Exhibit 4.5


 


PATENT LICENCE AGREEMENT made 10th October 2001


 


BETWEEN


 


PRAXIS PHARMACEUTICALS AUSTRALIA PTY LTD (ACN 082 811 530) of 60 Marcus
Clarke Street, Canberra, ACT 2601 (‘PRAXIS’)


 


AND


 


CENTRAL SYDNEY AREA HEALTH SERVICE of QE II Building.  RPAH Campus, Missender Road, Camperdown NSW (‘CSAHS’)


 


RECITALS


 


A                                      CSAHS
has knowledge in respect of powder technologies for use in the management of
respiratory disease.  Aspects of this
knowledge are protected by patents and patent applications in a number of countries.


 


B                                        CSAHS
proposes to provide the knowledge to PRAXIS and to enter into an exclusive licence
with PRAXIS to allow PRAXIS to exploit the knowledge on the following terms and
conditions.


 


C                                        CSAHS
also has an Ausindustry Start grant (GRA0078) related to the use of inhaled
mannitol as a test for airway hyperresponsiveness.  This grant is currently suspended.


 


D                                       CSAHS
proposes that PRAXIS enter into Start grant GRA0078 for the development of
inhaled mannitol and assume the rights and obligations currently held by Rhone
Poulenc Rorer, as part of this agreement.


 


AGREEMENT


 


Definitions


 


In this
Agreement:


 


‘Additional
Patents’ means patents applications and patents in respect of new inventions
pursuant to clause 3.


 


‘CSAHS
Intellectual Property’ means the Patents, Additional Patents and Knowledge in
respect of powder technologies.


 


‘Confidential Information’
means information (including methodology) treated by the disclosing party as confidential,
and disclosed to the other party in the course of exercising this licence.


 


‘Cost of Sales’
means


 


(a)                                  all
costs of direct materials, labour and overhead expenses incurred in the
manufacture, production and delivery of sales of Products and Services.


(b)                                 any
tax or government charge (other than an income tax) levied on the sale,
transportation or delivery of sales of Products and Services.


(c)                                  trade
and quantity discounts or rebates actually allowed and taken in respect of
sales of Products and Services, and


 





















 


(d)                                 credits
or allowances given or made for return of Products previously sold in the
Territory.


 


‘exploit’ means to do any act in relation to the Patents that would
infringe the Patents except for this license. 
It includes making or manufacture of powder products, marketing, selling
and hiring of powder products and provision of diagnostic or therapeutic
services involving powder, using powder products and processes involving
powders, including for or in research and development, importing powder
products, and keeping powder products for the purpose of doing any of these
things.


 


‘Gross Margin’ means Net Sales less Cost of Sales.


 


‘Knowledge’ in respect of powder technologies’ means the knowledge
outlined in Attachment I.


 


‘Net Sales’ means the aggregate of the invoiced price of Products sold
and Services provided in a country less returns and allowances in respect of
those sales.


 


‘Patents’ means patents and patent applications owned by CSAHS in the
countries listed in Attachment 2 and such other patents applied for by CSAHS or
Praxis which claims priority from any of those patents.


 


‘Product’ means a powder product manufactured and supplied by PRAXIS or
a PRAXIS licensee that exploits the Patents.


 


‘Service’ means a service provider by PRAXIS or a PRAXIS licensee that
exploits the Patents


 


‘Royalty Term’ means, in respect of Net Sales in a country, the period
of time equal to the longer of:


 


(a)                                  ten
years from the date of the first commercial sale of a Product or Service in
that country and


 


(b)                                 the
expiry of the last of the Patents registered in that country.


 


1.                                       Objectives


 


1.1                                 CSAHS
agrees that it shall use all reasonable endeavors to assist PRAXIS to enter
into Start grant GRA0078.


 


1.2                                 PRAXIS
agrees that it shall


 


(a)                                  use
all reasonable endeavours to secure the grant of the Patents; and


 


(b)                                 use
all reasonable endeavours to maintain the Patents in force.


 


1.3                                 PRAXIS
agrees that it shall


 


(a)                                  use
reasonable endeavours at its expense to:


 


(i)                                     exploit
the CSAHS Intellectual Property:


 


(ii)                                  undertake
either itself or through third parties further research and development based
on the CSAHS Intellectual Property: and


 


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(iii)                               as
and when required, undertake itself or through Related Corporations, or enter
into appropriate third party licensing or marketing arrangements, to optimise
the returns from sales of Products and Services at the earliest practicable and
economically and commercially prudent date; and


 


(b)                                 Use
reasonable endeavours to ensure that each Product sold:


 


(i)                                     is
of merchantable quality;


 


(ii)                                  is
fit for the purpose for which it is sold;


 


(iii)                               satisfies
any conditions and warranties implied by the law of that county in which it is
sold;


 


(iv)                              complies
with all laws and standards regulating manufacture, assembly, labelling,
packaging, storage and sale in the country in which it is sold.


 


2.  Intellectual Property Rights


 


2.1                                 Each
party agrees CSAHS owns the Patents.


 


2.2                                 CSAHS
will bear all past costs incurred in applying for registering and maintaining
the Patents in force up to the date of this agreement.


