March 13, 1956
`
`a. H. smug
`SYMPATHOMIMETIC PREPARATION
`
`2,738,303
`
`Filgd July 18. 1952
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`Hg. /
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`JNVENTOR.
`RUDOLPH H. BLYTHE
`
`“"&=m.3.»'n~‘;4%-17'
`
`ATTOR NEYS
`
`Amerigen Ex. 1024, p. 1
`Amerigen Ex. 1024, p. 1
`
`

`
`United States Patent Office
`
`2,733,303
`Fatented Mar. 13, 1956
`
` 1
`
`2,73 3,303
`SYMIPA'I'I-IOMIMETIC rnnrxnsnou
`
`Rudolph H. Blythe, Llanerch, l’a., agnor to Smith,
`Kline & French Laboratories, Philadelphia, Pa., a cor-
`ponifion of Pennsylvania
`
`Application July 18, 1952, Serial No. 299,556
`
`10
`
`5 Claims.
`
`(Cl, IG7—32)
`
`_
`
`This invention relates to a sympathomimetic prepara-
`tionand, more particularly, relates to such a preparation
`providing for timed release of a sympathomirnetic agent
`overa long period of time.
`The sympathomimetic agents useful with this inven-
`tion.are organic and inorganic acid addition salts of
`(racernic)
`amphetamine,
`dexlro-amphetamine,
`d-de-
`soxyephedrine and (racemic) desoxyephedrine.
`- Exem-
`plary salts are the hydrochloride, phosphate, sulfate,
`succinate, tartrate and citrate salts.
`In accordance with this invention one of the above
`sympathomimetic agents. or a combination thereof,__is con-
`tinuously released over a long period of time through the
`use of a large number of small pellets coated with va_ri~.'
`ous thicknesses of a material slowly digestible or dis-
`pessible in the gastrointestinal tract.
`_.
`- It has been unexpectedly found that the preparation
`in accordance with this invention controls the level of sleep
`throughout the entire period of sleep. By this invention
`it is practical
`to accurately control body levels so as
`to provide a desired level of sleep. The benefits stem»
`ming from this result are numerous. Of particular-in-i_-'
`portance, it has been found that the preparation of this
`invention controls nocturnal
`seizures associated with
`epilepsy. Other involuntary reactions occurring during
`sleep, such as eneuresis, are similarly controlled. -Again,
`unexpectedly, the preparation of this invention controls the
`incidence of migraine headaches occurring on awakening.
`Further, when used as an obesity remedy,
`the con-_
`stant release of the medicament of this "invention over a
`ten to twelve hour period controls the appetite uniformly
`throughout the waking hours and hence eliminates one of
`the greatest factors contributing to obesity, namely", snack-
`ing at times other than at regular meal times.
`-
`'
`-
`Other beneficial and surprising results have also-been
`noted.
`Single doses produce jitteriness at peak body
`levels and subsequently produce mood let-down -and
`irritability on dropping to a low body level. These un-
`desi_rable__'side_etIects have been substantially eliminated.
`A'::i'un'ex'pected increase in the feeling of well being is al_so_
`achieved.
`_
`"Again,
`this invention has surprisingly resulted in a
`very great increase in ‘reliability, since it has overcome
`the problem occurring with thesingle large dosage "form
`heretofore used which frequently became struck en route
`to the intestines with the resulting delay in medication.
`Further, the use of a large number of small-pellets "results
`in their wide dispersal throughout the intestines.
`The dosage unit form in accordance with-this inven-
`tion comprises a capsule containing an initial dose of
`2, to 10 mg. of the selected sympathomimetic; which is
`ready for immediate release to the -body, being. free of
`any time-delay’ gloating. This 2 to 10 mg. of the selected
`sympathomimetic can be in the form of numerous.lun-
`eoated pellets made as described hereafter, or can be
`simply‘ the crystalline or powdered form of‘ the selected‘
`sympathomimetic. This dosage is an amount sufficient to
`substantially immediately rai_se_ thebody level
`to‘the'
`
`'40
`
`45
`
`51}
`
`55
`
`60
`
`65
`
`2
`optimum effective range. The normal single dosage is
`larger than the initial dose of this invention in order to
`achieve long action and results in numerous side efiiects
`at peak body levels, particularly jitteriness, subsequent
`let-down and depression of mood.
