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EXHIBIT 1

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(12) United States Patent 

Calderari et al. 

(54) LIQUID PHARMACEUTICAL 

FORMULATIONS OF PALONOSETRON 

(71) Applicants: Helsinn Healthcare S.A., Lugauo (CH); 

Roche Palo Alto LLC. Palo Alto, CA 

(US); Simone Maccioccbi, Melide (CH); 

Giulio Macciocchi, Breganzona (Cl-I) 

(72) Inventors: Giorgio Calderari, Rancate (CH): 

Daniele Bonadeo, Casalzuiguo (lT): 

Roberta Cannella, Varese (IT); Alberto 

Macciocchi. Melide (Cl-I); Andrew 

Miksztal, Palo Alto, CA (US); Thomas 

Malefyt. Carmel Va lJey, CA (US): 

Kath.leeu M Lee, Palo Alto, CA (US); 

Carmine Panuccio, Casnate con Bemat 

(IT) 

(73) Assignees: Helsinn Hcaltbcare SA, 

Lugano/PaZ7..allo (CH); Roche Palo A.lto 

LLC. Palo Alto. CA (US) 

( *) Notice: Subject to any disclaimer, tbe term oftllis 

patent is extended or adjusted under 35 

U.S.C. 154(b) by 0 days. 

This patent is subject to a tenninal disclaimer. 

(21) Appl. No.: 13/901,437 

(22) 

(65) 

(63) 

(60) 

(51) 

(52) 

(58) 

(56) 

Filed: May 23, 2013 

Prior Publication Data 

US 2013/0261592 AI Oct. 3. 2013 

Related U.S. Application Data 

Continuation-in-part of application No. 13/087,012, 

filed on Apr. 14,2011 , now Pat. No. 8,518,981, whlch 

is a continuation of application No. I 11186.3 I 1. filed 

on Jul. 21.2005, now Pat. No. 7,947,724, which is a 

continuation of application No. PCf/EP2004/000888, 

flied on Jan. 30. 2004. 

Provisional application No. 60/444,351 , fi led on Jan. 

30.2003. 

Int. Cl. 

AOJN 43152 (2006.01) 

U.S.CI. 

USPC .......................................................... 514/397 

Field of Classification Search 

USPC .............................................. ...... ...... 514/397 

See application file for complete search history. 

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Primary Examiner- Shirley Gembeh 

(74) Aflorney. Agent. or Firm - Clark G. Sullivan; 

Troutman Sanders LLP 

(57) ABSTRACT 

The present invention relates to shelf-stable liquid formulations of palonosetron for reducing chemotherapy and radiotherapy induced emesis with palonosetron. Tbe formulations 

arc particularly useful in the preparation of intravenous and 

oral liquid medicaments. 

8 Claims, No Drawings 

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"' cited by examiner 

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US 8,598,219 B2 

1 

LlQUID PHARMACEUTICAL 

FORMULATIONS OF PALONOSETRON 

FIELD OF THE INVENTION 

2 

Ondansetron, its uses, and medicaments made with 

ondansctran are disclosed in U.S. Par. Nos. 4,695,578. 4, 753, 

789, 4,929,632. 5.240.954. 5,344,658, 5.578.628. 5.578,632, 

5,922,749, 5,622,720, 5,955,488, and 6,063,802. Coll1.1l1erTI1e present invention relates to shelf-life stable liquid formulations of palonosetron that are esp(.'Cially useful in the 

preparation of injectable and oral medicaments. 

5 cially it is d istributed by GlaxoSmithKline as Zofran® and is 

indicated for prevention of postoperative nausea and vomiting (PO NV), cancer chemotherapy-induced nausea and vomiting (ONV). and radiotherapy-induced nausea and vomiting 

(RINV) and it is available as an injection, tablets and solution, 

BACKGROUND OF THE INVENTION tO and as Zofran ODT® (ondansetron) Orally Disintegrating 

Tablets. 