 


2.3                                 The
parties will cooperate in prosecuting and maintaining the Patents in force and
both parties will be kept fully informed by the Patent Attorney.


 


2.4                                 Praxis
will be responsible for instructing patents attorneys in applying for,
registering and maintaining the Patents in force and for covering the cost of
this from the date of this agreement. 
Praxis will perform these tasks in consultation with CSAHS.  The expected costs for the years beginning 1 July and
ending 30 June are shown in Attachments 2.


 


25.                                 The
CSAHS has the right to register and maintain the Patents in force for countries
not selected by Praxis.


 


2.6                                 Each
party must in relation to the Patents:


 


(a)                                  Advise
the other party immediately on becoming aware of any anticipated, suspected or
actual infringement by any person of any of the Patents:


 


(b)                                 do
all things reasonably requested by CSAHS to enable it to protect, and to prove
ownership of the Patents, and


 


(c)                                  provide
all documents and assistance (other than financial assistance) required or
reasonably requested by CSAHS to allow it other prompt and good faith
negotiations between the parties, to protect (including in any litigation) the
Patents


 


2.7                                 Praxis
may institute any proceedings to protect the Patents if CSAHS fails to do so within
a reasonable time of a written request from Praxis


 


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3.                                       New
Intellectual Property Rights


 


3.1                                 With
respect to any new patentable inventions arising in the course of exploiting
the Patents:


 


(a)                                  PRAXIS
may prosecute a new patent application in the name of Praxis for the invention
or agree to treat the invention as new confidential information.


 


(b)                                 all
costs incurred in applying for, registering and maintaining those new patent
applications and subsequent patents in force are to the borne by PRAXIS


 


(d)                                 if
PRAXIS decides not to request patent protection for any new patentable
invention in any country, CSAHS may file patent applications at its own cost.


 


4.                                       Licences


 


4.1                                 CSAHS’s
grants PRAXIS a worldwide exclusive sub-licensable license to exploit the CSAHS
Intellectual Property.


 


4.2                                 Rights
to Sub-Licence


 


Subject to clause 4.3, CSAHS grants to Praxis
the right to sub-license CSAHS Intellectual Property. Praxis will inform CSAHS
in writing of the details of these sub-licences.


 


4.3                                 Sub-Licence
terms


 


Praxis may only grant a sub-licence of the CSAHS
Intellectual Property third parties if


 


(a)                                  the
third party being granted the sub-licence has the commercial capacity to
promote and exploit the CSAHS Intellectual Property and has at least sufficient
skills and resources to comply with obligations placed upon PRAXIS in relation
to the CSAHS Intellectual Property in the relevant country or countries;


 


(b)                                 the
sub-license a wholly consistent with the terms of this Licence and in
particular:


 


(i)                                     such
sub-license could not support to extend or continue in any circumstances where
this Licence may be terminated; and


 


(ii)                                  the
sub-licensee acknowledges that CSAHS owns the CSAHS Intellectual Property;


 


(c)                                  the
sub-licence prohibits the Sub-Licensee from taking any action or allowing any
action to be taken which detracts from the ownership of the CSAHS Intellectual
Property by CSAHS or conflicts with the provisions contained in this Licence in
relation to prosecuting or defending the


 


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Patents or defending any allegation of
infringement of the CSAHS Intellectual Property other than the Patents;


 


(d)                                 the
sub-licence is in the English language, executed by the sub-licensee and giving
its place of business;


 


(e)                                  the
sub-license requires the sub-licensee to maintain all books, records and
accounts necessary to enable verification of its sales and royalties and other
amounts required to be paid by Praxis the CSAHS and to allow CSAHS to inspect
those books, records and accounts on terms similar to those contained in clause
7.3, and


 


(f)                                    the
sub-license limits the duration of the sub-licence in respect of the CSAHS
Intellectual Property for the term of this Agreement and further provides for
the sub-licence to terminate automatically upon the termination of this
Agreement


 


5.                                       Product
Development


 


It is the intention of the parties to cooperate fully in the
development of the Products and Services


 


6.                                       Royalties


 


6.1                                 In
consideration of the rights granted is PRAXIS by the CSAHS in this Agreement
PRAXIS will pay to CSAHS royalties on Net Sales of Products and Services sold
in a country for the Royalty Term in respect of the country as follows:


 


(a)                                  in
respect of the upper and lower airway function test applications of the Patent;


 


(i)                                     no
royalties until aggregate Net Sales (ie. the aggregate of sales of Products and
Services from all countries) of A $500,000 have been achieved, and PRAXIS will
notify the CSAHS immediately in writing when this event occurs.


 


(ii)                                  a
royalty of 4% of the Gross Margin if the Net Sales of the Product or Service by
PRAXIS achieve a Gross Margin of 20% or less


 


(iii)                               a
royalty of 8% of the Gross Margin if the Net Sales of the Product or Service by
PRAXIS achieve a Gross Margin between 20% and 40%.


