(12) United States Patent
`Dean et al.
`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US006242442Bl
`US 6,242,442 Bl
`Jun.5,2001
`
`(10) Patent No.:
`(45) Date of Patent:
`
`(54) BRINZOLAMIDE AND BRIMONIDINE FOR
`TREATING OCULAR CONDITIONS
`
`96/37203
`97/01339
`
`11/1996 (WO) .
`1!1997 (WO) .
`
`(75)
`
`Inventors: Thomas R. Dean, Weatherford; Louis
`Desantis, Jr., Fort Worth; Billie M.
`York, Conroe, all of TX (US)
`
`(73) Assignee: Alcon Laboratories, Inc., Fort Worth,
`TX (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.:
`
`09/601,634
`
`(22) PCT Filed:
`
`Dec. 7, 1999
`
`(86) PCTNo.:
`
`PCT/US99/28987
`
`§ 371 Date:
`
`Aug. 4, 2000
`
`§ 102(e) Date: Aug. 4, 2000
`
`Int. Cl? ................................................... A67K 31/535
`(51)
`(52) U.S. Cl. ....................... 514/222.8; 514/912; 514/913;
`514/226.5; 514/363
`(58) Field of Search ................................. 514/363, 222.8,
`514/226.5, 912, 913
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,890,319
`5,378,703
`5,756,503
`5,948,801
`
`6/1975 Danielewicz et a!. ............ 260/256.4
`1!1995 Dean eta!. ....................... 514/222.8
`5/1998 Burke et a!. ... ... ... ... .... ... ... ... 514/249
`9/1999 Doshi et a!.
`... ... ... ... .... ... ... ... 514/363
`
`FOREIGN PATENT DOCUMENTS
`W096/13267 * 5/1996 (WO) .
`
`OTHER PUBLICATIONS
`
`Grunwald, et al., Acta Ophthalmologica Scandinavica, vol.
`75:236-238, 1997.
`Pillunat, et al., ARVO abstract, Investigative Ophthalmology
`& Visual Science, vol. 38( 4):S276, Abstract 1284, Mar. 15,
`1997.
`Shipman, et al., ARVO abstract, Investigative Ophthalmol(cid:173)
`ogy & Visual Science, vol. 38( 4):S783, Abstract 3633, Mar.
`15, 1997.
`Koller, et al., ARVO abstract, Investigative Ophthalmology
`& Visual Science, vol. 38( 4):S776, Abstract 3592, Mar. 15,
`1997.
`Harris, et al., Acta Ophthalmologica Scandinavica, vol.
`74:569-572, 1996.
`Sugrue, et al., Journal of Ocular Pharmacology and Thera(cid:173)
`peutics, vol. 12 (3):363-376, 1996.
`Sponsel, et al., ARVO abstracts, Investigative Ophthalmol(cid:173)
`ogy & Visual Science, vol. 37(3):S269, Abstract 1238, Feb.
`15, 1996.
`Sponsel, et al. ARVO abstracts, Investigative Ophthalmol(cid:173)
`ogy & Visual Science, vol. 38(4):S439, Abstract 2078, Mar.
`15, 1997.
`* cited by examiner
`
`Primary Examiner-Zohreh Fay
`(74) Attorney, Agent, or Firm-Sally S. Yeager
`
`(57)
`
`ABSTRACT
`
`Methods and compositions for treating ocular conditions
`which find their etiology in compromised ocular blood flow
`with brinzolamide and brimonidine are disclosed.
`
`4 Claims, No Drawings
`
`Page 1 of 6
`
`SLAYBACK EXHIBIT 1007
`
`

`

`1
`BRINZOLAMIDE AND BRIMONIDINE FOR
`TREATING OCULAR CONDITIONS
`
`US 6,242,442 Bl
`
`This invention relates to the treatment of ocular diseases
`and conditions which find their etiology in compromised 5
`blood flow with novel formulations of brinzolamide com-
`bined with brimonidine tartrate and the use of brinzolamide
`and brimonidine tartrate administered separately.