Granisetron. its uses, and medicaments made with granisetran arc disclosed in U.S. Pat. Nos. 4,886,808, 4.937.247, 

5,034,398 and 6,294,548. Coll1.1l1ercially it is distributed by 

15 Roche Laboratories Inc. as Kytril®. indicated for the prevention of nausea and vomiting associated with chemotherapy or 

radiation therapy, and is offered in tablet fonn, oral solution, 

and as au injection. 

Emesis is a devastating consequence of cytotoxic therapy, 

radiotherapy. and post-operative environments that drastically affects the quality of life of people undergoing such 

treatments. ln recent years a class of drugs referred to as 

5-HT3 (5-hydroxytryptamine) receptor antagonists has been 

developed that treat such emesis by amagonizing cerebral 

functions associated with the 5-HT3 receptor. See Drugs Acting on 5-Hydroxytryptamine Receptors: The Lancet Sep. 23. 

1989 and references cited therein. Dn1gs within this class 

include ondansetron, granisetron, alosetron, tropisetron, and 

dolasetron. ·n1esc 5-BT3 antagonists are often administered 

intravenously shortly before chemotherapy or radiotherapy is 

initiated, and can be administered more than once during a 25 

cycle of cbemotherapy or radiotherapy. In addition, they are 

often supplied as tablets or oral elixirs to either supplement an 

intravenous administration. or to ease home usage of the drug 

Alosetron, its uses, and medicaments made with alosetron 

20 are disclosed in U.S. Pat. Nos. 5,360,800 and 6.284, 770. 

Coll1.1l1ercially it is distributed by GlaxoSmithKJine as 

Lotronex®. 

Tropisetron is coll1.1l1ercially available as Navoban® (Novartis) CAS-89565-68-4 (tropisetron); CAS-l 05826-92-4 

(tropisetron hydrochloride) and it is indicated for treatment of 

PONY and CJNV. 

if the patient is self-administering the chemotberapeutic regimen. 

Dolasetron, its uses, and medicaments made with 

ond.ansetron are disclosed in U.S. Pat. Nos. 5.01 1,846, and 

4,906.755. Coll1.1l1ercially it is distributed by Aventis Phanna30 ceuticals Inc. as Anzemet®, indicated for prevention of both 

Because some chemotherapeutic agents can induce emesis PONY and CJNV, and it is offered in the form of a tablet or an 

over extended periods of several days even when they are 

administered only once, it would bedesirabletoadministeran 

emesis-inhibiting drug such as a 5-HT3 antagonist every day 

until the risk of emesis has substantially subsided. TI1e 35 

present class of 5-HT 3 antagonists has not proven especially 

helpful meeting tbis need, however. because the 5-HT3 receptor antagonists ctm·ently marketed have proven to be less 

effective in controlling delayed nausea and vomiting than 

they are at controlling acute emesis. Sabra, K. Choice of a 40 

5HT3 Receptor Antagonist for the Hospital Formulary . EHP, 

October 1996:2 (suppl l):Sl9-24. 

Recently. clinical investigations have been made concerning palonosetron, a new 5-HT 3 receptor antagonist reported in 

U.S. Pat. No. 5.202,333. These investigations have shown 45 

that the drug is an order of magnitllde more potent than most 

existing 5-HT 3 receptor antagonists. has a surprising half-life 

of about 40 hours, and is effective to reduce delayed-onset 

nausea induced by chemotherapeutic agents. However. formulating palonosetron in liquid formu lations has not proven 50 

an easy task, typically due to shelf-stability iss1tes. U.S. Pat. 

No. 5,202,333 discloses an intravenous fonnulation of palonosetron in example I 3 that contains the fo llowing ingredients: 

intravenous solution. 

Therefore, there exists a need for a palonosetron formulation with increased stability and thereby increased shelf life. 

There also exists a need for an appropriate range of concentrations for both the 5-HT3 receptor antagonist and its pharmaceutically acceptable carriers that would faci litate making 

a fo rmulation with this increased stability. 

It is an object of the present invention to provide a formulation ofPalonosetron hydrocbloride with increased phannaceutical stability for preventing and/or reducing emesis. 

