Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 1 of 54
`
`Kowa Company, Ltd. et al. v. Aurobindo Pharma Limited et al.,
`Civil Action No. 14-CV-2497 (PAC) (and related cases)
`
`
`
`
`
`Exhibit 3 to Declaration of Thomas R. Burns,
`dated May 8, 2015, in support of Defendants’
`Joint Opening Claim Construction Brief
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 2 of 54
`
`1W T158293
`
`\
`
`II'JIIL'J
`
`m&mmmm§a Emlim WQQMB
`
`UNITED STATES DEPARTMENT OF COMMERCE
`
`United States Patent and Trademark Office
`
`February 24, 2014
`
`THIS IS TO CERTIFY THAT ANNEXED IS A TRUE COPY FROM THE
`
`RECORDS OF THIS OFFICE OF THE FILE WRAPPER AND CONTENTS
`
`OF:
`
`
`
`
`
`
`
`
`Under Secretary of Commerce for Intellectual Property
`and Director of the United States Patent and Trademark Office
`
`APPLICATION NUMBER: 09/436,789
`
`FILING DATE: November 08, I999
`
`PATENT NUMBER: 6,465,4 77
`
`ISSUE DATE: October I5, 2002
`
`By Authority of the
`
`R. BLAKENEY
`
`Certifying Officer
`
`MYLAN Pitav 009406
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 3 of 54
`Case 1:14-cv702‘758-PAC Document 62-3 Filed:05‘/O8/15 Pagesof 54
`
`Express Mail Label No. TB553893373US
`
`Docket No. 46896-2
`
`STABLE PHARMACEUTICAL COMPOSITION
`
`%
`
`IELD OF THE INVENTION
`
`The present invention relates to a pharmaceutical composition with high stability
`
`and, more precisely, to a pharmaceutical composition comprising an HMG-CoA
`reductase inhibitor of which the stability varies depending on pH, especially
`(E)-3 , 5—dihydroxy-7—[4 ' -4 " ~fluorophenyl—2 ' -cyclopropyl—quinolin-3 '-yl]—
`
`5
`
`6-heptenoic acid, or its salt or ester.
`
`BACKGROUND OF THE INVENTION
`
`“fl:
`“'1.17“;
`10
`'
`
`
`It is known that 7—substituted-3,5—dihydroxy-6—heptenoic acids of a general
`formula:
`
`,
`
`'
`
`'
`
`.
`'R__
`\
`
`OH
`
`OH
`
`'
`
`OOH
`
`
`is?
`1'
`
`wherein R represents an organic group, have HMG—CoA reductase—inhibiting activity,
`
`and are useful as medicines for hyperlipemia and also as medicines for atherosclerosis
`
`(see U.S. Patent 4,739,073, U.S. Patent 5,001,255, U.S. Patent 4,751,235, U.S. Patent
`
`15
`
`4,804,679, EP—B—304,063).
`
`low pH, and require someparticular means for formulating them into preparations. A
`
`means of formulating them along with an alkaline medium, such as calcium carbonate
`
`20
`
`or sodium carbonate, into preparations with pH of 8 or higher (see U.S. Patent
`
`5,356,896), and ameans of formulating them alOng with a basic agent, such as
`magnesium oxide or sodium hydroxide, into preparations with pH of 9or higher (see
`
`MYLAN(Pitav)009412
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 4 of 54
`Case 1:14-cv;02,?58-PAC Document 62-3 FiledprOSx/O8/15 Page 4 of 54
`f" §"€,v3-E,;7
`'
`H.” =' E)
`
`_ 2 _
`
`BEE-336,298) have been proposed.
`
`(E)-3 ,5-Idihydroxy-7-[4 ' -4"-fluoropheny1—2'—cyclopropy1-quinolin—3 ' —yl]-
`6—heptenoic acid (hereinafter this may be referred to as NK-104) to be represented by a
`I 5 structural formula:
`
`
`
`10
`
`2,;
`
`"gt: ‘
`
` m
`
`é ,
`
`.5
`
`1
`
`15
`
`or its salt or ester 15 one of HMG—CoA reductase inhibitors that are represented by the
`above—mentioned general formula, and is known to be useful as armedicine for
`hyperlipemia and also as a medicine for atherosclerosis (see EP-B-304,063). NK-104 is
`
`also unstable at low pH, and many difficultles have been encountered in formulating 1t
`into preparations.
`
`20
`
`_
`
`'
`
`It has been reported that these HMG—CoA reductase inhibitors are formulated
`
`into preparations with pH 8 or higher, desirably pH 9 or higher, but unexpectedly, it
`
`has been found that NK—104 and its salts and esters are still unstable even within a high
`
`pH range.
`
`25
`
`Therefore, preparations comprising NK—104 or its salt or ester, if formulated
`
`conventional manners, have low time—dependent stability, and are problematic in that
`
`their outward appearance changes with the lapse of time. Given the situation, the
`
`development of stable preparations comprising it is desired.
`
`6 .
