Document:

Unassociated Document

    EXHIBIT
10.1(ii)

     

    ADDENDUM

     

    This
Addendum is made in Jerusalem as of this 22 day of November, 2005 (the “Effective Date”) and is
entered in to by and among Yissum the Research Development Company of the Hebrew
University of Jerusalem (hereinafter: “Yissum”) and Biocancell
Therapeutic Inc., a company incorporated under the laws of the State of Delaware
(hereinafter: “DBTI”)
and Biocancell Therapeutics Ltd., a company established under the laws of the
State of Israel (hereinafter: “DBTL”) (DBTI and DBTL shall
collectively be referred to as the “Company”), for the purposes of
amending certain provisions in the Exclusive License Agreement executed by
Yissum, DBTI and DBTL on November 14, 2005 (hereinafter: the “License Agreement”), all as
set forth hereunder.

     

    
      	
              1.

            	
              Capitalized
      terms used in this Addendum shall have the meaning ascribed to them in the
      License Agreement.

            

    

     

    
      	
              2.

            	
              This
      Addendum shall form an integral part of the License
    Agreement.

            

    

     

    
      	
              3.

            	
              Yissum
      and the Company agree that as of the Effective Date, the provisions set
      forth below in the License Agreement will be amended as
      follows:

            

    

     

    
      	
              
              

            	
              (a)

            	
              section
      3.2 of the License Agreement shall be replaced in its entirety with the
      following provision:

            

    

     

    Sixty
(60) days after the end of each calendar year commencing from the date of the
First Commercial Sale, Company shall furnish Yissum with an annual report
(herein the “Periodic
Report”) detailing the total sales effected during the reporting period
and the total Royalties and Sub-license Revenues due to Yissum in respect of
that period.

     

    
      	
              
              

            	
              (b)

            	
              section
      10.1 of the License Agreement shall be replaced in its entirety with the
      following provision:

            

    

     

    Unless
earlier terminated, as hereinafter provided, the term of this Agreement shall
expire on a country-by-country basis at such time when no Valid Claim exists, or
if no Patent was issued in a country, on the ninth anniversary of the First
Commercial Sale in such country, thereafter the License in such country shall
expire, provided in each case that Company may extend the term of the Agreement
on a country-by-country basis for an additional period of one year each by
continuing to pay the consideration set forth in section 3. Upon the expiration
of the License in a given country (as set forth above), the Company shall have a
perpetual, worldwide, royalty-free, fully paid-up License in that
country.

     

    
      	
              
              

            	
              (c)

            	
              All
      sections of the License Agreement not amended by the terms of this
      Addendum shall remain unchanged and of full force and
    effect.

            

    

     

    
      
        	
                4.

              	
                Yissum
      and Company agree that the Research Plan and budget attached hereto shall
      also be attached to the License Agreement and shall form Appendix 2 of the
      License Agreement.

              

      

    

    
      
         

      

      
         

        
          

        

      

      
         

      

    

     

    IN
WITNESS WHEREOF, the Parties hereto have executed and delivered this Agreement
in multiple originals by their duly authorized officers and representatives on
the respective dates shown below, but effective as of the Effective
Date.

     

    YISSUM
RESEARCH DEVELOPMENT COMPANY

    OF
THE
HEBREW UNIVERSITY OF JERUSALEM

     

    
      
        
          
            
              
                
                  
                    
                      
                        
                          
                            	
                                    By:

                                  	
                                    /s/
      Reuven Ron

                                  	 
      	
                                    By:

                                  	
                                    /s/
      Herve Bercovier

                                  
	 
      	 
      	 
      	 
      	 
      
	
                                    Name: 

                                  	
                                    REUVEN
      RON

                                  	 
      	
                                    Name: 

                                  	
                                    PROF.
      HERVE BERCOVIER

                                  
	 
      	 
      	 
      	 
      	 
      
	
                                    Title:

                                  	
                                    VICE
      PRESIDENT

                                  	 
      	
                                    Title:

                                  	
                                    Chairman

                                  
	 
      	 
      	 
      	 
      	
                                    Authority
      for Research and Development

                                  
	

                                    Date:

                                  	NOV
      22 2005	 
      	 
      	
                                    Hebrew
      University of Jerusalem

                                  
	 
      	 
      	 
      	 
      	 
      
	
                                     

                                  	
                                     

                                  	 
      	Date: 
      	
                                     

                                  

                          

                        

                      

                    

                  

                

              

            

          

        

      

    

     

     

    BIOCANCELL
PHARMACEUTICALS INC.

