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Confidential  

  
 

    Exhibit 10.11    
    

        ***Text Omitted and Filed Separately

Pursuant to a Confidential Treatment Request

Under C.F.R. §§ 200.80(b)(4) and Rule 406

of the Securities Act of 1933, as amended.  

 Study Addendum # 1  

	Study Title:	"A Randomized, Double-Blind, Placebo-Controlled Study of the Effects of KW-3902IV in Maintaining Renal Function and Improving the Clinical Outcomes of Patients with Congestive Heart Failure and Renal Impairment Who
Require Hospital Treatment with Intravenous Loop Diuretics for Fluid Overload."

Director of the Coordinating Center:                             [. . .***. . .] 

Protocol Number:    KW-3902IV 

This
Agreement is entered into by and between Duke University ("Duke") and NovaCardia, Inc.
("Sponsor" or "NovaCardia") as an Addendum to the Master Clinical Research Agreement which was entered
into by the parties effective June 1, 2006 and to establish specific terms for the conduct of the above referenced study (the "Study"). 

1.     Scope of Work.  

Duke
shall coordinate the Study at Duke, and at the other clinical sites participating in the Study in accordance with the Protocol (Appendix 1)
and the Scope of Work, Budget, and Payment Schedule (Appendix 2) which fully detail the research activities and responsibilities to be
undertaken. 

The
Director of the Coordinating Center at Duke shall direct and be responsible for Duke's activities in the Study. The Director of the Coordinating Center shall complete the  Disclosure of Financial Interests form attached hereto as Appendix 3. The Director of the
Coordinating Center at Duke for this Study shall be [. . .***. . .], who by signing below acknowledges the terms and
conditions of the Master Research Agreement and this Addendum. 

2.     Study Materials.  

Sponsor
shall provide such supplies for use in the Study as the parties may agree in writing. Sponsor represents that use of the material under the Study Protocol has been approved by the U.S. Food
and Drug Administration for investigational use. 

3.     Publications Committee.  

Publications
arising from the Study shall be coordinated by a Publications Committee in accordance with Article 9 of the Master Clinical Research Agreement and the Publications Committee
Charter attached hereto as Appendix 4. 

4.     Payments.  

***Confidential Treatment Requested  

1

 

Sponsor
agrees to reimburse Duke for expenses incurred in the conduct of the Study in accordance with the Budget and Payment Schedule (Appendix 3
and Appendix 4 respectively). 

Sponsor
agrees to fund the research and pay Duke for all pass through expenses incurred in the conduct of the Study in accordance with the Budget and Payment Schedule. Sponsor agrees to pay all
undisputed invoices received from Duke within thirty (30) days of receipt thereof in accordance with the terms of the Master Clinical Research Agreement. 

5.     Transfer of Obligations.  

In
accordance with 21 CFR § 312.52, Sponsor hereby transfers to Duke those obligations set forth in Exhibit B. Sponsor or its
representative retains the responsibilities for IND safety reports pursuant to 21 CFR § 312.32, the responsibility for annual reports pursuant to 21 CFR § 312.33, the
responsibility for discontinuing investigations pursuant to 21 CFR § 312.56(d) and the responsibility for informing investigators pursuant to 21 CFR § 312.55. 

6.     Term.  

This
Addendum shall become effective on the last date written below (the "Effective Date") and shall continue in effect until completion of the Study or
its earlier termination in accordance with the Master Clinical Research Agreement. The research shall be conducted during a two (2) year period commencing on the effective date and concluding
on or before May 2008. 

7.     Other:  

For
the purposes of the Study, all subcontractors engaged by Duke to perform obligations of Duke as may arise under the Master Clinical Research Agreement referenced above shall be considered "Duke
Indemnitees", as such term is defined in Section 12.1 of the Master Clinical Research Agreement, except for (i) Participating Institutions and Participating Investigators, which are
excluded from such definition pursuant to the last sentence of Section 12.1 of the Master Clinical Research Agreement and
(ii) [. . .***. . .]. 

AGREED:

	DUKE UNIVERSITY	 	NOVACARDIA, Inc.
	

By:	

/s/ R. Sanders Williams, MD
	
 	

By:	

/s/ H. Dittrich

	

R. Sanders Williams, MD

Dean, School of Medicine	
 	

Printed Name: H. Dittrich
	 	 	 	Title: CMO
	

Date executed: 9/15/06	
 	

Date executed: 9/21/06

***Confidential Treatment Requested  

2

Confidential  

APPENDIX 1  

 PROTOCOL  

(SENT BY SEPARATE COVER) 

Confidential  

PROTOCOL  

KW-3902IV
in the Treatment of Subjects with Acute Heart Failure Syndrome CKI-301 

[Protocol
comprised of technical description of methods for conducting the clinical trial.] 

Confidential  

PROTOCOL  

KW-3902IV
in the Treatment of Subjects with Acute Heart Failure Syndrome CKI-302 

[Protocol
comprised of technical description of methods for conducting the clinical trial.] 

   Confidential  

APPENDIX 2  

Presented by  

	

 	 	Duke Clinical Research Institute
 DUKE UNIVERSITY MEDICAL CENTER

Project  

"A Randomized, Double-Blind, Placebo-Controlled Study of the Effects of KW-3902IV in Maintaining Renal Function and Improving the Clinical Outcomes of Patients with
Congestive Heart Failure and Renal Impairment Who Require Hospital Treatment with Intravenous Loop Diuretics for Fluid Overload.

"Protect I & II"  

 Prepared For  

  

NovaCardia, Inc.

Revised
Submission Date: 14 July 2006 (R3)

Revised Submission Date: 29 June 2006

Revised Submission Date: 05 May 2006

Original Submission Date: 02 November 2005 (Ballpark) 

Duke
Clinical Research Institute

All Rights Reserved

Copyright ©2006 

1

   Confidential  

Table of Contents  

	Introduction	 	4
	 	
Project Summary	
 	
4
	
Study Specifications and Assumptions	
 	
7
	 	
Trial Specifications	
 	
7
	 	
Estimated Study Timeline	
 	
8
	 	
Task Responsibility Grid	
 	
8
	 	
Study Assumptions	
 	
12
	 	 	
 Project Protocols	
 	

13
	 	 	Site Selection and Start up	 	13
	 	 	CRF Development	 	14
	 	 	Informed Consent Template Development	 	14
	 	 	Other Study Documents	 	14
	 	 	Study Website Development	 	14
	 	 	Investigator Meetings	 	15
	 	 	Clinical Leadership	 	15
	 	 	Project Management	 	15
	 	 	Site Management	 	16
	 	 	Site Monitoring	 	16
	 	 	Data Management	 	18
	 	 	Safety Surveillance	 	20
	 	 	Data Monitoring Committee (DMC)	 	22
	 	 	Biostatistics	 	22
	 	 	Clinical Events Classification Management	 	23
	 	 	Medical Writing Clinical Study Report	 	23
	 	 	Medical Writing Manuscript	 	24
	
Cost Estimate Protect I & II	
 	
25
	
Payment Terms	
 	
26
	
Duration of Proposed Terms	
 	
27
	
Changes to Existing Proposal	
 	
27
	
Ultimate Authority	
 	
27

2

   Confidentiality  

        Duke Clinical Research Institute (DCRI) considers the information contained in this proposal, or other information provided to NovaCardia Incorporated
(NovaCardia) in connection with this proposal, proprietary and/or confidential to the DCRI. Accordingly, please do not copy use, distribute, or disclose to others without the DCRI's prior approval,
other than for evaluation of the proposal. 

Operational Strategies  

        This document represents ideas and strategies proposed by DCRI, a department of Duke University Medical Center (DUMC) at Duke University (Duke). This proposal and
DCRIs performance of research for NovaCardia does not represent a guarantee of, or imply (i) access to, or endorsement by Duke: (ii) inclusion of product(s) on the preferred drug list;
or (iii) access to DUMC's patients or providers. 

3

 

Introduction  

        The DCRI is pleased to present NovaCardia with this proposal revision for research activities in support of the CKI-301 and CKI-302
parallel studies entitled, "A randomized, double-blind, placebo-controlled study of the effects of KW-3902IV on clinical outcomes of patients with congestive heart
failure and renal impairment who require hospital treatment with intravenous loop diuretics for fluid overload." These research activities include Faculty Leadership, Project
Management, Site Management and Monitoring, Safety Surveillance, Website Creation and Maintenance, Data Management, Statistical activities including the creation and management of a Data Monitoring
Committee (DMC), select Clinical Events Classification Management (CEC) activities, and Medical Writing activities. 

        This
project budget is based on information received to date from Leeanne Pearson and Howard Dittrich of NovaCardia; including ongoing discussions with Howard Dittrich, NovaCardia
comments on the DCRI Proposal dated May 5th, 2006, and the original RFP and a protocol summary for the phase III project received on October 14th, 2005. In
addition, the DCRI faculty and staff have discussed operational parameters for this trial to formulate a cost estimate for this important project. 

Project Summary

Protect I & II Budget Revisions  

        The revised project budget includes the following changes. 

	•
	The
Estimated Study Timeline has been adjusted to show:

	•
	The
Study Start-Up Activities Begin at DCRI date is changed from 05 March 2006 to 01 May 2006

	•
	The
First Subject Enrolled date is changed from 04 July 2006 to 04 August 06

	•
	These
timeline changes reduce the Start-up activities period by one month, from four months to three months

	•
	The
Last Subject Ends Follow-up is changed from [. . .***. . .] to
[. . .***. . .]

	•
	This
timeline change increases the patient accrual period by [. . .***. . .], from
[. . .***. . .] to [. . .***. . .].

	•
	The
All Sites Closed period of [. . .***. . .] is removed from the chronological timeline. Sites
will be closed in conjunction with the other closeout activities. 

        These
changes increase the overall project timeline from [. . .***. . .] to
[. . .***. . .]. Please see Estimated Study Timeline with revisions below. 

	Estimated Study Timeline
 

	General Study Milestones
 
	 	Original Date
	 	Revised Date

	Letter Of Intent Signature (For Study Planning Tasks)	 	December 2005	 	December 2005
	Study Start-Up Activities Begin at DCRI	 	05 March 2006	 	01 May 2006
	First Subject Enrolled	 	04 July 2006	 	04 August 2006
	Last Subject Ends Follow-up	 	[. . .***. . .]	 	[. . .***. . .]
	Last CRF in-house, Database Locked	 	[. . .***. . .]	 	[. . .***. . .]
	All Sites Closed	 	[. . .***. . .]	 	[. . .***. . .]
	Statistical Reporting Completed	 	[. . .***. . .]	 	[. . .***. . .]
	Final Study Report Completed	 	[. . .***. . .]	 	[. . .***. . .]
	 	Estimated Total Project Duration	 	[. . .***. . .]	 	[. . .***. . .]

***Confidential Treatment Requested

4

 

	•
	The
level of effort involved in In-house Site Management and Faculty Thought Leadership has been reduced which is shown in decreased fees in both total and unit
costs in these line items.

	•
	The
number of internal team meetings and the number of teleconferences with NovaCardia are each increased from
[. . .***. . .] to [. . .***. . .] due to the
increased project timeline.

	•
	The
level of effort involved in line items, "Project Management & Administration", "Clinical Helpline", has been adjusted to reflect the same level of effort over the
longer period of time, thus you will note a lower monthly (average) unit cost in these cases.

	•
	In
addition, line items show a modest inflationary increase due to the shift in timelines further into the future. However, the total project budget is decreased.

	•
	The
number of DCRI attendees at the three Non-North American investigator meetings has been reduced from the entire project team attending to two investigators
and the project leader in attendance. This shows a decrease in the line item Investigator meetings for both DCRI labor and estimated pass-through expenses.

	•
	Text
is included to note that some study coordinator teleconferences may be replaced by sponsor web casts, web cast fees to be paid by NovaCardia, and that only study
coordinator
teleconferences that occur will be invoiced. Time for DCRI participation in sponsor web casts is not included in the project budget. No change is made to the project budget.

	•
	'Vaccine'
is replaced with 'Drug'. No change is made to the project budget.

	•
	Shipping
charges will be made to the DCRI account and passed through to NovaCardia. The estimated shipping fees remain in the project budget. The actual shipping fees plus
[. . .***. . .]% overhead fee will be invoiced to NovaCardia.

	•
	Line
items to the project budget summary have been added to show per trip travel estimates and maintenance effort by month for the following activities:

	•
	Evaluation,
Initiation and Interim Monitoring visits

	•
	Clinical
Database Creation

	•
	Clinical
Database Maintenance

	•
	Query
Programming

	•
	Query
Maintenance

	•
	Website
Development

	•
	Website
Maintenance

	•
	Develop
Randomization Scheme

	•
	Maintain
Randomization Scheme

	•
	IVRS
Randomization 

***Confidential Treatment Requested

5

   Budget Summary  

        The estimated Project Fees are shown in the summary below. Our estimate assumes that we will follow DCRI standard operating procedures and includes estimated
pass-through costs for travel, IVRS fees, IRB fees, Central Laboratory fees, shipping fees, and the project-specific Clinical Help Line. The estimated investigator payments, Hesperion, and
Outcomes fees are also included. Our project estimate depends primarily on the finalized protocols and operational plan from which we develop our project specifications and assumptions. Should the
project specifications and assumptions described in this document change, we may revise our estimate as needed pursuant to such changes. The Project Fees and Expenses are further detailed in the Cost
Estimate Section of this document. 

	 
	 	DCRI Fees
	 	Hesperion

Fees
	 	Estimated

Pass Through

Expenses

Total
	 	Investigator

Payments

Total
	 	Grand Total

	Global Activities	 	$	[. . .***. . .]	 	$	[. . .***. . .]	 	$	[. . .***. . .]	 	$	[. . .***. . .]	 	$	28,716,239

***Confidential Treatment Requested

6

 

Study Specifications and Assumptions  

Trial Specifications  

        The following specifications were used to generate our estimate for the trial. As previously stated, changes in the specifications and scope of work will result
in revisions of the project budget. 

	Trial Specifications
 

	Description
 
	 	Number

	Number of Patients Screened/Enrolled/Completed	 	1520/1520/1520
	Number of Sites	 	160
	Location of Sites	 	[. . .***. . .] in North America
	Location of Sites	 	[. . .***. . .] in Europe, [. . .***. . .] in Israel
	Length of Start-up Period	 	[. . .***. . .] Months
	Length of Enrollment Period	 	[. . .***. . .] Months
	Length of Treatment & Follow-up Period	 	[. . .***. . .] Months
	Length of Closeout Period	 	[. . .***. . .] Months
	Length of Total Timeline	 	=[. . .***. . .] Months
	Number of Site Evaluation Visits NA/EU/I	 	[. . .***. . .] Visits
	Number of Site Evaluation Calls NA/EU/I	 	[. . .***. . .] Visits
	Number of Site Initiation Visits NA/EU/I	 	[. . .***. . .] Visits
	Number of Interim Site Monitoring Visits NA/EU/Israel	 	NA, [. . .***. . .] 1-Day On-site Visits

EU, [. . .***. . .] 1-Day On-site Visits

Israel, [. . .***. . .] 1-Day On-site Visits
	Number of Site Audits	 	3/2/1 Site Audits
	Number of Site Closeout Visits NA/EU/I	 	[. . .***. . .] Visits
	Number of Investigator Meetings	 	4,

1 in United States

1 in Europe

1 in Israel

1 in Russia
	Number of Unique CRF Pages, Number of Total CRF Pages per Completed Patient	 	[. . .***. . .] Unique, [. . .***. . .] Total Pages Per Completed Patient Collected (Including Safety and CEC Pages)
	Number of DMC Meetings	 	[. . .***. . .] in Person, (Including [. . .***. . .] to Prepare charter) and [. . .***. . .] Teleconferences
	Number of DMC Analyses	 	[. . .***. . .]
	Number of SAS Data Transfers to Sponsor	 	1 Final Database Transfer Which will Include a Test Transfer
	Number of Tables, Figures & Listings (TFLs) for DMC and Final Analyses	 	83 Total TFLs,

45 Tables, 8 Figures, and 30 Listings

***Confidential Treatment Requested

7

   Estimated Study Timeline  

        The study timeline detailed in the table below are based on information provided by NovaCardia. Costs associated with the study are estimated based on the
information presented in the timeline below. Please note that the DCRI looks forward to discussing and revising the estimated study timeline as needed with NovaCardia should operational plans change. 