 


(iv)                              a
royalty of 10% of the Gross Margin if the Net Sales of the Product or Service
by PRAXIS achieve a Gross Margin greater than 40% and


 


(v)                                 20%
of any royalty received from a sub-licensee


 


(b)                                 In
respect of the mucociliary clearance and sputum induction applications of the
patent:


 


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(i)                                     no
royalties until sales representing a Gross Margin of $1.0 million have been
achieved then, when the Gross Margin achieved by product sales is between $1
million and $25 million a 3% royalty will apply, when it is between $25 million
and $75 million a 2.5% royalty will apply and when it is greater than $75
million a 2.0% royalty will apply, and


 


(ii)                                  20%
of any royalty received from a sub-licensee


 


(c)                                  The
allowances, that is the volume of samples provided free of charge or provided
at a discount, will be limited to eight per cent (8%) of the total volume of
sales on a country by country basis.  By
mutual agreement between PRAXIS and the CSAHS this volume of samples and
discounted Product may be varied during the first year in which sales of a
Product commences.


 


7.                                      Accounting


 


7.1                                 Within
45 days after the end of each calendar quarter PRAXIS must pay to the CSAHS all
royalties due under this Agreement and with that payment furnish to CSAHS an
operating statement in the agreed form to explain each royalty payment.


 


7.2                                 PRAXIS
will keep and maintain proper books of account and records fully written up in
accordance with generally accepted accounting standards and principles
consistently applied to record its operations as licencee under this Agreement
including details of all Net Sales Prices. 
Gross Revenue and royalties payable to CSAHS


 


7.3                                 Upon
request by CSAHS, PRAXIS will permit a representative appointed by CSAHS in
have access to the books and records of PRAXIS with the right to inspect, copy
and take extracts for the purpose of verifying the Net Sale Prices, the Gross
Revenue and the Cost of Sales and the royalties payable to CSAHS.


 


7.4                                 On
receipt of any statement pursuant to clause 7.1 CSAHS may require an
investigation of the books and records of PRAXIS by a chartered accountant
selected and paid for by CSAHS for the purposes of verifying the accuracy of
the statement and in which case CSAHS will notify PRAXIS in writing, PRAXIS
will permit the chartered accountant to inspect, copy and take extracts from
its books and records and shall promptly produce for inspection all vouchers,
invoices, statements, accounts and other evidence in support of the statement
as may be reasonably required.  If any
discrepancy occurs, it shall be subject to alteration at CSAHS’s option with
the arbitrator’s decisions binding.


 


7.5                                 In
the event that any amount due by PRAXIS to CSAHS under this Agreement is paid
on or before the due date for payment then without prejudice to any other
rights or remedies of CSAHS the unpaid amount shall carry interest at the
Australian 10 year period rate prevailing at that time, calculated on daily
balances from the due date to the date of payment in full


 


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8.                                      Confidential
Information


 


8.1                                 Each
party (‘first party’) must in relation to Confidential Information of the other
party (‘other party’) disclosed to further this Agreement and marked to
indicate its confidential nature:


 


(a)                                  to
the best of its ability keep it confidential;


 


(b)                                 to
the best of its ability use it only to further the objectives of clause 1 of
this Agreement;


 


(c)                                  use
its best endeavours not to disclose it to any person other than:


 


(i)                                     to
those of the first party’s employees who have a need to know (and only to the
extent that each such employee has a need to know) and who have first been
directed to keep if confidential and to use it only as permitted under this
Agreement (‘Direction’);


 


(ii)                                  to
other people (except to the extent permitted in accordance with clause 8.2),
such as contractors and visitors, who have a need to know (and only to the
extent that each such person has a need to know), and who have agreed in
writing (in a form similar to this Agreement) to keep it confidential and to
use it only as permitted under this Agreement (also a ‘Direction’);


 


(d)                                 enforce
each Direction at its cost;


 


(e)                                  not
copy it or any part of it that is in material form other than as strictly
necessary and must mark any such copy ‘confidential - (Owner)’;


 


(f)                                    safeguard
it in accordance with its usual security practices against unauthorised
copying, use or disclosure (whether that disclosure is oral, in writing or in any
other form);


 


(g)                                 notify
the first party immediately of or actual unauthorised copying, use or
disclosure; and


 


(h)                                 comply
with any reasonable direction issued regarding actual breach.


 


8.2                                 The
first party’s obligations of confidentiality under this Agreement do not apply
to information that (whether before or after this Agreement is executed):


 


(a)                                  the
first party creates (whether alone or jointly with any person) independently of
the other party’s Confidential Information and outside the scope of this
Agreement;


 


(b)                                 is
public knowledge (otherwise than as a result of a breach of confidentiality by
the first party);


 


(c)                                  is
rightfully known it or in the Possession or control of the first party and not subject
to an obligation of confidentiality on the first party; or


 


(d)                                 the
first party is required by law to retain or disclose (but only to the extent so
required)


 


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8.3                                 Each party must


 


(a)                                  ensure
that any of its personnel who attend the other party’s premises, comply with
that other party’s usual staff and security practices while attending those
premises; and


 


(b)                                 notify
the other party of its usual staff and security practices to enable the other
party to comply with paragraph (a).


 


9.                                      Exclusion
and Limitation of Liability


 


9.1                                 PRAXIS
agrees that it (and each PRAXIS licensee) exploits the Patents at its own risk.


