Case 1:21-cv-00425-UNA Document 1-1 Filed 03/24/21 Page 1 of 17 PageID #: 21
`Case 1:21-cv-00425—UNA Document 1-1 Filed 03/24/21 Page 1 of 17 PageID #: 21
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`EXHIBIT A
`EXHIBIT A
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`

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`Case 1:21-cv-00425-UNA Document 1-1 Filed 03/24/21 Page 2 of 17 PageID #: 22
`case 1:21'CV'00425'UNA D°°“"‘e“t 1'11lllll11111111111111Illlllllilllfll1|IllI|Illlllflflllfillllllfllll2
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`USOlO842780B2
`
`(12) Unlted States Patent
`(10) Patent No.:
`US 10,842,780 B2
`
`Takaishi et al.
`(45) Date of Patent:
`Nov. 24, 2020
`
`(54) PHARMACEUTICAL COMPOSITION FOR
`MODIFIED RELEASE
`.
`(71) Applicant: ASTELLAS PHARMA INC., Tokyo
`(JP)
`
`(72)
`
`Inventors: Yuuki Takaishi, Tokyo (JP); Yutaka
`Takahashi Tokyo (JP) Takashi
`N. h.
`t T k
`JP ’SD . k
`‘5 ”a 0:
`0 YO (
`)3
`a15“_ e
`Murayama, Tokyo (JP); Emlko
`Murayamas Tokyo (JP); Soichiro
`Nakamura, Tokyo (JP); Kazuhiro
`Sako, Tokyo (JP)
`
`(73) Assignee: ASTELLAS PHARMA INC., Tokyo
`(JP)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 15403) by 0 days.
`
`.
`(21) Appl. No.. 15/432,854
`.
`Flledi
`
`(22)
`
`Feb- 14, 2017
`
`(65)
`
`Prior Publication Data
`
`US 2017/0231965 A1
`
`Aug. 17, 2017
`
`Related US. Application Data
`
`(51)
`
`(63) Continuation of application No. 12/568,313, filed on
`Sep. 28’ 2009’ now abandoned.
`(60) Provisional application No. 61/101,338, filed on Sep.
`30 2008.
`5
`Int. Cl.
`jig; ‘3/12/‘0‘26
`A61K 9/28
`(52) US. Cl.
`CPC .......... A61K 31/426 (2013.01); A61K 9/2009
`(2013.01); A61K 9/2013 (2013.01); A61K
`9/2031 (2013.01); A61K 9/2054 (2013.01);
`A61K 9/2095 (2013.01); A61K 9/2853
`(2013.01); A61K 9/2866 (2013.01)
`(58) Field of Classification Search
`None
`
`(388281)
`(
`‘
`)
`(200601)
`
`See application file for complete search history.
`
`56
`
`(
`
`)
`
`C't d
`R f
`l e
`e erences
`U.S. PATENT DOCUMENTS
`
`§2£€§g :
`,
`,
`6,204,285 B1
`6,346,532 B1
`6,368,628 B1
`6,436,441 B1
`6,699,503 Bl
`g’gg’gfi 3%
`2001/0006982 A1
`2003/0198619 A1
`2003/0203024 A1
`2004/0033263 A1
`
`JGeiEGIY
`1(5); 133(7)
`1
`1 1s et a .
`3/2001 Fabiano et a1.
`2/2002 Maruyama et a1.
`4/2002 Seth
`8/2002 Sako et a1.
`3/2004 $21k? et 31~
`£383): $2E?$?;t :11'
`7/2001 Cruz et a1.
