##### 



EXHIBIT
10.58
 ***Text Omitted and Filed SeparatelyConfidential Treatment
RequestedUnder 17 C.F.R. §§ 200.80(b)(4)
and240.24b-2(b)(1)




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##### 



Confidential
    
    13-Nov-03
  CLAUSE
    
    PAGE1.
    
    DEFINITIONS & PURPOSE
    
    
    12.
    
    OBLIGATIONS OF BIOTECNOL
    
    
    63.
    
    OBLIGATIONS OF IDM
    
    
    74.
    
    PAYMENT
    
    
    85.
    
    PROGRAMME MANAGEMENT
    
    
    116.
    
    SUB-CONTRACTING AND OUTSOURCING
    
    
    127.
    
    INTELLECTUAL PROPERTY RIGHTS
    
    
    148.
    
    CONFIDENTIALITY
    
    
    169.
    
    WARRANTIES AND DISCLAIMER
    
    
    1710.
    
    DURATION AND TERMINATION
    
    
    1811.
    
    EFFECT OF TERMINATION
    
    
    1912.
    
    FORCE MAJEURE
    
    
    2013.
    
    COSTS
    
    
    2014.
    
    VARIATIONS
    
    
    2015.
    
    WAIVER
    
    
    2116.
    
    INVALIDITY
    
    
    2117.
    
    NOTICES
    
    
    2118.
    
    NO PARTNERSHIP
    
    
    2219.
    
    ASSIGNMENT
    
    
    2220.
    
    GOVERNING LAW AND JURISDICTION
    
    
    2321.
    
    ENTIRE AGREEMENT
    
    
    23SCHEDULE 1 Programme
    
    
    25SCHEDULE 2
    
    
    25




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##### 



BETWEEN:
 (1)
    
    BIOTECNOLSA having its principal place of business at Taguspark, Edificio Inovacao IV, 809
Porto Salvo, 2780-920 Oeiras, Portugal (Biotecnol);and(2)
    
    IDM IMMUNO-DESIGNED MOLECULES S.A.registered at Paris RCS under 632 382 263 and having its
main offices at 172 rue de Charonne 75011 Paris FRANCE (IDM).
 RECITALS
 (A)
    
    Biotecnol is a biotechnology company which owns or is licensee of systems for recombinant
protein expression in the bacterium Escherichia coli (E.coli)and has expertise and
know-how in the design and optimisation of recombinant protein production processes,
expression of recombinant proteins, fermentation media optimisation, fermentation design,
protein purification, protein characterisation, design and the scale-up of integrated
processes for the production of recombinant proteins, and in the general use of E. coli
as a host for the expression of proteins.(B)
    
    IDM is a biopharmaceutical company developing a new family of immunotherapy products called
Cell Drugs made of dendritic cells loaded with antigens to fight cancer , infectious diseases
and auto-immune diseases.(C)
    
    IDM and Biotecnol signed a Prototype Production Contract (Initial Contract)on March 8,
2001. The objective of the collaboration was to enable IDM to obtain a preliminary process for
the purposes of production of the molecule Interleukine 13 (IL-13) using E. coil
as a host. Based on the final report sent by Biotecnol, a success fee of [...***...] as
been paid on August 2002. Intellectual Property Rights resulting from the performance of the
Initial Contract shall be considered as Biotecnols Background Technology. The Initial
Contract shall be replaced by the Agreement.(D)
    
    Biotecnol and IDM have been pursuing the IL-13 development since April 1st,2003, based on a letter of intent executed by the Parties (Letter of Intentor LOI).THE PARTIES AGREE AS FOLLOWS:1.
    
    DEFINITIONS& PURPOSEIn this Agreement, unless the context otherwise requires, the following words and
expressions have the following meaning:Affiliatemeans any company, partnership or other entity which directly or indirectly
controls, is controlled by or is under the common control of either party, as applicable;
controlmeans possession, directly or indirectly, of more than 50% of the voting stock or
other ownership interest of another person or the power to direct or cause the direction of
the management and policies of such person.Agreementmeans this agreement, the Programme and other schedules.Background Rightsmeans the Biotecnol Background Patents, the Biotecnol
 *
    
    Confidential Treatment Requested
under 17 C.F.R. §§ 200.80(b)(4) and
240.24b-2(b)(1)




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##### 



Confidential
    
    13-Nov-03
 Background Technology, the IDM Background Patents, the IDM Background Technology and
the IDM Materials.Biotecnol Background Patentsmeans:(a)
    
    all patent applications and patents, and any and all patents issuing therefrom,
including utility models, design patents and inventors certificates, owned,
controlled or licensed by Biotecnol as of the Effective Date or developed, acquired,
licensed or otherwise obtained by Biotecnol, other than from IDM, during the term of
this agreement, together with any and all substitutions, extensions (including
supplemental protection certificates), provisionals, divisionals, continuations,
continuations-in-part, re-examinations, re-issues, renewals, revalidations, additions,
substitutions, confirmations and registrations, as well as all foreign counterparts or
equivalents thereof anywhere in the world, including without limitation all such
patents and patent applications.(b)
    
    all patent applications owned, controlled or licensed by Biotecnol that may be filed
anywhere in the world, which either are based on or claim priority from any of the
foregoing patent applications or patents, and any and all patents which may issue from
any such patent applications;
  Biotecnol Background Technology
 Business Day
 Confidential Information




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Date
 Delivery
 Drug Master File or DMF
 Effective Date st
 End of the Programme
 Expression System
 Expression Vectors
 Field
 Finished Product
 Foreground Rights
 Host Strain E. coli
 IDM
 IDM Background Patents




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Confidential
    
    13-Nov-03
   IDM Background Technology
 IDM Materials
 Intellectual Property Rights
 Manufacturing Period
 Process
 Product[s]
 Programme
 Programme Materials
 Regulatory Authority
 *
    
    Confidential Treatment Requested
under 17 C.F.R. §§ 200.80(b)(4) and
240.24b-2(b)(1)




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Value Added Tax
 1.2
    
    In this agreement unless otherwise specified, reference to:
 (a)
    
    a party means a party to this Agreement and includes its permitted assignees
and/or the respective successors in title to substantially the whole of its
undertaking;(b)
    
    a person includes any person, individual, company, firm, corporation,
government, state or agency of a state or any undertaking (whether or not having
separate legal personality and irrespective of the jurisdiction in or under the law of
which it was incorporated or exists);(c)
    
    a statute or statutory instrument or any of their provisions is to be
construed as a reference to that statute or statutory instrument or such provision as
the same may have been or may from time to time hereafter be amended or re-enacted;(d)
    
    words denoting the singular shall include the plural and vice versa and words
denoting any gender shall include all genders.
 1.3
    
    The index to and headings in this agreement are for information only and are to be ignored in
construing the same.1.4
    
    Purpose :
 A
    
    The Agreement intends to expand upon the Initial Contract. Under the Agreement,
Biotecnol is assigned to complete the development according to the Programme of a
Process of IL13 to be transferred to a designated GMP manufacturing sub-contractor for
subsequent cGMP manufacturing. The Process shall be developed as stated into the
Programme, and according to the current good manufacturing practices (cGMP)and the
current good laboratory practices (cGLP) accepted by a Regulatory Authority(as
defined below) and in particular the following applicable regulatory
guidance documents :
1.4.1 FDA Points to Consider in the Production and Testing of New Drugs and
Biologicals Produced by Recombinant DNA Technology (1985)
1.4.2 FDA Supplement to the Points to Consider in the Production and Testing of New
Drugs and Biologic & Produced by Recombinant DNA Technology: Nucleic Acid
Characterization and Genetic Stability (1992)
1.4.3 EMEA Production and Quality Control of Medicinal Products Derived by
Recombinant DNA Technology (1995)
 B
    
    IDM undertakes to let Biotecnol be in charge of the on-going management of the
outsourcing of manufacturing and release of Finished Product for renewable five years
period starting from the release of the first Finished Product batch.