	Estimated Study Timeline
 

	General Study Milestones
 
	 	Date

	Letter Of Intent Signature	 	December 2005
	Study Activities Begin at DCRI	 	01 May 2006
	First Subject Enrolled	 	04 August 2006
	Last Subject Ends Follow-up	 	[. . .***. . .]
	Last CRF in-house, Database Locked	 	[. . .***. . .]
	All Sites Closed	 	[. . .***. . .]
	Statistical Reporting Completed	 	[. . .***. . .]
	Final Study Report Completed	 	[. . .***. . .]
	 	Estimated Total Project Duration	 	[. . .***. . .] Months

Task Responsibility Grid  

        The grid below represents DCRI's understanding of the tasks that the DCRI will provide to NovaCardia. An "X" in either column denotes responsibility for
completion of the task. An "X" in both columns denotes shared responsibility for completion of the task. Any tasks that are not named or included in the grid are assumed to be the responsibility of
NovaCardia or their designee. 

        NovaCardia
has the ultimate authority and responsibility for this project. If selected, the DCRI will provide these project-specific activities to NovaCardia, all of which will be
subject to NovaCardia's approval and pursuant to NovaCardia's instructions. 

	Task Responsibility Grid

	Task
 
	 	NovaCardia

or Designee
	 	DCRI

or Designee

	Project Startup
	Distribute approved protocol to sites	 	 	 	X
	Identify investigative sites	 	 	 	X
	Select investigative sites	 	 	 	X
	Approve selected investigative sites	 	X	 	 
	Negotiate site budget and contract with investigative sites	 	 	 	X
	Collect regulatory documents from investigative sites	 	 	 	X

***Confidential Treatment Requested

8

 

	Task Responsibility Grid

	Task
 
	 	NovaCardia

or Designee
	 	DCRI

or Designee

	Assist sites with obtaining IRB regulatory approval (NA sites)	 	 	 	X
	Establish clinical trial insurances for participating countries	 	X	 	 
	Identify and select central IRB (US)	 	 	 	X
	Approve selected central IRB (US)	 	X	 	 
	Identify and select central laboratory	 	 	 	X
	Approve selected central laboratory	 	X	 	 
	Identify and select IVRS vendor	 	 	 	X
	Approve selected IVRS vendor	 	X	 	 
	Identify and select drug labeling and distribution vendor	 	X	 	 
	Approve selected drug labeling and distribution vendor	 	X	 	 
	Design CRF and instructions template	 	 	 	X
	Review and comment CRF and instructions template	 	X	 	X
	Approve CRF and instructions template	 	X	 	 
	Design informed consent template	 	X	 	X
	Approve informed consent template	 	X	 	 
	Provide certified translations of study documents (Hesperion)	 	 	 	X
	Distribute study documents including CRFs, CRF instructions, enrollment materials, and regulatory binders	 	 	 	X
	Prepare and conduct one 1/2-day CRA training to be held in conjunction with the investigator meetings	 	 	 	X
	Additional Study Materials
	Design, produce, and distribute all in-service materials	 	 	 	X
	Website Development and Maintenance	 	 	 	 
	Design Website for viewing by all study personnel	 	 	 	X
	Provide Website security and maintenance	 	 	 	X
	Investigator Meetings
	Organize and attend investigators meetings	 	X	 	X
	Design, produce, and distribute meeting materials	 	 	 	X
	Prepare and maintain attendance records	 	 	 	X
	Provide medical and scientific project relevant presentations	 	X	 	 
	Provide CRF and data management overview training at investigator's meetings	 	 	 	X
	Project Management
	Organize, prepare, and participate in regularly scheduled project teleconferences	 	X	 	X
	Organize, prepare, and participate in regularly scheduled project face-to-face meetings	 	X	 	X
	Organize, prepare, and manage study coordinator's teleconferences (10)	 	 	 	X

9

 

	Task Responsibility Grid

	Task
 
	 	NovaCardia

or Designee
	 	DCRI

or Designee

	Administer investigator grants	 	 	 	X
	Manage and administer payments to central IRB (US)	 	 	 	X
	Manage and administer payments to central Lab	 	 	 	X
	Manage and administer payments to IVRS vendor	 	 	 	X
	Manage Hesperion	 	 	 	X
	Manage and administer payments to drug distribution vendor	 	X	 	 
	Manage project team	 	 	 	X
	Provide project status reports	 	 	 	X
	Site Management
	Setup, maintain, and archive central files	 	 	 	X
	Manage & track non-clinical supplies (as specified in assumptions) to sites	 	 	 	X
	Create and maintain patient enrollment tracking tool	 	 	 	X
	Perform routine phone contact with study sites	 	 	 	X
	Provide study training of investigational site personnel according to approved monitoring plan	 	 	 	X
	Provide copies of Investigator and regulatory files to NovaCardia	 	 	 	X
	Assist with query resolution	 	 	 	X
	Site Monitoring
	Develop monitoring plan	 	 	 	X
	Approve monitoring plan	 	X	 	 
	Conduct site evaluation visits	 	X	 	X
	Conduct site evaluation telephone calls	 	 	 	X
	Prepare site evaluation reports and follow up letters	 	 	 	X
	Conduct site initiation visits	 	X	 	X
	Prepare site initiation visit reports and follow up letters	 	 	 	X
	Conduct interim site monitoring visits	 	 	 	X
	Prepare interim site monitoring visit reports and follow up letters	 	 	 	X
	Conduct site closeout visits	 	 	 	X
	Prepare site closeout visit reports and follow up letters	 	 	 	X
	Provide copies of monitoring reports and follow-up letters to NovaCardia with the monthly status reports	 	 	 	X
	Safety Surveillance and Medical Monitoring
	Create safety monitoring plan	 	 	 	X
	Collect and review SAE data	 	 	 	X
	Database SAEs (DCRI database)	 	 	 	X
	Provide SAE tracking logs and copy of SAE reports to NovaCardia regularly	 	 	 	X
	Prepare SAE narratives	 	 	 	X

10

 

	Task Responsibility Grid

	Task
 
	 	NovaCardia

or Designee
	 	DCRI

or Designee

	Prepare IND safety reports	 	 	 	X
	Submit safety reports to FDA	 	X	 	 
	Submit safety reports to Ex-US regulatory authorities	 	 	 	X
	Review patient safety data listings	 	X	 	X
	Data Management and Surveillance
	Provide data management plan	 	 	 	X
	Review data management plan	 	X	 	 
	Develop data transfer specifications for the central laboratory	 	 	 	X
	Design database specifications for clinical data	 	 	 	X
	Program project specific reports	 	 	 	X
	Approve data management plan and database specifications	 	X	 	 
	Provide data entry	 	 	 	X
	Provide query resolution	 	 	 	X
	Specify which coding dictionaries to be used	 	X	 	 
	Perform manual coding of adverse events, concomitant medications, concurrent diseases	 	 	 	X
	Receive electronic data files from central laboratory	 	 	 	X
	Receive electronic data files from IVRS	 	 	 	X
	Reconcile data transfers	 	 	 	X
	Design QA checks data cleaning & database lock	 	 	 	X
	Approve QA checks data cleaning & database lock.	 	X	 	 
	Quality Assurance	 	 	 	 
	Conduct site audits	 	X	 	X
	Audit database	 	 	 	X
	Audit trial master file	 	X	 	X
	Audit clinical study report	 	 	 	X
	Respond to audits by Novacardia	 	 	 	X
	Statistics
	Provide statistical review of protocol design	 	 	 	X
	Develop statistical analysis plan (SAP)	 	 	 	X
	Approve SAP	 	X	 	 
	Develop and maintain randomization scheme	 	 	 	X
	Approve randomization scheme	 	X	 	 
	Develop analysis file specifications	 	 	 	X
	Program and validate SAS analysis files	 	 	 	X
	Program, validate, and review tables, figures, and listings	 	 	 	X
	Produce final statistical analysis report	 	 	 	X
	Approve statistical report	 	X	 	 
	Archive project-specific SAS analysis files & SAS programs	 	 	 	X
	Select DMC members	 	X	 	 
	Approve DMC members	 	X	 	 

11

 

	Task Responsibility Grid

	Task
 
	 	NovaCardia

or Designee
	 	DCRI

or Designee

	Develop DMC Charter and analysis plan	 	 	 	X
	Develop and program DMC, table, figure, and listing shells	 	 	 	X
	Finalize DMC table, figure, and listing shells	 	 	 	X
	Review and approve DMC tables, figures, listings shells	 	X	 	 
	Prepare DMC reports	 	 	 	X
	Organize DMC meetings and teleconferences	 	 	 	X
	Attend DMC meetings and teleconferences as appropriate	 	 	 	X
	Approve SAS dataset transfer specifications	 	X	 	 
	Transfer DCRI SAS database to NovaCardia	 	 	 	X
	Provide all study documents to NovaCardia in electronic form	 	 	 	X
	Clinical Events Committee
	Develop CEC review forms	 	 	 	X
	Develop CEC CRF pages	 	 	 	X
	Identify CEC reviewers	 	X	 	X
	Contract with event reviewers to adjudicate events	 	 	 	X
	Administer payments to event reviewers	 	 	 	X
	Identify event triggers	 	 	 	X
	Work with data management to program database	 	 	 	X
	Event adjudication management	 	 	 	X
	Track events and event adjudication processing	 	 	 	X
	Clinical Study Report (CSR)
	Prepare annotated outline of CSR	 	 	 	X
	Review annotated outline of CSR	 	X	 	X
	Complete CSR with data from SAS files	 	 	 	X
	Review CSR with subsequent revisions	 	X	 	X
	Approve final CSR	 	X	 	 
	Manuscript
	Prepare manuscript	 	 	 	X
	Review manuscript	 	X	 	X

Study Assumptions  

        Below are the assumptions used by the DCRI faculty and staff to define the DCRI tasks for the CKI-301-302 protocols. Any task assumption
not mentioned is understood to be provided by NovaCardia or their designee. The cost associated with the performance of these tasks is detailed in the Cost Estimate Section of this document. 

12

  

 
 

Project Protocols    
    

	1.
	The DCRI will maintain version control and will submit revised protocols to the central IRB and provide revised protocols to the
investigative sites for submission to their local IRBs and to Hesperion for appropriate distribution and submissions. 

Site Selection and Start up  

	2.
	The DCRI will identify potential investigative sites, administer, compile, and review screening questionnaires via telephone and or fax,
and qualify potential investigative sites for participation in the trial. The DCRI will provide the list of investigative sites qualified to NovaCardia for review. NovaCardia will approve the
investigative sites selected to participate in the trial.

	3.
	The DCRI will execute confidentiality agreements with the interested sites prior to distributing the protocol, investigator's brochure,
and informed consent templates. The DCRI will use its standard confidentiality agreement template. All templates will be pre-approved by NovaCardia.

	4.
	The DCRI will conduct [. . .***. . .] on-site
evaluations visits to North American (NA) sites to verify site facilities and personnel for conducting the trial. These visits will include eight hours of travel, four hours on site, and four hours
for preparation and follow-up activities per visit. Hesperion will conduct [. . .***. . .] site evaluation
visits to European (EU) sites, these visits will include eight hours of travel, four hours on site, and four hours for preparation and follow-up activities per visit. Hesperion will also
conduct [. . .***. . .] site evaluation visits to sites in Israel (I). These visits will include four hours of travel, four
hours on site, and four hours for preparation and follow-up activities per visit.

	5.
	The DCRI will perform [. . .***. . .] site evaluation
telephone calls to NA sites. These calls will include two hours on the phone with site personnel and four hours for preparation and follow-up activities per call. Hesperion will conduct
[. . .***. . .] site evaluation calls to EU sites and
[. . .***. . .] site evaluation calls to I sites.

	6.
	The DCRI and Hesperion will prepare evaluation visit and call reports and follow-up letters The DCRI will review and provide
copies to NovaCardia.

	7.
	The DCRI will negotiate site budgets and contract with the
[. . .***. . .] NA sites selected for participation in the trial using NovaCardia pre-approved DCRI contract
templates. Hesperion will negotiate site budgets and contract with the [. . .***. . .] EU sites and
[. . .***. . .] I sites.

	8.
	NovaCardia will provide all site payment monies to the DCRI for the NA sites for deposit in a 'draw down account' so that the DCRI
remains in a 'cash neutral' position. The DCRI will prepare and present estimated site payment 'future needs' reports to NovaCardia who will replenish the site payment account as needed.

	9.
	The DCRI will collect, review, and verify completeness and accuracy of regulatory documents from the NA investigative sites. Hesperion
will collect, review, and verify completeness and accuracy of regulatory documents from the Non-NA investigative sites.

	10.
	The DCRI will assist the sites with obtaining IRB committee regulatory approval.

	11.
	Hesperion will establish clinical trial insurances for participating countries and will provide assistance with those sites in
obtaining Ethics Committee's regulatory approval. 

***Confidential Treatment Requested  

13

 
	12.
	The DCRI will identify and select a central IRB for the NA sites. NovaCardia will approve the selected IRB.

	13.
	The DCRI will identify an select a central laboratory (ICON). NovaCardia will approve the selected central laboratory.

	14.
	The DCRI will identify and select an IVRS vendor (ICTI). NovaCardia will approve the selected IVRS vendor.

	15.
	NovaCardia will identify, select, and administer payments to a drug labeling and distribution vendor. The DCRI will review drug
labeling. Hesperion will assist in label translations. DCRI will monitor drug supply. NovaCardia will approve initial drug shipments. 

CRF Development  

	16.
	The DCRI will design the CRF, which will include the data points, CEC, and SAE collection pages, and the CRF completion instructions.

	17.
	The DCRI assumes DCRI CRF templates will be used. Templated materials include demographics data, clinical laboratory panels,
concomitant medications, and adverse events assessments.

	18.
	NovaCardia will review the CRF design. The DCRI will coordinate and manage CRF design review and changes, assuming up to three rounds
of review. NovaCardia will approve the CRF design.

	19.
	DCRI will create the CRF pages and the CRF completion instructions. The DCRI assumes that
[. . .***. . .] of the CRF pages will be unique, and, including safety and CEC entry pages, a maximum of
[. . .***. . .] pages per completed patient.

	20.
	The DCRI will distribute the CRF and the CRF completion instructions to the investigative sites. 

Informed Consent Template Development  

	21.
	NovaCardia will design the informed consent template and finalize it with input from the DCRI and Hesperion. This template will meet
the informed consent form requirements set forth in 21 CFR Part 50.25, in the International Conference on Harmonization Guidelines for Good Clinical Practice, Section 4.8. The DCRI will
coordinate and manage informed consent template design review and changes, assuming up to two rounds of review.

	22.
	The DCRI will distribute the informed consent template to the investigative sites. 

Other Study Documents  

	23.
	The DCRI will design, produce, and distribute all in-service materials. These materials include: enrollment materials,
manual of operations, site regulatory binders, and site recruitment aids.

	24.
	Hesperion will provide certified translations of study documents. 

Study Website Development  

	25.
	The DCRI will design a study specific website for viewing by all study personnel.

	26.
	The DCRI will provide website security.

	27.
	The DCRI will maintain the study website over the life of the project. 

***Confidential Treatment Requested  

14

 
 Investigator Meetings  

	28.
	NovaCardia will hold four, two-day investigator meetings, one in Europe, one in North America, one in Israel or Cypress,
and one in Russia. The DCRI attendees will include [. . .***. . .]
and[. . .***. . .], the Project Leader, the Senior Statistician, the Data Manager, Safety Surveillance, CEC, and Site
Management team members for the meeting in North America. [. . .***. . .],
[. . .***. . .], and [. . .***. . .] will attend
also attend the other three meetings. The DCRI will prepare and present training discussions on the CRF and data handling at the meetings at the NA meeting.

	29.
	The DCRI will design, with input from NovaCardia, produce, and distribute the investigator meeting agendas, invitations, and meeting
binders, and will prepare the meeting attendance records.

	30.
	NovaCardia will provide medial and scientific project relevant presentations at the meetings.

	31.
	The DCRI will contract with an experienced vendor for meeting planning services such as space, travel food, lodging etc. The DCRI will
organize and conduct all the meetings. 

Clinical Leadership  

	32.
	[. . .***. . .] and
[. . .***. . .] will provide overall clinical leadership for the coordinating center. This will include clinical guidance
and consultation to project team members, the various Committees, the laboratory, and NovaCardia. They will attend team meetings, provide input on CRF and query development, present at the
investigator training meetings, act as a resource for the operations team, oversee the Clinical Helpline, provide input on the Clinical Study Report and develop the study manuscript. 

Project Management  

	33.
	One individual from the DCRI, the Project Leader
[. . .***. . .], and one individual from NovaCardia will be identified as the primary operational contacts.

	34.
	The DCRI will provide project leadership for
[. . .***. . .] months. The DCRI Project Leader will monitor and verify that work carried out is in accordance with Good
Clinical Practice (GCP) and complies with FDA requirements.

	35.
	The DCRI will participate in regularly scheduled teleconferences with NovaCardia.

	36.
	The DCRI will conduct regular internal team meetings to review project progress, resolve project-specific issues, and disseminate
project information.

