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Patent 2223259 Summary

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(12) Patent: (11) CA 2223259
(54) English Title: PHARMACEUTICAL FORMULATIONS OF HIGHLY LIPOPHILIC CAMPTOTHECIN DERIVATIVES
(54) French Title: FORMULATIONS PHARMACEUTIQUES A BASE DE DERIVES HAUTEMENT LIPOPHILES DE LA CAMPTOTHECINE
Status: Expired
Bibliographic Data
(51) International Patent Classification (IPC):
  • A61K 31/47 (2006.01)
  • A61K 9/107 (2006.01)
  • A61K 31/4745 (2006.01)
  • A61K 47/00 (2006.01)
  • A61K 47/18 (2017.01)
  • A61K 47/22 (2006.01)
  • A61K 47/10 (2017.01)
  • A61K 47/12 (2006.01)
  • A61K 47/26 (2006.01)
  • A61K 47/28 (2006.01)
(72) Inventors :
  • HAUSHEER, FREDERICK HERMAN (United States of America)
  • MURALI, DHANABALAN (United States of America)
  • HARIDAS, KOCHAT (United States of America)
  • REDDY, DASHARATHA GAURAVARAM (United States of America)
(73) Owners :
  • BIONUMERIK PHARMACEUTICALS, INC. (United States of America)
(71) Applicants :
  • BIONUMERIK PHARMACEUTICALS, INC. (United States of America)
(74) Agent: OSLER, HOSKIN & HARCOURT LLP
(74) Associate agent:
(45) Issued: 2007-08-14
(86) PCT Filing Date: 1996-06-04
(87) Open to Public Inspection: 1996-12-12
Examination requested: 2003-04-25
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): Yes
(86) PCT Filing Number: PCT/EP1996/002438
(87) International Publication Number: WO1996/039143
(85) National Entry: 1997-12-02

(30) Application Priority Data:
Application No. Country/Territory Date
08/461,385 United States of America 1995-06-05

Abstracts

English Abstract




A pharmaceutical formulation, as a solution or suspension of pH from 2 to 6,
of camptothecin or a lipophilic camptothecin derivative,
having a water solubility of less than 5 micrograms/ml, in N-methylpyrrolidin-
2-one.


French Abstract

Cette invention concerne une formulation pharmaceutique à base de camptothécine ou d'un dérivé lipophile de la camptothécine ayant une solubilité dans l'eau inférieure à 5 mg/ml, cette formulation se présentant sous la forme d'une solution ou d'une suspension à PH compris entre 2 et 6, dans un solvant à base de N-méthylpyrrolidin-2-one.

Claims

Note: Claims are shown in the official language in which they were submitted.




-13-


CLAIMS

1. A pharmaceutical formulation, as a solution or
suspension of pH from 2 to 6, of camptothecin or a
lipophilic camptothecin derivative, having a water
solubility of less than 5 micrograms/ml, in N-methylpyr-
rolidin-2-one.
2. A formulation according to Claim 1, further includ-
ing one or more pharmaceutically acceptable excipients.
3. A formulation according to Claim 2, wherein the
excipient(s) are polyethylene glycol, epoxylated castor
oil, an aliphatic alcohol of 1 to 4 carbon atoms or
benzyl alcohol.
4. A formulation according to Claim 3, wherein the
aliphatic alcohol is ethanol.
5. A formulation according to Claim 1, 2, 3 or 4,
further including taurocholic acid or a pharmaceutically
acceptable salt thereof.
6. A formulation according to Claim 1, 2, 3, 4 or 5,
further including a non-ionic surfactant.
7. A formulation according to Claim 1, 2, 3, 4, 5 or
6, wherein the concentration of the camptothecin or
derivative thereof is from 1.0 mg/ml to the solubility
or suspendibility limit.
8. A formulation according to Claim 1, 2, 3, 4, 5 or
6, wherein the camptothecin derivative is a 7-ethyl, 7-
ethyl-l0-hydroxy, 10,11-methylenedioxy, 10,11-ethylene-
dioxy, 9-methyl, 9-chloro-10,11-methylenedioxy, 9-
chloro, 10-hydroxy, 9,10-dichloro, 10-bromo, 10-chloro,
9-fluoro, 10-methyl, 10-fluoro, 9-methoxy, 9-chloro-7-
ethyl or 11-fluoro derivative.
9. A formulation according to Claim 1, comprising the
following components in proportions lying within the
following ranges, all weight/weight of the camptothecin
or derivative thereof:
a) 25-1,000 parts of N-methylpyrrolidin-2-one,