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##### 



Confidential
    
    13-Nov-03
 OBLIGATIONS OF BIOTECNOL
 Biotecnol shall undertake the work specified in the Programme and shall use its reasonable
endeavours to ensure that such work is undertaken in accordance with the time frames set out
in SCHEDULE 1 and with all appropriate necessary license. Outcome of the Programme shall be
considered in terms of (i) a Finished Product batch, (ii) a robust and
validation dependant, reproducible Process and all the documentation related as required by
the Regulatory Authority for registration and approvals of IDM Cell Drugsand iii) a master
validation plan2.1
    
    Upon IDM request, Biotecnol shall undertake to perform additional work described in Part 2 of
the Programme including comparability studies, formulation and filling of Product into
Finished Product, stability studies, implementation of the validation plan beyond the first
Finished Product batch and CMC section writing.2.2
    
    At IDMs request, Biotecnol shall be in charge of the timely preparation of a dossier
containing the chemistry, manufacturing and control information (CMC section)for the IL-13
in accordance with 1.4.1, 1.4.2 and 1.4.3 for submission to the Regulatory Authority. The
Parties agree that the CMC section shall include existing stability studies results. Biotecnol
shall also be in charge of updating the CMC section to reflect changes or updates to the
Process. Biotecnol shall also be in charge of providing a timely response to any question on
the CMC section from Regulatory Authorities. IDM shall have an access and right to review the
CMC section as well as any responses to questions from Regulatory Authorities related to the
CMC section.2.3
    
    Biotecnol shall perform its obligations in accordance with all applicable laws and generally
accepted good scientific practice, provided that Biotecnol shall not be required hereby to
seek or acquire any certification from any Regulatory Authority that its facilities or
procedures comply with the good manufacturing practices or other standards thereof.2.4
    
    Biotecnol shall co-operate reasonably with IDM in undertaking the Programme in accordance
with this Agreement and shall act at all times in such a way as to further the objectives of
the Programme, provided that Biotecnol shall be under no obligation to comply with any
recommendations or instructions of IDM, unless otherwise required so to do by the Programme,
the Joint Management Committee or the Agreement.
 2.5
    
    (a)
    
    Biotecnol shall ensure that the results of its work pursuant to the Programme are
recorded into laboratory notebooks. Such notebooks shall be recorded according to scientific
and intellectual property uses, such as but not limited to signature of each page by the
investigator undertaking such work, validation by competent authority and keeping in a safe
and secure place.(b)
    
    Such notebooks and the contents thereof shall be the property of Biotecnol,
subject to IDMs requirements regarding the filing, prosecution and maintenance of
Foreground Rights, although IDM shall, at its cost, be entitled on reasonable notice,
whether during or following the term of this Agreement, to inspect the same and to take
copies thereof.(c)
    
    Biotecnol shall keep such notebooks and identify the same as containing the
results of its work pursuant to the Programme.




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2.6
    
    Biotecnol shall, whether during or following the term of this Agreement, ensure that IDM has
reasonable access during working hours to all individuals involved in undertaking the
Programme for the purposes thereof, provided that such obligation shall cease in respect of
each such individual upon the termination of their employment by Biotecnol.2.7
    
    Biotecnol shall , according to the milestones defined on the Programme, and at the latest on
a quarterly basis, provide IDM with written reports of its progress in undertaking the
Programme.2.8
    
    Biotecnol will ensure that the Process shall be acceptable in terms of compliancy to the
guidelines of the Regulatory Authorities and third partys Intellectual Property Rights.During the Programme and the Manufacturing Period, Biotecnol shall ensure appropriate cGLP
or cGMP compliance either by internal resources or though appropriate consultancy whenever
the work is required to be carried out according to cGMP/cGLP.2.9
    
    During the Manufacturing Period, Biotecnol undertakes to oversee the manufacturing outsourcer
and sub-contractors to deliver in a timely manner at an agreed upon Transfer Price the batches
and or quantity of Finished Product according to IDM orders. Detailed terms and conditions
necessary to organise providing Finished Product to IDM shall be agreed upon in a
manufacturing agreement. The Parties agree to start negotiating upon initiation of the first
Finished Product batch.
 OBLIGATIONS OF IDM
 3.1
    
    IDM shall perform the work specified in the Programme to be undertaken by IDM and shall use
its reasonable endeavours to ensure that such work is undertaken in accordance with the time
frames set out therein.3.2
    
    IDM shall perform its obligations pursuant to clause 3.1 in accordance with all applicable
laws and generally accepted good scientific practices.3.3
    
    IDM shall co-operate reasonably with Biotecnol in undertaking the Programme in accordance
with this Agreement and shall act at all times in such a way as to further the objectives of
the Programme, provided that IDM shall be under no obligation to comply with any
recommendations or instructions of Biotecnol, unless otherwise required so to do by the
Programme, the Joint Management Committee or the Agreement.3.4
    
    IDM shall at its expense using reasonable efforts, deliver to Biotecnol, such of the IDM
Materials, the IDM Background Patents and the IDM Background Technology related to the
performance of the Programme as Biotecnol notifies IDM that it considers to be necessary for
Biotecnol to perform its obligations hereunder or as is otherwise specified in the Programme.3.5
    
    IDM shall render to Biotecnol without charge such technical assistance as Biotecnol may
request to interpret and explain any written information within those materials provided to
Biotecnol in accordance with clause 3.4 and as Biotecnol may otherwise reasonably require to
perform its obligations hereunder. Biotecnol undertakes not to consider IDM as Breaching Party
based on section 10.4 definition, because IDM (i) communicates information related to the
IL-13 development which interpretation is not certain, (ii) does not communicate information
related to the IL-13 development




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Confidential
    
    13-Nov-03
   3.7
    
    Should IDM decide to complete the validation of the Process as required by the Regulatory
Authority, IDM will pay     the number of Finished Product batches in excess to the one indicated in the
Programme which total shall amount to the number of consecutive successful batches required
by the Regulatory Authority,     the work necessary for implementation of the validation master plan. In that case,
any additional Finished Product batch necessary to validate the Process shall in no case be
charged to IDM.
 4. PAYMENT
 T P
  Milestones
    
    Payment
related
    
    Definition[...***...]
    
    upon execution of the LOI. Biotecnol hereby acknowledges that it
has already received such paymentT1P1
    
    [...***...]
    
    upon identification and confirmation of manufacturing facilityT2P2
    
    [...***...]
    
    upon successful processing of functional IL13 at 10mg/liter
according to the specifications defined in the Programme or agreed
upon by the Joint Management Committee. T2P2 Delivery will
trigger payments of: T4P2 and T5P2. Biotecnol hereby
acknowledges that it has already received such paymentT3P1
    
    [...***...]
    
    upon initiation of cell banking; Biotecnol hereby acknowledges
that it has already received such paymentT3P2
    
    [...***...]
    
    upon successful master and working cell bank production
 *
    
    Confidential Treatment Requested
under 17 C.F.R. §§ 200.80(b)(4) and
240.24b-2(b)(1)




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T3P3
    
    [...***...]
    
    upon master and working cell bank release according to
specifications defined in the PROGRAMME or agreed upon by the
Joint Management CommitteeT4P1
    
    [...***...]
    
    upon initiation of process development fermentation. Biotecnol
hereby acknowledges that it has already received such paymentT4P2
    
    [...***...]
    
    to pursue Process Development
Fermentation, Biotecnol hereby acknowledges that it has already received such paymentT4P3
    
    [...***...]
    
    upon fermentation protocol finalizationT4P4
    
    [...***...]
    
    upon report on reproducible laboratory fermentation process in
three batches at five (5) litres scaleT5P 1
    
    [...***...]
    
    upon initiation of process development Down Stream Processing
(DSP). Biotecnol hereby acknowledges that it has already
received such paymentT5P2
    
    [...***...]
    
    to pursue Process Development of DSP, Biotecnol hereby
acknowledges that it has already received such paymentT5P3
    
    [...***...]
    
    upon final downstream processing protocol finalizationT5P4
    
    [...***...]
    
    upon report on reproducible downstream process in three batches
at labs scaleT6P1
    
    [...***...]
    
    upon initiation of analytical methods development. Biotecnol
hereby acknowledges that it has already received such paymentT6P2
    
    [...***...]
    
    upon linked to SOPs for process analysis and Product release
testingT6P3
    
    [...***...]
    
    upon a transfer of methods to sub-contractor for validationT6P4
    
    [...***...]
    
    upon report of completion of assays validationT7P1
    
    [...***...]
    
    upon initiation of process transferT7P2
    
    [...***...]
    
    upon three successful lab scale runs demonstrating reproducible
process at sub-contractorT7P3
    
    [...***...]
    