	37.
	The DCRI will conduct ten, hour-long teleconferences with site study coordinators to review project progress, resolve
project-specific issues, and disseminate project information. The coordinators will be encouraged to share project-related successes. A sponsor web-cast may take the place of several of
these teleconferences, only study coordinator teleconferences that take place will be invoiced to NovaCardia.

	38.
	The DCRI assumes that all project work will be conducted according to DCRI SOPs.

	39.
	The DCRI will manage and administer payments to the central IRB (NA), the central laboratory, and the IVRS vendor.

	40.
	The DCRI will manage and administer payments to the NA investigative sites.

	41.
	The DCRI will manage Hesperion's project team and will review Hesperion invoices, NovaCardia will administer payments to Hesperion. 

***Confidential Treatment Requested  

15

 
	42.
	NovaCardia will provide investigator fees directly to Hesperion to administer investigator payments to the European and Israeli sites.

	43.
	The DCRI will plan, manage, and oversee project costs and schedules, including the identification of potential out of scope work before
it is performed for the contracted activities, and provide regular project status reports to NovaCardia. 

Site Management  

	44.
	The DCRI will prepare an Investigator and Regulatory file according to the DCRI SOPs for each of the NA sites participating in this
study. These files will contain all relevant study documentation that serves to demonstrate compliance with GCP and with all regulatory requirements and will include but may not be limited to: 

Form
FDA 1572

CV (including appropriate documentation of licensure) for the Investigator and Sub investigator)

Protocol signature page

Financial Disclosure Information

IRB membership lists or IRN assurances

IRB submission letter for investigator brochure and safety letter

IRB approved informed consent form

IRB approval letter (for protocol and informed consent form)

Laboratory certifications 

	45.
	Hesperion will create and maintain site study files for the European and Israeli sites.

	46.
	The DCRI will maintain these project files until study completion, and then will archive or transfer them to NovaCardia.

	47.
	The DCRI will manage and track the distribution of non-clinical supplies to the investigative sites.

	48.
	The DCRI will create and maintain a patient enrollment tracking tool with input from the IVRS.

	49.
	The DCRI will perform routine phone contact with the NA study sites to discuss study status and answer questions. Hesperion will
perform routine phone contact with the Non-NA study sites to discuss study status and answer questions.

	50.
	The DCRI will provide project specific training for the investigative sites via the investigator meetings, site initiation visits, and
regular telephone contact.

	51.
	The DCRI will provide originals of investigator and regulatory files to NovaCardia.

	52.
	The DCRI site management team will assist with NA sites query resolution. 

Site Monitoring  

	53.
	The DCRI will develop a monitoring plan with input from NovaCardia. NovaCardia will approve the monitoring plan. The DCRI will maintain
and follow the approved site monitoring plan.

	54.
	The DCRI will conduct [. . .***. . .] on-site
initiation visits at the NA sites. Each of these on-site initiation visits will include eight hours of travel, six hours on-site, and four hours for preparation and follow up
activities. Hesperion will conduct [. . .***. . .] on-site initiation visits at the 

***Confidential Treatment Requested  

16

 

EU
sites, each of these on-site initiation visits will include eight hours of travel, four hours on-site, and four hours for preparation and follow up activities. Hesperion
will also conduct [. . .***. . .] on-site initiation visits at the Israeli sites. Each of these
on-site initiation visits will include four hours of travel, four hours on-site, and four hours for preparation and follow up activities 

	55.
	The on-site initiation visits will include a review of the sites facilities and personnel, the protocol activities, and
will verify the site's readiness to begin screening patients for participation in the trial.

	56.
	The DCRI will prepare on-site initiation visit reports and follow up letters using the DCRI standard formats and will
provide copies to NovaCardia.

	57.
	The follow-up letters will include a summary of visit discussions, identification of action items and their resolution,
request(s) for outstanding documentation, etc., in accordance with the DCRI SOPs.

	58.
	The DCRI will conduct [. . .***. . .] interim site
monitoring visits at the [. . .***. . .] NA sites, an average of five per site, based on enrollment at the sites. Each of
these interim monitoring visits will include eight hour of travel, eight hours on site, and four hours of preparation and follow up activities. Hesperion will conduct
[. . .***. . .] interim site monitoring visits at the
[. . .***. . .] EU sites, an average of eight per site, based on enrollment at the sites. Each of these interim monitoring
visit wills include eight hours of travel, eight hours on site, and four hours of preparation and follow up activities. Hesperion will conduct
[. . .***. . .] interim site monitoring visits at the
[. . .***. . .] Isreali sites, an average of eight per site, based on enrollment at the sites. Each of these interim
monitoring visit wills include four hours of travel, 8 hours on site, and four hours of preparation and follow up activities.

	59.
	100% verification of critical variables as identified in the monitoring plan will be performed during the on-site
monitoring visits.

	60.
	The DCRI will provide interim monitoring visit reports and associated follow-up letters to NovaCardia.

	61.
	Monitoring visit preparation may include, but not be limited to, the following:

	(a)
	Determination of outstanding data and/or regulatory issues.

	(b)
	Site contact to schedule and review planned on-site monitoring activities.

	(c)
	Identification of other action items to be addressed while on-site.

 

	62.
	Periodic monitoring visits will include a review of patient records, CRFs, and other study related documentation. Site Monitors will be
responsible for the following:

	(a)
	Conducting drug accountability audits.

	(b)
	Monitoring of SAEs. Site Monitors will monitor SAEs for those participating sites scheduled for a monitoring visit and also document,
forward, and/or investigate any verbal report of an SAE.

	(c)
	Performing 100% Source Document Verification (SDV) of the ICFs, 100% verification of critical variables as identified in the monitoring
plan, and reportable SAEs on all randomized and treated subjects according to the Monitoring Plan.

	(d)
	Reviewing CRFs for accuracy and completeness of information, legibility, missing data including omission of specific individual data
elements and any concomitant drugs, intercurrent illness, serious adverse events, missing patient visits or examinations, and other pertinent items pursuant to the Protocol, and compatibility with
source documents. 

***Confidential Treatment Requested  

17

  

	(e)
	Verifying the investigator or an appropriate designee's review of the CRFs.

	(f)
	The DCRI monitor will prepare visit reports and follow-up letters after each routine monitoring visit. The DCRI will review
and approve all visit reports and follow-up letters. NovaCardia will be sent approved site visit reports and follow-up letters.

 

	63.
	The Monitors will assist the investigative sites in resolving data discrepancies as identified by Source Document Verification or
Clinical Data Management procedures.

	64.
	The DCRI will conduct three on-site audits at sites. An audit report will be prepared and forwarded to NovaCardia and the
DCRI project team for each audit. The DCRI project team will assist the audited sites with resolution of any audit findings.

	65.
	The DCRI will conduct [. . .***. . .] on-site
closeout visits at the NA sites. Each closeout visit will include eight hours of travel, eight hours on-site, four hours for preparation and follow up activities. Hesperion will conduct
[. . .***. . .] on-site closeout visits at the European sites. Each closeout visit will include eight hours of
travel, six hours on-site, four hours for preparation and follow up activities. Hesperion will conduct
[. . .***. . .] on-site closeout visits at the Israeli sites. Each closeout visit will include four hours of
travel, six hours on-site, four hours for preparation and follow up activities.

	66.
	Site closeout activities will include:

	(a)
	Final review, inventory, and collection of outstanding data.

	(b)
	Final review, inventory, and return unused supplies and study drug to NovaCardia or its designated vendor within five business days of
the study close out visit.

	(c)
	Final review, inventory, and archival requirements of study files.

	(d)
	Final review and resolution of any outstanding action items.

	(e)
	Complete and forward a detailed close out summary letter outlining pertinent details discussed and agreed upon action to the
investigator.

 

	67.
	The DCRI monitor will document close out activities by written reports and follow-up letters after trip return. NovaCardia
will be provided with approved reports and letters. 

Data Management  

	68.
	The DCRI will provide a lead Data Manager (Clinical Data Specialist) who will be responsible for overseeing data processing activities.

	69.
	The DCRI will develop a data management plan. This plan will comply with the ICH GCPs and FDA regulations. The data management plan
will detail the data validation plan, data management guidelines-data retrieval processes, CRF handling, and data entry instructions and conventions which will include the override
guidelines.

	70.
	The DCRI will create an annotated CRF. Database structure, field names, and data types will be specified on the annotated CRF following
the DCRI standards whenever possible. The DCRI will provide these specifications to NovaCardia for approval and sign-off prior to programming.

	71.
	The DCRI will develop data validation check specifications and the DCRI will program, test, and edit them.

	72.
	The DCRI will provide Validation Reports to NovaCardia. 

***Confidential Treatment Requested  

18

 
	73.
	NovaCardia will approve the clinical and laboratory database specifications for the project.

	74.
	The DCRI will create one study database in ClintrialTM 4.4, including designing and programming data entry screens, and
programming the database to receive core lab data.

	75.
	DCRI will program a total of 170 queries or programmed validations. Any increase change to the number of programmed queries may be
considered a change in scope.

	76.
	A total of 46,200 pages will require data entry and query resolution. Screen failure data will not be data-entered and
queried.

	77.
	A maximum of 2 CRF submissions per patient is assumed.

	78.
	The monitor will pick up completed CRFs to deliver to the DCRI. A copy of the CRF and all data changes will be maintained at the
clinical sites. DCRI's overnight courier account number for CRF shipping will be used. Some sites, chosen by NovaCardia and the DCRI, may be notified to overnight completed but not monitored CRF pages
directly to the DCRI.

	79.
	All study-related submissions will be directed to a central location. Document handling will include, but may not be limited to, the
following:

	(a)
	Creating patient-specific file folders

	(b)
	Distributing folders for data entry

	(c)
	Providing overall security of project documents

 

	80.
	The DCRI will review the CRFs prior to data entry and confirm that all pages have been received for data entry. Preparation for data
entry will follow this review in accordance with the DCRI SOPs and standards.

	81.
	The DCRI will perform data entry using independent, double-key data entry methods in accordance with the DCRI SOPs and
standards. The DCRI will enter the data twice, with each entry performed by a different data technician.

	82.
	All CRFs data entered into the database will be supported and logged with system generated audit trails. These audit trails will remain
as a part of the final clean study database.

	83.
	The DCRI will generate the queries electronically by patient.

	84.
	The DCRI will enter data and review the CRF for discrepancies. Discrepancies will be handled as described in the Discrepancy Management
Work Instructions. The Discrepancy Management Work Instructions will be developed with input from NovaCardia and the project team.

	85.
	The DCRI and NovaCardia will review data listings on an ongoing basis to monitor data entry quality and data processing guideline
adherence.

	86.
	The DCRI will enter computer-generated and manually-generated query replies into the database.

	87.
	The DCRI will track queries and distribute reports about query status (by patient and overall) via weekly/monthly project status
reporting.

	88.
	The DCRI will identify and distribute information concerning highly queried items to site management clinical operations (who
distributes to the applicable CRA(s)) and communicate trends to NovaCardia. 

19

 
	89.
	The DCRI will be responsible for manual medical coding. An estimate three AE terms, two concomitant medication terms, and two medical
history terms per patient are included for a total of 10,640 terms to be manually coded.

	90.
	The DCRI will provide the coding dictionaries and guidelines for review and approval by NovaCardia. In compliance with DCRI's licensing
agreements, NovaCardia is required to hold current software license(s) for the requested dictionaries (MeDRA) in order for DCRI to provide the coded data to NovaCardia.

	91.
	The DCRI will test and validate coding and provide validation reports to NovaCardia.

	92.
	There will be two external sources of data electronically transferred to the DCRI during the course of the study; a central laboratory
(ICON) and the IVRS vendor (ICTI).

	93.
	The DCRI assumes that the IVRS vendor will transfer IVRS data daily during the enrollment period.

	94.
	The DCRI will develop data transfer specifications for each provider and verify and reconcile all lab data.

	95.
	The DCRI will perform an audit on the database and provide documentation of the results of the audit that is reflected as an error
rate. The audit will include 100% QC of selected key data to be determined by the NovaCardia and DCRI project team and 100% QC of 10% of all CRFs.

	96.
	The DCRI will provide data listings as needed within 24-hours of receipt of the request from NovaCardia or the DMC.

	97.
	The DCRI will lock the database within four-weeks after receipt of the last patient's last follow- up visit CRF pages.

	98.
	The DCRI will perform a final CRF inventory prior to completion of the study to verify that all CRFs have been collected. After
completion of the study, original CRFs will be transmitted to NovaCardia for archival.

	99.
	One data transfer to NovaCardia will be required at the end of the study. This transfer will be in SAS format and generated after final
approved study report. 

Safety Surveillance  

	100.
	All NA investigative sites will report SAE forms directly to the DCRI Safety Surveillance. All other sites will send SAE forms to
Hesperion who will then forward to the DCRI the translated information.

	101.
	The DCRI assumes an SAE rate of approximately
[. . .***. . .]% for a total of [. . .***. . .]
SAEs out of [. . .***. . .] patients enrolled in the study.

	102.
	The DCRI Safety Surveillance will fax SAE forms for those events confirmed to meet SAE reporting criteria to NovaCardia within 1
business day of receipt.

	103.
	The DCRI Safety Surveillance will be responsible for preparing events for reporting to the regulatory authorities by generating a
MedWatch/CIOMS report for those SAEs that are assessed as drug related by the investigator and determined to meet regulatory reporting criteria per DCRI's Medical Safety Monitor. DCRI Regulatory
Services will submit the CIOMS form to Health Canada in accordance with Canadian regulations. NovaCardia will submit IND Safety Reports to the FDA in accordance with 21 CFR 312.32. 

***Confidential Treatment Requested  

20

 
	104.
	Hesperion will be responsible for reporting adverse events to the specific country authorities in accordance with ICH and country specific regulatory
requirements.

	105.
	The DCRI Safety Surveillance will complete an IND Safety Alert letter and forward to DCRI Site Management and Hesperion for
distribution to all participating investigators. The DCRI assumes that [. . .***. . .]% of the reported expedited events for
the study will require reporting to the regulatory authorities for a total of [. . .***. . .] IND Safety Reports for the
study.

	106.
	DCRI Safety Surveillance assumes the investigational sites will be responsible for the following activities:

	•
	Fax
copies of SAE forms to DCRI Safety Surveillance within specified timeframe

	•
	Respond
to queries for additional data/data clarification

	•
	Record
adverse events on Case Report Form (CRF) per protocol

	•
	Inform
site's IRB of adverse events in accordance with IRB guidelines

 

	107.
	The DCRI Safety Surveillance will be responsible for the following activities:

	•
	Participate
in development of adverse event section of protocol

	•
	Write
in-service material for SAE reporting process

	•
	Design
trial-specific SAE reporting plan

	•
	Provide
SAE form and instructions using DCRI standard template

	•
	Write
trial-specific working instructions for SAE form processing using DCRI standard template

	•
	Provide
input on development of adverse event related CRF pages

	•
	Participate
in conference calls and teaching sessions with trial personnel and sites as needed

	•
	Participate
in North American Investigator's Meeting

	•
	Receive
and track SAE forms directly from U.S. and Canadian sites

	•
	Receive
and track international SAE forms received from Hesperion

	•
	Perform
clinical review of all SAE forms to confirm reportability, completeness, consistency, and/or need for further data and/or data clarification

	•
	Follow-up
directly with U.S. and Canadian sites to obtain additional information and/or data clarifications

	•
	Follow-up
with Hesperion to obtain additional information and/or data clarifications for Israel and EU sites

	•
	Write
clinical narratives using DCRI standard template

	•
	Enter
data from SAE forms into Clintrace safety database

	•
	Code
expedited events using the MedDRA dictionary

	•
	Forward
SAE forms (and Medical Monitor regulatory evaluation) to NovaCardia within 1 business day of receipt

	•
	Respond
to NovaCardia's queries for data clarification and/or to obtain additional information from sites

 

	108.
	The DCRI Safety Surveillance will be responsible for the following regulatory reporting activities:

	•
	Obtain
medical monitor review for medical clarity and regulatory reporting criteria

	•
	Generate
MedWatch/CIOMS form

	•
	Perform
analysis of similar events (if applicable)

	•
	Write
Safety Alert Letters for regulatory reportable events 

***Confidential Treatment Requested

21

 

	•
	Submit
MedWatch/CIOMS forms and appropriate reports and line listings to NovaCardia (U.S. submission), DCRI Regulatory Services (Canadian submission), and Hesperion for
review and submission to international regulatory authorities

	•
	Provide
Safety Alert reports to DCRI Site Management to distribute to sites

	•
	Copy
Safety Alert reports to NovaCardia and international regulatory CRO

	•
	Provide
clinical narratives and line listings to DCRI Regulatory for final study report

 

	109.
	The DCRI Safety Surveillance will reconcile Hesperion event tracking with DCRI's Clintrace database and assist with reconciliation of
DCRI's Clintrace safety database with DCRI's clinical database. 

