I.	Background and Principles of the Collaboration

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

(1)	Seek regulatory approval from FDA, EMEA and other international jurisdictions to commercialize DAG for Injection outside of China for the treatment of glioblastoma multiforme (GBM) or more indications.

 

 

(2)	DelMar will support Wuzhou by developing and providing new non-clinical and clinical data in order to support marketing and sales of DAG for Injection based on approved indications in China.

 

 

(3)	To support market approval of DAG for Injection outside of China, Wuzhou will assist and support DelMar to initiate the development work in one or more Clinical Center(s) in China (“China Clinical Centers”) as part of international multi-center clinical development strategy.

 

 

(4)	DelMar will provide non-clinical and clinical data to Wuzhou for approval of new indications including glioblastoma multiforme (GBM) for DAG for Injection by SFDA.

 

 

(5)	DelMar and Wuzhou will work together to establish Wuzhou as an FDA and GMP certified manufacturer of DAG and DAG for Injection.

 

 

 

 

 

 

1.

Intellectual Property

 

 

1.1	Definitions

 

1.1.1

“Confidential Information” means all information, regardless of its form, of either Party that is not generally known to the public or persons skilled in the art of drug discovery and development, except that “Confidential Information” does not include information:

 

 

·	Legally possessed by the recipient (the “Recipient”) prior to receipt from the disclosing Party (the “Discloser”), other than through prior confidential disclosure by the Discloser, as evidenced by the Recipient’s business records,

 

 

·	published or available to the general public otherwise than through a breach of this Agreement,

 

 

·	obtained by the Recipient from a third party with a valid right to disclose it, provided that the third party is not under a confidentiality obligation to the Discloser in respect of the same, or

 

 

·	independently developed by employees, agents or consultants of the Recipient who had no knowledge of or access to the Discloser’s information as evidenced by the Recipient’s business records;

 

 

 

1.1.2

“DelMar Intellectual Property” means, any and all knowledge, know-how, technique(s), technology or other intellectual property which are conceived, invented, developed, improved or acquired solely by DelMar before signing this agreement and during the term of the Agreement in the performance of the Collaboration;

 

 

1.1.3

“DelMar Methods” means new HPLC and titration methods required by DelMar for the identification, determination of DAG content, epoxide content and related substances and any manufacturing quality assurance methods developed by DelMar for GMP compliance by the FDA and EMEA.  The DelMar Methods are DelMar Intellectual Property.

 

 

1.1.4

“Wuzhou Intellectual Property” means, any and all knowledge, know-how, technique(s), technology or other intellectual property which are conceived, invented, developed, improved or acquired solely by Wuzhou before signing this agreement and during the term of the Agreement in the performance of the Collaboration;

 

 

1.1.5

“Joint Intellectual Property” means any and all knowledge, know-how, technique(s), technology or other intellectual property which are conceived, invented, developed, improved or acquired jointly by Wuzhou and DelMar during the term of the Agreement in the performance of the Collaboration, or by either party using the other party’s IP.

 

 

1.2

DelMar Intellectual Property and Wuzhou Intellectual Property are respectively owned by each Party, however, each Party is entitled to the free use of the other Party’s Intellectual Property for the performance of this Agreement. Joint Intellectual Property is co-owned by the Parties. For the performance of this Agreement, Wuzhou has free use of Joint Intellectual Property in China and DelMar outside of China. Any other use or disposal of Joint Intellectual Property by either Party shall be subject to the Parties’ mutual consent.

 

 

1.3	Confidential Information disclosed one Party to the other Party shall be clearly identified in writing as “Confidential” either at the time of disclosure or, if orally disclosed, within 30 calendar days thereafter.

 

 

1.4

The Parties agree that unauthorized disclosure of Confidential Information would or could reveal commercial, scientific or technical information and would significantly harm the Parties’ competitive position. Each Party agrees keep and use the other Party’s Confidential Information in confidence and will not, without the other Party’s prior written consent, disclose the other Party’s Confidential Information to any person or entity. Anyone who is not involved in any activities related to this agreement should not be exposed to Confidential Information.

