Document:

Exhibit 4.2(n)

 

“CONFIDENTIAL TREATMENT REQUESTED. CONFIDENTIAL PORTIONS OF THIS
DOCUMENT HAVE BEEN OMITTED AND HAVE BEEN SEPARATELY FILED WITH THE
COMMISSION.  CONFIDENTIAL TREATMENT HAS
BEEN REQUESTED WITH RESPECT TO THE OMITTED PORTIONS.”

 

	
  VARIATION
  AGREEMENT dated

  	
   

  	
  2003

  

 

BETWEEN

 

AUTOGEN
RESEARCH PTY LIMITED ABN 84 074 636 847 of Pigdons Road,
Waurn Ponds Victoria 3217, Australia (“Autogen Research”)

 

AND

 

SOUTHWEST
FOUNDATION FOR BIOMEDICAL RESEARCH of 7620 NW Loop, 410 San Antonio, Texas 78227-5301,
USA (“SFBR”)

 

RECITALS

 

A.                                   On
31 December 2002 Autogen Research and SFBR entered into an agreement
entitled Research, License and Commercialization Agreement (the “Research
Agreement”) setting out the terms and conditions for the R&D Program to be
carried out with the participation of the parties.

 

B.                                    In
accordance with clause 20.3 of the Research Agreement the parties now agree to
vary the Research Agreement on the terms and conditions set out in this
Variation Agreement.

 

OPERATIVE
PROVISIONS

 

1.                                     INTERPRETATION

 

1.1                              Research
Agreement definitions

 

Unless defined in this Variation
Agreement, words and phrases defined in the Research Agreement have the same
meaning in this Variation Agreement. 
Where there is any inconsistency in a definition between this Variation
Agreement and the Research Agreement, this Variation Agreement prevails.

 

1.2                              Interpretation

 

The provisions of clause 1.2 of the
Research Agreement apply to this Variation Agreement as if set out in this
Variation Agreement in full.

 

2.                                     VARIATION OF RESEARCH AGREEMENT

 

2.1                              Expansion
of Project and Additional Funding

 

With effect on and from 1 July 2003
the parties agree to vary the R&D Program and the Budgets and Workplans
under the Research Agreement, by:

 

(a)                                 expanding
the Project by:

 

(i)                                    including
a fourth and fifth research aim,

 

(“Expanded
Project”); and

 

1

 

(b)                                increasing
the Funding for the Initial Term (“Additional
Funding”),

 

in the manner set out in the schedule to
this Variation Agreement.

 

2.2                              Confirmation
of execution clause

 

The parties acknowledge that an error
appears on page 25 of the Research Agreement such that AUTOGEN LTD should
be read as AUTOGEN RESEARCH PTY LTD.

 

3.                                     MISCELLANEOUS

 

3.1                              Continuing
effect

 

Except for the variations set out in this
Variation Agreement, the terms and conditions of the Research Agreement are
unaffected by this Variation Agreement and remain in full force and
effect.  In the event of any
inconsistency between the terms of the Research Agreement and the terms of this
Variation Agreement, the terms of this Variation Agreement will prevail to the
extent of the inconsistency.

 

3.2                              Further
assurances

 

Each party must do all things and execute
all further documents necessary to give full effect to this Variation Agreement
and must refrain from doing anything that might hinder the performance of this
Variation Agreement.

 

3.3                              Amendments
in writing

 

No amendment to this Variation Agreement
has any force unless it is in writing and signed by both of the parties to this
Variation Agreement.

 

3.4                              Governing
law and jurisdiction

 

This Variation Agreement is governed by
the laws of Victoria and the Commonwealth of Australia.  Each party irrevocably submits to the
exclusive jurisdiction of the courts of Victoria.

 

3.5                              Counterparts
and facsimile execution

 

This Variation Agreement may be executed
in a number of counterparts, all of which taken together will be deemed to
constitute one and the same agreement, provided that this Variation Agreement
will be of no force and effect until the counterparts are exchanged.  A facsimile copy of this Variation Agreement
lawfully executed will be sufficient evidence of execution.