     

    
      
        
          
            
              
                
                  
                    
                      
                        	
                                By:

                              	
                                /s/
      Avi Barak

                              	 
      	
                                By:

                              	
                                /s/
      Uri Danon

                              
	 
      	 
      	 
      	 
      	 
      
	
                                Name: 

                              	 
      	 
      	
                                Name: 

                              	
                                URI
      DANON

                              
	 
      	 
      	 
      	 
      	 
      
	
                                Title:

                              	 
      	 
      	
                                Title:

                              	
                                PRESIDENT

                              
	 
      	 
      	 
      	 
      	 
      
	
                                Date:

                              	 
      	 
      	
                                Date:

                              	
                                NOV
      22,
2005

                              

                      

                    

                  

                

              

            

          

        

      

    

     

     

    BIOCANCELL
PHARMACEUTICALS LTD.

    

    
      
        
          
            
              
                
                  
                    
                      
                        	
                                By:

                              	
                                /s/
      Avi Barak

                              	 
      	
                                By:

                              	
                                /s/
      Uri Danon

                              
	 
      	 
      	 
      	 
      	 
      
	
                                Name: 

                              	 
      	 
      	
                                Name: 

                              	
                                URI
      DANON

                              
	 
      	 
      	 
      	 
      	 
      
	
                                Title:

                              	 
      	 
      	
                                Title:

                              	
                                PRESIDENT

                              
	 
      	 
      	 
      	 
      	 
      
	
                                Date:

                              	 
      	 
      	
                                Date:

                              	
                                NOV
      22,
2005

                              

                      

                    

                  

                

              

            

          

        

      

    

    
      
         

      

      
         

        
          

        

      

      
         

      

    

     

    Research
Plan

     

    General
Aims:

     

    
      	
               
      

            	
              1)

            	
              To
      develop additional novel DNA based therapy strategies for bladder cancer.
      The goals of the present project are accordingly the development of
      molecular markers for TCC prognosis and of a DNA-based gene therapy
      tailored to the properties of each tumor, by implementing new molecular
      diagnostic methods. A novel therapy approach based on patient-specific
      gene expression profiles in each cancer tailored to individual patients by
      using selected transcriptional regulatory sequences for DNA-based therapy
      will be developed. It should enable us to identify likely non-responders
      in advance, thereby avoiding treatment failures with unnecessary suffering
      and costs.

            

    

    
      	
               
      

            	
              2)

            	
              Evaluation
      of the therapeutic effect of new toxin vectors now carrying kanamycin
      driven by the H19 regulatory
sequences.

            

    

    
      	
               
      

            	
              3)

            	
              To
      continue testing the therapeutic potential of our toxin vector in
      compassionates patients (case study), to base the safety and efficacy of
      the treatment for a long term..

            

    

    
      	
               
      

            	
              4)

            	
              In
      order to perform the clinical trials a large amount of plasmid will be
      required that can no longer be generated using bench protocols, thus
      scaling-up nuclei acid purification protocol will be
      developed.

            

    

    
      	
               
      

            	
              5)

            	
              To
      use the regulatory sequences of the imprinted genes H19 and Insulin growth
      factor 2 (IGF-2) for preclinical development of DNA based therapy of human
      colorectal cancer liver metastasis. The therapeutic potential of the toxin
      vector will be tested in compassionate patients suffering of liver colon
      metastases, preparing a platform for a Phase I clinical
    study.

            

    

    
      	
               
      

            	
              6)

            	
              To
      further validate the role of H19 acting as an oncogene, to determine the
      potential dowstream targets of H19, and to
      substantiate the potential therapeutic value of knocking down H19 in human
      tumors.

            

    

     

    Research
Program

     

