1. Field of the Invention
This invention relates to the field of implantable medical devices, such as stents. More particularly, this invention is directed to coatings for devices, the coatings including peptides such as polymers and/or oligomers of L-arginine.
2. Description of the Background
In the field of medical technology, there is frequently a necessity to administer a therapeutic substance locally. To provide an efficacious concentration to the treatment site, systemic administration of medication often produces adverse or toxic side effect for the patient. Local delivery is a preferred method in that smaller total levels of medication are administered in comparison to systemic dosages, but are concentrated at a specific site. Thus, local delivery produces fewer side effects and achieves more effective results. For the treatment of vascular occlusions, such as restenosis, stents are being modified to administer therapeutic substances locally. One method of medicating a stent is with the use of a polymer coating impregnated with a therapeutic substance. The coating allows for the sustained release of the substance at the treatment site. L-arginine, or polypeptide oligomeric derivatives or analogs thereof, for example, those containing 5 to 20 amino acid units are one example of a therapeutic substance that can be used in conjunction with a stent.
L-arginine is a known precursor of endothelium derived nitric oxide (NO). NO is synthesized from L-arginine, or its polymeric and/or oligomeric derivatives, by the enzyme NO synthase oxygenase, a homodimeric flavo-hemoprotein that catalyzes the 5-electron oxidation of L-arginine to produce NO and L-citrulline. Among other therapeutic properties, NO regulates vascular tone, inhibits platelet aggregation, and inhibits vascular smooth muscle proliferation. These therapeutic properties are believed to contribute to the reduction or elimination of neo-intimal hyperplasia in vascular injury models.
U.S. Pat. No. 5,861,168 to Cooke et al. teaches that NO activity is reduced after vascular injury. Cooke et al. also teach that administering L-arginine as the NO precursor helps to restore vascular NO activity in patients with endothelial vasodilator dysfunction due to restenosis. It has been also taught that oligomeric peptides comprising 6 to 15 units of L- or D-arginine can be effective transfectors of cells (see, Mitchell, et al., J. Peptide Res., vol. 56, p. 318 (2000)) and, using a rabbit vein-graft model, it has been demonstrated that oligomers of L- or D-arginine can inhibit vascular smooth cell proliferation by efficiently transfecting cells. See, Uemura, et al., Circulation, vol. 102, p. 2629 (2000). Using the rabbit model, it has also been shown that intramural administration of L-arginine inhibits lesion formation in a hypercholesterolemic balloon injury. See, Schwarzacher et al. Circulation, vol. 95, p. 1863 (1997).
Accordingly, it is desirable to incorporate L-arginine, or its polymers and/or oligomers into a stent coating. The present application describes the methods that can be used to achieve this goal.
A method of coating an implantable medical device is provided. The method comprises applying an emulsion of a polymer and a polycationic peptide on the device to form a coating for the device. The device can be, for example, is a stent. The polycationic peptide can be poly(L-arginine), poly(D-arginine), poly(D,L-arginine), a racemic mixture of poly(L-arginine) and poly(D-arginine), poly(L-lysine), poly(D-lysine), poly(δ-guanidino-α-aminobutyric acid), or mixtures thereof.
The polymer can be, for example, an acrylic polymer, a vinyl polymer, a polyurethane, or a combination thereof. Representative examples of the acrylic polymer include poly(butyl methacrylate) and poly(methyl methacrylate). Representative examples of the vinyl polymer include poly(ethylene-co-vinyl alcohol) and poly(vinyl acetate). In one embodiment, the emulsion can include first surfactant. This first surfactant can have hydrophilic-lipophilic balance between about 3 and about 6. The emulsion can additionally include a second surfactant having has a hydrophilic-lipophilic balance exceeding the value of 10.
A method for incorporating a polycationic peptide into a coating for an implantable medical device, e.g., a stent, is provided comprising fabricating microspheres containing the polycationic peptide; dispersing the microspheres in a polymer solution; and applying the solution onto the device. The fabrication of the microspheres can include emulsification of an aqueous solution of the polycationic peptide in an organic solvent medium. The organic solvent medium can be, for example, cyclooctane, cyclohexane, cycloheptane, para-xylene, dimethylformamide, dimethylsulfoxide, chloroform, methylene oxide, dimethylacetamide, and mixtures thereof.
A method for incorporating a polycationic peptide into a coating for an implantable medical device is provided, comprising: fabricating liposomes containing the polycationic peptide; dispersing the liposomes in a polymer solution; and applying the solution onto the device. The fabrication of the liposomes car include suspending a lipid in an aqueous medium solution in the presence of the polycationic peptide. The lipid can be phosphatidyl choline.
A medical device, such as a stent is also disclosed comprising a coating, the coating including a polymer phase and a polycationic peptide phase separate and distinguishable from the polymer phase.
L-arginine, also known as 2-amino-5-guanidinovaleric acid, is an amino acid having a formula NH═C(NH2—NH—CH2—CH2—CH2—CH(NH2)—COOH. Polymers and/or oligomers of L-arginine that can be used are hereinafter referred to as “PArg” which comprise a plurality of repeating monomeric amino acid units connected with peptide bonds. PArg has a general formula H[NH—CHX—CO]p—OH, where “p” can be within a range of 5 and 1,000, typically, within a range of between 6 and 20. For example, a heptamer (designated R7), having p=7, can be used. In the formula of PArg “X” is 1-guanidinopropyl radical having the structure —CH2—CH2—CH2—NH—C(NH2)═NH. The terms “polymers and/or oligomers of L-arginine,” “poly-L-arginine,” and “PArg” are intended to include L-arginine in both its polymeric and oligomeric form.