 


9.2                                 Each
party excludes all implied conditions and warranties except to the extent that
any such exclusion would contravene any applicable law or cause this clause to
be void.


 


9.3                                 PRAXIS
indemnifies CSAHS against all loss and damage (including costs on a solicitor
and client basis) that the CSAHS may sustain or incur as a result of any
actions, claims, suits, proceedings or demands arising directly or indirectly
out of the breach of this Agreement by Praxis


 


9.4                                 PRAXIS
undertakes that during the term of this Agreement and for six years after its
termination it will, subject to such policy being available on commercially
reasonable terms, maintain a policy of product liability insurance with a
reputable underwriter for an amount acceptable by CSAHS (acting reasonably) in
respect of all loss or damage occasioned directly or indirectly by the exploitation
of the Patents by PRAXIS and each PRAXIS licensee.  CSAHS shall be named in that insurance as an
additional insured and PRAXIS shall provide to CSAHS upon request a copy of the
policy and all endorsements with evidence of the payment of premiums.


 


10                                  Indemnity


 


Each party (‘first party’) indemnifies the other party (each an ‘indemnified
party’) against all loss and damage (including costs of a solicitor and own
client basis) that an indemnified party may sustain, or incur as a result of
any damage to the first party’s property or injury to or death of any of the
first party’s personnel arising out of this Agreement.


 


11                                  Resolution
of Disputes


 


11.1                           A party
must not start arbitration or court proceedings (except proceedings seeking interlocutory
relief) about a dispute arising out of this Agreement (“Dispute”) unless it has
complied with the clause.


 


11.2                           A party
claiming that a Dispute has arisen must notify the other party to the Dispute
giving details of the Dispute (‘Notification’)


 


11.3                           On
receipt of a Notification each party must refer the Dispute for resolution by its
Chief Executive Officer or the CEO’s nominee.


 


11.4                           If the
Dispute is not received under the clause 11.3 within 30 days (or longer period
agreed between the parties), the parties must refer the Dispute for mediation
by the Australian Commercial Dispute Centre Limited (ACDC) for resolution in
accordance with the conciliation Rules of ACDC


 


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11.5                           If the
Dispute is not resolved under clause 11.4 within 60 days (or longer period
agreed between the parties) either party may require binding arbitration.


 


12                                  Termination


 


12.1                           This
agreement shall commence on the date of its signing and shall unless earlier
terminated in accordance with clause 12.2 or 12.4, continue in respect of each
country until the expiry of the royalty term in respect of that country.


 


12.2                           Either
party (“termination party”) may terminate this Agreement at any time with
immediate effect by giving the other party notice if the other party breaches
any other provision of this Agreement and fails to remedy the breach within 30
days after receiving notice requiring it to do so.


 


12.3                           Praxis
may terminate this agreement on 60 days notice if in its commercial judgment it
is not prudent to continue the agreement.


 


12.4                           Termination
for Insolvency


 


Subject to clause 12.6 and notwithstanding
anything contained in clause 12.2(a), this agreement may be terminated by a
party giving notice to the other party upon the happening of any of the
following events in respect of that other party.


 


(a)          the expiration of four
weeks from the other party having a receiver, manager, receiver and manager or
agent in possession validly appointed for the whole or any substantial part of
its assets or from a court order being validly made for the winding up of the other
party other than for the purpose of reorganization or reconstruction.


 


(b)         immediately a resolution
of the other party’s shareholder passed for the winding up of that party other
than for the purpose of reorganisation or reconstruction.


 


(c)          in the event that the
other party files a petition in bankruptcy or similar proceedings or is
adjudicated bankrupt or if a petition for bankruptcy or similar proceedings is
filed against the other party and is not stayed or discharged within 45 days
of  such filing or if the party becomes
insolvent or makes an assignment for the benefit of creditors or enters into
any agreement , arrangement or composition pursuant to bankruptcy law or
otherwise acknowledges insolvency or is adjudged bankrupt or of the other party
discontinues business.


 


(d)         the other party is in breach of an undertaking given pursuant to
clause 12.2(a).


 


12.5                           Reconstruction
Exception


 


A winding up or liquidation for the purposes
of reconstruction or amalgamation by the other party shall not be an event
permitting or giving rise to termination if after that reconstruction or
amalgamation the resulting corporation becomes bound by the terms of this Agreement
by way of assignment or notation.


 


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12.6                           Termination
to be without prejudice


 


Any termination of this agreement shall be
without prejudice to the rights which a party has against the other in respect
of anything done or omitted to be done hereunder prior to such termination or
in respect of any sums or other claims outstanding at the time of termination.


 


12.7                           In the
event that PRAXIS chooses not to obtain or seek approval or seek registration
in any Country, then PRAXIS will not unreasonably refuse to convert the licence
granted by this Agreement into a non-exclusive licence in that country.