    1. Since our results so far
are based on limited study populations, quantitative expression profiles for
H19 and IGF2 (P3
and P4 transcripts) will be determined in a large number of bladder carcinoma
specimens using a computerized in situ RNA hybridization analysis technology and
quantified by “TMP” (telemolecular pathology) software that permits high
resolution quantitative analysis of in situ hybridization photomicrographs and
real-time transmission of the resulting images. The goal is to correlate both
the numbers of cells expressing H19 and other genes with
different stages of bladder cancer and their co-expression in human bladder
tumors. This study will be extended to each gene identified as highly expressed
in TCC but not expressed in normal tissue. From published data sets on gene
expression in TCC and from our own Micro array-based gene expression profiling
in bladder cancer, we will extract genes that are not expressed in normal
bladder tissue but become induced in invasive or papillary TCC. This expression
pattern will be confirmed by RT-PCR on a set of RNAs from TCC and normal bladder
tissues from different stages available in the lab and on TCC cell lines. For
the following investigation, genes will be selected that are not significantly
expressed in other adult tissues (except in testes), i.e. oncofetal markers
(like H19) or
cancer-testis antigens (like the MAGE-A genes). In parallel to
the ongoing investigation of tissue specimens, collection of follow-up data for
the patients will be continued to determine whether expression of transcripts of
H19, IGF2 or other genes identified using expression profiling with DNA
Microarrays, differs not only between different stages and grades of bladder
cancer, but has also prognostic value. Genes yielding significant prognostic
results in univariate analysis will be tested further in multivariate analysis
together with established prognostic parameters (TNM stage, tumor grade,
multifocality etc.). Further, selected regulatory sequences confirmed as
differentially expressed in normal tissue/cells and cancer tissues/cells will be
tested for promoter activity in transfection experiments.

    
      
         

      

      
         

        
          

        

      

      
         

      

    

     

    Subsequently
to the studies on tumor tissues, we aim to evaluate at least one urine-based DNA
TCC marker each or a combination of markers that supersedes the diagnostic
accuracy and reproducibility, and preferably also the economy, of presently
known markers.

     

    2. The experiments in this
part of the work program aim at expanding the repertoire of transcriptional
activating sequences that are differentially expressed in bladder cancer to
become capable of treating a broader range of TCC beyond those that express
H19. The research plan
calls for invoking tumor specific-dependent regulatory sequences to selectively
express cytotoxic effectors in tumor cells. Currently, the arsenal of our
therapeutic vectors comprises constructs carrying regulatory sequences of H19 and of IGF2. H19-DT-A constructs
have been developed to the point of using them in patients. The selected
regulatory elements will be incorporated into plasmid vectors (“naked DNA”)
containing reporter (β-galactosidase,
luciferase or GFP) or toxin genes. The plasmid vector to be used as backbone for
the regulatory sequence analyses will be pGL3 (Promega). Delivery via plasmid
vector (“naked DNA”), has been found to be surprisingly efficient in vivo
according to our Preliminary Studies. Activity of the plasmid constructs will be
assessed ex vivo in human and murine tumor cell lines selected by their pattern
of expression and in normal urothelial cells for comparison. By the end of these
ex vivo analyses, we expect to assemble a variety of optimized vectors, with
both reporter and toxin genes, to be entered into animal in vivo efficacy
studies as described below. The therapeutic potential of toxin expression
constructs driven by the selected tumor specific regulatory sequences will be
studied in distinct animal models of bladder cancers which are complementary and
permit the study of tumors with distinctive histopathologies. All animal models
and techniques for investigation of the animal tumors are established and have
been used in previous work. (A) Since BBN-induced rat bladder tumors share
histological features with human papillary bladder TCC, we will employ this
animal model. Once rumors have been BBN induced, our therapeutic vectors will be
evaluated by intravesical gene delivery. Naked DNA expression constructs
complexed with a DNA/PEI (polyethylenimine) will be delivered intravesically via
catheter, after removing the urine. Intravesical delivery enables local
administration and efficient delivery of therapeutic genes to cancer cells with
minimal systemic exposure. We will start with marker experiments, using reporter
expression constructs (β-gal, GFP and Luc)
to monitor delivery efficiency and check the selective activity of
tumor-specific promoters. Then the DT-A toxin and the CD expression vectors will
be evaluated. (2) The second animal model
will consist of human bladder carcinoma cell lines implanted into nude mice. We
will study the therapeutic potential of our toxin vectors on orthotopically
implanted cell lines (UMUC-3, RT-112) in female CD-1 nude mice. DNA will be
administered transurethrally 4 and 7 d after cells implantation. We will use
these human bladder cancer cells engineered to stably express the GFP protein in
vivo to visualize the tumor burden over time by intravital imaging using a
Macro-illumination imaging system, allowing us to reduce the number of animals
used in these experiments.