In addition to PArg, other polycationic peptides can be incorporated into the stent coatings. Examples of alternative polycationic peptides include racemic mixtures of poly(L-arginine), poly(D-arginine), racemic mixtures of poly(D-arginine), poly(L-lysine), poly(D-lysine), and poly(δ-guanidino-α-aminobutyric acid). Those having ordinary skill in the art may choose to use other appropriate peptides if desired.
In accordance with one embodiment, an emulsion containing a polymer and a polypeptide, for example, R7 is prepared. To make the emulsion, R7 can be dissolved in water to form the aqueous phase (solution I). The concentration of R7 in solution I can be between about 5 and 15 mass %. A polymer is then dissolved in a suitable organic solvent, such as dimethylformamide, dimethylsulfoxide, chloroform, methylene chloride, or dimethylacetamide, to form the organic phase (solution II). The concentration of the polymer in solution II can be between about 1 and 15 mass %.
One example of the polymer that can be used for making the organic phase is poly(ethylene-co-vinyl alcohol), the copolymer of ethylene and vinyl alcohol also known under the trade name EVAL and distributed commercially by Aldrich Chemical Company of Milwaukee, Wis. EVAL is also manufactured by EVAL Company of America of Lisle, Ill. EVAL has the general formula —[CH2—CH2]m—[CH2—CH(OH)]n—. EVAL is a product of hydrolysis of ethylene-vinyl acetate copolymers. Those having ordinary skill in the art of polymer chemistry will understand that EVAL may also be a terpolymer and may include up to 5% (molar) of units derived from styrene, propylene and other suitable unsaturated monomers.
Other polymers can be used in lieu of or in addition to EVAL to for preparation of solution II. Examples of such polymers include other vinyl polymers such as poly(vinyl acetate) (PVA), acrylic polymers such as poly(butyl methacrylate) (PBMA) or poly(methyl methacrylate) (PMMA), polyurethanes, and combinations thereof.
The organic phase can also optionally include a surfactant or a mixture of surfactants. The surfactant or the mixture of surfactants can have a hydrophilic-lipophilic balance (HLB) within a range of between about 3 and about 6. Examples of suitable surfactants having HLB between 3 and 6 include SPAN 80 (sorbitan oleate), SPAN 60 (sorbitan monostearates), ARLACEL 83 (sorbitan sesquioleate), TX-4 (polyoxyethylene alkylphenol ether), MOA-3 (polyoxyethylene aliphatic alcohol ether), polyoxamers such as poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) block-copolymer, egg lechitin, BRIJ 93 (polyoxyethylene oleyl ether), IGEPAL CO-210 (polyoxyethylene nonyl phenyl ether), propylene glycol monostearate, propylene glycol monolaurate, glycerol monolaurate and mixtures thereof.
Surfactants having high HLB (>10) can be also blended with low HLB surfactants described above. Example of suitable high HLB surfactants include TWEEN 20 and TWEEN 21 (polyoxyethylene sorbitan monolaurates), TWEEN 80 (polyoxyethylene sorbitan monooleate), TWEEN 85 (polyoxyethylene sorbitan trioleate), BRIJ 76 and BRIJ 78 (polyoxyethylene stearyl ethers). TWEEN, SPAN, BRIJ, ARLACEL and IGEPAL are trade names of the surfactants. TWEEN, SPAN, BRIJ and ARLACEL are available from ICI Americas, Inc. of Bridgewater, N.J. IGEPAL is available from Rhone-Poulenc, Inc. of Cranbury, N.J.
Solution I is added to solution II and the mixture is sonicated or homogenized to make the water-in-oil emulsion. “Sonication” is defined as agitation by high-frequency sound waves applied to the mixture. The conditions under which the sonication or homogenization is carried out can be determined by one having ordinary skill in the art. The ratio between solution I and solution II can be between about 1:9 and about 1:1 by volume. The R7-containing emulsion can then be applied to a stent by any conventional technique, for example, by spraying or dipping, to form the reservoir matrix of the stent coating. The amount of R7 in this layer can be between about 10 and 200 micrograms.
Optionally, a therapeutic agent or a drug can be incorporated into the coating, for example by dispersing or dissolving the drug in solution I or II prior to mixing the solutions. The agent could be for inhibiting the activity of vascular smooth muscle cells. It can be directed at inhibiting abnormal or inappropriate migration and/or proliferation of smooth muscle cells to inhibit restenosis. The active agent can include any substance capable of exerting a therapeutic or prophylactic effect in the practice of the present invention. The drug may include small molecule drugs, peptides, proteins, oligonucleotides, or double-stranded DNA. The active agent can also be conjugated to R7 either by covalent attachment or by ionic interaction.