 

 

 

 

 

 

1.5	Any Party required by judicial or administrative process to disclose the other Party’s Confidential Information will promptly notify the other Party and allow it reasonable time to oppose the process before disclosing the Confidential Information.

 

 

1.6	The Parties acknowledge and agree that either Party may identify the title of the Project and the Parties to this Agreement.

 

 

1.7	Notwithstanding any termination or expiration of this Agreement, the obligations of confidentiality set out in this Section 1 and elsewhere in this Agreement shall survive and continue to bind the Parties, their successors and assigns until five (5) years after such termination or expiration.

 

 

1.8

DelMar acknowledges and agrees that Wuzhou owns all right, title and interest in and to Wuzhou Intellectual Property.  At its sole discretion, Wuzhou will be responsible for filing patents related to the Wuzhou Intellectual Property and will bear all costs incurred in connection with the preparation, filing, prosecution and maintenance of its patent applications.

 

 

1.9

Wuzhou acknowledges and agrees that DelMar owns all right, title and interest in and to DelMar Intellectual Property.  At its sole discretion, DelMar will be responsible for filing patents related to the DelMar Intellectual Property and will bear all costs incurred in connection with the preparation, filing, prosecution and maintenance of its patent applications.

 

 

1.10	Patents and Inventions

 

 

1.10.1

The Parties will promptly notify one another in writing of any Joint Intellectual Property within 30 days of invention.

 

 

1.10.2

The Parties acknowledge and agree that Wuzhou and DelMar have joint right, title and interest in and to Joint Intellectual Property.  Notwithstanding any contrary provisions in the applicable patent or other intellectual property laws in any jurisdiction, the Wuzhou shall have an exclusive right to exploit any Joint Intellectual Property in China and DelMar shall have an exclusive right to exploit any Joint Intellectual Property outside of China without notice or payment to the other Party.

 

 

1.10.3

DelMar will be responsible for filing international patents application (including China) in the Parties’ names related to the Joint Intellectual Property and will bear all costs incurred in connection with the preparation, filing, prosecution and maintenance of the patent applications, provided however, that Wuzhou shall reimburse DelMar for costs incurred in connection with the preparation, filing, prosecution and maintenance of the patent applications in China.  Wuzhou will assist Delmar in a timely manner to ensure that the patent applications cover, to the best of Wuzhou’s knowledge, all items of commercial interest and importance.

 

 

 

 

1.10.4

If Wuzhou wishes to obtain patent protection for Joint Intellectual Property over and above that for which DelMar wishes to provide its financial support Wuzhou will be free to file any patent applications, including new applications, at its own expense.  If DelMar discontinues its financial support for prosecution or maintenance of any patents or patent applications for Joint Intellectual Property (the “DelMar Abandoned Patent”) for good reason,  a 30 calendar days notice prior to the discontinuance by DelMar to Wuzhou is required. After receipt of said notice, Wuzhou will be free to continue the prosecution or maintain such patents or patent applications at its own expense.  In such a situation, DelMar and Wuzhou shall negotiate in good faith to determine proportion of costs related to the prosecution or maintenance of the DelMar Abandoned Patent to be paid by DelMar, if DelMar decides not to bear any cost after negotiation, the DelMar Abandoned Patent will be solely owned by Wuzhou, DelMar will transfer the right according to the terms.

 

 

1.10.5

In the event that DelMar wishes to discontinue the financial support for prosecution or maintenance of any patents or patent applications for Joint Intellectual Property without good reason, DelMar will provide Wuzhou with a written notice at least 30 calendar days prior to the discontinuance and Wuzhou will be free to continue the prosecution or maintenance of any such patents or patent applications for the Joint Intellectual Property related to said patent or patent application and. Joint Intellectual Property claimed in said patent or patent application will be become solely owned by Wuzhou, DelMar will transfer the right according to the terms.

 

 

1.10.6

In the event that Joint Intellectual Property is infringed upon by any third party, either Party shall have the right to take action against such infringement and relevant costs shall be borne  by both Parties, each party’s share to be discussed.

 

 

 

2.