`
`
`MYLAN(Pitav)009413
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 5 of 54
`Case 1:14-cv-O'2758-PAC Document 62-3 Filed O§l08l15 Page 5 of 54
`
`-3-
`
`I:
`
`2
`fe‘
`
`
`
`Ta?
`
`.52, x
`it“
`
`Ul
`
`10
`
`SUMMARY OF THE INVENTION
`
`We the present inventors have variously studied in order to obtain stable
`
`pharmaceutical compositions comprising NK-104 and, as a result, have found
`
`unexpectedly that NK—104 is stable within a relatively low pH range. On the basis of
`
`this finding, we have completed the present invention.
`
`Furthermore, we investigated decomposition products of NK-104 and fluvastatin
`
`in an aqueous solution of pH3. The decomposition product of NK-104 was found in
`small quantity and consisted only of the lacto'nized form of NK—104 (see Figure 1). 0n
`the other hand, decomposition products of fluvastatin were found in relatively large
`quantities consisting of more than one ‘type of products which are believed to include an
`optical isomer and a lactonized form of fluvastatin (see Figure 2). These results
`
`15
`
`showed that the decomposition pattern and stability of NK-104 and fluvastatin were
`
`different in the same pH.
`
`In addition, we have further found that, if a basic substance is added to a
`
`pharmaceutical composition comprising NK-104 in such a manner that the aqueous
`
`20
`
`solution or dispersion of the composition may have pH of from 6.8 to 8. the
`
`composition is stable.
`
`/
`
`An'object of the present invention is to provide a pharmaceutical composition
`
`comprising NK-104, or its salt or ester, of which the aqueous solution or dispersion has
`
`25
`
`pH of from 6.8 to less than 8, preferably has pH of from 6.8 to 7.8.
`
`The active ingredient of the composition of the present invention is NK-104 to
`
`be represented by the above—mentioned structural formula. The configuration in this
`
`substance, NK—104 is not specifically defined herein.
`
`In addition, NK-104 may be in
`
`Ll
`
`
`
`MYLAN(Pitav)009414
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 6 of 54
`Case lil4-CYfQ_23758-PAC Document 62-3 File.g':‘_Q,l5/O8/15 Page 60f 54
`
`-4_
`
`any form of its salts and esters. The salts include, for example, sodium salt, potassium
`salt and calcium salt. Preferred is calcium salt of NK—lO4.
`
`BRIEF DESCRIPTION OF DRAWINGS
`
`5
`
`FIG. 1 is a histogramof NK-104 decomposition products analyzed by HPLC.
`
`FIG. 2 shows histograms of fluvastatin decomposition products analyzed by
`
`HPLC.
`
`10 DETAILED DESCRIPTION OF THE INVENTION
`
`The pH as referred to herein indicates the pH value to be determined. in such a,
`'
`manner that a unit dose of a solid preparation comprising NK—104 or its salt or ester is
`sampled and dissolved or dispersed in from 1 to 10 ml of pure water, and the pH of the
`resulting aqueous solution or dispersion is measured.
`
`I
`
`»
`
`15
`
`
`
`513:?its1-55in.
`
`A basic substance may be added to the pharmaceutical compositioncompr'ising
`
`NK-104 to control the pH of the composition, which may be any of antacidsand pH
`
`regulators including, for example, antacids such as magnesium aluminometasilicate,
`
`20
`
`magnesium aluminosilicate, magnesium aluminum silicate, magnesium aluminate, dry
`aluminum hydroxide, synthetic hydrotalcite, synthetic aluminum silicate, magnesium
`carbonate, precipitated calcium carbonate, magnesium oxide, aluminum hydroxide, and
`
`sodium hydrogencarbonate; and pH regulators such as L—arginine, sodium phosphate,
`disodium hydrogenphosphate, sodium dihydrogenphosphate, potassium phosphate, '
`'
`
`dipotassium hydrogenphosphate, potassium dihydrogenphosphate, disodium citrate,
`sodium succinate, ammonium chloride, and sodium benzoate. Of these, preferred are
`
`25
`
`magnesium aluminometasilicate, magnesium aluminosilicate, and L—arginine.
`
`Even more preferred are basic substances that may be added to the
`
`pharmaceutical composition comprising NK-104 to control the pH of the composition
`
`(3
`
`MYLAN(Pitav)009415
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 7 of 54
`Case 1:14-cy'fpg758-PAC Document 62-3 Fileflzd'935/O8/15 Page 70f 54
`
`-5-
`
`and that maintain the outward appearance and stability of said composition. These may
`be any of alkaline earth metal silicates including aluminum, and organic base
`
`,
`
`compounds. For example, alkaline earth metal means magnesium, calcium, barium, etc.
`Preferred is magnesium. Particularly preferred alkaline earth metal silicates including
`
`5
`
`aluminum are magnesium aluminometasilicate (NEUSILIN FH2), magnesium
`
`aluminosilicate (NEUSILIN A), and magnesium aluminum silicate (VEEGUM F). The
`
`preferred organic base is arginine.’ An even more preferred base is L-arginine.
`
`10
`
`15
`
`.
`
`p
`
`‘11:?