 


13                                  After
Termination


 


13.1                           On
termination of this Agreement (unless otherwise agreed between the parties and
each party agrees to negotiate in good faith with the other to reach such an
agreement):


 


(a)                                  the
licences granted under clause 4 (Licenses) cease, and PRAXIS and each PRAXIS
licensee must stop exploiting and may not grant any further sub-licences
(except that PRAXIS and PRAXIS licensees will fill existing orders and may
continue to supply any Products manufactured before termination, and must then
pay the CSAHS royalties on these Products in accordance with clause 6
(Royalties): and


 


(b)                                 PRAXIS
must in relation to the Confidential Information of CSAHS.


 


(i)                                     stop
using that Confidential Information; and


 


(ii)                                  at
the option of CSAHS return that Confidential Information.


 


(c)                                  PRAXIS
must pay CSAHS all royalties due under clause 6.


 


13.2                           The
obligations of confidentiality (but not the right to use and disclose) under
clause 8 (Confidential Information) continue to apply to the parties to this
Agreement (in addition to any assignee) after the termination of this
Agreement.


 


13.3                           Clauses
9 (Exclusion and Limitation of Liability) and 10 (Indemnity) continue after
termination of this Agreement


 


13.4                           Termination
of this Agreement will not affect any accrued rights and remedies either party
may have


 


14                                  Force
Majeure


 


14.1                           Force
Majeure Event affecting a party means anything outside that party’s reasonable
control, including but not limited to, acts or omissions of the other party,
fire, storm, flood and earthquake, war, transportation embargo or failure or
delay in transportation, act or omission (including laws, regulations,


 


10





















 


disapprovals or failures to approve) of any
third person (including but not limited to, subcontractors, customers,
governments or government agencies)


 


14.2                           If a
Force Majeure Event affecting a party precludes that party (“precluded party”) partially
or wholly from complying with its obligations under this Agreement then:


 


(a)                                  as
soon as reasonably practicable after that Force Majeure Event arises, the
precluded party must notify the other party of the Force Majeure Event, and


 


(b)                                 to
the extent and for the period that the precluded party is precluded by the Force
Majeure Event from complying with its obligations under this Agreement, those
obligations will be suspended.


 


14.3                           This
clause does not apply to any obligation to pay money.


 


15                                  Relationships


 


This Agreement does not create a relationship of employment, agency or
partnership between the parties.


 


16                                  Assignment


 


A party must not assign or attempt to assign or otherwise transfer any
right arising out of this Agreement except as implied in relevant sublicencing
clause 4 without the written consent of the other party.


 


17                                  Severability


 


If the whole or any part of any clause of this Agreement that is
illegal or unenforceable, it will be severed from this Agreement and will not
affect the continued operation of the remaining provisions of this Agreement.


 


18                                  Waiver


 


The failure of a party at any one time to insist on performance of any
obligation of another party under this Agreement is not a waiver of its right.


 


(a)                                  to
insist on performance of, or claim damages for breach of, that obligation unless
that party acknowledges in writing that the failure is a waiver; and


 


(b)                                 at
any other time to insist on performance of that or any other obligation of another
party under this Agreement


 


19                                  Notices


 


19.1                           A
party notifying or giving notice under this Agreement must give notice


 


(a)                                  in
writing


 


(b)                                 addressed
to the address of the recipient specified in this Agreement or as altered by
notice given in accordance with this clause; and


 


(c)                                  left at or sent by prepaid post or by
fax to that address


 


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19.2                           A
notice given in accordance with clause 19.1 will be deemed received


 


(a)                                  if
left at the recipient’s address, on the date of delivery;


 


(b)                                 if
sent by prepaid post, 2 days after the date of posting, and


 


(c)                                  if
sent by fax, when the sender’s facsimile system generates a message confirming successful
transmission of the total number of pages of the notice.


 


20                                  Headings


 


Headings are for ease of reference only and do not affect the construction
of this Agreement.


 


21.                               Governing
Law


 


This Agreement is governed by the laws of New South Wales.


 


22                                  Entire
Agreement


 


This Agreement:


 


(a)                                  is
the entire agreement between the parties as to its subject matter and supersedes
all prior representations and agreements in connection with that subject
matters and


 


(b)                                 may
only be altered in writing signed by both parties


 


EXECUTED AS AN AGREEMENT


 


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  SIGNED for and on behalf of

  	
  )

  
	
  PRAXIS PTY LIMITED by a duly

  	
  )

  
	
  authorised director in the presence

  	
  )

  
	
  of:

  	
  )

  
	
   

  
	
  /s/ Alan D.
  Robertson

  	
   

  
	
  Signature of Authorised Person

  
	
   

  
	
  /s/ Lewis Schulz

  	
   

  
	
  Witness

  
	
   

  
	
  General Manager

  	
   

  
	
  Title of Authorized Person

  
	
   

  
	
  Alan D. Robertson

  	
   

  
	
  Name of Authorized Person

  
	
   

  
	
   

  
	
  SIGNED for and on behalf of

  	
  )

  
	
  CENTRAL SYDNEY AREA

  	
  )

  
	
  CSAHS by its Chief Executive

  	
  )

  
	
  Officer Dr Diana B

  	
  )

  
	
  Horvath in the presence of:

  	
  )

  
	
   

  
	
  /s/ Diana Horvath

  	
   

  
	
   

  
	
   

  	
  /s/ Michael Wallace

  	
   

  
	
  Witness

  	
  Michael Wallace

  
	
