Free Redacted Document - District Court of Delaware - Delaware

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CONTAINS CONFIDENTIAL INFORMATION UNDER PROTECTIVE ORDER
IN THE UNITED STATES DISTRICT COURT DISTRICT OF DELAWARE
GLAXO GROUP LIMITED,
Plaintiff,
v.

Civil Action No. 04-171-KAJ

TEV A PHARMACEUTICALS USA, INC. AND TEV A PHARMACEUTICAL INDUSTRiES LIMITED.
Defendants.

BRADLEY D. ANDERSON, Ph.D. FED. R. CIV. P. 26(a)(2) EXPERT WITNESS REPORT CONCERNING THE ISSUE OF INFRINGEMENT OF GLAXO'S '249 PATENT

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03/'6/2036
16:56
Uk RSTECC 257-2489 7 912123096001P4511758~
NO.

4'38 9002

10 L. I may supplement or amend my opinions expressed in this Expert Witness Report
if new or additional infonnation is provided 10 me or becomes available from

Teva or Tcva 's expert witnesses. ¡ understand that expert rcpori may be
provided hy Teva. I reserve the right to respond to all mat1ers raised by Teva and
to testimony and opinions offered by Teva's witnesses.

Date: March -- 2006

Bradley D. An erson, Ph.D.

ß~Qr CU~

38

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EXHIBIT 2

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Ranitidine Oral Solution USP, 15mg/mL
Team Leader: Angelique Masucci

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EXHIBIT 3

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Information Package: Ranitidine Hei Syrup Revision: April 22, 2003

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IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWAR

_ _ _ _ __ __ ___ ___ ___ _ _ _. _. _ __ _ _- _ -- --- - --- - -- ----- - - -- --- - ---- - - --x

GLAXO GROUP LIMITED

Plaintiff,
v.

Civil Action No. 04-171-KA

TEV A PHARMACEUTICALS USA, INC. and TEV A PHARMACEUTICAL INDUSTRIES LIMITED Defendants.
__ _____._n___ _ _ _ _ ____ _ n n_ _____ nn_ _n____ __ - ____n____ nn_ X

PLAINTIFF GLAXO GROUP Ul\TED'S OBJECTIONS AND RESPONSES TO DEFENDANTS' FIRST SET OF REQUESTS FOR AD:MSSJON NOS. 1-15.26.27.83-99,101,105 and 108-115
Pursuant to Rule 36 of the Federal Rules of Civil Procedure Plaintiff Glaxo Group
Limited ("Glaxo") respond to Defendants', Teva Pharaceuticals USA. Inc. and Teva

Phannaceutical Industries Ltd. (collectively "Teva"), First Set of Requests For Admission Nos.
1-15,26,27,83-99,101, 105 and 108-115.

GENERAL OBJECTIONS
1. Glaxo objects to the Requests to the extent

they seek information protected from

disclosure by the attorney-client privilege, the work product immunity, and/or any other

applicable privilege or protection. Inadvertent production of information shall not be deemed a
waiver of any privilege or immunity.
I.NY/2016300.1

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Response
Denied.

Request No.4
Admit that propylene glycol is an alcohoL.

Response
Glaxo admits that in the context of the '249 patent, propylene glycol and ethanol are both
organic compounds comprising a lower aliphatic hydrocarbon group wiÙ1 at least one -OH

group, and that propylene glycol is an equivalent alcohol to the extent both are used in a

stabilizing effective amount to stabilze ranitidine, otherwise denied.

Request No.5
Admit that propylene glycol is an aliphatic alcohoL.

Response
Glaxo admits that in the context of the '249 patent, propylene glycol and ethanol are both
organic compounds comprising a lower aliphatic hydrocarbon group and at least one -OH group,

and that propylene glycol is an equivalent alcohol to the extent both are used in a stabilzing

effective amount to stabilze ranitidine, otherwise denied.

Request No.6
Admit that propylene glycol is a lower aliphatic alcohoL.

Response
Glaxo admits that in the context of the '249 patent, propylene glycol and eÙ1anol are both

organic compounds comprising a lower aliphatic hydrocarbon group with at least one -OH

group, and that propylene glycol is an equivalent alcohol to the extent both are used in a

stabilzing effective amount to stabilize ranitidine, otherwise denied.
5

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4,567,178 during prosecution of the patent applications that issued as U.S. Patent No. 5,068,249 or that there was any reason to submit the patent for consideration by the U.S. Patent and

Trademark Offce, and therefore denies the request and leaves defendants to their proof.
Request No. 85

Admit the Teva's accused ranitidine fOffuJation does not contain a "stabilizing effective

amount of ethanol" as claimed in claims i through i 0 of U.S. Patent No. 5,068,249.

Response
Denied.
Request No. 86

Admit the Teva's accused ranitidine fOffulation does not contain a "7% to 8%
weight/volume ethanol based on the complete fonnulation" as claimed in claims i 1 and 12 of

. U.S. Patent No. 5,068,249.

Response
Denied.
Request No. 87

Admit the Teva's accused ranitidine fOffulation does not literally infringe any claim of
U.S. Patent No. 5,068.249.