Examples of the drugs include antiproliferative substances such as actinomycin D, or derivatives and analogs thereof. Synonyms of actinomycin D include dactinomycin, actinomycin IV, actinomycin I1, actinomycin X1, and actinomycin C1. The active agent can also fall under the genus of antineoplastic, anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic and antioxidant substances. Examples of such antineoplastics and/or antimitotics include paclitaxel, docetaxel, methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride, and mitomycin. Examples of such antiplatelets, anticoagulants, antifibrin, and antithrombins include sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor antagonist antibody, recombinant hirudin, and thrombin. Examples of such cytostatic or antiproliferative agents include angiopeptin, angiotensin converting enzyme inhibitors such as captopril, cilazapril or lisinopril, calcium channel blockers (such as nifedipine), colchicine, fibroblast growth factor (FGF) antagonists, fish oil (ω-3-fatty acid), histamine antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol lowering drug), monoclonal antibodies (such as those specific for Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, steroids, thioprotease inhibitors, triazolopyrirnidine (a PDGF antagonist), and nitric oxide. An example of an antiallergic agent is permirolast potassium. Other therapeutic substances or agents which may be appropriate include alpha-interferon, genetically engineered epithelial cells, rapamycin and dexamethasone.
Prior to the application of the reservoir layer, a polymer primer layer can be formed on the bare stent. The polymers for the optional primer layer can be the same polymers that are used to make the reservoir layer.
The coated stent can be optionally freeze-dried to remove the residual solvent and/or moisture. The process of freeze-drying can be carried out using techniques and equipment known to those having ordinary skill in the art. Also, the R7-coated stent can be over-coated with a diffusion limited hydrophobic polymer topcoat if desired. The use of the topcoat is optional. The polymers used for fabrication of the topcoat can include poly(vinylidene fluoride), PBMA, PMMA, or combinations thereof.
In accordance with other embodiments, microspheres or liposomes containing a polypeptide, for example R7, can be dispersed in a polymer composition. The polymer composition, containing the microspheres incorporating R7, is then applied to the stent.
In accordance with one embodiment, an encapsulating polymer is dissolved in a suitable organic solvent such as methylene chloride, cyclooctane, cyclohexane, cycloheptane, para-xylene, dimethylformamide, dimethylsulfoxide, chloroform, dimethylacetamide, or mixtures thereof. The encapsulating polymers can include EVAL, other vinyl polymers such as poly(vinyl acetate) (PVA), acrylic polymers such as poly(butyl methacrylate) (PBMA) or poly(methyl methacrylate) (PMMA), polyurethanes, poly(L-lactide), poly(D,L-lactide), poly(glycolide), poly(caprolactone), polyanhydrides, polydiaxanone, polyorthoesters, polyamino acids, poly(trimethylene carbonate), and combinations thereof. The R7 is then added to the polymer solution either as an aqueous solution containing an emulsifying agent such as poly(vinyl alcohol), or as a solid dispersion, and stirred, homogenized or sonicated to create a primary emulsion of R7 in the polymer phase. Surfactants such as poly(vinyl alcohol), albumin (either bovine or human serum), gelatin, lipophilic emulsifiers such as PLURONIC or TETRONIC, or a combination thereof can be optionally added to stabilize the primary emulsion. PLURONIC is a trade name of poly(ethylene oxide-co-propylene oxide). TETRONIC is a trade name of a family of non-ionic tetrafunctional block-copolymer surfactants. PLURONIC and TETRONIC are available from BASF Corp. of Parsippany, N.J.
The primary emulsion is stirred with an aqueous solution containing an emulsifying agent such as poly(vinyl alcohol) to create a secondary emulsion of protein containing polymer in the aqueous phase. The secondary emulsion is stirred in excess water, optionally under vacuum to remove the organic solvent and harden the microspheres. The hardened microspheres are collected by filtration or centrifugation and lyophilized.
According to another technique, a primary emulsion of R7 in an aqueous phase is formed as in the first technique described above. This emulsion is then stirred with a non-solvent for the polymer, such as silicone oil to extract the organic solvent and form embryonic microspheres of polymer with trapped R7. The non-solvent is then removed by the addition of a volatile second non-solvent such as heptane, and the microspheres harden. The hardened microspheres are collected by filtration or centrifugation and lyophilized.
According to yet another technique, the R7, formulated as lyophilized powder is suspended in a polymer phase consisting of polymer dissolved in a volatile organic solvent such as methylene chloride. The suspension is then spray dried to produce polymer microparticles with entrapped R7.
According to yet another technique, the R7, formulated as a powder is suspended in a polymer phase consisting of polymer dissolved in a volatile organic solvent such as methylene chloride. The suspension is sprayed into a container containing frozen ethanol overlaid with liquid nitrogen. The system is then warmed to about −70° C. to liquefy the ethanol and extract the organic solvent from the microspheres. The hardened microspheres are collected by filtration or centrifugation and lyophilized.
Liposomes are aqueous compartments pouches which are typically made of phospholipids. Liposomes can be fabricated according to standard techniques known to those having ordinary skill in the art. One way of forming of the liposome can be by suspending a suitable lipid, such as phosphatidyl choline in an aqueous medium followed by sonication of the mixture. An alternative way of preparing the lipid vesicles can be by rapidly mixing a solution of the lipid in an ethanol-water blend, for example, by injecting the lipid through a needle into a agitated ethanol-water solution. Besides phospholipids, other amphophilic substances can be used, for example, shingomyelin or lipids containing polymerized portions of poly(ethylene glycol). Liposomes having a diameter of about 500 Angstroms can be fabricated.