`10/2003 Dong et a1.
`10/2003 Sako et a1.
`2/2004 Seroff et a1.
`
`2004/0213845 A1
`2005/0100602 A1
`2005/0100603 A1
`2005/0261328 A1
`2005/0287185 A1
`2006/0099257 A1
`2006/0115540 A1
`
`2008/0275076 A1
`2009/0011018 A1
`2009/0093529 A1
`2010/0144807 A1
`
`10/2004 Sugihara et a1.
`5/2005 Sako et a1.
`5/2005 Sako et a1.
`11/2005 Wienrich
`12/2005 Wong et 31.
`5/2006 Langridge et a1.
`6/2006 Takasu et a1.
`
`11/2008 Holm et al.
`1/2009 Kondo et 31.
`4/2009 Takasu et a1.
`6/2010 Takaishi et a1.
`
`FOREIGN PATENT DOCUMENTS
`
`AU
`CA
`
`CA
`CA
`CA
`CA
`CA
`CA
`CA
`CA
`EP
`EP
`EP
`EP
`EP
`
`EP
`GB
`JP
`
`199889288 B2
`2263659 A1
`
`5/1999
`2/1998
`
`2315235 A1
`2336853 A1
`2328348 A1
`2507266 A1
`2144077 C
`2490299 C
`2305802 C
`2387705 C
`1 205 190 A1
`1 440 969 A1
`1 559 427 A1
`1 974 725 A1
`2 345 410 A1
`
`6/ 1999
`1/2000
`10/1999
`6/2004
`5/2005
`8/2008
`11/2008
`6/2009
`5/2002
`7/2004
`8/2005
`10/2008
`7/2011
`
`2 554 168 Bl
`2356197 A
`S40-2053
`
`1/2018
`5/2001
`2/1965
`(Continued)
`
`OTHER PUBLICATIONS
`Daewoong Pharmaceutical C0., Ltd.; Petitioner’s Brief; 2017 Dang
`473 Patent InValidAtiOIl Action; Feb 21, 2017.
`Australian Patent Application No. 2009300752, Examination Report,
`dated Dec. 14, 2012, 11 pages.
`Canadian Patent Application No. 2,740,342, Office Action, dated
`Jun. 3, 2013, 3 pages.
`Canadian Patent Application No. 2,740,342, Second Ofiice Action,
`dated Feb. 14, 2014, 2 pages.
`Chinese Patent Application No. 2009801386919, Decision on
`Rejection, dated Feb. 14, 2014, 5 pages.
`(Continued)
`
`Primary Examine/’7 Jeffrey S Lundgren
`Assistant Examiner 7 Michael J Schmitt
`(74) Attorney, Agent, or Firm iVenable LLP
`
`(57)
`
`ABSTRACT
`.
`.
`.
`.
`A pharmaceutical composmon for modified release, com-
`prising (1)
`(RH-(2-amin0thiaz01-4-y1)-4'-[2-[(2-hydroxy-
`2-phenylethyl)amino]ethyl]acetic acid anilide, or a pharma-
`ceutically acceptable salt thereof, (2) at least one additive
`-
`-
`-
`-
`Wthh ensures penetration of water into the pharmaceutical
`composmon and Wthh has a solubility such that the volume
`of water required for dissolving 1 g of the additive is 10 mL
`or less, and (3) a hydrogel-forming polymer having an
`average molecular weight of approximately 100,000 or
`more, or a viscosity of 12 mPa~s or more at a 5% aqueous
`5011111011 at 25° C 15 (115010539
`
`25 Claims, 1 Drawing Sheet
`
`

