US RE38,743 E1Grant
Mixtures of particular LMW heparinic polysaccharides for the prophylaxis/treatment of acute thrombotic events
Issue Date:2005-06-14
•32 Claims
Abstract
Heterogeneous intimate admixtures of sulfated heparinic polysaccharides, well suited for the prophylaxis/treatment of acute thrombotic episodes in a human patient, comprise immixture of sulfated polysaccharides having a weight average molecular weight less than that of heparin and which include from 9% to 20% of polysaccharide chains having a molecular weight less than 2,000 daltons and from 5% to 20% of polysaccharide chains having a molecular weight greater than 8,000 daltons, the ratio between the weight average molecular weight and the number average molecular weight thereof ranging from 1.3 to 1.6.
Metadata
Assignee
- Aventis Pharma S.A.
Inventor
- Roger Debrie
Application Information
Application Number:US 10/430,435
Filing Date:2003-05-07
Priority Date:1990-06-26
Art Unit:1623
Patent Drawings
This patent does not have any drawings.
Description
[0001] This application is a continuation, of application Ser. No. 07/721,315, filed Jun. 26, 1991, now abandoned.
Background of the Invention
[0002] 1. Field of the Invention
[0003] The present invention relates to novel mixtures of low molecular weight (LMW) polysaccharides and, more especially, to novel mixtures of LMW heparinic polysaccharides will adopted for the prevention of venous thromboses.
[0004] 2. Description of the Prior Art
[0005] The heparins are biologically active agents of the glycosaminoglycan family, extracted from natural sources, and have valuable anticoagulant and antithrombotic properties. In particular, they are useful in the treatment of postoperative venous thromboses. However, in their native state, the heparins present a number of disadvantages which limit the extent of their effective use. Indeed, the marked anticoagulant activity of the heparins can cause hemorrhaging, and their sensitivity to certain serum factors such as pf4 mandates the administration of relatively large doses thereof. Hence, it is necessary to favor the antithrombotic activity, attributed, notably, to the antiprothrombinase activity, at the expense of the anticoagulant activity, attributed to the antithrombin effect.
[0006] Thus, it is known to this art to fragment the heparins into molecules of lower average molecular weights. For example, European Patent EP 40,144 describes the preparation of mixtures of sulfated polysaccharides of which heparin is comprised, including an ethylenic double bond at one end of their polymer chains and having a weight average molecular weight ranging from 2,000 to 10,000 daltons. These mixtures are produced by depolymerization and saponification of a heparin ester. They are said to have high antithrombotic activity and an overall anticoagulant activity lower than that of heparin.
[0007] However, one of the principal difficulties associated with the heparins is that they are very heterogeneous products. Therefore, it is difficult to assess the contribution of each of the species to the activity of heparin, to determine the behavior of these species during depolymerization and, finally, to control the structure of such species and their respective proportions in the final products. For these reasons, it has not to date been possible to resolve completely satisfactorily the difficulties indicated above. In particular, the processes described in the prior art, and especially in EP 40,144, do not permit the production of mixtures possessing the requisite pharmacological properties for improved therapeutic applications, namely, a sufficiently long plasma half-life, a fairly high absorption rate, a high bioavailability or, alternatively, a low clearance.
[0008] Other processes are also known to this art for the fragmentation of heparin with a view towards diminishing the adverse effects thereof (compare Johnson et al, Thrombos.Haemostas.Stuttg., 35, 586(1976); Lane et al, Thrombosis Research, 16, 651; Lasker et al, U.S. Pat. No. 3,766,167)). Each appears to indicate that the desired activity is favored when the degree of fragmentation of heparin increases (see also published European Patent Application EP 301,618 relating to pentasaccharides possessing antithrombotic activity).
[0009] Likewise, recent studies on the mechanism of action of the heparins in thrombin formation have demonstrated an influence of the average molecular weight of the heparins on their activity in vitro (Béguin et al, Thromb. Haemost., 61, 30 (1989)). It is reported that low molecular weight heparins tend to possess an antiprothrombinase activity, and heparins of higher molecular weight an antithrombin activity.
[0010] It too has been proposed to this art to fractionate the heparins in order to extract mixtures of more homogeneous average molecular weight therefrom. European Patent application EP 337,327 thus describes a process for preparing oligosaccharide fragments derived from heparin, permitting mixtures having a reduced molecular weight dispersion to be obtained. According to this process, the fractions having a molecular weight below 3,000 daltons are first removed, whereby the final product is devoid of fragments containing less than 10 to 16 saccharides, and then the species having a molecular weight above 7,000 daltons. This treatment is said to provide a more homogeneous final mixture having decreased anticoagulant activity while at the same time preserving the desired antithrombotic activity.
[0011] Nonetheless, these final mixtures continue to elicit a residual hemorrhagic effect, or too low an antithrombotic response. In addition, the prior art is essentially silent in respect of which particular properties have to be combined to provide optimum biological activity. This is reflected in the above publication, where the authors conclude, “We do not know what combination of the properties of heparin is optimal. The precise characterization of different preparations and the correlation of these properties with clinical observations might possible provide an answer.”
Summary of the Invention
[0012] Accordingly, a major object of the present invention is the provision of novel combinatory immixtures of particular heparinic polysaccharide fractions, such novel immixtures being especially useful for the prophylaxis and treatment of acute thrombotic events/episodes.
[0013] Indeed, it has now surprisingly and unexpectedly been found that mixtures of both high and low molecular weight heparinic polysaccharides, nonetheless having an average molecular weight less than that of heparin, exhibit desirable balance of antithrombotic/anticoagulant activity. Contrary to the direction of the prior art, a certain fraction of relatively high molecular weight heparinic polysaccharides and a certain degree of heterogeneity are required to provide such balance of biological activity.
[0014] A pharmacokinetic study of the mixtures of the invention evidences that they combine a plurality of essentially advantageous properties.
[0015] For example, the mixtures of the invention exhibit a half-life longer than other known preparations, and also longer than mature heparin. Moreover, in relation to the latter, it will be appreciated that the half-life of the mixtures of the invention is independent of the dose injected. This is desirable in that the effect elicited is much more predictable than in the case of heparin.
[0016] In addition, in humans, the mixtures of the invention display excellent bioavailability, as measured by the anti-Xa activity. Thus, this value is approximately 30 IU % for heparin, but is approximately 90 IU % for the mixtures of the invention. This too is desirable in that it permits the doses administered to be reduced and the therapeutic potential to be improved.
[0017] Moreover, another desirable property of the mixtures of the invention is their high rate of absorption. This permits virtually instantaneous biological activity to be attained, and hence affords greater safety in treatment by providing for more rapid patient protection.
[0018] Another characteristic of the mixtures according to the invention is their low clearance compared with other products and with mature heparin. As a result of their chemical structure, their molecular weight or their sulfate content, these mixtures effectively display a particular pronounced resistance to degradation (desulfation, hydrolysis) and to elimination, which further enhances their therapeutic availability.
[0019] The preparations of the invention additionally exhibit an increased residence time compared with the heparin starting material. This property is reflected by a prolongation of the time during which the product remains active in vivo, and hence in a better therapeutic efficacy.
[0020] Too, these preparations also exhibit a reduced sensitivity to serum factors, which enhances their duration of action in vivo and permits them to be used in low doses.
[0021] These especially desirable properties are provided by controlling, during the preparation of the mixtures according to the invention, certain structural aspects of the heparinic species present therein, as well as their molecular weight distribution. The mixtures thereby obtained have a favorable ratio of the fractions of high to those of low molecular weights, which endows them with the requisite antithrombotic properties with but slight risk of hemorrhagic effect.
[0022] This characteristic of the invention is expressed both by the percentage of high molecular weight chains and of low molecular weight chains and by the ratio of the weight average molecular weight of the mixtures to their number average molecular weight, which reflects the molecular dispersion.
[0023] Briefly, the present invention features combinatory immixtures of sulfated polysaccharides having the general structure of the polysaccharides of which heparin is composed, such polysaccharides having a weight average molecular weight less than that of heparin and comprising from 9% to 20% of polymer chains of molecular weight less than 2,000 daltons and from 5% to 20% of polymer chains of molecular weight greater than 8,000 daltons, and in which the ratio weight average molecular weight/number average molecular weight ranges from 1.3 to 1.6.
Detailed Description of the Preferred Embodiments of the Invention
[0024] More particularly according to the present invention, it has now also been found that it is possible to improve the properties of the mixtures further by decreasing their content of impurities. As is known to this art, the majority of the heparins contain contaminants such as nucleic acids, polypeptides or various polysaccharides. Among the latter, chondroitin sulfates and heparan or dermatan sulfate are especially representative. Each of these contaminants, as a result of its very high molecular weight and as a result of the substituents which it bears or its degree of sulfation, is capable of interfering during the preparation of the product (e.g., in the depolymerization sequence) and adversely affecting the final molecular weight distribution, or directly the activity, by modifying the respective proportions of the active polymer chains.
[0025] The present invention, by means of particular pretreatment, not only provides for the removal of such impurities, but also enhances the desirable properties of the mixtures thus pretreated. The effect of this pretreatment may be measured using dermatan sulfate as a control impurity.
[0026] In a preferred embodiment of the present invention, the subject mixtures of sulfated heparinic polysaccharides have the desirable properties indicated above and contain less than 2% of dermatan sulfate.
[0027] In another preferred embodiment of the invention, the mixtures of sulfated polysaccharides have a weight average molecular weight ranging from approximately 3,500 daltons to approximately 5,500 daltons.
[0028] Also preferably, the backbones of the sulfated polysaccharides comprising the mixtures according to the invention have a 2-O-sulfo-4-enopyranosuronic acid at one of their chain ends.
[0029] This invention also features a process for preparing mixtures of sulfated polysaccharides having a weight average molecular weight less than that of heparin, comprising from 9% to 20% of polymer chains having a molecular weight less than 2,000 daltons and from 5% to 20% of polymer chains having a molecular weight greater than 8,000 daltons, and in which the ratio weight average molecular weight/number average molecular weight ranges from 1.3 to 1.6.
[0030] This process comprises (a) first salifying a starting material heparin in an aqueous medium by means of a long-chain quaternary ammonium salt, (b) next esterifying the salt thus produced to form an ester having a degree of esterification ranging from 9.5% to 14%, and (c) then depolymerizing such ester having a degree of esterification ranging from 9.5% to 14%.