 

2

 

SCHEDULE

 

Variation
of Research Agreement

 

1.             Expanded Project

 

In Schedule 2 to the Research
Agreement:

 

(a)                                 (Insert
a new research aim)

 

4)             QTL Identification in the San Antonio Family Heart Study

 

This aim launches a
gene discovery research program based around DNA samples from the San Antonio
Family Heart Study.  Two chromosomal
regions (chromosomes 17 and 2) that SFBR investigators have shown harbor QTLs
relating to obesity/metabolic syndrome will be followed up using fine-mapping
and gene identification procedures.  SFBR
will provide Autogen with approximately 1,200 DNA samples from families that
show evidence of QTL linkage to these regions. 
Autogen will perform extensive SNP typing in these two regions in an
attempt to discover association between the obesity-related traits and the
variants in positional candidate genes within these areas. SNP typing will be
performed at the AGT Biosciences Human Genetics Laboratory in Melbourne.
Initially, a number of STRs (to approximately a 2 cM interval) will be typed to
help to improve the linkage signal. 
Following the typing of the STRs, it is anticipated that at least 150
SNPs will be typed focusing on genes within the region that have been
prioritized based on bioinformatic analysis performed by Autogen.  All subsequent data analysis will be
performed by SFBR at the AGT Biosciences Center for Statistical
Genomics.  No phenotypic or pedigree data
will be transferred off SFBR premises. 
SFBR plans to take these existing well defined and localized QTLs and
attempt identification of novel genes in the original family material to refine
localization interval and to identify the causal genes and variants.  It is anticipated that additional QTL may be
included in this research plan contingent upon the joint agreement of both SFBR
investigators and Autogen.

 

Milestones: Specific
milestones will include 1) delivery of DNA samples to Autogen at the AGT
Biosciences Human Genetics Laboratory, 2) refined QTL localization using
additional STRs, 3) QTN analysis of SNP variants within QTL regions, and 4)
identification of QTL. While the first three of these milestones are guaranteed
results, the last one is not.

 

(b)                                insert
a new research aim 5) as follows:

 

5)                                      Positional
Candidate Gene Prioritization Using Expression Microarrays on Baboon Tissues

 

This aim launches a
research program that will utilize fat and other tissues from specially chosen
baboons to aid in the search for positional candidate genes influencing
obesity/metabolic syndrome.  This
approach will tie in with the ongoing QTL prioritization scheme in the human
family studies. Differentially expressed genes within focal QTL chromosomal
regions will be searched for in baboon material.  The identification of such differentially
expressed genes will then serve to prioritize positional candidate genes for
more exhaustive study in the human samples. 
SFBR will provide Autogen with RNA extracted from

 

3

 

5 matched pairs
(one obese, one lean) of baboons (ie 10 samples in total).  RNA will be extracted from omental fat,
skeletal muscle, hypothalamus, liver, and peri-renal tissue.  Dr. Tony Comuzzie of SFBR will supervise
this part of the aim. These are samples already in the possession of Dr. Comuzzie
as part of his long-running research on obesity in baboons. The additional
funds required to cover the costs of the material collection and RNA extraction
will be paid by Autogen following direct invoice to Dr.  Comuzzie’s SFBR
account.  Once the RNA is provided to
Autogen, expression microarrays will be used to identify differentially expressed
genes.  The resulting quantitative
expression data will be used by the AGT Biosciences Center for Statistical
Genomics to form objective prioritization indices for choosing positional
candidate genes to be sequenced and tested for causal effects on
obesity/metabolic syndrome-related traits in the human samples.

 

Milestones:
Specific milestones will include 1) delivery of 5 matched pairs
(ie 10 samples) of baboon RNA to the AGT Biosciences Human Genetics
Laboratory in Melbourne, and 2) prioritization of positional candidate genes
based on expression microarray results.