Data Monitoring Committee (DMC)  

	110.
	NovaCardia will identify seven DMC members.

	111.
	After obtaining a CDA from DMC members, the DCRI will send each DMC member the protocol and Investigator Brochure (IB).

	112.
	The DCRI will negotiate agreements and honoraria and will administer payments to seven DMC members.

	113.
	The DCRI senior statistician will develop a draft and a final DMC Charter with input provided by DMC members and the DCRI faculty
statistician including one round of review after a face-to-face meeting with the DMC members. This meeting will be to provide training to the DMC members on the protocol and
the IB and to discuss the DMC Charter.

	114.
	NovaCardia and the DMC members will approve the DMC charter.

	115.
	The DMC will meet twice more face-to-face and twice via teleconference to review the analyses.

	116.
	The DCRI statistician will develop the DMC analysis plan and draft tables and listings.

	117.
	The DCRI statistician will finalize 15 unique tables, four unique figures, and ten unique listings for DMC reports to be reviewed by
the DMC.

	118.
	There will be four DMC analyses prepared for the committee's review. 

Biostatistics  

	119.
	The DCRI's statistical team will review the statistical and DMC sections of the protocol.

	120.
	The DCRI SOPs will be followed in all statistical tasks.

	121.
	The DCRI statistical team will assist in the development of the CRF and will provide oversight of data and programming issues.

	122.
	The DCRI statistics team will provide one randomization scheme and review enrollment data on an ongoing basis.

	123.
	The DCRI statistics team will participate in the selection of critical variables for querying and will review queries that will be
programmed into ClintrialTM.

	124.
	The DCRI statistics team will provide a review of the ClintrialTM database setup and CRF annotation.

	125.
	The DCRI statistics team will develop the Final Statistical Analysis Plan. 

22

  

	126.
	The DCRI statistics team will use descriptive statistics or unadjusted tests of significance for the analysis.

	127.
	DCRI's statistics team will create SAS analysis file specifications and programming for the analyses files to be used in report
generation.

	128.
	DCRI's statistics team will prepare, validate, and review all tables, listings and figures for the final analysis. The final analysis
will include 15 unique and 15 repeat tables, four repeat figures, and 10 unique and 10 repeat listings.

	129.
	NovaCardia will review and approve all tables, listings, and figures for the final analysis. Additional tables, figures or listings
will be considered a change in scope.

	130.
	DCRI's statistics team will see that the database meets the specified quality and completeness criteria, specified by DCRI and
NovaCardia, before it is locked.

	131.
	The DCRI statistics team will produce the final analysis per the final statistical plan.

	132.
	DCRI's statistics team will provide statistical support for the clinical study report.

	133.
	DCRI's statistics team will archive the database.

	134.
	DCRI's statistics team will archive the SAS analysis files, programs, and all reports that are generated throughout the trial.

	135.
	The DCRI statistician will attend all team meetings including teleconferences with NovaCardia.

	136.
	DCRI's statistics team will provide a test data transfer and the final data transfer to NovaCardia in DCRI SAS format with the
appropriate documentation via an FTP site or secure electronic data transfers. 

Clinical Events Classification Management  

	137.
	The DCRI CEC team will work with NovaCardia and the DCRI data management and statistical teams to design event triggers programming,
10 triggered events are assumed.

	138.
	The event triggers will be programmed into the clinical database.

	139.
	The DCRI CEC team will prepare events packets and coordinate independent CEC physician reviews. Four hundred events are assumed.

	140.
	The DCRI CEC team will track the flow of forms received from the sites, reports received from the DCRI, and event packages sent to and
from the reviewers.

	141.
	The DCRI assumes 400 events to be adjudicated.

	142.
	The DCRI CEC team will enter the final adjudication results into the database and will maintain the CEC files.

	143.
	The DCRI will identify, contract with, and pay honorarium to the CEC physician reviewers. 

Medical Writing Clinical Study Report  

	144.
	The DCRI will develop and prepare the final clinical study report (CSR).

	145.
	The DCRI Medical Writer will attend team meetings and teleconferences on an as needed' basis, determined by the DCRI project leader or
at the request of NovaCardia. 

23

 
	146.
	The DCRI Medical Writer will prepare the CSR using a DCRI document template compliant with ICH and FDA guidance, or if preferred, an
appropriate template provided by NovaCardia.

	147.
	Before final data are available, the DCRI Medical Writer will prepare an annotated outline (shell) of the CSR to include title pages,
introductory and study design sections, the proposed format for results presentation, and appendices to the report.

	148.
	DCRI regulatory services, Clinical Cardiology Representatives, the Project Leader, and the Lead Statistician will provide internal
review and comments.

	149.
	The CSR annotated outline will then be sent to NovaCardia for review and comments.

	150.
	Once the SAS display of the final analyses is available, the DCRI Medical Writer will complete the populated draft CSR with
statistical support from the DCRI statistician. A maximum of three review cycles of the draft CSR are assumed.

	151.
	For each review cycle, the draft populated CSR would undergo 1) DCRI internal review initially by the DCRI project team;
2) revisions from DCRI incorporated by the Medical Writer; 3) review by NovaCardia project team members, designated by NovaCardia; 4) NovaCardia reviewers' comments incorporated
by the DCRI Medical Writer.

	152.
	NovaCardia will approve the final CSR.

	153.
	This estimate assumes that the DCRI Medical Writer will generate descriptive content for all endpoints. 

Medical Writing Manuscript  

	154.
	The DCRI will provide a publications manager to work with the project team.

	155.
	The DCRI will prepare one manuscript.

	156.
	NovaCardia will review the manuscript. 

24

   Cost Estimate Protect I & II  

[. . .***. . .]

***Confidential Treatment Requested

25

 

[. . .***. . .]

	Project GRAND TOTAL	 	$[. . .***. . .]	 	$[. . .***. . .]	 	$	28,716,239

        Hesperion
detailed budgets and scope-of-work was included in the June 29th proposal as Attachment 1 and the Outcomes Analysis budget and scope of work were
included as Attachment 2. 

Payment Terms  

        The DCRI will invoice completed units on a monthly basis. The DCRI will also invoice on 30 day projected expenditures for investigator grant payments. All
invoices will be payable by NovaCardia within 30 days of the invoice date. An invoice upon execution of this document for 'upfront' payments will be issued to NovaCardia for the following
amount: 

***Confidential Treatment Requested

26

  

$[. . .***. . .]
Payment July 1, 2006 

$[. . .***. . .]
Payment August 1, 2006 

        The
upfront payments received for fees, estimated pass through expenses, and investigator grants payments will be applied to the final project invoices. Please note that NovaCardia will
pay only actual pass-through expenses as invoiced plus the agreed upon % overhead fee. 

Duration of Proposed Terms  

        The terms described in this proposal are a current statement of the terms upon which the DCRI would be willing to proceed with this project. The terms are subject
to negotiation and execution of a written agreement, which will supersede the contents of this proposal. The terms and conditions contained in this proposal shall remain in effect until
August 2006. After that date, the terms and descriptions may be subject to change. 

Changes to Existing Proposal  

        This proposal is an integrated document. A change to the scope or terms of one portion of the document may result in a change to terms or descriptions contained
in another section, including the fees payable to the DCRI for its activities. All descriptions of activities and the fees included in this proposal are based upon the information received to date
from NovaCardia. If that information changes or an assumption proves to be incorrect based upon changes in the underlying information, certain of the descriptions included in this proposal may change. 

Ultimate Authority  

        NovaCardia has the ultimate authority and responsibility for this project. If selected, the DCRI will provide activities to NovaCardia relative to the study, all
of which will be subject to NovaCardia' approval and pursuant to NovaCardia' instructions. 

***Confidential Treatment Requested

27

 
APPENDIX 3  

 DISCLOSURE OF FINANCIAL INTERESTS AND ARRANGEMENTS  

        As a condition of participating as a clinical investigator in the protocol entitled,
"                        " (the "Study") sponsored by NovaCardia, Inc.
("NovaCardia"), please provide the appropriate information and responses to the following statements. 

	Name:	

	Title:	

	Organization/CRO:	
	 	Date:	

Please
mark the applicable checkboxes. 

	[    ]	None.
	

o	

I have financial arrangement(s) with NovaCardia in which the value of the compensation for conducting the Study could be influenced by the outcome of the Study.
	

o	

I have received or will receive from NovaCardia, previously and during the time of the Study and for one year after its completion, payment(s) of other sorts (e.g., grants to fund other ongoing research, compensation in the form of equipment not for
the Study, retainer for ongoing consultation, or honoraria) that have a monetary value of more than $25,000. Such payment(s) exclude the costs of conducting the Study or other clinical studies.
	

o	

I have any proprietary interest(s) in the product tested in the Study.
	

o	

During the time of the Study and for one year after its completion, I will hold significant equity interest in NovaCardia. "Significant equity interest" means any (1) ownership interest, stock options or other financial interest whose value
cannot be readily determined through reference to public prices; or (2) equity interest in a publicly traded corporation that exceeds $50,000.

        For
those statements I have checked, details of the individual financial arrangements (if any) and interests are attached, along with a description of steps taken to minimize the
potential bias of Study results by any of the disclosed arrangements or interests. 

        NovaCardia
agrees to treat as confidential all financial arrangements and interests attached to this Exhibit and to use such disclosure to meet the requirements placed on NovaCardia
under 21 C.F.R. Part 54. Investigator acknowledges and agrees that NovaCardia may use such disclosure for this purpose. During the time of the Study and for one year after its completion,
Investigator shall notify NovaCardia in writing of any change to the information provided in this Exhibit. 

	

 	
 	

 	
 	

 	
 	

 
	

Signature:	
 	

	
 	

Date:	
 	

28

 
APPENDIX 4  

 PUBLICATIONS COMMITTEE CHARTER  

        The purpose of the Publications Committee pertaining to the Study shall be to further the communication of medical research and scientific data gathered in the
Study. 

        The
composition of the Publications Committee shall be as follows, with NovaCardia selecting its representatives, Duke selecting its representatives and NovaCardia selecting all other
representatives: 

	•
	The
two pivotal study co-chairs

	•
	Two
representatives from Duke University

	•
	The
European principal investigator

	•
	Two
at-large investigators

	•
	Two
representatives from NovaCardia

	•
	Duke
University Statistician (non-voting) 

        Notwithstanding
the foregoing, if the nature of the Study so requires, NovaCardia and Duke may agree to change the composition of the Publications Committee. The co-chairs of
the Publications Committee shall be one pivotal study co-chair and one representative of NovaCardia. NovaCardia may, in consultation with the Study co-chairs, fill any
vacancies on the Publications Committee due to resignations or the removal of members by NovaCardia "for cause". Any replacement will retain the relative academic balance of the Committee. 

        Decisions
of the Publications Committee shall be made by consensus, and there shall be no restrictions on the topics or analytical approaches used in developing manuscripts, other than
those imposed by the Publication Committee. 

        The
Publications Committee will act as an independent body of scientific and medical experts with the following responsibilities: 

        1)    The
Publications Committee shall review and approve analyses suggested by the investigators and participating institutions in the study. 

        2)    The
Publications Committee shall read and constructively critique all manuscripts that result from an approved analysis regarding the Study prior to submission for
presentation or publication. 

        3)    The
Publications Committee shall consider each such manuscript proposal with due regard for the scientific merit of the proposed publication with the aim of promoting the
dissemination of scientific and medical knowledge, and shall vote as to whether each such manuscript is appropriate for publication. 

29

 

        4)    The
Publications Committee shall require that all manuscripts approved by the Publication Committee conform to the Uniform Requirements for Manuscripts Submitted to
Biomedical Journals guidelines of the International Committee of Medical Journal Editors (http://www.icmje.org) (the "Uniform Requirements"). The Publications Committee shall require that all
publications give NovaCardia and NovaCardia's personnel appropriate credit for any direct contribution made by them, and shall acknowledge NovaCardia's support in all publications and presentations. 

        The
Publications Committee shall submit to NovaCardia, at least thirty (30) calendar days prior to submission for publication, each publication which has been approved by the
Publications Committee. If NovaCardia determines that the proposed publication contains patentable subject matter which requires protection, NovaCardia may require the delay of such publication for an
additional period of time not to exceed sixty (60) calendar days for the purpose of filing patent applications. 

30

QuickLinks

Exhibit 10.11

Project ProtocolsQuickLinks
 -- Click here to rapidly navigate through this document
  

 
 

Exhibit 10.12    
    

        ***Text Omitted and Filed Separately

Pursuant to a Confidential Treatment Request

Under C.F.R. §§ 200.80(b)(4) and Rule 406

of the Securities Act of 1933, as amended.  

 LICENSE AGREEMENT  

        This Agreement made and entered into by and between KYOWA HAKKO KOGYO CO., LTD., a Japanese corporation
having its principal offices at 1-6-1 Ohtemachi, Chiyoda-ku, Tokyo, 100-8185, Japan (hereinafter referred to as
"KH") and NOVACARDIA, INC., a Delaware corporation having its principal offices at 12230 El
Camino Real, Suite 300, San Diego, California, 92130, United States of America (hereinafter referred to as "NC"). 

WITNESSETH  

        WHEREAS, KH has developed a certain valuable compound; 

        WHEREAS, KH has through such development acquired certain useful technology and intellectual property rights; 

        WHEREAS, NC highly appreciates and wishes to utilize such technology and intellectual property rights; 

        WHEREAS, KH wishes to transfer such technology to NC and to grant a license to NC under such technology and intellectual property rights;
and 

        WHEREAS, NC wishes to accept such technology and to be granted such license; 

        NOW, THEREFORE, the parties agree as follows: 

SECTION 1.    DEFINITION    

        In
this Agreement the following term shall have the following meaning, respectively: 

        1.1   The term "Affiliate" of a party shall mean a person, corporation,
partnership or other entity which Controls, is Controlled by or is under common Control with the party. 

        1.2   The term "Authority" shall mean a governmental authority having
jurisdiction over import, export, development, manufacture, marketing or sales of medicinal products, including the FDA. 

        1.3   The term "Business Day" shall mean a day other than a Saturday, Sunday,
national or bank holiday in Japan or the United States of America. 

        1.4   The term "Combination Product" shall mean the Product which contains the
KW-3902 and one or more other therapeutically active ingredients. 

        1.5   The term "Control" over an entity shall mean (1) directly or
indirectly to hold more than fifty percent (50%) of (i) the nominal value of the issued share capital or (ii) the ownership interest in the entity or (2) the ability to direct the
affairs of the entity by means of (i) possession of the share capital or ownership interest in the entity, (ii) the articles of association or other internal regulations of the entity or
(iii) any contracts binding the entity. 

1

 

        1.6   The term "[. . .***. . .]" shall mean
[. . .***. . .] having its offices at
[. . .***. . .]. 

        1.7   The term "Derivative Patent" shall mean the divisional patents,
continuation patents, continuation-in-part patents, extension patents, substitution patents, renewals, registrations, revalidation, reissues, additions, confirmations of or to
the Original Patent and the Future Patent as well as the SPC of the Original Patent, the Future Patent and the Derivative Patent. 

        1.8   The term "Effective Date" shall mean the last date when either party
signs this Agreement. 

        1.9   The term "Exhibit 1",
"Exhibit 2" or "Exhibit 3" shall mean the exhibit attached hereto and made integral part
hereof. 

        1.10 The term "Expiration" of a patent shall mean the expiration, abandonment
or cancellation of the patent, or, the declaration of invalidity or non-enforceability of all the claims of the patent by a court or other governmental authority of competent jurisdiction
(including final rejection in re-examination or re-issue proceedings) from which no further appeal has been taken during the applicable appeal period or is not allowed to be
taken against such declaration. 

        1.11 The term "FDA" shall mean the Food and Drug Administration of the United
States Department of Health and Human Services. 

        1.12 The term "Field" shall mean (1-1) the treatment of
[. . .***. . .], (1-2) the treatment of edema caused by
[. . .***. . .], cardiac [. . .***. . .]
failure, (1-3) the treatment of [. . .***. . .] (these three categories of treatment shall be hereinafter
collectively referred to as "First Indication"), (2) the treatment of congestive heart failure (hereinafter referred to as
"Second Indication"), (3-1) the treatment of [. . .***. . .],
(3-2) the treatment of [. . .***. . .] or (3-3) the treatment of
[. . .***. . .] (these three categories of treatment shall be hereinafter collectively referred to as
"Third Indication"). 