   

  	
  DCEO CSAHS

  
					



 


 


Attachment 1.  Knowledge in
respect of powder technologies


Attachment 2.  Patents


 


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ATTACHMENT 1

EXISTING KNOLWEDGE

for mannitol as Diagnostic Test for bronchial hyperresponsiveness and

for the therapeutic use of mannitol to increase mucociliary clearance


 


Dr
Anderson and her colleagues have experimental evidence to show that the airways
of persons with clinically recognised asthma, whose airways narrow in response
to inhaling a wet aerosol of 4.5% saline and, whose airways narrow with
hyperpnea with dry air as experienced during exercise, also narrow in response
to inhaling dry powders of substances capable of increasing the osmolarity of
the airways.  (Australian Patent No
682,756, US Patent No. 5817.028  ,   PCT  
AU 95/00086)


 


Airway
narrowing has been measured indirectly by measuring a reduction in forced
expiratory volume in one second (FEV1).  A fall in FEV1 of 15% or more is
considered an abnormal airway response. 
Healthy subjects had a mean fall of 2.1% ± 2.3% (SD) at the highest
dose tested.


 


The
powders used include mannitol and sodium chloride but other powders, capable of
increasing airway osmolarity, such as mineral salts, organic salts, sugars and
sugar alcohols would be expected to do the same.  The powders of mannitol and sodium chloride
were required to be biologically active i.e. to have an adequate proportion of
particles, by weight, within the respirable range (less than 7 microns) to
cause airway narrowing as described in the patent.


 


The
powder was encapsulated  (5mg,  10 mg, 
20 mg,  and  40 mg capsules) and inhaled from a
Halermatic, a Dinkihaler or a Boehringer Inhalator in increasing doses
5mg,  10 mg, 20 mg, 40 mg, 80 mg ( 2×40 ),
160 mg ( 4×40 ), 160 mg ( 4×40 ),  160 mg 
( 4×40 ) to a cumulative dose of 635 mg.  The FEV1 was measured in duplicate
after inhaling each dose.  It was found
that all devices worked well and devices of a similar nature should work easily
as well.  Other measurements included
inspiratory flow rates, oxygen saturation and recovery of lung function.


 


REFERENCES


 


Anderson SD, Brannan J, Spring J, Spalding N,
Rodwell LT, Chan K, Gonda I, Walsh A, Clark AR. 
A new method for bronchial provocation testing in asthmatic subjects
using a dry powder mannitol.  Am J Respir
Crit Care Med 1997; 156:  758-765.


 


Brannan JD, Koskela H, Anderson SD, Chew N.  Responsiveness to mannitol in asthmatic
subjects with exercise and hyperventilation-induced asthma.  Am J Respir Crit Care Med, 1998:  158:1120-1126.


 


Subbarao P, Brannan JD, Ho B, Anderson SD, Chan H-K,
Coates AL.  Inhaled mannitol identifies
methacholine-responsive children with current asthma.  Pediatr Pulmonol 2000; 29:291-298.


 


Brannan JD, Anderson SD, Freed R, Leuppi JD, Koskela
H, Chan H-K.  Nedocromil sodium inhibits
responsiveness to inhaled mannitol in asthmatic subjects.  Am J Respir Crit Care Med 2000; 161;
2096-2099.


 


Leuppi JD, Salome CM, Jenkins CR, Anderson SD, Xuan
W, Marks GB, Koskela H, Brannan JD, Freed R, Andersson M, Chan H-K, Woolcock AJ


 





















 


Predictive markers of asthma exacerbation during
stepwise dose reduction of inhaled corticosteroids.  Am J Respir Crit Care Med 2001; 163:406-412.


 


Högman M, Lúdviksdóttir D, Anderson SD, George S,
Hakansson L, Chan HK, Meriläinen P, Hedenström H.  Inhaled mannitol shifts exhaled nitric oxide
in opposite directions in asthmatic and healthy subjects.  Respiration Physiology 2001; 124:141-150.


 


Brannan JD, Anderson SD, Gomes K, King GG, Chan H-K,
Seale JP.  Fexofenadine decreases
sensitivity to and montelukast improves recovery from inhaled mannitol.  Am J Respir Crit Care Med 2001; 163:1420-5.


 


Leuppi JD, Salome CM, Jenkins CR, Koskela H,
Anderson SD, Andersson M, Chan H-K, Woolcock AJ.  No relationship between markers of airway
inflammation and airway hyperresponsiveness in patients with well-controlled asthma.  Eur Respir J 2001, in press


 


Dr
Anderson and her colleagues also have experimental evidence, in a small number
of subjects, to show that in healthy persons, persons with clinically
recognised asthma, persons with bronchiectasis, persons with cystic fibrosis
there is a measurable increase in mucociliary clearance as measured by
clearance of the radio nuclide 99Mtechnetium sulphur colloid after
inhalation of powdered mannitol in a dose up to a cumulative does of 300mg.