CMC/GMP Development

 

 

Section 1.

 

Section 2.

 

2.1	Wuzhou and DelMar will to work together to implement DAG and DAG for Injection specifications in compliance with FDA and SFDA requirements.

 

 

2.2	DelMar will assist Wuzhou to develop systems to ensure GMP compliance for meeting FDA and SFDA requirements-by evaluating the current GMP compliance and by conducting a gap analysis (“Gap Analysis”) to identify areas to be improved (the GMP Improvement Project).

 

 

 

 

 

 

2.2.1

Implementing GMP improvements, including, but not limited to, the DAG and DAG for Injection related facility, equipment, QC testing, manufacturing process and controls, standard operating procedure (SOP) and documentation systems, stability studies, and other such documentation which shall be provided in both Chinese and English.

 

 

2.2.2

Providing technical support for the development of new manufacturing process and controls of known and unknown impurities in DAG in accordance with FDA and SFDA regulations.

 

 

2.2.3

Providing support for the training of Wuzhou personnel and establish a drug master file (“DMF”) for the manufacturing of DAG drug substance and preparation for inspection by FDA and SFDA.

 

 

2.2.4

Providing input and advice related to the establishment of limits for impurities and adopting a GC method for determination of residual solvents and current USP methods for residue on ignition and heavy metals to meet FDA and SFDA regulations.

 

 

2.2.5

Providing consulting support to assist Wuzhou in adopting and validating the DelMar Methods and other manufacturing and quality controls according to FDA Guidelines.

 

 

2.2.6

Advising on the improvement on formulation, manufacturing process controls in order to enhance the stability of the drug product with the possibility of achieving commercially relevant stability under ambient conditions.  Such advice is intended to include research into the optimization of freeze-drying cycle and other manufacturing process.

 

 

2.3	In return for exclusivity and other compensation granted under this Agreement, DelMar shall grant Wuzhou a royalty free license to exclusively use DelMar Methods in China.

 

 

2.4	Wuzhou shall be responsible for costs associated with the GMP Improvement Project with the goal of achieving compliance with relevant GMP standards of SFDA, FDA and EMEA.

 

 

2.5	The Parties shall work together to support the development of new Joint Intellectual Property, including improved formulations and other improvements to DAG and DAG for Injection.

 

 

 

 

Section 3.

Development of New Clinical and Non-Clinical Data to Support DAG for Injection Sales in China

 

 

3.1	The Parties believe that the development of new clinical data through the conduct of clinical trials will generate immediate clinical interest and improved sales for DAG for Injection in China.

 

 

3.2	Wuzhou plans to conduct a clinical safety study in China (the “China Safety Study”) to support the re-launch of DAG for Injection in China.

 

 

3.2.1

Wuzhou shall bear the cost of the China Safety Study.

 

 

3.2.2

Dosing in the China Safety Study shall be based on the current SFDA label for DAG and the primary endpoint shall be safety and tolerability in cancer patients

 

 

3.2.3

Wuzhou will provide the China Safety Study protocol to DelMar no less than 21 days prior to the initiation of study and DelMar will provide input to the study design for Wuzhou’s consideration.

 

 

3.2.4

To support the China Safety Study, DelMar will provide summary highlights from the US GLP Toxicity study and the Physicians Brochure upon request from Wuzhou.  Wuzhou should bear  the cost if translation into Chinese is needed.

 

 

3.3	The Parties recognize and agree that clinical efficacy data generated under the oversight of the FDA or EMEA, or similar regulatory agency such as Health Canada in Canada will maximize the value of such data in China, and will also support the commercialization of DAG outside of China by DelMar.

 

 

3.4

The Parties will jointly agree upon specific clinical trials to be conducted to promote sales of DAG for Injection in China (Efficacy Trials).  DelMar will be responsible for establishing protocols for and conducting Efficacy Trials in accordance with relevant standards required by SFDA, FDA and EMEA guidelines.  Unless otherwise agreed between the Parties, Wuzhou will bear the cost of the Efficacy Trials in accordance with section 3.8 of this Agreement.