Response
Glaxo admits that Teva's accused ANDA product, Ranitidine Oral Solution USP. 15

mglml does not liierally contain "ethanol" as stated in the '249 patent claims. but Teva's accused
ANDA product otherwise literally satisfies the claim elements in claims i -12 of the '249 patent.

and it satisfies the "ethanol" claim element by the equivalent substitution of a stabilizing
effective amount of propylene glycol in place of the ethanoL.
12

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Administration ("FDA") a Notice of Claime~ Investigational Exemption for a New Drug for
ZantacQY (ranitidine hydrochloride) Syrup" (Glaxo v. Pharmadyne. 32 F. Supp. 2d at 277), and

that Judge Davis' statement must be put in the proper context of the entire opinion and
testimony, including his finding that the use

of propylene glycol in Pharmadyne's ranitidine oral

solution product was the functional equivalent of ethanol in Glaxo's '249 patent. that
Pharmadyne infringed the '249 patent claims and that the '249 patent claims were not invalid or
unenforceable. (Jd. at 287,293,303 and 313).
ReQuest No. 90

Admit that the original formulation for ZamacQY syrup included a preservative system
composed of thee parabensi me.thylparaben, propylparaben and butylparaben, but it did not

contain any alcohol, and that Dr. Long noticed there was a decrease in the concentration of one

of the parabens as reported in Glaxo v. Pharmadyne, 32 F. Supp. 2d 265 at 278.

Response
Glaxo admits only those facts to which Dr. Long testified at the trial of the Glaxo v.

Pharmad)'l1t action (see Trial Transcript pages 277-278 and PTX 63), which Judge Davis
referred 10 in his opinion: "that the original formulation for ZantacQY syrup included a

preservative system composed of Ù1ree parabens: meÙ1ylparaben, propylparaben and

butylparaben, but it did not contain any alcohol, and that Dr. Long noticed Ù1ere was a decrease in Ù1e concentration of one of the parabens" (Glaxo v. Pliarmadyne, 32 F. Supp. 2d at 277), and
that Judge Davis' statement must be put in Ù1e proper context of the entire opinion and

testimony, including his finding thai the use of propylene glycol in Pharmadyne's ranitidine oral
solution product was the functional equivalent of eÙ1anol in Glaxo's '249 patent, that

14

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Phannadyne infringed the '249 patent claims and that the '249 patent claims were not invalid or

unenforceable. (ld. at 287,293,303 and 313).
Request No. 91

Admit that Dr. Long was surprised at this decrease because there was data from a study

of the fonnulation in sealed bottles showing there was little change in the product over a two

year period as reported in Glaxo v. Phannadyne, 32 F. Supp. 2d 265 at 278.

Response
Glaxo admits only those facts to which Dr. Long testified at the tral of the Glaxo v.
Phamiadyne action (see Trial Transcript pages 280-281), which Judge Davis referred to in his

opinion: "Dr. Long was surprised at this decrease because there was data from a study of the

fonnulation in sealed bottles showing there was little change in the product over a two year

period" (Glax v. Pharmadyne, 32 F. Supp. 2d at 278), and that Judge Davis' statement must be
put in the proper context of the entire opinion and testimony, including his finding that the use of

propylene glycol in Pharmadyne's ranitidine oral solution product was ile functional equivalent

of ethanol in Glaxo's '249 patent, ilat Pharmadyne infringed the '249 patent claims and ilat the
'249 patent claims were not invalid or unenforceable. (ld. at 287, 293,303 and 313).
Request No. 92

Admit that the degradation of the paraben concentration did not fit any known law of
degradation of parabens as reported in Gla;o v. Pharmad)'17e, 32 F. Supp. 2d 265 at 278.

Response
Glaxo admits only those facts to which Dr. Long testified at ile trial of ile Glaxo v.
Pharmadyne action (see Trial Transcript page 281), which Judge Davis referred to in his

opinion: "the degradation of the paraben concentration did not fít any known law of degradation
15

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of parabens" (Glaxo v. Phannadyne, 32 F. Supp. 2d at 278), and that Judge Davis' statement
must be put in the proper context of the entire opinion and testimony, including his finding that
the use of propylene. glycol in Pharmadyne's ranitidine oral solution product was the functional

equivalent of ethanol in Glaxo's '249 patent, that Pharmadyne infnged the '249 patent claims
and that the '249 patent claims were not invalid or unenforceable. (Jd. at 287, 293, 303 and 313).
Request No. 93

Admit that Dr. Long had the product analyzed by Glaxo microbiologists who discovered
that it contained a microbial named pseudomonas cepaciaas reported in Glaxo v. Phannadyne,

32 F. Supp. 2d 265 at 278.

Response
Glaxo admits only those facts to which Dr. Long testified at the trial of the Glaxo v.

Phannadyne action (see Trial Transcript pages 281-283 and PT 239), which Judge Davis
referred to in his opinion: "Dr. Long had the product analyzed by Glaxo microbiologists who
discovered that it contained a microbial named pseudomonas cepacia" (Glaxo v. Phannadyne,

32 F. Supp. 2d at 178), and that Judge Davis' statement must be put in the proper context of the
entire opinion and iestimony, including his finding that the use of propylene glycol in
Pharadyne's ranitidine oral solution product was the functional equivalent of ethanol in

Glaxo's '249 patent, that Pharmadyne infringed the '249 patent claims and that the '249 patent

claims were not invalid or unenforceable. (Id. at 287,293,303 and 313).
Request No. 94

Admit that to combat the contamination problem, Dr. Long devised a strategy that included the exploration of the use of ethanol, chlorhexidine, phenoxyethanol, benzalkonium

chloride, and propylene glycol as reponed in Glaxo v. Phannadyne, 32 F. Supp. 2d 265 at 278.
16

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Request No. 110

Admit that U.S. Pat. No. 4,521,431 has expired.

