Chemical apparatus and process disinfecting – deodorizing – preser – Control element responsive to a sensed operating condition
Reexamination Certificate
1998-08-05
2001-08-14
Low, Christopher S. F. (Department: 1653)
Chemical apparatus and process disinfecting, deodorizing, preser
Control element responsive to a sensed operating condition
C435S214000, C435S007240, C435S002000, C435S004000, C435S007800, C435S242000, C435S177000, C435S262000, C435S283100, C604S083000, C604S246000, C604S058000, C604S005010, C607S088000
Reexamination Certificate
active
06274090
ABSTRACT:
FIELD OF THE INVENTION
The following invention relates generally to the preparation of thrombin enzyme from a given unit of plasma, which is sufficiently stable that it provides rapid clotting of a fibrinogen-rich solution of clotting and adhesive proteins for more than six hours.
BACKGROUND OF THE INVENTION
Formulation of a fibrin sealant mimics the last step of the coagulation cascade wherein the enzyme thrombin cleaves fibrinogen which is then cross-linked into a semi-rigid or flexible fibrin clot. This fibrin clot adheres to wound sites, forming a barrier to fluid leaks and generates adhesion between tissues, while providing hemostatic and healing properties to the treated site.
Presently marketed, applicant's CryoSeal™ system is a device which harvests cryoprecipitated, concentrated clotting and adhesive proteins, including fibrinogen and Factor XIII from a donor's plasma in approximately one hour. The one hour cryoprecipitation harvesting, provided by the CryoSealT system, compared to the 1 to 2 day cryoprecipitation process routinely practiced in Blood Banks, means that CryoSeal™ harvesting of clotting and adhesive proteins can occur right in the perioperative theater with the patient close by, thereby avoiding the need to initiate the process days in advance.
These CryoSeal™ harvested clotting and adhesive proteins, when combined with bovine or human thrombin, forms a biological glue useful for surgical hemostasis and tissue adhesion. Commercially available thrombin, however, is generally sourced from bovine or human plasma pools, so the patient would still be at risk of negative immune reactions or contamination by infectious blood born viruses and, possibly Crutzfeld-Jacobs Disease (CJD) or new variants of CJD (NVCJD). An advantage of the CryoSeal™ cryoprecipitation invention is that the harvested clotting and adhesive proteins sourced from the patient's own blood eliminates the risk of contamination by infectious blood-borne disease when these clotting and adhesive proteins are topically applied to the patient's surgical wound sites.
It has long been understood, however, that the safest condition for a surgical patient would result from a two component biological sealant preparation in which the thrombin component would be harvested from the same donor in which the clotting and adhesive protein component was harvested—forming a fully autologous biological sealant or glue.
For instance, Cederholm-Williams PCT Patent (WO94/00566-Jan. 6 1994) clearly describes an improved fibrin glue in which the thrombin component whose preparation method,—adjusting the ionic strength of the blood and pH of the plasma to cause precipitation of a thrombin component for later resolubalization was described therein, would be combined with a fibrinogen component also sourced from the plasma of the same donor. These steps are so time consuming they become impractical for use in the perioperative theater where processing times should be less than one hour.
Three years later, in 1997, Hirsh, et al. (U.S. Pat. No. 5,643,192) follows the lead of Cederholm-Williams by also teaching a method of preparing fibrin glue in which both the fibrinogen and thrombin components of a fibrin glue are sourced from the same donor's plasma. The Hirsh patent describes a method of preparing thrombin in which the fibrinogen in the plasma is first precipitated to prepare a supernatant and then clotting the residual fibrinogen in the supernatant which is different than the method taught by Cederholm-Williams, but does not result in a commercially useful thrombin in that (see figure 1 of Hirsh, et al.) the thrombin provides clotting speeds of five seconds or less for only 4 minutes, and less than 10 seconds for only 47 minutes.
These clotting speeds are unsuitable to the needs of surgeons who could not plan their entire surgeries around the limitations of the Hirsh, et al. fibrin glue.
