In May 2013, we entered into a clinical supply agreement with Nordion (Canada), Inc. (Nordion) for the manufacture and supply of NAV5001 clinical trial material.  The initial three-year term expires in May 2016.  Navidea may terminate this agreement without cause or penalty upon 180 days prior written notice to Nordion.  Upon such termination, Nordion will be entitled to retain all amounts paid by Navidea, and Navidea shall pay to Nordion any undisputed, unpaid amounts due or earned by Nordion.  Either party may terminate upon material breach by the other party which is not cured within 30 days from the date of written notice of the breach.  In August 2014, in connection with the Company’s decision to refocus its resources, the Nordion agreement was amended to provide for a suspension period during which the Company is to pay a monthly fee to maintain production space at Nordion’s facility until such time as manufacture may resume.  Total purchases under the clinical supply agreement were $244,000, $505,000 and $771,000 for the years ended December 31, 2015, 2014 and 2013.  As of December 31, 2015, we have issued purchase orders under the agreement with Nordion for approximately $150,000 to maintain production space in Nordion’s facility through June 2016.

In August 2013, we entered into a manufacturing services agreement with PETNET Solutions, Inc. (PETNET) for the manufacture and distribution of NAV4694.  The initial three-year term of the agreement expires in August 2016.  The agreement will automatically renew for additional one-year terms, unless either party gives written notice to the other at least 60 days prior to the end of the initial term.  Either party may terminate upon material breach by the other party which is not cured within 30 days from the date of written notice of the breach.  Total purchases under the manufacturing agreement were $855,000, $2.2 million and $1.4 million for the years ended December 31, 2015, 2014 and 2013.  As of December 31, 2015, we have issued purchase orders under the agreement with PETNET for $132,000 of our products for delivery through February 2016.

In September 2013, we entered into a manufacturing services agreement with OSO BioPharmaceuticals Manufacturing, LLC (OsoBio) for contract pharmaceutical development, manufacturing, packaging and analytical services for Lymphoseek.  The initial term of the agreement expires in December 2016, and automatically renews for additional two-year periods unless written notice is provided at least 12 months prior to the expiration of the initial term.  Either party has the right to terminate the agreement upon mutual written agreement, or upon material breach by the other party which is not cured within 60 days from the date of written notice of the breach.  During the term of agreement, OsoBio will be the primary supplier of the manufacturing services for Lymphoseek.  In consideration for these services, the Company will pay a unit pricing fee.  In addition, the Company will also pay OsoBio a fee for regulatory and other support services.  Total purchases under the manufacturing services agreement were $472,000, $96,000 and $1.2 million for the years ended December 31, 2015, 2014 and 2013.  As of December 31, 2015, we have issued purchase orders under the agreement with OsoBio for $680,000 of our products for delivery through March 2016.

Also in September 2013, we completed a service and supply master agreement with Gipharma S.r.l. (Gipharma) for process development, manufacturing and packaging of reduced-mass vials to be sold in the EU.  The agreement has an initial term of three years and automatically renews for additional one-year periods unless written notice is provided at least six months prior to the expiration of the current term.  Navidea may terminate the agreement for any reason by providing 60 days prior written notice.  Either party may terminate the agreement upon material breach which is not cured within 30 days from the date of written notice of the breach, or upon written notice following the other party’s dissolution or cessation of normal business.  In consideration for these services, the Company will pay fees as defined in the agreement.  Total purchases under the service and supply master agreement were $677,000, $272,000 and $34,000 for the years ended December 31, 2015, 2014 and 2013, respectively.  As of December 31, 2015, we have issued purchase orders under the agreement with Gipharma for $241,000 of services for delivery through January 2016.

In April 2008, we completed a second license agreement with UCSD for an expanded field of use allowing Lymphoseek to be developed as an optical or ultrasound agent.  The license agreement was effective until the expiration date of the longest-lived underlying patent.  Under the terms of the license agreement, UCSD granted us the exclusive rights to make, use, sell, offer for sale and import licensed products as defined in the agreement and to practice the defined licensed methods during the term of the agreement.  We could also sublicense the patent rights, subject to certain sublicense terms as defined in the agreement.  In consideration for the license rights, we agreed to pay UCSD a license issue fee of $25,000 and license maintenance fees of $25,000 per year.  We also agreed to make payments to UCSD upon successfully reaching certain clinical, regulatory and cumulative sales milestones, and a royalty on net sales of licensed products subject to a $25,000 minimum annual royalty.  In addition, we agreed to reimburse UCSD for all patent-related costs and to meet certain diligence targets.  Total costs related to the UCSD license agreement for the use of Lymphoseek as an optical or ultrasound agent were $25,000 and $29,000 in 2014 and 2013, respectively, and were recorded in research and development expenses.  The license agreement for the use of Lymphoseek as an optical or ultrasound agent was canceled in July 2014.