Response
GJaxo admits that the patent tenn of U.S. Patent No. 4,521,431 expired on June 4, 2002,

but that Glaxo received the benefit of FDA pediatric exclusivity for Zantac(ß syrp until
December 4, 2002.
Request No. 111

Admit the claims of U.S. Pat. No. 4,521,431 were not enforceable on or after December

9,2003.
Response
Denied.
Request No. 112

Admit thm U.S. Pat. No. 4,672,133 has expired.

Response
Glaxo admits that the tenn of U.S. Patent No. 4,672.133 expired on June 9, 200.
Request No. 113
Admit the claims of

U.S. Pat. No. 4,672,133 were not enforceable on or after

December 9, 2003.

Response
Denied.
Request No. 114

Admit that U.S. Pat. No. 4,585,790 has expired.

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Response
Glaxo admits that the patent tem of U.S. Patent No. 4,585,790 expired on May 11, 2004

but that Glaxo recei~ed the benefit of FDA pediatric exclusivity for Zantac(Ë syrp until
November 11, 200.
ReQuest No. 115

Admit the claims of U.S. Pat. No. 4,585,790 were not enforceable on or afer
December 9, 2003.

Response
Denied.

22

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Dated: March 20, 2005

~rÐ(:J-i5\I~/~
Francis DiGiovanni (#3189) The Nemour Building 1007 NOrÙ Orange Street P.O. Box 2207 Wilmington, DE i 9899-2207 (302) 888-6316 Attorneys for Plaintiff Glaxo Group Limited

CONNOLLY BOVE LODGE & HUTZ LLP

OF COUNSEL:

Brian P. Murphy
Thomas Puppa

Morgan Lewis & Bockius LLP 101 Park Avenue New York, New York 10178-0060 (212) 309-6000 Attorneys for Plaintiff Glaxo Group Limited
45395o_1

23

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~ Ranitidine Oral Salurian USP, J 5 mglmL

Abbreviated New Dntg Application

SECTION VIA
BIOA V AILABILITYIBIOEQUIV ALENCE:

Formulation Comparison
This section contains:

" Statement of Composition of the TEV A Phanaceuticals USA Product
" Percent Composition of

the TEV A Phanaceuticals USA Product

" Qualitative Formulation Comparison \'lith Reference Listed Drug

. Functional Summar oflngredients

" llG Comparson

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íl Ranitidíne Oral Soluiíon US?, j 5 mglmL

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RANITlDlNE ORAL SOLUTION USP, 15 mg/mL EXCIPIENT FUNCTION

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201
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1 2
3 4 5 6

Trial Day 1 Volume 2 of 2 November 12, 1997

IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF MPRYLN~D NORTHERN DIVISION

GLAXO WELLCOME INC., et al. )
7
8
9

v. )
Defendants )
) )

Plaintiffs )

)

Civil Docket No. AMD-96-455
Jl.nd

)

Civil Docket No. N~D-96-i853

)

P~A~~YNE CORPORP.TION, et al.)
10 11
12
13

(Consolidated)

Baltimore, Maryland November 12, 1997 2:00 p.m.

\

14
15 16

The above-entitled matter came on for trial before The Honorable Andre M. Davis

17
18

APPEARANCES
On behalf of the Plaintiffs: Stephen Judlowe, Esquire John Henry Lewin, Jr., Esquire Brian P. Murphy, Esquire Robert Gibbons, Esquire

19
20

Regina ~~ery, Esquire Jason Lief, Esquire
On behalf of the Defendants: James Rubin, Esquire Alan H. Bernstein, Esquire Robert S. Silver, Esquire John M. Seeberger, Esquire Deborah K. Besche, Esquire

21
22 23 24

25 Reported by: Betty Lou Walls, RPR

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W.ALLS REPORTING, INC. 714 PARK AVENUE, BALTIMORE, MD 21201

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G027685

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Document 111-2

Filed 07/10/2006

Page 50 of 85

REDACTED VERSION ­ PUBLICLY FILED

EXHIBIT 9

Case 1:04-cv-00171-GMS

Document 111-2

Filed 07/10/2006

Page 51 of 85

REDACTED VERSION ­ PUBLICLY FILED

~ev.

1-eÒ ..~C\;

GU¡XO I¡EUCOME rNC. RND 13L.xO GROIJP UNITED v. PHHRD'r I)JRPORrrON

CIVIL RCTIÜfi r1O. Af %-455 HIGHY COWID8lTRL UliDf FRTECT!\! ORDER

Y084325
G026730

A042
CONRDENTIAL UNDER PROTECTWE ORDER

Case 1:04-cv-00171-GMS

Document 111-2

Filed 07/10/2006

Page 52 of 85

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..'êc\e ~eU

Ò

êL~(O I.ELCOI£ INC. !lD 6"':~(O GROUP LIMITED v. PHARD'r CORORTI(~j CIilL RCTIUli riD. RMD 96-455 HIGHlY cariFID8ínRL UtfER PROTECTIVE ORDE

Y084326
G026731

A043
CONFIDENTIAL UNDER PROTECTIVE ORDER

Case 1:04-cv-00171-GMS

Document 111-2

Filed 07/10/2006

Page 53 of 85

REDACTED VERSION ­ PUBLICLY FILED

EXHIBIT 10

Case 1:04-cv-00171-GMS

Document 111-2

Filed 07/10/2006

Page 54 of 85

REDACTED VERSION ­ PUBLICLY FILED

~eÒ

~eÒflV

":1: 'l.iK~~r ,;-. .:-"C._;..-ä

A044
CONFIDENTIAL UNDER PROTECTIVE ORDER

G005295

Case 1:04-cv-00171-GMS

Document 111-2

Filed 07/10/2006

Page 55 of 85

REDACTED VERSION ­ PUBLICLY FILED

øÒ

~ø

ò'l

v~

. ~",:'":,

..