`
`The pharmaceutical composition of the present invention can be formulated into
`
`various forms of preparations, but preferred are peroral solid preparations. For
`example, the compositiOn may be formulated into tablets, granules, powders, troches,
`capsules, chewables, film—coated preparations of these, and even sugar—coated
`preparations thereof.
`
`,
`Where the pharmaceutical composition of the present invention is formulated
`into such peroral solid preparations, any of vehicles (excipients), binders, disintegrators
`and lubricants can be added thereto, if desired. The preparations may be formulated
`from the composition along with any of these, in any ordinary manner.
`
`20
`
`The vehicles (excipients) include, for example, lactose, corn starch, denatured
`
`corn starch, mannitol, sorbitol, wood cellulose, fine crystalline cellulose and calcium
`
`carbonate, which can be used either singly or as combined.
`
`The binders include,lfor example, hydroxypropyl cellulose,
`
`25 ' hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, and partial
`
`saponificates of these, which can be used either singly or as combined. Especially
`
`preferred is hydroxypropylmethyl cellulose.
`
`MYLAN(Pitav)009416
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 8 of 54
`v Case 1:14-0\/,_—Q_2.758—PAC Document 62-3 Filed'11052/O8/15 Page80f 54
`
`-6-
`
`The disintegrators include, for example, low substituted hydroxypropyl
`
`cellulose, carmellose, sodium carboxystarch, calcium Carmellose, corn starch,
`
`partially—alphatized starch, sodium closcarmellose and clospovidone, which can be used
`
`either singly or as combined. Especially preferred. is low substituted hydroxypropyl
`cellulose.
`
`5
`
`The lubricants includes, for example, magnesium stearate, stearic acid, palmitic
`
`acid, calcium stearate and talc, which can be used either singly or as combined.
`
`10
`
`The amounts of the ingredients constituting the composition of the present 7
`
`
`
`-
`
`.
`
`,
`
`15
`
`20
`
`invention are not specifically defined. For example, the amount of NK—104 or its salt
`
`or ester may be from 0.01 to 40 % by weight, preferably from 0.05 to 10 % by weight,
`
`more preferably from 0.5 to 5 % by weight; and the basic substance may be added to
`
`the composition in such an amount that is necessary for making the aqueous solution or
`
`dispersion of the composition have pH of from 6.8 to less than 8. Where the
`composition is formulated into peroral solid preparations, it is desirable that the vehicle
`is added thereto in an amount of from 30 to 95 % by weight, the binder in an amount
`of from 1 to 20 % by weight, the disintegrator in an amount of from 1 to .30 % by.
`weight, and the lubricant in an amount of from 0.5 to 10 % by weight.
`
`If further desired, any additional components, such as sweeteners, flavorings
`
`and colorants may also be added to the composition of the present invention.
`
`25
`
`The necessary amount of the basic substance to be added to the composition of
`the invention in order to make the aqueous solution or dispersion of the composition
`have pH of from 6.8 to less than 8 may be from about 1 to 6.5 % by weight or so, if
`
`magnesium aluminometasilicate (NEUSILIN FH2) is used, from about 0.5 to 2%by
`
`weight or so, if magnesium aluminosilicate (NEUSILIN A) is used, from about 2 to 8%
`
`by weight or so, if magnesium aluminium silicate (VEEGAM F) is used, or from abOut
`
`MYLAN(Pitav)009417
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 9 of 54
`Case 1:14-cy-QZ758-PAC Document 62-3 Filed 05/08/15 Page 9 of 54
`
`_7_
`
`0.01 to 0.1% by weight or so,
`
`if L—arginine is used singly. As mentioned above, it is
`
`preferable that the basic substance is used singly. However, two or more such basic
`
`substances can be used in Combination.
`
`5
`
`The composition of the present invention can be coated to give film-coated
`
`tablets or sugar-coated tablets. As the coating base, for example, usable are celluloses
`such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose; and also aminoalkyl
`methacrylate copolymer E, white sugar, and pullulan. As the plasticizer for the base,
`
`for example, usable are macrogol 6000, triethyl citrate, and triacetylpropylene glycol;
`
`10
`
`15
`
`20
`
`The pharmaceutical composition of the present invention can be produced
`according to any ordinary methods employable in producing peroral solid preparations.
`If stirring granulation is employed, this may be conducted as follows. First, NK—104,
`a basic substance, a vehicle, a binder and a disintegrator are mixed. Next, water is .
`added to the resulting mixture, then granulated with stirring, dried and dressed to give
`dry granules. Further, the granules are mixed with a lubricant, and pelletized With a '
`pelletizer into pellets. Also employable is fluidized bed granulation, which may be
`conducted as follows. First, NK-104, a basic substance, a vehicle and a disintegrator
`are mixed. Then, an aqueous solution of a binder is sprayed over the resulting mixture,
`using a fluidized bed granulator, to prepare granules. These granules are'm-ixed With a
`
`lubricant, and then pelletized with a pelletizer into pellets.
`
`Using ordinary coating devices, the pellets as produced according to the
`
`above-mentioned methods can be coated with a solution or suspension comprising a
`
`25
`
`coating base-and optionally a plasticizer and a colorant to give film—coated tablets or
`
`sugar-coated tablets.
