Wadham, C. & Mangoni, A. A. Dimethylarginine dimethylaminohydrolase regulation: a novel therapeutic target in cardiovascular disease. Expert opinion on drug metabolism & toxicology 5, 303–319, doi: 10.1517/17425250902785172 (2009).

Investigation of continuous processing has not been limited to chemical syntheses. There has also been significant interest in developing continuous biocatalytic reactions, which are more complex and challenging to implement. German researchers reported the integration of microfluidic reactor technology with solid-liquid biocatalytic reactions (13). As a case study, they reported the biocatalytic conversion of styrene to (S)-styrene oxide using catalytic biofilms in a microreactor.

1. G.A. Boswell and R.M. Scribner, inventors; E. I. du Pont de Nemours and Company, assignee. “Polylactide drug mixtures,” US Patent 3,773,919, March 20, 1973. 2. T.J. Roseman, Journal of Pharmaceutical Sciences 61 (1) 46-50 (1972). 3. L. Beck and D. Cowsar, Acta Europaea Fertilitatis 11 (2) 139-150 (1980). 4. L.R. Beck et al., (1984). “Poly(DL-lactide-co-glycolide)/norethisterone microcapsules: Clinical study,” in Long-Acting Contraceptive Delivery Systems, G.I. Zatuchni, A. Goldsmith, J.D. Shelton, and J.J. Sciarra, Eds. (Harper and Row Publishers, Philadelphia, 1984) pp. 407-417. 5. L. M. Sanders et al., J. Pharm. Sci. 73 (9) 1294-1297 (1984). 6. J.S. Kent, D.H. Lewis, L.M. Sanders, and T.R. Tice, inventors; Syntex, Inc., assignee. “Microencapsulation of water-soluble polypeptides,” US Patent 4,675,189. June 23, 1987. 7. Debiopharm, Decapeptyl, Neo Decapeptyl, Trelstar, Pamorelin. 8. AbbVie, www.lupronprostatecancer.com. 9. T. Kissel et al., J Controlled Release, 16 (1-2) 27-41 (1991). 10. PR Newswire, Novartis Achieves Dynamic Sales Growth in First Full Year, Press Release, Jan. 22, 1998. 11. FDA, Drug Approval Package, Nutropin (somatropin (rDNA Origin)) Injection. 12. J.A. Setterstrom, T.R. Tice, W.E. Meyers, “Development of encapsulated antibiotics for topical administration to wounds” in Recent Advances in Drug Delivery Systems, J.M. Anderson; S.W. Kim, Eds. (Plenum Publishing Corp., New York, 1984) pp. 185-198. 13. R.L. Dunn, J.P. English, D.R. Cowsar, D.P. Vanderbuilt, inventors, Atrix Laboratories, Inc., assignee, Biodegradable in-situ forming implants and methods of producing the same, US Patent 5,990,194, Nov. 23, 1999. 14. PR Newswire, Attrix announces launch of Eligard 22.5 mg (leuprolide acetate for injection, Press Release, Sept. 4, 2002. 15. T.Y. Kim et al., Clin. Cancer Res. 10 (11) 3708-3716 (2004).

We conducted our audits in accordance with the standards of the PCAOB. Those standards require that we plan and perform the audit to obtain reasonable assurance about whether the financial statements are free of material misstatement, whether due to error or fraud. The Company is not required to have, nor were we engaged to perform, an audit of its internal control over financial reporting. As part of our audits, we are required to obtain an understanding of internal control over financial reporting but not for the purpose of expressing an opinion on the effectiveness of the Company’s internal control over financial reporting. Accordingly, we express no such opinion.

Our net loss for the year ended December 31, 2018 was approximately $9.9 million, representing a decrease of approximately $2.4 million, or approximately 20%, compared to approximately $12.3 million for the year ended December 31, 2017. The decrease primarily resulted from the above-mentioned decrease in research and development expenses and as well the increase in revenues due to the milestone payment received from Samil.

        The Company considers all highly liquid investments with a maturity when purchased of three months or less to be cash equivalents. As of December 31, 2018 and 2017, cash equivalents were comprised primarily of money market funds.

We have provided financing to GRD from time to time, pursuant to which the Company and GRD have executed several capital notes for an aggregate outstanding principal amount of $121.8 million. The par value of such notes is in NIS, and they bear no interest nor repayment date; provided, however, that no repayment shall be made before the fifth anniversary from the issuance date of each note. 

The Companies Law codifies the fiduciary duties that Office Holders owe to a company. Each person listed in the table under “Item 6. Directors, Senior Management and Employees—A. Directors and Senior Management” is an Office Holder under the Companies Law.

        In addition to the protection afforded by patents, we also rely on trade secret protection for certain aspects of our intellectual property. For example, a majority of the patents underlying our proprietary peptide chemistry technology expire by 2022. As a result, we anticipate that we will rely on trade secrets as the primary protection for the know-how behind our proprietary platform. We seek to protect these trade secrets, in part, by entering into non-disclosure and confidentiality agreements with parties who have access to them, such as our employees, consultants, independent contractors, advisors, contract manufacturers, suppliers and other third parties. We also enter into confidentiality and invention or patent assignment agreements with employees and certain consultants. Any party with whom we have executed such an agreement may breach that agreement and disclose our proprietary

        Collaborations are complex and time-consuming to negotiate and document. Further, there have been a significant number of recent business combinations among large pharmaceutical companies that have resulted in a reduced number of potential future collaborators. Any collaboration agreements that we enter into in the future may contain restrictions on our ability to enter into potential collaborations or to otherwise develop specified product candidates. We may not be able to negotiate collaborations on a timely basis, on acceptable terms, or at all. If we are unable to do so, we may have to curtail the development of the product candidate for which we are seeking to collaborate, reduce or delay its development program or one or more of our other development programs, delay its potential commercialization or reduce the scope of any sales or marketing activities, or increase our expenditures and undertake development or commercialization activities at our own expense.

Aastrom Biosciences, Inc. (NasdaqCM: ASTM ) is developing expanded autologous cellular therapies for the treatment of severe cardiovascular diseases. The company’s proprietary cell manufacturing technology enables the production of cellular therapies expanded from a patient’s own bone marrow and delivered directly to damaged tissues. Aastrom has advanced its cell therapies into late-stage clinical development, including a planned Phase 3 clinical program for the treatment of patients with critical limb ischemia and two ongoing Phase 2 clinical trials in patients with dilated cardiomyopathy.

RNA was isolated from mouse kidney tissues from the various experimental groups using an RNeasy Mini Kit (QIAGEN, 74104), and cDNA was synthesized using a First Strand cDNA Synthesis Kit (TOYOBO, FSK-100). Real-time PCR analysis of mouse cDNA was performed with the 7500 Real-Time RCR System (Applied Biosystems) and SYBR Green. Expression values were normalized to GAPDH expression. The primer sequences were as follows: TGFβ1: 5′-CCGCAACAACGCCATCTATG-3′ and 3′-CTCTGCACGGGACAGCAAT-5′; TβR I: 5′-TCCCAACTACAGGACCTTTTTCA-5′; and 3′-G