`
`BACKGROUND OF THE INVENTION
`
`2
`Sciences, Vol. 38, No.4 (Mar. 15, 1997) showed that topical
`dorzolamide did not change peripapillary blood flow. A
`study by Harris, et al., Acta Ophthalmologica, 74:4896
`(1996) said dorzolamide accelerated blood velocity in the
`retina and superficial optic nerve head; and another study by
`Sugrue, et al. J. Ocular Pharm., 12 (3) 363-376 (1996)
`teaches that topical dorzolamide does not decrease blood
`flow to the iris, ciliary processes, optic nerve, or retina in
`rabbits. Sponsel has presented a few studies which suggest
`10 that topical dorzolamide has a positive effect on ocular blood
`flow. See ARVO abstracts, Investigative Ophthalmology &
`Visual Sciences, Vol. 37, No.3 (Feb. 15, 1996) and Vol. 38,
`No. 4 (Mar. 15, 1997). Healthy subjects treated with dor(cid:173)
`zolamide exhibited accelerated artereovenous passage time
`15 and an increase in optic nerve head velocity is described in
`WO 96/37203. The publication further discloses the use of
`topical carbonic anhydrase inhibitors (CAls) to increase
`retinal and optic nerve head blood velocity. Brinzolamide is
`not disclosed in any of these references.
`
`SUMMARY OF THE INVENTION
`This invention is directed to the use of brinzolamide in
`combination with brimonidine to treat ocular diseases which
`have their etiology in compromised blood flow. These
`diseases include, but are not limited to glaucoma, occlusion
`conditions, diabetic retinopathy, and ocular neovasculariza(cid:173)
`tion. These agents can be used either alone, in separate
`compositions dosed within 5 to 10 min of each other, or
`together in a single formulation.
`
`20
`
`25
`
`Brinzolamide R-( + )-4ethylamino-3,4-dihydro-2-(3-
`methoxy)propyl-2H thieno[3,2,e ]1,2thiazene-6sulfonamide-
`1,1dioxide) is a carbonic anhydrase inhibitor disclosed in
`U.S. Pat. No. 5,378,703 and sold in a topical ophthalmic
`formulation (Azopt™) for lowering elevated intra-ocular
`pressure (lOP) in patients with open-angle glaucoma or
`ocular hypertension (OH1) (Alcon Laboratories, Inc., Fort
`Worth, Tex.).
`((5-bromo-6-2-
`tartrate
`Brimonidine
`imidzolidisnylideneamino) quinozoline L-tartrate) hereinaf-
`ter "brimonidine" is a relatively selective alpha-2-adrenergic
`agonist sold in a topical ophthalmic formulation
`(Alphagan™) for lowering elevated lOP in patients with
`open angle-glaucoma or ocular hypertension (Allergan, Inc.,
`Irvine, Calif.).
`U.S. Pat. No. 3,890,319 discloses a class of compounds,
`including brimonidine, and their usefulness as antihyperten(cid:173)
`sive agents. Certain compounds in the group have also been
`disclosed for treating physical pain, anaesthetizing the cen- 30
`tral nervous system, to constrict blood vessels, treat
`ischemia, decongest nasal passages, effect reduction of one
`or more effects of an inflammatory disorder to increase
`retinal blood flow, and effect an altration in the rate of fluid
`transport in the gastrointestinal tract, see U.S. Pat. No. 35
`5,756,503 (Column 1, lines 16-22). WO 97/01339 discloses
`the use of brimonidine to protect the optic nerve and the
`retina from "noxious provocations," see page 1, first para(cid:173)
`graph.
`Oral and i.v. administration of the CAls, acetazolamide
`and methazolamide, are known to increase both ocular and
`cerebral blood flow. The dosages used to achieve meaningful
`results are relatively high and is due to a number of factors.
`These compounds have relatively low affinity for carbonic
`anhydrase II as measured by their Ki (disassociation
`constant) values and are only modest inhibitors of the
`enzyme as measured by their IC50 values. They have low
`distribution coefficients ( octanol/water determined at pH
`7.4) which is a measure of their lipophilicity. This low
`lipophilicity limits their ability to cross the blood retinal
`barrier. Finally, these compounds have relatively short half(cid:173)
`lives in whole blood. This relatively rapid elimination rate
`limits their ability to redistribute into the back of the eye and
`maintain adequate drug concentrations.
`The preclinical and clinical data for the effect of topically 55
`dosed CAis, in particular dorzolamide, on ocular blood flow
`are conflicting. Gruenwald, et al., Acta Ophthalmologica,
`75:236-238 (1997) disclosed that the use of dorzolamide has
`no effect on retinal vein blood flow in normal volunteers.