-14-



b) 100-5,000 parts of a pharmaceutically acceptable
acid,
c) 0-10 parts of a taurocholic acid or a pharmaceutic
ally acceptable salt thereof,
d) 0-2.5 parts of glycerol,
e) 100-10,000 parts of polyethylene glycol,
f) 100-5,000 parts of an aliphatic alcohol having 1 to
4 carbon atoms or benzyl alcohol,
g) 100-10,000 parts of a non-ionic surfactant,
h) 0-10,000 parts of epoxylated castor oil.
10. A formulation according to Claim 9 diluted with a
pharmaceutically acceptable diluent to form a deliver-
able solution, wherein the concentration of the campto-
thecin or derivative thereof is from 0.001 to 1.0 mg/ml.

Description

Note: Descriptions are shown in the official language in which they were submitted.



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WO 96/39143 PCT/EP96/02438
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PHARMACEUTICAL FORMULATIONS OF HIGHLY LIPOPHILIC
CAMPTOTHECIN DERIVATIVES

Field of the Invention
This invention relates to useful, novel and non-
obvious formulations of camptothecin derivatives, and
will have particular application to formulations of
poorly water soluble (<5}ig/ml) camptothecin derivatives.
Background of the Invention
For the purpose of this invention, poorly water
soluble and highly lipophilic camptothecin derivatives
(referred to as "HLCD" for the purposes of this inven-
tion) are defined interchangeably as any unsubstituted
or any A-ring and/or B-ring substituted camptothecin
which has a water solubility of less than 5 micrograms
per mililiter (<5}ig/ml) of water. Also for the purposes
of the instant invention, the terms "highly lipophilic"
and "poorly water soluble" are used interchangeably to
describe the fundamental bioavailability and chemical
behaviour of the camptothecin derivatives.
Utilizing HPLC and NMR techniques, researchers have
demonstrated that camptothecin and many of its deriva-
tives undergo an alkaline, pH-dependent hydrolysis of
the E-ring lactone. The slow reaction kinetics allow
one to assess whether both the lactone and non-lactone
forms of the drug stabilize the topoisomerase I-cleaved
DNA complex. Studies indicate that only the closed
lactone form of the drug helps stabilize the cleavable
complex. This observation provides reasoning for the
high degree of drug activity observed in solid tumor
models. Tumor cells, particularly hypoxic cells preva-
lent in solid neoplasms, have relatively lower
intracellular pH levels than normal cells. At pH levels
below 7.0, the lactone E-ring form of camptothecin
CONFIRMATION COPY


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WO 96/39143 PCT/EP96/02438
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predominates.
Formulations of camptothecin and its derivatives In the lactone form are
difficult to prepare, due to the

factors cited above. The poor solubility of these
compounds in aqueous solution prohibits administration
of effective doses. The opening of the lactone ring in
alkaline formulations precludes their utility as well,
due to a substantial reduction in the anti-tumor potency
of the compounds.
The prior art teaches the use of various organic
solvents useful for camptothecin formulations. This
prior art is identified in the Information Disclosure
Statement accompanying this application. Such solvents
include lipid-based oils, such as cottonseed oil, peanut
oil, IL-20 and others, and organic solvents such as N,N-
dimethylacetamide (DMA), dimethylisosorbide (DMI), and
others. Solubility of the compounds in lipid-based
solvents is generally less than lmg/ml, while the solu-
bility increases to as high as about 6.7mg/ml in certain
organic solvents.