 


The
powders used was mannitol but other powders, capable of increasing airway
osmolarity, such as mineral salts, organic salts, sugars and sugar alcohols
would be expected to do the same.  The
powdered mannitol was required to be biologically active i.e. to have an adequate
proportion of particles, by weight, within the respirable range (less than 7
microns) to cause deposition in the lower airway.  The use of such powders to increase
mucociliary clearance is covered by Australian Patent No  682,756, US Patent No 5817.028 , PCT AU
95/00086.


 


The
data supporting this is summarised below in the form of abstracts of published
studies.  However considerable amount of
research would need to bring this therapeutic application to market
particularly in the area of toxicology.


 


Daviskas
E, Anderson SD, Brannan JD, Chan H-K, Eberl S, Bautovich G.  Inhalation of dry powder mannitol increases
mucociliary clearance.  Eur Resp J, 1997;
10: 2449-2454.


 


Inhalation of hypertonic saline stimulates
mucociliary clearance (MCC) in healthy subjects and those with obstructive lung
disease.  We investigated the effect of
inhaling the osmotic agent mannitol on MCC. 
We used a dry-powder preparation of mannitol British Pharmacopea (BP)
which was encapsulated and delivered using a Dinkihaler.  MCC was measured for 75 min in six asthmatic
and six healthy subjects on two occasions before and after the mannitol
inhalation or its control, using 99mTc-suphur colloid and a gamma camera.   The inhaled dose of mannitol was 267+/-171
mg (mean +/-SD) and 400 mg and the percentage fall in forced expiratory volume
in one second (FEV1) was 22 +/-3% and 4 +/-2% in the asthmatic and healthy
subjects, respectively.  The total
clearance in the whole right lung for the 60 min from the start of inhalation
of mannitol was greater by 263+/-11.9% in the asthmatic and 18.1+/-4.9% in the
healthy subjects compared to the control. 
The total clearance over 75 min was 54.7+/-9.6% and 33.6+/-9.4% on the
mannitol and control day (p<0.002), respectively, in the asthmatic subjects
and 40.5+/-7.1% and 24.8+/-7.8% (p<0.002) in the healthy subjects.  In conclusion, inhalation of dry-powder


 





















 


mannitol increases mucociliary clearance in asthmatic and healthy
subjects and may benefit patients with abnormal mucociliary clearance.


 


Daviskas E, Anderson SD, Eberl S, Chan H-K, Bautovich G.  Inhalation of dry powder mannitol improves
mucociliary clearance in patients with bronchiectasis.  Amer Rev Respir Crit Care Med 1999;
159:1843-8.


 


Bronchiectasis is a disease characterized by
hypersecretion and retention of mucus requiring physical and pharmacologic
treatment.  Recently we reported that
inhalation of dry powder mannitol markedly increases mucociliary clearance
(MCC) in asthmatic and in healthy subjects. 
Inhalation of dry-powder mannitol increases mucociliary clearance.  In this study we investigated the effect of
mannitol on MC in patients with bronchiectasis. 
Eleven patients 40 to 62 yr of age inhaled mannitol (approximately 300
mg) from a Dinkihaler.  MCC was measured
over 90 min, in the supine position, on three occasions involving:  mannitol or control or baseline, using a
radioaerosol technique.  On the control
day patients reproduced the breathing maneuvers and the number of coughs
induced by the mannitol.


 


Mannitol significantly increased MCC over the 75 min
from the start of the intervention compared with control and baseline in the
whole right lung, central, and intermediate region.  Mean (+/- SEM) clearance with mannitol was
34.0 +/- 5.0% versus 17.4 +/- 3.8% with control and 11.7 +/- 4.4% with baseline
in the whole right lung (p < 0.0001). 
The mean number of coughs induced by mannitol was 49 +/- 11.  In conclusion, inhalation of dry powder
mannitol increased clearance of mucus and thus has the potential to benefit
patients with bronchiectasis.


 


Robinson M, Daviskas E, Eberl S, Baker J, Anderson SD, Bye PTP.  The effects of inhaled mannitol on
bronchial mucus clearance in cystic fibrosis patients: a pilot study.  Eur Respir J 1999: 14(3):678-685.


 


It has been postulated that hypertonic saline (HS)
might impair the antimicrobial effects of defensins within the airways.  Alternative non-ionic osmotic agents such as
mannitol may thus be preferable to HS in promoting bronchial mucus clearance
(BMC) in patients with cystic fibrosis (CF). 
This study reports the effect of inhalation of another osmotic agent,
dry powder Mannitol (300 mg), compared with its control (empty capsules plus
matched voluntary cough) and a 6% solution of HS on BMC in 12 patients with
cystic fibrosis (CF).  Mucus clearance
was measured using a radioaerosol/gamma camera technique.  Post-intervention clearance was measured for
60 min, followed by cough clearance for 30 min. 
Neither mannitol nor HS improved BMC during the actual intervention
period compared with their respective controls. 
However during the post-intervention measurement there was a significant
improvement in BMC for both the mannitol (8.7+/-3.3% versus 2.8+/-0.7%) and HS
(10.0+/-2.3% versus 3.5+/-0.8%).  There
was also a significant improvement in cough clearance with the Mannitol
(9.7+/-2.4%) compared with its control (2.5+/-0.8%).  Despite premedication with bronchodilator, a
small fall in forced expiratory volume in one second (FEV1) was seen
immediately after administration of both the mannitol (7.3+/-2.5%) and HS
(5.8+/-1.2%).  Values of FEV1 returned to
baseline by the end of the study. 
Inhaled mannitol is a potential mucoactive agent in cystic fibrosis
patients.  Further studies are required
to establish the optimal dose and the long-term effectiveness of mannitol.