`Pillunat, et al.. ARVO abstract, Investigative Ophthalmology
`& Visual Sciences, Vol. 38, No. 4 (Mar. 15, 1997) showed
`that topical dorzolamide did not alter optic nerve head blood
`flow in healthy subjects. Shipman, et al., ARVO abstract.
`Investigative Ophthalmology & Visual Sciences, Vol. 38,
`No. 4 (Mar. 15, 1997) found that dorzolamide did not alter
`the choroidal pressure flow relationships. Koller, et al.,
`ARVO abstract, Investigative Ophthalmology & Visual
`
`DESCRIPTION OF PREFERRED
`EMBODIMENTS
`Brimonidine is a potent and relatively selective a 2 agonist
`which has been shown to effectively lower lOP in rabbits,
`monkeys and man. Upon topical ocular administration bri(cid:173)
`monidine causes vasoconstriction in scieral vessels.
`However, brimonidine does not appear to be a vasoconstric(cid:173)
`tor in vessels in the back of the eye. While brimonidine is a
`relatively safe compound it has been shown to cause the side
`40 effects of sedation and ocular hyperemia in an allergic like
`reaction in some patients. These side effects are thought to
`be due to the relatively high concentration of the drug
`administered topically. The sedation like side effects are
`believed to be caused by the drug crossing the blood brain
`45 barrier and triggering the sedative effects. The mechanism
`by which brimonidine causes hyperemia is not well under(cid:173)
`stood. It is likely that the frequent instillation of relatively
`high drug concentrations causes this side effect. Thus, low(cid:173)
`ering the overall dose ofbrimonidine while maintaining lOP
`50 control would be advantageous.
`Combinations of brimonidine and brinzolamide represent
`a novel approach to producing potent and long lasting lOP
`lowering medications with fewer side-effects than observed
`when these are administered alone.
`When two separate formulations of brinzolamide and
`brimonidine are used, the preferred administration sequence
`is brimonidine first and brinzolamide second. In this case,
`brimonidine serves to constrict ocular vessels and thereby
`reducing the flux of blood through the anterior portion of the
`60 eye. When brinzolamide is administered the reduced circu(cid:173)
`lation in the eye should result in an increase in the bioavail(cid:173)
`ability of the CAl. Overall this sequence is expected to result
`in an increase in efficacy and duration of actions thereby
`reducing the frequency of administration (i.e., from tid to
`65 bid). This would also result in improved patient compliance.
`When a single formulation of both agents is used the
`above advantages are believed to apply. In addition, the
`
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`

`US 6,242,442 Bl
`
`5
`
`4
`one drop of vehicle for one-week. Optic nerve head (ONH)
`blood flow was then measured by LDF in the anesthetized,
`spontaneously breathing felines. The experiment was
`repeated after a one-week interval in the same cats to assess
`the reproducibility of the technique. Averaging the two
`blood flow measurements showed that ONH flow was
`increased by an average of 21.8% over that measured in the
`control group. In anesthetized, ventilated cats, ONH blood
`flow was increased on average 16.5%±8% at 60 minutes
`following a single topical dose. Intravenous brinzolamide
`produced a 46±17% increase (p~0.05) in ONH blood flow;
`ONH vascular resistance, a measure of vascular tone in the
`ONH microcirculation, was reduced by 35±8% (p~0.05).
`
`3
`novel compositions contemplated have relatively high vis(cid:173)
`cosity and are expected to increase the retention of brimoni(cid:173)
`dine in the cul-de-sac of the eye. The net impact allows for
`lowering the dose of brimonidine.
`It is well established that blood flow is impaired in
`glaucoma; many researchers think there is a direct relation(cid:173)
`ship between insufficient blood flow and neural damage.
`Thus, improving blood flow should decrease the rate of
`damage. Clearly, any vascular occlusive event in the eye
`leads to damage to the region with restricted blood flow; 10
`improving blood flow in this region or in close-by tissue
`should minimize the severity of this damage. The standard
`treatment for advanced diabetic retinopathy is retinal pho(cid:173)
`tocoagulation; this is thought to be effective by decreasing
`oxygen demand and thus decreasing the hypoxic signal 15
`released by the oxygen-starved tissue that leads to angio(cid:173)
`genesis. Treatment that improves oxygen supply by improv(cid:173)
`ing ocular blood flows as proposed here would be preferable
`to this tissue destruction and should lead to the same benefit.