 

2.             Additional Funding

 

In Item 2 of Schedule 1 to the
Research Agreement, add [$] to the
costs to account for the Additional Funding provided for material collection
and RNA extraction to be performed under research aim 4).  This Additional Funding is payable by Autogen
to SFBR by [insert date].  The grant total for Funding during the
Initial Term will now equal [$[*] plus insert
Additional Funding].

 

4

 

EXECUTED AS AN AGREEMENT

 

 

	
  SIGNED on behalf
  of

  	
  )

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  AUTOGEN
  RESEARCH PTY LIMITED

  ABN 84 074 636 847 by
  GREG COLLIER in the

  presence of:

  	
  )

  )

  )

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Ù

  	
  Signature
  of Greg Collier

  Director

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Ù

  	
  Signature of
  witness

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Ù

  	
  Name of witness
  (print)

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  SIGNED on behalf
  of

  	
  )

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  SOUTHWEST
  FOUNDATION FOR

  BIOMEDICAL RESEARCH by

                                                             in
  the presence

  of:

  	
  )

  )

  )

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Ù

  	
  Signature of

  Treasurer

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Ù

  	
  Signature of
  witness

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Ù

  	
  Name of witness
  (print)

  	
   

  	
   

  	
   

  	
   

  

 

5Exhibit 4.2(o)

 

“CONFIDENTIAL
TREATMENT REQUESTED. CONFIDENTIAL PORTIONS OF THIS DOCUMENT HAVE BEEN OMITTED
AND HAVE BEEN SEPARATELY FILED WITH THE COMMISSION.  CONFIDENTIAL TREATMENT HAS BEEN REQUESTED
WITH RESPECT TO THE OMITTED PORTIONS.”

 

EXTENSION
AGREEMENT dated July 1, 2004

 

BETWEEN

 

AUTOGEN RESEARCH PTY LIMITED(1)
ABN 84 074 636 847 of Pigdons Road, Waurn Ponds Victoria
3217, Australia (“Autogen Research”)

 

AND

 

SOUTHWEST FOUNDATION FOR
BIOMEDICAL RESEARCH of
7620 NW Loop, 410 San Antonio, Texas 78227-5301, USA (“SFBR”)

 

RECITALS

 

A.                                   On
31 December 2002 Autogen Research and SFBR entered into an agreement entitled
Research, License and Commercialization Agreement (the “Research Agreement”)
setting out the terms and conditions for the R&D Program to be carried out
with the participation of the parties.

 

B.                                    In
accordance with clause 20.3 of the Research Agreement the parties now agree to
vary the Research Agreement on the terms and conditions set out in this Extension
Agreement.

 

OPERATIVE PROVISIONS

 

1.                                     INTERPRETATION

 

1.1                              Research
Agreement definitions

 

Unless
defined in this Extension Agreement, words and phrases defined in the Research
Agreement have the same meaning in this Extension Agreement.  Where there is any inconsistency in a
definition between this Extension Agreement and the Research Agreement, this Extension
Agreement prevails.

 

1.2                              Interpretation

 

The
provisions of clause 1.2 of the Research Agreement apply to this Extension Agreement
as if set out in this Extension Agreement in full.

 

2.                                     EXTENSION AGREEMENT

 

2.1                              Extension
of Term

 

With effect on and
from 1 July 2004 the parties agree that the term of the Research Agreement is
extended until 30 June 2005 (“Extended Term”)
(unless the Research Agreement is earlier terminated in accordance with its
terms).  During the Extended Term the
terms and conditions of

 

(1) Autogen Research Pty Ltd is a wholly-owned subsidiary of ChemGenex
Pharmaceuticals Limited (ABN 79 000 248 304).

 

1

 

the Research Agreement
will continue to apply except to the extent to which they are inconsistent with
anything set out in this Agreement, in which case the provisions of this
Agreement will prevail to the extent of the inconsistency.