To trap R7 inside the liposomes, the liposomes can be formed in the presence of R7. For example, in the process of forming the liposomes described above, the aqueous or ethanol-water medium can contain R7. R7 can be dissolved in the medium. For example, if 500 Angstrom vesicles are formed in an approximately decimolar solution of R7 (i.e., the concentration of R7 in the medium is about 0.1 moles per liter), about 2,000 molecules of R7 can be trapped in the inner compartment of each liposome. Following the formation of the R7-filled lipid vesicles, the vesicles can be separated from the surrounding solution and purified, for example, by dialysis or gel-filtration chromatography. Other suitable methods of separation can be employed as is understood by one having ordinary skill in the art.
The R7-containing microspheres or liposomes can then be dispersed in a solution of an appropriate polymer to form a polymer-microsphere or polymer-liposome suspension. The mass ratio between the liposome and the polymer in the suspension can be within a range of between about 1:5 and 1:2. Examples of polymers that can be used, include, but are not limited to, EVAL, other vinyl polymers such as PVA, acrylic polymers such PBMA or PMMA, polyurethanes, and combinations thereof.
The coatings and methods of the present invention have been described in conjunction with a stent. The stent can be used in any part of the vascular system, including neurological, carotid, coronary, renal, aortic, iliac, femoral or any other peripheral vascular sites. The stent can be balloon-expandable or self-expandable. There are no limitations on the size of the stent, its length, diameter, strut thickness or pattern. The use of the coating is, however, not limited to stents and the coating can also be used with a variety of other medical devices. Examples of the implantable medical device, that can be used in conjunction with the embodiments of this invention include stent-grafts, grafts (e.g., aortic grafts), artificial heart valves, cerebrospinal fluid shunts, pacemaker electrodes, axius coronary shunts and endocardial leads (e.g., FINELINE and ENDOTAK, available from Guidant Corporation). The underlying structure of the device can be of virtually any design. The device can be made of a metallic material or an alloy such as, but not limited to, cobalt-chromium alloys (e.g., ELGILOY), stainless steel (316L), “MP35N,” “MP20N,” ELASTINITE (Nitinol), tantalum, tantalum-based alloys, nickel-titanium alloy, platinum, platinum-based alloys such as, e.g., platinum-iridium alloy, iridium, gold, magnesium, titanium, titanium-based alloys, zirconium-based alloys, or combinations thereof. Devices made from bioabsorbable or biostable polymers can also be used with the embodiments of the present invention. “MP35N” and “MP20N” are trade names for alloys of cobalt, nickel, chromium and molybdenum available from Standard Press Steel Co. of Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum.
While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications can be made without departing from this invention in its broader aspects. Therefore, the appended claims are to encompass within their scope all such changes and modifications as fall within the true spirit and scope of this invention.
Number | Name | Date | Kind |
---|---|---|---|
2072303 | Herrmann et al. | Mar 1937 | A |
2386454 | Frosch et al. | Oct 1945 | A |
3773737 | Goodman et al. | Nov 1973 | A |
3835175 | Carpino et al. | Sep 1974 | A |
3849514 | Gray, Jr. et al. | Nov 1974 | A |
4226243 | Shalaby et al. | Oct 1980 | A |
4329383 | Joh | May 1982 | A |
4343931 | Barrows | Aug 1982 | A |
4529792 | Barrows | Jul 1985 | A |
4611051 | Hayes et al. | Sep 1986 | A |
4656242 | Swan et al. | Apr 1987 | A |
4733665 | Palmaz | Mar 1988 | A |