It is another object o.ftbe invention to provide <ltl acceptable 

range of concentrations which will stabilize a fonnulation 

containing Palonosetron hydrochloride. 

It is a f11rther object of the invention to provide a formulation of Palonosetron wbich would allow for prolonged storage. 

It is also an object of the invention to provide a fonnulation 

of Palonosetron which would allow tenninal sterilization. 

SUMMARY OF THE INVENTION 

111e inventors have made a series of discoveries that support a surprisingly effective and versatile formulation for tbe 

55 treatment and prevention of emesis using palonosetron. 

lngrediem 

Palonosetron HCI 

Dextrose Monohydrate 

Citric Acid Monohydrate 

Sodium Hydroxide WFJ 

M g 

10· 100 mg. 

q.s. to make Isotonic 

1.05 mg. 

O.t8 mg. 

To I.Oml. 

60 

The formu lation has a pH of3. 7 and a shelf stability ofless 65 

than the I -2 year time period required by health authorities in 

various countries. 

These formulations are shelf stable for periods greaterthau 24 

months at room temperature, and thus can be stored without 

refrigeration, and manufactllred using non-aseptic, terminal 

sterilization processes. 

ln one aspect, the inventors have discovered that formulations which include the active ingredient palonosetron require 

in some instances only Vto'" the amount of other previously 

known compounds for treating emesis. which surprisingly 

allows the use of concentrations of palonosetron far below 

those that would ordinarily be expected. Thus, in one embodiment the invention provides a pharmaceutically stable solution for preventing or reducing emesis comprising a) from 

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 14 of 39 PageID: 3972
US 8,598,219 B2 

3 

about 0.01 mglmL to about 5 mglmL palonosetron or a pharmaceutically acceptable salt d1ereof: and b) a pharmaceutically acceptable carrier. 

The inventors have further discovered that by adjusting the 

formulation's pH an<ilor excipient concentrations it is possible to increase the stability of palonosetron fo nnulations. 

'TI1erefore. in another embodiment. the invention provides a 

pharmaceutically stable solution for preventing or reducing 

emesis comprising a) palonosetron or a phannaceutically 

acceptable salt ·thereof; and b) a pharmaceutically acceptable 

carrier. at a pH from about 4.0 to about 6.0. In another 

embodiment the invention provides a pharmaceutically stable 

solution for preventing or reducing emesis comprising from 

about 0.01 to about 5.0 mg/ml palonoset.ron or a phannaceutically acceptable salt thereof; fi·om about 10 to about 100 

mi llimoles citrate buffer; and from about 0.005 to about J .0 

mg/ml EDTA. 

"llie inventors have further discovered that the addition of 

mannitol and a chelating agent can increase the stability of 

palonosetron formulations. Therefore, in still another 

embodiment the invention provides a pharmaceutically stable 

solution for preventing or reducing emesis comprising a) 

palonosetron or a pharmaceutically acceptable salt thereof 

ru1d b) a pharmaceutically acceptable carrier, wherein the 

pharmaceutically acceptable carrier comprises a chelating 

ageut and mannitol. 

DETAILED DESCRIPTION OF THE INVENTION 

Definitions 

4 

weight of the free base. Concentrations of all other ingredients are given based on the weight of ingredient added to the 

solution. 

"Pharmaceutically acceptable" means that whlch is usefi.1l 

5 in preparing a pharmaceutical composition that is generally 

safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary 

use as well as human pharmaceutical use. 

"Pharmaceutically acceptable salts" meru1s salts which are 

tO phannaceutically acceptable. as defined above, and whlch 

possess the desired pharmacological activity. Such salts 

include acid addition salts fonned with inorganic acids such 

as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric 

acid, phosphoric acid, and the like; or with organic acids such 

t5 as acetic acid. propionic acid, hexanoic acid, heptanoic acid. 

cyclopentrulepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid. succinic acid. malic acid, maleic acid, 

111maric acid, tartaric acid, citric acid, benzoic acid, o-( 4-

hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, 

20 methanesulfonic acid, ethanesulfonic acid, I ,2,-ethanedisulfonic acid, 2-hydroxyedlanesulfonic acid, benzenesulfonic 

acid p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic 

acid, p-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo[2.2.2]oct-2-ene-1 -carboxylic acid, glucoheptonic 

25 acid, 4.4'-medlyleuebis(3-hydroxy-2-ene-J -carboxylic acid), 

3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid. Iaury) sulfi.1ric acid, gluconic acid. glutamic acid, 

hydroxynaphthoic acid, salicylic acid, stearic acid, muconic 

acid, and the like. 