[0031] Thus, it has now been determined that the level of depolymerization, and hence the molecular characteristics of the final product, may be controlled by varying the degree of esterification of the heparin salt starting material.
[0032] According to the invention, it is thus possible to directly and reproducibly produce mixtures of sulfated polysaccharides having the characteristics indicated above.
[0033] The heparin starting material employed in the process of the invention is preferably a porcine heparin, and, in particular, a porcine mucosal heparin. It has also been determined that the activity of the final mixtures could vary substantially in consequence of the origin of the heparin starting material. In particular, when the heparin starting material is of bovine origin, mixtures are produced having an anticoagulant activity greater than that of mixtures produced from porcine intestinal mucosal heparin.
[0034] Furthermore, in an especially advantageous embodiment of the invention, the heparin starting material is preliminarily precipitated by means of an alcohol upstream of the salification thereof. This pretreatment enables the content of impurities of the chondroitin sulfate or heparan sulfate to be decreased.
[0035] A representative alcohol providing good results is, e.g., methanol.
[0036] The degree of purity of the heparin sodium may then be determined by steric exclusion liquid chromatography.
[0037] This preliminary step permits, in particular, the preparation of a heparin having a dermatan sulfate content of less than 2%.
[0038] More particularly, the salification of the starting heparin is carried out in the following manner.
[0039] The heparin salt may be prepared by the interaction of a stoichiometric excess of the corresponding salt with a heparin sodium, in an aqueous medium, at a temperature in the region of 20° C. Advantageously, the quaternary ammonium salt used is preferably a benzethonium salt such as, in particular, benzethonium chloride, which facilely reacts with the heparin sodium.
[0040] In the second step (b) of the subject process, the esterification is preferably carried out under the following conditions.
[0041] The partial ester of heparin in salt form, the degree of esterification of which ranges from 9.5% to 14%, may be prepared by esterification of the long-chain quaternary ammonium salt of heparin in a chlorinated organic solvent, in the presence of a chlorine derivative. In addition, the efficiency of the reaction is increased by controlling the proportions of the various reactants and the reaction temperature and time.
[0042] Advantageously, the partial ester of heparin is an aromatic ester.
[0043] Also preferably, the chlorine derivative is benzyl chloride and the chlorinated solvent is either chloroform or methylene chloride.
[0044] To attain a degree of esterification ranging from 9.5% to 14%, it can be especially advantageous to use approximately 1 part by volume of chlorine derivative per 1 part by weight of the heparin salt in 3 to 5 parts by volume of chlorinated organic solvent, and to carry out the reaction for a period of time ranging from 15 to 48 hours at a temperature of from 25° to 45° C., and preferably from 30° to 40° C.
[0045] In another preferred embodiment of the invention, the partial ester of heparin is in the form of a sodium salt.
[0046] The esters thereby formed may be recovered by precipitation by means of an alcohol such as, in particular, methanol, in the presence of sodium acetate. Preferably, from 1 to 1.2 volumes of alcohol are used per volume of reaction medium. The degree of esterification of the ester may then be determined by high performance liquid chromatography. In particular, in the case of the benzyl ester, the amount of benzyl alcohol produced by saponification of the ester at 0° C. may be measured.
[0047] The final step (c) of the process of the invention is advantageously carried out in the following manner.
[0048] Preferably, the depolymerization is carried out by treating the ester with a strong base in aqueous solution. More preferably, sodium hydroxide is used therefor.
[0049] Advantageously, the weight ratio base/ester ranges from 0.05 to 0.2, and preferably from 0.08 to 0.15.
[0050] The temperature of the reaction medium is adjusted to a value ranging from 50° to 70° C., and preferably from 55° to 65° C., and the reaction is carried out for a period of time ranging from 30 minutes to 3 hours, and preferably from 1 to 2 hours.
[0051] It is also preferable to carry out the reaction in a medium in which the weight ratio water/ester ranges from 15 to 30.
[0052] In an especially preferred embodiment of the depolymerization of the invention, one part by weight of an aromatic ester of heparin as prepared in step (b), in salt form, the degree of esterification of which ranges from 9.5% to 14%, is admixed with from 0.08 to 0.15 part by weight of sodium hydroxide, as well as with from 20 to 30 parts by weight of water, and the resulting admixture is then maintained at a temperature of from 55° to 65° C. for from 1 to 2 hours.
[0053] The product may then be recovered by neutralization of the reaction medium with a dilute inorganic acid, and preferably hydrochloric acid, and precipitation in the presence of an alcohol such as methanol.
[0054] In this manner, an immixture of sulfated heparinic polysaccharides is directly and reproducibly prepared, containing:
-
- [0055] (1) from 9% to 20% of polymer chains having a molecular weight less than 2,000 daltons, and
- [0056] (2) from 5% to 20% of polymer chains having a molecular weight greater than 8,000 daltons, and having an average molecular weight ranging from 3,500 to 5,500 daltons and a ratio weight average molecular weight/number average molecular weight ranging from 1.3 to 1.6.
[0057] The mixtures of the present invention are advantageously used as antithrombotic agents, typically when formulated with a pharmaceutically acceptable carrier or diluent therefor.
[0058] In particular, they are useful therapeutic compositions for the prevention of venous thromboses in patient risk situations. This is also valid for prolonged-risk situations. More especially, administration of these mixtures provides, for the first time, at fixed doses, a decrease in the risks of acute thrombotic events attendant orthopedic surgery. This risk, which is 70% in the absence of any treatment and approximately 25% on administration of heparin, is only about 10% on administration of the mixtures of the invention, or even less.
[0059] Similarly, when injected into the tubing of an artificial kidney, the subject mixtures can reduce the likelihood of any thromboses developing therein. This latter application may be extended to the prevention of thromboses in surgical equipment.
[0060] Another advantageous therapeutic use of the mixtures of the invention is in the prevention of acute arterial thrombotic events, particularly myocardial infarction.
[0061] Moreover, an especially advantageous application of the mixtures according to the present invention is in their use in a postoperative regimen for the prevention of venous thromboses in surgical patients. This application is particularly desirable, since it permits avoiding the risks of hemorrhage during an operation, and the problems of type and dose of anesthetic, which characterize a preoperative regimen of prevention.
[0062] These collective properties demonstrate the therapeutic potential of the immixtures of the invention.
[0063] In order to further illustrate the present invention and the advantages thereof, the following specific examples are given, it being understood that same are intended only as illustrative and in nowise limitative.
[0064] In said examples to follow, the analytical procedures included:
ASSAY TECHNIQUES:
[0065] The molecular weights and molecular weight distributions of the products were determined by high pressure liquid chromatography using two columns in series, i.e., those marketed under the trademarks TSK G 3000SW (30×0.75 cm) and Lichrosorb 100 Diol 10u (25×0.75 cm), or TSK G 2000SW, coupled to a refractometer detector. The solvent used was a 0.3M phosphate buffer pH 7, and the flow rate was 0.7 ml/min. The system was calibrated with standards prepared by fractionation of enoxaparin (PHARMUKA) by exclusion chromatography on agarose-polyacrylamide (IBF) according to the technique described by Barrowcliffe et al. Thromb. Res., 12, 27-36 (1977-78) or D.A. Lane et al, Thromb. Res., 12, 257-271 (1977-78). The results were calculated using GPC6 software (Perkin Elmer).
[0066] The overall anticoagulant activity of the mixtures was measured by turbidimetry using the Primary International Standard of low molecular weight heparin. The anti-factor Xa (antithrombotic) activity was measured by the amidolytic method on a chromogenic substrate, described by Teien et al, Thromb. Res. 10, 399-410 (1977), using the Primary International Standard of low molecular weight heparin.
Example 1
[0067] This example illustrates the preliminary step of treatment of heparin sodium, enabling the content of impurities of the chondroitin sulfate and heparan sulfate type to be reduced.
[0068] Methanol (80 ml) was added to commercial heparin (sodium salt) (10 g) dissolved in water (100 ml) containing sodium chloride (3 g). After precipitation, the product obtained was filtered off, rinsed and then dried. The degree of purity of the heparin sodium thereby obtained was measured by steric exclusion liquid chromatography, using two columns in series, marketed under the trademarks TSK 2000SW (60×0.75 cm) and TSK 3000 SW (60×0.75 cm), coupled to a UV detector adjusted to 206 nm. The mobile phase employed was 0.5M aqueous sodium sulfate solution flowing at a rate of 1 ml.min−1. The test sample was compared with a control heparin containing dermatan sulfate (2%).
[0069] Under the conditions described above, the heparin obtained contained less than 2% of dermatan sulfate.
Example 2
[0070] This example illustrates the preparation of the quaternary ammonium salt of heparin.
[0071] A solution of benzethonium chloride (25 g) in water (125 ml) was added to a solution of heparin sodium (10 g) prepared as in Example 1, containing less than 2% of dermatan sulfate, in water (100 ml). The product obtained at room temperature was then filtered off, washed with water and thereafter dried.
[0072] In identical manner, the benzethonium salt of a heparin which has not been subjected to the treatment of Example 1 was prepared.
Example 3
[0073] This example illustrates the preparation and properties of the mixtures according to the invention.
1. Esterification:
[0074] Benzyl chloride (15 ml) was added to a solution of benzethonium heparinate (15 g), preliminarily treated according to the procedure of Example 1, in methylene chloride (75 ml). The solution was heated to a temperature of 35° C., which was maintained for 25 hours. A 10% solution (90 ml) of sodium acetate in methanol was then added, the mixture was filtered and the product was washed in methanol and dried. Heparin benzyl ester (6.5 g) was thereby obtained in the form of a sodium salt, the degree of esterification of which, determined as described above, was 13.3%.
2. Depolymerization:
[0075] The heparin benzyl ester (10 g) obtained above in the form of a sodium salt was dissolved in water (250 ml). To this solution, heated to 62° C., sodium hydroxide (0.9 g) was added. The temperature was maintained for 1 hour, 30 minutes, at 62° C. the reaction mixture was then cooled to about 20° C. and neutralized by adding dilute hydrochloric acid. The concentration of the reaction medium was then adjusted to 10% with respect to sodium chloride. The product was finally precipitated in methanol (750 ml), filtered off and dried. A heparin possessing the following structural characteristics was thereby obtained:
-
- [0076] (a) Weight average molecular weight: 3,900 daltons,
- [0077] (b) Molecular weight distribution: (i) 20% of polymer chains of molecular weight less than 2,000 daltons, (ii) 5.5% of polymer chains of molecular weight greater than 8,000 daltons,
- [0078] (c) Dispersion: d=1.39,
- [0079] (d) Anti-Xa activity: 106 IU IU/mg,
- [0080] (e) Anticoagulant activity: 22.6 IU IU/mg.