     

    3. An expression vector
expressing the human gene TNF-α under the
control of the H19 promoter will be generated and its function will be assessed
ex-vivo in various bladder carcinoma cell lines selected by their pattern of
expression of H19. The anti-proliferation and in vitro killing effect of
TNF-α will be
verified by cell counting and MTT assay. The TNF-α expression level
following transfection will be assayed by ELISA in the supernatant. Effects of
the H19-TNF-α
vector will be compared to those of DTA-H19 and the combined effect of
both vectors. These experiments will serve to test the potential synergisim
between DT-A and TNF-α in TCC. In
particular, the combined effect of the two plasmids expressing the DT-A or the
TNF-α will be
tested in cell lines that are resistant to the cytotoxic effect of either DT-A
or TNF-α. The
therapeutic potential of the expression vectors for TNF-α and their
potential synergistic antitumor effect with DT-A vectors will then be explored
in two animal models: (A) immunocompromised CD-1 mice implanted with human
bladder carcinoma cell lines. Two weeks after tumor cell inoculation the tumor
size will be measured. One group of mice will then be treated with the toxin
vector DTA-H19, a second group with the vector expressing the TNF-α under the
control of the H19
promoter, a third group will be treated with the combination of both
toxin vectors. A fourth control group will be treated with luciferase reporter
vector, containing H19 transcriptional
regulatory sequences. The mice will receive three intratumoral injection of the
vectors every 2 days. The animals will be sacrificed 3 days after the last
injection, the tumors will be excised and their ex-vivo weight and volume will
be measured. Samples of the tumors will be processed for histological
examination for evidence of necrosis and persistent tumor. To monitor the in
vivo TNF-α
expression at the mRNA level, RNA from the tumors will be isolated and RT-PCR
will he performed. (B) bladder tumors induced by subcutaneous injection of
syngenic mouse bladder carcinoma cells into the back of female C3H/He mice. Two
weeks after tumor development the mice will be randomized into four groups and
treated as described in (A).

    
      
         

      

      
         

        
          

        

      

      
         

      

    

     

    4. We have previously reported
the construction of expression vectors carrying the gene for diphtheria toxin A
(DT-A under the control of a 814 bp 5’-flanking region of the H19 gene). The
cell killing activity of these constructs corresponded to the activity of the
H19 regulatory sequence in the transfected cells. The therapeutic potential of
toxin expression constructs driven by H19 regulatory sequences was evaluated in
distinct animal models of bladder cancers. The Food and Drug Administration
(FDA) advises strongly against the use of β-lactam resistance
markers in plasmids that will be used as therapeutics. Thus, the β-lactam resistance
marker cassette in the plasmid expressing either the DT-A gene or the reporter
gene will be replaced by kanamycin resistance gene. Governmental regulatory
issues and plasmid efficacy should be taken into account when designing the
plasmid vector intended for use in clinical trials. In order to validate the
biological activity of the vectors now carrying the kanamicyn resistance gene,
in vitro and in vivo experiments will be performed. The biologic or
pharmacologic activity of the constructs carrying the kanamycin resistance gene
will be tested by in vitro bridging experiments, and compared to that obtained
using the plasmids carrying the Amp resistance gene. The therapeutic potential
and the safety of the kanamycin carrying toxin expression constructs driven by
H19 regulatory sequences will be evaluated in two distinct animal models of
bladder cancers which are complementary and permit the study of tumors with
distinctive histopathologies: I) a rat carcinogen-induced bladder tumor model
(with a prominent papillary component) that parallels superficial papillary TCC
in humans at varying stages of tumor progression, and II) immunocompromised SCID
mice implanted with human bladder carcinoma cell lines.

     

    5. The therapeutic potential
of the kanamycin carrying toxin expression constructs driven by H19 regulatory
sequences will be tested in compassionate patients (including the patients that
were already treated with the toxin vector carrying the Amp resistance gene)
that underwent several transurethral resection of superficial low-grade tumor,
while no adjuvant intravesical treatments succeeded to stop the recurrences.
Patients will receive DTA-H19 intravesically on day 1. Treatment will continue
once a week for a total of 6 weeks in the absence of unacceptable toxicity. The
patient will receive escalating doses of DTA-H19. In the absence of grade III
toxicity or worse in the first cohort treated, subsequent cohorts of patients
each will receive escalating doses of DTA-H19 on the same schedule. If no
toxicity will be observed dose escalation will continue. If the patient
experiences grade IV toxicity, dose escalation will cease and the MTD (maximal
tolerated dose) will be defined as the previous dose level. One week after
completion of treatment the patient will be evaluated by video-cytoscopy,
urinary cytology and bladder biopsy, monitoring of residual H19-DTA in body
fluids including urine, blood and nose smear will be performed by PCR. Patients
will be tested for electrolytes, kidney and liver function. Six weeks after
treatment completion patients will undergo video-cytoscopy, urinary cytology and
biopsy, monitoring of residual DTA-H19 in body fluids including urine, blood and
nose smear by PCR, and testing for electrolytes, kidney and liver function.
Follow-up will continue every three
months by video-cytoscopy during the first year after treatment and by
routine clinical monitoring after that.