`In the case of a dextro-amphetamine salt this initial
`dosage preferably should be from 3 to 5 mg.
`In the
`case of a racemic amphetamine salt this iuitialdosage
`preferably should be from 5 to 10 mg.
`In the case of a
`dextro-desoxyephedrine salt this initial dosage preferably
`should be from 2 to 5 mg.
`In the case of a racemic
`desoxyephedrine salt this initial dosage preferably should
`be from 4 to 10 mg.
`'
`'
`in addition the capsule contains-from 50 to about 400,
`preferably about 100,-wax-fat covered-pellets of these-
`lected sympathomimetic, each coated pellet containing
`about the ‘same amount of drug. The wax-fat coatings
`are selected so as to provide a continuous release of_tbe
`selected sympathomirnetic in an amount to maintain sub-
`stantially constant the body level established by.th_e on-.
`coated amount of the selected sympathomimetic. _-These
`coated pellets will contain a total amount of the-selected
`sympathomimetic of from about 200% to 400%-by
`weight of the uncoated initially released dosage. _
`Where desired, a sedative, such as, for example, a
`barbiturate,
`such as 5-isoamyl-5-ethylbarbituric -acid
`(amobarbital), 5-phenyl-5-ethylbarbituric acid (pheno-
`barbital), 5 - ethyl - 5-(1-methylbutyl)-barbituric acid
`(phentobarbital),
`sodium-5—secbutyl-5-ethyl barbiturate
`(butabarbital
`sodium), 5-al1yl-5-(l-methylbutyl)-barbi-.
`turic acid (secobarbital), or N-niethyl-5-ethyl-35-phenyl-
`barbituric acid may be used iriadmixture with the
`sympathomirnetic agent
`to form the initially released
`dosage and in the was-fat coated pellets. The sedative,
`when used, should be from about 2 to 8 times the weight
`of sympathomimetic agent with which it is admixed.
`The addition of the sedative permits the use of the in-
`vention in_ patients who are very sensitive to sympa-
`tlromimetics and provides a quieting effect without -the
`depression usually associated with sedatives.
`.
`-
`The desired product can be achieved, for example,
`by combining the uncoated selected sympathomimetic
`-with a plurality of different groups of coated pellets.
`It"
`is preferred to use 3 groups as a practical matter, but.
`from two to eight groups are satisfactory.
`It has been
`found that if the required thickness of coating for re-
`lease at the end of nine hours is X and the number of
`coated groups is Y, the first coated group may have"-a
`median coating of X/Y, the next group a median coat-
`ing of 2X/Y, the next 3X/Y, and so on, depending on
`the number of groups. Following-this formula,
`it has
`been found that if either of the following techniques are
`used to make a predetermined median coating-for any
`one group,
`the coatings will vary "within the range of
`from about 30% to about 40% on either side of the
`median
`coating. A satisfactory
`approximation
`is
`achieved where the median coating weights are made up
`using the above formulae with X representing the weight
`of the median coating of the group which is released
`last.
`.
`'
`Sympathomimetic pellets in accordance "with "this in-
`vention are readily prepared by utilizing a crystalline or
`powder
`form of
`the selected sympathomimetic and
`sucrose using procedure well known to the art for mak-
`ing sugar pellets
`(see,
`for example, “Confectioners
`Journal, January 1951, page 41}. By way of more spe-
`cific example, following the teachings ofthis publica-
`tion 20.0 kg. of extended d-amphetamine sulfate is pre-
`pared from a mixture of 2.2 kg. of crystalline d-amphet-
`amine sulfate and 17.8 kg. of sucrose. About 200 pellets
`having a mesh size of from 12-40 are screened out "per
`Amerigen Ex. 1024, p. 2
`Amerigen Ex. 1024, p. 2-
`
`

`
`2,183,303‘
`
`A.
`
`3
`each gram. The d-amphetamine sulfate content of the-
`pellets is 10-12% of the total weight.
`As is also well known to the art, pellets of the selected
`sympathomimetic can be readily prepared by "placing
`small‘ sugar pellets‘ {non-pareil seeds) of from about 12'
`to 40' mesh size in a rotating coating pan and. coating
`them with a powder of the selected sympathomimetic.
`Before the addition of the powder the sugar pellets are
`wetted in the conventional manner using, for'exampI'c,.