Surgeons predominately require a fast acting clotting time (<5 seconds) for hemostasis and tissue sealing or adhesion. Slow clotting biological glues (>5 seconds) will often be transported away from the wound site by oozing and bleeding before they can perform their function. A surgeon utilizing the Hirsh fibrin glue would be required to arrange his surgery so that the hemostasis and tissue sealing intended for treatment with the Hirsh fibrin glue would occur within the 4 minute window where the clotting time was less than 5 seconds, making the Hirsh invention totally impractical for most surgeries which predominantly require rapid hemostasis and tissue adhesion throughout the surgery, the time span of which could extend to six hours.
The following prior art reflects the state of the art of which applicant is aware and is included herewith to discharge applicant's acknowledged duty to disclose relevant prior art. It is stipulated, however, that none of these references teach singly nor render obvious when considered in any conceivable combination the nexus of the instant invention as disclosed in greater detail hereinafter and as particularly claimed.
U.S. PATENT DOCUMENTS
U.S. PAT NO.
ISSUE DATE
INVENTOR
5,648,265
July 15, 1997
Epstein
5,510,102
April 4, 1996
Cochrum
5,585,007
December 17, 1996
Antanavich, et al.
5,605,887
February 25, 1997
Pines, et al.
5,614,204
March 25, 1997
Cochrum
5,631,019
May 20, 1997
Marx
5,643,192
July 1, 1997
Hirsh, et al.
FOREIGN PATENT DOCUMENTS
PATENT NO.
ISSUE DATE
INVENTOR
WO 94/00566
January 6, 1994
Cederholm-Williams, et al.
EU 0 592 242 A1
April 13, 1994
E. R. Squibb & Sons
The other prior art listed above, not all of which are specifically discussed catalog the prior art of which the applicant is aware. These undiscussed references diverge even more starkly from the instant invention specifically distinguished below.
SUMMARY OF THE INVENTION
The instant invention addresses the long felt need for a simple, practical, fast method of preparing stable human thrombin from a donor's blood, which will provide fast clots (<5 seconds) throughout a lengthy surgery (e.g. six hours) to combine with the clotting and adhesive proteins harvested and concentrated from the same unit of blood to form a biological sealant with no patient exposure to microbial or possible CJD or NVCJD contaminations. Previous works in the field (Hirsch, et al.) exemplified a thrombin with minimal stability in that the thrombin achieved rapid clotting of fibrinogen (i.e., less than 5 seconds) during only a very narrow four to five minute time period, totally impractical for the broad range of surgeries.
The present invention provides a stable thrombin enzyme which can cause precise, repeatable fast or slow polymerization of clotting and adhesive proteins over a duration of up to six hours—throughout even a long surgery. Further, the use of clotting and adhesive proteins and thrombin all sourced from a single donor will eliminate various disease risks posed from the use of commercial fibrin glues where the fibrinogen is sourced from plasma pooled from thousands of donors and the thrombin is either sourced from a similar pool of human plasma or of bovine origin. The speed and simplicity of the production of stable thrombin by use of this invention allows it to be prepared just prior to or during operative procedures and it will provide fast clotting throughout even the longest surgeries. The thrombin produced by this invention can be diluted in saline to provide precise, slower clotting times thereby allowing any preferred time from less than four seconds to longer than 2 minutes.
The procedure of the invention is comprised of three steps, the first two of which should occur at the same time:
1. Preparing a fraction enriched in prothrombin by use of Ethanol to substantially enhance the concentration of prothrombin and at the same time remove or denature naturally occurring ingredients within plasma, such as Thrombinodulin and Antithrombin III which can bind to, block, interfere with or inhibit prothrombin or its subsequent activation to long-term functional thrombin.
2. Adding calcium ions to
Brausch Jim
Coelho Philip Henry
Godsey James H.
Kingsley Phil
Rock Gail
Kreten Bernhard
Low Christopher S. F.
Robinson Hope A.
ThermoGenesis Corp.
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