 

2.2          Payment and research proposal during extended term

During the
Extended Term:

 

(a)                                  the
budget set out in Schedule 1 to this Extension Agreement will be substituted
for any payment program previously applying under the Research Agreement; and

 

(b)                                 the
research plan (including any milestones set out therein) set out in Schedule 2
to this Extension Agreement will be substituted for any research proposal and
workplans previously applying under the Research Agreement.

 

3.                                     MISCELLANEOUS

 

3.1                              Continuing
effect

 

Except
for the variations set out in this Extension Agreement, the terms and
conditions of the Research Agreement are unaffected by this Extension Agreement
and remain in full force and effect.  In
the event of any inconsistency between the terms of the Research Agreement and
the terms of this Extension Agreement, the terms of this Extension Agreement
will prevail to the extent of the inconsistency.

 

3.2                              Further
assurances

 

Each
party must do all things and execute all further documents necessary to give
full effect to this Extension Agreement and must refrain from doing anything
that might hinder the performance of this Extension Agreement.

 

3.3                              Amendments
in writing

 

No
amendment to this Extension Agreement has any force unless it is in writing and
signed by both of the parties to this Extension Agreement.

 

3.4                              Governing
law and jurisdiction

 

This
Extension Agreement is governed by the laws of Victoria and the Commonwealth of
Australia.  Each party irrevocably
submits to the exclusive jurisdiction of the courts of Victoria.

 

3.5                              Counterparts
and facsimile execution

 

This
Extension Agreement may be executed in a number of counterparts, all of which
taken together will be deemed to constitute one and the same agreement,
provided that this Extension Agreement will be of no force and effect until the
counterparts are exchanged.  A facsimile
copy of this Extension Agreement lawfully executed will be sufficient evidence
of execution.

 

2

 

SCHEDULE
1: BUDGET

 

(a)                                 Item
1: Commencement Date July 1, 2004

 

 

Item 2: Total Budget for the
Intial Term is US$[*], payable in quarterly payments of $[*] (due July 1, 2004),
$[*] (October 1, 2004), $[*] (January 1, 2005) and $[*] (April 1, 2005)

 

	
  Personnel:

  	
   

  	
   

  	
   

  
	
  John
  Blangero ([*]%) PI

  	
   

  	
  [*]

  	
   

  
	
  Tom
  Dyer ([*]%) Co-I/Senior Progammer

  	
   

  	
  [*]

  	
   

  
	
  Eric
  Moses ([*]%) Co-I

  	
   

  	
  [*]

  	
   

  
	
  Tricia
  Curry ([*]%) Admin. Assistant

  	
   

  	
  [*]

  	
   

  
	
  Vicki
  Mattern ([*]%) Sr. Res. Assoc.

  	
   

  	
  [*]

  	
   

  
	
  Sub
  Total Salaries

  	
   

  	
  [*]

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  Supplies:

  	
   

  	
   

  	
   

  
	
  Computer
  Supplies

  	
   

  	
  [*]

  	
   

  
	
  Laboratory
  Supplies

  	
   

  	
  [*]

  	
   

  
	
  Communication

  	
   

  	
  [*]

  	
   

  
	
  Sub
  Total Supplies

  	
   

  	
  [*]

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  Equipment:

  	
   

  	
   

  	
   

  
	
  Computers
  (cluster addition)

  	
   

  	
  [*]

  	
   

  
	
  Sub
  Total Equipment

  	
   

  	
  [*]

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  Total Research Costs:

  	
   

  	
  $

  	
  [*]

  	
   

  
	
  Indirect Costs:

  	
   

  	
  $

  	
  [*]

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  TOTAL

  	
   

  	
  $

  	
  [*]

  	
   

  

 

3

 

Schedule 2: Project

 

ChemGenex
Center for Statistical Genomics:

 

Southwest
Foundation for Biomedical Research

 

(b)                                Research
Aims:

 

1)              Analysis of [*] ISR Candidate Genes for
Diabetes/Obesity in Human Populations.