`syrup U. S.- P., or a gelatin coating solution such as one
`having the following formula:
`
`Parts by weight
`Sucrose __________________________________ __ 1'00
`Gelatin ___________________________________ --
`8-
`Acacia ___________________________________ - -
`6
`Water ____________________________________ - _
`70
`
`CI
`
`[0
`
`'15
`
`are in random distribution, there being approximately an
`equal number of each group or type of pellet.
`As shown in Figure 2, each of the pellets 4, 6 and 8
`has a center or core 10 of the selected sympathomirnetic.
`The pellets 4 have a wax—Eat coating 12 which is of greater
`thickness than the wax-fat coating 14 of pellets 6, which
`in turn is of greater thickness than the wax-fat coating 16
`of pellets 8. Coatings 12, 14 and 16 shown in Figure 2
`represent the. median coatings of the groups formed. by
`pellets 4, 6 and 8, it being appreciated that as previously
`described the coatings of each group of pellets will vary
`in order to provide gradual release of the selected sympa-
`Ihomimetic over a ten‘ to twelve hour period.
`The following examples are illustrative of dosage unit
`forms in accordance with this invention and their prepa-
`ration:
`
`Example I
`
`If'desired', the" powdered sympathornimetic can be extended‘
`with-, for example, calcium sulfate" dihydrate, powdered
`starch or powdered acacia prior to being used ‘in the
`process. The coating operation is repeated until each
`pellet contains the desired amount of selected sympathe-
`mimetic. After the sympathomimetic pellets have been
`formed, a number of them are provided with a wax-
`fat coating" which‘ is capable of being slowly disintegrated
`in- the gastro-intestinal
`tract. Such coatings and‘ their
`applit:a'liO1't-' are all well known to the art,
`the most
`common method being to place: the desired wax—fat com-
`bination -in solution and spray it over the pellets‘ during
`the operation of .the coating pan holding the pellets.
`The wax-fat coating will preferably be a mixture of
`glyccryl monostearate and beeswax, the glyccryl mono-
`stearate being within the range of from 50 to 95% by
`weight‘ of the total coating.
`It is preferred to have the
`glyceryl rnonostearate about 90% by weight of th'e total
`coating. Any other water-insoluble ingestible wax can
`be substituted for beeswax. Thus, for example, Japan
`wax, paraflin, carnauba wax, bayberry wax, and other
`animal, insect, plant or other water-insoluble, non-toxic,
`wax-like substances, such as sterols, as, for example,
`cholesterol, are satisfactory. Any other slowly digestible
`or dispersible solids, such as slowly digestible fatty csters,.
`slowly dispersible fatty acids and slowly dispersible higher
`fatty alcohols may be used in place of glyceryl mono-
`stearate. Thus, for example, stearic acid, palmitic acid‘,
`glyceryl
`tristcarate, cetyl palmitate, diglycol stearate,
`glyceryl myristate, triethylcne glycol monostea'rate,. cetyl
`alcohol, stearyl alcohol, and the like, are satisfactory.
`It
`is-preferred to. use solid fatty acids and alcohols having
`from 12 to" 22 carbon atoms or esters of said solid‘ fatty
`acids.
`In order to. spray the wax-fat coating, the wax-fat con-
`stituent can be admixed with a suitable warmed solvent.
`such as carbon tetrachloride heated to about 60°‘ C.,_the.
`wax-fat".solids'_being within the range of from 5-25% by
`weight of the solution.
`Mixturesof the. selected sympathomlrnetic and sedative
`can be similarly prepared as pellets and coated.
`It will be appreciated" that the above described method
`is merely illustrative of how the product of this" inven-
`tion can be achieved,
`there being multitudinous other‘
`equally satisfactory methods within the scope of
`the-
`invention.
`This invention-will be further clarified by reading the
`following description in conjunction with the drawings, in
`which:.
`Figure I is a plan view of a capsule containing pellets-
`in-accordance with this invention.
`Figure 2 is a sectional view of typical pellets contained‘
`in the capsule of Figure 1.
`As shown. ir1.Figure 1 a two piece gelatin capsnle.2
`contains. pellets 3 of a selected sympathomimctic,
`the
`pellets being uncoated. Capsule 2 further contains wax-
`fat. coated sympathomimetic pellets 4, 6-and 8. As.wiIl-
`be apparent from a study of Figure 1. these various pellets
`
`20
`
`25
`
`30
`
`-10
`
`firU!