`
`8%,
`
`MYLAN(Pitav)009418
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 10 of 54
`Case 1:14-cvj'QZ-y58-,PAC Document 62-3 Filed 05/08/15 Page 10 of 54
`
`-3-
`
`BEST MODES OF CARRYING OUT THE INVENTION
`
`V
`
`Examples of the pharmaceutical composition of the present invention are
`
`mentioned below, which, however, are not intended to restrict the scope of the
`invention.
`
`Example 1 Decomposition Products of NK-104 and Fluvastatine
`
`Decomposition‘products of NK-104 were analyzed by HPLC after incubation for
`
`two days at40°C in aqueous solution of pH 3. NK-104 produced a single product, a
`
`lactoniZed form of NK-104 .(see Figure 1). The decomposition products of fluvastatin
`
`10 were also analyzed for comparison. Fluvastatin produced many types of products,
`which are believed to include an optical isomer of fluvastatin and a lactonized form of
`fluvastatin (see Figure 2).
`
`The conditions under which NK—104 and Fluvastatine decomposition products
`15 were analyzed areas follows:
`HPLC system:
`Column:
`Mobil Phase:
`Sample:
`Detector:
`
`V
`
`20
`
`,
`
`1
`
`Type LC—10~(Shimadz, Japan) '
`DEVELOSIL ODS-HG-5 (NOMURA CHEM., Japan)
`MeOH/0.02mol/L phosphate buffer (pH 3) =7/3
`NK-lO4 or fluvastatin/pH 3/40°C, 2 days
`I
`SPD—IMIOAVP, UV 245 nm
`
`*
`
`.
`
`r
`
`_
`
`7
`
`NK—104 and fluvastatin have common B—S-dihydroxy-e-ene carboxylic acid
`
`chemical struCture. However, NK—lO4 and fluvastatin differ in the types and amount of
`
`25
`
`decomposition products. Namely, NK-104 provides a small quantity of one type of
`deComposition product while fluvastatin provides comparatively large quantities of
`different types of decomposition products (see Figures -1 and 2). Such differences show
`that stability of each depends not only on the chemical structure of B—S-dihydroxy-a-ene -
`
`carboxylic acid but also on the chemical structures that are unique to each.
`
`MYLAN(Pitav)009419
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 11 of 54
`Case 1:1'4-cv30‘2758-PAC Document 62-3 Filed‘-jQ5/O8/15 Page 11 of 54
`
`_9_
`
`In the following examples, the low substituted hydroxypropyl cellulose was
`
`commercially available as sold for a medicine additive and contains from 5—16% of
`
`-OC3HGOH group. Hydroxypropylmethyl cellulose 2910 contains 28-30% V—OCH3 and
`
`7—12% ~0C3H6—OH. Both low substituted hydroxypropyl cellulose and
`
`> 5
`
`hydroxypropylmethyl cellulose 2910‘as used in the examples are described in The
`
`Pharmacopoeia of Japan, 12th edition.
`
`Example '2:
`Herein produced were tablets each having the composition mentioned below.
`
`7
`
`'
`
` Calcium Salt of NK—104
`
`V
`Lactose
`Low Substituted Hydroxypropyl Cellulose
`
`Hydroxypropylmethyl Cellulose 2910
`
`_
`
`15
`
`Magnesium Aluminometasilicate
`p Magnesium Stearate
`Total (one tablet)
`
`‘
`
`1.0 mg
`
`- 101.4
`12.0
`
`2.0
`
`2.4
`1.2
`120.0
`
`.
`
`
`
`‘ The components of the above—mentioned composition, except magnesium
`stearate, were mixed to prepare a homogeneous powdery mixture, to which was added
`
`20
`
`a suitable amount of pure water. The resulting mixture Was granulated with surfing;
`
`" ‘
`
`'
`
`and pelletized to give pellets. Magnesium stearate was added to and mixed with these
`
`pellets, which Were then tabletted into NK-104-containing tablets.
`
`Example 3:
`
`25
`
`In the same manner as in Example 2, herein produced were tablets each having
`
`the composition mentioned below.
`
`1.0
`
`MYLAN(Pitav)009420
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 12 of 54
`Case 1:14-cy502758-PAC Document 62-3 Filgdp§l08l15 Page 12 of 54
`
`.
`
`— 10 —
`
`///——\
`-
`
`2<
`
`I
`
`Calcium Salt of NK—104
`
`' Lactose
`
`Low Substituted Hydroxypropyl Cellulose
`Hydroxypropylmethyl Cellulose 2910
`
`5
`
`Dipotassium Hydrogenphosphate
`
`Magnesium Stearate
`
`
`
`Total (one tablet)
`
`Example 4:
`
`I
`
`1.0 mg
`
`102.8‘
`
`12.0
`2.0
`
`1.0
`
`1. .2
`
`120.0
`
`In the same manner as in Example 2, herein produced were tablets each having
`
`10
`
`the composition mentioned below.