Summary of the Invention
The formulations of this invention include as the
primary solvent the compound N-methylpyrrolidin-2-one,
also referred to as N-methylpyrrolidinone, or simply,
NMP. The solubility of highly lipophilic, poorly water
soluble camptothecin derivatives is increased to between
15.0 and 20.0mg/ml in NMP, which allows for much more
concentrated solutions to be prepared in advance of
formulating. The resulting higher drug concentration
attained by the instant invention allows greater utility
for preparing oral and parenteral formulations.
The preferred formulations of this invention in- ~
clude the following: (a) HLCD; (b) NMP; (c) polyethylene
glycol (PEG) or propylene glycol; (d) an acid; (e) a


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non-ionic surfactant; and (f) a low MW alcohol. In
addition, certain formulations may also include (g) a
heavy oil, such as epoxylated castor oil; (h) glycerol;
and (i) taurocholic acid or a pharmaceutically accept-
able salt thereof, or a similar intestinal absorption
enhancing agent.
The solutions and formulations of this invention
are able to contain a high concentration of effective
ingredient due to the unpredictably high solubility of
the compounds in NMP. This allows a lower solvent
volume delivery to the patient to deliver the same
amount of effective ingredient, which in turn results in
reduced risk of toxicity and greater patient acceptance.
The formulations of this invention can be tailored
for various types of delivery, including parenteral,
subcutaneous and oral, among others. Specific examples
of oral and parenteral formulations are given in the
description of the preferred embodiments which follows.

Description of the Preferred Embodiments
The preferred formulations disclosed below are not
intended to be exhaustive or to limit the invention to
the precise forms disclosed. Rather, they have been
chosen and described to explain the principles of the
invention, and their application and practical use to
best enable others skilled in the art to follow its
teachings.
The pharmaceutical formulations which comprise this
invention include as basic ingredients, a pharmaceutic-
ally effective amount of a highly lipophilic camptothe-
cin derivative (HLCD) dissolved or suspended in N-
methylpyrrolidin-2-one (NMP). The solubility of most
HLCDs in NMP is between 15.0 and 20.0mg/ml. In formula-
ting solutions it is desirable to use enough NMP to
completely dissolve the HLCD prior to adding any other


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excipients or diluents. Approximate ratios for formula-
ting solutions are between 25 parts by weight to 1,000
parts by weight NMP per part by weight of HLCD, prefer-
ably between 50 to 500 parts by weight NMP per part
HLCD, and most preferably between 100 to 300 parts by
weight NMP per part HLCD. In the most preferred case,
this will yield an initial NEAT solution concentration
of about lmg/ml to about 40mg/ml.
Suspensions, typically employed in orally adminis-
tered formulations, may include significantly higher
concentrations, up to 400mg/ml of the NEAT formulation.
Other pharmaceutically acceptable diluents and
excipients may also be included in the preferred formu-
lations, as outlined below. Typically, a pharmaceutical
formulation of HLCD will include from 1.0 to 40.0 mg of
HLCD per ml of solution or lmg/ml to 400mg/ml suspen-
sion.
The pharmaceutically acceptable excipients and
diluents preferably will be chosen from the following
groups, keeping in mind that the exact nature of the
formulation will depend upon the intended method of
delivery.
One of the pharmaceutically acceptable excipients
included in the formulation is a pharmaceutically ac-
ceptable acid, which is included to lower the pH of the
formulation to between 2.0-6.0 (most preferably between
3.0-5.0) to keep the HLCD in its active lactone confi-
guration. The preferred acid may be chosen from any one
of a number of pharmaceutically acceptable mineral acids
or organic acids, including hydrochloric acid, phosphor-
ic acid, tartaric acid, lactic acid, ascorbic acid,
citric acid, gluconic acid, fumaric acid, maleic acid
and others. The acid will preferably be employed at the
ratio of 10 to 5,000 parts by weight of the HLCD, most
preferably between 100 to 2,500 parts by weight per part


