK cells were measured following treatment with B16F10 cells labeled with cell tracker orange CMRA (red). Arrow indicates the time of addition of B16F10 cells. (Scale bars, 10 μm). Shown is a representative of three independent experiments.

        Patients who are provided medical treatment for their conditions generally rely on third-party payors to reimburse all or part of the costs associated with their treatment. Therefore, our ability, and the ability of any future collaborators to commercialize any of our product candidates will depend in part on the extent to which coverage and adequate reimbursement for these products and related treatments will be available from third-party payors including government health programs and private health coverage insurers. Third-party payors each individually decide which medications they will cover and establish reimbursement levels. We cannot be certain that coverage or adequate reimbursement will be available for zilucoplan or any of our product candidates. Also, we cannot be certain that reimbursement policies will not reduce the demand for, or the price paid for, our products. The insurance coverage and reimbursement status of newly-approved products for orphan diseases is particularly uncertain, and failure to obtain or maintain adequate coverage and reimbursement for zilucoplan or any other product candidates would limit our ability to generate revenue.

Endocrinolgists now think a good Hemoglobin A1c range for a NON-diabetic is between 4 to 5.9 percent.

we may need to develop alternate product candidates from these programs by either accessing or developing alternate active ingredients, resulting in increased development costs and delays in commercialization of these product candidates. If we are unable to gain or maintain continued access rights to the desired active ingredients on commercially reasonable terms or develop suitable alternate active ingredients, we may not be able to commercialize product candidates from these programs.