4800882 | Gianturco | Jan 1989 | A |
4882168 | Casey et al. | Nov 1989 | A |
4886062 | Wiktor | Dec 1989 | A |
4908404 | Benedict et al. | Mar 1990 | A |
4917309 | Zander et al. | Apr 1990 | A |
4931287 | Bae et al. | Jun 1990 | A |
4941870 | Okada et al. | Jul 1990 | A |
4977901 | Ofstead | Dec 1990 | A |
5019096 | Fox, Jr. et al. | May 1991 | A |
5025001 | Loscalzo et al. | Jun 1991 | A |
5100992 | Cohn et al. | Mar 1992 | A |
5112457 | Marchant | May 1992 | A |
5133742 | Pinchuk | Jul 1992 | A |
5155137 | Keefer et al. | Oct 1992 | A |
5163952 | Froix | Nov 1992 | A |
5165919 | Sasaki et al. | Nov 1992 | A |
5187183 | Loscalzo et al. | Feb 1993 | A |
5202129 | Samejima et al. | Apr 1993 | A |
5219980 | Swidler | Jun 1993 | A |
5258020 | Froix | Nov 1993 | A |
5272012 | Opolski | Dec 1993 | A |
5292516 | Viegas et al. | Mar 1994 | A |
5298260 | Viegas et al. | Mar 1994 | A |
5300295 | Viegas et al. | Apr 1994 | A |
5306501 | Viegas et al. | Apr 1994 | A |
5306786 | Moens et al. | Apr 1994 | A |
5328471 | Slepian | Jul 1994 | A |
5330768 | Park et al. | Jul 1994 | A |
5356890 | Loscalzo et al. | Oct 1994 | A |
5366997 | Keefer et al. | Nov 1994 | A |
5380299 | Fearnot et al. | Jan 1995 | A |
5405919 | Keefer et al. | Apr 1995 | A |
5417981 | Endo et al. | May 1995 | A |
5424077 | Lajoie | Jun 1995 | A |
5428070 | Cooke et al. | Jun 1995 | A |
5447724 | Helmus et al. | Sep 1995 | A |
5455040 | Marchant | Oct 1995 | A |
5462990 | Hubbell et al. | Oct 1995 | A |
5464650 | Berg et al. | Nov 1995 | A |
5482720 | Murphy et al. | Jan 1996 | A |
5485496 | Lee et al. | Jan 1996 | A |
5516881 | Lee et al. | May 1996 | A |
5536723 | Loscalzo et al. | Jul 1996 | A |
5543099 | Zhang et al. | Aug 1996 | A |
5569463 | Helmus et al. | Oct 1996 | A |
5578073 | Haimovich et al. | Nov 1996 | A |
5584877 | Miyake et al. | Dec 1996 | A |
5605696 | Eury et al. | Feb 1997 | A |
5607467 | Froix | Mar 1997 | A |
5609629 | Fearnot et al. | Mar 1997 | A |
5610241 | Lee et al. | Mar 1997 | A |
5616338 | Fox, Jr. et al. | Apr 1997 | A |
5624411 | Tuch | Apr 1997 | A |
5628730 | Shapland et al. | May 1997 | A |
5639441 | Sievers et al. | Jun 1997 | A |
5644020 | Timmermann et al. | Jul 1997 | A |
5649977 | Campbell | Jul 1997 | A |
5650442 | Mitchell et al. | Jul 1997 | A |
5658995 | Kohn et al. | Aug 1997 | A |
5667767 | Greff et al. | Sep 1997 | A |
5670558 | Onishi et al. | Sep 1997 | A |
5674242 | Phan et al. | Oct 1997 | A |
5679400 | Tuch | Oct 1997 | A |
5700286 | Tartaglia et al. | Dec 1997 | A |
5702754 | Zhong | Dec 1997 | A |
5711958 | Cohn et al. | Jan 1998 | A |
5716981 | Hunter et al. | Feb 1998 | A |
5721131 | Rudolph et al. | Feb 1998 | A |
5723219 | Kolluri et al. | Mar 1998 | A |
5735897 | Buirge | Apr 1998 | A |
5746998 | Torchilin et al. | May 1998 | A |
5759205 | Valentini | Jun 1998 | A |
5776184 | Tuch | Jul 1998 | A |
5783657 | Pavlin et al. | Jul 1998 | A |
5788979 | Alt et al. | Aug 1998 | A |
5800392 | Racchini | Sep 1998 | A |
5804318 | Pinchuk et al. | Sep 1998 | A |
5820917 | Tuch | Oct 1998 | A |
5824048 | Tuch | Oct 1998 | A |
5824049 | Ragheb et al. | Oct 1998 | A |
5830178 | Jones et al. | Nov 1998 | A |
5837008 | Berg et al. | Nov 1998 | A |
5837313 | Ding et al. | Nov 1998 | A |
5849859 | Acemoglu | Dec 1998 | A |
5851508 | Greff et al. | Dec 1998 | A |
5852058 | Cooke et al. | Dec 1998 | A |
5854376 | Higashi | Dec 1998 | A |
5858746 | Hubbell et al. | Jan 1999 | A |
5861168 | Cooke et al. | Jan 1999 | A |
5865814 | Tuch | Feb 1999 | A |
5869127 | Zhong | Feb 1999 | A |
5873904 | Ragheb et al. | Feb 1999 | A |
5874165 | Drumheller | Feb 1999 | A |
5876433 | Lunn | Mar 1999 | A |
5877224 | Brocchini et al. | Mar 1999 | A |
5879713 | Roth et al. | Mar 1999 | A |
5891459 | Cooke et al. | Apr 1999 | A |
5902875 | Roby et al. | May 1999 | A |