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- 5 -

of HLCD. Citric acid is the most preferred acid.
Other excipients will include polyethylene glycol
(PEG) or propylene glycol, and a non-ionic surfactant.
The preferred PEG has a molecular weight of 300 to 400,
most preferably 300 for parenteral formulations and 400
for oral formulations. PEG is included in the formula-
tion at a ratio of between 100 to 10,000 parts by weight
of PEG to each part by weight HLCD.
The preferred surfactant is a polysorbate-based
compound, most preferably polysorbate-80 (PSB-80). The
surfactant is included in the formulation at a range of
100 to 10,000 parts by weight of PSB to each part by
weight HLCD. Most preferably the ratio is between 250
and 6500 parts by weight PSB per part of HLCD.
Parenteral formulations can optionally include a
quantity of a lower alcohol, most preferably ethyl
alcohol and/or benzyl alcohol, and a lipid based exci-
pient, preferably castor oil, most preferably an epoxy-
lated castor oil such as CremaphorTM-80.
The lower alcohol is incorporated into the formula-
tion at between 0 to 5,000 parts by weight of each
alcohol used per part by weight HLCD, with the maximum
alcohol content being 10,000 parts by weight alcohol per
part by weight of HLCD.
Lipid based excipient (Cremaphor-80) is incorpora-
ted into the formulation at between 0 to 10,000 parts by
weight per part of HLCD.
Oral formulations will include the above ingre-
dients and may optionally include a quantity of glycer-
ol. Preferred ratio of glycerol is 0 to 5 parts by
weight glycerol per part by weight of HLCD, most prefer-
ably 0.5 to 2.5 parts by weight per part by weight HLCD.
Oral formulations may further include an intestinal
absorption facilitating compound, most preferably a bile
acid such as taurocholic acid or a salt thereof at from


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WO 96/39143 PCI'/EP96/02438
-6--
1 to 10 parts by weight per part by weight of HLCD.
Oral formulations are also preferably formulated and
incorporated into a pharmaceutically acceptable carrier,
such as soft or hard gelatin capsules, among others, to
facilitate swallowing.
Table 1 below illustrates a typical pharmaceutical-
ly acceptable formulation of HLCD/NMP adapted for par-
enteral administration to a patient.

TABLE 1
COMPONENT PARTS FOR
PARENTERAL FORMULATIONS OF HLCD

Ingredients pts by wt
HLCD 1 (1-40mg/mi)
Ethyl Alcohol 0 to 5,000
Benzyl Alcohol 0 to 5,000

Acid 100 to 5,000
PEG 400 100 to 10,000
NMP 25 to 10,000
Cremaphor-EL 100 to 10,000
Glycerol 0 to 2.5

Taurocholic Acid 0 to 10
Polysorbate 80 100 to 10,000
( TweenT"'- 8 0

Parenteral formulations are typically diluted with
a common delivery solution such as 5$ dextrose USP,
lactated Ringer's solution or aqueous saline prior to
administration to the patient.
Preferred oral formulations of HLCD/NMP are illu-
strated in Table 2.