30 

"Vial" me.:ms a small glass container sealed with the most 

suitable stopper and seal, other suitable primary containers 

may be used. for instance, but not limited to, pre-filled 35 

syringes. Vial also means a sealed container of medication 

ln addition, phannaceutically acceptable salts may be 

termed when an acidic proton present is capable of reacting 

with inorganic or organic bases. Acceptable inorganic bases 

include sodium hydroxide, sodium carbonate, potassium 

hydroxide, a luminum hydroxide and calcium hydroxide. 

Acceptable organic bases include ethanolamine, diethrulolamine, triethanolamine, tromethamine, N-methylglucamine that is used one time only, and includes breakable and nonbreakable glass vials. breakable plastic vials, miniature 

screw-top jars, and any other type of container of a size 

capable of holding only one unit dose of palonosetron (typi- 40 

cally about 5 mls.). 

and the I ike. 

Discussion 

The fact that palouosetron can be formulated in some 

instances at concentrations of only about !/Jo'" the amount of 

other previously known compounds for treating emesis. surprisingly allows the use of concentrations of palonosetron far 

below those that would ordinarily be expected. Thus, in one 

embodiment dle invention provides a pharmaceutically stable 

Throughout this specification the word "comprise," or 

variations such as "comprises" or "comprising," will be 

understood to imply the inclusion of a stated element, integer 

or step, or group of elements. integers or steps, but not the 45 

exclusion of any other element, integer or step, or group of 

elements, integers or steps 

solution for preventing or reducing emesis comprising a) 

from about 0.01 mg/mL to about 5 mglmL palonosetron or a 

pham1aceutically acceptable salt thereof; and b) a pharmaceutically acceptable carrier. Simjlarly, in aJJOther embodiment the invention provides a method offormulatlng a pharmaceutically stable solution of palonosetron comprising 

admixing from about 0.01 mglmL to about 5 mg!mL pal-

"PaJonsetron" means (3aS)-2,3,3a,4,5,6-Hexahydro-2-

f (S)-l-Azabicyclo[2.2.2)oct-3-yl)2,3,3a,4,5,6-hexahydro-loxo-1Hbenz[de)isoquinoline, and is preferably present as the so 

monohydrochloride. Palonosetron monohydrochloride can 

be represented by the following chemical structme: 

0 

•HCt 

_.t[l 

N' ~ H 

Concentrations- When concentrations of palonosetron 

are given herein. the concentra tion is measured in terms of the 

onosetron or a phannaceutically acceptable salt tl1ereof; with 

a pharmaceutically acceptable carrier. In alternative embodiments, the formulation includes palonosetron or a phanna55 ceutically acceptable salt tl1ereof in a concentra tion from 

about 0.02 mglmL to about 1.0 mg!mL, from about 0.03 

mglmL to about 0.2 mg!mL, and most optimally about 0.05 

mg/ml. 

A particular advantage associated with the lower dosages 

60 of intravenous palonosetron is the ability to administer the 

dmg in a single intravenous bolus over a short, discrete time 

period. Tills time period generally extends from about 10 to 

about 60 seconds, or about 10 to about 40 seconds. and most 

preferably is about 10 to 30 seconds. In one particular 

65 embodiment the palonosetron is supplied in vials that comprise 5 mi. of solution. which equates to about 0.25 mg of 

palonosetron at a concentration of about 0.05 mg/ml. 