`Neovascularization of the retinal, choroidal, or iridial tissues
`arises by the action of angiogenic substance(s). Generally,
`these angiogenic substances are produced in ocular tissue
`which is suffering from hypoxia. Thus, it is believed that
`enhancing blood flow in these tissues will effectively pre(cid:173)
`vent or stop neovascularization by alleviating the hypoxia. 25
`Brinzolamide is a carbonic anhydrase inhibitor which has
`been found to be effective in lowering the elevated intraocu-
`lar pressure associated with ocular hypertension and glau(cid:173)
`coma. The distribution coefficient, IC50 and Ki values for
`brinzolamide are 6.56, 3.19 nM and 0.13 nM respectively.
`Further studies discussed in the examples show that it
`penetrates to the back of the eye following topical ocular
`delivery and is also effective in increasing blood flow in
`ocular tissues including the optic nerve head. Ocular dis(cid:173)
`eases and conditions which find their etiology in compro(cid:173)
`mised blood flow can be treated with brinzolamide. These
`diseases and conditions include glaucoma including but not
`limited to primary open angle glaucoma (POAG) and nor(cid:173)
`mal tension glaucoma also known as low tension glaucoma
`or angle closure glaucoma, occlusion conditions, such as, 40
`branch vein occlusion and retinal artery or vein occlusion,
`diabetic retinopathy, and retinal or iris neovascularization
`from any cause.
`The distribution coefficients for other well known CAls, 45
`methazolamide, acetazolamide and dorzolamide, are 0.64,
`0.23, and 1.72 respectively. The IC50 values (determined
`against human carbonic anhydrase II) are 12.5 nM, 9.04 nM,
`and 3.74 nM respectively. The Ki values are 29.3 nM, 33.8
`nM, and 0.51 nM respectively. Dorzolamide is significantly 50
`more potent than either acetazolamide or methazolamide as
`measured by Ki and IC50 and is only slightly, -2x, more
`lipophilic as measured by its distribution coefficient. Thus,
`it is not expected to efficiently cross the blood retinal barrier.
`None of these compounds have the requisite characteristics 55
`to efficiently improve ocular blood flow. Thus there is a need
`to identify superior agents to improve blood flow to the back
`of the eye.
`The effect of brinzolamide on regional microvascular
`ocular blood flow of the cat and rabbit was evaluated using
`the laser Doppler flowmetry (LDF) and colored microsphere
`techniques as shown in Examples 1-3. Example 4 describes
`the tissue distribution of brinzolamide in the eyes of rabbits.
`
`EXAMPLE 2
`Intravenous administration of 0.5, 2.5, and 5 mg/kg of
`brinzolamide to anesthetized, ventilated New Zealand albino
`rabbits produced a significant dose-related increase in total
`ocular blood which reflected increases in blood flow to the
`20 tissues of the eye measured by the colored microsphere
`technique. Optic nerve head blood flow, measured by LDF,
`was also increased above baseline. Ocular vascular tone was
`reduced since total ocular vascular resistance was decreased
`dose-dependently. In this experiment it was also possible to
`compare blood flows of the normal eye to the contralateral
`eye that was mildly hypofused due to unilateral carotid
`occlusion. Baseline blood flow was 657±36 ,ul/min in the
`hypo fused eye. Intravenous doses of brinzolamide produced
`similar increases in total ocular blood flows of 29%, 68%,
`30 and 90% in normal eyes and increases of 21%, 64%, and
`90% in hypofused eyes. The highest intravenous brinzola(cid:173)
`mide dose returned regional blood flows to the hypofused
`eye to baseline levels found in the normal eye. Percentage
`wise, the blood flow increase to the hypofused eye was
`35 greatest to iridial, ciliary, and choroidal tissues, respectively.
