Title:
`
`Pub/Pat no:
`
`Pub/Issue Date:
`
`Inventor(s):
`
`Applicant(s):
`
`Classification:
`
`Bibliographic data
`
`PIRENZEPINE OPHTHALMIC GEL
`
`WO020964 TSA
`
`2002-12-05
`
`TAKRURI, HARUN
`
`VALLEY FORGE PHARMACEUTICALS[US]| TAKRURI
`HARLIN[US]
`
`COTD4ATLO4AT, AGIKOAOOAT, AGI K31/205AT, 461K31/42AT;
`ASIB31/S5513AL A6LK31/S5517AT, AGIK47/02AT. AGIE47/18ATL,
`ASIERA7/38AL: AGTP27/02AT; A6TP43/00AT
`
`Application number:
`
`WO2002US 13823 2002-05-01
`
`Priority number:
`
`U$20010293731P 2001-05-25:
`
`Abstract of WO02096418A1
`
`It'is a:primary objectof the present invention to provide an aqueous ophthalmic formulation, for
`treating myopia, comprising pirenzepine in combination with a pharmaceutically acceptable gel
`carrier.
`
`

`

`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATIONTREATY(PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`5 December 2002 (05.12.2002)
`
`
`
`PCT
`
`(10) International Publication Number
`WO 02/096418 Al
`
`(31)
`
`International Patent Classification’:
`
`AG6I1LK 31/42
`
`(21)
`
`International Application Number:
`
`=PCT/US02/13823
`
`(22)
`
`International Filing Date:
`
`1 May 2002 (01.05.2002)
`
`(25)
`
`Filing Language:
`
`(26)
`
`Publication Language:
`
`English
`
`English
`
`(39)
`
`Priority Data:
`60/293,731
`
`25 May 2001 (25.05.2001)
`
`US
`
`(7)
`
`Applicant (for all designated States except US): VALLEY
`FORGE PHARMACEUTICALS[US/US]; 18301 Von
`Karman Avenue,Suite 420, Irvine, CA 92612 (US).
`
`(72)
`(75)
`
`Inventor; and
`Inventor/Applicant (for US only): TAKRURI, Harun
`[US/US]; 2900 Corte Portofino, Newport Beach, CA 92660
`(US).
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ (utility model), CZ, DE (utility model), DE, DK (utility
`model), DK, DM, DZ, EC, EE (utility model), EE, ES, FI
`(utility model), FI, GB, GD, GE, GH, GM, HR, HU, ID, IL,
`IN,IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU,
`LV, MA, MD, MG, MK, MN, MW,MX, MZ, NO, NZ, OM,
`PH, PL, PT, RO, RU, SD, SE, SG, SL SK (utility model),
`SK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VN,
`YU, ZA, ZM, ZW.
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
`Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European patent (AT, BE, CH, CY, DE, DK, ES, FI, FR,
`GB, GR, TE, IT, 1-U, MC, NI, PT, SE, TR), OAPI patent
`(BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR,
`NE, SN, TD, TG).
`
`Declaration under Rule 4.17:
`
`of inventorship (Rule 4.17(iv)) for US only
`
`Published:
`
`with international search report
`
`(74)
`
`Agent: ARAI, Katsuhiro; Knobbe, Martens, Olson &
`Bear, LLP, 620 Newport Center Drive, 16th Floor, New-
`port Beach, CA 92660 (US).
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes andAbbreviations" appearing at the begin-
`ning of each regular issue ofthe PCT Gazette.
`
`WO02/096418Al
`
`(54) Title: PIRENZEPINE OPHTHALMIC GEL
`
`(57) Abstract: It is a primary object of the present invention to provide an aqueous ophthalmic formulation, for treating myopia,
`comprising pirenzepine in combination with a pharmaceutically acceptable gel carrier.
`
`