Example 4
[0081] Following the procedure of Example 3, beginning Beginning with esters having a degree of esterification ranging from 9.5 to 14%, solutions of depolymerized heparin having the following structural characteristics were prepared:
[0082] Solution A:
-
- [0083] (a) Weight average molecular weight: 4,425 daltons,
- [0084] (b) Molecular weight distribution:
- [0085] (i) 12.4% of polymer chains of molecular weight less than 2,000 daltons,
- [0086] (ii) 9.3% of polymer chains of molecular weight greater than 8,000 daltons,
- [0087] (c) Dispersion: d=1.37,
- [0088] (d) Anti-Xa activity: 102 IU IU/mg,
- [0089] (e) Anticoagulant activity: 33 IU IU/mg.
[0090] Solution B:
-
- [0091] (a) Weight average molecular weight; 4,579 daltons,
- [0092] (b) Molecular weight distribution:
- [0093] (i) 11.2% of polymer chains of molecular weight less than 2,000 daltons,
- [0094] (ii) 10.4% of polymer chains of molecular weight greater than 8,000 daltons,
- [0095] (c) Dispersion: d=1.37,
- [0096] (d) Anti-Xa activity: 104 IU IU/mg,
- [0097] (e) Anticoagulant activity: 37 IU IU/mg.
[0098] Solution C:
-
- [0099] (a) Weight average molecular weight: 4,446 daltons,
- [0100] (b) Molecular weight distribution:
- [0101] (i) 12.6% of polymer chains of molecular weight less than 2,000 daltons,
- [0102] (ii) 9.5% of polymer chains of molecular weight greater than 8,000 daltons,
- [0103] (c) Dispersion: d=1.38,
- [0104] (d) Anti-Xa activity: 100 IU IU/mg,
- [0105] (e) Anticoagulant activity: 32 IU IU/mg.
Example 5
[0106] This example illustrates the preparation of a mixture not in accordance with the invention.
1. Esterification:
[0107] Benzyl chloride (12 ml) was added to a solution of benzethonium heparinate (15 g), treated preliminarily according to the procedure of Example 1, in methylene chloride (60 ml). The solution was heated to a temperature of 28° C., which was maintained for 30 hours. A 10% solution (90 ml) of sodium acetate in methanol was then added, the mixture was filtered and the product was washed with methanol and dried. Heparin benzyl ester (6.3 g) was thereby obtained in the form of a sodium salt. The degree of esterification of this product, determined by measurement, in high performance liquid chromatography, of the quantity of benzyl alcohol liberated on saponification of the ester at 0° C., was 9.2%.
2. Depolymerization:
[0108] The heparin benzyl ester (10 g) obtained above in the form of a sodium salt was dissolved in water (200 ml). To this solution, heated to 58° C., sodium hydroxide (1.1 g) was added. The temperature was maintained for 1 hours hour at 58° C. The reaction mixture was then cooled to about 20° C. and neutralized by adding dilute hydrochloric acid. The concentration of the reaction medium was then adjusted to 10% with respect to sodium chloride. The product was finally precipitated in methanol (600 ml), filtered off and dried. A heparin possessing the following structural characteristics was thereby obtained:
-
- [0109] (a) Weight average molecular weight: 5,425 daltons,
- [0110] (b) Molecular weight distribution:
- [0111] (i) 9.6% of polymer chains of molecular weight less than 2,000 daltons,
- [0112] (ii) 19.5% of polymer chains of molecular weight greater than 8,000 daltons,
- [0113] (c) Dispersion: d=1.44,
- [0114] (d) Anti-Xa activity: 122 IU IU/mg,
- [0115] (e) Anticoagulant activity: 68.6 IU IU/mg.
[0116] These results, which evidenced a high anticoagulant activity, demonstrated the superiority of the mixtures prepared according to the invention and possessed the noted characteristics.
Example 6
[0117] This example illustrates the increase in stability, in vivo, of the mixtures of the invention, expressed by their plasma half-life.
[0118] A first pharmacokinetic study was carried out on volunteers between 21 and 30 years of age. Subcutaneous injections of doses ranging from 20 to 80 mg/ml were performed. At intervals of time, samples were drawn (4.5 ml) and stored at approximately 4° C. The samples were then centrifuged for 15 minutes at 2,300 g and the platelet-poor plasma was separated and frozen prior to analysis. The half-life of the mixtures was then determined by measuring the anti-Xa activity. The results obtained were as follows:
-
- [0119] (1) From the mixtures produced in Examples 3 and 4:
- [0120] 40 mg dose: in 75% of the cases, the half-life was longer than 4 hours, and was even longer than 4½ hours in approximately 45% of the cases;
- [0121] 60 mg dose: in 75% of the cases, the half-life was longer than 3.7 hours.
- [0122] (2) Under identical dosage conditions, intact heparin injected intravenously possessed a half-life of approximately 0.6 hours.
- [0123] (3) When the product was prepared according to the process described in European Patent EP 40,144, the half-life was longer than 4½ hours in 17% of the cases.
- [0124] (4) A second study carried out under similar conditions on 20 patients provided the following results for the mixtures according to the present invention:
- [0125] 40 mg dose: in 80% of cases, the half-life was longer than 4 hours, and it was longer than 4½ hours in approximately 40% of the cases;
- [0126] 20 mg dose: in 60% of the cases, the half-life was longer than 3.9 hours.
- [0119] (1) From the mixtures produced in Examples 3 and 4:
[0127] While the invention has been described in terms of various preferred embodiments, the skilled artisan will appreciate that various modifications, substitutions, omissions, and changes may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the present invention be limited solely by the scope of the following claims, including equivalents thereof.
Claims
1. A heterogeneous intimate admixture of sulfated heparinic polysaccharides, such sulfated polysaccharides having a weight average molecular weight less than that of heparin and said admixture consisting essentially of
from 9% to 20% of polysaccharide chains having a molecular weight less than 2,000 daltons,
from 5% to 20% of polysaccharide chains having a molecular weight greater than 8,000 daltons, and
from 60-86% of polysaccharide chains having a molecular weight of between 2,000 and 8,000 daltons,
the ratio between the weight average molecular weight and the number average molecular weight thereof ranging from 1.3 to 1.6
said admixture (i) exhibiting a bioavailability and antithrombotic activity greater than heparin and (ii) having an average molecular weight of between approximately 3,500 and 5,500 daltons.
2. The heterogeneous polysaccharide admixture as defined by claim 1, comprising less than 2% of dermatan sulfate.
3. The heterogeneous polysaccharide admixture as defined by claim 1, such sulfated polysaccharides comprising a 2-O-sulfo-4-enopyranosuronic endgroup.
4. The heterogeneous polysaccharide admixture as defined by claim 1, exhibiting an anti-Xa activity of about 90 IU.
5. The heterogeneous polysaccharide admixture as defined by claim 1, comprising sulfated polysaccharides of porcine heparin origin.
6. The heterogeneous polysaccharide admixture as defined by claim 1, comprising polysaccharides of bovine heparin origin.
7. A process for the preparation of the heterogeneous polysaccharide admixture as defined by claim 1, comprising (a) salifying a heparin with a long-chain quaternary ammonium salt in an aqueous medium, (b) esterifying the salt thus produced to a degree of esterification ranging from 9.5% to 14%, and then (c) depolymerizing such ester having a degree of esterification ranging from 9.5% to 14%.
8. The process as defined by claim 7, comprising (b) esterifying said salt in a chlorinated organic solvent, in the presence of a chlorine compound.
9. The process as defined by claim 8, said chlorinated organic solvent comprising chloroform or methylene chloride and said chlorine compound comprising benzyl chloride.
10. The process as defined by claim 8, said esterification step (b) comprising mixing 1 part by weight of said heparin salt with about 1 part by volume of said chlorine compound in from 3 to 5 parts by volume of said chlorinated organic solvent at a temperature ranging from 25° C. to 45° C.
11. The process as defined by claim 10, said temperature ranging from 30° to 45° C.
12. The process as defined by claim 7, said depolymerization step (c) comprising treating said ester with a strong base in aqueous solution.
13. The process as defined by claim 12, wherein said strong base and said ester are present in a weight ratio which ranges from 0.05 to 0.2.
14. The process as defined by claim 13, said ratio ranging from 0.08 to 0.15.
15. The process as defined by claim 12, wherein water in said aqueous solution and said ester are present in a weight ratio which ranges from 15 to 30.
16. The process as defined by claim 12, wherein said depolymerization is carried out at a temperature adjusted to a value ranging from 50° to 70° C. and said depolymerization is carded carried out therein for from 30 minutes to 3 hours.
17. The process as defined by claim 16, said temperature being adjusted to a value ranging from 55° to 65° C. and said depolymerization being carried out for from 1 to 2 hours.
18. The process as defined by claim 7, comprising (a) salifying the heparin with a benzethonium salt.
19. The process as defined by claim 18, said benzethonium salt comprising benzethonium chloride.
20. The process as defined by claim 7, the partial ester prepared in step (b) comprising an aromatic ester.
21. The process as defined by claim 7, the partial ester prepared in step (b) comprising a sodium salt thereof.
22. The process as defined by claim 7, said starting material heparin having been precipitated from an alcohol.
23. The heterogeneous intimate admixture of sulfated heparinic polysaccharides produced by the process as defined by claim 7.
24. A method for the prevention of thrombotic episodes in a human patient, comprising administering to a human in need of such prevention, a therapeutically effective amount of the heterogeneous polysaccharide admixture as defined by claim 1.
25. A method for the prevention of venous thromboses in a postoperative human patient, comprising administering to such patient a therapeutically effective amount of the heterogeneous polysaccharide admixture as defined by claim 1.