In July 2014, the Company replaced the license agreement for the use of Lymphoseek as an optical or ultrasound agent with an expanded license agreement for the exclusive world-wide rights to all diagnostic and therapeutic uses of tilmanocept (other than Lymphoseek).  The license agreement is effective until the third anniversary of the expiration date of the longest-lived underlying patent.  Under the terms of the license agreement, UCSD has granted us the exclusive rights to make, use, sell, offer for sale and import licensed products as defined in the agreement and to practice the defined licensed methods during the term of the agreement.  We may also sublicense the patent rights, subject to certain sublicense terms as defined in the agreement.  In consideration for the license rights, we agreed to pay UCSD a license issue fee of $25,000 and license maintenance fees of $25,000 per year.  We also agreed to make payments to UCSD upon successfully reaching certain clinical, regulatory and cumulative sales milestones, and a royalty on net sales of licensed products subject to a $25,000 minimum annual royalty.  In addition, we agreed to reimburse UCSD for all patent-related costs and to meet certain diligence targets.  Total costs related to the UCSD license agreement for tilmanocept were $152,000 and $25,000 in 2015 and 2014, respectively, and were recorded in research and development expenses.

In December 2011, we executed a license agreement with AstraZeneca AB for NAV4694, a proprietary compound that is primarily intended for use in diagnosing Alzheimer’s disease and other central nervous system disorders.  The license agreement is effective until the later of the tenth anniversary of the first commercial sale of NAV4694 or the expiration of the underlying patents.  Under the terms of the license agreement, AstraZeneca granted us an exclusive worldwide royalty-bearing license for NAV4694 with the right to grant sublicenses.  In consideration for the license rights, we paid AstraZeneca a license issue fee of $5.0 million upon execution of the agreement.  We also agreed to pay AstraZeneca up to $6.5 million in contingent milestone payments based on the achievement of certain clinical development and regulatory filing milestones, and up to $11.0 million in contingent milestone payments due following receipt of certain regulatory approvals and the initiation of commercial sales of the licensed product.  In addition, we agreed to pay AstraZeneca a royalty on net sales of licensed and sublicensed products.  Total costs related to the AstraZeneca license agreement were $80,000, $81,000 and $5,000 in 2015, 2014 and 2013, respectively, and were recorded in research and development expenses.

In July 2012, we entered into an agreement with Alseres Pharmaceuticals, Inc. (Alseres) to sublicense NAV5001, an Iodine-123 radiolabeled imaging agent being developed as an aid in the diagnosis of Parkinson’s disease and other movement disorders, with a potential use as a diagnostic aid in dementia.  Under the terms of the sublicense agreement, Alseres granted Navidea an exclusive, worldwide sublicense to research, develop and commercialize NAV5001.  The terms of the agreement required Navidea to make a one-time sublicense execution payment to Alseres equal to (i) $175,000 in cash and (ii) 300,000 shares of our common stock.  The sublicense agreement also provided for contingent milestone payments of up to $2.9 million, $2.5 million of which would have principally occurred at the time of product registration or upon commercial sales, and the issuance of up to an additional 1.15 million shares of Navidea common stock, 950,000 shares of which would have been issuable at the time of product registration or upon commercial sales.  In addition, the sublicense terms anticipated royalties on annual net sales of the approved product which were consistent with industry-standard terms and certain sublicense extension fees, payable in cash and shares of common stock, in the event certain diligence milestones were not met. In April 2015, the Company entered into an agreement with Alseres to terminate the Alseres sublicense agreement.  Under the terms of this agreement, Navidea transferred all regulatory, clinical and manufacturing-related data related to NAV5001 to Alseres.  Alseres agreed to reimburse Navidea for any incurred maintenance costs of the contract manufacturer retroactive to March 1, 2015.  In addition, Navidea has supplied clinical support services for NAV5001 on a cost-plus reimbursement basis.  However, to this point, Alseres has been unsuccessful in raising the funds necessary to restart the program and reimburse Navidea.  As a result, we have taken steps to end our obligations under the agreement and notified Alseres that we consider them in breach of the agreement.  We are in the process of trying to recover the funds we expended complying with our obligations under the termination agreement. Total costs related to the Alseres sublicense agreement were $5,000, $42,000 and $366,000 in 2015, 2014 and 2013, respectively, and were recorded in research and development expenses.