    
      
         

      

      
         

        
          

        

      

      
         

      

    

     

    6. After testing the selected
regulatory sequences in animal models, optimization of therapy strategies in
human will be performed. In order to perform a clinical trial using one of the
validated therapeutic vectors a large amount of plasmid will be required that
can no longer be generated using bench protocols, thus scaling-up nuclei acid
purification protocol will be developed. Following the scale-up procedure,
lot-to-lot release tests will be established, monitoring consistency and lot
reproducibility. Govermental regulatory issues and plasmid efficacy will he
taken into account when designing the plasmid vetor intended for use in clinical
trials. In accordance with regulatory requirements, a master cell bank will be
generated for small-scale GMP production. A pilot batch of the plasmid will be
produced and evaluated in pre-clinical studies. A process for the production of
65 liter will be developed, in comparison to the current lab procedure, that
produces only 0.5 liter. GMP manufacture of plasmid for use in human clinical
studies will include the performance and documentation of Quality Control (QC)
tests. The production process will be free of RNase for the generation of media
lysates to avoid potential contamination of the final product with any animal
derived component, and hence putative human pathogens (e.g. bovine spongiform
encephalopathy), which is in compliance with FDA regulations and deals with the
challenges related to the large-scale production of E. Coli, which includes
optimization of the biologicals system (vector/host/fermentation media).
Essentially the process involves fermentation, cell lysis and purification
through a series of centrifugation and wash steps, endotoxin removal and plasmid
purification on a DEAE anion exchange chormatography column, and plasmid
concentration by isopropanol. The plasmid product will be tested for
specifications and lot-to-lot release. The DNA contenst in the plasmid and the
presence of other cell-derived contaminants, such as RNA and proteins, will be
evaluated by measuring the A260/280 ratio of absorbance. The homogeneity of size
and structure, supercoiled vs. linear, will be tested by gel
electrophoresis.

     

    The
identity of the DNA plasmid will be determined by restriction enzyme digestion
with multiple enzymes. A test for sterility to detect aerobic and anaerobic
bacteria and Mycoplasm testing will be performed.

     

    7. We have previously showed
that the human H19 and IGF2-P3 regulatory sequences were able to drive the DT-A
expression in the rat colon carcinoma CC531 cells (Ohana et al 2005). The cell
killing activity of these constructs corresponded to the activity of the H19
regulatory sequence in the transfected cells. Therefore, these cells proved to
be suitable for the generation of the orthotopic animal model used in this study
to examine the anti-tumor effect of DTA-H19 and DTA-P3 expression vectors in
vivo. This therapy was shown recently to successfully reduce subcapsular induced
liver tumors in a metastatic model of rat CC531 colon carcinoma (Ohana et al.
2005). Although a connection between IGF II expression and the development of
liver metastases from colorectal cancers has been shown thus far H19 expression
in liver metastases in humans, has not been studied. We investigated the
expression of the imprinted oncofetal H19 gene in hepatic metastases derived
from a range of human carcinomas, and assessment of its prognostic value in
order to establish the basis for developing a DNA based therapy for such
metastases. The positive results using the toxin vector DTA-H19, prompted us to
test during the next year the antitumoral effect of the toxin vector DTA-P3 and
DTA-P4 injected intraperitoneally in combination with the transfection enhancer
PEI, into the rat orthotopic model for colon metastases in the liver.
Preliminary experiments support the concept that regional arterial delivery of
the expression vectors might be an effective treatment for colorectal liver
metastases. The therapeutic potential of the toxin constructs DTA-H19, DTA-P3
and DTA-P4, will be evaluated in the established liver metastases animal model
following repeated regional delivering of the toxin vectors using intrahepatic
injection. In this approach we combine the use of the regulatory sequences of
the H19 and IGF2-P3 genes that drive the expression of the cytotoxic gene in the
tumors only and regional arterial delivery of these toxin vectors. Like in
clinical practice, implantable ports will be used to allow repeat administration
of the vector.

     

    The
replacement of the Amp resistance gene by the Kan resistance gene in the
expression vectors DTA-P3 and DTA-P4 will also be performed.