`
`60
`
`75
`
`15.5-kg. of non-pareil seeds (sugar pellets) all passing
`through" a- 12 mesh screen, 90% passing through a‘ 40'
`mesh screen and not over 10% through a 28' mesh screen,
`were placed in a 36_ inch coating pan. The pan was set
`in rotation and 240 cc. of syrup U. S. P. was added by
`slowly pouring it on the pellets to evenly wet them.
`750-
`grams of powder, consisting of 80% dextro-amphetamine
`sulfate and 20% calcium sulfate dihydrate was sprinkled
`on the wetted mass of non-pareil seeds. Thepellets were
`dried in warm air. The addition of the syrup, dextro-
`amphetamine sulfate, coating powder and the dryingwere
`repeated to apply three additional coats. Talc as a fifth
`coat was added by wetting the pellets with 240 cc. of
`syrup and‘ then dusting on 600 gm. of tale. The pellets
`were rolled until dry and the excess talc wasremoved by
`vacuum.
`20.0 kg. of dextro-amphetamine sulfate-coated
`pellets were yielded through a 12 mesh screen; One-
`quarter of the yielded pellets were removed and set aside.
`The three-quarters of the batch remaining in the coating
`pan was-coated with a wax-fat coating solution made by
`admixing 6300 gm. glyceryl monostearate, 700 gm. white
`beeswax (U. S. P.) and 21,000 cc. of carbon tetrachloride.
`The wax-fat solution was at a temperature of 70° C.
`After" applying 425 cc‘. of wax-fat solution,
`the" pellets"
`were-dried with‘ air and the coating operation‘ repeated
`until‘ the weight of the material being coated had increased
`10%, at which point one-third of the remaining batch"
`was removed‘ and dusted with" talc in a separate coating
`pan;
`The‘ remainder of the batch was further repeatedly
`co-ateri"wi'th' the wax-fat solution and dried until
`the
`weight of the material
`increased 10%, over what
`it.
`weighed when it was‘ separated from the first‘ group of
`coated pellets; atwhich time one-half of the remaining
`pellets were removed and dusted with tale in a separate
`coating. pan.
`The remaining pelletswere subiected to'.further'repea'te'd'
`coating with the wax‘-fat solution and‘ drying until’ the
`weight‘ of‘ this group of ' pellets had" increased about 10%
`over -the weight of the group from which.it had been
`separated immediately previously. These pellctswere
`then.dusted with tale. The weight of the coating of each
`group was-' found to vary about :35% of the median"
`weight 0f- coating of. the group involved.
`The four: groups of-pellets thus formed were all placed.
`in a single container and thoroughly mixed to provide
`a-uniform. mixture;
`Size No; 3 gelatin capsules were then filled with the‘
`thus-mixed pellets to provide" a total dosage-of 15 mgs;
`of" dextro'-amphetamine sulfate per capsule. Each cap"-
`sulecontained about 100 pellets.
`Each No. 3 capsule providedthe desired body']evel‘of'
`dextro-_ampheta‘mine.sulfate in about one-half hour. The
`coatedl groups provided" a continuous release-of dextro-
`amplietamine sulfate and. maintained this desired body
`level for approximately eleven hours.
`
`Amerigen Ex. 1024, p. 3
`Amerigen Ex. 1024, p. 3
`
`

`
`2,fzas_,aos
`
`5
`_
`.
`I
`_
`Example 2
`._
`The steps of Example 1' were repeated with the ex-
`ception that d-desoxyephedrine hydrochloride was sub-
`stituted for dextro-amphetamine sulfate.
`Example 3
`The steps of Example 1 were repeated with the excep-
`tion that racemic amphetamine phosphate was substituted
`for dextroamphetamine sulfate and No. 1 gelatin capsules
`used.
`
`GI
`
`10
`
`15
`
`20
`
`30
`
`4.0
`
`6
`and a salt of d'extr'o-desoxyephedrineto provide a pre-
`determined body levelof the selected sympathomimetic, a
`minimum of 50 pellets containing the selected sympath-
`omirnetic in an amount of about 200 to 400% by weight
`of said initial dosage and having ingestible coatings resist-
`‘ ant to disintegration in the gastro-intestinal tract, the coat-
`ings being of varying thicknesses to provide for the grad-
`ual release of the selected sympathotnimetic, said prepa-
`ration maintaining a substantially constant body level of
`the selected sympathomimetic over a period of about ten
`to twelve hours.