..

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A045

~--

CONFIDENTIAL UNDER PROTECTIVE ORDER

G005296

Case 1:04-cv-00171-GMS

Document 111-2

Filed 07/10/2006

Page 56 of 85

REDACTED VERSION ­ PUBLICLY FILED

~eÒ'lC

\.eÒ

f'

~" ._.,

. .---

..-

,,:r..:...~

A046
CONFIDENTIAL UNDER PROTECTIVE ORDER

G005297

Case 1:04-cv-00171-GMS

Document 111-2

Filed 07/10/2006
." \...:=\ '-

Page 57 of 85

DTALHEALTH ¡ ì VyTHERE ¡, irrfutable evòcoc tht chronic

REDACTED VERSION ­ PUBLICLY FILED
~t:..:-- " .S~\-. .
hie below il1ieatc: those prouct which
.r. are suga-fTee. W. are gra~efu to ~he

Sugar-free medicinegJ 7' .-.
ey M. BRADON, epha MPhli. "'PS and E. e. SADlE eSe MPS

. '. ninufacturers for ôltace in prepanng the lis and their pe~n (or publiction If it is not poble to Slpply a Slgar.
fr liquid formulatin or a lablet. the

admiistrtion of liquid medci sweet-

than the touJ am""ni ingeste.. Sua.,.. is

ene. with sucr or oth.. feierible

prbably the mos ""rigenic su but
glu", and (ruos:a als highly potClL
There is no evidence that the -aificiaJ

the incidence o( dental dis in children'. Many o( these children may, be= o( th.ir und.rl~;ng illnes. have serious protr
lems with denta dÍ5as. It may. (or eUmpie. lead to an incead number of dental
frequency

sugars. suct as gluco orfrctosc. incr

ct1dnn rc:ving -suga~ me.icinc: to
the.childs teeth after dosng,
REFERENCES

pho.ad mould advi the p;enis o(

rins the c!ld. mouth well and to bru

swcetetCI"" or sorbitol. mannitol and xy¡¡~

tol ar earigenic'.
Concrn has bc expr= by varous

=ctÇlns in c!ldreo who presnt a por tric mi:cines and a number of pharmaceuaneseûc òsic. li has ben sugges tht
of sugar intake is more importt

authrities regarding the adver elfeQ of the regular us o( sugar-SWeeene l"eda.

tica companies has oow formulated itS

1. P/i",""m:uæaJJOW.I98I.z.'7.69S. 2. Rokns. 1. f. .nd Robe-u. G. J.. Bnii
Medeo Jour. 1m. 2.14

~ "'-~""-- =. -~""", -b1~~ "" -. --- r~~ lr~ . ---.-..~ - ~~ ~i.~ "~ ."" ~.a~ '*~ "". --"" ~ .. -i ~~~ ~ .."" 0 "' ~~~=rSa
MI_~ni Ai ~Oo
T~:Su_ ~Iel

A:~~

'= eo

"" ~~

~... T~

.. i-.. ""-" ~lo~ ~~~ "" ---~.. ~~7"
-.. -""
~..~-

product with suga-fr diluents Th la.

3. Hob. P,. Cowi DmcJ HcaiJ.
1985.2.51

~ Mr Brandoll is priåpaJ pharacit.
&i ~ngli Regional Dru Inforron Sake. Jpswù: hO$piraJ, am Mrs Sadler is

~ti-cr~

staf plu. Norrh W"""m Regiona
Drug Inforron Seria. St Mar's hospi.

ta Mandus,.,

mr-'

o.~

ii 5... -- u=P_""
""''", ~'alCnni '* ""
T.._ v.."" ""''
T~lY

CAAS Io

Society joins in campaign against sugar in medicines
TH Pli.åCutica Soeiy has joined
with th Briti Denta Astiol1 in
wntig to the Depanent of Heath and

.. "" ~"'u. v_ ~~ ~~lA=ET ,~.. M;~ ""'' ~ ..,,.. ~ ~ """ t.~~ ""

Hf'shtil'oct\sc~Nv~~orP'~..~l\bll"'~wn"'~
824

.. ~~~=~~~~~~Ql~~~~an
~p~

~~ ~~ --""SF_ "". l.Qt~ ~ -"""" ::~""~"' .. ~..~ Fc ~.. ~~ ~""~ .A~Ci ---~

~ ~ -l. -"" i. -~ ~~ ~¥' ~~~=-~ .""