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 15 of 39 PageID: 3973
US 8,598,219 B2 

5 

The inventors have further discovered that by adj usting the 

formu lation's pH and/or excipient concentrations it is possible to increase the stability of palonosetron formulations. 

Therefore. in another embodiment, the invention provides a 

pharmaceutically stable solution for preventing or reducing 5 

emesis comprising a) palonosetron or a phanuaceuiically 

acceptable salt thereof; and b) a pharmaceutically acceptable 

carrier. at a pH from about 4.0 to about 6.0. Sinli.larly, in 

another embodiment the invemion provides a method of formulating a pharmaceutically stable solution of palonosetron 10 

comprising adnli.xing a) palonosetron or a pharmaceutically 

acceptable salt thereof; and b) a pbanuaceutically acceptable 

carrier. at a pH from about 4.0 to about 6.0. ln alternative 

embodiments, the pH is from about 4.5 to about 5.5, and most 

optimally about 5.0. There are many examples to those of skill t5 

in the art of suitable solutions to adj ust the pH of a fommlation. Two exemplary solutions are sodium hydroxide and 

bydrochloJic acid solution, either of which could be used to 

aqjust the pH of the tbnnulation. 

ln another embodiment the invention provides a phanna- 20 

ceutically stable solution for preventing or reducing emesis 

comprising from about 0.01 to about 5.0 mg/ml palonosetron 

or a phannaccutically acceptable salt thereof ru1d (i) from 

about 10 to about 100 millimoles citrate buffer, and/or (ii) 

from about 0.005 to about 1.0 mg/ml EDTA. Sinli.larly, in 25 

another embodiment the invention provides a method of formulating a pharmaceutically stable solution of palonosetron 

comprising adnli.xing from about O.Ql to about 5.0 mglml 

palonosetron or a pharmaceutically acceptable salt thereof 

and (i) from about 10 to about 100 millimolcs citrate buffer, 30 

and/or (ii) from about 0.005 to about 1.0 mg/ml EDTA. TI1e 

citrate buffer can be in the fonn of citric acid ru1d/or a salt of 

citric acid such as trisodium citrate. ln various embodiments, 

6 

tion of from about 10.0 mg/ml to about 80.0 mg/ml. from 

about20.0 mg/mL to about 60.0 mg/ml, or from about 40.0 to 

about 45.0 mg/ml. 

Injectable formu lations are typically formulated as aqueous solutions in which water is the primary excipient. Oral 

formulations will di1Ter from injectable fonuulations generally by the additional presence of flavoring agents. coloring 

agents, or viscosity agents. Natural or synthetic sweeteners 

include, among others, mannitol, sorbitol. saccharose. saccharine. aspartame, acelsuJphame K. or cyclamate. These 

agents are generally present in concentrations in excess of 

100 mglml or 250 mglml when used as sweetening agents, in 

contrast to the 41.5 mg/ml concentration of mannitol 

described in some of the embodiments of the invention. in 

which mannitol is acting simply as a tonicifying agent. 

The formulations of the present invention arc particularly 

suited for use in injectable and oral liquid formulations. but it 

will be understood that the solutions may have a ltemative 

uses. For example, they may be used as intermediates in the 

preparation of other pharmaceutical dosage forms. Sinli.larly, 

they may have other routes of administration including intranasal or inhalation. lf\jcctable fonnulations may take any 

route including intrruuuscular, intravenous or subcutru1eous. 

Still further embodiments relate to improvements in the 

ease with which the palonosetron formulation can be stored 

or manufactltred. Jn particular. tl1e inventors have discovered 

that the formulations of the present invention allow storage of 

the product for extended periods at room temperature. Thus. 

in yet another embodiment the invention provides a method of 

storing one or more containers in which are contained a 

solution of palonosctrou or a phamlaccutically acceptable 

salt thereof comprising: a) providing a room comprising said 

the ranges of one or more of the foregoi11g ingredients can be one or more containers; b) adjusting or maintaining the temmodified as follows: 

The formulation may comprise palonosetron or a pharmaceutically acceptable salt thereof ina concentration from 

about 0.02 mglmL to about J .0 mg/mL, 11-0Lu about 0.03 

mg/mL to about 0.2 mglmL palonosetron hydrochloride, and most optimally about 0.05 mglml. 