    Upon successful pre-GMP pilot run, GMP process at large scaleof pilot plant allowing
for cGMP manufacturing meeting the specifications
defined during development work.
 *
    
    Confidential Treatment Requested
under 17 C.F.R. §§ 200.80(b)(4) and
240.24b-2(b)(1)




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Confidential
    
    13-Nov-03
 T7P4
    
    [...***...]
    
    upon successful audit of cGMP documentation prior to initiation
of cGMP manufacturingT9P1
    
    [...***...]
    
    upon initiation of first Product batchT9P2
    
    [...***...]
    
    upon release of first Product batchT10P1
    
    [...***...]
    
    The Programme success fee allowing to use the Finished Product
in Clinical trials, upon successful release of Finished
Product
 4.1
    
    Shall Biotecnol fail to deliver to IDM the first Finished Product batch on the Date, due to
the non performance, fault or negligence from Biotecnol, , Biotecnol shall be liable of late
penalty payment. In the case of an Event of Force Majeure, then Biotecnol shall not be liable
for late penalty payment.Such penalty payment shall amount to [...***...] per month of delay with a maximum not
exceeding [...***...] of total amount intended for the performance of the Programme (i.e.
total amount : [...***...]). Penalty payment shall be credited against future invoices.Biotecnol shall not be subject to late penalty payment terms so long as the delay is the
consequence of IDM late decision or action .
  *
    
    Confidential Treatment Requested
under 17 C.F.R. §§ 200.80(b)(4) and
240.24b-2(b)(1)




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##### 



4.3
    
    IDM shall make all payments due pursuant to this clause 4 within twenty (20) days of
receipt of invoice. An invoice shall be paid by IDM only if the invoice is following a
Delivery .4.4
    
    Any payments due in accordance with this clause 4 but not paid on the due dates shall incur
interest at a rate of four (4%) percent above the lending rate from time to time of 3 M
EURIBOR, such interest to be compounded monthly.4.5
    
    The sums specified in this clause 4 as payable by IDM shall be exclusive of any due Value
Added Tax.4.6
    
    The price of IL-13 (Transfer Price)charged to IDM shall be the Cost of Goods of the IL-13
calculated annually on the basis of Biotecnols manufacturing expenses plus reasonable
allocations of sales and administrative overhead and a management fee not to exceed twenty
percent of the Costs of Good.The Cost of Goodsshall also include any payments or share of payment made by Biotecnol to
its direct and indirect licensors through multiple tiers of licenses that become due as a
result of the performance of this Agreement by Biotecnol or IDM. The Cost of Goods shall not
include any transportation insurance policy and related cost, which shall remain IDMs.
Taxes if applicable and goods transportation cost are not included in the Cost of Goods but
subject to reimbursement by IDM.Upon reasonable advance written notice, IDM shall have the right to audit the accounting
documents related to the Transfer Price during the Manufacturing Period at Biotecnol.
Detailed definition of Cost of Goods shall be agreed upon in the manufacturing agreement
referred to in section 2.10.4.7
    
    IDM may decide not to renew after the Manufacturing Period the outsourcing of manufacturing
and release of IL-13 to Biotecnol upon payment of cancellation fees. First termination notice
shall be communicated no later that than twelve (12) months prior to the end of the
Manufacturing Period. The amount of the cancellation fees shall be agreed upon in good faith
by the Parties and shall not exceed the management fee of one Finished Product batch. This
amount shall decrease by twenty (20) percent per year following the end of the Manufacturing
Period.




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Confidential
    
    13-Nov-03
 PROGRAMME MANAGEMENT
 5.1
    
    (a)
    
    Following the Effective Date, the parties shall form a joint management committee (the
Joint Management Committee),which shall be responsible for promoting the co-operation of
the parties in accordance with this Agreement and in particular but without limitation for
assisting each party in:
 (i)
    
    monitoring and evaluating its progress in undertaking the Programme;(ii)
    
    reporting such progress to the other party;(iii)
    
    co-ordinating the parties co-operation in advancing the Programme; and(iv)
    
    proposing timelines in respect of advancing the
Programme and possibly modifying/updating the Programme(v)
    
    agreeing on the completion of milestones and in particular
Delivery linked to payments as defined in clause 4(vi)
    
    agreeing on the choice of outsourcing company for cGMP, Cell
Banking, Quality Control development, Quality Control testing etc... based on
expertise, risk assessment, timing and pricing.
 5.2
    
    (a)
    
    The Joint Management Committee shall comprise three (3) core representatives of each
party, who shall each be an employee, officer or consultant of the party which they represent.
IDMs representatives shall be the Director, Business Expansion, the Director Manufacturing
and the Director Quality System. Biotecnols representatives shall be the Chief Scientific
Officer, the Chief Operating Officer and the Development Manager .Other persons, including but not limited to regulatory representative will be asked to
contribute on an adhocbasis.(b)
    
    All members of the Joint Management Committee shall have an ongoing familiarity
with the Programme and appropriate knowledge having regard to the Joint Management
Committees responsibilities.5.3
    
    
    
    Each party may replace those core members of the Joint Management Committee which it has
appointed at will and at any time upon written notice to the other party.5.4
    
    (a)
    
    The Joint Management Committee shall meet as frequently as it chooses but in any event no
less often than once every twenty (20) Business Days.(b)
    
    The Joint Management Committee shall meet either by telephone conference call or in
person, provided that where the Joint Management Committee meets in person, such meetings
shall alternate between the parties respective principal places of business or such
other locations as the Joint Management Committee may agree.(c)
    
    All meetings of the Joint Management Committee shall be conducted in English or
such




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##### 



other language as the Joint Management Committee may unanimously agree.(d)
    
    The quorum for any key decision of the Joint Management Committee to be valid
shall be of at least one (1) core member appointed by each of the parties(e)
    
    In the event that both parties consent, third parties may attend meetings of
the Joint Management Committee as observers, provided that such representatives are
subject to binding obligations of confidentiality in favour of the parties at least as
restrictive as those in this Agreement.(f)
    
    Each party shall bear its own costs in connection with meetings of the Joint
Management Committee.(e)
    
    Joint Management Committee minutes shall be draft by each party alternatively
no later than five (5) Business Days after the meeting. The non-drafting party shall
comment within five (5) Business Days so as to communicate the final Joint Management
Committee minutes within ten (10) Business Days to interested persons at each party.
 5.5
    
    Each party shall provide all reasonable assistance to the Joint Management Committee in
assisting the Joint Management Committee to execute its responsibilities hereunder.5.6
    
    The Joint Management Committee shall have no authority to require either party to take or to
refrain from taking any particular steps or other action, provided that this clause 5.6 shall
not operate to exempt either party from fulfilling its obligations pursuant to this Agreement
or the Programme.5.7
    
    If the Joint Management Committee members disagree as to whether any and/or what steps should
be taken during the Programme, either party may within twenty (20) days of such disagreement
refer the disagreement to the President of IDM and the CEO of Biotecnol. In the event that
within forty (40) days of referral to the President & CEO of IDM and the CEO of Biotecnol the
Parties have failed to resolve the disagreement, either Party may refer the disagreement to
arbitration in Belgium who shall appoint an expert to determine the dispute (the Expert).
The decision of the Expert, who shall act as expert and not as arbitrator shall be final and
binding on the Parties. The costs of the Expert shall be shared equally.
 6.  SUB-CONTRACTING AND OUTSOURCING


6.1        Principles to be applied by Biotecnol during the Programme and the Manufacturing Period: 6.1.1      Biotecnol shall in all circumstances remain liable to IDM with regard to any part of the
Programme or Process it decided to sub-contract to third parties. 6.1.2      Outsourcing and sub-contracting agreements shall comply with the terms and conditions set
forth herein. 6.1.3      Biotecnol undertakes in its name and on behalf of its outsourcers or sub-contractors to
cooperate with IDM if inspections by health authorities are required with respect to Product,
Finished Product and Process. 6.1.4      Upon reasonable advance written notice, IDM shall have the right to inspect the facilities
and the means used to perform the Programme or the Process and later on during the Manufacturing
Period at Biotecnol and/or chosen sub-contractors or outsourcers to ensure that the Programme or
the Process is carried out in accordance with cGMP, cGLP, rules and regulations, whenever the work
needs to be carried out according to the said cGMP, cGLP, rules and regulations.