`
`Calcium Salt of NK—104
`Lactose
`_
`Low Substituted Hydroxypropyl Cellulose
`
`h
`
`Hydroxypropylmethyl Cellulose 2910
`
`L—arginine
`
`‘
`
`I
`
`1.0 mg
`103 .7
`12.0
`
`2.0
`
`0.1
`
`Magnesium Stearate
`
`Total (one tablet)
`
`1.2
`
`120.0
`
` "
`
`-
`
`'
`
`r
`
`,
`
`1
`
`I
`
`
`
`
`20 Example 5:
`
`In the same manner as in Example 2, herein produced were tablets each having. ,
`
`the composition mentioned below.
`
`Calcium Salt of NK-104
`
`I
`
`Lactose
`
`252/
`
`T
`
`Low Substituted Hydroxypropyl Cellulose
`Hydroxypropylmethyl Cellulose 2910
`
`Magnesium Aluminometasilicate
`
`_
`
`Magnesium Stearate
`
`Total (one tablet)
`
`’
`
`ll
`
`1.0 mg
`
`103.2
`
`12.0
`2.0
`
`0.6
`
`1,2
`
`120.0
`
`
`MYLAN(Pitav)009421
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 13 of 54
`Case 1:14-cv702758-PAC Document 62-3 Filed‘05/08/15 Page 13 of 54
`
`-11-
`
`Test '1:
`
`The pH of a 5 % suspension of tablets produced in any of Examples 2 to 5 (the
`
`.
`
`suspension was prepared by suspending one tablet in 2.4 ml of pure water) was
`5 measured.
`
`After having been stored at 60°C for 2 weeks, the percentage retention of
`
`calcium salt of NK-104 in the tablets was measured according to HPLC. After having .
`
`been stored at 60°C for 3 days, the change in the outward appearance of the tablets was
`
`10
`
`observed. The test results are shown in Table I.
`
`I
`
`V
`
`
`
`1
`
`Example
`
`.
`
`92%
`r
`
`_
`
`No change
`I
`
`_
`
`
`
`
`V
`
`Example 4
`
`93 %
`
`No change
`
`
`
`
`
`able 1
`
`— Example 2
`
`Example 3
`
`
`
`
`Percentage Retention of
`. Ca NK-104
`
`Change in Outward
`Appearance
`
`g
`
`97 %
`
`97%
`
`No change
`
`. No change
`
`
`
`
`
`he
`'
`v
`Control Examples 1 to 3:
`
`‘
`
`I
`
`‘ y
`
`'
`
`' 15 p
`
`In the same manner as in Example 2, herein produced were control tablets each .
`having the composition mentioned below. These tablets were tested in the same manner
`
`I
`
`'
`
`~
`
`as in Test 1, to determine the pH of; the 5 % suspension of each tablet, the percentage
`retention of Ca NK—lO47 and the change in the outward appearance of the ta-lets. The
`test results are shown in Table 2.
`
`
`MYLAN(Pitav)009422
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 14 of 54
`Case 1:14-_cv_-'QZ_=758-PAC Document 62-3 FileelpS/O8/15 Page 14 of 54
`
`-12-
`
`Control
`
`EXample
`1
`
`Control
`
`Example
`’)
`
`Control
`
`Example
`’2
`
`
`
`
`
`
`
`
`
`12.0
`
`2.0
`
`12.0
`
`t.
`
`2.0
`
`12.0
`
`2.0
`
`120;0
`
`-
`
`120.0
`
`88 %
`
`.
`,No change
`
`77%
`
`'
`
`No change
`
`-
`
`'
`
`
`
`120.0
`~
`
`38%
`
`.
`
`I
`
`No change
`'
`
`’
`
`
`
`=
`
`
`
`
`
`
`
`7
`
`.
`
`2
`
`
`
`'
`
`Table 2
`
`
`
`Low Substituted Hydroxypropyl
`Cellulose
`
`Hvd'ro'xypropyl Cellulose
`2910
`
`Total (one tablet)
`
`
`
`
`
`
`5:113
`
`Egg
`
`‘ Percentage Retention of Ca NK-104,
`after stored at 60°C for 2 weeks
`Change in Outward Appearance, after
`stored at 60°C for 3 days
`
`if"!
`
`f3:
`kin?
`M
`
`5
`
`As in Tables 1 and 2 showing thetest results, it is obvious that the percentage
`retention oi Ca NK-104 in the 5 % suspension of the composition having pH of 7 or '
`higher is high, after having been stored at 60°C for 2 weeks, while the same in the 5 %
`
`suspensron thereof havmg pH of lower than 6.6 becomes lower m
`
`pH value thereof.
`
`10
`
`Example 6, and Control Example 4:
`
`In the same manner as in Example 2, herein produced were tablets each having
`
`the composition mentioned below. These tablets were tested in the same manner as in
`
`\E.
`
`'
`
`
`MYLAN(Pitav)009423
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 15 of 54
`Case 1:14-cy70g758-PAC Document 62-3 Filed'Q5/O8/15 Page 15 of 54
`
`-13-
`
`Test 1, to determine the pH of the 5 % suspension of each tablet, and the change in the
`
`outward appearance of the tablets. The test results are shown in Table 3.