26. The method as defined by claim 24, such human suffering risk of myocardial infarction.
27. A therapeutic composition of matter useful for the prevention of thrombotic episodes in a human, comprising the heterogeneous polysaccharide admixture as defined by claim 1 and a therapeutically acceptable carrier or diluent therefor.
28. The heterogeneous polysaccharide admixture as defined by claim 1, exhibiting an anti-Xa activity of about 100 IU IU/mg.
29. A method for the treatment of thrombotic episodes in a human, comprising administering to a human in need of such treatment, a therapeutically effective amount of the heterogeneous polysaccharide admixture as defined by claim 1.
30. A therapeutic composition of matter useful for the treatment of thrombotic episodes in a human, comprising the heterogeneous polysaccharide admixture as defined by claim 1 and a therapeutically acceptable carrier or diluent therefor.
31. A heterogenous intimate admixture of sulfated heparinic polysaccharides, such sulfated polysaccharides having a weight average molecular weight less than that of heparin and said admixture comprising:
from 9% to 20% of polysaccharide chains having a molecular weight less than 2,000 daltons,
from 5% to 20% of polysaccharide chains having a molecular weight greater than 8,000 daltons, and
from 60% to 86% of polysaccharide chains having a molecular weight of between 2,000 and 8,000 daltons,
the ratio between the weight average molecular weight and the number average molecular weight thereof ranging from 1.3 to 1.6,
said admixture (i) exhibiting a bioavailability and antithrombotic activity greater than heparin, (ii) having an average molecular weight of between approximately 3,500 and 5,500 daltons, and (iii) including less than 2% of dermatan sulfate.
32. A heterogeneous intimate admixture of sulfated heparinic polysaccharides, such sulfated polysaccharides having a weight average molecular weight less than that of heparin and said admixture consisting essentially of:
from 9% to 20% of polysaccharide chains having a molecular weight less than 2,000 daltons,
from 5% to 20% of polysaccharide chains having a molecular weight greater than 8,000 daltons, and
from 60% to 86% of polysaccharide chains having a molecular weight of between 2,000 and 8,000 daltons,
the ratio between the weight average molecular weight and the number average molecular weight thereof ranging from 1.3 to 1.6,
said admixture (i) exhibiting a bioavailability and antithrombotic activity greater than heparin and (ii) having an average molecular weight of between approximately 3,500 and 5,500 daltons, said admixture being prepared by the process comprising the steps of:
(a) salifying a heparin with a long-chain quaternary ammonium salt in an aqueous medium,
(b) esterifying the salt thus produced to a degree of esterification ranging from 9.5% to 14%, and
(c) depolymerizing such ester having a degree of esterification ranging from 9.5% to 14%.
Patent Citations (39)
| Patent | Date | Inventor | Cited By |
|---|---|---|---|
| US3766167(A) | 1973-10-01 | Lasker et al. | Applicant |
| US3891622(A) | 1975-06-01 | Mardiguian et al. | Examiner |
| US4303651(A) | 1981-12-01 | Lindahl et al. | Applicant |
| US4351938(A) | 1982-09-01 | Barnett | Applicant |
| US4401662(A) | 1983-08-01 | Lormeau et al. | Applicant |
| US4440926(A) | 1984-04-01 | Mardiguian | Applicant |
| US4486420(A) | 1984-12-01 | Lormeau et al. | Applicant |
| US4652555(A) | 1987-03-01 | Goulay et al. | Applicant |
| US4692435(A) | 1987-09-01 | Lormeau et al. | Applicant |
| US4981955(A) | 1991-01-01 | Lopez | Applicant |
| US4987222(A) | 1991-01-01 | De Ambrosi et al. | Applicant |
| US4990502(A) | 1991-02-01 | Lormeau et al. | Applicant |
| US5019649(A) | 1991-05-01 | Lormeau et al. | Applicant |
| US5106734(A) | 1992-04-01 | Nielsen | Applicant |
| AU70519/81(B) | 1981-11-01 | Applicant | |
| DK160764(B) | 1987-04-01 | Applicant | |
| EP40144 | 1981-11-01 | Examiner | |
| EP66908(A1) | 1982-12-01 | Applicant | |
| EP40144(B1) | 1984-08-01 | Applicant | |
| EP133078(A1) | 1985-02-01 | Applicant | |
| EP293539(B1) | 1987-01-01 | Applicant | |
| EP244235(A2) | 1987-11-01 | Applicant | |
| EP244236(A2) | 1987-11-01 | Applicant | |
| EP301618(A2) | 1989-02-01 | Applicant | |
| EP337327(A1) | 1989-10-01 | Applicant | |
| EP380719(A1) | 1990-08-01 | Applicant | |
| ESA-8206555 | 1982-11-01 | Applicant | |
| ES2003197 | 1988-10-01 | Applicant | |
| ESA-2006891 | 1989-05-01 | Applicant | |
| FR2739(M) | 1964-08-01 | Applicant | |
| FR2548672 | 1985-01-01 | Applicant | |
| FR2663639 | 1991-12-01 | Applicant | |
| GB1501095 | 1978-02-01 | Applicant | |
| HU188667 | 1989-04-01 | Applicant | |
| IE51283 | 1986-11-01 | Applicant | |
| IT1248557 | 1995-01-01 | Applicant | |
| JP36492/85 | 1985-02-01 | Applicant | |
| JP283103/87 | 1987-11-01 | Applicant | |
| WO81/03276 | 1981-11-01 | Applicant |
Non-Patent Literature (337)
- English language translation of EP 0 040 144 B1.Applicant
- English language translation of EP 0 293 539 A2.Applicant
- English language abstract of ES 2 003 197.Applicant
- Paragraph IV certification letter of Jun. 24, 2003, from Teva Pharmaceuticals, USA.Applicant
- Béguin, S. et al., The Mode of Action of Low Molecular Weight Heparin Preparation (PK10169) and Two of its Major Components on Thrombin Generation in Plasma, Thrombos. Haemostas. 61(1): 30-34 (1989).Applicant
- Dahan, R. et al., “Prevention of Deep Vein Thrombosis in Elderly Medical In-Patients by Low Molecular Weight Heparin (Enoxaparin): Randomized Double Blind Trial,” Abstract SS36 from the Xth International Congress on Thrombosis and Haemostasis, Thrombos. Haemostas. 54(1):309 (1985).Applicant
- Fareed, J. et al., “Biochemical and Pharmacologic Inequivalence of Low Molecular Weight Heparins,” Ann. N.Y. Acad. Sci. 556:333-353 (1989).Applicant
- Fareed, J. et al., “Chemical and Biological Heterogeneity in Low Molecular Weight Heparins: Implications for Clinical Use and Standardization,” Seminars in Thrombosis and Hemostasis, 15(4):440-463 (1989).Applicant
- Fareed, J. et al., “Comparative Study on the in vitro and in vivo Activities of Seven Low-Molecular-Weight Heparins,” Haemostasis 18 (Suppl. 3), pp. 3-15 (1988).Applicant
- Forbes, C.D., “Prevention of Deep Vein Thrombosis—Use of the Low Molecular Weight Heparin Enoxaparin,” British J. Clin. Prac. 43(11): 396-400 (1989).Applicant
- Frydman, A.M. et al., “The Antithrombolic Activity and Pharmacokinetics of Enoxaparine, a Low Molecular Weight Heparin, in Humans Given Single Subcutaneous Doses of 20 to 80 mg,” J. Clin. Pharmacol. 28:609-618 (1988).Applicant
- Linhardt, R.J. et al., “Oligosaccharide Mapping of Low Molecular Weight Heparins: Structure and Activity Differences,” J. Med. Chem. 33:1639-1645 (1990).Applicant
- Planes, A. et al., “Enoxaparin, Low Molecular Weight Heparin (LMWH): Its Use in Prevention of Deep Venous Thrombosis (DVT) Following Total Hip Replacement (THR),” Abstract SS35 from the Xth International Congress on Thrombosis and Haemostasis, Thrombos, Haemostas. 54(1):309 (1985).Applicant
- Declaration Pursuant to 37 C.F.R. §1.132, by Dr. Uzan, in U.S. Appl. No. 08/072,577. Jun. 9, 1994.Applicant
- Second Declaration Pursuant to 37 C.F.R. §1.132, by Dr. Uzan, In U.S. Appl. No. 08/072,577. Jun. 9, 1994.Applicant
- Office Action of Apr. 2, 1992 in U.S. Appl. No. 08/072,577.Applicant
- Office Action of Nov. 16, 1993 in U.S. Appl. No. 08/072,577.Applicant
- Paragraph IV certification letter of Jun. 19, 2003, from Amphastar Pharmaceuticals, Inc.Applicant
- Neville, G. A. et al., “Monitoring the Purity of Pharmaceutical Heparin Preparations by High-Field 1H-Nuclear Magnetic Resonance Spectroscopy,” J. Pharm. Sci. 78(2):101-104 (1989).Applicant
- Turpie, A.G.G. et al., “A Randomized Controlled Trial of a Low-Molecular-Weight Heparin (Enoxaparin) to Prevent Deep-Vein Thrombosis in Patients Undergoing Elective Hip Surgery,” N. Engl. J. Med. 315(15):925-929 (1986).Applicant
- Huet, Y. et al., “Low Molecular Weight Heparin Fraction PK10169: A New Therapeutic Means for Anticoagulant Therapy?” Haemostasis 16:165-172 (1986).Applicant
- Dahan, R. et al., “Prevention of Deep Vein Thrombosis in Elderly Medical In-Patients by a Low Molecular Weight Heparin (Enoxaparin): A randomized Double-Blind Trial,” Haemostasis 16: 159-164 (1986).Applicant
- Planes, A. et al., “Enoxaparine Low Molecular Weight Heparin: Its Use in Prevention of Deep Venous Thrombosis Following Total Hip Replacement,” Haemostasis 16: 152-158 (1986).Applicant
- U.S. District Court Civil Docket (District of New Jersey; Aventis Pharma SA, et al. v. Amphastar Pharmaceut, et al.).Applicant
- U.S. District Court Civil Docket (District of California; Aventis Pharma SA, et al. v. Amphastar Pharmaceut., et al.).Applicant
- Aventis' Complaint, filed in District Court of New Jersey on Aug. 4, 2003.Applicant
- Teva Pharmaceuticals USA's Answer and Counterclaims, filed Aug. 28, 2003, in the New Jersey court.Applicant