 

 

3.5	GBM:  DelMar promises that it has initiated and is currently conducting a Phase I/II clinical trial to evaluate DAG as a treatment for glioblastoma multiforme (GBM) (the “Phase I/II GBM trial”).

 

 

3.5.1

DelMar is responsible for funding the cost of the Phase I/II GBM trial

 

 

3.5.2

DelMar shall provide Wuzhou with regular updates on the progress of the Phase I/II GBM clinical trial.   Acopy of the reports made to FDA will be provided to Wuzhou by mail or email.

 

 

 

 

3.5.3

The Parties shall consult with the SFDA to determine a strategy to expand the label for DAG in China to include GBM.  The Parties shall use commercially reasonable efforts to determine this strategy by September 30, 2012.

 

 

 

 

3.5.4

DelMar shall use commercially reasonable efforts to fund the GBM Registration Trial through proceeds of an initial public offering (IPO) by mid-2013.  Wuzhou shall be given an opportunity to participate in the IPO which will enable Wuzhou to participate in the value of the commercialization of DAG outside of China through an equity ownership position in DelMar.

 

 

3.6

CML and Lung Cancer:  The Parties recognize that DAG is currently approved in China for the treatment of CML and Lung Cancer and expansion of this label may require additional clinical trials to be conducted in China or another jurisdiction as required by the SFDA.  The Parties further recognize that recent data suggests that the BIM co-deletion polymporphism (the “BIM phenotype”) unique to East Asian populations may be responsible for high-resistance to standard tyrosine kinase therapy in CML and EGFR lung cancer.

 

3.6.1

DelMar will conduct non-clinical studies designed to the activity of DAG against CML and lung cancer tumors resistant to tyrosine kinases, including the BIM phenotype.

 

3.6.2

DelMar will be responsible for including feedback from Key Opinion Leaders in China and the United States in the design of the non-clinical studies.

 

 

3.6.3

DelMar will provide detail of the non-clinical study protocols and communicate preliminary results to Wuzhou on a regular basis.  A copy of the reports made to FDA will be provided to Wuzhou by mail or email.

 

 

3.6.4

DelMar shall complete such studies and publish or present the results in China and Western peer-reviewed settings such as scientific conferences or publications before December 31, 2012.

 

 

3.6.5

DelMar will fund the cost of the non-clinical studies and Wuzhou will provide testing samples according to the study protocol.

 

 

3.6.6

In the event that the Parties determine that Phase IV clinical trials are needed to further support the marketing of DAG under the current label, DelMar and Wuzhou will jointly agree upon an Efficacy Trial to be conducted to promote sales for CML and Lung Cancer in China (the “China CML/Lung Trials”).

 

 

 

 

3.7	The Parties shall work together to research new indications for DAG.

 

 

3.7.1

DelMar shall be responsible for conducting non-clinical and clinical studies to support new indications for DAG for Injection.

 

 

3.7.2

The Parties shall bear their share of the cost to support new indications for DAG for Injection in accordance with a plan and budget to be agreed by the Parties from time-to-time.  Unless otherwise agreed between the Parties, Wuzhou will bear the cost of the clinical trials in China in accordance with section 3.8 of this Agreement.

 

 

3.7.3

The Parties shall use commercially reasonable efforts to identify new indications for DAG by December 31, 2012.

 

 

3.8

Except as otherwise agreed under the terms of this Agreement, the Parties shall jointly fund the cost of clinical studies.  Wuzhou shall be responsible for the cost associated with the China Safety Study and Efficacy Trials conducted in China.  DelMar will be responsible for clinical studies outside China.   To support these efforts under the terms a budget will be developed and agreed to by the Parties for a specific Efficacy Trials. Wuzhou shall pay to DelMar its portion for the cost prior to the commencement of an Efficacy Trial.

 

 

3.9	The Parties shall use commercially reasonable efforts to ensure that key opinion leaders from China are involved in the design and oversight of clinical trials conducted under the terms of this Agreement.

3.10	DelMar shall provide Wuzhou with access to data developed through the Clinical Trials outside China for use in publications and marketing materials to support sales and marketing of DAG for Injection in China.