~~

~~~ -. ""~ r~ 0Q~ J.Pk~ T_ ""..

-

other influelltia boies to expres concern about the presnc of suga in chíldrei's
me.icil1cs.
A lener Was sent 011 .June 20. voicing concern about the "advei. elf= of the

~

~.~""

r"" ii ""~

PT~~'~~li ~FM~ i. ~ """' "' "" Vti~ "" ""~ ..""

P"" ~ !XTu:

~::..;. ~~ ~.i.ç ~-l~~~t: ~an ~~ ~iir~..

~ ~er ~~':":I ~=~
RETQRy AGH

joit meeting at the Phanaautica Soet iii 1981 the phaactica incl wa
urged 10 pruce a grter rage o( medi.

loog-term us of suga-bas mecines on the teeth o( sic~ childrel1-. (t..Y' th at a

ci amtaning non-cogen SWeec:c:

(or us by clldri. Althgh a smil

number of manufactrers has iael1 a le

and is co proucog sugar-fr meicine. -th majoriiy- of clld/lI1's meci stl o:mta suga. The letter sugges that"t

be dintinued.

us of suga in chíld,.'s meddne.suld

behaf of ilS dèntal health and scenc ctmmiiiee. th. Pharmaceutca Soety.

The letter was sel by tbe BDA on

the Britih Asation for tbe Study of

tric Soet. th British Pacdntk S0
ety and the Health Education ConciL.

Oiwmuniiy Deotistiy. the Briti Padja-

Two types of Nystan
SQUfBB s:ys that it believes tht many
phamcilS aod docors arc unwa of the availability of NY'lan.granules for suspension. a prouct which is suga.free. aod

V1.u ,v !f SVs

V~9l1C li 0 ~ ~l ko VQ: A. B JJwiC.& Vlt'l A.a.c.i 0 VlU

.

als free.of l.ctose and rom siard.

The prouct is recnsiitute. with waier to provide an' oral suspenson C1ntaning
100.00 unilS nY'latin per mI. It is ..ail able in bottles of 24 dos. at a irade price 01 £1.67. The standard Nysian oral suspen-

sion doe contain sugar.
TlE PHARMACEUTCAL JOURNAL.. JUNE 29. 193

A047
CONFIDENTIAL UNDER PROTECTIVE ORDER

G005298

Case 1:04-cv-00171-GMS

Document 111-2

Filed 07/10/2006

Page 58 of 85

REDACTED VERSION ­ PUBLICLY FILED ... ':.'.' .'.. // '-ý/ß? ():/

MEMORANDOÝ'

RECEIV¡:n
i 1 JUL 1985

ni 'l :

9 July 1985

Redacted

¡

,
.i
a
'I ~

~

~

-',

l

~.

A048
CONFIDENTIAL UNDER PROTECTIVE ORDER

G005299

Case 1:04-cv-00171-GMS

Document 111-2

Filed 07/10/2006

Page 59 of 85

REDACTED VERSION ­ PUBLICLY FILED

EXHIBIT 11

Case 1:04-cv-00171-GMS

Document 111-2

Filed 07/10/2006

Page 60 of 85

REDACTED VERSION ­ PUBLICLY FILED

l'21 UK Patent Application 1191GB (ill 2 142820 A
(4.31 .Apø1qt.Ot' PU~"l\.-d JO Jlçi 1985
(21) A.øHafio No ..12l0.

(i2) 0.1. ot fiLìi; 11 M.y 1;'"
1301 Pror.. (3-1) SJ\:Z17

tSii fNrcii
"'l1K i1/J.c
t52) ~ui.¡.c dU.l4ti'loOA

(32) '3 ..., 1 ui (331 os

.us 1130 ".... .o.46 ',y 4.51 .cS'r 540 S4. SõS SSY

en H l H
UU '31G A5E
(56) Ooenwnu e2fe(S8) f...w of UUQ'

(71)~Gtv Ur.w (Un.1.. 1G~. Oluo
W,y IOH

"-

ci- H~... '/1% CirG' Sc~ Lo

AU

(2) In..lO Jo. M~ r.,w.J. l..n ICth Wi.i.
(74) .lO."l If\dlc."A4(Jc-i to( S.. elitif\(Ol an ref.,
WClVGSH

H~h Holb4 H~... 52/S04 H19h Holbo. ~n4

lS,) Aqultul çompoiiitlon, of nanitidin.

(511 ÄquO(us larmuliiians al ,.nidiiine havo lxn lound 10 have onhan""d ,holllile provided Ih., 'h.y at. la'muliioQ wirt i pH in tho 'inge 6.5-7.5. 5uiiable aqueou, lormulai'on, include inj'Clion. lot
intra;v4Inous ~nc; intnmusculir .dmini"iraIÎon. continuous infu3:ions ¡nd oral prep~r.Hion$ :si.ch ¡.i syn;PJ.

G:

N
OJ

.t

..

t\

OJ

0
073

N

):

A049
G 000078

Case 1:04-cv-00171-GMS

Document 111-2

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Page 61 of 85

REDACTED VERSION ­ PUBLICLY FILED

GS 2 142 820A
SPEClFlCAnON

Ph.rm'''utki ""_Ilin.

5 Th pr_i i""..lkin ..hlt.. 10 . ph.rmaucal eornpoiition contiining .. letivo ingrlKi.nt 5
th.. hiillmin. Hz antlgooii ranitdin.. Riniidin. (N-(2-a5-(dilTlhyl.rninolmlth2.furonyl¡m.thYljùiO¡.,hYI)-w.rn.lhYl-2..iiro-l. ,.
ltln-.i.uni""i ind iti phyiiolog;.ily icc¡iblo "It¡ .r. cálCb.d in Briti./i Paten, Specifica. iio No. 1565966. In th.i lpocaiio Il.. ii r.f.,.1\ 10 liquid forrnui.tion. f", oral and

1 0 p".nlO..1 .dminirttkni 'nd Ihtl. ii . dnpton 0' In aqu*"w blUd formui.tion for 10 innvon... .dminiivùo" .nd ina.. of in ""i SYp. 80th of ill", formulition. coi.in
.uffci.ni hydrolo .ad 10 .ø.. i pH of 5.0. In ..ditn inj4cton /omulaiioni ...