- Aventis' Reply to Answer and Counterclaims of Teva, filed Aug. 29, 2003, in the New Jersey court.Applicant
- Aventis' Complaint, filed in District Court of California on Aug. 4, 2003.Applicant
- Amphastar Pharmaceuticals' Answer and Counterclaims, filed Aug. 25, 2003, in the California court.Applicant
- Aventis' Reply to Answer and Counterclaims of Amphastar, filed Aug. 29, 2003, in the California court.Applicant
- Teva's Answer and Counterclaims, filed Aug. 26, 2003, in the California court.Applicant
- Aventis' Reply to Teva's Answer and Counterclaims, filed Aug. 29, 2003, in the California court.Applicant
- English language translation of EP 0 133 078 A1.Applicant
- (1) Verbale di Apetura delle Operazioni Peritali.Applicant
- English language translation of (1). (Record of Initiation of Proceedings for Expert Opinion.).Applicant
- (2) Prima memoria tecnica in favore delle attrici.Applicant
- English language translation of (2). (First Technical Brief in Favor of Plaintiffs.).Applicant
- (3) Seconda memoria tecnica in favore delle attrici.Applicant
- English language translation of (3). (Second Technical Brief in Favor of Plaintiffs.).Applicant
- (4) Terza memoria tecnica in favore della attrici.Applicant
- English language translation of (4). (Third Technical Brief in Favor of Plaintiffs.).Applicant
- (5) Quarta memoria tecnica in favore della attrici.Applicant
- English language translation of (5). (Fourth Technical Brief in Favor of Plaintiffs.).Applicant
- (6) Quinta memoria tecnica in favore della attrici.Applicant
- English language translation of (6). (Fifth Technical Brief in Favor of Plaintiffs.).Applicant
- (7) Prima memoria al C.T.U. nell'interresse della Aventis Pharma S.A.Applicant
- English language translation of (7). (First Technical Brief in the Interest of Aventis Pharma S.A.).Applicant
- (8) Seconda memoria tecnica al C.T.U. neli'interesse della Aventis Pharma S.A.Applicant
- English language translation of (8). (Second Technical Brief in the Interest of Aventis Pharma S.A.).Applicant
- (9) Terza memoria al C.T.U. nell'interesse di AVENTIS PHARMA S.A.Applicant
- English language translation of (9). (Third Technical Brief in the Interest of Aventis Pharma S.A.).Applicant
- (10) Quarta memoria tecnica a favore di AVENTIS S.A.Applicant
- English language translation of (10). (Fourth Technical Brief in the Interest of Aventis Pharma S.A.).Applicant
- (11) Quinta memoria tecnica a favore di AVENTIS S.A.Applicant
- English language translation of (11). (Fifth Technical Brief in the Interest of Aventis Pharma S.A.).Applicant
- (12) Sesta memoria tecnica a favore di AVENTIS S.A.Applicant
- English language translation of (12). (Sixth Technical Brief in the Interest of Aventis Pharma S.A.).Applicant
- (13) Milano, 30 maggio 2003/alla Dottoressa T. Santoro/dei/G. Dragotti & R. Pistolesi.Applicant
- English language translation of (13). (Correspondence.).Applicant
- (14) Milano, 3 giugno, 2003/alla Dottoressa Tiziana Santoro/dei/Dottore A. Coppo & Dottoressa A. de Gregori.Applicant
- English language translation of (14). (Correspondence.).Applicant
- (15) Verbale dell'incontro presso lo Studio Marietti, Gilson e Trupiano.Applicant
- English language translation of (15). (Minutes of a meeting between the parties).Applicant
- (18) Memoria tecnica finale a favore di AVENTIS S.A.Applicant
- English language translation of (18). (Final Technical Brief on behalf of Aventis S.A.).Applicant
- (19) alla Dottoressa T. Santoro/dei G. Dragotti & R. Pistolesi.Applicant
- English language translation of (19). (Correspondence.).Applicant
- (20) Milano, 14 luglio, 2003/alla Dottoressa Tiziana Santoro/del Dottore A. Coppo.Applicant
- English language translation of (20). (Correspondence.).Applicant
- (21) 17 Luglio 2003/alla Dottoressa Tiziana Santoro/del G. Dragotti.Applicant
- English language translation of (21). (Correspondence.).Applicant
- (22) 3 giugno 2003/ai G. Dragotti; R. Pistolesi; A. Coppo; & A. De Gregori/della Dottoressa Tiziana Santoro.Applicant
- English language translation of (22). (Correspondence).Applicant
- (23) Elenco allegati.Applicant
- English language translation of (23). (Index of Exhibits.).Applicant
- (D3) Second Declaration Pursuant to 37 C.F.R. §1.132, by Dr. Uzan, in U.S. Appl. No. 08/072,577, Jun. 9, 1994.Applicant
- (D4) Farmacopea ufficiale. (Excerpts from European Pharmacopoeia).Applicant
- (D5) Ripetizione degli esempi 2 e 3 del brevetto Aventis.Applicant
- English language translation of (D5) (Repeat of Examples 2 and 3 from EP 0 40 144.).Applicant
- (D6) Ripetizione degli esempi 9 e 10 de EP-40144.Applicant
- English language translation of (D6) (Repeat of Examples 9 and 10 from EP 0 40 144.).Applicant
- (D7) M. Aiach et al., “A New Low Molecular Weight Heparin Derivative, In Vitro and In Vivo Studies” Thromb. Res. 31:611-621 (1983).Applicant
- (D9) G.A. Neville et al., “Chemical Composition, Particle Size Range, and Biological Activity of Some Low Molecular Weight Heparin Derivatives,” J. Pharm. Sci. 79(4):339-343 (Apr., 1990).Applicant
- (D11) B. Casu et al., “Glycosaminoglycans from Pig Duodenum,” Drug Research 30(11):1889-92 (1980).Applicant
- (D15) Descrizione prova di lab. n. 239 (ripetizione esempio 9 di EP40144).Applicant
- English language translation of (D15) (Repetition of Example 9 of EP 0 40 144.).Applicant
- (D16) Methods in Enzymology, vol. XXVIII, Complex Carbohydrates, Part B, (V. Ginsburg, Ed.) pp. 100-109 (1972).Applicant
- (D17) The Merck Index, 11th edition, p. 562 (1989).Applicant
- (D18) The Merck Index, 13th edition, p. 636 (2001).Applicant
- (D19) Duncan P. Thomas et al., “Low Molecular Weight Heparin: A Better Drug?” Haemostasis 16: 87-92 (1986). (pp. 88, 90, and 92 missing from court record).Applicant
- Duncan P. Thomas et al., “Low Molecular Weight Heparin: A Better Drug?” Haemostasis 16: 87-92 (1986).Applicant
- (D21) C. Doutremepuich et al., “Comparative Pharmacology of Low Molecular Weight Heparins: Implications of Manufacturing Processes on Biological Effects,” Thromb. Res. 55:419-426 (1989).Applicant
- (D22) L.D. Brace et al., “Biochemical and Pharmacological Studies on the Interaction of PK10169 and Its Subfractions with Human Platelets,” Haemostasis 16:93-105 (1986). (first page incomplete in court record).Applicant
- (D24) A. Vinazzer and M. Woler, “A New Low Molecular Weight Heparin Fragment (PK10169): In vitro and in vivo Studies,” Haemostasis 16:106-115 (1986).Applicant
- (D25) J. Dawes et al., “Relationship Between Biological Activity and Concentration of a Low-Molecular-Weight Heparin (PK10169)” Haemostasis 16: 116-122 (1986): J. Fareed et al., “Unfractionated Heparin After Intravenous and Subcutaneous Administration,” Haemostasis 16: 123 (1986).Applicant
- (D26) J. Parvulesco, “La Prévention des Complications Thrombo-emboliques Post-opératoires par <Clexane> (Héparine de Bas Poids Moléculaire) dans la Chirurgie des Varices,” pp. 117-119.Applicant
- English language translation of (D26).Applicant
- (D27) L.N. Jørgensen and O. Hauch, “Enoxaparin (Clexane), et Lavmolekylaert heparin til tromboseprofylakse,” Ugeska Laeger, 27 Novembre 1989, +Corrispondente Traduzione in Italiano.Applicant
- English language translation of (D27).Applicant
- (D28) Martindale, The Complete Drug Reference, Thirty-second Edition. (One-page excerpt.).Applicant
- (D29) Richiesta di registrazione (NDA) depositata presso l'FDA dalla Aventis per il farmaco Lovenox. (FDA correspondence, with attachments, in English).Applicant
- (D30) O. Iqbal et al., “A Comparison of the Pharmacokinetic and Pharmacodynamic Profiles of Clexane and Lovenox in Dogs,” Seminars in Thrombosis and Haemostasis 19(Suppl. 1): 199-209 (1993).Applicant
- (D31) Commission de la Transparence—9 Gennaio 2002.Applicant
- English language translation of (D31).Applicant
- (D32) Estratto dell'EPO Patent Register Relativo ad EP40144. (Online European Patent Register, database search result, in English).Applicant
- (D33) Dictionnaire Vidal, pp. 957-958 (1988).Applicant
- English language translation of (D33).Applicant
- (D34) Estratto Banca Dati FPAT Relativo ad FR2482611.Applicant
- English language translation of (D34) (Patent search results.).Applicant
- (D35) Domanda di CPC Relativo ad FR2482611 per il Lovenox. (May, 1992).Applicant
- English language translation of (D35). (Request for Supplementary Certificate of Protection).Applicant
- (D37) Certificato di Analisi del Lovenox, Lotto 8407-05-2003.Applicant
- English language translation of (D37). (Certificate of Analysis of Lovenox© lot 8407-05-2003.).Applicant
- (D39) Ripetzione dell'Esempio 9 di EP40144. (Repetition of Example 9 of EP 0 40 144.).Applicant
- English language translation of (D39). (Repetition of Example 9 of EP 0 40 144.).Applicant
- (D40) Ripetizione dell'Esempio 3 del Brevetto Aventis.Applicant
- English language translation of (D40). (Repetition of Example 3 of EP 0 40 144.).Applicant
- (D41) “Analisi Effettuate dall'Istituto ‘G. Ronzoni’”. (pages were missing from the court record).Applicant