`
`Table 3 '
`
`
`
`
`
`
`
`
`* -
`
`
`
`-
`
`
`
`. .
`
`at 60°C for 3 days
`'
`
`
`
`
`_ yellowishubrown >
`
`_‘
`
`“
`
`
`
`
`
`
`£33
`
`ii"
`lwé'
`
`7
`5
`
`7
`
`_
`
`I
`Example 7, and Control Examples 5 and 6:
`herein produced were tablets each having.
`In the same mannerias in Example
`the composition mentioned below. These tablets were tested in the same manner as in »
`
`‘
`
`10 Test *1, to determine the pH of the 5 % suspension of each tablet, and the change in'the
`
`outward appearance of the tablets. The test results are shown in Table 4.
`
`I ll
`
`
`MYLAN(Pitav)009424
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 16 of 54
`Case 1:14-cv7‘02g758-‘PAC Document 62-3 Filed 05/08/15 Page 16 Of 547
`
`-14_
`
`Table 4
`
`Ca NK-104
`
`green
`
`pH of 5% Suspension
`
`_
`
`NK-104 remaining (%) after 2 weeks at 60°C
`
`Change in Outward Appearance, after 2 weeks .
`at 60°C
`
`Change in Outward Appearance, after stored at
`60°C for 3 days
`'
`
`yellowish,
`
`5 Example 8, and Control EXample 7:
`
`In the same manner as in Example 2, herein produced were tablets each having
`
`the composition mentioned below. These tablets were tested in the same manner as in
`Test 1, to determine the pH of the 5 % suspension of each tablet, and the change in the
`outward appearance of the tablets. The test results are shown in Table 5.
`
`, ,(
`
`MYLAN(Pitav)009425
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 17 of 54
`Case 1:14-Cv-0‘2‘75’8-PAC Document 62-3 Filed 05/08/15 Page 17 of 54
`
`-15_
`
`\ T
`
`able 5
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`l 101.8
`12.0
`2.0
`2.0 _
`
`
`
`
`
`Lactose
`Low Substituted Hydroxypropyl Cellulose
`Hydroxypropylmethyl Cellulose 2910
`Sodium Hydrogencarbonate
`
`Total (one tablet)
`
`120.0
`
`120.0
`
`pH of 5 % Suspension
`
`Change in Outward Appearance, after stored at
`60°C for 3 days
`
`7.8
`
`No change
`
`
`
`Changed to dark navy
`blue
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Example 9, and Control EXample 8:
`
`5
`
`In the same manner as in Example 2, herein produced were tablets each having
`
`the composition mentioned below. These tablets were tested in the same manner as in
`
`Test 1, to determine the pH of the 5 % suspension of each tablet, and the change in the
`
`outward appearance of the tablets. The test results are shown in Table 6.
`
`
`MYLAN(Pitav)009426
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 18 of 54
`Case 1:14-civng758-PAC Document 62-3 Filed‘95/08/15 Page 18 of 54
`
`_ 16 _
`
`x
`
`\\
`
`Table 6
`
`'
`
`.
`
`Ca NK~104
`
`Lactose
`
`1.0 mg
`
`1.0 mg
`
`Low substituted Hydroxypropyl Cellulose
`
`':Hydroxypropy1methyl Cellulose 2910
`Dipotassium Hydrogenphosphate
`
`Magnesium Stearate
`
`‘
`
`Total (one tablet)
`
`pH of 5% Suspension
`
`.
`
`2.0
`1.0
`
`1.2
`
`120.0
`
`7.7
`
`-
`
`1.2
`
`120.0
`
`8.4
`
`60°C for 3 days
`
`Change in Outward Appearance, after stored at
`
`N0 change.
`
`7
`
`Changed to orange
`
`Lt.
`
`5
`
`As is obvious from the test results in Tables 3 to 6, no change in the outward
`appearance of the tablets was found when the 5 % suspensions of the tablets had pH of
`
`8 or lower, even after having been stored at 60°C for 3 days, but the outward
`appearance of the tablets _changed when the 5
`suspensions of the tablets had pH Of
`higher than 8.
`r
`i
`s
`
`-
`
`10
`
`Example 10 Magnesium Aluminometasilicate
`
`In the same manner as in Example 2, herein produced were tablets each having.
`
`the composition mentioned below. The tablets were tested in the same manner as in
`
`Test 1 to determine the pH of the 5 % suspension of each tablet, but the percentage
`
`15
`
`retention of Ca NK-104 and the change in outhard appearance of the tablets were
`
`observed one month after storing at 60°C. The test results are ’shown in Table 7.
`
`f7
`
`
`MYLAN(Pitav)009427
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 19 of 54
`Case 1:14-cij0‘2g758-PAC Document 62-3 Filed 05/08/15 Page 19 of 54
`
`-17-
`
`‘
`Lactose
`Low substituted Hydroxypropyl
`Cellulose
`Hydroltypropylmethyl Cellulose
`
`101.4
`12.0
`2.0
`
`'
`
`1 n
`12.0
`12.0
`12.0
`12.0
`p
`2.0
`2.0
`2.0
`2.0
`
`.