     

    These
experiments may serve as a platform for the design of a clinical study on
compassionate patients.

    
      
         

      

      
         

        
          

        

      

      
         

      

    

    8. Preliminary in vitro
experiments using Hep3B hepatocarcinoma cells showed that H19 RNA was knockdown
as determined by RT-PCR analysis. Recent results showed that HCC tumors fromed
from Hep3B in vitro transfected with H19 siRNA encountered a significant
retardation of tumor growth, and in some cases tumor did not form at all. These
preliminary observations encourages us to assess H19 as a therapeutic target for
HCC and possibly for other tumors in which H19 is significantly increased. Our
initial experiments will be to explore the hypothesis that H19 act as an
oncogene both in vitro and in vivo based in our preliminary results. Our next
step will be to explore the molecular mechanism of this effect. Our initial
observations are suggestive of a therapeutic potential for siRNA against H19
inhibiting tumor growth. We will assess the anti tumor growth effect in vitro in
a panel of H19 positive cell lines. The experiments will be performed both in
normal and serum starvation conditions. For controls we would apply H19 negative
cell lines, from the same lineages and also non-relevant siRNAs with potential
low off target effects. The effect of the siRNA against H19 will be assessed by
cell proliferation studies and metabolic read-outs. We will investigate and
employ different siRNA delivery methods for in vitro and in vivo delivery. To
check the therapeutic potential of siRNA duplexes targeting the human H19 RNA,
CD-1 nude mice will be implanted with H19 expressing Hep3B cells or other tumor
cell lines. For the assessment to the anti-tumor effect in vivo, all tested cell
lines will be stably transduced with the luciferse (luc) expression vector;
then, luc expression will be assessed with the sensitive CCCD system to monitor
and quantify the levels of luc. This will enable us to measure the efficiency of
siRNA delivery and also will serve to assess the effect of anti H19 siRNA on
tumor growth. We would also determine the anti tumor effect through tumor volume
measurements, and by survival studies. The mechanism of the anti-tumor effects
will also be investigated in vivo as described above for the in vitro
studies.

    
      
         

      

      
         

        
          

        

      

      
         

      

    

    Research
Budget

    

    Hochberg’ lab
costs

    All
figures are in US
$K                                           Updated:
October 31, 2005

    

    Lab costs (for year #1
only)

    

    
      
        
          
            
              
                
                  
                    
                      
                        
                          
                            
                              
                                
                                  
                                    
                                      
                                        
                                          
                                            
                                              
                                                
                                                  
                                                    
                                                      
                                                        	
                                                                Study
      group

                                                              	 	
                                                                Cost
      item

                                                              	 	
                                                                Total

                                                              
	
                                                                Bladder
      studies

                                                              	 	
                                                                
                                                                  Bridging
      studies

                                                                

                                                              	 	
                                                                10

                                                              
	 
      	 	
                                                                
                                                                  Immunology
      studies, cell necrosis caused by DTA-H19 treatment might induce an immune
      reaction

                                                                

                                                              	 	
                                                                5

                                                              
	 
      	 	
                                                                
                                                                  Compassionate
      use

                                                                

                                                              	 	
                                                                4

                                                              
	 
      	 	
                                                                IGF2,
      siRNA and TNF studies

                                                              	 	
                                                                12

                                                              
	
                                                                Liver
      studies

                                                              	 	
                                                                
                                                                  Intra
      arterial administration studies

                                                                

                                                              	 	
                                                                14

                                                              
	 
      	 	
                                                                
                                                                  IGF2,
      siRNA and TNF studies

                                                                

                                                              	 	
                                                                12

                                                              
	
                                                                Annual
      personnel costs (detailed below)

                                                              	
                                                                219

                                                              
	
                                                                Total
      costs

                                                              	
                                                                276

                                                              
	
                                                                University
      overhead of 35%

                                                              	
                                                                97

                                                              
	
                                                                Total
      Research Cost

                                                              	
                                                                373

                                                              

                                                      

                                                    

                                                  

                                                

                                              

                                            

                                          

                                        

                                      

                                    

                                  

                                

                              

                            

                          

                        

                      

                    

                  

                

              

            

          

        

      

    

    

    The
Total Research Cost as set forth in this Research Budget shall be paid to Yissum
in advance, in four (4) equal installments. 

     

    The
first installment shall be on July 1, 2006 and the remaining installments shall
be paid thereafter at the beginning of each 3 month period.