- English language translation of (D41). (Correspondence.).Applicant
- (D42) Dictionnaire Vidal, 2002. (Excerpt, pp. 1062-5.).Applicant
- English language translation of (D42).Applicant
- (D43) Parere Parexel. (Regulatory opinion, Jan., 2003, in English).Applicant
- (D44) Confezioni di Lovenox del 1987.Applicant
- English language translation of (D44).Applicant
- (D45) J.X. De Vries, “Analysis of Heparins by Size-Exclusion and Reversed-Phase High-Performance Liquid Chromatography with Photo-Diode-Array Detection,” J. Chromatography 465:297-304 (1989).Applicant
- (D46) S. Béguin et al., “The Mode of Action of Low Molecular Weight-Heparin Preparation (PK 10169) and Two of its Major Components on Thrombin Generation in Plasma,” Thromb. Haemost. 61(1):30-34 (28.02.1989). (pages were missing from the court record).Applicant
- (D48) Regolamento CE n. 541/95 del 10.03.1995.Applicant
- English language translation of (D48). (Regulation (EC) No. 541/95, Mar. 10, 1995).Applicant
- (D49) Syndicat National de l'Industrie Pharmaceutique, Fevrier 1990.Applicant
- English language translation of (D49).Applicant
- (D50) www.vademecum.medicom.es. (Extract obtained Jan. 29, 2003).Applicant
- English language translation of (D50).Applicant
- (D51) B. Casu, “Structure and Biological Activity of Heparin,” Advances inCarbohydrate Chemistry and Biochemistry, 43:127-134 (1985).Applicant
- (D52) P.W. Atkins, Chapter 28: The Rates of Chemical Reactions, pp. 687-703, in Physical Chemistry, Third Edition, (1988).Applicant
- (D53) Notifica dell'Ufficio Brevetti Tedesco + traduzione in lingua inglese. (Excerpt from prosecution of Application No. P 41 21 115.4-43 in the German Patent Office + English translation).Applicant
- (D54) Riproduzione in Scala dell'Esempio 9 di EP-40144.Applicant
- English language translation of (D54). (Repetition of Example 9 of EP 0 40 144.).Applicant
- (D55) Certificato di analisi del Clexane (lotto n. 653).Applicant
- English language translation of (D55). (Certificate of Analysis of Clexane batch No. 653.).Applicant
- Relazione di consulenza technica.Applicant
- English language translation of Expert Evidence Report of Dr. Tiziana Santoro, Jul. 28, 2003.Applicant
- Letter from Amec Planning s.r.l. to the Deutsche Patentamt (German Patent Office) regarding German Patent Application No. DE 4121115/91, Nov. 2, 2000.Applicant
- Letter from Amec Planning s.r.l. to the Bureau voor de Industriele Eigendom (Dutch Patent Office) regarding Dutch Patent Application No. NL 101049/91, Dec. 21, 2000.Applicant
- Attachment to Letters from Amec Planning s.r.l. to German and Dutch Patent Offices: Letter from M. F. Savitzky to Mr. Werth, May 24, 1995.Applicant
- English language translation of EP 0 133 078 A1.Applicant
- English language translation of FR 2 663 639.Applicant
- English language abstract of FR 2 548 672.Applicant
- English language abstract of FR 2 739 M.Applicant
- Derwent Abstract of EP 0 293 539 A from file history of U.S. Appl. No. 08/092,577.Applicant
- Derwent Abstract of EP 0 040 144 from file history of U.S. Appl. No. 08/092,577.Applicant
- Derwent Abstract of EP 0 380 719 A from file history of U.S. Appl. No. 08/092,577.Applicant
- Barrowcliffe, T. W. et al., “Anticoagulant Activities of Lung and Mucous Heparins,” Thromb. Res. 12:27-36 (1977).Applicant
- Barrowcliffe, T. W. et al., “Low Molecular Weight Heparins: Antithrombotic and Haemorrhagic Effects and Standardization,” Acta. Chir. Scand., Suppl. 543:57-64 (1988).Applicant
- Bender et al., Chemical Abstracts 109:31802m (1988).Applicant
- Fareed et al., Chemical Abstracts 109:31559n (1988).Applicant
- Henny, Ch.P. et al., “A Randomized Blind Study Comparing Standard Heparin and a New Low Molecular Weight Heparinoid in Cardiopulmonary Bypass Surgery in Dogs,” J. Lab. Clin. Med. 106:187-196 (1985).Applicant
- Hirsh, J. “The Development of LMW Heparins for Clinical Use; Biochemical, Experimental, and Clinical Findings,” Adv. Appl. Biotechnol. (Protein C Related Anticoagulants) 11:67-82 (1990).Applicant
- Johnson, E. A. et al., “Four Heparin Preparations: Anti-Xa Potentiating Effect of Heparin After Subcutaneous Injection,” Thromb. Haemost. 35:586-591 (1976).Applicant
- Lane, D.A. et al., “Molecular Weight Dependence of the Anticoagulant Properties of Heparin: Intravenous and Subcutaneous Administration of Fractionated Heparins to Man,” Thromb. Res. 16:651-662 (1979).Applicant
- Lane, D. A. et al., “Anticoagulant Activities of Four Unfractionated and Fractionated Heparins,” Thromb. Res., 12:257-271 (1978).Applicant
- Oestergaard et al., Chemical Abstracts 107:541e (1987).Applicant
- Ofosu, F.A., “The Importance of thrombin Inhibition for the expression of the anticoagulant activities of heparin, dermatan sulfate, low molecular weight heparin and pentosan polysulfate,” Br. J. Haematol. 60(4):695-704 (1985).Applicant
- Teien, A.N. et al., “Evaluaton of an Amidolytic Heparin Assay Method: Increased Sensitivity by Adding Purified Antithrombin III,” Thromb. Res. 10:399-410 (1977).Applicant
- Tew et al., Chemical Abstracts 110:50607p (1989).Applicant
- French Search Report issued in FR 90 08013 (published as FR 2 663 639), the priority document for U.S. Pat. No. 5,389,618, dated Mar. 25, 1991.Applicant
- Examiner's Search Request Form in U.S. Appl. No. 08/092,577, dated Nov. 1, 1993.Applicant
- Computer print out of results from Examiner's search in U.S. App. No. 08/092,577.Applicant
- U.S. App. No. 08/092,577 as filed (now issued as U.S. Pat. No. 5,389,618) from file history.Applicant
- English language abstract of ES-A-2006891.Applicant
- English language abstract of ES-A-8206555.Applicant
- English language abstract of JP 283103/87.Applicant
- English language abstract of JP 36492.85.Applicant
- Holmer, E. et al., “Heparin and Its Low Molecular Weight Derivatives: Anticoagulant and Antithrombotic Properties,” Haemostasis 16, Suppl. 2, pp. 1-7 (1986).Applicant
- Lasker, S. E., “Molecular-weight derivative of heparin that is orally active in mice,” Adv. Exp. Med. Biol., 52:119-130 (1975).Applicant
- Miklautz, H., et al., “The Molecular-Weight Distribution of Heparin Determined with a HPLC-Lalls Coupling Technique,” Journal of Liquid Chromatography, 9(10):2073-2093 (1986).Applicant
- Oestergaard et al., “The Effect of Low Molecular Weight Heparin on Experimental Thrombosis and Hemostasis—The Influence of Production Method,” Chemical Abstracts 107:541e; Thromb. Res. 45:739-749 (1987).Applicant
- Samama, M., “Les Nouvelles Héparines,” La Presse Médicale 15:1631-1635 (1986).Applicant
- U.S. Form PTO 892 from U.S. Appl. No. 08/092,577.Applicant
- Foster, A. B., “The Chemistry of Heparins,” Adv. Carbohyd. Chrm., 10:335-368 (1955).Applicant
- Protest Under 37 C.F.R. §1.291(a), filed in U.S. Appl. No. 10/430,435 dated Apr. 27, 2004.Applicant
- English language translation of Samama, M., “Les Nouvelles Héparines,” La Presse Médicale 15:1631-1635 (1986).Applicant
- U.S. District Court Civil Docket (District of New Jersey: Aventis Pharma SA, et al. v. Amphastar Pharmaceut., et al.).Applicant
- Public version of Amphastar's Jan. 5, 2004, responses to Aventis's First Set of Interrogatories.Applicant
- Frishman et al., “Anticoagulation in Myocardial Infarction; Modern Approach to an Old Problem,” The American Journal of Cardiology 43:12071213 (1979).Applicant
- Aventis's Initial Claim Construction Contentions dated May 3, 2004.Applicant
- Aventis's Declaration of Geoffrey Mason dated May 3, 2004.Applicant
- (3) L. Bara et al., “Comparative Pharmacokinetics of a Low Molecular Weight Heparin (PK 10 169) and Unfractionated Heparin After Intravenous and Subcutaneous Administration,” Thrombosis Research 39:631-636 (1985).Applicant
- (7) J. Dawes, “Comparison of the Pharmacokinetics of Enoxaparin (Clexane®) and Unfractionated Heparin,” Acta Chir. Scand. Suppl. 556:68-74 (1990).Applicant
- Teva's Initial Claim Construction Contentions (Letter from Lee J. Papageorge to Allen Sokal) dated May 3, 2004.Applicant
- Amphastar's Preliminary Claim Construction Contentions filed May 3, 2004.Applicant
- Amphastar's Responsive Claim Construction Contentions filed May 17, 2004.Applicant
- Teva's Responsive Claim Construction Contentions filed May 17, 2004.Applicant
- Aventis's Responsive Claim Construction Contentions filed May 17, 2004.Applicant
- Opocrin Spa Atto di Citazione—Tribunale Civile di Milano Sezione Specializzata in Materia di Proprieta Industriale ed Intellettuale dated Mar. 31, 2004.Applicant
- English translation of Opocrin Spa Atto di Citazione. (Writ of Summons filed by Opocrin Spa in Milan Civil Court Section Specialised in Industrial and Intellectual Property.).Applicant
- 1/A) Application for a change in name for Aventis Pharma SA dated Feb. 20, 2001.Applicant
- 1/B) Data sheet for Clexane T and Clexane dated Jan. 2, 2001.Applicant
- 3) Opocrin patent application MI 2003 A001679 filed Aug. 29, 2003.Applicant
- 6) JDR on Clexane, 1989. (In German and English).Applicant