`

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`Case 1:21-cv-OO425-UNA Document 1-1 Filed 03/24/21 Page 3 of 17 PageID #: 23
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`US 10,842,780 B2
`
`Page 2
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`(56)
`
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`

`

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`

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`US. Patent
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`Nov. 24,2020
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`US 10,842,780 B2
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`US 10,842,780 B2
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`1
`PHARMACEUTICAL COMPOSITION FOR
`MODIFIED RELEASE
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`The present application is a continuation of US. patent
`application Ser. No. 12/568,313, filed Sep. 28, 2009, which
`application claims the benefit of priority to US. Patent
`Application No. 61/101,338, filed Sep. 30, 2008, the teach-
`ings of which are hereby incorporated by reference.
`
`TECHNICAL FIELD
`
`The present invention relates to a pharmaceutical com-
`position for modified release capable of reducing food
`elfects, which are observed in conventional
`tablets, by
`combining an active ingredient with specific ingredients to
`control a releasing rate of the active ingredient.
`More particularly, the present invention relates to a phar-
`maceutical composition comprising (R)-2-(2-aminothiazol-
`4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic
`acid anilide or a pharmaceutically acceptable salt thereof, an
`additive which ensures penetration of water into the phar-
`maceutical composition (hereinafter sometimes referred to
`as a hydrophilic base), and a polymer which forms a
`hydrogel, in which the changes in AUC and Cmax caused by
`the intake of food can be decreased by controlling a releas-
`ing rate of the active ingredient.
`
`BACKGROUND ART
`
`(R)-2-(2-aminothiazol-4-yl)-4'—[2-[(2-hydroxy-2-phenyl-
`ethyl)amino]ethyl]acetic acid anilide has been created by
`Astellas Pharma Inc., and it has been reported that this
`compound has not only both an activity of promoting insulin
`secretion and an activity of enhancing insulin sensitivity, but
`also an antiobestic activity and an antihyperlipemic activity
`based on an activity of selectively stimulating a [33 receptor,
`and is useful in treating diabetes (see, for example, patent
`literature 1).
`Further, it has been reported that the compound can be
`used as a therapeutic agent for overactive bladder, such as
`overactive bladder accompanied by prostatic hyperplasia, or
`overactive bladder accompanied by urinary urgency, urinary
`incontinence, and urinary frequency (see, for example, pat-
`ent literature 2).
`A clinical trial of (R)-2-(2-aminothiazol-4-yl)-4'—[2-[(2-
`hydroxy-2-phenylethyl)amino]ethyl]acetic acid anilide in
`the form of conventional formulations revealed disadvan-
`
`tages, for example, that pharmacokinetic data unexpectedly
`varied according to the presence or absence of the intake of
`food (not published). For example, the rate of decrease of
`Cmax in a fed state was 67%, and the rate of decrease of
`AUC in the fed state was 47%, in comparison with those in
`a fasted state. In this case, Cmax in the fasted state was three
`times higher than that in the fed state. These problems are
`considered to be raised by, for example,
`the changes in
`pharmacokinetics caused by food, and therefore, the devel-
`opment of a formulation capable of avoiding the effects by
`food intake is desired.
`
`As a technique of preparing a formulation for modified
`release, a hydrogel sustained release tablet containing an
`additive which ensures penetration of water into the tablet,
`and a hydrogel-forming polymer is disclosed (see,
`for
`example, patent literature 3).
`
`5
`
`10
`
`15
`
`20
`
`25
`
`3 0
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`
`However, patent literature 3 does not refer to (R)-2-(2-
`aminothiazol-4-yl)-4'—[2-[(2-hydroxy-2-phenylethyl)amino]
`ethyl]acetic acid anilide, and further improvements are
`needed to produce a pharmaceutical composition.
`
`CITATION LIST
`
`Patent Literature
`
`International Publication No. WO
`literature 1]
`[patent
`99/20607 (Example 41)
`[patent literature 2] International Publication No. WO 2004/
`041276
`
`literature 3]
`[patent
`94/06414
`
`International Publication No. WO
`
`SUMMARY OF INVENTION
`
`Technical Problem
`
`An object of the present invention is to provide a phar-
`maceutical composition for modified release comprising
`(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenyl-
`ethyl)amino]ethyl]acetic acid anilide or a pharmaceutically
`acceptable salt thereof, in which the pharmaceutical com-
`position has efficacy the same as or higher than those of
`conventional formulations and has no limitations on food
`
`intake, and a process of manufacturing the pharmaceutical
`composition.
`
`Solution to Problem
`
`The elimination half-life (Tl/2) of (R)-2-(2-aminothiazol-
`4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic
`acid anilide is long (approximately 18 to 24 hours), and thus,
`a formulation thereof for modified release is not necessarily
`needed to maintain its blood level. Taking into consideration
`the results of the clinical trial described above, the present
`inventors conducted intensive studies to design the formu-
`lation by paying attention to the control of a release rate of
`the drug from a formulation to the extent that the release is
`not affected by food intake or the like, rather than the
`addition of release control.
`
`On the basis of blood concentration profiles (in a fasted
`state/after the intake of food) after administration of a
`conventional formulation (rapid release formulation), the
`absorption rate of the drug in a fed state was calculated by
`a deconvolution method to predict continuous absorption for
`about 4 hours. The present inventors considered from this
`result that a formulation capable of continuous drug release
`for 4 hours or more would be able to reduce the effects by
`food, because the drug release from the formulation would
`become the rate-limiting step for absorption.
`The present inventors carried out a clinical trial in human
`using three types of formulations in which the release rate of
`the drug was controlled (Time when the release percentage
`of the drug from the unit formulation was 80% (T80%):4 hr,
`6 hr, and 10 hr), and found that all formulations could reduce
`the effects by food, to complete the present invention.
`It
`is generally known that
`the retention time in the
`stomach and the rel