`

`WO 02/096418
`
`PCT/US02/13823
`
`PIRENZEPINE OPHTHALMIC GEL
`
`Field of the Invention
`
`Background of the Invention
`
`The present inventionis in the field of aqueous ophthalmic pharmaceutical
`
`formulations.
`
`Background of the Invention
`
`10
`
`Myopia, axial elongation of the eye, affects a large proportion of the population.
`
`Commonly, the onset of myopia is during the grade school years and progresses until
`
`growth of the eye is completed. A pharmacologic therapy which preventsor retards the
`
`developmental abnormality of myopia would represent a major advance in the treatment of
`
`myopia.
`
`15
`
`The potential use for a pharmacologic therapy has been stimulated by evidence that
`
`atropine prevents the development of myopia in humans (DA Goss. 1982. Attempts to
`
`reduce the rate of increase of myopia in young people--a critical literature review. Amz. J.
`
`Optom. Physiol. Opt. 59: 828-841.), tree shrews (McKanna JA, and VA Casagrande.
`
`1978. Reduced lens development in lid-suture myopia. Exp. Eve Res. 26: 715-723.),
`
`20
`
`stump-tailed monkeys and chicks (McBrien NA, Moghaddam HO, Reeder AP,and S.
`
`Moules. 1991a. Structural and biochemical changes in the sclera of experimentally
`
`myopic eyes. Biochem. Soc, Trans. 19: 861-865; McBrien NA, Moghaddam HO, and AP
`
`Reeder. 1991b. Atropine reduces axial elongation and myopia in visually impaired chick
`
`eyes. Invest. Ophthalmol. Vis. Sci. 32: 1203; Tigges M, Sugrue MF, Mallorga P, Stone
`
`25
`
`RA, Laties AM, Fernandes A, and PM Iuvone. 1996. Effects of atropine, ATR, and
`
`pirenzepine, PIR, on ocular growth and muscarinic cholinergic receptors in young rhesus
`
`monkeys. Invest. Ophthalmol. Vis. Sci. 37: S$326.). The clinical use of atropine as a
`
`therapy has been limited dueto its ocular side effects including glare from pupillary
`
`dilation and blurred vision due to loss of accommodation. Mild cycloplegic agents like
`
`30
`
`tropicamide have been effective in a numberofstudies but failed in other studies (Curtin
`
`BJ and DB Karlin. 1971. Axial length measurements and fundus changes of the myopic
`
`eye. Am. J. Ophthalmol. 71: 42-53.).
`
`-1-
`
`

`

`WO 02/096418
`
`PCT/US02/13823
`
`Stone and Laties found that subconjunctival injections of atropine, a nonselective
`
`muscarinic antagonist, and pirenzepine,a relatively selective M1l-antagonist marketed for
`systemic use in Europeforits anti-dyspepsia properties, attenuated axial eye growth in a
`
`chick model of myopia. M2 and M3 antagonists did not prevent axial elongation (Stone
`
`RA, Lin T, and AM Laties. 1991. Muscarinic antagonist effects on experimental chick
`
`myopia. Exp. Eye Res. 52: 755-758; U.S. Patent No. 5,112,522, Filed May 11, 1990.).
`
`Unlike atropine, a selected concentration of pirenzepine may prevent myopia without
`
`inducing unwantedside effects such as disabling mydriasis and cycloplegia.
`
`Pirenzepineis a relatively selective M1-muscarinic antagonist. It is being
`
`10
`
`investigated for its topical ocular use to moderate and halt the progressionof pediatric
`
`myopia. Administered as a solution in up to 2% strength, it was found comfortable and
`
`without systemic effects in adult volunteers (Shedden AH, Sciberras D, HutzelmannJ, and
`
`C van Nispen. 1998. Tolerability of pirenzepine ophthalmic solution in adult male
`
`volunteers. Jnvest. Ophthalmol. Vis. Sci. 39: $279.).
`
`15
`
`However, work on a solution dosage form of pirenzepine indicated a physical
`
`appearance problem. Pirenzepineis stable in solution especially at pH 5, butits
`
`degradation productis insoluble in water. Thus, the accumulation of even a small amount
`
`of degradation product over the shelf-life of the solution results in an unacceptable product
`
`due to the unattractive appearance of the precipitate in the solution.
`
`There are no “‘standard” formulation solutions for such a problem. One approachis
`
`to use arefrigerated solution. Another approachis to use a lyophilized product for
`
`reconstitution prior to dispensing to the patient. However, neither of these approachesis
`
`optimal. Lyophilization adds considerablyto the cost of the product and requires
`
`cumbersomereconstitution processes. Refrigeration is not always convenient. Thus, there
`
`is aneed for pirenzepine in a dosage form that solves the physical appearance problem
`
`using a formulation approachthat is deemeddesirable.
`
`Summary of the Invention
`
`30
`
`Accordingly, it is a primary object of the present invention to provide an aqueous
`
`ophthalmic formulation, for treating myopia, comprising pirenzepine in combination with a
`
`pharmaceutically acceptable gel carrier.
`
`