35 perature of the room at greater than about ten, 15, or 20 

degrees celcius: and c) storing said containers in said room for 

one mouth. 3 months, 6 months. one year, 18 months, 24 

months or more (but preferably not exceeding 36 months), 

wherein (i) the palonosetron or pharmaceutical salt thereof is 

TI1e formulation may comprise citrate buffer in a concentration of from about I 0 to about 40 nli.llinloles, or 15-30 

nli.llimo I es. 

40 present ina concentration off rom about 0.01 mglmL to about 

5.0 mglmL, (ii) the pf-1 of the solution is from about 4.0 to 

about 6.0, (iii) the solution comprises from about 0.01 to 

about 5.0 mg/ml palonosetron or a pharmaceutically acceptThe fomllllation may comprise EDTA in a concentration of 

from about 0.005 mg/ml to about 1.0 mglml, or about 0.3 45 

to about 0.7 mg/ml, ru1d most optimally about 0.5 

mg/ml. 

TI1e iuventors have further discovered that the addition of 

mannitol and a chelating agent can increase the stability of 

palonosetron formulations. Therefore, in still another 50 

embodiment the invention provides a pharmaceutically stable 

solution for preventing or reducing emesis comprising a) 

palonosetron or a pharmaceutically acceptable salt thereof 

and b) a pharmaceutically acceptable carrier, wherein the 

pharmaceutically acceptable carrier comprises a chelatiug 55 

agent and mannitol. Sinli.larly. in another embodiment the 

invention provides a method of formulating a pharmaceutically stable solution of palonosetron comprising adnli.xing a) 

palonosetron or a pharmaceutically acceptable salt thereof 

and b) a pharmaceutically acceptable caJTier, wherein the 60 

pharmaceutically acceptable carrier comprises a chelating 

agent and mannitol. The chelating agent is preferably EDTA, 

and. in various embodiments the chelating agent is present in 

a concentration of from about 0.005 to about 1.0 mg/mL or 

from about 0.05 mg/mLto about l.Omg/mLorfromabout 0.3 65 

to about 0.7 mg/ml. or most optimally about 0.5 mg/mL. In 

various embodiments the mannitol is present in a concentraable salt thereof. from about 10 to about 100 nli.llimoles 

citrate bu1Jerand from about 0.005 to about 1.0 mg/mJ EDTA, 

(iv) tl1e solution comprises a chelating agent. or (v) the solution comprises from about I 0 to about 100 nli.lliMoles of a 

citrate buffer. 

The stability of the foregoing formulations also lends itself 

well to ternli.nal steruizatiou processes in the manufactuJing 

process. Therefore. in still another embodiment the invention 

provides a method of filling a container in which is contained 

a solution of palonosetron or a pharmaceutically acceptable 

salt thereof comprising: a) providing one or more sterile open 

containers (preferably 5 mi. vials): b) filling said containers 

with a solution of palonosetron in a non-aseptic environment; 

c) sealing said filled containers; and d) steJilizing said sealed, 

filled containers, wherein (i) the palouosetron or pharmaceutical salt tl1ereof is present in a concentration of from about 

0.01 mg/mL to about 5 mglmL, (ii) the pH oftl1e solution is 

from about 4.0 to about 6.0, (iii) the solution comprises from 

about O.OJ to about 5.0 mg/ml palonosetron or a pharmaceutically acceptable salt thereof, from about 10 to about 100 

nli.llimoles citrate buffer and from about 0.005 to about 1.0 

mg/ml EDT..<\, (iv) the solution comprises a chelating agent, 

or (v) the solution comprises from about J 0 to about I 00 

milliMoles of a citrate bu ll'er. 