- English translation of Exhibit 1), Aventis Patent IT 1248557.Applicant
- English translation of Exhibit 1/A), Application for a change in name for Aventis Pharma SA.Applicant
- English translation of Exhibit 1/B), Data sheet for Clexane T and Clexane.Applicant
- English translation of Exhibit 3), Opocrin patent application MI 2003 A001679.Applicant
- (24) Osservazioni alla consulenza tecnica d'ufficio, dated Dec. 15, 2003.Applicant
- English language translation of (24). (Comments on the Court Technical Report.).Applicant
- (25) Memoria tecnica per Aventis sui chiarimenti richesti dal Giudice al consulente all'udienza in data 11 marzo 2004, dated Apr. 15, 2004.Applicant
- English language translation of (25). (Technical Report for Aventis on the clarifications requested by the Judge to the Court technical expert at the hearing on Mar. 11, 2004.).Applicant
- (26) Sesta memoria tecnica in favore della attrici, dated Apr. 15, 2004.Applicant
- English language translation of (26). (Sixth Technical Brief in Favour of the Plaintiffs.).Applicant
- (27) Aventis's Italian Reply Brief to Plaintiffs' Sixth Technical Brief, dated Apr. 22, 2004.Applicant
- English language translation of (27). (Aventis's Reply Brief).Applicant
- (28) Biofer-Chemi's Italian Reply Brief to Aventis's Reply Brief on Apr. 22, 2004, dated Apr. 28, 2004.Applicant
- English language translation of (28). (Biofer-Chemi's Reply Brief).Applicant
- Supplemento di Consulenza Tecnica, dated May 15, 2004.Applicant
- English translation of Supplemento di Consulenza Tecnica.Applicant
- Response to Office Action in copending German Patent Application No. P 41 21 115.4-43 dated Jan. 14, 2004.Applicant
- (1) New claims 1 to 13.Applicant
- English translation of Response to Office Action in copending German Patent Application No. P 41 21 115.4-43.Applicant
- English translation of new claims 1 to 13.Applicant
- Public version of Teva's Apr. 15, 2004, responses to Aventis's First Set of Interrogatories.Applicant
- Text of an Office Action in copending German Patent Application No. p 41 21 115.4-43.Applicant
- English translation of text of an Office Action in copending German Patent Application No. P 41 21 115.4-43.Applicant
- Avnetis's Opening Brief on Claim Construction, dated Jul. 19, 2004.Applicant
- Declaration of Michael J. McCabe II, dated Jul. 19, 2004.Applicant
- (2) “The Merck Manual of Diagnosis and Therapy,” pp. 2559-2561 (Mark H. Beers & Robert Berkow eds., 17th ed. 1999).Applicant
- (3) Ganong, “Review of Medical Physiology,” p. 421 (10th ed. 1981).Applicant
- (17) “Dorland's Illustrated Medical Dictionary,” pp. 94 and 1365 (26th ed. 1981).Applicant
- (19) Holmer, et al., “Anticoagulant and Antithrombotic Effects of Heparin and Low Molecular Weight Heparin Fragments in Rabbits,” Thrombosis Res. 25:475-485 (1982).Applicant
- (20) Hemker, “The Mode of Action of Heparin in Plasma,” Thrombosis & Haemostasis, 17-36 (1987).Applicant
- Defendant Amphastar's Opening Claim Construction Brief, dated Jul. 19, 2004.Applicant
- Declaration of Steven M. Hanle in Support of Defendant Amphastar's Opening Claim Construction Brief, dated Jul. 19, 2004.Applicant
- (F) Labeling for Aventis's drug Lovenox® as of Jan. 2003.Applicant
- (G) Definition of bioavailability from On-line Medical Dictionary.Applicant
- (K) Definition of International unit from On-line Medical Dictionary.Applicant
- Public version of Opening Brief on Claim Construction of Defendant Teva Pharmaceuticals USA, Inc., dated Jul. 19, 2004.Applicant
- Declaration of Lee J. Papageorge, dated Jul. 19, 2004.Applicant
- (B) Barrowcliffe, “Low Molecular Weight Heparin,” pp. 1-3, 6, 7, 16-19, 48-51, and 54-61 (John Wiley & Sons, Inc. 1992).Applicant
- (E) Kristensen, et al., “Development and Validation of a Size Exclusion Chromatography Method for Determination of Molecular Masses and Molecular Mass Distribution in Low Molecular Weight Heparin,” Thrombosis Res. 64:131-141 (1991).Applicant
- (I) Billmeyer, “Textbook of Polymer Science,” pp. 198-201 (John Wiley & Sons, Inc. 1984).Applicant
- Aventis's Opposition Brief on Claim Construction, dated Aug. 4, 2004.Applicant
- Second Declaration of Michael J. McCabe II, dated Aug. 4, 2004.Applicant
- (25) Scheduling Order, dated May 21, 2004.Applicant
- (26) Selected pages of “Webster's Revised Unabridged Dictionary” (1913).Applicant
- (27) “The American Heritage College Dictionary,” 3d ed., p. 17.Applicant
- Defendant Amphastar's Opposition Brief Re Claim Construction, dated Aug. 4, 2004.Applicant
- Supplemental Declaration of Steven M. Hanle in Support of Defendant Amphastar's Opposition to Aventis' Claim Construction Brief, dated Aug. 4, 2004.Applicant
- Response Brief on Claim Construction of Defendant Teva Pharmaceuticals USA, Inc., dated Aug. 4, 2004.Applicant
- Declaration of Lee J. Papageorge, dated Aug. 4, 2004.Applicant
- Aventis's Reply Brief on Claim Construction, dated Aug. 20, 2004.Applicant
- Third Declaration of Michael J. McCabe II, dated Aug. 20, 2004.Applicant
- (40) Planes et al., “Prevention of Postoperative Venous Thrombosis: A Randomized Trial Comparing Unfractionated Heparin with Low Molecular Weight Heparin in Patients Undergoing Total Hip Replacement,” Thrombosis and Haemostasis 60(3):407-410 (1988).Applicant
- Defendant Amphastar's Reply Brief Re Claim Construction, dated Aug. 20, 2004.Applicant
- Declaration of Jennifer A. Trusso in Support of Amphastar's Markman Claim Construction Brief, dated Aug. 20, 2004.Applicant
- (B) Court Order, dated Dec. 22, 2003.Applicant
- Reply Brief on Claim Construction of Defendant Teva Pharmaceuticals USA, Inc., dated Aug. 20, 2004.Applicant
- Declaration of Lee J. Papageorge, dated Aug. 20, 2004.Applicant
- English translation of HU 188 667.Applicant
- Fareed et al., “A Modified Stasis Thrombosis Model to Study the Antithrombotic Actions of Heparin and Its Fractions,” Seminars in Thrombosis and Hemostasis 11(2):155-175 (1985).Applicant
- Court's Construction of Certain Claims in U.S. Pat. No. 5,389,618 (“Markman Ruling”) dated Oct. 21, 2004.Applicant
- Hearing Transcript from hearing on Oct. 4, 2004.Applicant
- Public version of Teva's Supplemental Response to Interrogatories 2(a), (f), (h), and 3 dated Oct. 29, 2004.Applicant
- Public version of Teva's Second Supplemental Response to Interrogatory 2(g) dated Oct. 21, 2004.Applicant
- Markman Hearing Transcript from hearing of Oct. 1, 2004.Applicant
- Spiro et al., “Efficacy and Safety of Enoxaparin to Prevent Deep Venous Thrombosis after Hip Replacement Surgery,” Ann. Int. Medicine 121(2):81-89 (1994), USA.Applicant
- Colwell et al., “Use of Enoxaparin, a Low-Molecular-Weight Heparin, and Unfractionated Heparin for the Prevention of Deep Venous Thrombosis after Elective Hip Replacement,” J. Bone and Joint Surgery 76-A(1):3-14 (1994), USA.Applicant
- Laboratory notebook pages showing Viskov's syntheses reproducing Mardiguian '144 Example 3 and English translation of same.Applicant
- Laboratory notebook pages showing Viskov's syntheses reproducing Mardiguian '144 Example 6 and English translation of same.Applicant
- Laboratory notebook pages showing Viskov's syntheses reproducing Mardiguian '144 Example 7 and English translation of same.Applicant
- Laboratory notebook pages showing Viskov's syntheses reproducing Mardiguian '144 Example 8 and English translation of same.Applicant
- Laboratory notebook pages showing Viskov's syntheses reproducing Mardiguian '144 Example 9 (Run 9(a)) and English translation of same.Applicant
- Laboratory notebook pages showing Viskov's syntheses reproducing Mardiguian '144 Example 9 (Run 9(b)) and English translation of same.Applicant
- Laboratory notebook pages showing Viskov's syntheses reproducing Mardiguian '144 Example 10 (Run 10(a)) and English translation of same.Applicant
- Laboratory notebook pages showing Viskov's syntheses reproducing Mardiguian '144 Example 10 (Run 10(b)) and English translation of same.Applicant
- Laboratory notebook pages showing Viskov's syntheses reproducing Mardiguian '144 Example 10 (Run 10(c)) and English translation of same.Applicant
- Laboratory notebook pages showing Viskov's syntheses reproducing Mardiguian '144 Example 10 (Run 10(d)) and English translation of same.Applicant
- Seconde Memoria Autorizzala Di Replica Dopo II Supplemento Di C.T.U. Nell'Interesse Delle Societa' Attrici.Applicant
- English language translation of P00372.Applicant
- “Document 18”—M. Samama et al., “Introductory Remarks,” Haemostasis 16:69-70 (1986).Applicant
- “Document 17”—S. Massonnet-Castel et al., “Partial Reversal of Low Molecular Weight Heparin (PK 10169) Anti-Xa Activity by Protamine Sulfate: In vitro an in vivo Study during Cardiac Surgery with Extrecorporeal Circulation,” Haemostasis 16:139-146 (1986).Applicant
- “Document 21”—M. Mestre et al., “Comparative Effects of Heparin and PK 10169, A Low Molecular Weight Fraction, In a Canine Model of Arterial Thrombosis,” Thrombosis Research 38:389-399 (1985).Applicant