`

`WO 02/096418
`
`PCT/US02/13823
`
`Detailed Description of the Preferred Embodiment
`
`The ophthalmic aqueous gel formulation of the present invention for treating
`myopia comprises a pharmaceutically effective amount of pirenzepine in combination with
`
`a water soluble cellulose derivative.
`
`The concentration of the pirenzepine in the present formulation may range from
`
`about 0.001 to 3% (w/v), preferably about 0.005 to 2% (w/v). Pirenzepine andits
`
`dihydrochloride salt are knownintheart.
`
`Below is the structure of pirenzepine dihydrochloride:
`
`H
`
`oO
`
`NCL *)
`Oo“,
`
`N
`
`2HCl*H2O
`
`10
`
`Molecular formula:
`
`Cj9H2:NsO02*2 HCl*H20
`
`Molecular weight:
`
`442.3; 351.4 (anhydrousfree base)
`
`Chemical Names:
`
`5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H
`
`pyrido[2,3-b][1,4]-benzodiazepin-6-one dihydrochloride
`
`monohydrate
`
`15
`
`11-[(4-methyl-1-piperazinylacetyl]-pyrido[2,3-b][1,4]-
`
`benzodiazepin-6(5H)-one dihydrochloride monohydrate
`
`Cellulose derivatives are used as gelling agents in the formulationofthis invention.
`
`Most preferred is hydroxypropyl methylcellulose. Any cellulose derived gelling agent,
`
`however, that forms an aqueousgel at the desired viscosity, i.e., is soluble in water and
`
`forms a gel, can be used. Such derivatives are well known,as are their properties, and are
`
`described, e.g., in the U.S. Pharmacopeia (2000) (UNITED STATES PHARMACOPEIAL
`
`CONVENTION,INC., THE UNITED STATES PHARMACOPEIA/THE NATIONAL
`
`FORMULARY(2000)). Such gelling agents include, but are not limited to, methyl
`
`cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, and
`
`cellulose gum. Combinations of various derivatives may also be used. Cellulose based
`
`-3-
`
`

`

`WO 02/096418
`
`PCT/US02/13823
`
`gelling agents are advantageousover, for example, cross-linked acrylic polymers. For
`example, Carbopol™, a cross-linked acrylic polymer, has been used to form an aqueousgel
`containing pilocarpine hydrochloride for ophthalmic use. Cellulose based gelling agents,
`
`however, are less likely to cause adverse reactions.
`
`The formulations of the invention are substantially viscous enough to form a
`
`viscous gel. The viscosity preferably is in the range of 10,000 to 300,000 centipoise (cps),
`most preferably 15,000-200,000 cps, at about 20 °C and shearrate of 1s’ based on
`Brookfield RVDVanalysis.
`
`In the aqueousgel for ophthalmic use, the amount of cellulose based gelling agent
`
`10
`
`is preferably from about 0.5 wt. % to 5 wt. %, most preferably from about 1 wt. % to 5 wt.
`
`%.
`
`Suitable cellulose based preparations for use in the invention are commonly
`
`commercially available. For example, sources of hydroxypropyl methylcellulose that are
`
`suitable for making a cellulose based ophthalmic gel according to the invention include
`
`15
`
`Ashland Distribution Co., Asiaamerica International Inc., Biddle Sawyer Corp., Carbomer
`
`Inc., Colorcon Inc., Dow Chemical Co., FOB Chemicals, Hercules Inc., MutchlerInc.,
`
`Penta Mfg Co., Spectrum Laboratory Products Inc.,. Van Waters & Rogers Inc., and Warner
`
`Jenkinson.
`
`The formulation maycontain additional pharmaceutically inactive substances. For
`
`20
`
`example, it may contain one or more solubilizing agents, such as polysorbate 20,
`
`polysorbate 40, polysorbate 60, or polysorbate 80. The formulation may also contain a
`
`dispersant, such as lecithin or glycerin. Collagen can also be added. Other additives
`
`include cyclodextrins, in particular alpha, beta, and gamma cyclodextrins. Also, vitamin E,
`
`particularly in solubilized form, or other antioxidants, including butylate hydroxyanisole
`
`(BHA)and butylate hydroxytoluene (BHT), may be added. Someadditional examples of
`
`inactives follow: sodium chloride, cetrimide, thimerosal, benzalkoniumchloride, boric
`
`acid, sodium carbonate, potassium chloride, propylene glycol, polyoxyethylene,
`
`polyoxypropylene, polyoxyl 40 stereate, polyvinyl alcohol, poloxamer 188, sodiumcitrate,
`
`sodium thiosulfate, sodiumbisulfite, dextran 70, acetic acid, polyethylene glycol, povidone,
`
`30
`
`dextrose, magnesium chloride, alginic acid, sodiumacetate, sodium borate, edetate
`
`disodium, sodium hydroxide, and hydrochloric acid. The optimal amountofinactive
`ingredient employed in the formulation can be conventionally determined based on the
`
`particular active pharmaceutical, and the intended use.
`
`-4-
`
`