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 16 of 39 PageID: 3974
US 8,598,219 B2 

7 

EXAMPLES 

Example I 

Stabilizing pll 5 

Ingredient 

Palonosetron Hydrocb Iori de 

Mannitol 

EOTA 

Trisodium citralc 

Citric acid 

WFJ 

8 

mg/mL 

o.o5• 

!50 

0 .5 

3.7 

1.56 

q.S. IO I ml 

pH 5.0 :t 0.5 

A study was conducted to determine the effect of pH on 

formulations containing palonosetron hydrochloride, measuring the stability at 80° C. at pll2.0, 5.0, 7.4, and 10.0. The 

results indicated that palonosetron hydrochloride is most 

stable at pH 5.0. tO 

Sodium hydroxide solution a.ndlor 

hydrocbloric acid solution 

Flavorll1g q.s. 

Example 2 

Stabilizing Concentration Ranges 

A formula tion optimization study was performed using an 

experimental design software. Twenty-four lots of drug prod15 Example 6 

Stability ofPalonosetron without Dexamethasone 

uct were analyzed to investigate the appropriate concentration ranges for palonosetron hydrochloride (0.05 mglmL to 

5.0 mg/mL), citrate buffer (0 to 80 mM) and EDTA (0 to 20 

0. 10%). 1l1e level of EDTA and citrate buffer were selected 

based on the optimal formulation, which was shown to be 

formulated with EDTA 0.05% and 20 mM citrate buffer at pi-1 

5.0. The results of this st11dy indicated that palonosetron 

concentration was also a crit·ical factor in chemical stability, 25 

with greatest stability seen at the lowest palonosetron concentrations. 

The physical and chemjcal stability of palonosetron HCI 

was studies in concentrations of5 ~tg/m nd 30 ~tg/mL in 5% 

dextrose injection, 0.9% sodium chloride injection, 5% dextrose in 0.45% sodium chloride injec6on, and dex-trose 5% in 

lactated Ringer's injection. The admixtures were evaluated 

over I 4 days at 4° C. in the dark and for 48 hours at 23° C. 

under fluorescent light. 

Test samples of palonosetron FICI were prepared in polyvinyl chloride (PVC) bags of the infi.1sion solutions at concentrations of 5 and 30 ~tg/mL. Evaluations for physical and 

Example3 chemical stability were performed on samples taken initially 

Tonicifying Agent 

Formulations of palonosetron hydrochloride in citrate 

bu !fer were prepared including either a) sodium cb Iori de orb) 

mamutol. Tile palonosetron hydrochloride lommlation 

including mannitol showed superior stability. The optimum 

level of mannitol required for an isotonic solution was found 

to be 4.15%. 

Example 4 

Fonnulation I 

30 and after I. 3. 5, 7. and 14 days of storage at 4° C. and after 1, 

4, 24, and 48 hours at 23° C. Physical stability was assessed 

using visual observation ill normal room light and using a 

hjgh-intensity monodirectional light beam. In addition, turbidity and particle content were measured electronically. 

35 Chemical stability of the dntg was evaluated by using a stability-indicating high performance liquid chromatograpruc 

(HPLC) analytical technique. 

All samples were physically stable throughout the study. 

The solution remained clear. and little or no change in par40 ticu late burden and haze level were found. Additiona lly, little 

or no loss ofpalonosetron HCI occurred in any of the samples 

at either temperature throughout the entire study period. 

The following is a representative pharmaceutical formulation containing palonosetron that is useful for intravenous 45 

formulations, or other liquid formulations of the drug. 

Example 7 

Stability of Palonosetron with Dexamethasone 

Ingredient 

Palonoselron Hydrochloride 

M:mnitol 

EDTA 

Trisodium citrate 

Citticncid 

WFJ 

Sodium hydroxide solution and/or 

hydrochloric acid soluJjon 

• calculated as a Cree base 

Example 5 

Formulation II 

mglmL 

0.05* 

41.5 

0.5 

3.7 

1.56 

q.s.to I ml 

pH 5.0:0.5 

The following is a representative pharmaceutical formula -

tion containing palonosetron that is useful for oral fommlations, or other liquid formulations of the drug. 