`
`2910
`
`”
`
`Magnesium
`Aluminometasilicate
`
`r
`
`I
`
`2.4
`
`3.0
`
`12.0
`
`‘ 50.0 ,
`
`103.8
`'
`
`
`
`/
`'k "'
`
`.
`
`7
`
`.
`
`/g
`
`_
`
`2:;
`
`'
`
`H
`it.-
`
`gag;-
`
`pH of 5 % Suspension
`NK—104 remaining rate (%)
`after 1 month at 60°C
`.
`Change in Outward
`Appearance, after stored at
`60°C for 1 month
`
`97.4
`
`-
`No
`Chang
`e
`
`96.5 .
`
`'
`
`Pale
`yellow
`
`69.1
`,
`
`92.2
`
`-
`
`84.5 I
`a
`No
`Pale
`Pale
`yellow yellow change
`-
`
`
`
`5
`
`Example 11 Magnesium aluminosilicate
`In the same manner as in Example 2, herein produced were tablets each having
`the composition mentioned below. The tablets were tested. in the same manner as in
`
`Test 1 to def .rmine the pi
`
`of the 5 ‘7 sllspennign 0f each f2 let, but ThF‘ pol-Pena P
`,
`no.
`..
`- m“-
`.. H-
`- -
`. g-
`
`retention of Ca NK—104 was observed at both 2 weeks and one month after storing at
`
`10
`
`60°C and the change in outward appearance of the tablets was observed one month after,
`
`storing at 60°C. The test results are shown in Table 8.
`
`is
`
`
`MYLAN(Pitav)009428
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 20 of 54
`Case 1:14-oy-02‘758-PAC Document62-3 Filed0§l08l15 Page 20 of 54
`
`-13-
`
`Table 8
`
`—
`
`Low substituted Hydroxypropyl
`
`'
`
`12.0
`
`12.0
`
`12.0
`
`12.0
`
`12.0
`
`Cellulose
`
`\
`
`Hydroxypropylmethyl Cellulose
`2910
`/
`
`2.0
`
`2.0 _
`
`2.0
`
`2.0
`
`2.0
`
`
`
`NK—104 remaining rate (%) after
`two weeks'at 60°C
`NK—104 remaining rate (%) after
`1 month at 60°C
`
`97.3
`
`98.5
`
`97.5
`
`I 93.5
`
`91.7
`
`87.2
`
`87.4
`
`80.7
`
`86.8
`
`79.1
`I
`
`Change in Outward Appearance,
`after stored at 60°C for 1 month
`
`No
`change
`
`No
`change ‘
`
`No
`change
`
`No
`change
`
`No
`change
`
`‘
`
`g
`
`I
`
`>
`
`
`
`<
`
`.% s.
`
`-
`
`-
`
`.
`
`'
`
`,
`_
`
`’7
`
`1'”?
`
`‘
`
`p
`
`W
`
`Example 12 Magnesium aluminum silicate
`
`In the same manner as in Example 2, herein produced were tablets each having
`
`10
`
`the composition mentioned below. The tablets were tested in the same manner as in
`
`Test 1 to determine the pH of the 5 % suspension of each tablet, but the percentage
`
`retention of Ca NK-104 and the change in outward appearance of the tablets were
`
`observed one month after storing at 60°C. The test results are shown in Table 9.
`
`if?"
`
`
`MYLAN(Pitav)009429
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 21 of 54
`Case 1:14-cv-0275.8—PAC Document 62-3 Filed 05/08/15 Page 21 of 54
`
`_19-
`
`\‘g/
`
`
`Table 9
`
`
`— 1
`
`
`
`
`
`Low substituted Hydroxypropyl
`Cellulose
`
`HydroxyprOpylmethyl Cellulose
`2910
`
`Magnesium Aluminum Silicate
`
`12.0
`
`12.0
`
`12 O
`
`12.0
`
`12.0
`
`2.0
`
`2.0
`
`2.0
`
`2.0
`
`2.0
`
`3 m
`6
`.2
`
`m
`
`NK—104 remaining rate (%) after 1
`month at 60°C
`
`r 97.7
`
`98.8
`
`98 2
`
`92.5
`
`84.3
`
`
`
`
`
`
`
`
`
`
`gar:
`
`
`
`
`
`
`
`
`
`
`Change in Outward Appearance,
`after stored at 60°C for 1 month
`
`
`
`No
`change
`
`
`
`No
`change
`
`Pale
`yellow
`
`Pale
`gray
`
`Gray
`
`
`
`INDUSTRIAL APPLICABILITY OF THE INVENTION
`
`10
`
`The pharmaceutical composition of the present invention has good
`
`time-dependent stability, with having no change in the outward appearance thereof even
`
`after having been stored long. Therefore, the composition is good in medical use,
`
`especially in the form of peroral solid preparations.
`
`15
`
`90
`
`
`MYLAN(Pitav)009430
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 22 of 54
`Case 1:14-cy-QZE75'8-PAC Document 62-3 Filed 05/08/15 Page722 of 54
`
`-20;
`
`The pharmaceutical compositions of the present invention that contains NK—104
`
`or salt or ester thereof are especially useful for treating a patient, particularly a human,
`
`that is suffering from or susceptible to hyperlipemia or atherosclerosis by administering
`
`the pharmaceutical composition to such patient.