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Confidential
    
    13-Nov-03
 6.1.5
    
    Biotecnol, its sub-contractors and out-sourcers shall be held liable for any
default in supply, such as but not limited to contamination issue that may arise during
the Programme and the Manufacturing Period. IDM shall not be bound to financial
compensation in excess of the agreed upon Programme fees and Transfer Price.6.1.6
    
    Regarding any outsourcing and sub-contracting agreements, Biotecnol shall
negotiate that
 (a)
    
    in case of early termination of the Agreement,(b)
    
    in case of expiration of the Agreement,(c)
    
    in case of Biotecnols bankruptcy, then
  6.2
    
    Principles specific to the Programme performance :
 6.2.1
    
    Biotecnol is not authorised to sub-contract or out-source the performance of
its obligations pursuant to clause 2.1 unless otherwise specified in the Programme, the
Agreement or authorised by the Joint Management Committee.6.2.2
    
    However, IDM will allow Biotecnol to outsource or sub-contract activities
such as Cell Banking, QC development, QC testing. Choices of sub-contractors or
outsourcers shall be agreed upon in accordance with section 5.1 (vi).6.2.3
    
    During the performance of the Programme, Biotecnol shall be bound by late
delivery penalties as defined in Clause 4.2 even though the delay is due to Biotecnols
sub-contractors.
 6.3
    
    Principles specific to the Manufacturing Period :
 -
    
    Biotecnol undertakes that it shall take all reasonable means to sustain
continued manufacturing capabilities during the Manufacturing Period.-
    
    Biotecnol is not authorized to substitute any sub-contractor or out-sourcer in
charge of part or all of the Process, which have been agreed upon during the Programme
performance by the Joint Management Committee without prior adequate notice and
authorization by IDM.-
    
    The Parties evaluate the time for transferring the Process at 18 (eighteen)
months. As a consequence the production agreement signed by the sub-contractor or
out-sourcer and Biotecnol shall provide that:
 
    
    in the case where said production agreement is terminated, expired or
assigned, then IDM or any other person IDM may decide, shall benefit from
the production agreement rights and obligations
    
    any without cause termination shall be given eighteen (18) months in
advance to ensure manufacturing continuity.




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##### 



7. INTELLECTUAL PROPERTY RIGHTS
 7.1
    
    (a)
    
    Subject as expressly provided in clause 7.5, Biotecnol is and shall remain the sole
owner or the licensee, as applicable, of all Intellectual Property Rights in the Biotecnol
Background Patents and Biotecnol Background Technology.
  7.2
    
    IDM acknowledges and agrees to the findings and recommendations contained in the preliminary
Biotecnols study of the freedom to operate received On November 28, 2002 which drove some
technical choices of the Process. However during the development of the Process, Biotecnol
will take appropriate measures to verify that the Process developed for IL-13 production and
commercialisation is not dependant upon third parties intellectual property rights and will
keep IDM informed, through a study update, of this verification before executing the milestone
of transfer to pilot facility (T7P1). In case of such dependence, Biotecnol will negotiate the
license agreement required, and provide IDM or any third party IDM shall require, with the
opportunity to be assigned in cases described below. In all cases where a license is to be
negotiated by Biotecnol, IDM shall be informed and will be given a reasonable opportunity to
comment on or discuss the proposal.
  (a)
    
    IDM shall be entitled, at no costs and at its sole discretion, to substitute to
Biotecnol itself or its affiliated, merging or acquiring company vis-à-vis the
licensing party.(b)
    
    IDM shall remain the sole owner of all Foreground Rights.
 7.3
    
    IDM hereby grants Biotecnol a non-exclusive royalty-free licence to use any and all IDM
Materials, IDM Background Technology and IDM Background Patents disclosed or otherwise
provided or available to Biotecnol pursuant to this Agreement or otherwise, for the purpose of
permitting and assisting Biotecnol in performing its obligations under the scope of the
Agreement and exercising it rights pursuant hereto.7.4
    
    Foreground Rights shall be jointly owned by the Parties.




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##### 



Confidential
    
    13-Nov-03
     7.5
    
    Biotecnol hereby grants IDM a payment-free non-cancelable worldwide exclusive license solely
for the Field (including the right to grant sub-licences thereunder) of its share in respect
of the Foreground Rights and shall grant a licence on like terms under any patent which IDM
obtains pursuant to clause 7.3 (for the purposes of this clause 7, a Patent), in all the
countries in which such patent protection is obtained, for the full duration of such Patent.
Should the Foreground Rights be used or licensed by Biotecnol to manufacture IL-13 for use
outside of the Field, subject to Sanofi-Synthelabo S.A.s approval  or from Sanofi
Synthelabos Affiliates approval, a royalty compensation or a fixed payment to IDM shall be
due to IDM. For the sake of clarity and avoidance of doubt the choice between receiving a
royalty compensation or a fixed payment will be at IDMs sole discretion, and in either way
will be negotiated in good faith between the parties.
 7.6
    
    (a)
    
    Each party shall inform the other party of any infringement or suspected infringement of
any Patent forthwith upon such infringement or suspected infringement coming to its notice and
shall provide such other party with full particulars thereof.(b)
    
    If either party becomes aware that any other person alleges that any Patent
is invalid or that the use of any Foreground Rights infringes any rights of another
party or that any such Patent is otherwise attacked or attackable by a third party, it
shall immediately give the other party full particulars in writing thereof and shall
make no comment or admission to any third party in respect thereof.7.7
    
    (a)
    
    Both Biotecnol and IDM shall have the conduct of all judiciary proceedings relating to
any Patents and shall jointly decide what action if any to take in respect of any infringement
or alleged infringement thereof or any other claim or counterclaim brought or threatened in
respect of the use or registration thereof.




---



##### 



7.8
    
    Nothing in this Agreement shall give or grant to either party any right in any trademark,
patent or other Intellectual Property Right of the other party expect as specifically provided
herein.
 8. CONFIDENTIALITY
 8.1
    
    Each party shall, during the full term of this Agreement and thereafter, keep secret and
confidential the contents of this Agreement and all Confidential Information of the other
party and shall not use or disclose the same to any person, save to the extent necessary to
perform its obligations pursuant to this Agreement in accordance with its terms or save as
expressly authorised in writing to be disclosed by the other party.8.2
    
    The obligation of confidentiality contained in clause 8.1 shall not apply or (as the case may
be) shall cease to apply to details of the contents of this Agreement or to Confidential
Information which:
 (a)
    
    at the time of its disclosure by the disclosing parry is already in the public
domain or which subsequently enters the public domain other than by breach of the terms
of this agreement by the receiving party;(b)
    
    is already known to the receiving parry (as evidenced by written records) at
the time of its disclosure by the disclosing party and was not otherwise acquired by
the receiving party from the disclosing party under any obligations of confidence;(c)
    
    is at any time after the date of this Agreement acquired by the receiving party
from a third party having the right to disclose the same to the receiving party without
breach of obligation owed by that third party to the disclosing party; or(d)
    
    is required to be disclosed by applicable law or order of a court of competent
jurisdiction or government department or agency or the rules and requirements of any
other regulatory body, provided that prior to such disclosure the receiving party shall
advise the disclosing party of the proposed form of the disclosure.
 8.3
    
    Notwithstanding the foregoing, each parry may disclose Confidential Information of the other
party and details of the contents of this Agreement to its professional advisors, and for IDM
to Sanofi-Synthelabo S.A. or Sanofi-Synthelabo S.A.s Affiliates provided that they are
subject to obligations of confidentiality at least as restrictive as those herein and the
parties may disclose:
 (a)
    
    the existence of this Agreement to its actual or potential financial backers
for the purposes of seeking or obtaining finance therefrom; and




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##### 



Confidential
    
    13-Nov-03
 (b)
    
    the scope of the Programme for the procurement of subcontractors for pursuing
any work according to cGMP or cGLP and thus for obtaining quotes;(c)
    
    in the event that IDM needs to use technology belonging to third parties,
Biotecnol can disclose to its licensors any rights sub-licensed to IDM thereunder,
IDMs identity, the Effective Date, the definition[s] of Field, Finished Product
and Product(s) and such other terms defined herein as are necessary to understand
[its][their] meaning, and the scope of the licence granted hereunder.
 8.4
    