    

    Lab wages
breackdown:

    
      
        
          
            
               

            

          

        

      

    

    
      
        
          
            
              
                
                  
                    
                      
                        
                          
                            
                              
                                
                                  
                                    
                                      
                                        
                                          
                                            
                                              	
                                                      Name

                                                    	 	
                                                      Role

                                                    	 	
                                                      Annual
      wage

                                                    	 	 	
                                                      Effort
      (%)

                                                    	 
	
                                                      Prof.
      Avraham Hochberg

                                                    	 	 
      	 	 	0	 	 	 	 
	
                                                      Dr.
      Patricia Chana

                                                    	 	
                                                      Laboratory
      Manager

                                                    	 	 	60	 	 	 	100	%
	
                                                      Prof.
      Suhail Ayash

                                                    	 	
                                                      Diagnostics
      and immunology

                                                    	 	 	50	 	 	 	100	%
	
                                                      Dr.
      Birman Tatiana

                                                    	 	
                                                      Pathology
      and Animal studies

                                                    	 	 	45	 	 	 	100	%
	
                                                      Aya
      Mizrahi, PhD student

                                                    	 	
                                                      Liver
      studies

                                                    	 	 	10	 	 	 	50	%
	
                                                      Blumberg
      Yair, Msc

                                                    	 	
                                                      Bladder
      studies

                                                    	 	 	10	 	 	 	100	%
	
                                                      Tamar
      Snieder

                                                    	 	
                                                      Lab
      Technichian

                                                    	 	 	18	 	 	 	100	%
	
                                                      Doron
      Amit PhD student

                                                    	 	
                                                      IGF2-P4
      studies

                                                    	 	 	20	 	 	 	100	%
	
                                                      Colel
      Turgemam

                                                    	 	 
      	 	 	6	 	 	 	25	% 
	 	 	 	 	 	 	 	 	 	 	 
	Total
      of annual wages	 	 	 	 	219	 	 	 	 	 

                                            

                                          

                                        

                                      

                                    

                                  

                                

                              

                            

                          

                        

                      

                    

                  

                

              

            

          

        

      

    

     

    
      
        
          	
                  Lab
      R&D costs

                	
                  Confidential

                	
                  Page
      1Unassociated Document

    EXHIBIT 10.1(iii)

     

    AMENDMENT
TO LICENSE AGREEMENT

     

    Made in
Jerusalem this 11 day of September 2007, by and between:

     

    YISSUM RESEARCH DEVELOPMENT COMPANY OF THE HEBREW
UNIVERSITY OF JERUSALEM, of Hi Tech Park, Edmond J. Safra Campus, Givat
Ram, Jerusalem 91390 Israel, Fax: +972-2-658 6689; ( “Yissum”); and

     

    BIOCANCELL THERAPUEUTICS LTD., of Beit Beck,
Har Hotzvim, Jerusalem (the “Company”)

    

    
      
        	
                WHEREAS:

              	 
      	
                the
      Company and Yissum executed an amended and restated license agreement on
      November 14, 2005 (the “License
      Agreement”), pursuant to which the Company obtained an exclusive
      license to certain patents owned by Yissum based upon the inventions of
      Professor Abraham Hochberg (the “Researcher”); and

              
	 
      	 
      	 
      
	
                WHEREAS:

              	 
      	
                The
      Parties wish to amend certain aspects of the License
      Agreement.

              

      

    

     

    NOW
THEREFORE THE PARTIES DO HEREBY AGREE AS FOLLOWS:

     

    
      	
              1.

            	
              Interpretation
      and Definitions

            

    

     

    
      
        	
              	
                1.1.

              	
                The
      preamble constitutes an integral part this Amendment and shall be read
      jointly with its terms and
conditions.

              

      

    

     

    
      
        	
              	
                1.2.

              	
                Capitalized
      terms set forth in this Amendment and which are not defined, shall have
      the meaning ascribed thereto in the License
  Agreement.

              

      

    

     

    
      
        	
              	
                1.3.

              	
                Unless
      otherwise indicated herein, the terms and conditions of the License
      Agreement shall apply to this
Amendment.

              

      

    

     

    
      
        	
              	
                1.4.

              	
                The
      headings of the sections in this Amendment are for the sake of convenience
      only and shall not serve in the interpretation of the
      Amendment.

              

      

    

     

    
      	
              2.

            	
              Ownership

            

    

     

    
      	
            	
              2.1.