        1.13 The term "Force Majeure" shall mean such event or circumstance as Act of
God, storm, earthquake, flood, epidemic, governmental acts or omissions, acts of public enemies and terrorists, wars, civil disorders, failure of public utilities or common carriers, riots,
rebellions, strikes, lockouts, sabotages and other, labor disturbances and fire, which is beyond the reasonable control of the party suffering therefrom and which such party is not expected to take
into account on the Effective Date and which results in and causes such party's failure to perform any of its obligations hereunder. 

        1.14 The term "Future Patent" shall mean the patents which would issue from
the Original Patent Application. 

***Confidential Treatment Requested

2

 

        1.15 The term "GLP" means the then current "GLP Standard for Toxicity Studies
of Drugs" (Notification No. 313) issued by the Director-General of the Pharmaceutical Affairs Bureau, the Ministry of Health and Welfare as Japanese Authority, as of March 31, 1982, as
amended as of October 1, 1983 and October 5, 1988. 

        1.16 The term "Gross Sales" of the Product made by NC or the Sublicensee
shall mean the total amount of the invoice prices charged for the first time for such Product in its at-arm's-length sales transactions. Sales, transfer or other disposition of the Product
among NC, the Sublicensee and their respective Affiliates shall not be considered at-arm's-length and shall not be the transactions for the Gross Sales, however, the subsequent sales,
transfer or other disposition of such Product by NC, the Sublicensee or their respective Affiliates in at-arm's-length sales transactions shall be included in the Gross Sales. 

        1.17 The term "IV Product" shall mean the Product formulated for intravenous
administration. 

        1.18 The term "KH Data" shall mean any clinical, non-clinical and
other data which has been developed or acquired in relation to the KW-3902 and the Product by KH as of the Effective Date. 

        1.19 The term "KH Developed Data" shall mean any clinical,
non-clinical and other data which may be developed in relation to the KW-3902 and the Product by KH from the Effective Date until the expiration or termination of this
Agreement. 

        1.20 The term "KH Improvement" shall mean (1) the modification or
refinement, whether patentable or not, which KH may make to the KH Invention from the Effective Date until the expiration or termination of this Agreement and which solely relates to the manufacture
of the KW-3902 or the Product (hereinafter referred to as "KH Improved Invention") and (2) the patents and patent applications which
cover the KH Improved Invention and which may be filed or registered by KH (hereinafter referred to as "KH Improved Patent"). The KH Improvement shall
not include any technology, knowhow, patent and patent application not related to the KW-3902 or the Product. 

        1.21 The term "KH Information" shall collectively mean the KH Technology, the
KH Improvement and the KH Developed Data. 

        1.22 The term "KH Invention" shall mean any technology and knowhow which is
related to the KW-3902 and the Product or is necessary or useful for manufacture of the KW-3902 and the Product and which has been developed or acquired by KH as of the
Effective Date. 

        1.23 The term "KH Technology" shall collectively mean the KH Invention and
the KH Data. 

        1.24 The term "KH Territory" shall mean Japan and the other Asian countries
listed in the Exhibit 1 and the successors thereof. 

3

 

        1.25 The term "KW-3902" shall mean
[. . .***. . .]. 

        1.26 The term "Major Market" shall mean the United States of America, the
United Kingdom, Germany, France, Italy and Spain. 

        1.27 The term "Material" shall mean the bulk substance of the
KW-3902. 

        1.28 The term "Metabolite" shall mean
[. . .***. . .]. 

        1.29 The term "Milestone Payment" shall mean the payment to be made when the
scheduled event takes place. For instance, each payment under Section 9.1 is the Milestone Payment. 

        1.30 The term "M Invention" shall mean the technology and knowhow, whether
patentable or not, which KH may develop from the Effective Date until the expiration or termination of this Agreement and which solely relates to the manufacture of the Metabolite or the M Product. 

        1.31 The term "M Patent" shall mean (1) US Patent No.
[. . .***. . .], European Patent No.
[. . .***. . .] and Canadian Patent No.
[. . .***. . .] and (2) the patents and patent applications which cover the M Invention and which may be filed or
registered by KH. 

        1.32 The term "M Product" shall mean that preparation in the finished product
form which contains the Metabolite as therapeutically active ingredient. 

        1.33 The term "NC Data" shall mean any clinical, non-clinical and
other data which may be developed in relation to the KW-3902 and the Product by NC or, if applicable, the Sublicensee from the Effective Date until the expiration or termination of this
Agreement. 

        1.34 The term "NC Improvement" shall mean (1) the modification or
refinement, whether patentable or not, which NC or the Sublicensee may make to the KH Invention from the Effective Date until the expiration or termination of this Agreement and which solely relates
to the manufacture of the KW-3902 or the Product (hereinafter referred to as "NC Improved Invention") and (2) the patents and patent
applications which cover the NC Improved Invention and which may be filed or registered by NC or the Sublicensee (hereinafter referred to as "NC Improved
Patent"). The NC Improvement shall not include any technology, knowhow, patent and patent application not related to the KW-3902 or the Product. 

        1.35 The term "NC Information" shall collectively mean the NC Improvement and
the NC Data. 

        1.36 The term "NC Territory" shall mean the entire world except for the KH
Territory. 

***Confidential Treatment Requested

4

 

        1.37 The term "NDA" shall mean the new drug application to be filed with the
FDA or any similar application to be filed with the appropriate Authority anywhere in the world. 

        1.38 The term "Net Sales" shall mean the Gross Sales of the Product made by
NC or the Sublicensee, less the following deductible items to the extent that they are paid or credited in relation to sales of such Product, provided that the items 1, 4, 5 and 6 below should be
deducted from such Gross Sales only when such Gross Sales include those items: 

        1.     the
cost of packaging, transportation and insurance; 

        2.     the
cost of rebates and allowances; 

        3.     the
sum of trade, quantity and cash discounts; 

        4.     the
cost of refunds as cash, credit or free goods supplied due to price reduction, including retroactive price reduction, or billing errors; 

        5.     the
cost of refunds as cash, credit or free goods supplied in compensation for the Product damaged, rejected, returned or recalled; and 

        6.     the
sum of taxes, tariffs, customs duties and other governmental charges including mandated credits, refunds and rebates paid with respect to such sales, however,
excluding income or franchise taxes of any kind. 

The
Net Sales shall be calculated according to the generally accepted accounting principles consistently applied in the United States of America. The Net Sales of the Combination Product shall be the
Gross Sales thereof (after the above deductible items) multiplied by the fraction which the parties determine by mutual written agreement, estimating each relative contribution in value that the
KW-3902 and the other therapeutically active ingredients contained in such Combination Product would make to the total value of such Combination Product, as well as, the cost of
development, the cost of goods and other relevant information with respect to such Combination Product, provided that such fraction should not go below
[. . .***. . .]. 

        1.39 The term "Original Patent" shall mean the patents listed in the
Exhibit 2. 

        1.40 The term "Original Patent Application" shall mean the patent
applications listed in the Exhibit 2. 

        1.41 The term "Patent" shall collectively mean the Original Patent, the
Original Patent Application, the Future Patent and the Derivative Patent. 

        1.42 The term "Pivotal Registration Trial" shall mean a clinical study
necessary for submission to the appropriate Authority for the purpose of obtaining registration or other approval of manufacturing, marketing or selling the Product. 

        1.43 The term "Product" shall mean that preparation in the finished product
form which contains the KW-3902 as therapeutically active ingredient. 

***Confidential Treatment Requested

5

 

        1.44 The term "Quarter" shall mean each three (3) consecutive calendar
month period which commences on the first (1st) date of January, April, July or October in any calendar year. 

        1.45 The term "Quasi Field" shall mean
[. . .***. . .]. 

        1.46 The term "SPC" shall mean the supplementary protection certificates in
Europe and any similar rights elsewhere in the world. 

        1.47 The term "Sublicensee" shall mean an entity to which NC grants a
sublicense under the Patent and the KH Technology according to Section 4. 

SECTION 2.    INTERPRETATION    

        In
this Agreement: 

        2.1   Headings and titles are inserted for convenience only and shall not affect the interpretation hereof; 

        2.2   References to a particular Section shall be to that Section in this Agreement; 

        2.3   Unless the context requires otherwise, neither singular nor plural of a word shall not affect the interpretation hereof; 

        2.4   The term "entity" shall include a natural person, partnership, company,
corporation, trust, association, organization or any other entity, whether with separate legal personality or not; and 

        2.5   The terms "include" and
"including" shall not be interpreted to limit the generality of the preceding word. 

SECTION 3.    LICENSE    

        3.1   KH hereby grants an exclusive license to NC under the Patent and the KH Technology as they relate to the
KW-3902 to research, develop, make, have made, use, import, market, offer for sale, sell and distribute the Product in the NC Territory within the Field. The license provided for in this
Section 3.1 shall be hereinafter referred to as "License". 

        3.2   When, on the basis of certain terms and conditions (referred to as "Primal
Condition" in this Section 3.2), KH negotiates with a third party for a license to practice the Patent and the KH Technology, as they relate to the KW-3902,
in the NC Territory within the Quasi Field, KH shall simultaneously propose the Primal Condition to NC. If, within
[. . .***. . .] of KH's such proposal, NC notifies KH in writing that KH's such proposal is acceptable to NC, the parties
shall faithfully negotiate [. . .***. . .].
During the [. . .***. . .] period immediately following NC's such notification,
[. . .***. . .]. If, after such [. . .***. . .],
KH negotiates such license with a third party [. . .***. . .], KH shall immediately notify NC in writing of such terms and
conditions. 

***Confidential Treatment Requested

6

 

        3.3   When KH intends to practice the Patent and the KH Technology, as they relate to the KW-3902, in the NC
Territory within the Quasi Field, KH shall notify NC in writing of such intent. During the [. . .***. . .] period
immediately following KH's such notification (referred to as "Deliberation Period" in this Section 3.3), NC shall notify KH in writing of NC's
interest or lack of interest in a license to practice the Patent and the KH Technology, as they relate to the KW-3902, in the NC Territory within the Quasi Field. If NC has notified KH in
writing of NC's interest in such license during the Deliberation Period, or if, not in response to KH's such notification, NC has for the first time notified KH in writing of NC's interest in a
license to practice the Patent and the KH Technology, as they relate to the KW-3902, in the NC Territory within the Quasi Field, the parties shall negotiate the terms and conditions of
such license in good faith and, during the [. . .***. . .] period immediately following NC's such notification, KH shall
neither [. . .***. . .] by itself practice the Patent and the KH Technology, as they relate to the KW-3902, in
the NC Territory within the Quasi Field. If NC does not notify KH in writing of NC's interest or lack of interest in such license during the Deliberation Period, NC shall be deemed not to be
interested in such license. 

        3.4   When KH intends to practice the Patent and the KH Technology, as they relate to the KW-3902, in the NC
Territory [. . .***. . .] or to negotiate with a third party for a license to practice the Patent and the KH Technology, as
they relate to the KW-3902, in the NC Territory [. . .***. . .], KH shall notify NC in writing of such intent.
During the [. . .***. . .] period immediately following KH's such notification (referred to as
"Consideration Period" in this Section 3.4), NC shall notify KH in writing of NC's interest or lack of interest in such license. If NC has
notified KH in writing of NC's interest in such license in response to KH's such notification during the Consideration Period, or if, not in response to KH's such notification, NC has for the first
time notified KH in writing of NC's interest in a license to practice the Patent and the KH Technology, as they relate to the KW-3902, in the NC Territory
[. . .***. . .], the parties shall negotiate the terms and conditions of such license in good faith and, during the
[. . .***. . .] period immediately following NC's such notification, KH shall neither
[. . .***. . .] by itself practice the Patent and the KH Technology, as they relate to the KW-3902, in the NC
Territory [. . .***. . .]. If NC does not notify KH in writing of NC's interest or lack of interest in such license during
the Consideration Period, NC shall be deemed not to be interested in such license. 

        3.5   During the Non-Negotiation Period (defined below) KH shall not negotiate with a third party for a license to
practice the M Patent and the M Invention, as they relate to the Metabolite, in the NC Territory within the Field, if NC pays
[. . .***. . .] US dollars to KH within thirty (30) days of the Effective Date. The Non-Negotiation
Period shall be the [. . .***. . .] period immediately following the Effective Date and will be extended
[. . .***. . .] times by [. . .***. . .] if NC
pays [. . .***. . .] US dollars to KH by the end of the then current Non-Negotiation Period. If the
Non-Negotiation Period is so extended [. . .***. . .] times
[. . .***. . .], such Non-Negotiation Period will be further extended by
[. . .***. . .] if NC pays [. . .***. . .] US
dollars to KH by the end of such Non- 

***Confidential Treatment Requested

7

 

Negotiation
Period. At any time during the Non-Negotiation Period NC may notify KH in writing of NC's interest in a license to practice the M Patent and the M Invention, as they relate to
the Metabolite, in the NC Territory within the Field and if so, the parties shall negotiate the terms and conditions of such license in good faith during the
[. . .***. . .] period immediately following NC's such notification. 

        3.6   When, on the basis of certain terms and conditions (referred to as "Primary
Condition" in this Section 3.6), KH negotiates with a third party for a license to practice the M Patent and the M Invention, as they relate to the Metabolite, in the NC
Territory within the Field after the Non-Negotiation Period, KH shall simultaneously propose such Primary Condition to NC for NC's consideration. Whenever the Primary Condition for the
same opportunity has subsequently changed to the Primary Condition [. . .***. . .] the previous Primary Condition for the
same opportunity, KH shall simultaneously propose such subsequent Primary Condition to NC for NC's consideration. If, within
[. . .***. . .] of KH's such proposal, NC notifies KH in writing that KH's such proposal is acceptable to NC, the parties
shall faithfully negotiate such license for [. . .***. . .] after NC's such notification. If, within
[. . .***. . .] of KH's such proposal, NC does not notify KH in writing of whether KH's such proposal is acceptable to NC or
not, KH is not obligated to propose to NC the later Primary Condition for the same opportunity. 

        3.7   In the event that KH grants an exclusive license to NC to practice the M Patent and the M Invention, as they relate to
the Metabolite, in the NC Territory within the Field, [. . .***. . .]. If NC terminates this Agreement according to
Section 19.3, 26.2 or 26.3, [. . .***. . .]. This Section 3.7 shall survive the expiration hereof or the
termination hereof which is effected according to Section 19.3, 26.2 or 26.3. 

        3.8   When KH begins to negotiate with a third party for a license to practice the
[. . .***. . .] KH shall notify NC in writing thereof. 

SECTION 4.    SUBLICENSE    

        NC
shall be entitled to grant a sublicense under the License, provided: 

        4.1   that NC should obtain KH's prior written approval of such sublicense, which shall not be unreasonably withheld and shall
be deemed to have been given to NC by KH if KH does not notify NC in writing of KH's objection to such sublicense within
[. . .***. . .] after NC in writing requests KH's approval of such sublicense from KH, and that, at such intended
sublicensee's written request, KH shall faithfully negotiate with such intended sublicensee for the agreement whose terms and conditions are analogous to the terms and conditions hereof (except for
Sections 4, 5, 6 and 7), whose material financial terms are not different from the material financial terms hereof and which would become effective when this Agreement is terminated by KH according to
Section 19.3 or 26.3.3 through 26.3.7; 

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        4.2   that, for the purpose of the above proviso 4.1, NC should notify KH in writing of (a) the identity of such
intended sublicensee and (b) the key terms and conditions of such intended sublicense; 

        4.3   that, when the key terms and conditions of the sublicense have been substantially changed, NC should notify KH in writing
of such change; 

        4.4   that the sublicense should prohibit the Sublicensee from granting a further sublicense thereunder; 

        4.5   that the sublicense should be accompanied by the terms and conditions to obligate the Sublicensee to perform what KH
requests NC to have such Sublicensee perform hereunder; 

        4.6   that NC should be responsible for the Sublicensee's compliance with the terms and conditions referred to in the above
proviso 4.4; 

        4.7   that, under Section 18.1, NC should defend and indemnify KH with respect to the sublicense; and 

        4.8   that the sublicense should terminate at the time when the License terminates for any cause. 

SECTION 5.    TECHNOLOGY TRANSFER    

        5.1   Within three (3) months of the Effective Date, KH shall transfer the substance of the KH Technology to NC in
tangible form. Notwithstanding this three (3) month period, KH shall proceed with such transfer immediately after the Effective Date, shall make reasonable efforts to expedite such transfer and
shall accept NC's employees, officers or directors at KH's administered premises at NC's written request according to Section 7.1.3. 