    Each party shall procure that all its employees, contractors, consultants, advisers and
sub-licensees pursuant to this agreement (if any) who have access to any information of the
other to which the obligations of clause 8.1 apply shall be made aware of and subject to these
obligations and shall further procure that so far as is reasonably practicable, all such
employees, contractors and sub-licensees shall enter into undertakings in favour of the other
party to this end.
 9. WARRANTIES AND DISCLAIMER
 9.1
    
    Biotecnol warrants that as far as it is aware after making due and careful enquiry, that the
use of the Biotecnol Background Technology and the Biotecnol Background Patents in the
Programme and during the Manufacturing Period as contemplated in this Agreement, the Process
for production of the Product and the Finished Product, will not constitute an infringement of
any Intellectual Property Rights of any third party.9.2
    
    To IDMs best knowledge, the use of part or all of IDM Background Technology in connection
with the Programme as contemplated herein does not conflict with, misappropriate, or infringe
the intellectual property rights of any third party. Furthermore IDM warrants that it has
secured a non-exclusive licence for the use, development and manufacturing of IL-13 in the
Field and is therefore allowed to subcontract Biotecnol to perform the Programme.9.3
    
    Each party warrants to the other that it is not party to and shall not enter into any
agreement, arrangement, understanding or negotiations with any third party, which prevent it
entering into or performing its obligations hereunder, and that it is a duly organised and
validly existing corporation in good standing under the laws of its own jurisdiction.9.4
    
    Nothing contained in this Agreement shall be construed as a warranty by Biotecnol that any
Products or Finished Product will be suitable for any particular purpose, including without
limitation, for therapeutic or other use in humans, expect for the intended use in the Field.9.5
    
    Subject to clause 9.6, neither party shall be liable to the other under or in connection with
this Agreement, whether in contract, tort (including negligence), misrepresentation (other
than where made fraudulently), breach of statutory duty or otherwise for any:




---



##### 



9.6
    
    Nothing in this Agreement shall limit either partys liability in respect of:
 (a)
    
    any claim for death or personal injury caused by its negligence or that of its
employees, contractors or agents; or(b)
    
    any other liability which may not be limited or excluded at law.
 10.
    
    DURATION AND TERMINATION10.1
    
    This Agreement shall enter into force on the Effective Date and unless terminated as provided
herein, shall remain in force not before the end of the Manufacturing Period.10.2
    
    The Parties agree that the Joint Management Committee may recommend to stop the Programme at
 
    
    the end of stage T2 if IL-13 is not functional according to the
specifications defined in the Programme or agreed upon by the Joint Management
Committee and/or
    
    the end of stage T5 if the process is not reproducible according to the
specifications defined in the Programme or agreed upon by the Joint Management
Committee and/or
    
    if the yield is not amounting to [...***...] and/or
    
    before the manufacturing of the first Product batch is initiated (T9).
   10.3
    
    During the Manufacturing Period, IDM shall not be allowed to terminate the Agreement but
within the terms agreed upon in section 4.7. Biotecnol shall be entitled to terminate the
Process performance at any time with an eighteen (18) months prior notice to IDM.
 10.4
    
    A party (the Initiating Party)may terminate this agreement with immediate effect by written
notice to the other party (the Breaching Party)on or at any time after the occurrence of
any of the
 *
    
    Confidential Treatment Requested
under 17 C.F.R. §§ 200.80(b)(4) and
240.24b-2(b)(1)




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##### 



Confidential
    
    13-Nov-03
  (a)
    
    the Breaching Party being in breach of a material obligation under this
agreement and, if the breach is capable of remedy, failing to remedy the breach within
ten (10) Business Days starting on the Business Day after receipt of written notice
from the Initiating Party giving full details of the breach and requiring the Breaching
Party to remedy the breach;(b)
    
    the Breaching Party passing a resolution for its winding-up or a court of
competent jurisdiction making an order for the Breaching Partys winding-up or
dissolution;(c)
    
    the making of an administration order in relation to the Breaching Party or the
appointment of a receiver over, or an encumbrancer taking possession of or selling, an
asset of the Breaching Party;(d)
    
    the Breaching Party making an arrangement or composition with its creditors
generally or making an application to a court of competent jurisdiction for protection
from its creditors generally; and
 10.5
    
    For the purpose of clause 10.4 (a) above, a breach will be considered capable of remedy if
time is not of the essence in performance of the obligation in question and if the Breaching
Party can comply with the obligation within the ten (10) Business Day period referred to in
clause 10.4(a).
 11. EFFECT OF TERMINATION
 11.1
    
    Upon the termination or expiry of this Agreement, each party shall at the instruction of the
other, either destroy or return all Confidential Information of the other and in particular:
 (a)
    
    Biotecnol shall at the instruction of IDM, either destroy or return all
quantities of IDM Background Technology and IDM Materials remaining in its possession;
and(b)
    
    IDM shall at the instruction of Biotecnol, destroy or return all quantities of
Biotecnol Background Technology remaining in its possession.
 11.2
    
    In cases detailed in the section 10.4 b, c or d and in the case where Biotecnol is the
Breaching Party in section 10.4 a, the remaining party shall be entitled to full ownership on
Foreground Rights issuing from the last milestone payment.11.3
    
    The provisions of clause 11.1 shall be subject to the rights of IDM pursuant to clause 7.5,
such that IDM may retain such Confidential Information as is necessary for it the exploit the
licence granted thereby.
   12. FORCE MAJEURE




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##### 



Event of Force Majeure Claiming Party)
  Non-Claiming Party)
 (a)
    
    the Claiming Party could not have avoided the effect of the Event of Force
Majeure by taking precautions which, having regard to all matters known to it before
the occurrence of the Event of Force Majeure and all relevant factors, it ought
reasonably to have taken but did not take; and(b)
    
    the Claiming Party has used reasonable endeavours to mitigate the effect of the
Event of Force Majeure and to carry out its obligations under this Agreement in any
other way that is reasonably practicable.
  12.4
    
    If the Event of Force Majeure in question prevails for a continuous period in excess of three
(3) months after the date on which it began, the Non-Claiming Party may give notice to the
Claiming Party terminating this Agreement. The notice to terminate must specify the
termination date, which must not be less than thirty (30) clear days after the date on which
the notice to terminate is given. Once the notice to terminate has been validly given, this
Agreement will terminate on the termination date set out in the notice. Neither party shall
have any liability to the other in respect of termination of this Agreement due to an Event of
Force Majeure. In such circumstances, section 11.4 conditions shall apply
 13. COSTS
  14. VARIATIONS
  15. WAIVER
 15.1
    
    A waiver of any term, provision or condition of, or consent granted under, this Agreement
shall be effective only if given in writing and signed by the waiving or consenting party and
then only in the




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##### 



Confidential
    
    13-Nov-03
 instance and for the purpose for which it is given.15.2
    
    No failure or delay on the part of any party in exercising any right, power or privilege
under this Agreement shall operate as a waiver thereof, nor shall any single or partial
exercise of any such right, power or privilege preclude any other or further exercise thereof
or the exercise of any other right, power or privilege.15.3
    
    No breach of any provision of this Agreement shall be waived or discharged except with the
express written consent of the parties.15.4
    
    The rights and remedies herein provided are cumulative with and not exclusive of any rights
or remedies provided by law.16.
    
    INVALIDITY
  (a)
    
    the validity, legality and enforceability under the law of that jurisdiction of
any other provision; and(b)
    
    the validity, legality and enforceability under the law of any other
jurisdiction of that or any other provision,
  17. NOTICES
 17.1
    
    Any notice, demand or other communication given or made under or in connection with the
matters contemplated by this agreement shall be in writing and shall be delivered personally
or sent by fax or prepaid internationally recognised courier (e.g. DHL, FedEX), except when
otherwise indicated.
 In case of Biotecnol to:TagusparkEdificio Inovacao IV N° 8092780-920 OeirasPortugalAttention: CEOFax:+351 21 422 0529
 In case of IDM to:172 rue de Charonne75545Paris Cedex 11FranceAttention: President & CEOFax:+33 (0)1 40 090 425
  (a)
    
    if personally delivered, upon delivery at the address of the relevant party;




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##### 



(b)
    
    if sent by an internationally recognised courier (e.g. DHL, FedEX), two
Business Days after the date of posting;(c)
    
    if sent by air mail, five (5) Business Days after the date of posting; and(d)
    
    if sent by fax, one Business Days after the date of sending;
  17.2
    
    A party may notify the other party to this Agreement of a change to its name, relevant
addressee, address or fax number for the purposes of clause 17.1, provided that such
notification shall only be effective on:
 (a)
    
    the date specified in the notification as the date on which the change is to
take place; or(b)
    
    if no date is specified or the date specified is less than five (5) Business
Days after the date on which notice is given, the date falling five (5) Business Days
after notice of any such change has been given.