`

`WO 02/096418
`
`PCT/US02/13823
`
`The formulation of the invention can be placed in any desired dispensing device
`
`suitable for an ophthalmic formulation. The device can be an ophthalmic delivery system
`suchasasterile ophthalmic tube, for example, a conventional 3.5-5 g tube having an
`ophthalmic tip and containing the ophthalmic formulation of the invention,ora sterile,
`single or daily use container containing 0.1-0.5 g of the formulation.
`
`The pharmaceutical formulations can be administered via various routes including
`ocularinstillation, subconjuctival administration, and intravitreal administration. A typical
`
`daily dose of pirenzepine may range 6 mg orless/whole body weight, preferably 4 mg or
`
`less/whole body weight, and can be administered in a single dose or in divided doses.
`
`10
`
`However,it should be understood that the amount of pirenzepine actually administered
`
`ought to be determined in light of various relevant factors including the myopia to be
`
`treated, the chosen route of administration and the severity of the patient’s symptom; and,
`
`therefore, the above dose should not be intendedto limit the scope of the invention in any
`way.
`.
`The stability data generated on the gel and solution dosage forms show the
`
`15
`
`superiority of the gel over the solution in maintaining an acceptable physical appearance in
`
`the presence of the small amounts of the water-insoluble degradation product referred to in
`
`the background of the invention.
`
`The following Examples are intended to furtherillustrate the scope of the invention
`
`20
`
`without limiting its scope.
`
`An aqueous ophthalmic gel of 2.0% pirenzepine for the treatment of myopia
`
`according to the present invention was prepared as follows:
`
`Example 1
`
`25
`
`5-
`
`

`

`WO 02/096418
`
`PCT/US02/13823
`
`Table 1. Pirenzepine ophthalmic gel formulations.
`
`
`Ingredient 0.5% (in mg/g)|1.0% (inmg/g)|2.0% (in mg/g)
`
`
` a)
`
`Pirenzepine dihydrochloride
`(base equivalent)
`
`Hydroxypropyl Methyl-
`Cellulose (K100M, Dow
`Cheniical Co.)
`
`20
`
`
`
`Sodium Hydroxide (q.s. to pH)
`
`.
`
`Purified Water, q.s. to
`
`5
`
`0
`
`1.00g
`
`5.0
`
`1.00g
`
`Part 1: Purified water was heated to 80-90 °C. Hydroxypropyl methylcellulose
`
`(HPMC) was added and mixed until it was uniformly dispersed. The pH was adjusted to
`
`5.0 + 1.0 with sodium hydroxide, but this was not a critical step and can be eliminated.
`
`After being placed in a pressure vessel, the mixture wassterilized at 121 °C for 30-45
`
`minutes. In another embodiment, autoclaving is conducted under nitrogen when oxygen
`
`plays a role in viscosity loss upon autoclaving. The mixture was cooled to 25° to 30 °C and
`
`mixed for several hours to yield a homogenousviscous gel. Batches manufactured in the
`appropriate jacketed pressure vessel showedthat chilling Part 1 (the hydroxypropyl
`
`methylcellulose phase) to about 10 °C rather than to 25° to 30 °C after autoclaving greatly
`
`enhanced the hydration and consequently the viscosity of the gel. The gel was stored at 25°
`
`to 30 °C for several hours to aid in dissolution and then maintained at 25° to 30 °C for
`
`storage.
`
`Part 2: The rest of the ingredients were mixed and dissolved in water until a clear
`
`solution was obtained. The pH wasadjusted to 5.0 + 1.0 with sodium hydroxide, The
`
`solution was sterilized by membranefiltration (0.2 microns).
`
`10
`
`15
`
`-6-
`
`