        5.2   For the purpose of Section 5.1, NC shall notify KH in writing of where and how the KH Technology should be sent. 

        5.3   When the KH Technology is transferred to NC by KH for the transactions contemplated hereunder, such KH Technology shall
be transferred "as it is". Notwithstanding the foregoing, in the event that NC requests KH to translate some part of the so transferred KH Technology from the Japanese language to the English
language, whether after or before the Effective Date, and that KH accepts such request, the part of such KH Technology may be transferred to NC by KH in the English language after the reasonable time
for such translation. The costs and expenses of such translation shall be incurred by NC and shall be paid to KH by NC in Japanese yen within one (1) month of NC's receipt of KH's invoice
therefor. 

        5.4   The ownership of the KH Technology transferred to NC by KH for the transactions contemplated hereunder shall remain with
KH. For clarification, NC may utilize such KH Technology only for exercise of the rights granted to NC by KH hereunder. In this connection, NC may prepare and file submissions with the Authority to
obtain the approval of the NDA of the Product. 

9

 

        5.5   The information disclosed to NC through
[. . .***. . .] or directly by KH under the April 16, 2002 Secrecy Agreement between KH and
[. . .***. . .] or the December 16, 2002 Secrecy Agreement between KH and NC shall be deemed to be the KH Technology
transferred to NC by KH as of the Effective Date hereunder. 

SECTION 6.    MATERIAL SUPPLY    

        6.1   Within three (3) months of the Effective Date, KH shall supply
[. . .***. . .] grams of the Material to NC. Notwithstanding this three (3) month period, KH shall proceed with such
supply immediately after the Effective Date and shall make reasonable efforts to expedite such supply. 

        6.2   For the purpose of Section 6.1, NC shall notify KH in writing of where and how the Material should be sent. 

        6.3   When the Material is supplied to NC by KH for the transactions contemplated hereunder, such Material shall be supplied
"as it is" and is neither compliant with the GMP requirements nor for human use. For clarification, KH is not obligated to reanalyze such Material or to provide NC with any documentation relating to
such Material, including the certificates for analysis. 

        6.4   For human bodies shall NC not use the Material supplied to NC by KH for the transactions contemplated hereunder. 

        6.5   The parties agree that, as regards the Material supplied to NC by KH for the transactions contemplated hereunder, it is
NC's sole responsibilities to respond to the inquiries from and to cope with the audit or inspection by the Authority. 

        6.6   The ownership of, and risk of loss to the Material supplied to NC by KH for the transactions contemplated hereunder shall
pass from KH to NC at the time of its delivery from KH to NC. 

SECTION 7.    TECHNICAL ASSISTANCE    

        7.1   During the [. . .***. . .] period immediately
following the Effective Date, KH shall at NC's written request render technical assistance to NC, as regards the KH Technology transferred to NC by KH for the transactions contemplated hereunder, in
the following ways: 

        1.     KH's
designated person shall answer by letter, facsimile or email the questions which NC's designated person ask of KH's such designated person by letter, facsimile or
email, provided that such technical assistance should not include translation from the Japanese language to the English language. Either party shall notify the other party in writing of whom such
party designates among its employees, officers and directors for such technical assistance. 

        2.     KH
shall send its employees, who are familiar with the KH Technology, to NC's designated premises in order to instruct NC's employees, officers or directors there during
NC's normal business hours as far as such employees are available to KH in the normal course of KH's business. NC shall incur (1) the costs and expenses of such technical assistance, 

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including
those of hotel accommodation and business class air transportation, and (2) the instruction fees of
[. . .***. . .] US dollars per working man-hour for such technical assistance. Travel time shall not be
considered the time for such technical assistance. NC shall pay such costs and expenses and such instruction fees to KH in Japanese yen within one (1) month of NC's receipt of KH's invoice
therefor. The amount of such costs and expenses shall be exchanged for Japanese yen at the average TTS rate of the Bank of Tokyo-Mitsubishi, Ltd. for the month preceding such invoice. The
schedule for such technical assistance shall be negotiated in good faith and separately agreed to by the parties, provided that the total working man-hours for such technical assistance
should not exceed [. . .***. . .] working man-hours. In determining such schedule, the parties shall gravely
consider the safety of KH's employees to be sent for technical assistance. Especially such schedule may be delayed for the reason of war or epidemic. 

        3.     KH
shall accept NC's employees, officers or directors at KH's administered premises in order to instruct them there during KH's normal business hours as far as such
acceptance is possible for KH in the normal course of KH's business. NC shall incur the travel and lodging expenses for such technical assistance, however, shall not incur the instruction fees for
technical assistance to the extent that the grand total of the total hours when each of NC's such people is so instructed do not go over
[. . .***. . .] hours. In the event that such grand total goes over
[. . .***. . .] hours, NC shall pay to KH for the difference between such grand total and
[. . .***. . .] hours at the rate of
[. . .***. . .] US dollars per hour within one (1) month of NC's receipt of KH's invoice therefor. 

        4.     The
monetary terms of Sections 7.1.2 and 7.1.3 shall apply to the case where NC sends its people to KH and accepts KH's employees for technical assistance of the NC
Information, mutatis mutandis. 

        7.2   For [. . .***. . .] after and during the term
hereof, NC shall not execute or shall not have a third party execute an employment, consulting or similar Agreement with KH's employees sent to NC according to Section 7.1.2. 

        7.3   Such technical assistance as provided for in Sections 7.1.1, 7.1.2 and 7.1.3 is intended just for understanding and
handling of the KH Technology "as it is" and is neither to supplement or to improve the KH Technology nor to develop, invent or discover technology. 

SECTION 8.    DILIGENCE    

        NC
shall make and shall have the Sublicensee make commercially reasonable efforts to develop, to manufacture, to market, to sell the Product within the NC Territory. By the end of the
month immediately following the month in which an anniversary of the Effective Date comes, NC shall provide KH with the written report outlining such efforts made by NC and the Sublicensee during the
previous one (1) year period between anniversaries of the Effective Date. 

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SECTION 9.    MILESTONE PAYMENT    

        9.1   In consideration of the license granted to NC by KH hereunder, NC shall pay to KH a non-refundable and
non-creditable fees of: 

        1.     two
million (2,000,000) US dollars within thirty (30) days of the Effective Date; 

        2.     one
and a half million (1,500,000) US dollars by whichever comes earlier, the fourth (4th) anniversary of the Effective Date or the thirtieth
(30th) day from NC or the Sublicensee [. . .***. . .]; 

        3.     [. . .***. . .]
US dollars within thirty (30) days of NC's or the Sublicensee's
[. . .***. . .]; 

        4.     [. . .***. . .]
US dollars within thirty (30) days of NC's or the Sublicensee
[. . .***. . .]; 

        5.     [. . .***. . .]
US dollars within thirty (30) days of NC's or the Sublicensee
[. . .***. . .]; 

        6.     [. . .***. . .]
US dollars within thirty (30) days of NC's or the Sublicensee's
[. . .***. . .]; and 

        7.     [. . .***. . .]
US dollars within thirty (30) days of NC or the Sublicensee
[. . .***. . .]. 

It
is confirmed that each Milestone Payment under this Section 9.1 shall not be made twice or more. The Milestone Payment for the Third Indication shall be faithfully negotiated for and
separately agreed to by the parties if and before NC or the Sublicensee submits the NDA of the Product for the Third Indication to the Authority of the Major Market. 

        9.2   Within ten (10) Business Days after
[. . .***. . .] as provided for in Sections 9.1.2 and 9.1.5, NC shall inform KH in writing of
(1) [. . .***. . .] and
(2) [. . .***. . .]. 

        9.3   Within ten (10) Business Days after
[. . .***. . .] as provided for in Sections 9.1.3, 9.1.4, 9.1.6 or 9.1.7, NC shall inform KH in writing of
(1) [. . .***. . .] and
(2) [. . .***. . .]. 

        9.4   Sections 9.2 and 9.3 shall survive the expiration or termination hereof for ten (10) Business Days after such
expiration or termination. 

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   SECTION 10.    ROYALTY PAYMENT    

        10.1    In consideration of the license granted to NC by KH hereunder, NC shall pay to KH the royalty of: 

        1.     X
percent of the total Net Sales during a calendar year in the case that such total Net Sales are not over
[. . .***. . .] US dollars during the calendar year, or 

        2.     X
percent of [. . .***. . .] US dollars 

        plus

        Y
percent of (the total Net Sales during a calendar year [. . .***. . .]) 

        in
the case that such total Net Sales are over [. . .***. . .] US dollars during the calendar year. 

        X
and Y shall represent [. . .***. . .] and
[. . .***. . .] respectively, however, if the
[. . .***. . .], and if the [. . .***. . .], the
X and Y applicable to the Net Sales of the IV Product by NC and the Sublicensee after such commercial sales shall represent
[. . .***. . .] and [. . .***. . .]
respectively. 

        The
payment under this Section 10.1 shall be hereinafter referred to as "Royalty". The parties agree that, if NC or the Sublicensee
supplies the Product for the clinical trial purpose at no charge, then no Royalty shall be payable on such supply transactions. 

        10.2    The Royalty for the Net Sales during each Quarter shall be paid to KH by NC in Japanese yen within
[. . .***. . .] days of the end of such Quarter. For calculation of the Royalty, currencies of the Net Sales during the
Quarter shall be exchanged for Japanese yen at the average TTS rate of the Bank of Tokyo-Mitsubishi, Ltd. for such Quarter. 

        10.3    NC shall send to KH a royalty statement (hereinafter referred to as
"Statement") within [. . .***. . .] days of the end of the Quarter during or
before which the Net Sales have for the first time occurred. The Statement shall specify at least the following categories of information for each country where the Net Sales occur and shall sum up
such figures for each such country. 

        1.     the
names of such countries 

        2.     the
Gross Sales in each such country during the Quarter 

        3.     the
types (dosage, package unit) and quantities of such Gross Sales 

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        4.     the
Net Sales for such Gross Sales 

        5.     the
exchange rates applicable to such Net Sales 

        10.4    NC shall keep and shall have the Sublicensee keep the books of account, which contain the information necessary for
calculation of the Royalty, for [. . .***. . .] years after the end of the calendar year when the Net Sales for such Royalty
occur. KH may have such books of account audited by its designated certified public accountant at its expense not more frequently than once per calendar year. For the purpose of such audit, NC shall
at KH's written request and at reasonable advance notice disclose and have such Sublicensee disclose such books of account to KH's designated certified public accountant on the premises of NC and such
Sublicensee during their normal business hours. NC shall cooperate and shall have such Sublicensee cooperate faithfully with the certified public accountant in order to facilitate such audit. The
total number of the Business Days when the certified public accountant may stay on the premises of NC and such Sublicensee for such audit shall not exceed
[. . .***. . .] days during a calendar year unless the parties otherwise agree. Notwithstanding the foregoing, the cost of
such audit on one occasion shall be borne by NC if overdue payment indicated by such audit on the occasion exceeds three percent (3%) of the whole payment determined by such audit on the occasion and
paid to KH by NC within ten (10) Business Days after NC's receipt of KH's invoice therefor. If overdue payment indicated by such audit on the occasion does not exceed such percent, the cost of
such audit on the occasion shall be borne by KH. NC shall pay to KH such overdue amount with the interest thereon within ten (10) Business Days after NC's receipt of KH's invoice therefor. In
the event that NC has overpaid KH for any amount payable to KH by NC hereunder, NC may credit such overpayment against the future payment to be made to KH by NC hereunder
[. . .***. . .], provided that KH may have a certified public accountant audit such overpayment at reasonable advance notice
at NC's expense. This Section 10.4 shall survive the expiration or termination hereof for [. . .***. . .] years after
the end of the calendar year when such expiration or termination occurs. 

SECTION 11.    PAYMENT  

        11.1    The payment to KH by NC hereunder shall be made to the following bank account by wire transfer. 

Bank
Name: [. . .***. . .]

Branch Name: Head Office

Account Number: [. . .***. . .]

Swift Code: [. . .***. . .]

Bank Address: [. . .***. . .] 

KH
may change the above bank account to other bank account, notifying NC in writing of such other bank account. The fees for such wire transfer shall be incurred by NC. 

        11.2    Interest shall accrue on overdue amount of the payment to be made to KH by NC hereunder until the day when such overdue
amount is paid. The rate of such interest shall be a daily rate of [. . .***. . .] percent
([. . .***. . .]%) to the extent permitted by the applicable law. 

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        11.3    As provided for in the "Convention between Japan and the United States of America for the Avoidance of Double Taxation
and the Prevention of Fiscal Evasion with respect of Taxes on Income", NC shall withhold income tax from its payment to KH under Sections 9 and 10, shall pay such withheld income tax to the US
Government on behalf of KH and shall timely send to KH the tax certificate for such payment. 

SECTION 12.    PATENT PROSECUTION  

        12.1    KH hereby confirms that KH has filed the Original Patent Application and obtained the Patent as of the Effective Date as
listed in the Exhibit 2. 

        12.2    KH shall make reasonable efforts to prosecute the patent applications in the Patent and to maintain the patent rights
therein. A copy of the main communication between KH and patent offices in relation to the Patent shall be sent to NC or NC's designated law firms by KH at NC's direction as soon as practicably
possible. 

        12.3    NC shall incur the costs and expenses, including attorneys' fees and
translation fees, in connection with such prosecution and maintenance, which accrue as from the Effective Date. Notwithstanding the foregoing, NC shall incur the costs and expenses, including
attorneys' fees and translation fees, in connection with (1) filing a request of examination of Canadian Patent Application Number
[. . .***. . .], (2) filing a request of reinstatement of Canadian Patent Application Number
[. . .***. . .], (3) registering and maintaining the patents based on European Patent Application Number
[. . .***. . .] in the European countries listed in Part B of the Exhibit 2 and (4) in the event that
European Patent Application Number [. . .***. . .] is allowed, registering and maintaining the patents based on such patent
application in the European countries where NC in writing requests KH to register such patents, whether such costs and expenses accrue before or after the Effective Date or not. In the event that KH
practices the Patent by itself or grants a license to a third party to practice the Patent according to Section 3.2 or 3.3, the parties shall negotiate in good faith to fairly apportion between
the parties the costs and expenses, including attorneys' fees and translation fees, in connection with prosecuting the patent applications in the Patent and maintaining the patents therein, which
accrue after KH so practices or grants. 

        12.4    Once European Patent Application Number
[. . .***. . .] is allowed, KH shall immediately notify NC in writing of such allowance and shall register and maintain the
patents based on such patent application in the European countries where NC in writing requests KH to register such patents, provided that such request should be made in writing within ten
(10) Business Days after NC is notified in writing of such allowance by KH. 

        12.5    The costs and expenses which NC incurs according to Section 12.3 shall be paid to KH or KH's designated law firms
by NC at KH's direction within one (1) month of NC's receipt of KH's or such law firms' invoices therefor, respectively. 

        12.6    If KH is notified in writing by patent offices that any interference, revocation, opposition or similar proceedings are
instituted against the Patent by a third party, KH shall immediately after such notification inform NC in writing of the substance of such proceedings. KH shall retain the right to do what KH
considers appropriate for such proceedings at KH's 

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expense
and shall defend such Patent against or contest such proceedings with a view to keeping as wide a scope of such Patent as possible only in the event that, within ten (10) Business Days
after being so informed, NC in writing requests KH to undertake such defense or contest, [. . .***. . .].
[. . .***. . .]. KH shall from time to time inform NC in writing of the substantive development of such proceedings on a
timely manner. In such proceedings, KH shall not enter into any agreement that would impose any monetary or other responsibilities or liabilities on NC or limit or reduce NC's rights hereunder without
NC's prior written consent thereto. 

        12.7    Within ten (10) Business Days after NC or the Sublicensee is officially notified by the Authority that sales of
the Product in the NC Territory is granted by such Authority, NC shall notify or have such Sublicensee notify KH in writing of the date and substance of such grant and shall send or have such
Sublicensee send to KH a copy of (1) the certificates for such grant and (2) any related documentation. In the event that, after being notified in writing of such grant, KH informs NC or
the Sublicensee in writing that KH intends to follow the proceedings for (1) extension of the term of the Patent or (2) the SPC for the Patent, NC shall cooperate or have such
Sublicensee cooperate with KH in such proceedings by means of document offering or otherwise. 

        12.8    KH shall notify NC in writing of such substantial status changes of the Patent as grant (allowance), registration
(issuance), the Expiration, the SPC grant and term extension on a timely manner and shall send to NC the related documentation as soon as practicable. 