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##### 



Confidential
    
    13-Nov-03
 18.
    
    NO PARTNERSHIP18.1
    
    Nothing in this Agreement and no action taken by the parties pursuant to this Agreement shall
constitute, or be deemed to constitute, the parties a partnership, association, joint venture
or other co-operative entity.
  19.
    
    ASSIGNMENT
  
    
    to any of its Affiliates or
    
    to any other person with which such party may merge, consolidate or transfer all or
substantially all of such Partys assets related to the Product, Finished Product or
Process.
 provided,
 20.
    
    GOVERNING LAW AND JURISDICTION20.1
    
    This Agreement (and any dispute, controversy, proceedings or claims of whatever nature
arising out of or in any way relating to this Agreement or its formation) shall be governed by
and construed in accordance with Belgium law.20.2
    
    Each of the parties to this Agreement irrevocably agrees that any dispute arising out of or
in connection with this Agreement shall be settle by arbitration, except for the settlement
described in section 5.8, where an Expert shall file a binding decision. Such arbitration
shall be held in English in accordance with the rules of Cepani (Centre Belge pour lEtude et
la Pratique de lArbitrage National et International) by a three arbitrators appointed in
accordance with such rules. The place of arbitration shall be Brussels. Language of
arbitration shall be English.The arbitrators shall be appointed by agreement between the parties or failing agreement
within a period of twenty one (21) Business Days shall be appointed at the request of any
party by the Secretary-General for the time being of CEPANI. So far as possible the decision
of the arbitrators shall be given within twenty one (21) Business Days of their appointment
and shall be final and binding on the parties who renounce any right of appeal against such
arbitration award.21.
    
    ENTIRE AGREEMENT21.1
    
    Subject to clause 21.2, this Agreement constitutes the entire and only agreement between the
parties relating to the subject matter hereof and neither party has been induced to enter into
this Agreement in reliance upon, nor has any such party been given, any warranty,
representation, statement, assurance, covenant, agreement, undertaking, indemnity or
commitment of any nature whatsoever other than as are expressly set out herein and, to the
extent that any of them has been, it unconditionally and irrevocably waives any claims, rights or remedies which any of
them might otherwise have had in relation thereto.




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##### 



Confidential
    
    13-Nov-03
   IN WITNESS
 Biotecnol
 /s/ Pedro de Noronha Pissara
    
    /s/ Luis AmadoCEO
    
    COOSigned byfor and on behalf of IDM SA/s/ Jean-Loup Romet-LemonnePresident & CEO




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##### 



Confidential
    
    13-Nov-03
 SCHEDULE 1
 PROGRAMME
 
 Process development and cGMP production of clinical grade Interleukin 13 (IL-13) for ex-vivo cell therapy. Revised outline of Work Program
 
 Biotecnol SA
 www.biotecnol.com
 Email: pjc@biotecnol.com




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##### 



Confidential
    
    13-Nov-03
 1. INTRODUCTION
    
    
    32. OBJECTIVES
    
    
    43. THE APPROACH
    
    
    54. WORK PROGRAM
    
    
    6T1 IDENTIFICATION OF MANUFACTURING FACILITY
    
    
    6T2
PRODUCTION OF IL13 FROM BIOTECNOLS PR EXPRESSION SYSTEM
    
    
    7T3 CELL BANKING
    
    
    8T4 PROCESS DEVELOPMENT  FERMENTATION
    
    
    9T5 PROCESS DEVELOPMENT: DSP
    
    
    12T6 DEVELOPMENT OF ANALYTICAL METHODS FOR PROCESS MONITORING, AND LOT RELEASE TESTING
    
    
    18T7 PROCESS TRANSFER TO CGMP FACILITY
    
    
    23T9 CGMP BATCH PRODUCTION AND ANALYSIS
    
    
    25PART II
    
    
    26T1O FILLING AND FINISHING OF PRODUCT TO DELIVER FINISHED PRODUCT
    
    
    26T11 GENERATION OF PRELIMINARY DATA TO DEMONSTRATE PRODUCT STABILITY
    
    
    27T12 STABILITY STUDIES ON CGMP GRADE PRODUCT AND FINISHED PRODUCT
    
    
    29




---



##### 



1. Introduction
   ant




---



##### 



Confidential
    
    13-Nov-03
 2. Objectives
    1.
    
    Produce, characterise a sample of IL13 using Biotecnols pR expression
system, for comparison with the IL13 previously used by IDM.2.
    
    Outsource the production and testing, according to regulatory
requirements, of Master and Working Cell Banks of the chosen expression system.3.
    
    Develop a manufacturing process that can be effectively validated and
used for commercial manufacture of IL13 of a specification, equivalent to Sanofi
Synthelabos reference standard and specifications defined by further analysis
beyond that carried out by Sanofi Synthelabo (SaSy), in full compliance with cGMP
for production of recombinant protein Product Finished Product for implementation at
minimally 50 litre fermenter yielding up a minimum of 35 mg/I.4.
    
    Biotecnol will co-ordinate the effective transfer and implementation of
the manufacturing process at a cGMP facility chosen in consultation with IDM to
produce an initial batch of Finished Product to be used as a raw material for ex
vivo processing of human cell therapy products that are intended for phase III
clinical trials and commercial distribution.5.
    
    Biotecnol will have responsibility to develop the analytical protocols,
either in house, or in collaboration with a suitable CAL (Contract Analytical Lab),
said CAL agreed upon with IDM.6.
    
    Biotecnol will have responsibility to oversee the CAL to validate the
analytical protocols in compliance with GLP/cGMP.7.
    
    Biotecnol will have responsibility to oversee the CAL for lot release
testing.8.
    
    Biotecnol will have responsibility to oversee the contract manufacturer
to validate the process, equipment, or facility in compliance with GLP/cGMP.




---



##### 



9.
    
    Biotecnol will have responsibility to oversee the contract manufacturer
to release the drug product to IDM requirements10.
    
    Biotecnol will manage and oversee all aforementioned activities to ensure
the production and control of IL13, at the chosen contract manufacturer or CAL ,
suitable for use in phase III clinical trials and commercial distribution of IDMs
cell therapy in the US and Europe. This will cover Prevention of cross contamination
during manufacturing, raw material control and management and minimum validation of
all processes, equipment, facility and personal that affect the safety of IL13 (e.g.
cleaning, aseptic steps, etc;) for clinical trial and commercialisation.
  1.
    
    Formulation, containment and filling to produce the Finished Product.2.
    
    Stress testing to identify stability indicating assays to be used in stability
testing.3.
    
    Stability testing of the Product and Finished Product.4.
    
    Process Validation for commercialisation.
 3. The Approach




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##### 



Confidential
    
    13-Nov-03
    4. Work Program
 PART ONE
 T1 Identification of manufacturing facility.
 Milestone  September 2003 -
    Deliverables T1P1
 Initial Screening Reports  Biotecnol Visits
reports  Biotecnol
Audit reports  IDM
Comparison  Report Biotecnol Recommendation
Confirmation of manufacturing facility to move forward
 T2 Production of IL13 from Biotecnols pR expression system.
 Milestone 30 th September 2003
 Processing of pR sample for evaluation using existing protocol and comparison with SaSys IL13.




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##### 



i.
    
    Reverse Phase HPLC  Typical profile to that obtained with Sasys IL13.ii.
    
    SDS PAGE  Reducing and Non reducing  Typical profile compared with
that of Sasys IL13.iii.
    
    N terminal sequencing  identical N terminal sequence to that of
Sasys IL13.iv.
    
    Amino Acid Composition  As expected for Sasys IL13v.
    