5905168 | Dos Santos et al. | May 1999 | A |
5910564 | Gruning et al. | Jun 1999 | A |
5914387 | Roby et al. | Jun 1999 | A |
5919893 | Roby et al. | Jul 1999 | A |
5925720 | Kataoka et al. | Jul 1999 | A |
5932299 | Katoot | Aug 1999 | A |
5945452 | Cooke et al. | Aug 1999 | A |
5955509 | Webber et al. | Sep 1999 | A |
5958385 | Tondeur et al. | Sep 1999 | A |
5962138 | Kolluri et al. | Oct 1999 | A |
5971954 | Conway et al. | Oct 1999 | A |
5980928 | Terry | Nov 1999 | A |
5980972 | Ding | Nov 1999 | A |
5997517 | Whitbourne | Dec 1999 | A |
6010530 | Goicoechea | Jan 2000 | A |
6011125 | Lohmeijer et al. | Jan 2000 | A |
6015541 | Greff et al. | Jan 2000 | A |
6033582 | Lee et al. | Mar 2000 | A |
6034204 | Mohr et al. | Mar 2000 | A |
6042875 | Ding et al. | Mar 2000 | A |
6051576 | Ashton et al. | Apr 2000 | A |
6051648 | Rhee et al. | Apr 2000 | A |
6054553 | Groth et al. | Apr 2000 | A |
6056993 | Leidner et al. | May 2000 | A |
6060451 | DiMaio et al. | May 2000 | A |
6060518 | Kabanov et al. | May 2000 | A |
6060534 | Ronan et al. | May 2000 | A |
6063432 | Maxwell et al. | May 2000 | A |
6077543 | Gordon et al. | Jun 2000 | A |
6080488 | Hostettler et al. | Jun 2000 | A |
6095134 | Sievers et al. | Aug 2000 | A |
6096070 | Ragheb et al. | Aug 2000 | A |
6099562 | Ding et al. | Aug 2000 | A |
6110188 | Narciso, Jr. | Aug 2000 | A |
6110483 | Whitbourne et al. | Aug 2000 | A |
6113629 | Ken | Sep 2000 | A |
6117872 | Maxwell et al. | Sep 2000 | A |
6120491 | Kohn et al. | Sep 2000 | A |
6120536 | Ding et al. | Sep 2000 | A |
6120788 | Barrows | Sep 2000 | A |
6120904 | Hostettler et al. | Sep 2000 | A |
6121027 | Clapper et al. | Sep 2000 | A |
6129761 | Hubbell | Oct 2000 | A |
6136333 | Cohn et al. | Oct 2000 | A |
6143354 | Koulik et al. | Nov 2000 | A |
6153252 | Hossainy et al. | Nov 2000 | A |
6159978 | Myers et al. | Dec 2000 | A |
6165212 | Dereume et al. | Dec 2000 | A |
6172167 | Stapert et al. | Jan 2001 | B1 |
6177523 | Reich et al. | Jan 2001 | B1 |
6180632 | Myers et al. | Jan 2001 | B1 |
6183783 | Benoit et al. | Feb 2001 | B1 |
6203551 | Wu | Mar 2001 | B1 |
6211249 | Cohn et al. | Apr 2001 | B1 |
6214901 | Chudzik et al. | Apr 2001 | B1 |
6228346 | Zhang et al. | May 2001 | B1 |
6231600 | Zhong | May 2001 | B1 |
6240616 | Yan | Jun 2001 | B1 |
6245753 | Byun et al. | Jun 2001 | B1 |
6245760 | He et al. | Jun 2001 | B1 |
6248129 | Froix | Jun 2001 | B1 |
6251136 | Guruwaiya et al. | Jun 2001 | B1 |
6254632 | Wu et al. | Jul 2001 | B1 |
6258121 | Yang et al. | Jul 2001 | B1 |
6258371 | Koulik et al. | Jul 2001 | B1 |
6262034 | Mathiowitz et al. | Jul 2001 | B1 |
6270788 | Koulik et al. | Aug 2001 | B1 |
6277449 | Kolluri et al. | Aug 2001 | B1 |
6283947 | Mirzaee | Sep 2001 | B1 |
6283949 | Roorda | Sep 2001 | B1 |
6284305 | Ding et al. | Sep 2001 | B1 |
6287628 | Hossainy et al. | Sep 2001 | B1 |
6299604 | Ragheb et al. | Oct 2001 | B1 |
6306166 | Barry et al. | Oct 2001 | B1 |
6306176 | Whitbourne | Oct 2001 | B1 |
6306993 | Rothbard et al. | Oct 2001 | B1 |
6331313 | Wong et al. | Dec 2001 | B1 |
6335029 | Kamath et al. | Jan 2002 | B1 |
6344035 | Chudzik et al. | Feb 2002 | B1 |
6346110 | Wu | Feb 2002 | B1 |
6358556 | Ding et al. | Mar 2002 | B1 |
6379381 | Hossainy et al. | Apr 2002 | B1 |
6387379 | Goldberg et al. | May 2002 | B1 |
6395326 | Castro et al. | May 2002 | B1 |
6419692 | Yang et al. | Jul 2002 | B1 |
6451373 | Hossainy et al. | Sep 2002 | B1 |
6482834 | Spada et al. | Nov 2002 | B1 |
6494862 | Ray et al. | Dec 2002 | B1 |
6503538 | Chu et al. | Jan 2003 | B1 |
6503556 | Harish et al. | Jan 2003 | B1 |
6503954 | Bhat et al. | Jan 2003 | B1 |
6506437 | Harish et al. | Jan 2003 | B1 |
6524347 | Myers et al. | Feb 2003 | B1 |
6527801 | Dutta | Mar 2003 | B1 |
6527863 | Pacetti et al. | Mar 2003 | B1 |