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WO 96/39143 PCT/EP96/02438
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TABLE 2
COMPONENT PARTS FOR ORAL FORMULATION
OR HLCD
J _.
Ingredients pts by wt
HLCD 1 (1-400mg/ml)
NMP 25 to 1,000
Citric Acid 100 to 5,000
EtOH 100 to 5,000
Polysorbate-80 100 to 10,000
(Tween-80)

PEG-400 100 to 10,000
Glycerin 1.5 to 2.5
Taurocholic Acid 1 to 10

Oral formulations are preferably encapsulated in a
suitable carrier for oral delivery, typically gelatin
capsules.
Preferred HLCD's used as active ingredients in the
above formulations include camptothecin (CPT) and its
derivatives which have a solubility of less than 5
micrograms per millileter of water. Included in this
group are CPT derivatives which have substitutions at
one or more of the following positions on the molecule:
(a) 7-substitutions; (b) 9-substitutions; (c) 10-
substitutions; and (d) 11-substitutions; or any combina-
tion of the.above in a di- or tri-substituted CPT deri-
y , . . . . _ . - .
vative having a solubility of <5pg/ml in water. Most
preferred derivatives of CPT which fit into the category
of HLCD are 10,11-methylenedioxy camptothecin, 10,11-
ethylenedioxy camptothecin, 7-ethyl camptothecin, 7-
ethyl-l0-hydroxy camptothecin, 9-methyl camptothecin, 9-


CA 02223259 2006-09-11
ra
s

- 8 -
chloro-10,11-methylenedioxy camptothecin, 9-chloro
camptothecin, 10-hydroxy camptothecin, 9,10-dichloro
camptothecin, 10-bromo camptothecin, 10-chloro camptothecin,
9-fluoro camptothecin, 10-methyl camptothecin, 10-fluoro
camptothecin, 9-methoxy camptothecin, 9-chloro-7-ethyl CPT,
and 11-fluoro camptothecin. Other HLCDs will also fit the
profile for the most preferred active compounds and their
inclusion into these formulations can be achieved with a
minimum amount of experimentation.
The preferred concentration of the camptothecin or
derivative thereof is from 0.001 to 1.0 mg/ml.
The following specific examples illustrate the most
preferred formulations which constitute this invention.
These formulations are included to illustrate the best modes
of making the formulations are not introduced to limit the
invention in any way.

Examples 1 and 2
Solubility of CPT and 7-ethyl CPT in NMP

(1) A mixture of CPT (14mg) and NMP (lml) was sonicated in a
clean vial at 50 degrees Celsius for 30 minutes. The
solution appeared clear and no precipitation or cloudiness
appeared even after 72 hours at ambient temperature.
(2) A mixture of 7-ethyl CPT (11.5mg) and NMP (0.5ml) was
sonicated in a clean vial at 50 degrees Celsius for 30
minutes. The solution appeared clear and no precipitation
or cloudiness appeared even after 1 week at ambient
temperature.
Examples 3 and 4

The Following NMP Formulations were Prepared


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WO 96/39143 PCT/EP96/02438
- 9 -

Formulation #1

Ethanol 6.4m1
Citric Acid 1.Og
PEG 300 50g
NMP 10.7m1
TWEEN 80 lOg

The above ingredients were mixed in the above
order. First citric acid was dissolved in ethanol by
sonication at 50 degrees Celsius for 30 minutes.
Formulation #2
Ethanol 20.3ml
Benzyl Alcohol 3.44m1
Citric Acid 4.Og

PEG 300 40g
NMP 8.55ml
TWEEN 80 8.Og

The above ingredients were mixed in the above
order. First citric acid was dissolved in ethanol by
sonication at 50 degrees Celsius for 30 minutes.

Example 3: Solubility of CPT in Formulation #1
Solutions of CPT in above Formulation #1 were
prepared at concentrations of 0.3, 0.4, and 0.5mg of CPT
in lml of formulation. The mixtures were sonicated at
50 degrees Celsius for 60 min. There were no cloudi-
J -
ness, suspension or precipitation. The mixtures were
filtered through 0.2 micron filter. The mixtures were
diluted with 0.9% sodium chloride solution and studied


CA 02223259 1997-12-02

WO 96/39143 PCT/EP96/02438
- l0 -

for the appearance of Tyndall effect as given in the
following tables:

V
Table 1: CPT 0.3mg/ml of formulation #1, with dilution
by 0.9t NaCl solution

Dilution 0 min 15 min 30 min 45 min 60 min 90 niin 120 min 1 day
1:1 clear clear clear clear clear clear clear ---
1:2 clear clear clear clear clear clear clear --
1:5 cicar clear clear clear clear elcar clear

1:10 clear clear clear clear clear clear clear 1:100 clear clear clear clear
clear clear clear clear

Table 2: CPT 0.4mg/ml of formulation #1, with dilution
by 0.9t NaCl solution

Dilution 0 min 15 min 30 min 45 min 60 min 90 min 120 min 1 day
1:1 clear clear clear cicar clear clear clear ---
1:2 clear clear clear clear clear clear clear 1:5 clear clear clear clear
clear clear clear 1:10 cicar clear -- -- --- - --

1:100 clear clear clear clear cicar clear clear clear
Table 3: CPT 0. 5mg/ml of formulation #1, with dilution by 0.9t
NaCl solution

Dilution 0 min 15 min 30 min 45 min 60 min 90 min 120 min 1 day
1:1 clear cicar clear clear cicar clear --- ---

1:2 clear clear clear clear clear --- --- -- ~
1:5 cicar clear clear clear -- --- --- ---
1:10 clcar clear --- --- --- --- --- ---
1:100 clear clear clcar clcar clear clear clear clear
SUBSTiTUTE SHEET (RULE 26)


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WO 96/39143 PCT/EP96/02438
- I1 -

Example 4: Solubility of 7-ethyl CPT in Formulation #1
Solutions of 7-ethyl CPT in above Formulation #t1
were prepared at concentrations of 0.5, 0.6, 0.7 and
l.Omg of 7-ethyl CPT in lml of formulation. The mix-
tures were sonicated at 50 degrees Celsius for 60 min.
There were no cloudiness, suspension or precipitation.
The mixtures were filtered through 0.2 micron filter.
The mixtures were diluted with 0.9% sodium chloride
solution and studied for the appearance of Tyndall
effect as given in the following tables:

Table 4: 7-ethyl CPT 0.5mg/ml of formulation #1, with
dilution by 0.9t NaC2 solution

Dilution 0 min 15 min 30 min 45 min 60 min 90 min 120 min 1 day
1:1 clear clear clear clcar clear clear clcar clear
1:2 clear clear clear clear clear clear clear clear
1:5 clear clear clear clear clear clear clear clear
1:10 clear clear elcar clear clear clear clear dear
1:100 clear clcar clear clear clear clear clear clear

Table 5: 7-ethyl CPT 0.6mg/ml of formulation #1, with
dilution by 0.9% NaCl solution

Dilution 0 min 15 min 30 min 45 min 60 min 90 niin 120 min 1 day
1:1- clear clear clear clear clear clear clear clear
1:2 clear clear clcar clear clear clear clear clear
1:5 clear clear clear cicar clear clear clear clear
,
1:10 clear clear clear clear clcar clear clear clear
1:100 ciear clear clcar clcar clear clear clear clear
SUBSTffUTE SHEET (RULE 26)


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WO 96/39143 PCT/EP96/02438
- 12 -

Table 6: 7-ethyl CPT 0.7mg/ml of formulation #1, with
dilution by 0.9t NaCl solution

Dilution 0 min 15 min 30 miii 45 min 60 min 90 min 120 min 1 day
1:1 clear clear clear elear clear clear clear clear
1:2 clear clear clear clear clear clear clear clear
1:5 clear clcar clear clear clear clear clear clear
1:10 clear clear ciear clear clear clear clear clear
clear
1:1 00 clear ctear cicar clear clear clear clear

Table 7: 7-ethyl 1.Omg/mi of formulation #1, with dilu-
tion by 0.9% NaC1 solution

Dilution 0 min 15 min 30 niin 45 min 60 min 90 min 120 min 1 day
1:1 clear clear clear clear clear clear clear clear
1:2 clear clear clear clear clear clear clear ---
1:5 clear clear clear clear clear clear clear 1:10 clear clear
-- --- --- --- --- ~-
1:100 clear clear clcar clear clear clear clear clear

.
~
SUBSTITUTE SHEET (RULE 26)

Representative Drawing

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Administrative Status

For a clearer understanding of the status of the application/patent presented on this page, the site Disclaimer , as well as the definitions for Patent , Administrative Status , Maintenance Fee  and Payment History  should be consulted.