    Mass determination  Expected Molecular Massvi.
    
    Bioactivity  Activity in the range of the activity of Sasys IL13
  Genetic Stability of the construct in the laboratory fermentation process
  i.
    
    Selective plating  plasmid retention > 80%ii.
    
    Restriction mapping  expected banding patter form restriction digest of
plasmid with several enzymesiii.
    
    Sequence of insert  sequence equivalent at end of fermentation to that
page 7 of 31 of the sequence of the vectoriv.
    
    Expression levels  expression levels reproducible by SDS PAGE analysis.
 Deliverables  T2P2
 Reports on activities undertaken including methods used and results obtained
 Successful processing and characterisation of functional IL13 at 10 mg/l.
 Genetic stability of the vector construct during fermentation




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##### 



Confidential
    
    13-Nov-03
 T3 Cell Banking
 Dependent on successful completion of T2
 T3P1 Milestone  Initiation of cell banking October 2004
 T3P2
 T3P2 Milestone  Production of MCB and WCB 23rd January 2004
  T3P3 Milestone  Testing and Release of MCB/WCB 21st May 2004
  Phenotype Characterisation
    
    API20E
    
    Conforms with CSSGenotype
    
    RAPD
    
    Conforms with CSSViability
    
    Plating assay
    
    > 1X107 CFUs/mlCopy Number
    
    PhotometricSequence Identity
    
    Restriction Map
    
    Expected patternSequencing insert
    
    Conforms to ref. sequence
 Contamination
    
    Selective Plating
    
    Absence of contaminantsMicroscopyGram StainingPhage Plaque Assay
    
    Absence of PhagePlasmid Stability
    
    Replica PlatingGrowth Characteristics
    
    OD
    
    Conforms with CSSBiomass
    
    Conforms with CSSSDS PAGE
    
    Conforms with CSS
 Deliverables  T3
 Development Report for establishment of the CSS Executed Batch Records
for MCB and WCB SOPs for preparation of buffers and media
CofA for all raw materials
Testing records
CofA for final release of MCB and WCB




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##### 



T4 Process Development  Fermentation
 T4P1 Milestone Initiation of development activities  fermentation April 1st 2003
 T4P2 Milestone Continued development  fermentation September 30 th 2003
 T4P3 Milestone  Fermentation Protocol  September 2003
  1.
    
    Shake Flask Evaluations.2.
    
    Initial evaluation in the fermenter.3.
    
    Optimisation and verification of a batch process.4.
    
    Optimisation and verification of fed batch process.5.
    
    Comparison of productivity.
  §
    
    Medium components  Inoculum and fermentation
  §
    
    Inoculum Regime.§
    
    Feeding strategy.§
    
    Dissolved Oxygen  DO.§
    
    pH.§
    
    Temperature.§
    
    Point of induction.§
    
    Harvest time  post induction.
  §
    
    Growth Characteristics  OD and Cell Dry Weight.§
    
    SDS PAGE analysis of expression levels.§
    
    On line data for DO, Agitation, pH and temperature.
 Deliverables T4P3
 Detailed report describing work carried out and conditions defining the process for further
characterisation.




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##### 



Confidential
    
    13-Nov-03
 T4P4 Milestone  Consistent Laboratory Fermentation Process  December 2003.
   
    
    Inoculum Regime
    
    +/- 15%
    
    Feeding strategy
    
    +/- 15%
    
    Dissolved Oxygen  DO
    
    +/- 10%
    
    PH
    
    +/- 0.5
    
    Growth Temperature
    
    +/- 3°C
    
    Induction temperature
    
    +/- 3°C
    
    Point of induction
    
    +/-10%
    
    Harvest time
    
    +/- 15%
  
    
    On line data DO, pH, temperature
    
    Growth Profiles OD , CDW
    
    Acetate Levels
    
    Expression Levels
    
    SDS PAGEHPLC
    
    Plasmid Stability
    
    selective plating
    
    
    On line data DO, pH, temperature, CO2, 02
    
    Growth Profiles OD , CDW
    
    Acetate Levels
    
    Expression Levels
    
    SDS PAGEHPLC
    
    Plasmid Stability
    
    restriction mapsselective platingsequence analysis of the IL13 insert.




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##### 




    
    On line data DO, pH, temperature
    
    Growth Profiles OD , CDW
    
    Acetate Levels
    
    Expression Levels
    
    SDS PAGEHPLC
    
    Plasmid Stability
    
    restriction mapsselective plating
 Deliverables T4P4
 A report will be compiled of the work carried out and the results obtained.
 A full process description will be produced defining the medium components, their source and
preparation, operating parameters, limit values. Methods used in analysis of outputs and the
data obtained from the consistency batches. This will serve as the technology transfer working
document for the fermentation process.
  T5P1
    
    Milestone  Initiation of development work  DSP. April 1st 2003T5 P2
    
    Milestone  Continuation of development work  DSP . September 30th 2003T5 P3
    
    Milestone  DSP protocol  December 2003
  Step 1




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##### 



Confidential
    
    13-Nov-03
 Step 2
  
    
    Equipment model, manufacturers
    
    Buffer pH and composition
    
    Concentrations at resuspension  OD and or wet weights
    
    Pressures
    
    Temperatures
    
    Centrifugal forces
    
    Cycles / Passes
    
    Temperatures
    
    Storage conditions
    
    Times
   §
    
    Protein quantification and SDS PAGE analysis
  Step 3
   
    
    Equipment model and manufacturer
    
    Temperature
    
    Composition and pH of solubilising agent
    
    Concentration for resuspension  wet weight
    
    Time
    
    Agitation
    
    Viscocity of solubilised inclusion bodies




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
    
    HPLC analysis
    
    Solids Remaining
 Step 4
   
    
    Equipment Model and manufacturer
    
    Membrane Specifications
    
    Volumes
    
    Flow rates
    
    Pressures
    
    Time
    
    Temperature
  
    
    Reverse phase analysis
    
    Dry weight determinations
 Step 5
   
    
    Composition and pH of refolding buffer
    
    Concentration/dilution factor for refolding
    
    Dilution Rate
    
    pH adjustments
    
    Time
    
    Temperature
    
    Agitation
  
    
    Reverse phase analysis  quantification of refolding process




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Confidential
    
    13-Nov-03
 Step 6
   
    
    Equipment Model and manufacturer
    
    Membrane Specifications
    
    Volumes
    
    Flow rates
    
    Pressures
    
    Time
    
    Temperature
   
    
    Reverse phase analysis and quantification of losses
 Step 7
   
    
    Feed conditioning requirements
    
    Protein concentration of feed
    
    Feed pH, conductivity and pH
    
    Equipment model and manufacturer
    
    Chromatography media specifications
    
    Column Specifications
    
    Packing Protocol and specifications
    
    Temperatures
    
    Pressures
    
    Buffer compositions, pH and conductivity.
    
    Equilibration flow rates and volumes
    
    Feed flow rates, volumes/capacity
    
    Wash volumes and flow rates
    
    Elution conditions, volumes, flow rate, gradients.
    
    Regeneration, flow rates and volumes.
    
    Eluate volume, concentration, pH and conductivity.




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
    
    SOP for column packing and testing
    
    Chromatograms
    
    HPLC analysis  quantification and identification
    
    SDS PAGE analysis
    
    Bioactivity
   
    
    DNA determination
    
    Host Cell Protein Determination
    
    Endotoxin determination
 Step 8
  T5P3 Deliverables
 A report will be compiled covering the results of activities and defining the process for
extraction and purification (DSP) for further characterization




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Confidential
    
    13-Nov-03
 T5P4 Milestone  Consistent DSP protocol  April 2004
     
    
    Resuspension concentrations
    
    +/- 20 %
    
    Feed pH
    
    +/- 0.5
    
    Temperature
    
    +/- 3°C
    
    Load capacity
    
    +/- 15%
    
    Dilution rate / volume
    
    +/- 15 %
    
    Elution profiles
    
    +/-15%
    
    Conductivity
    
    +/- 10%
  
    
    On line data  chromatograms, UV absorbance, pH , conductivity, pressure, flow rates
    
    In process analytical data  SDS PAGE, Reverse Phase HPLC, DNA and HCPs
    
    Final Product  SDS PAGE, Reverse Phase HPLC, SEC HPLC, Bioactivity, HCPs, DNA and
endotoxins, n-terminal sequencing.