SECTION 13.    PATENT INFRINGEMENT  

        13.1    Either party shall notify the other party in writing of any infringement or possible infringement on the Patent by a
third party in the NC Territory immediately after the notifying party becomes aware of such infringement and shall simultaneously provide the notified party with the related information. KH is
obligated neither to prevent such infringement nor to incur the cost of such prevention, however, shall retain the right to do what KH considers appropriate for such prevention at KH's expense,
provided that, in such prevention, KH should not do what would impose any monetary or other responsibilities or liabilities on NC or would limit or reduce NC's right hereunder without NC's prior
written consent thereto. NC may also prevent such infringement at NC's expense, provided that NC should notify KH in writing of NC's such intent in advance and that, from time to time, NC should
notify KH in writing of the substantive development of NC's such prevention. KH shall render reasonable assistance for NC's such prevention at NC's written request and expense. Such assistance shall
include being named as a party or providing NC a power-of-attorney, as permitted by applicable law, in the action which NC would bring for NC's such prevention. Any damage or
other compensation which NC might obtain from the infringing party as a result of NC's such prevention shall be first allocated to reimbursement for KH's cost for NC's such prevention, if any, and the
remainder shall inure to the benefit of NC. 

        13.2    Either party shall notify the other party in writing of any allegation that the Product may infringe a third party's
patents or patent applications in the NC Territory 

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immediately
after the notifying party becomes aware of such allegation and shall simultaneously provide the notified party with the related information. KH is obligated neither to defend NC or such
Product against nor to contest such allegation nor to incur the cost of such defense or contest, however, NC shall at NC's expense defend itself or such Product against or contest such allegation. NC
may settle such a case, provided that such settlement should not impose any monetary or other responsibilities or liabilities upon KH. In the event that NC pays to the alleging party the royalty of
some percent of the Net Sales (hereinafter referred to as "Settlement Rate") for such settlement, each royalty rate provided for in Section 10.1
shall be decreased by [. . .***. . .], provided that NC should obtain KH's prior written approval of the monetary conditions
of such settlement, which shall not be unreasonably withheld, and that the Product should not technically or economically expected to be manufactured outside the scope of the alleging party's such
patents and patent applications. Such [. . .***. . .]. 

        13.3    Section 13.2 shall not apply to the following patents and patent applications
[. . .***. . .]; 

        1.     [. . .***. . .] 

        2.     [. . .***. . .].

SECTION 14.    IMPROVEMENT  

        14.1    Nothing herein shall be construed to transfer or to assign KH's ownership of or title to the Patent and the KH
Information. 

        14.2    The ownership of or title to the NC Information shall vest in NC or the Sublicensee, however, such vesting shall not
affect KH's ownership of or title to the Patent and the KH Information. 

        14.3    As soon as practicable after NC has made the NC Improved Invention and the NC Data, NC shall transfer such NC Improved
Invention and such NC Data to KH in tangible form. Such transfer may be delayed due to the prosecution procedures of the NC Improved Patent. In negotiation with an intended Sublicensee for a
sublicense under the License, NC shall make reasonable efforts to obligate such intended Sublicensee to transfer its NC Improved Invention or its NC Data to KH in tangible form. Such transfer may be
delayed due to the prosecution procedures of the NC Improved Patent. 

        14.4    For the purpose of Section 14.3, KH shall notify NC in writing of where and how the NC Improved Invention and the
NC Data should be sent. 

        14.5    As soon as practicable after NC has filed the NC Improved Patent, NC shall notify KH in writing of such patent
application. From time to time, NC shall provide KH with the written summary of such patent prosecution. In negotiation with an intended Sublicensee for 

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a
sublicense under the License, NC shall make reasonable efforts to obligate such intended Sublicensee to notify NC in writing of its filing the NC Improved Patent. If the Sublicensee files the NC
Improved Patent and if such Sublicensee notifies NC of such filing or NC otherwise becomes aware of such filing, NC shall notify KH in writing of such patent application as soon as practicable and
shall provide KH with the written summary of such patent prosecution from time to time. 

        14.6    Section 14.5 does not allow NC or the Sublicensee to disclose KH's Confidential Information to any entities,
including patent offices and law firms. NC and the Sublicensee may so disclose only after obtaining KH's written approval thereof. 

        14.7    NC shall grant and make reasonable efforts to have the Sublicensee grant to KH a non-exclusive and
paid-up license (with the right to grant a sublicense) (1) to practice the NC Information in the KH Territory and (2) to practice the NC Information in the NC Territory
outside the Field as far as such practice does not compete with NC's or such Sublicensee's business related to the Product. KH may, with the prior written consent of NC, disclose the NC Information to
an entity for such sublicense under appropriate confidentiality and shall be responsible for such limited-usage and confidentiality, with which the entity is obligated to comply as such sublicensee. 

        14.8    As soon as practicable after KH has made the KH Improved Invention and the KH Developed Data, KH shall transfer such KH
Improved Invention and such KH Developed Data to NC in tangible form. Such transfer may be delayed due to the prosecution procedures of the KH Improved Patent. 

        14.9    For the purpose of Section 14.8, NC shall notify KH in writing of where and how the KH Improved Invention and the
KH Developed Data should be sent. 

        14.10    As soon as practicable after KH has filed the KH Improved Patent, KH shall notify NC in writing of such patent
application. From time to time, KH shall provide NC with the written summary of such patent prosecution. 

        14.11    Section 14.10 does not allow KH to disclose NC's Confidential Information to any entities, including patent
offices and law firms. KH may so disclose only after obtaining NC's written approval thereof. 

        14.12    KH shall grant to NC a non-exclusive and paid-up license (with the right to grant a sublicense
to the Sublicensee) to practice the KH Improvement and the KH Developed Data, as they relate to the KW-3902, in the NC Territory in the Field, provided that such Sublicensee should grant a
license (with the right to grant a sublicense) to KH under its NC Information as provided for in Section 14.7, that such Sublicensee should permit NC to transfer its NC Improved Invention and
its NC Data as provided for in Section 14.3 and that such Sublicensee should permit NC to provide KH with the information with respect to its NC Improved Patent as provided for in
Section 14.3. NC may, with the prior written consent of KH, disclose the KH Improvement and the KH Developed Data to such Sublicensee for such sublicense under appropriate confidentiality and
shall be responsible for such limited-usage and confidentiality, with which such Sublicensee is obligated to comply as such sublicensee. 

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SECTION 15.    CONFIDENTIALITY  

        15.1    For [. . .***. . .] years after and during
the term hereof, either party shall neither disclose to any third party any information which is disclosed to it by the other party for the transactions contemplated hereunder nor utilize such
information for any other purpose than the purposes hereof, if such information is marked as confidential when so disclosed visually or if such information is designated as confidential when so
disclosed orally and is confirmed as confidential visually within fifteen (15) Business Days of such oral disclosure, unless 

        1.     such
information is part of the public domain before its disclosure to the disclosed party by the disclosing party; or 

        2.     such
information becomes part of the public domain after its disclosure to the disclosed party by the disclosing party not due to any breach hereof by the disclosed
party; or 

        3.     such
information is known to the disclosed party without confidentiality at the time of its disclosure to the disclosed party by the disclosing party, as evidenced by
credible documentation; or 

        4.     such
information is provided to the disclosed party legally and without confidentiality by a third party; or 

        5.     the
disclosed party can demonstrate by credible documentation that the disclosed party has independently developed or discovered such information. 

The
information to be kept confidential according to this Section 15.1 is hereinafter referred to as "Confidential Information". A party's
Confidential Information shall mean the Confidential Information disclosed to the other party by the party. The KH Technology, the KH Improved Invention and the KH Developed Data shall be deemed to be
part of KH's Confidential Information unless they fall within the scope of the above five (5) categories. The NC Improved Invention and the NC Data shall be deemed to be part of NC's
Confidential Information unless they fall within the same. For [. . .***. . .] years after and during the term hereof,
either party shall preserve the other party's Confidential Information as it is and maintain the written record of receipt thereof. Either party shall ensure that only those of their directors,
officers and employees who have a need to know the other party's Confidential Information should be given access thereto and that such directors, officers and employees should keep and utilize such
Confidential Information so that the party of such directors, officers and employees may not breach this Section 15.1. 

        15.2    Notwithstanding Section 15.1, either party may disclose the other party's Confidential Information (1) to
the extent necessary to obtain the Authority's approval of import, export, manufacture, use, marketing or sales of the Product, (2) to the extent required by law and regulation or (3) to
the extent requested by orders and judgments of such competent governmental authorities as administrations and courts, provided that such party should make reasonable efforts, if appropriate, to
obtain or to permit the other party obtain confidential treatment of such Confidential Information. 

***Confidential Treatment Requested

19

 

        15.3    Notwithstanding Section 15.1, either party may disclose the other party's Confidential Information to
professional entities such as attorneys-at-law and certified public accountants only for the purposes hereof under mandatory or contractual confidentiality. 

        15.4    Notwithstanding Section 15.1, NC may disclose KH's Confidential Information to the Sublicensee for the purpose of
Section 4, provided that NC should, through a written agreement, have such Sublicensee not disclose such Confidential Information to other entity if not permitted by such written agreement, and
utilize the same only for the purpose of Section 4, and that the confidentiality of such written agreement should not be less stringent than and should be consistent with the confidentiality
imposed on NC hereunder. 

        15.5    Once KH's Confidential Information is disclosed to the Sublicensee by NC according to Section 15.4, NC shall be
responsible for such Sublicensee's compliance with such confidentiality and limited-usage as provided for in Section 15.4. If such Sublicensee has breached such confidentiality or
limited-usage, NC shall indemnify KH from the damages which might be caused in relation to such breach. 

        15.6    When an entity has ceased to be the Sublicensee after KH's Confidential Information has been disclosed to the entity as
provided for in Section 15.4, NC shall have such Sublicensee immediately return to NC or destroy such Confidential Information. 

        15.7    Sections 15.4, 15.5 and 15.6 shall apply mutatis mutandis to the case
where each party's Confidential Information is disclosed to an entity by the other party for exercise of the sublicense right provided for in Sections 14.7 and 14.12. 

        15.8    Neither party shall disclose the contents hereof to any third party without first obtaining the other party's written
consent thereto. Notwithstanding the foregoing, either party may disclose the main terms and conditions hereof to its potential investors, acquirers or lenders to the extent necessary for such party's
contemplated transactions with them, provided that such disclosure should be made under appropriate confidentiality no less strict than the confidentiality imposed on such party hereunder. 

        15.9    Neither party shall make any publicity, news release or other public announcement, visual or oral, relating hereto
without the other party's prior written approval thereof, which shall not be unreasonably withheld or delayed, except as required by law or regulation. 

        15.10    In the event that either party intends to make the scholarly publication detailing the results of clinical trials and
other studies conducted hereunder and that such party submits the draft for such publication to the other party for review, the other party, shall be deemed to approve of such publication if the other
parry does not provide such party with the other party's written comments thereon within ninety (90) days of such submission. 

20

 

SECTION 16.    REPRESENTATION AND WARRANTY  

        16.1    Each party represents and warrants: 

        1.     that
such party has the power and right to enter into this Agreement as of the Effective Date and to perform its obligations hereunder; and 

        2.     that
such party is not a party to any agreement with a third party, whether written or not, which would prevent such party from fulfilling any of its obligations
hereunder. 

        16.2    KH represents and warrants: 

        1.     that
KH is the owner of the Original Patent, the Original Patent Application and the KH Technology; 

        2.     that
KH is entitled to grant to NC the rights granted to NC by KH hereunder; 

        3.     that
KH does not grant any right to any third party in inconsistent ways with the rights granted to NC by KH hereunder; and 

        4.     that
those documents in the KH Technology which are listed in the Exhibit 3 are made according to the GLP. 

        16.3    KH neither represents nor warrants and disclaims: 

        1.     the
scope, validity and enforceability of the Patent, the KH Improved Patent and the M Patent; 

        2.     future
grant (allowance) and registration (issuance) of the Patent, the KH Improved Patent and the M Patent; 

        3.     future
filing, prosecution and maintenance of the KH Improved Patent and the M Patent; 

        4.     future
development of the KH Improved Invention, the KH Developed Data and the M Invention; 

        5.     non-infringement
by any product, material or information on the intellectual property or other rights vested in or enforceable by a third party; 

        6.     successful
development of the Product; 

        7.     approval
of the Product by the Authority; and 

        8.     merchantability
and fitness for a particular purpose. 

21

 

        16.4    NC neither represents nor warrants and disclaims: 

        1.     the
scope, validity and enforceability of the NC Improved Patent; 

        2.     future
grant (allowance) and registration (issuance) of the NC Improved Patent; 

        3.     future
filing, prosecution and maintenance of the NC Improved Patent; 

        4.     future
development of the NC Improved Invention and the NC Data; 

        5.     non-infringement
by any product, material or information on the intellectual property or other rights vested in or enforceable by a third party; 

        6.     successful
development of the Product; 

        7.     approval
of the Product by the Authority; and 

        8.     merchantability
and fitness for a particular purpose. 

        16.5    Except as expressly provided for herein, neither party makes any representation or warranty, whether implied, statutory
or otherwise, with respect of the subject matter hereof. 

SECTION 17.    LIMITED LIABILITY  

        With the exception of the liability for breach of confidentiality, neither party shall be liable to the other party or any third party for (1) any
consequential, indirect, incidental, special or exemplary damages and (2) any losses of goodwill, business, contracts, revenues, profits or savings, which would be caused in relation hereto,
through contract, tort (including negligence, but not gross negligence), misrepresentation (but not fraudulent misrepresentation), breach of statutory duties or otherwise, even if such party is
advised of the possibility of such damages or losses. 

SECTION 18.    INDEMNIFICATION  

        18.1    NC shall defend, indemnify and hold harmless KH, KH's Affiliate, their respective directors, officers and employees from
and against any and all claims, actions, judgments, expenses (including legal expenses and reasonable attorneys' fees), losses and damages incurred by them, arising from any third party claim in
relation to (1) NC exercising the license under Sections 3.1 and 14.12, (2) the Sublicensee exercising the sublicense under Sections 4 and 14.12 and (3) the Material and the
related documentation, if any, which are supplied to NC by KH unless such claims, actions, judgments, expenses, losses and damages result from gross negligence, wrongful intentional actions or
omissions or fraud on the part of KH, KH's Affiliate, their respective directors, officers or employees. Such claims, actions, judgments, expenses, losses and damages include those related to the
products or materials manufactured by or on behalf of NC or the Sublicensee, especially those related to the claim that such products or materials have caused death or bodily injury or have infringed
intellectual property rights. 

22

 

        18.2    KH shall defend, indemnify and hold harmless NC, NC's Affiliate, the Sublicensee, their respective directors, officers
and employees from and against any and all claims, actions, judgments, expenses (including legal expenses and reasonable attorneys' fees), losses and damages incurred by them, arising from any third
party claim in relation to (1) KH exercising the license under Section 14.7 and (2) an entity exercising the sublicense under the same unless such claims, actions, judgments,
expenses, losses and damages result from gross negligence, wrongful intentional actions or omissions or fraud on the part of NC, NC's Affiliate, the Sublicensee, their respective directors, officers
or employees. Such claims, actions, judgments, expenses, losses and damages include those related to the products or materials manufactured by or on behalf of KH or KH's sublicensee under
Section 14.7, especially those related to the claim that such products or materials have caused death or bodily injury or have infringed intellectual property rights. 

        18.3    In the event that an entity is notified of a third party claim and seeks the indemnification for such claim under
Section 18.1 or 18.2, the entity shall (1) inform the indemnifying party in writing of such claim as soon as practicable after such notification, (2) permit the indemnifying party
to assume the direction and control of the defense against such claim, (3) cooperate with the indemnifying party in such defense at the indemnifying party's written request and expense and
(4) undertake all reasonable steps to mitigate any expenses, losses and damages arising in relation to such claim. Further, the indemnifying party may settle such claim at its sole discretion,
provided that such settlement should not impose any obligation on or otherwise adversely affect the entity or the indemnified party. 

SECTION 19.    FORCE MAJEURE  

        19.1    Although either party is unable to perform its obligations hereunder due to the Force Majeure, this Agreement shall
still remain in effect, however, such obligations of such party as well as the related obligations of the other party shall be suspended during the period during which such Force Majeure continues,
provided that: 

        1.     such
suspension should be of no wider scope than directly affected by such Force Majeure; 

        2.     the
invoking party should notify the other party in writing of such Force Majeure immediately after the occurrence thereof and, if such notification is prevented by such
Force Majeure, immediately after such notification becomes possible; 

        3.     such
notification should include (1) the outline of such Force Majeure, (2) the duration during which the invoking party expects such Force Majeure would
continue and (3) which obligations hereunder are suspended due to such Force Majeure; 

        4.     the
invoking party should from time to time notify the other party in writing of any development of such Force Majeure; and 

        5.     the
invoking party should make reasonable efforts to remedy its inability to perform such suspended obligations and to mitigate any effects caused by such Force Majeure. 

23

 

        19.2    Once the Force Majeure is invoked as provided for in Section 19.1, the parties shall faithfully discuss how best
to perform as far as possible according hereto. 