6528526 | Myers et al. | Mar 2003 | B1 |
6530950 | Alvarado et al. | Mar 2003 | B1 |
6530951 | Bates et al. | Mar 2003 | B1 |
6540776 | Sanders Millare et al. | Apr 2003 | B1 |
6544223 | Kokish | Apr 2003 | B1 |
6544543 | Mandrusov et al. | Apr 2003 | B1 |
6544582 | Yoe | Apr 2003 | B1 |
6555157 | Hossainy | Apr 2003 | B1 |
6558733 | Hossainy et al. | May 2003 | B1 |
6565659 | Pacetti et al. | May 2003 | B1 |
6572644 | Moein | Jun 2003 | B1 |
6585755 | Jackson et al. | Jul 2003 | B1 |
6585765 | Hossainy et al. | Jul 2003 | B1 |
6585926 | Mirzaee | Jul 2003 | B1 |
6605154 | Villareal | Aug 2003 | B1 |
6616765 | Hossainy et al. | Sep 2003 | B1 |
6623448 | Slater | Sep 2003 | B1 |
6625486 | Lundkvist et al. | Sep 2003 | B1 |
6645135 | Bhat | Nov 2003 | B1 |
6645195 | Bhat et al. | Nov 2003 | B1 |
6656216 | Hossainy et al. | Dec 2003 | B1 |
6656506 | Wu et al. | Dec 2003 | B1 |
6660034 | Mandrusov et al. | Dec 2003 | B1 |
6663662 | Pacetti et al. | Dec 2003 | B1 |
6663880 | Roorda et al. | Dec 2003 | B1 |
6666880 | Chiu et al. | Dec 2003 | B1 |
6673154 | Pacetti et al. | Jan 2004 | B1 |
6673385 | Ding et al. | Jan 2004 | B1 |
6689099 | Mirzaee | Feb 2004 | B1 |
6695920 | Pacetti et al. | Feb 2004 | B1 |
6706013 | Bhat et al. | Mar 2004 | B1 |
6709514 | Hossainy | Mar 2004 | B1 |
6712845 | Hossainy | Mar 2004 | B1 |
6713119 | Hossainy et al. | Mar 2004 | B1 |
6716444 | Castro et al. | Apr 2004 | B1 |
6723120 | Yan | Apr 2004 | B1 |
6733768 | Hossainy et al. | May 2004 | B1 |
6740040 | Mandrusov et al. | May 2004 | B1 |
6743462 | Pacetti | Jun 2004 | B1 |
6746481 | Larik et al. | Jun 2004 | B1 |
6749626 | Bhat et al. | Jun 2004 | B1 |
6753071 | Pacetti et al. | Jun 2004 | B1 |
6758859 | Dang et al. | Jul 2004 | B1 |
6759054 | Chen et al. | Jul 2004 | B1 |
6764505 | Hossainy et al. | Jul 2004 | B1 |
20010007083 | Roorda | Jul 2001 | A1 |
20010014717 | Hossainy et al. | Aug 2001 | A1 |
20010018469 | Chen et al. | Aug 2001 | A1 |
20010020011 | Mathiowitz et al. | Sep 2001 | A1 |
20010029351 | Falotico et al. | Oct 2001 | A1 |
20010037145 | Guruwaiya et al. | Nov 2001 | A1 |
20010051608 | Mathiowitz et al. | Dec 2001 | A1 |
20020005206 | Falotico et al. | Jan 2002 | A1 |
20020007213 | Falotico et al. | Jan 2002 | A1 |
20020007214 | Falotico | Jan 2002 | A1 |
20020007215 | Falotico et al. | Jan 2002 | A1 |
20020009604 | Zamora et al. | Jan 2002 | A1 |
20020016625 | Falotico et al. | Feb 2002 | A1 |
20020032414 | Ragheb et al. | Mar 2002 | A1 |
20020032434 | Chudzik et al. | Mar 2002 | A1 |
20020051730 | Bodnar et al. | May 2002 | A1 |
20020071822 | Uhrich | Jun 2002 | A1 |
20020077693 | Barclay et al. | Jun 2002 | A1 |
20020082679 | Sirhan et al. | Jun 2002 | A1 |
20020087123 | Hossainy et al. | Jul 2002 | A1 |
20020091433 | Ding et al. | Jul 2002 | A1 |
20020094440 | Llanos et al. | Jul 2002 | A1 |
20020111590 | Davila et al. | Aug 2002 | A1 |
20020120326 | Michal | Aug 2002 | A1 |
20020123801 | Pacetti et al. | Sep 2002 | A1 |
20020142039 | Claude | Oct 2002 | A1 |
20020155212 | Hossainy | Oct 2002 | A1 |
20020165608 | Llanos et al. | Nov 2002 | A1 |
20020176849 | Slepian | Nov 2002 | A1 |
20020183581 | Yoe et al. | Dec 2002 | A1 |
20020188037 | Chudzik et al. | Dec 2002 | A1 |
20020188277 | Roorda et al. | Dec 2002 | A1 |
20030004141 | Brown | Jan 2003 | A1 |
20030028243 | Bates et al. | Feb 2003 | A1 |
20030028244 | Bates et al. | Feb 2003 | A1 |
20030031780 | Chudzik et al. | Feb 2003 | A1 |
20030032767 | Tada et al. | Feb 2003 | A1 |
20030036794 | Ragheb et al. | Feb 2003 | A1 |
20030039689 | Chen et al. | Feb 2003 | A1 |
20030040712 | Ray et al. | Feb 2003 | A1 |
20030040790 | Furst | Feb 2003 | A1 |
20030059520 | Chen et al. | Mar 2003 | A1 |
20030060877 | Falotico et al. | Mar 2003 | A1 |
20030065377 | Davila et al. | Apr 2003 | A1 |