`
`-2. A.thera_peutic preparation in dosage unit form com-
`prising a capsule containing an initial dosage of from
`2 to 10 mg. of a sympathomimetic selected from the
`group consisting of a. salt of racemic amphetamine, a salt
`of dextro-amphetamine, a salt of racemic desoxyephe-
`tlrine and a salt of dextro-desoxyephedrine to provide a
`predetermined body level of the selected syn::pathorni-
`metic, 50 to about 400 pellets containing the selected
`sympalliornimetic in an amount of about 200 to 400%
`by weight of said initial dosage and having ingestible wax-
`far coatings resistant to disintegration in the gastro-in-
`testinal tract, the coatings being of varying thicknesses
`to provide for the gradual release of the selected sympa-
`tholnimetic, said preparation maintaining a substantially
`constant body level of the selected sympathornimetic over
`a period of about ten to twelve hours.
`3. A therapeutic preparation in dosage unit form com-
`prising a capsule containing an initial dosage of from 2
`to 10 mg. of a syrnpathomimetic selected from the group
`consisting of a salt of racemic amphetamine, a salt of
`dextro-amphetamine, a salt of racemic desoxyephedrine.
`and a salt of dextro-desoxyephedrine and a sedative to
`provide a predetermined body level of the selected sym-
`pathotnimetic, 30 to about 400 pellets containing the se-
`lected sympathomirrietic in an amount of about 200 to
`400% by weight of said initial dosage and a sedative and
`having ingestible waxvfat coatings resistant to disintegra-
`tion in the gastro-intestinal tract, the coatings being of
`varying thicknesses to provide for the gradual release
`of the selected sympathomimetic, said preparation main-
`taining a substantially constant body level of the selected
`sympathomirnetic over a period of about ten to twelve
`hours.
`
`4. A therapeutic preparation in dosage unit forrn com-
`prising a capsule containing an initial dosage of from 2
`to 10 mg. of sympathomimetic selected from the group
`consisting of a salt of racemic amphetamine, a salt of
`dextro-amphetamine, a salt of racemic desoxyephedrine
`and a salt of dextro-desoxyephedrine to provide a pre-
`determined body level of the selected sympathomimetic,
`a minimum of 50 pellets containing the selected sympa-
`thomimetic in an amount of about 200 to 400% by
`weight of said initial dosage and having ingestible coat-
`ings resistant
`to disintegration in the gastro-intestinal
`tract, the coatings being of varying thicknesses to provide
`for the gradual release of the selected sympathornimetic,
`each of said pellets having a substantially spherical core
`containing the selected sympathomirnetic, and said prep-
`aration maintaining a substantially constant body level
`of the selected sympathornimetic over a period of about
`ten to twelve hours.
`5. A therapeutic preparation in dosage unit form com-
`prising a capsule containing an initial dosage of from 2
`to 10 mg. of sympathornimetic selected from the group
`consisting of a salt of racemic amphetamine, a salt of
`dextro-amphetamine, a salt of racemic desoxyephedrine
`and a salt of dextro-desoxyephedrine to provide a predeter-
`mined body level of the selected sympathomimetic, a mini-
`mum of 50 pellets containing the selected syn1pathorni-
`rnetic in an amount of about 200 to 400% by weight of
`said initial dosage and having ingestible coatings resistant
`to disintegration in the gastro-intestinal tract, the coatings
`being of varying thicknesses to provide for the gradual
`release of the selected sytnpathomimetic, each of said
`
`'50
`
`L‘: GI
`
`80
`
`B5
`
`70
`
`75
`
`Amerigen Ex. 1024, p. 4
`Amerigen Ex. 1024, p. 4
`
`Example 4
`The Steps of Example 1 were repeated with the excep-
`tion that racemic desoxyephedrine citrate was substituted
`for dextroamphetamine sulfate and No. 2 gelatin cap-
`sules used.
`_
`
`Example 5
`4 kg. of nompareil seeds (sugar pellets), all passing
`through a 20 mesh screen, were placed in a 24 inch coating
`pan. The pan was set in rotation and 120 cc. of gelatin
`coating solution, having the formula set out in column 3
`herein, at 60" C. was slowly added to the pellets in such
`a manner as to evenly wet the sugar seeds.