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##### 



Deliverables T5P4
 A report will be prepared describing the work and conditions used in testing reproducibility of the
DSP strategy.
 A full process description will be produced defining the buffer components, their source and
preparation operating parameters, limit values. Methods used in analysis of outputs and the data
obtained from the consistency batches. This will serve as the technology transfer working document
for the DSP process.
 T6 Development of analytical methods for process monitoring, and lot release testing.
 T6P1 Milestone  Initiation of analytical development  April 1 st 2003
 T6P2 Milestone  Analytical SOPs  December 2003
   Reverse Phase HPLC 
 SEC HPLC 
 SDS PAGE 




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Confidential
    
    13-Nov-03
  Ion Exchange HPLC 
 Host cell DNA.
 Host Cell Proteins
 Peptide mapping.
 Sequence and amino acid analysis,
 Endotoxins.
 In vitro biological activity 
 Process Related Impurities.




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Deliverables T6P2
 For all the above methodologies SOPs will be written detailing
 
    
    Instruments used.
    
    Column specifications and suppliers
    
    Reagents and suppliers
    
    Kits and their suppliers
    
    Procedures.
 T6P3 Milestone  Methods Transferred to CMO  19th March 2004
 T6P4 Milestone  Validated Analytical Protocols  30th July 2004
   System Suitability 
 Specificity 
 Linearity 
 Accuracy 
 Repeatability

 Intermediate precision 




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Confidential
    
    13-Nov-03
  Robustness 
 I.
    
    Stability of analytical proceduresII.
    
    Variations of reagentsIII.
    
    Timing of stepsIV.
    
    TemperatureV.
    
    PHVI.
    
    Variation of, columns, gels, etc,.
             
  System Suitability 
 Specificity 
 Linearity 
 Accuracy 
 Repeatability

 Intermediate Precision 
 Robustness.
 I.
    
    Variations of reagentsII.
    
    Timing of stepsIII.
    
    Temperature




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##### 



IV.
    
    pHV.
    
    Variation of equipment
  
   Deliverables T6P4
 Reports
 Instrument specifications, Materials and Methods
 Analytical results, Chromatograms, Gels, Bioactivity Specifications of test methods
 T7 Process Transfer to cGMP facility.
 T7P1 Milestone  Initiation of transfer  January 2004
 Following review and approval by IDM of a protocol for the transfer. IDM needs to define clearly
the information required in such a protocol for the transfer otherwise this is not a clear
milestone
 T7P2 Milestone  Lab Scale process consistency at CMO  May 13th 2004




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Confidential
    
    13-Nov-03
 Deliverables T7P2
 A report describing three runs at laboratory scale demonstrating process performance equivalent to
that obtained at Biotecnol.
 Identification of the key issues which will need to be addressed further in consideration of scale
up and implementation  report to be prepared by CMO and discussed with Biotecnol
 Material from the three runs for further testing at Biotecnol.
 Material from these runs can be further used as reference material by the CMO. Identification of
materials to be procured and qualified.
 Product and process specification, test methods, online analysis and expected outcome required at
each stage of the process and for product release.
  T7P3 Milestone  Non-cGMP Process Demonstration at Scale  September 9th 2004
   Deliverables T7P3  Step 1
   Step 2




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Deliverable T7P3 Step 2
 Report detailing the Process, equipments, raw materials, procedures, on line data and off line
analysis demonstrating consistency and robustness of the process.
 Cleaning and aseptic validation plan.
 Equipment and facility validation plan
 Qualification of raw materials
 Step 3
   Deliverables T7P3 Step 3
 Process functioning at scale in cGMP meeting specifications defined in T7P2 Batch of IL13,
non-cGMP
 Batch production record and analytical SOPs for review.
 CofA
 T7P4 Milestone  cGMP Documentation Reviewed  September 16th 2004
 Deliverables T7P4
 All SOPs and Master batch production records will be finalised by CMO and reviewed by
Biotecnol and IDM.
 T9 cGMP Batch Production and Analysis.
 T9P1
Milestone  Initiation of Production  September 17th 2004
 T9P2
Milestone  Release of cGMP Product  December 15 2004




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Confidential
    
    13-Nov-03
 Deliverables T9P2
 One batch run, cGMP compliant, at the manufacturing facility producing clinical/commercial
grade IL13 of the required specification for subsequent clinical use and commercial use Per IDM
requirements.
 Documentation
 SOPs  Manufacturing, Cleaning and Analytics
 Batch Manufacturing Record and test results
 CofA
 PART II
 T8  Validation Master Plan
 T8P1   Milestone  Initiation of Validation Master Plan  June 15th 2004
  T8P2  Milestone  Delivery of Validation Master Plan  September 16th 2004
 Deliverables T8P2
 The Validation Master Plan will be finalised by CMO and reviewed by Biotecnol and IDM.
 T10 Filling and finishing of Product to deliver Finished Product .
 Milestone  Selection of manufacturer  March 2004




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##### 



Milestone  Initiation of manufacture  November 2004
 Milestone  Release of Finished Product  January 2005
  
    
    100 ug /ml (to be confirmed )
    
    2 ml type I glass vials
    
    Halobutyl stoppered
    
    fill volume between 0.5 ml to 3 ml
    
    Storage at -70°C.( to be confirmed with preliminary stability results)
    Deliverables T1OP3
 One batch of finished Finished Product (No of vials to be specified by IDM)
SOPs
Batch Manufacturing Records
CofA




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Confidential
    
    13-Nov-03
 T11
Generation of Preliminary Data to Demonstrate Product Stability.
 Milestone  Initiation  October 2003
  Milestone  Preliminary Stability Data  January 2004




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Deliverables T11 P2
 Instrument specifications, materials and methods
 Analytical results, chromatograms, gels, bioactivity
 Indication of the need for further formulation
 Indication of assays ability to detect degradation.
 Milestone  Intermediate Stability Data  November 2004
  Deliverables T11 P3
 Reports
 Instrument specifications, materials and methods
Analytical results, chromatograms, gels, bioactivity
Indication of the need for further formulation
Indication of assays ability to detect degradation.
 Validation of Stability Indicating Assays.




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##### 



Confidential
    
    13-Nov-03
 T12 Stability Studies on cGMP Grade Product and
 Finished Product .
 Milestone  Initiation of Stability Studies  February 2005.
   
    
    Sterility
    
    single assay
    
    Endotoxin
    
    single assay
    
    Appearance
    
    single observation
    
    PH
    
    single measurement
    
    Bioactivity
    
    triplicate assay
    
    SEC HPLC
    
    triplicate assay
    
    SDS PAGE
    
    duplicate assay
    
    Reverse Phase HPLC
    
    triplicate assay
    
    IonX HPLC
    
    triplicate assay
   Deliverables T12
  T12P2 25°C, February 30 th 2005.
 T12P3 2-8°C May 30 th 2005
 A completed stability report detailing the methods and results will be provided after 12, 24 and
36 months for the temperature at which the product is intended to be stored long term (-70°C)




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##### 



T12P4 August 2005             6 months stability data  interim report.
 T12P5 February 2006        1 year stability data  completed report.
 T12P6 August 2006            1.5 years stability data  interim report
 T12P6 2 years stability data  complete report
 T12P6 August 2007           2.5 years stability data  interim report
 T12P6 February 2008       3 years stability data  complete report




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##### 



Confidential
    
    13-Nov-03
  
 200320042005
IDNameJ F M A M J J A S 0 NFA M J J ,à0
1TOP01-04
2Tl PIidentif CMG
TIP1150
3T2P2functional Bî_13
T2P50
4T3P130-09
5T3P2MOB WCBprod
T3P230
5T3P3 MOB WCB releaseT3P3 i 40
7T4P1 initiation fermentation
T4P150
8T4P2
30-09
9T4P3fermep tation protocol
T4P375
10T4P4reproducible lab ferment proc
T4P4 +100
11T5P101-04
12T5P2; 30-09
13T5P3DSPprotocol
T5P3
14T5P475 reproduc ble lab DSP proc T5P4100
T6P1 01-04
T6P2analyticals SOPs T6P2
17T6P3
18T6P4
19T7P1
20T7P2
21T7P31
22T7P4
23T9P1
24T9P2