            	
              Section
      5 shall be amended to read as
follows:

            

    

     

    
      
        	
              	
                5.1

              	
                All
      rights in and to the Licensed Technology shall be owned by Yissum, and the
      Company shall hold the rights granted pursuant to the License hereunder
      and make use of them exclusively in accordance with the terms of this
      Agreement. The Research Results resulting from the Research conducted in
      Section 4.4 shall be exclusively owned by Yissum, shall form part of the
      Licensed Technology and shall be licensed to the Company under the same
      terms and conditions of this
Agreement.

              

      

    

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

    
      
        	
              	
                5.2

              	
                Notwithstanding
      the foregoing, in light of the current requirements of the Office of the
      Chief Scientist of the Israel Ministry of Industry, Trade and Labor (the
      “OCS”), the Parties agree that all intellectual property rights developed
      pursuant to this Agreement using OCS funding, including, but not limited
      to, intellectual property rights arising from the conduct of clinical
      trials funded by the OCS, (“OCS
      IP”) will be fully and absolutely owned by the Company. In the
      event that the Company receives such OCS funding, it will provide Yissum
      with sufficient written documentation to enable the Parties to define what
      intellectual property will be subject to provisions of this section.
      Nevertheless, (i) should there be a change in OCS requirements concerning
      ownership of intellectual property that are applicable to the OCS IP; or
      (ii) should the Company be voluntarily or involuntarily dissolved, all
      rights in OCS IP shall revert, as far as legally possible and appropriate,
      to Yissum, subject, if required, to the approval of the OCS. The Company
      agrees to take all reasonable steps necessary to assign or have assigned
      ownership of such OCS IP to
Yissum.

              

      

    

     

    REST
OF PAGE LEFT DELIBERATELY BLANK

    
      
         

      

      
        Page 2 of
3

        
          

        

      

      
         

      

    

     

    IN
WITNESS THE HANDS OF THE PARTIES

     

    
      
        
          
            
              
                
                  
                    
                      
                        
                          
                            
                              
                                
                                  	
                                          YISSUM

                                        	 
      	
                                          THE
      COMPANY

                                        	 
	 
      	 
      	 
      	 
      	 
      	 
	
                                          By:

                                        	
                                          /s/ Nava Swerky

                                        	 
      	
                                          By:

                                        	
                                          /s/ Avi Barak

                                        	 
	 	 	 	 	 	 
	
                                          Name:

                                        	
                                          Nava Swerky

                                        	 
      	
                                          Name:

                                        	
                                          Avi
      Barak

                                        	 
	 	 	 	 	 	 
	
                                          Title:

                                        	
                                          Pres
      & CEO

                                        	 
      	
                                          Title:

                                        	
                                          Chief Executive Officer

                                        	 
	 	 	 	 	 	 
	
                                          Date:

                                        	
                                          16.9.07

                                        	 
      	
                                          Date:

                                        	
                                          Sep
      11, 2007

                                        	 

                                

                              

                            

                          

                        

                      

                    

                  

                

              

            

          

        

      

    

    

    
      
        
          
            
              
                
                  
                    
                      
                        
                          
                            
                              
                                
                                  
                                    	
                                            By:

                                          	
                                            /s/ Bob Frantenberg

                                          	 
      	
                                            By:

                                          	
                                            /s/ Ira Weinstein

                                          	 
	 	 	 	 	 	 
	
                                            Name:

                                          	
                                            Bob Frantenberg

                                          	 
      	
                                            Name:

                                          	
                                            Ira Weinstein

                                          	 
	 	 	 	 	 	 
	
                                            Title:

                                          	
                                            General
      Counsel

                                          	 
      	
                                            Title:

                                          	
                                            CFO

                                          	 
	 	 	 	 	 	 
	
                                            Date:

                                          	
                                            16.9.07

                                          	 
      	
                                            Date:

                                          	
                                            Sept.
      10, 2007

                                          	 

                                  

                                

                              

                            

                          

                        

                      

                    

                  

                

              

            

          

        

      

    

     

    I the
undersigned, Prof. Abraham Hochberg, have reviewed, am familiar with and agree
to all of the above terms and conditions. I hereby undertake to cooperate
fully with Yissum in order to ensure its ability to fulfill its obligations
hereunder, as set forth herein.

    

    
      
        
          
            
              	 	
                      /s/
      Abraham Hochberg

                    	 
      	
                      16/9/07

                    	 
	 	
                      Prof.
      Abraham Hochberg

                    	 
      	
                      Date
      signed

                    	 

            

          

        

      

    

    
      
         

      

      
        Page 3 of
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