`
`EXAMPLE 3
`Topical ocular administration of brinzolamide 2%
`suspension, one drop twice daily, in a one-week multidose
`crossover study in nine acepromazine tranquilized Dutch(cid:173)
`Belted rabbits significantly increased blood flow to the optic
`nerve head as measured by LDF. Baseline values for optic
`nerve head (ONH) blood flow, blood pressure, heart rate,
`intraocular pressure (lOP), and acid-base balance were
`determined before treatment began and 7-14 days after
`completion of a treatment arm; baseline values for the
`measured variables did not significantly change during the
`experiment. Treatment measurements were made 90 minutes
`after the last dose on day eight. Optic nerve head blood flow
`and measured systemic variables were not changed by
`vehicle treatment. Minimal disturbance of acid-base balance
`occurred in brinzolamide treated animals. lOP was
`decreased by 16.8±2.2% (p<0.05 versus vehicle; p<O.OOl
`versus baseline) and ONH blood flow was significantly
`increased by 11.2±1.6% (mean±SEM; p<0.05) following
`topical brinzolamide. It is established that the vasculature of
`the ONH responds to increases in arterial 0 2 or C0 2 tension
`by a reduction or an enhancement of ONH blood flow
`respectively. Since the blood flow increase in this experi-
`60 ment occurred when arterial C0 2 tension was below and 0 2
`tension was above baseline levels. It can be suggested that
`brinzolamide has a local ocular action on the optic nerve
`head vasculature independent of effects on blood gases.
`
`EXAMPLE 1
`
`In a topical study, four cats were bilaterally treated twice
`a day with one drop of 1% brinzolamide and three cats with
`
`65
`
`EXAMPLE 4
`The tissue distribution of brinzolamide was determined in
`New Zealand Albino (NZW) and Dutch belted rabbits after
`
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`

`US 6,242,442 Bl
`
`5
`
`5
`a single topical ocular dose of 1% 14C-brinzolamide. In both
`species brinzolamide was found to slowly redistribute into
`the retina. The T max values in the retina were 20 days and 36
`days in the NZW and Dutch belted rabbits respectively.
`These data demonstrate that brinzolamide is slowly deliv-
`ered to the retina over time and likely comes for the red
`blood cells. The Cmax values were 0.330 and 0.338 ?g
`equivalents/g in the NZW and Dutch belted rabbits respec(cid:173)
`tively. These data show that the drug distribution is not
`influenced by the presence/absence of pigment and is not 10
`simply a measure of red blood cell concentration.
`Brinzolamide is preferably formulated as a topical oph(cid:173)
`thalmic suspension with a pH of about 4.5-7.8. It will
`normally be contained in the formulation at a concentration
`of 0.1%-10% by weight preferably 0.25% ~5.0% by weight. 15
`Thus, for topical presentation 1-3 drops of these formula(cid:173)
`tions would be delivered to the surface of the eye 1-4 times
`a day according to the routine discretion of a skilled clini(cid:173)
`Cian.
`Brimonidine is preferably formulated as a topical oph- 20
`thalmic solution with a pH of about 4.5-7.8. It will normally
`be contained in the formulation at a concentration of
`0.01%--0.2% by weight, preferably 0.1%--0.2% by weight.
`Thus, for topical presentation 1-3 drops of these formula(cid:173)
`tions would be delivered to the surface of the eye 1-4 times 25
`a day according to the routine discretion of a skilled clini(cid:173)
`Cian.
`The combinations of brinzolamide and brimonidine are
`preferably formulated as topical ophthalmic suspensions 30
`with a pH of about 6.5 to 7.8. Brinzolamide will normally be
`contained in the formulations at concentrations of
`1.0%-2.0% by weight. preferably 1.0% by weight. Brimoni(cid:173)
`dine will normally be contained in the formulations at
`concentrations of 0.01%-0.2% by weight, preferably 35
`0.05%--0.2% by weight. For these formulations 1-2 drops
`would be delivered to the surface of the eye 1-3 times a day
`according to the routine discretion of a skilled clinician.
`The following example is the preferred brinzolamide
`formulation for use according to the present invention.