- “Document 22”—“Copy of the chapter of ‘PROPERTIES’ of the product leaflet of the products commercialized in France in 1987.”Applicant
- Ofosu; Haemostasis 20 (suppl. 1): 180-192 (1990).Examiner
- Statement of Claim filed by Aventis Pharma S.A. and Aventis Pharma Inc. in Canadian Federal Court, dated Mar. 11, 2005.Applicant
- Public Version of Amphastar's Memorandum of Points and Authorities in Support of Motion for Summary Judgment of, in the Alternative, Summary Adjudication Re Prior Art Invalidity Pursuant to 35 USC § 102, dated Mar. 14, 2005, including Exhibit A.Applicant
- Public Version of Amphastar's Statement of Uncontroverted Facts and Conclusions of Law in Support of Amphastar's Motion for Summary Judgement or, in the Alternative, Summary Adjudication Re Prior Art Invalidity Pursuant to 35 USC § 102, dated Mar. 14, 2005.Applicant
- Defendant Amphastar Pharmaceuticals, Inc.'s Notice of Motion and Motion for Summary Judgement, or in the Alternative, Summary Adjudication of Issues, Re Prior Art Invalidity Pursuant to 35 USC § 102, dated Mar. 14, 2005.Applicant
- Public Version of Declaration of Steven M. Hanle in Support of Amphastar's Motion for Summary Judgement, or in the Alternative Summary Adjucication of Invalidity Pursuant to 35 USC § 102, dated Mar. 14, 2005.Applicant
- Public Version of Declaration of Geert-Jan Boons in Support of Amphastar's Motion for Summary Judgment, or in the Alternative, Summary Adjudication of Invalidity Pursuant to 35 USC § 102, dated Mar. 7, 2005.Applicant
- Public Version of Declaration of Alma Mack in Support of Amphastar's Motion for Summary Judgement, or in the Alternative, Summary Adjudication of Invalidity Pursuant to 35 USC §102, dated Mar. 8, 2005.Applicant
- Public Version of Declaration of Dingyan Fei, a.k.a. Robert Fei in Support of Amphastar's Motion for Summary Judgement, or in the Alternative, Summary Adjudication of Invalidity Pursuant to 35 USC § 102, dated Mar. 4, 2005.Applicant
- Public Version of Declaration of Paul Yu in Support of Amphastar's Motion for Summary Judgment, or in the Alternative, Summary Adjudication of Invalidity Pursuant to 35 USC § 102, dated Mar. 4, 2005.Applicant
- Public Version of Declaration of Yu-Ying Chao in Support of Amphastar's Motion for Summary Judgment, or in the Alternative, Summary Adjudication of Invalidity Pursuant to 35 USC § 102, dated Mar. 4, 2005.Applicant
- Public Version of Declaration of Stephen A. Campbell in Support of Amphastar's Motion for Summary Judgement, or in the Alternative, Summary Adjudication of Invalidity Pursuant to 35 USC § 102, dated Mar. 7, 2005.Applicant
- Public Version of Defendant Amphastar's Rule 26(A)(2)(C) rebuttal to Expert Reports of Robert Linhardt and Jeffrey Weitz by Geert-Jan Boons, dated Feb. 10, 2005.Applicant
- Public Version of Teva's Reply Expert Report of Dr. Richard Mateles, dated Feb. 10, 2005.Applicant
- Public Version of Teva's Reply Expert Report of Michael Sofocleous, dated Feb. 10, 2005.Applicant
- Amphastar's Rebuttal Expert Report of John T. Goolkasian, dated Feb. 10, 2005, including Attachment A.Applicant
- Public Version of Teva's Reply Expert Report of Harry R. Buller, dated Mar. 1, 2005, including Dr. Buller's Curriculum Vitae and list of documents reviewed by Dr. Buller.Applicant
- Page 3/19 of Information Disclosure Statement, filed Nov. 26, 2003.Applicant
- Page 18/19 of Information Disclosure Statement, filed Nov. 26, 2003.Applicant
- Letter to Mr. Thomas L. Irving from John W. Herr, dated Jan. 13, 2005.Applicant
- Public Version of Teva's Expert Report of Dr. H.C. Hemker, dated Dec. 10, 2004, Including Dr. Hemker's Curriculum Vitae and list of documents reviewed by Dr. Hemker.Applicant
- Order Granting Plaintiffs Aventis Pharma S.A. and Aventis Pharmaceuticals Inc.'s Motion to Disqualify H.C. Hemker As An Expert For Defendant Teva Pharmaceuticals Inc., dated Jan. 7, 2005.Applicant
- Public Version of Amphastar's Disclosure of Expert Testimony by Dr. Geert-Jan Boons Pursuant to Rule 26(a)(2) Fed.R.Civ.P., dated Dec. 10, 2004, including Dr. Boons's Curriculum Vitae and list of documents reviewed by Dr. Boons.Applicant
- Public Version of Teva's Expert Report of Dr. Richard Mateles, dated Dec. 10, 2004, including Dr. Mateles's Curriculum Vitae and list of documents reviewed by Dr. Mateles.Applicant
- Public Version of Aventis's Expert Report of Robert Linhardt, Ph.D., on Behalf of Aventis, Pursuant to Fed. R. Civ. Pro. 26(a)(2)(B), dated Jan. 10, 2005, including Dr. Linhardt's Curriculum Vitae and list of documents reviewed by Dr. Linhart.Applicant
- Public Version of Aventis's Rebuttal Expert Report of Jeffrey Ian Weitz, M.D. in Behalf of Aventis, Pursuant to Fed. R. Civ. Pro. 26(a)(2)(B), dated Jan. 10, 2005, including Dr. Weitz's Curriculum Vitae and list of documents reviewed by Dr. Weitz.Applicant
- Public Version of Teva's Expert Report of Michael Sofocleous, dated Dec. 10, 2004, including Mr. Sofocleous's Curriculum Vitae and list of documents reviewed by Mr. Sofocleous.Applicant
- Public Version of Amphastar's Expert Report of John T. Goolkaslan, dated Dec. 10, 2004, including Mr Goolkasian's Curriculum Vitae and list of documents reviewed by Mr. Goolkaslan.Applicant
- Public Version of Aventis's Rebuttal Expert Report of Mark E. Nusbaum, dated Jan. 10, 2005, including Mr. Nusbaum's Curriculum Vitae and list of documents review by Mr. Nusbaum.Applicant
- Public Version of Amphastar's Memorandum of Points and Authorities in Support of Motion for Summary Judgement, or in the Alternative Summary Adjudication of Issues, Re Patent Invalidity Based of Indefiniteness, dated Nov. 29, 2004.Applicant
- Public Version of Amphastar's Statement of Uncontroverted Facts and Conclusions of Law in Support of Defendant Amphastar's Motion for Summary Judgement, or in the Alternative, Summary Adjudication of Issues, Re Patent Invalidity Based on Indefiniteness, dated Nov. 29, 2004.Applicant
- Public Version of Declaration of Steven M. Hanle in Support of Amphastar's Motion for Summary Judgement, or in the Alternative, Summary Adjudication of Issues, Re Patent Invalidity Based of Indefinitess, dated Nov. 29, 2004.Applicant
- Public Version of Aventis's Opposition to Amphastar's Motion for Summary Judgement of Invalidity of Based on Indefiniteness, dated Dec. 17, 2004.Applicant
- Aventis's Statement of Genuine Issues in Opposition to Amphastar's Motion for Summary Judgement of Invalidity, dated Dec. 17, 2004.Applicant
- Declaration of Michael J. McCabe II, dated Dec. 17, 2004.Applicant
- Declaration of Dr. Jeffrey Ian Weitz, dated Dec. 17, 2004.Applicant
- Amphastar's Reply Breif in Support of Motion for Summary Judgement of Invalidity Based on Indefinateness and Requests for Oral Argument, dated Dec. 27, 2004.Applicant
- Aventis's Notice of Motion, Motion, and Supporting Memorandum Re: Motion of Plaintiffs for Reconsideration of the Court's Claim Construction Order, dated Nov. 29, 2004.Applicant
- Declaration of Michael J. McCabe II, dated Nov. 28, 2004.Applicant
- Amphastar's Opposition to Aventis' Motion for Reconsideration, dated Dec. 17, 2004.Applicant
- Declaration of Steven M. Hanle in Opposition to Aventis' Motion for Reconsideration, dated Dec. 17, 2004.Applicant
- Opposition to Teva Pharmaceuticals USA, Inc. to Aventis's Motion for Reconsideration of the Court's Claim Construction Order, dated Dec. 20, 2004.Applicant
- Aventis's Reply Brief in Support of its Motion for Reconsideration of the Court's Claim Construction Order, dated Dec. 27, 2004.Applicant
- Declaration of Michael J. McCabe II, dated Dec. 23, 2004.Applicant
- Public Version of Defendant Teva Pharmaceuticals USA, Inc.'s Opposition to Plaintiffs' Motion for A Protective Order Regarding Deposition of Aventis Pursuant to Fed. R. Civ. P. 30(b)(6) by Teva, dated Nov. 8, 2004.Applicant
- Declaration of Lee J. Papageorge, dated Nov. 8, 2004.Applicant
- Public Version of Joint Stipulation Re: Plaintiffs' Motion for a Protective Order Regarding Deposition of Aventis Pursuant to Fed. R. Civ. Pro. 30(b)(6) by Amphastar, dated Dec. 17, 2004.Applicant
- Public Version of Supplemental Joint Stipulation Pursuant to Court Order Re: Aventis's Motion for a Protective Order Regarding the Deposition of Aventis on Topic 7 Pursuant to Fed. R. Civ. P. 30(b)(6) by Amphastar, dated Jan. 13, 2005.Applicant
- Public Version of Supplemental Memorandum Re: Aventis's Motion for a Protective Order Regarding the Deposition of Aventis of Topic 7 Pursuant to Fed. R. Civ. P. 30(b)(6) by Amphastar, dated Jan. 14, 2005.Applicant
- Chiarimenti A Completamento Della Consulenza Tecnica, dated Nov. 15, 2004.Applicant
- English translation of P00411. (Clarifications to Complete the Technical Report.).Applicant
- Court Order in Italian Nullity Action, dated Jan. 10, 2005.Applicant
- English translation of P00413.Applicant
- Memoria Ex Art. 180 C.P.C. in Opocrin S.p.A. Interest, dated Dec. 22, 2004.Applicant
- English translation of P00415.Applicant