        19.3    In the event that the invoking party's material obligations hereunder are suspended for six (6) months as
provided for in Section 19.1, the other party may terminate this Agreement by means of written notice to the invoking party. 

SECTION 20.    WAIVER  

        Neither party shall be deemed to have waived any of its rights or remedies conferred to such party hereunder unless such waiver is made in writing and signed by a
duly authorized representative of such party. In particular, no delay or failure of either party in exercising or enforcing any of its rights or remedies conferred to such party hereunder shall
operate as waiver of such rights or remedies or so as to preclude or to impair the exercise or enforcement of such rights or remedies. Further, partial exercise or enforcement of such rights or
remedies shall not preclude or impair any other exercise or enforcement of such rights or remedies. 

SECTION 21.    ENTIRE AGREEMENT  

        This Agreement constitutes the entire agreement and understanding between the parties relating to the subject matter hereof and supersedes any and all prior oral
or written agreement, understanding, representation or warranty between them relating to the same. The parties understand and confirm that, as regards the subject matter hereof, no director, officer,
employee or agent of either party is authorized to make any representation or warranty to the other party and that neither party relies on such representation or warranty, if made whether orally or in
writing. 

SECTION 22.    AMENDMENT  

        No amendment, modification or supplement of or to this Agreement shall be valid unless made in writing and signed by duly authorized representatives of both
parties. 

SECTION 23.    INDEPENDENT CONTRACTOR  

        The relation between the parties is that of independent contractors. Nothing herein is construed to create any other relation, such as partnership or agency,
between the parties. Neither party shall have any right or authority to create, assume or incur any obligations, liabilities or expenses on behalf of the other party. 

SECTION 24.    ASSIGNMENT  

        Neither party shall wholly or partially assign or pledge its rights and obligations hereunder to any third party without the other party's prior written consent
thereto. Notwithstanding the foregoing, either party may assign its rights and obligations hereunder to a successor of such party's whole or substantially whole business, provided that such party
should timely notify the other party in writing of the fact and outline of such assignment. 

24

   SECTION 25.    SEVERABILITY  

        25.1    In the event that the whole or any part hereof has been declared illegal, invalid or unenforceable in any jurisdiction
either by any laws or regulations or by any orders or judgments of such competent governmental authorities as administrations or courts: 

        1.     in
the case of the illegality, invalidity or unenforceability of the whole hereof, this Agreement shall terminate only in relation to such jurisdiction; or 

        2.     in
the case of the illegality, invalidity or unenforceability of any part hereof, such part shall be severed herefrom in relation to such jurisdiction and such
illegality, invalidity or unenforceability shall not prejudice or affect the remainder hereof, which shall continue in full force and effect. 

        25.2    If either party considers that any severance under Section 25.1 would materially affect the purposes hereof, the
parties shall faithfully discuss possible ways to eliminate or to mitigate such material affectation. 

SECTION 26.    TERM AND TERMINATION  

        26.1    This Agreement shall come into effect as of the Effective Date and shall, unless earlier terminated according hereto,
continue to be effective until and expire on the last Expiration of the Patent or the [. . .***. . .] anniversary of the day
when the Net Sales have for the first time occurred in the Major Market, whichever comes later. 

        26.2    NC may at any time terminate this Agreement at ninety (90) day written notice to KH. 

        26.3    Either party may terminate this Agreement forthwith at written notice to the other party when any of the following
events has occurred: 

        1.     the
other party has committed the material breach hereof which is not capable of remedy (the breach of confidentiality hereunder shall be deemed to be such material
breach not capable of remedy); 

        2.     the
other party has committed the material breach hereof which is capable of remedy and which has not been remedied within thirty (30) days of receipt of the
written notice identifying such breach and requiring the remedy thereof (the overdue payment hereunder shall be deemed to be the material breach hereof); 

        3.     the
other party has become bankrupt or insolvent or has suspended payment of its debts for a period of longer than forty five (45) days; 

        4.     a
note or check drawn or endorsed by the other party has been dishonored twice or more in any six (6) month period; 

        5.     a
petition for bankruptcy, reorganization, composition, readjustment, receivership or similar procedures under any applicable bankruptcy, insolvency, reorganization, 

***Confidential Treatment Requested

25

 

moratorium
or similar law affecting creditors' rights and interests (hereinafter referred to as "Petition") has been filed for the other party by
itself; 

        6.     the
Petition has been filed against the other party by other entity and the court procedures for such Petition have been pending for more than forty five
(45) days; and 

        7.     the
other party has been wound up, dissolved or liquidated not for merger and acquisition or the procedures therefor have been started. 

        26.4    After this Agreement expires (as not earlier terminated according hereto) as provided for in Section 26.1: 

        1.     the
provisions of Sections 3.1 (License), 4.4 through 4.7 (Sublicense), 7.1.4 (Technical Assistance Fee), 14.3 through 14.12 (Improvement) and this Section 26.4
shall survive such expiration; and 

        2.     NC
shall, within forty five (45) days of such expiration, pay to KH any amount which accrues prior to such expiration and is payable to KH by NC hereunder and
shall within the same period send to KH the statement for such amount (this amount shall be exchanged for Japanese yen at the average TTS rate of the Bank of Tokyo-Mitsubishi, Ltd. for the
month preceding such expiration). 

        26.5    When this Agreement is terminated by NC according to Section 26.2 or by KH according to Section 19.3 or
26.3: 

        1.     any
and all rights and licenses granted to NC by KH hereunder shall terminate; 

        2.     Notwithstanding
Section 26.5.1, in the event that this Agreement is terminated by KH according to Section 19.3 or 26.3.3 through 26.3.7, KH shall, at the
Sublicensee's written request, negotiate with such Sublicensee for a license under the Patent, the KH Technology and, if applicable, the KH Improvement and the KH Developed Data and shall, subject to
KH's management approval, enter into such license agreement with such Sublicensee, provided that the terms and conditions of such license agreement (referred to as "Replacing
Terms" in this Section 26.5.2) should be analogous to the terms and conditions hereof (except for Sections 4, 5, 6 and 7), that the Replacing Terms in each aspect should
not be unbeneficial to KH in comparison with the terms and conditions hereof, that such license agreement should become retroactively effective on the date of such termination, and that the Replacing
Terms should not contradict the terms and conditions of any agreements previously entered into by KH; 

        3.     NC
shall, within forty five (45) days of such termination, pay to KH any amount which accrues prior to such termination and is payable to KH by NC hereunder and
shall within the same period send to KH the statement for such amount (this amount shall be exchanged for Japanese yen at the average TTS rate of the Bank of Tokyo-Mitsubishi, Ltd. for the
month preceding such termination); 

        4.     NC
shall immediately return to KH or destroy KH's Confidential Information at KH's direction; and 

26

 

        5.     the
provisions of Sections 7.1.4 (Technical Assistance Fee), 14.3 through 14.7 (Improvement) and this Section 26.5 shall survive such termination. 

        26.6    When this Agreement is terminated by NC according to Section 19.3 or 26.3: 

        1.     the
provisions of Sections 3.1 (License), 4.4 through 4.7 (Sublicense), 12 (Patent Prosecution), 13 (Patent Infringement), 14.8 through 14.12 (Improvement) and this
Section 26.6 shall survive such termination; 

        2.     KH
shall immediately return to NC or destroy NC's Confidential Information at NC's direction; and 

        3.     NC
shall, within forty five (45) days of such termination, pay to KH any amount which accrues prior to such termination and is payable to KH by NC hereunder and
shall within the same period send to KH the statement for such amount (this amount shall be exchanged for Japanese yen at the average TTS rate of the Bank of Tokyo-Mitsubishi, Ltd. for the
month preceding such termination). 

        26.7    The provisions of Sections 6.4 and 6.5 (Material), 7.2 (No Solicitation), 11 (Payment), 12.5 (Prosecution Cost), 14.1
and 14.2 (Ownership), 15.1 through 15.9 (Confidentiality), 16.3, 16.4 and 16.5 (Representation and Warranty), 17 (Limited Liability), 18 (Indemnification), 24 (Assignment), 27 (Arbitration) and 28
(Governing Law) and this Section 26.7 shall survive the expiration or termination hereof. Notwithstanding such expiration or termination, NC shall pay to KH the Milestone Payment, which accrues
prior to such expiration or termination under Section 9.1, within the period provided for in Section 9.1. 

SECTION 27.    ARBITRATION  

        If there is any dispute, controversy, difference or question between the parties with respect to any matter, including whether some breach hereof is material or
has been cured in time, arising out of or relating to this Agreement, the parties shall first make efforts to solve such issue amicably. If such issue is not solved through such amicable efforts, the
parties shall waive any rights which they may have to injunctive relief for such issue and shall settle such issue according to the Rules of Conciliation and Arbitration of the International Chamber
of Commerce. Such arbitration shall be conducted in the English language in Paris, France and shall be determined by three (3) arbitrators appointed according to the said rules. 

SECTION 28.    GOVERNING LAW  

        28.1    This Agreement shall be governed by and construed according to the laws of Japan. 

        28.2    The parties agree that the arbitration decisions according to Section 27 shall be enforceable by the courts of
competent jurisdiction in Japan and the United States of America and shall submit to the jurisdictions of such courts solely for such enforcement. 

27

        IN WITNESS WHEREOF, the parties have caused this Agreement to be executed by their duly authorized representatives. 

	KYOWA HAKKO KOGYO CO., LTD.	 	NOVACARDIA, INC.
	
By:	
 	

/s/ Toru Doiuchi
	
 	

By:	
 	

/s/ Kenneth J. Widder

	

Name:	
 	

Toru Doiuchi	
 	

Name:	
 	

Kenneth J. Widder
	

Title:	
 	

Senior Managing Director	
 	

Title:	
 	

Chief Executive Officer
	

Date:	
 	

May 9, 2003
	
 	

Date:	
 	

August 14, 2003

[SIGNATURE PAGE TO LICENSE AGREEMENT] 

EXHIBIT 1 (THE OTHER ASIAN COUNTRIES)  

Afghanistan

Kingdom of Bahrain

People's Republic of Bangladesh

Kingdom of Bhutan

Brunei Darussalam

Kingdom of Cambodia

People's Republic of China

Republic of China (Taiwan)

Republic of Cyprus

India

Republic of Indonesia

Islamic Republic of Iran

Republic of Iraq

State of Israel

Hashemite Kingdom of Jordan

Republic of Kazakhstan

Republic of Korea

Democratic People's Republic of Korea (North Korea)

State of Kuwait

Kyrgyz

Lao People's Democratic Republic

Republic of Lebanon

Malaysia

Republic of Maldives

Mongolia

Union of Myanmar

Kingdom of Nepal

Sultanate of Oman

Islamic Republic of Pakistan

Republic of the Philippines

State of Qatar

Kingdom of Saudi Arabia

Republic of Singapore

Democratic Socialist Republic of Sri Lanka

Syrian Arab Republic

Republic of Tajikistan

Kingdom of Thailand

Democratic Republic of Timor Leste

Republic of Turkey

Turkmenistan

United Arab Emirates

Republic of Uzbekistan

Socialist Republic of Viet Nam

Republic of Yemen 

EXHIBIT 2 (THE PATENT)  

	Part A [. . .***. . .]	 	 
	

[. . .***. . .]	
 	

Application Number: [. . .***. . .]	
 	

Application Date: [. . .***. . .]
	 	 	Registration Number: [. . .***. . .]	 	Registration Date: [. . .***. . .]
	 	 	Expiration Date: [. . .***. . .]	 	Status: [. . .***. . .]
	[. . .***. . .]	 	Application Number: [. . .***. . .]	 	Application Date: [. . .***. . .]
	 	 	Registration Number: [. . .***. . .]	 	Registration Date: [. . .***. . .]
	 	 	Expiration Date: [. . .***. . .]	 	Status: [. . .***. . .]
	 	 	Designated Country: [. . .***. . .]	 	 
	[. . .***. . .]	 	Application Number: [. . .***. . .]	 	Application Date: [. . .***. . .]
	 	 	Registration Number: [. . .***. . .]	 	Registration Date: [. . .***. . .]
	 	 	Expiration Date: [. . .***. . .]	 	Status: [. . .***. . .]
	

Part B: [. . .***. . .]	
 	

 
	

[. . .***. . .]	
 	

Application Number: [. . .***. . .]	
 	

Application Date: [. . .***. . .]
	 	 	Registration Number: [. . .***. . .]	 	Registration Date: [. . .***. . .]
	 	 	Expiration Date: [. . .***. . .]	 	Status: [. . .***. . .]
	[. . .***. . .]	 	Application Number: [. . .***. . .]	 	Application Date: [. . .***. . .]
	 	 	Registration Number: [. . .***. . .]	 	Registration Date: [. . .***. . .]
	 	 	Expiration Date: [. . .***. . .]	 	Status: [. . .***. . .]
	 	 	Designated Country: [. . .***. . .]	 	 
	[. . .***. . .]	 	Application Number: [. . .***. . .]	 	Application Date: [. . .***. . .]
	 	 	Registration Number: [. . .***. . .]	 	Registration Date: [. . .***. . .]
	 	 	Expiration Date: [. . .***. . .]	 	Status: [. . .***. . .]
	

Part C: [. . .***. . .]	
 	

 
	

[. . .***. . .]	
 	

Application Number: [. . .***. . .]	
 	

Application Date: [. . .***. . .]
	 	 	Registration Number: [. . .***. . .]	 	Registration Date: [. . .***. . .]
	 	 	Expiration Date: [. . .***. . .]	 	Status: [. . .***. . .]
	[. . .***. . .]	 	Application Number: [. . .***. . .]	 	Application Date: [. . .***. . .]
	 	 	Registration Number: [. . .***. . .]	 	Registration Date: [. . .***. . .]
	 	 	Expiration Date: [. . .***. . .]	 	Status: [. . .***. . .]
	[. . .***. . .]	 	Application Number: [. . .***. . .]	 	Application Date: [. . .***. . .]
	 	 	Registration Number: [. . .***. . .]	 	Registration Date: [. . .***. . .]
	 	 	Expiration Date: [. . .***. . .]	 	Status: [. . .***. . .]

***Confidential Treatment Requested  

 EXHIBIT 3 (THE GLP DOCUMENTS)  

	Report type
 
	 	Report No.
	 	Title
	 	Author

	GLP	 	A-92-036	 	[. . .***. . .]	 	[. . .***. . .]
	GLP	 	A-92-039	 	[. . .***. . .]	 	[. . .***. . .]
	GLP	 	A-92-053	 	[. . .***. . .]	 	[. . .***. . .]
	

	GLP	 	A-92-059	 	[. . .***. . .]	 	[. . .***. . .]
	GLP	 	A-92-063	 	[. . .***. . .]	 	[. . .***. . .]
	GLP	 	A-92-064	 	[. . .***. . .]	 	[. . .***. . .]
	GLP	 	A-92-072	 	[. . .***. . .]	 	[. . .***. . .]
	GLP	 	A-92-085	 	[. . .***. . .]	 	[. . .***. . .]
	

	GLP	 	A-92-096	 	[. . .***. . .]	 	[. . .***. . .]
	GLP	 	A-92-097	 	[. . .***. . .]	 	[. . .***. . .]
	GLP	 	A-92-102	 	[. . .***. . .]	 	[. . .***. . .]
	GLP	 	A-92-104	 	[. . .***. . .]	 	[. . .***. . .]
	GLP	 	A-92-122	 	[. . .***. . .]	 	[. . .***. . .]
	GLP	 	A-94-088	 	[. . .***. . .]	 	[. . .***. . .]
	

	GLP	 	A-95-042	 	[. . .***. . .]	 	[. . .***. . .]
	GLP	 	A-95-119	 	[. . .***. . .]	 	[. . .***. . .]
	GLP	 	A-95-181	 	[. . .***. . .]	 	[. . .***. . .]
	GLP	 	A-96-009	 	[. . .***. . .]	 	[. . .***. . .]
	

	GLP	 	A-96-085	 	[. . .***. . .]	 	[. . .***. . .]
	GLP	 	A-96-106	 	[. . .***. . .]	 	[. . .***. . .]
	

	GLP	 	A-96-130	 	[. . .***. . .]	 	[. . .***. . .]
	GLP	 	A-97-032	 	[. . .***. . .]	 	[. . .***. . .]
	GLP	 	A-97-054	 	[. . .***. . .]	 	[. . .***. . .]
	GLP	 	97.0700	 	[. . .***. . .]	 	[. . .***. . .]
	

	GLP	 	97.0759	 	[. . .***. . .]	 	[. . .***. . .]
	GLP	 	SBL25-35	 	[. . .***. . .]	 	[. . .***. . .]
	

***Confidential Treatment Requested  

QuickLinks

Exhibit 10.12

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