 

 

 

Section 4.

Exclusive Clinical and Commercial Drug Supply

 

 

4.1	The Parties wish for Wuzhou to be a primary or exclusive supplier of DAG for Injection and for development, the sales and marketing of products containing DAG.

 

 

4.2

Wuzhou shall supply DAG for Injection at production price to DelMar for clinical trials.  Upon receipt of regulatory approval in the United States, Canada or the European Union, the Parties shall negotiate the price of the commercial supply of DAG for Injection for sales and marketing in good faith (“Commercial Supply Price”), whereby Commercial Supply Price shall not exceed the price charged by Wuzhou to any third party in China.

 

 

4.3	Wuzhou will manufacture, ship, distribute and warehouse DAG for Injection in accordance with applicable laws and regulations for China and for the United States, Canadian and European markets.

 

 

4.4

DelMar agrees that Wuzhou shall be the exclusive supplier of DAG for Injection for clinical trials and sales and marketing of products for China and for the United States, Canadian and European markets, subject to Wuzhou obtaining and maintaining cGMP certification by the FDA, EMEA or appropriate regulatory agency in other jurisdictions and to being able to meet volumes ordered by DelMar；for other markets, if DelMar has any purchasing demands, Wuzhou shall give priority to meet them. The detailed exclusivity agreement will be discussed by both parties separately.

 

 

4.5 For Chinese market, DelMar including any third party appointed by DelMar shall have preemptive right under the condition of same sales target and price. [*]

 

 

4.6 In return for the royalty free license granted by DelMar under Section 2.3 and in recognition of the investment being made by DelMar to support the marketing of DAG in China and the commercialization of DAG outside of China, Wuzhou agrees not to sell DAG or DAG for Injection to any party other than DelMar, or its licensee or assignee in markets outside of China. On the condition that DelMar or its licensee or assignee is capable of selling all the DAG for Injection by Wuzhou, DelMar, or its licensee or assignee, will use commercially reasonable efforts to begin marketing DAG for Injection in territories outside of China within 120 days of receiving regulatory clearance to market DAG for Injection in a respective territory. In addition, DelMar shall meet the minimum sales target of DAG for Injection required by Wuzhou for each country or territory where DAG for Injection receives regulatory clearance for marketing (the “Market Plan”).  The Market Plan shall define Del Mar’s obligation on a semi-annual basis for the first three years following regulatory approval in a respective country or territory. If DelMar fails meet its obligations under a Market Plan for two consecutive periods as defined by said Market Plan, Wuzhou will have the option to sell DAG to any third party in the country or territory covered by said Market Plan at prices not lower than those offered to DelMar.

 

 

 

Section 5.

Other Opportunities for Collaboration

 

 

5.1	The Parties wish for this Agreement to serve as the basis for a broader collaboration to involve additional products and product candidates.  Such opportunities may include, but are not limited to:

 

 

5.1.1

DelMar could assist Wuzhou to evaluate opportunities for the commercialization of its flagship cardiovascular product, XueShuan Tong, Sodium fluorescein Injection outside of China, particularly in the United States, Canada and the European Union specifically by:

 

 

5.1.1.1

Working with Wuzhou to conduct a feasibility analysis of developing and registering Wuzhou’s XueShuan Tong for Injection product to evaluate quality control and establish product specifications, including range of impurities in compliance with FDA and EMEA regulations.

 

 

5.1.1.2

Assisting Wuzhou to develop analytical methods to quantitate active components of XueShuan Tong and to develop a purification process to enrich the active components in the current XueShuan Tong drug formulation and to develop a dose form containing one active component or other such formulation as may be determined to be appropriate for development and registration in the United States and Europe.

 

 

5.1.2

The Parties could identify other drugs that would meet unmet medical need due to global supply issues including, but not limited to, obratide, clopidogrel bisulfate and dasudil HCL, bleomycin, cisplatin, cytarabine, doxorubicin, etoposide, fluorouracil, mitomycin, mustargen, ontak, paclitaxel, thiotepa, vincristine.  Wuzhou could provide manufacturing support and DelMar could provide regulatory and clinical development support such products which could rapidly be approved for marketing by the FDA, EMEA, SFDA and other international jurisdictions.