`

`WO 02/096418
`
`PCT/US02/13823
`
`The concentration of pirenzepine is calculated based on the free base. However, we
`
`addedits dihydrochloride salt. By adjusting the pH to 5.0 + 1.0 with sodium hydroxide, the
`
`dihydrochloride salt is partially or completely converted to the monohydrochloridesalt.
`
`The solution of Part 2 was aseptically added to the gel of Part 1. Sufficient sterile
`
`water was addedto q.s. to the final weight of the batch. A final pH adjustment was made,
`
`if necessary. The batch was mixed for about 48 hours to achieve homogeneity. A gel
`
`resulted that was used to aseptically fill pre-sterilized ophthalmic containers.
`
`10
`
`Example 2
`
`The ophthalmic pirenzepine gel preparation made in Example 1 was administered
`
`as follows(the ophthalmic tip of the dispensing mechanism did not touch any surface to
`
`avoid contamination). The lowerlid of the eye to be administered was pulled down and a
`
`small amount of gel (approximately 0.25 inches) was applied to the inside of the eyelid.
`
`15
`
`The gel was applied to the afflicted eye twice per day. A gel formulation in a target
`
`population of pediatric subjects was well tolerated.
`
`Example 3
`
`Procedure for Viscosity Measurement: A Brookfield Cone and Plate Viscometer
`(Model RVDV-III+) was used to measure viscosity at about 20°C and shearrate of 1s”.
`
`The viscosities of 0.5 — 2 g samples of various gels were measured. Gels with viscosities
`
`of 5,000 to less than 600,000 cps were tested with a CP452 spindle, and other spindles are
`
`used depending onthe viscosities of the gels.
`
`25
`
`While the present invention has been described in some detail for purposes of
`
`clarity and understanding, one skilled in the art will appreciate that various changes in form
`
`and detail can be made without departing from the true scope of the invention. All patents,
`
`applications, and publications, referred to above, are hereby incorporated by reference.
`
`-7-
`
`

`

`WO 02/096418
`
`PCT/US02/13823
`
`WHAT JIS CLAIMED JS:
`
`1.
`
`An aqueous ophthalmic gel formulation for the treatment of myopia
`
`comprising pirenzepine and an amountof gelling agent effective to form an aqueous gel,
`
`said gel having a Brookfield RVDV viscosity of from about 10,000 to about 300,000 cps at
`about 20°C and sheer rate of 1s! , wherein said gelling agent is a water soluble cellulose
`
`derivative.
`
`2.
`
`A formulation according to claim 1 wherein the concentration of said
`
`pirenzepine is from about 0.001 to 3 % (w/v).
`
`3.
`
`A formulation according to claim 1 wherein the concentration of said
`
`10
`
`pirenzepine is from about 0.005 to 2 % (w/v).
`
`4.
`
`A formulation according to claim 1 wherein said water soluble cellulose
`
`derivative is soluble in said aqueous formulation at a viscosity of about 15,000 to about
`200,000 cps at about 20°C and sheerrate of 1s" .
`
`5.
`
`A formulation according to claim 1 wherein said water soluble cellulose
`
`15
`
`derivative is soluble in said aqueous formulation at a viscosity of about 100,000 cps at
`about 20°C andsheerrate of 1s"! .
`
`6.
`
`A formulation according to claim 1 wherein said amount of gelling agentis
`
`an amount of from about 0.5 to 5 wt. %.
`
`7.
`
`A formulation according to claim 1 wherein said amountof gelling agentis
`
`an amount of from about 1 to 5 wt. %.
`
`8.
`
`A formulation according to claim 1, further comprising at least one member
`
`selected from the group consisting of sodium chloride, cetrimide, thimerosal, benzalkonium
`
`chloride, boric acid, sodium carbonate, potassium chloride, propylene glycol,
`
`polyoxyethylene, polyoxypropylene, polyoxyl 40 stereate, polyvinyl alcohol, poloxamer
`
`188, sodium citrate, sodiumthiosulfate, sodium bisulfite, dextran 70, acetic acid,
`
`polyethylene glycol, povidone, dextrose, magnesiumchloride, alginic acid, sodium acetate,
`
`sodium borate, edetate disodium, sodium hydroxide, and hydrochloric acid.
`
`9.
`
`A formulation according to claim 1 wherein said gelling agent is at least one
`
`memberselected fromthe group consisting of hydroxypropyl methylcellulose, methyl
`
`30
`
`cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, and
`
`cellulose gum.
`
`10.
`
`A formulation according to claim 1 wherein said gelling agent is
`
`hydroxypropyl] methylcellulose.
`
`-8-
`
`