`
`40
`
`6
`
`-continued
`
`Ingredient
`
`Benzalkonium Chloride
`Sodium Chloride
`odium Hydroxide/Hydrochloric Acid
`Purified Water
`
`Percent w/v
`
`0.01 + 5% excess
`0.25
`pH 7.5
`QS 100
`
`EXAMPLE 7
`
`Ingredient
`
`Brinzolamide
`Brimonidine Tartrate
`Mannitol
`Carbopol 974P
`Tyloxapol
`Disodium EDTA
`Benzalkonium Chloride
`Sodium Chloride
`Sodium Hydroxide/Hydrochloric Acid
`Purified Water
`
`Percent w/v
`
`1.0
`0.05
`3.3
`0.4
`0.025
`0.01
`0.01 + 5% excess
`0.25
`pH 6.5
`QS 100
`
`EXAMPLE 8
`
`Ingredient
`
`Brinzolamide
`Brimonidine Tartrate
`Mannitol
`Carbopol 974P
`Tyloxapol
`Disodium EDTA
`Benzalkonium Chloride
`Sodium Chloride
`Sodium Hydroxide/Hydrochloric Acid
`Purified Water
`
`Percent w/v
`
`1.0
`0.2
`3.3
`0.4
`0.025
`0.01
`0.01 + 5% excess
`0.25
`pH 7.5
`QS 100
`
`EXAMPLE 5
`
`EXAMPLE 9
`
`Ingredient
`
`Brinzolamide
`Mannitol
`Carbopol 974P
`Tyloxapol
`Disodium EDTA
`Benzalkonium Chloride
`Sodium Chloride
`Sodium Hydroxide/Hydrochloric Acid
`Purified Water
`
`Percent w/v
`
`1.0
`3.3
`0.4
`0.025
`0.01
`0.01 + 5% excess
`0.25
`pH 7.5
`QS 100
`
`EXAMPLE 6
`
`Ingredient
`
`Brinzolamide
`Brimonidine Tartrate
`Mannitol
`Carbopol 974P
`Tyloxapol
`Disodium EDTA
`
`Percent w/v
`
`1.0
`0.4
`3.3
`0.4
`0.025
`0.01
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Ingredient
`
`Brinzolamide
`Brimonidine Tartrate
`Mannitol
`Carbopol 974P
`Tyloxapol
`Disodium EDTA
`Benzalkonium Chloride
`Sodium Chloride
`Sodium Hydroxide/Hydrochloric Acid
`Purified Water
`
`Percent w/v
`
`1.0
`0.02
`3.3
`0.4
`0.025
`0.01
`0.01 + 5% excess
`0.25
`pH 6.5
`QS 100
`
`EXAMPLE 10
`
`Ingredient
`
`Brimonidine Tartrate
`Polyvinyl Alcohol
`Benzalkonium Chloride
`Citric Acid
`
`Percent w/v
`
`0.2
`1.4
`0.005%
`0.042
`
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`

`US 6,242,442 Bl
`
`7
`
`-continued
`
`Ingredient
`
`Sodium Citrate
`Sodium Chloride
`Sodium Hydroxide/Hydrochloric Acid
`Purified Water
`
`Percent w/v
`
`0.53
`0.69
`QS pH 6.3-6.5
`QS 100
`
`We claim:
`1. A method for treating ocular conditions selected from
`the group consisting of occlusion conditions, diabetic
`retinopathy, and neovascularization which comprises
`
`5
`
`8
`administering a pharmaceutically effective amount of brin(cid:173)
`zolamide and brimonidine.
`2. The method of claim 1 wherein the brinzolamide and
`brimonidine are dosed separately.
`3. The method of claim 1 wherein the brinzolamide and
`the brimonidine are dosed simultaneously in a single for(cid:173)
`mulation.
`4. A composition for treating ocular conditions selected
`from the group consisting of occlusion conditions, diabetic
`10 retinopathy, and neovascularization comprising pharmaceu(cid:173)
`tically effective amounts of brinzolamide and brimonidine.
`
`* * * * *
`
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`

`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`
`PATENT NO.
`DATED
`INVENTOR(S)
`
`: 6,242,442 Bl
`:June 5, 2001
`:Thomas R. Dean, Louis DeSantis, Jr., and Billie M. York
`
`Page 1 of 1
`
`It is certified that error appears in the above-identified patent and that said Letters Patent is
`hereby corrected as shown below:
`
`Title page,
`Item [86], add application claims priority from "PCT/US99/28987 filed December 7,
`1999, which claims priority from U.S. application No. 60/112,750 filed December 17,
`1998.
`
`Signed arid Sealed this
`
`Ninth Day of April, 2002
`
`Attest:
`
`Attesting Officer
`
`JAMES E. ROGAN
`Director of the United States Patent and Trademark Office
`
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`