Administrative Status

Title Date
Forecasted Issue Date 2007-08-14
(86) PCT Filing Date 1996-06-04
(87) PCT Publication Date 1996-12-12
(85) National Entry 1997-12-02
Examination Requested 2003-04-25
(45) Issued 2007-08-14
Expired 2016-06-06

Abandonment History

There is no abandonment history.

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Registration of a document - section 124 $100.00 1997-12-02
Application Fee $300.00 1997-12-02
Maintenance Fee - Application - New Act 2 1998-06-04 $100.00 1998-03-27
Maintenance Fee - Application - New Act 3 1999-06-04 $100.00 1999-05-17
Maintenance Fee - Application - New Act 4 2000-06-05 $100.00 2000-04-12
Maintenance Fee - Application - New Act 5 2001-06-04 $150.00 2001-06-04
Maintenance Fee - Application - New Act 6 2002-06-04 $150.00 2002-05-17
Request for Examination $400.00 2003-04-25
Maintenance Fee - Application - New Act 7 2003-06-04 $150.00 2003-05-27
Maintenance Fee - Application - New Act 8 2004-06-04 $200.00 2004-06-01
Maintenance Fee - Application - New Act 9 2005-06-06 $200.00 2005-05-26
Maintenance Fee - Application - New Act 10 2006-06-05 $250.00 2006-05-31
Final Fee $300.00 2007-03-27
Maintenance Fee - Application - New Act 11 2007-06-04 $250.00 2007-05-24
Maintenance Fee - Patent - New Act 12 2008-06-04 $250.00 2008-05-20
Maintenance Fee - Patent - New Act 13 2009-06-04 $250.00 2009-05-19
Maintenance Fee - Patent - New Act 14 2010-06-04 $250.00 2010-05-17
Maintenance Fee - Patent - New Act 15 2011-06-06 $450.00 2011-05-17
Maintenance Fee - Patent - New Act 16 2012-06-04 $450.00 2012-05-17
Maintenance Fee - Patent - New Act 17 2013-06-04 $450.00 2013-05-17
Maintenance Fee - Patent - New Act 18 2014-06-04 $450.00 2014-06-02
Maintenance Fee - Patent - New Act 19 2015-06-04 $450.00 2015-06-01
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
BIONUMERIK PHARMACEUTICALS, INC.
Past Owners on Record
HARIDAS, KOCHAT
HAUSHEER, FREDERICK HERMAN
MURALI, DHANABALAN
REDDY, DASHARATHA GAURAVARAM
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Description 2006-09-11 12 464
Abstract 1997-12-02 1 44
Description 1997-12-02 12 460
Claims 1997-12-02 2 57
Cover Page 1998-03-19 1 29
Cover Page 2007-07-19 1 32
Correspondence 2007-03-27 1 48
Assignment 1997-12-02 5 186
PCT 1997-12-02 11 401
Prosecution-Amendment 2003-04-25 1 37
Fees 2003-05-27 1 42
Fees 1998-03-27 1 55
Fees 1999-05-17 1 58
Fees 2000-04-12 1 57
Fees 2001-06-04 1 55
Fees 2002-05-17 1 59
Fees 2004-06-01 1 48
Prosecution-Amendment 2004-06-08 1 45
Fees 2005-05-26 1 44
Prosecution-Amendment 2006-03-31 2 43
Fees 2006-05-31 1 41
Prosecution-Amendment 2006-09-11 5 156
Fees 2007-05-24 1 57