`
`Particularly preferred unitdosages have been described in the examples above.
`
`It will be appreciated the specifically preferred dosage amounts of a pharmaceutical
`composition of the invention used in a given therapy will vary according to various
`known factors such as the particular compositions formulated, the “specific compound
`
`10
`
`utilized, the mode of application, the particular site of administration, etc. Optimal
`
`‘
`
`administration rates for a given protocol of administration can be readily ascertained by
`
`those skilled in the art using conventional dosage determination tests conducted with
`
`regard to the foregoing guidelines.
`
`_ 15
`
`The invention has been described in detail with reference to preferred
`
`embodiments thereof. However, it will .be appreciated that those skilled in the art,
`
`upon consideration of this disclosure, may make modifications and improvements
`
`within the spirit and scope-of the invention as set forth in the following claims.
`
`
`
`MYLAN(Pitav)009431
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 23 of 54
`Case 1:14-cy—O‘2j758—PAC Document 62-3 File'dl'035/O8/15 Page 23 of 54
`
`-21'-
`
`What is claimed is:
`
`
`
`V A phar
`eutical composition comprising
`—[4'-4"—fluorophenyl—Z'-cyclopropyl-quinolin-3'-y1]—6—heptenoic
`E)—3,5-dihydro
`$9
`
`Q \Q acid, or its
`t or ester, and a pharmaceutically acceptable carrier, of which the
`
`
`olution or dispersion has pH of from 6.8 to less than 8.
`
`aqueou
`
`
`
`2.
`
`The pharmaceutical composition as claimed in claim 1, wherein the salt
`
`of (E)-3 ,5—dihydroxy—7— [4 ' —4 " -fluoropheny1-2 ’ —cyclopr0pyl-quinolin—3 ' -y1]
`
`—6-heptenoic acid is a calcium salt of the acid.
`
`
`The pharmaceutical comps'tionas claimed in claim 1 or 2, wherein the
`
`3.
`
`basic substance is one or more selected n the alkaline earth metal silicates including
`
`aluminum and organic base compounds
`
`
`
`4.
`
`The pharm ceut cal cmposition as claimed in claim 3, wherein the
`
`alkaline earth metal silic te in
`
`g aluminum is magnesium salt.
`
`V
`
`
`
`The pha a -
`5.
`’
`alkaline earth metal sil at in
`
`l composmon as- claimed 1n claim 4, wherein the
`
`uding - uminum is one or more selected'from
`magnesiumaluminome as‘ ic e m nesium aluminosilicate and magnesium aluminum
`
`
`- silicate.
`
` .
`
`i1 .'
`
`:‘L-‘i
`'tvrcr
`
`.
`
`:vik'
`
`‘
`
`6.
`
`The pharm ceutical composition as claimed in claim 3, wherein the
`
`organic basic compound s L—arginine.
`
`.7.
`
`The ph rmaceutical composition as claimed in claims 1 to 6, which
`
`further comprises at east one material selected from the group consisting of vehicles,
`
`V disintegrators, bind s and lubricants.
`
`
`
`MYLAN(Pitav)009432
`
`

`

`Case 1:14-Cui05‘758-PAC Document 62-3 FiledOL-i/O8/15 Page 24 of 54
`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 24 of 54
`
`_ 22 _
`
`8.
`
`The pharmaceutica composition as claimed in claim 7, which is a
`
`peroral solid preparation.
`
`9.
`
`The pharmaceu‘ ca 7
`
`' position as claimed in claim 8, wherein the
`
`pharmaceutical composition
`
`5 a vehicle of lactose.
`
`10.
`
`pharmaceutical co
`substitution.
`
`as claimed in claim 8, wherein the
`
`a oxypropyl cellulose with a low degree of
`
`
`
`
`11.
`
`he ,1. maceutical composition as claimed in claim 8, wherein the
`
`pharmaceutica c ises a binder of hydroxy propylmethyl cellulose.
`
`
`
`
`MYLAN(Pitav)009433
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 25 of 54
`Case 1:14-cfi-OZ758—PAC Document 62-3 Filefifdf'O5/O8/15 Page 25 of 54
`
`.-23-
`
`ABSTRACT
`
`_
`Disclosed is a pharmaceutical composition comprising
`(E)~3 ,5-dihydroxy—7—[4 ' —4 " —fluorophenyl-2 '—cyclopropy1-quinolin-3 ' -yl]-6-heptenoic
`
`acid, or its salt or ester, of which the aqueous solution or dispersion has pH of from 6.8
`to 8. The composition has good time-dependent stability and has no change in its
`
`outward appearance even after having been stored long.
`
`2':
`a
`ii...
`.r'r
`HF! ‘
`
`
`
`.first;
`
`
`MYLAN(Pitav)009434
`
`

`

`Case 1:14-cv-02758-PAC Document 62-3 Filed 05/08/15 Page 26