 

In order to conclusively test for the
effects of variation in Autogen proprietary genes on diabetes/obesity related
phenotypes in humans, we will perform an exhaustive series of statistical
genomic analyses on human samples. The possible sample sources (to be
negotiated independently of this document) for these studies include (but are
not limited to) the Wisconsin families from the MRCOB study, Mexican American
families from the San Antonio Family Heart Study, and Autogen’s extant samples
from Pacific Island populations.

 

Tasks:

 

a)              Genotype cleaning: Mendelian error checking,
elimination of double recombinants. This task is limited to family-based
samples.

b)             Haplotype inference and genotype imputation.

c)              Quantitative trait nucleotide analysis using the
Bayesian model selection/model averaging approach.

d)             Conditional linkage analysis to test whether best SNP
Gene Action model accounts for linkage. 
This task is limited to family-based samples.

 

These analyses will allow us to
determine whether or not variants in a given gene appear to have functional
effects on relevant human phenotypes and whether or not the gene completely
identifies the underlying human QTL. 
Final analyses will include estimates of the posterior probability that
a given variant has functional effects for each DNA variant examined. It is
anticipated that the expected total time per ISR gene for completion of these
tasks is 16 weeks.

 

Milestones: For each gene, the completion of
tasks a – d will be considered a substantial milestone.

 

2)              Gene Discovery for Diabetes/Obesity in Human Families

 

This aim launches a gene discovery
research program based around samples from human families.  We plan to take existing well defined and
localized QTLs and attempt identification of novel genes in the original family
material. It is anticipated (although not mandatory) that these

 

4

 

analyses will be performed on samples
from current ChemGenex collaborations (including the MRCOB Wisconsin family
study or the San Antonio Family Heart Study). Currently, the specific QTLs
being assessed include: 1)  obesity QTL
at chromosome [*] in the SAFHS families; 2) obesity QTL at chromosome [*] in
the SAFHS families; and 3) diabetes-related QTL at [*] in Indo-Mauritian
families.

 

Tasks:

 

a)              Strategy 1: Focal positional candidate gene
approach. For SNPs within positional candidate genes chosen via bioinformatic
methods, a similar set of tasks to those described in Aim 2 will be performed.
These will include genotype cleaning, haplotype inference and genotype imputation,
quantitative trait nucleotide analysis, and conditional linkage analysis to
verify QTL dissection.

 

b)             Strategy 2: Positional candidate region
approach without obvious candidate genes. For QTL regions, which lack obvious
positional candidate genes, a general SNP coverage strategy will be pursued. :
Specific analytical tasks to be performed include: analysis of linkage
disequilibrium followed by optimal choice of independent SNPs; preliminary
association analysis on reduced set of unrelated founders; SNP analyses within
families including genotype cleaning, haplotype inference and genotype
imputation, QTN analysis and conditional linkage analysis.

 

Milestones: Specific milestones for each QTL
will include reporting of: 1) refined QTL localization, 2) QTN analysis of any
positional candidate gene, and 3) identification of the QTL. While the first
two of these milestones are guaranteed results, the last one is not.

 

5

 

	
  EXECUTED as an AGREEMENT

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  SIGNED on behalf of

  	
  )

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  AUTOGEN
  RESEARCH PTY LIMITED

  ABN 84 074 636 847 by
  GREG COLLIER in the

  presence of:

  	
  )

  )

  )

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Ù

  	
  Signature of Greg
  Collier

  Director

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Ù

  	
  Signature of witness

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Ù

  	
  Name of witness (print)

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  SIGNED on behalf of

  	
  )

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  SOUTHWEST
  FOUNDATION FOR

  BIOMEDICAL RESEARCH by

                                                             in
  the presence

  of:

  	
  )

  )

  )

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Ù

  	
  Signature of

  Treasurer

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Ù

  	
  Signature of witness

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Ù

  	
  Name of witness (print)

  	
   

  	
   

  	
   

  	
   

  

 

6

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