15 i iimpll aq~ IOltlÌO of ..nitin. hydrolod. al ii niiul' pH. Li. ibo 5.5. Whils 15
iucl fo""laiionl coining "'nitidi". .ndl", Ît phyiioloicaily """pttbl. i.iu "a th.raP'~
W. ho. no lurp1iniify found thai tho ahlf fife of aqu..,, boUd '''mUII'ionl ""ntaining
20 ranidina andlor OM or m",. 01 Ît phyiioi¡.iiy icipublo safts may be significantl 20
cally .ffiii they sutt.r from th diiain~. 01 hiving a raliti.iy ihon .h.lf liii duo to the

SYm¡m S.ria 5. Oxf:M..icinl Publiing F..mulition 1982 PI' 18-(2) in tho fo of

duelH by I'dfHid on of (T Ctmici U.. of Rinitidirw. Mtdk:n. Publiihinii Found.iio

br..kdOW of th ..nitidi... .nhincad il th pH 01 th formulatin ia adjus witin th rang. of 6.5-7.5.

lormulation of "'nitiin. andl.. one or mol ¡iyiogieily acpUbl, ..It thar..'. hIving a pH

Thui in l"""ni i""aniion P""ida a phllc:l compoiton whic ii in aqu""

25 svdl th.t it ia lUitbi lo .dminiiirati to P*ntt. 25
whin c:mpirtd with formul'lion. lt a lo.. pH. Thu. fa; aicrnlo. in Ih, co" 0' a 25 mg/rnl
"ni,idin. hydroelorida injK1 iolutkn bur.. 10 tho apprOP/la pH with Phoaph... ..113

within Ih, ..ng. of 6.5-7.5. Th. aqueoi foruLation is pi.p*rtd uling ingrtdian.. 01, pur

Th, Iqu..UI baud ranitina forvlCliol ""ding 10 ih. invantin a" p'riic:l,rl nabla

:i0 fas" 10; a iolut bult to pH 5.5 thin fo a solut butt.,td 10 pH 7.0. 30
wil\n in ~ &.S-7.5 by ITln. 01 m. usa of suÍlbl. buff ..!t. for ...mpl.. po....ium
Conv.nietl th pH of tho fouLation l=ng to tho inWltion ia .djUSO( on ~nuftc:lO

~nd iubjactd 10 stOtg. at 20'C. tho raa of br..kdow 01 iha rinitidina ia abo tan 'im..

dihydtog Othophat. and diSOium hydro.n ortP~hli. 01 citric .cid .nd diioium hydrog.n Gth.t..
:iS Pr.f""od foul.ti. aarding 10 th invontion ora th.. wh...in lha pH ia ..ithin tha ionga 3S 6.7 10 7.3. lo .icmpl. 5.8 to 7.1.

A pr.(.lTe- emboiment 01 th invlt\tio i. in IqlJl-U. formulltion (or pirtnt.f.1 adminiur.. tion. Such i farmutltion miy eomprii. wlter iuitibl. (Of injtelofl in whidi ë:s diuolv6-

40 Preferably lhe ioution ii adjusttd 10 tonicity by Ih. 'ddiiion of th. .oorop,i". eonveniion,i 40
excipienti ..g. sodium chlorid.. Optionally the compoi.tion m.y .Iso conti pres'Nltie, tor .x:.mpl. phenoL. in an "mimicrobj.J' Tht cornntttio of ranrtini in formutltion syii.bli for in;.ion. ..g. intniVtnoul O.

nnitidin. ,ndlor on. or mora of Ît phyiiologiclly lCptablo ..iu and luÌUbla buH.r 1011..

in"amuoelar injltn ii c:nvani.nify ..iihin lh. 'ang. 10-100 mg I mI. for e..mpl. 25 45 mg/ml. .xl"... a. It., b.... It doiirO(. lhe iotlion m,y be diluted pel", 10 u.. wilh. for 45
e..amplt. .n i$Otonk; uliii 20luti-on or . d.i:ttow solution. ScHutions suit,ble tor ~ntjnuous infuiion mty have . conc.n"ation 01 raniiidina of 0.1-2.0 Ol/ml. prefenbly 0.5-1.0 mg/ml.
eipra~ IS fr.. b.... Th, sOfutictU tOf ccntinuoi inhii.iOl m,¡y b- preUnltd in thit form, (Of

50 10-100 mi/m!. ..g. 25 mg/ml, for IUIn.qUllt diltlion bot",. U1. wiih. ''' ..ampl.. en 50
iSOtonic si1ln- .olution or . doxtou wlotion. Th, 'quecx, formulations for pl:ronteral idminittfltiol' ir, eonvonicsntfy prepire- by áis.lv~ ing nniiidin. and/or oni or mOra ot it. physloically accepiibl. ..i.. and the ..cipi.n.. in water iuitabla for injacioni, Th. ..Iution. whic conviniently ii 'P&rgld with an in.n g.. .uch
55 as niirog.n. ii ii"i1.O( prifer.bfy by filtration and ihon Uapti.,11y plCed inio iuil1bl. 55

lxampli in packi 0' 50-100 ml. or mey bo P(l"nttd in a moe eonc.ntrlttd lorm. i.a.

cont.inert. e.g. .mpo-l.. viili or COniainiri fOlinfusion. under in atmosphere of nittogan. AlternltivllY the lormul.iiion miy b. t.rminally si.rifiiO(. (or ..ample by h.eiing. A Ivrthl( prtfotT-d .mboimont of the jnvlntio is an iqueoui lormuliiion (or or.' iåministr.tion. Such · (ormvl-tion may compriu ranhidi"" and/or one Of more of ib
60 phy.iol09icaliy acc.pt.bl. ..it i diuolvlK in Wat... ,og.iher with buH.r ..ill. l "'."lVoiiv. and .. viscsity enhancing agent. Optioilly the eompihion may lilt? COntain other Con"ention¡.!

60