20030072868 | Harish et al. | Apr 2003 | A1 |
20030073961 | Happ | Apr 2003 | A1 |
20030083646 | Sirhan et al. | May 2003 | A1 |
20030083739 | Cafferata | May 2003 | A1 |
20030097088 | Pacetti | May 2003 | A1 |
20030097173 | Dutta | May 2003 | A1 |
20030099712 | Jayaraman | May 2003 | A1 |
20030105518 | Dutta | Jun 2003 | A1 |
20030113439 | Pacetti et al. | Jun 2003 | A1 |
20030150380 | Yoe | Aug 2003 | A1 |
20030157241 | Hossainy et al. | Aug 2003 | A1 |
20030158517 | Kokish | Aug 2003 | A1 |
20030190406 | Hossainy et al. | Oct 2003 | A1 |
20030207020 | Villareal | Nov 2003 | A1 |
20030211230 | Pacetti et al. | Nov 2003 | A1 |
20040018296 | Castro et al. | Jan 2004 | A1 |
20040029952 | Chen et al. | Feb 2004 | A1 |
20040047978 | Hossainy et al. | Mar 2004 | A1 |
20040047980 | Pacetti et al. | Mar 2004 | A1 |
20040052858 | Wu et al. | Mar 2004 | A1 |
20040052859 | Wu et al. | Mar 2004 | A1 |
20040054104 | Pacetti | Mar 2004 | A1 |
20040060508 | Pacetti et al. | Apr 2004 | A1 |
20040062853 | Pacetti et al. | Apr 2004 | A1 |
20040063805 | Pacetti et al. | Apr 2004 | A1 |
20040071861 | Mandrusov et al. | Apr 2004 | A1 |
20040072922 | Hossainy et al. | Apr 2004 | A1 |
20040073298 | Hossainy | Apr 2004 | A1 |
20040086542 | Hossainy et al. | May 2004 | A1 |
20040086550 | Roorda et al. | May 2004 | A1 |
20040096504 | Michal | May 2004 | A1 |
20040098117 | Hossainy et al. | May 2004 | A1 |
Number | Date | Country |
---|---|---|
42 24 401 | Jan 1994 | DE |
0 301 856 | Feb 1989 | EP |
0 396 429 | Nov 1990 | EP |
0 514 406 | Nov 1992 | EP |
0 604 022 | Jun 1994 | EP |
0 623 354 | Nov 1994 | EP |
0 665 023 | Aug 1995 | EP |
0 677 332 | Oct 1995 | EP |
0 701 802 | Mar 1996 | EP |
0 716 836 | Jun 1996 | EP |
0 809 999 | Dec 1997 | EP |
0 832 655 | Apr 1998 | EP |
0 850 651 | Jul 1998 | EP |
0 879 595 | Nov 1998 | EP |
0 910 584 | Apr 1999 | EP |
0 923 953 | Jun 1999 | EP |
0 953 320 | Nov 1999 | EP |
0 970 711 | Jan 2000 | EP |
0 982 041 | Mar 2000 | EP |
1 023 879 | Aug 2000 | EP |
1 192 957 | Apr 2002 | EP |
1 273 314 | Jan 2003 | EP |
2001-190687 | Jul 2001 | JP |
872531 | Oct 1981 | SU |
876663 | Oct 1981 | SU |
905228 | Feb 1982 | SU |
790725 | Feb 1983 | SU |
1016314 | May 1983 | SU |
811750 | Sep 1983 | SU |
1293518 | Feb 1987 | SU |
WO 9112846 | Sep 1991 | WO |
WO 9409760 | May 1994 | WO |
WO 9428721 | Dec 1994 | WO |
WO 9510989 | Apr 1995 | WO |
WO 9524929 | Sep 1995 | WO |
WO 9640174 | Dec 1996 | WO |
WO 9710011 | Mar 1997 | WO |
WO 9716983 | May 1997 | WO |
WO 9745105 | Dec 1997 | WO |
WO 9746590 | Dec 1997 | WO |
WO 9806389 | Feb 1998 | WO |
WO 9808463 | Mar 1998 | WO |
WO 9817331 | Apr 1998 | WO |
WO 9832398 | Jul 1998 | WO |
WO 9836784 | Aug 1998 | WO |
WO 9849199 | Nov 1998 | WO |
WO 9900070 | Jan 1999 | WO |
WO 9901118 | Jan 1999 | WO |
WO 9938546 | Aug 1999 | WO |
WO 9959433 | Nov 1999 | WO |
WO 9963981 | Dec 1999 | WO |
WO 9966921 | Dec 1999 | WO |
WO 0002599 | Jan 2000 | WO |
WO 0012147 | Mar 2000 | WO |
WO 0018446 | Apr 2000 | WO |
WO 0046395 | Aug 2000 | WO |
WO 0064506 | Nov 2000 | WO |
WO 0074701 | Dec 2000 | WO |
WO 0101890 | Jan 2001 | WO |
WO 0108684 | Feb 2001 | WO |
WO 0113957 | Mar 2001 | WO |
WO 0115751 | Mar 2001 | WO |
WO 0117577 | Mar 2001 | WO |
WO 0145763 | Jun 2001 | WO |
WO 0149338 | Jul 2001 | WO |
WO 0151027 | Jul 2001 | WO |
WO 0162297 | Aug 2001 | WO |
WO 0174414 | Oct 2001 | WO |
WO 0203890 | Jan 2002 | WO |
WO 0226162 | Apr 2002 | WO |
WO 0234311 | May 2002 | WO |
WO 02056790 | Jul 2002 | WO |
WO 02058753 | Aug 2002 | WO |
WO 02102283 | Dec 2002 | WO |
WO 03000308 | Jan 2003 | WO |
WO 03022323 | Mar 2003 | WO |
WO 03028780 | Apr 2003 | WO |
WO 03037223 | May 2003 | WO |
WO 03039612 | May 2003 | WO |
WO 03080147 | Oct 2003 | WO |
WO 03082368 | Oct 2003 | WO |
WO 04000383 | Dec 2003 | WO |
WO 04009145 | Jan 2004 | WO |