 

 

5.1.3

DelMar will use commercially reasonable efforts to identify and introduced to Wuzhou for 2 – 3 pharmaceutical products not currently available in China which could be developed for China without infringing third-party patents by June 30, 2013.

 

 

5.1.3.1

For each such product, Parties will conduct an analysis of the sales potential opportunity to obtain new intellectual property and plan for obtaining SFDA approval including API synthesis, drug formulation, and regulatory strategy, and participation to help at site, if necessary.

 

 

Section 6.

Steering Committee

 

 

6.1

To ensure regular and open communication between the Parties, a committee (the “Steering Committee”) is hereby established to have as its overall purpose the management and governance of the Collaboration.  Unless otherwise agreed by Wuzhou and DelMar, the Steering Committee shall consist of three (3) senior representatives of each Party and shall report to the Chairman of each company, or their designee.

 

 

 

 

 

 

 

 

 

 

 

 

 

6.2

The Steering Committee should meet at least quarterly at a date and at a location to be agreed to by the Parties, or upon written request by either Party, in which case a meeting will be held within twenty one (21) calendar days of such notice.  Any meetings of the Steering Committee should be held in person, or if an in-person meeting is impracticable, by videoconference or teleconference.

 

 

6.3	It is contemplated that the Steering Committee may, from time to time, establish subordinate committees to oversee specific aspects of the collaboration.  For example, a CMC or QC/QA committee or a Commercial Development Committee may be established at the discretion of the Steering Committee.

 

 

 

Section 7.

Other Terms & Conditions

7.1	Each of Wuzhou and DelMar shall be solely responsible for its own respective fees and costs incurred relating to this Agreement.

 

梧州制药和德玛各自承担本方发生的与本协议有关的费用及成本。

7.2	This Agreement may be terminated:

 

 

7.2.1

on the written agreement of all Parties;

 

 

7.2.2

by either Party if the other Party breaches any material term of this Agreement and fails to remedy the breach within 30 days after receipt of notice of the breach;

 

 

7.2.3

by either Party if any action or decision which is to be taken or made hereunder is not unanimously agreed or is subject to disagreement, provided that the matter first has been referred to the chief executive officer of each Party and the chief executive officers have been unable to resolve or reach agreement on the matter within 90 days of the date that such matter is referred to them.

 

 

7.3	This Agreement shall be governed by and construed in accordance with the laws of China, excluding application of any conflict of laws principles that would apply a different body of law and excluding the United Nations Convention on Contracts for the International Sale of Goods.

 

 

7.4

Any dispute, controversy or claim arising out of or relating to this contract, including the validity, invalidity, breach or termination thereof, shall be settled by arbitration in The China International Economic and Trade Arbitration Commission (CIETAC) in Beijing under its arbitration Rules in force when the arbitration is filed.

 

 

7.5

This Agreement is not assignable by either Party in whole or in part without the prior written consent of the other Party, except that either Party may assign this Agreement to an affiliate, or as part of the sale of all or any part of the business or assets of the Party, or pursuant to any merger, consolidation, plan of arrangement or reorganization.   Any attempt by either Party to this Agreement except as permitted by this clause is void.  This Agreement will enure to the benefit and be binding upon the Parties and their respective successors and permitted assigns.

 

 

7.6	The Chinese language version of this Agreement is the authoritative one.

 

 

 

GUANGXI WUZHOU PHARMACEUTICAL (GROUP) CO. LTD. 广西梧州制药（集团）有限公司     By: /s/ Ming Chen		DEL MAR PHARMACEUTICALS (BC) LTD. 德玛制药有限公司     By: /s/ Jeffrey A. Bacha
Name:  Ming Chen   Title:  Vice  President of Zhongheng Group   Date: 2012.10.25		Name:  Mr. Jeffrey A. Bacha 姓名： 杰夫•巴察, Title:  cofounder / President & CEO  职称： 共同创始人，总裁，首席執行官 Date: 日期

 

 

 

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