65 Eumple. of 'U~ibll viico.ity enhancing ag.n" includi )(nthan gum. .orbltol. glycerol. 65

l!icipionts ,uch It a iweetentr~ l nlVour ,nd/or flavouring aids. Suitable butter iall$ for tho oral lormulaiion incud. pOUssium dihydrogen onhopho'Oh.l. and diiodium hydrogen onhophoiphate or ciiric lCid and di",diurn hydrogen ~rihoOho,phato.

074

A060
G 000079

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REDACTED VERSION ­ PUBLICLY FILED

i
G8il42820A
OU(;OO" or · ""iiulo.. d"riaiiv. suh .. etrt.ym.thyf ""lIulo.. (K In "mer Iho'fOf 'uch 10 on allel and/or a hydro.yalkyl oihor of collulo.. .. I(K ..impl. hydroiyP'o!' m"thyk.llulo... Suitablt pr..orvti.o indud. th" ollel hydro.ybon.OII... ouch.. m.ihy. tthyl. propyl
2

5 Suitiblo O"'"IOnl" indud. UC.òn oôdium. soium eydim.i.. SObilOI a", 'UCla". 5
within U\f "ng. 01 20-400 mg IHr 10 rn, lor ..ampla 20-200 mg IHr 10 mi. ma. pariieiI.i1 1 50 mg IHr 10 ml do... Th" Iqu.ouO 10rmulaMn '.r ."'1 IdminiarltÌj If. conv.niontly P'o""rod by odding In
10 in aqUeol lIltJ or d4Pfio ollh. viieli inhancing agini.

and/or buty hydro"Yn.OlI...

Th. c:C1m"lion of tanitidiri in tho onllormulalÌj. ..pr....d .. fr.. bo.. .. conveni"niiy

iO Iqu"""O ""Iulion of tani¡.. 'nd/or On.. or more of it sa tOi.ih.r with tho ot.r ..cipion" 1 0

in ihe lor of it hydrlo "'t.
U1uwiti ..impla .1 foula

Th. iqu.. lanulitionl ""ding 10 th inwntio ., P'.f..ably prlP"od uoing raniiidi",

1 5 eumpl.. th. ,,'iliv. Pfna of tiona Ilding 10 th.. ÌllrtiM l" .. "Ill Irt iuch th.t ..ch 1 5 ranIldin. hydroclo. and buff.. loll... In ih...
formUI"ion h.. i pH at IPpt..i",ttl 7.

Raniditine In 'ection for Intravenous administration

20 125 mq/ml)
Example 1

Rani tid1ne hydrOchloride
25 POtassium dihYdrogen orthophospha te DisOd1um hydrogen
orth°Pho.phate, anhydrous

MO'Lml

20

28

0.96
2. .

25

30 Phenol a1'
Water Sui table for Injection. 51' to
JS R.nitidi". hydrodlodo. tho bulfr ..ti ind ih. phonal

5

30
in Wlldf fa, Injecon. 35

1 IlldiUQIvtWOrt

Th. ootJ Wli IIHrg wi nitOi.n. Ittri¡¡ud by fition i", thon ...piicolly pickod "'10
viali u"'.. In """pli of nion ind ...IW wi . lUÌ\b! closure.

-40

Example 2
Ran1tidina hydrochloride

Potass ium dihydrogen orthophos pha te
45 Disodium hydrogen Orthophosphate, anhydrous SOdium chloride BP
50 Wa ter Sui table for

~
28

40

0.96

2.4 1.6
1 inl

45

Injections BP to
50

An 9QUOS ""Iution 01 the "nÎtdin. hydrodlorid.. th lxf1.., ullt and soiu,m chlord. ..11
pnipor-- uiing Weter lor fnj~ian. Th. ioution .... IP"'It- wi n1trQ9n. ltorillWd by

55 filir"Ûon ind ihen n"ptic:lly Pick-- inio impoule- under an iirn.pfl" of Mrogon.
55

075

A051
G 000060

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REDACTED VERSION ­ PUBLICLY FILED

J'3

G82 142 820A

Ranitidine oral liquid formulation
Eicample 3

(lSo ma/10 mll

5 Ranitidine hydrochloride

Hydroxypropyl methylcellUlose

~
1.68

Paraben3 (preservative)
10 Pota3sium dihydrogen orthophosphate

q.s. q.s.
0.095

5

Oisodium hydrogen orthopho'Phate, anhydrous
15 SWeetening agent(s) F14vour
Purified Water SP to

10

0.350

q.s.

q...
.100 ml

15

20 A ""lutKl of ii ronidin. hydroiodo to'lU wit tho oin excipicttt. excopt hYdroxy. 20

p'op mcyic.llukn. in p"dfitd Wlte- wll .ddtd wi mixing to i diipol"on at lh hydn",'fopy mltyic.lluio in puntitd w.t...
Rani tidine formU14tions for
2S

intravenous infusion.
Examp 1 e 4

ExAJc 1 e 5 For a 50 ml For a 100 ml

25

30
Rani tidine hydrochloride

Infusion
i:g/ml

Infusion
mglml
30

35 Citric acid SP Oisodium hydrogen ortho.

1.12 0.3

0.5ó 0.3
1. 8

35

pho.ph.ite, iinhydroiia

40

Sodium chloride BP

1.8
(, 5

Hater Suitable for
Injection. BP

4.5
40

to 50.0 rol

to

Al 6q1H1 iolutÍO of in ro"itidi~ hydrocloridi. tho buffor ..là ind TI ~ium chlarido 45 ii prlP'ro uoing Wlter for Inj+oni. The sol..n ii spargtd with nmogon. fillod into 45
coniaiMf wiubf. fOf l-minmiring thi ialvtion by int!vtnoul infui.on. ind nerillS&d by

100 .0 l11

lutediving.
CLAIMS