`

`WO 02/096418
`
`PCT/US02/13823
`
`11.
`12.
`
`An ophthalmic delivery system containing the formulationofclaim 1.
`The ophthalmic delivery system of claim 11 comprising an ophthalmic tube
`
`having an ophthalmic tip and containing said aqueousgel.
`
`13.
`
`A method of treating myopia comprising administering the formulation of
`
`5
`
`claim 1 to the eye of a humanindividual, whereby myopiais treated.
`
`14.
`
`The method of claim 13 wherein said humanindividualis a pediatric
`
`subject.
`
`15.
`
`Use of the formulation of claim 1 in the preparation of a medicamentfor the
`
`10
`
`treatment of myopia.
`16.
`Use of the formulation of claim 1 in the preparation of a medicamentforthe |
`
`treatment of myopia in a pediatric subject.
`17.
`A method of making the formulation of claim 1 comprising autoclaving a
`mixture comprised of said gelling agent and water,sterile filtering a solution comprising
`said pirenzepine and water, and aseptically admixing them.
`
`15
`
`18,
`
`The methodof the claim 17 wherein said autoclaving step is conducted
`
`under nitrogen.
`
`19,
`
`A formulation according to claim 1 wherein the formulationis selected from
`
`the group consisting of the formulations of Table 1.
`
`20.
`
`A formulation according to claim 1 in sterile form.
`
`20
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`International application No.
`PCT/US02/ 13823
`
`
`A.
`CLASSIFICATION OF SUBJECT MATTER
`IPC(7)
`: A61K 31/42
`US CLs: 514/874, 912
`According to International Patent Classification (IPC) or to both national classification and IPC
`B.
`FIELDS SEARCHED
`
`Minimum documentation searched (classification system followed by classification symbols)
`U.S.
`:
`514/874, 912
`
`WEAST
`
`Documentation searched other than minimum documentation to the extent that such documents are included in the fields
`searnhege
`
`Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
`
`Cc.
`
`DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Citation of document, with indication, where appropriate, of the relevant passages
`
`Y
`
`A,j
`5,637,604
`Database USPT on WEST,US
`(PENNSYLVANIA),LATIES et al, 10 June 1997, see the entire
`document.
`
`1-20
`
`wy
`
`[| Further documents are listed in the continuation of Box C.[| See patent family annex.
`
`Special categories of cited documents:
`later document published after the intemmational filing date or priority
`dato and not in conflict with the application but cited to understand
`
`
`"A"
`documentdefining the general state of the art which is not considered.
`the principle or theory underlying the invention
`to be of particular relevance
`
`
`wpe
`:
`’
`.
`:
`_—
`document of particular relevance; the claimed invention cannot be
`
`
`E
`sarlier document published on or after the international filing date
`considered novel or cannot be considered to involve an inventive step
`
`
`“Lt
`document which may throw doubts on priority claim(s) or which is
`when the documentis taken alone
`
`
`cited to establish the publication date of another citation or other
`:
`.
`:
`
`
`special reason (as specified)
`“x
`document of particular relevance; the claimed invention cannot be
`
`
`considered to involve an inventive step when the documentis combined
`
`
`"oO"
`document referring to an oral disclosure, use, exhibition or other
`with one or more other such documents, such combination being
`
`means obvious to a person skilled in the art
`
`
`document published prior to the international filing date but later=«gu
`
`document memberof the same patent family
`than the priority date claimed
`
`
`
`
`Date of mailing of the international search report
`Date of the actual compjetion of the international search
`07 Aus 2002
`13 JULY 2002
`
`
`
`“WBNSBobl-Hahrea AO
`Name and mailing address of the ISA/US
`Commissioner of Patents and Trademarks
`Box PCT
`
`Washington, D.C, 20231
`
`
`
`Facsimile No.
`708) 805-8230
`Form PCT/ISA/210 (second sheet) July 1998)%
`'
`
`ZOHREH FAY
`
`Telephone No.
`
`(703) 308-1233
`
`
`
`