`200 grams
`of “Dexamyl” coating powder, having the following com-
`position, was scattered over the wetted mass of sugar
`pellets:
`
`Grams
`Amoharbital (5»-isoanlyl-5-ethylbarbituric acid)“ 3250.0
`d-Amphetamine sulfate______________________
`500-9
`(Passed through #80 mesh screen)
`The pellets were then dried using warm air. The addi-
`tion of the warm gelatin coating solution. amobarbital-
`dextro-amphetamine sulfate coating powder was repeated
`13 times. The pellets were dried with warm air and loose
`powder in pan was sucked out with a vacuum. The
`product was freed of lamps by passing through a #14
`screen and Via of the yield was set aside.
`The two-thirds of the batch remaining in the coating
`pan was coated with a wax-fat coating solution, made by
`admixing 1800 grams of glyceryl monostearate, 200 grams
`of white beeswax (U. S. P.}, and 6,000 cc. of carbon tetra-
`chloride. The wax-fat solution was at a temperature of
`70° C. After applying 300 cc. of wax-fat solution, the
`pellets were dried with air and the coating operations re-
`peated until the weight of the material being coated had
`increased 12.5%. At this point, one-half of the wax-
`fat coated pellets were removed from the pan and set
`aside to dry overnight.
`The remaining pellets in the coating pan were sub-
`jected to further repeated coating, using the warm wax-
`fat solution until the batch of the material being coated
`had increased an additional 12.5% in weight. The
`coated pellets were then dried overnight.
`The three groups of pellets thus formed were all placed
`in a single container and thoroughly mixed to provide a
`uniform mixture
`No.
`1 gelatin capsules were then filled with the thus
`mixed pellets to provide a total dosage of 97.5 mg. of
`amobarbital and 15 mg. of dextro-amphetamine sulfate.
`Each capsule contained about 350 pellets.
`Each #1 capsule provided the desired body level of
`amobarbital and dextro-amphetamine sulfate in about
`45 minutes. The coated groups provided a continuous
`release of amobarbital and dextro-amphetamine sulfate
`and maintained this desired body level for approximately
`12 hours.
`It is not desired to be -limited except as set forth in the
`following claims, the above description being by way of
`illustration only.
`What is claimed is:
`1. A therapeutic preparation in dosage unit form com-
`prising a capsule containing an initial dosage of from 2
`to 10 mg. of sympathomimetic selected from the group
`consisting of a salt of racemic amphetamine, a salt of
`dextro-amphetamine, a salt of racemic desoxyephedrine
`
`

`
`2,733"-$03‘
`
`7.
`pellets. having a. subslanflalfy spherical‘ core containing
`tl-1e.selected'sympatfiomirnctii: with themedicament oVe‘r-
`lyiiag-. a substantially spherical innocuous‘ seed; and' said‘
`prl;-.p_aration maintaining a. substantially constant: hcidy.
`level" of the selected synlpathomimetid over a period‘ of
`about ten to twelve hours.
`R'eferences‘CiieIl 'm‘the'file of‘ this'pate'nt
`-
`UNITED STATES PA'.l'.ENTS-
`Miller _______________-- July 16,- 1940
`Goggin ............... __ Jan. 2, 1951
`
`2,207,990
`2;5'36,168
`
`5
`
`10
`
`2.5j‘l0.979_
`2'.5'19?4'47"
`'
`139335
`
`Cl_}mper_ efall __.........—- Felt 6. 1951
`Mfilcblrfi Gt‘ 3!‘————————...- N0?--2'5; 1952
`--
`-
`-
`-
`~
`'-
`" '~
`FOREIGN PATENTS
`2
`Australia --——_________-_ Nov.
`OTHERREFERENCES
`.19.l532i:i.‘lIE;::]_;'1'§'g'e'lNe'(.1,|'-_:',“'- volume; 2.7, No; 54;. February" 13’
`Clinical M‘edicine, September 1948, page 16.
`Chain Store Age. Drug Store Mgr.’s ed., sec. 1. June
`1949, p. 95-
`
`2, 1938
`
`Amerigen Ex. 1024, p. 5
`Amerigen Ex. 1024, p. 5