 





















 


Daviskas E, Anderson SD, Eberl S, Chan H-K, Young IH.  The 24 hr effect of mannitol on the clearance
of mucus in patients with bronchiectasis. 
Chest 2000; 199:  414-421.


 


An
investigation was carried out on the acute effect of mannitol on the clearance
of mucus, and (1) the 24-h mucus retention, and (2) the mucus clearance rate
and lung function 24 h after inhalation of a single dose of mannitol.  Clearance of mucus was measured on 3
consecutive days using (99m)Tc-sulfur colloid radioaerosol and a gamma
camera.  Mannitol, 330 +/- 68 mg (mean+/-
SD), was inhaled using a dry powder inhaler only on day 2. Eight patients with
bronchiectasis (age range, 29 to 70 years). 
Measurements and results:  On each
day, lung images were collected over 2 h and at 24 h.  Key findings of the study are as
follows:  (1) the 24-h retention of mucus
was reduced the day after mannitol had been inhaled, compared to the day
without mannitol (day 1) in the whole right lung (57.6 +/- 6.2% vs 68.1 +/-
5.9%), central (47.5 +/- 6.7% vs 56.9 +/- 6.5%), intermediate (61.7 +/- 5.6% vs
73.8 +/- 5.5%), and peripheral regions (70.9 +/- 4.3% vs 86.6 +/- 4.6%) (p <
0.02);  and  (2) mannitol helped patients clear mucus
within 2 h that might otherwise take up to 24 h, from the whole right lung and
defined regions.  However, clearance over
60 min measured 24 h after mannitol inhalation was not significantly
different to baseline clearance without mannitol (8.7 +/- 1.9% on day 1 vs 9.7
+/- 3.7% 24 h after mannitol; p > 0.8). 
The patients maintained the same lung function the day before and after
mannitol had been inhaled: FEV(1) (percent predicted), 79 +/- 5 on day 1 vs 80
+/- 5 on day 3; and forced expiratory flow, midexpiratory phase (percent
predicted), 50 +/- 6 on day 1 vs 51 +/- 6 on day 3; p > 0.6).  Mannitol inhalation acutely increases
clearance of mucus, and this effect extends beyond the acute study period,
resulting in decreased mucus retention at 24 h.


 





















 


Attachment
2


 


	
  Country

  	
   

  	
  Official Number

  (Patent or

  Application)

  	
   

  	
  2001/2002

  (expected

  cost)

  	
   

  	
  2002/2003

  (expected

  cost)

  	
   

  	
  2003/2004

  (expected

  cost)

  	
   

  
	
  Australia

  	
   

  	
  682756

  	
   

  	
  A$300

  	
   

  	
  A$345

  	
   

  	
  A$390

  	
   

  
	
  Canada

  	
   

  	
  2183471

  	
   

  	
  A$655

  	
   

  	
  A$5,655

  	
   

  	
  A$5,655

  	
   

  
	
  Europe (EPO)

  	
   

  	
  95910331.8

  	
   

  	
  A$6,520

  	
   

  	
  A$6,570

  	
   

  	
  A$31,620

  	
   

  
	
  Japan

  	
   

  	
  7-522021

  	
   

  	
   

  	
   

  	
  A$10,000

  	
   

  	
  A$10,000

  	
   

  
	
  Malaysia

  	
   

  	
  P19603590

  	
   

  	
  A$3,640

  	
   

  	
  A$3,675

  	
   

  	
  A$705

  	
   

  
	
  New Zealand

  	
   

  	
  281522

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  A$500

  	
   

  
	
  Peoples
  Republic Of China

  	
   

  	
  95191808.7

  	
   

  	
  A$5,405

  	
   

  	
  A$5,405

  	
   

  	
  A$405

  	
   

  
	
  Republic Of
  Korea

  	
   

  	
  96-704666

  	
   

  	
  A$5,660

  	
   

  	
  A$5,831

  	
   

  	
  A$831

  	
   

  
	
  Singapore 

  	
   

  	
  34525

  	
   

  	
  A$777

  	
   

  	
  A$777

  	
   

  	
  A$917

  	
   

  
	
  The
  Philippines

  	
   

  	
  I-54034

  	
   

  	
  A$3,640

  	
   

  	
  A$3,700

  	
   

  	
  A$750

  	
   

  
	
  United
  States Of America

  	
   

  	
  5817028

  	
   

  	
   

  	
   

  	
  A$1,528

  	
   

  	
   

  	
   

  
	
  Viet Nam

  	
   

  	
  SC0131/96

  	
   

  	
   

  	
   

  	
  A$5,000

  	
   

  	
  A$5,000

  	
   

  
	
  TOTAL

  	
   

  	
   

  	
   

  	
  A$26,597

  	
   

  	
  A$48,486

  	
   

  	
  A$56,773