SO 1. A phirm-ttcl compocin which is In IqUOOl lormul.tion of flnitdi"" ind/or oM 50 Of mor Phyogiclly ""opubli s.lts theriot. dlo lomui.tion hoving 0 pH withn the ringo 6.5-7.5. 2. A phrm""''tic compoion .. Ci.i"'ed in cliim 1 hiving a pH in TI ring. 6.7 to 7.3. 3. A phirm-tic e.mpQ.ition II cliimtd in eliim 1 hoving a pH in TI 'ingi 6.8 10 7.1.
55 4. A phiimic.uticl compotin II ol.i~ in .ny of cliimt 1 to 3 in wlich tho pH i. 55

adjulttd by mufI of ..rtbl. buffi, ..IU.
dii0ium hydrogen OIÙ0pph.t..

5. A phirmlCiutical c:mpoilÍDn II ci.imtd in oliim 4 in which m. buff.r "ito i,"

poui"m dihyd,oii.n Oioph~hlf' ind di~ium hydrO'.n anhophosph.ti or citric acid .nd

60 6. A pharmllc.1 copoition II cl.im~ in any of claim. 1 10 5 in a la'm suiiibl. for 60
plr.nt".1 idministtion.

i:niiining 10 to 100 mg/ml rinitidin., UPIO.. IS tr.. biil.
65

7. A ph.rmiieutieal COmposiion II claimed in c1lim 6 in a form suitabl. for injecion .nd
65

8. A phirmac.utical com""sition II claimed in claim 6 in i larm sui iab I. a. Ire. b.... infusion and containing 0.1-2.0 mglml ,.nnidin., uptestdf", continuou.

076

AOó2
G 000061

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REDACTED VERSION ­ PUBLICLY FILED

4

ori/ .iminltilÎon.
dou.

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EXHIBIT 12

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-

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c.

Subj"ct: EFFECl OF E1HAHOL Oil THE ~YAß1L!Tï OF RAHlTiotilE SYkUf'

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EFFECT OF ETHOL CONCENTTION ON TH

STABIL OF, RAIN SYUP

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EFCT OF ETOL ON TH ST.AIIOF

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. EFCT OF ALCOHOL ON TH STABIL OF

RAIN S¥IJP (USA rnGREDIE)

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EFFCT OF INCLUDING ETHOL ON TH.

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EXHIBIT 13

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CONTAINS CONFIDENTIAL INFORMTION UNER PROTECTIVE ORDER
IN THE UNITED STATES DISTRICT COURT DISTRICT OF DELAWARE
GLAXO GROUP LIMITED,
Plaintiff,
v.

Civil Action No. 04-171-KAJ

TEV A PHAACEUTICALS USA, INC. AN
TEV A PHARMACEUTICAL INDUSTRIES LIMITED,

Defendants.

BRt\DLEY D. ANDERSON, Ph.D. FED. R. Cry. P. 26(a)(2) REBUTTAL EXPERT WITNESS REPORT

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Redacted

75. ¡ may supplement or amend my opinions expressed in tlús Expert Witneöö

Report if new or additional informon is provided to me or bemes
available from Teva or Tcva's expert witnesses, l rerve the rìghtto

repond to all matters rased by Teva and to tetimony an opinions
offered by

Teva's witnesses.

Date: April ~-M006

Bradley D. Anderon, Ph.D.

1~J)~

29

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EXHIBIT 14

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1

~
1

i0~ ~?::" r¡,-.".: .-,,\ ./

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2 IN THE UNITED STATES DISTRICT COURT

3 FOR THE DISTRICT OF DELAWARE

4 ------- ------- -- --------- ----- - ----- - --x

6-Plaintiff, 7 against 5 GLAXO GROUP LIMITED,
8 TEVA PHARMACEUTICALS USA, INC. i

9 and TEVA PHARMACEUTICAL INDUSTRIES

10 LIMITED,

11 Defendants.
12

Civil Action No. 04-171

~

13 -------------- --- - - -- -- ---- --- - - - - -----x

14 101 ParkNew York, New York Avenue
15

June 8, 2006
16
17

9:05 a.m.

18

Videotaped Deposition of Expert Witness,

1 9 BRA D LEY .A N DE R SON, Ph. D, t a ken pur sua n t to A 9 r e em en t

20 before Rita Persichetty, a Notary Public of the
21 State of New York.
22

23
24
:~i:.

ELLEN GRAUER COURT REPORTING CO. LLC 126 East 56th Street, Fifth Floo New York, New York 10022

25

212-750-6434
REF: 80918

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AN DERSON

Redacted

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r.iiN DERSON

60

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AN DERSON

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AN DERSON

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.AN DERSON

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