The physical and chemical stability of palonosetron HCI 

0.25 rug admixed with dexamethasone (as sodium phosphate) 

50 10 mg or 20 mg in 5% dextrose injection or 0.9% soditun 

chloride ~jection in polyvinyl chloride (PVC) mini bags, and 

also admixed with dcxametllasone (as sodimu phosphate) 3.3 

mg in 5% dextrose injection or 0.9% soditUll chloride injecl'ion in polypropylene syringes at 4° C. in the dark for 14 days 

55 and at 23° C. exposed to normal laboratory fluorescent light 

over 48 hours, was studied. 

Test samples of palonosetron HCJ 5 ~tg/mL with dexameiliasone (as soditun phosphate) 0.2 mg/mL and also 0.4 

mg/mL were prepared in polyvi11yl chloride (PVC) mini bags 

60 of each infusion solution. Additionally, palonosetron HCI 25 

~tg/mL with dexamethasone (as sodium phosphate) 0.33 

mglmL in each infusion solution were prepared as 10 mL of 

test solution in 20-mL polypropylene syringes. Evaluations 

for physical and chemical stability were performed on 

65 samples taken initially and after 1, 3, 7, and 14 days of storage 

at 4° C. and after !. 4. 24, and 48 hours at 23° C. Physical 

stability was assessed using visual observation in nonual 

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 17 of 39 PageID: 3975
US 8,598,219 B2 

9 room light and using a high-intensity monodirectional light 

beam. In addition, mrbidity and particle content were measured electronically. Chemical stability of the drug was evaluated by using a stability-indicating high performance liquid 

chromatographic (I-IPLC) analytical technique. 

10 

What is clainled is: 

1. A phannaceutical single-use, unit-dose formulation for 

intravenous administration to a human to rt'<luce the like lihood of cancer chemotherapy-induced nausea and vomiting, 

5 comprising a 5 mL sterile aqueous isotonic solution, said 

All samples were physically compatible throughout the 

study. The solutions remained clear, and little or no change in 

particulate burden and haze level were found. Additionally, 

little or no loss of palonosetron HCI and dexamethasone 

occurred in any of the samples at either temperature through- 10 

olll the entire study period. 

solution comprising: 

palonosetron hydrochloride in an amount of0.25 rug based 

on the weight of its free base; 

from 0.005 mg/mL to 1.0 mg/mL EDTA; and 

from J 0 mg/mL to 80 mg/mL mannitol, 

wherein said formulation is stable at 24 months when 

stored at room tempemtlrre. 

Example 8 

Formulation Ill 

TI1e following is a representative phannaceutical formulation and container closure for palonosetron that is use.fi.tl Jor 

intmvenous infusion fomllllations. 

Ingredient 

Palonosetron Hydrochloride 

Sodiwn Chloride 

EDTA 

Sodiwn ciu-a1e 

Citric acid monohydrate 

WFJ 

Soditun hydroxide solution :tnd!or 

hydrochloric acid solution 

Container closure system 

"'Calcul31C:d ba5ed on the weight of free base 

b>J>ol)><lhyleoe multilo)'<f film infusion bag. 

<-> Jsopreoc: rubber stopper. 

Amomtt (mg) 

0.75") 

450.0 

2.5 

18.5 

7.8 

q.s. to 50 rnL 

pH 4.8>: 0.5 

plastic containcrb) 

plus rubber stopperl 

This invention has been described with reference to its 

preferred embodinlents. Variations and modifications of the 

invention will be obvious to those skilled in the art from the 

foregoing detailed description oftl1e invention. 

t5 

2. The pharmaceutical formulation of claim 1, wherein said 

EDTA is in an amomlt of0.5 mg/mL. 

3. The pharmaceutical formu lation of claim 1, wherein said 

mannitol is in an an10unt of 41.5 mg/mL. 

4. The pharmaceutical formulation of claim 1, wherein said 

solution further comprises a citmte buffer. 

5. lbe pham1aceutical formulation of claim 4, wherein said 

20 citrate buffer is at a concentration of 20 millinlolar. 

6. The pharmaceutical formu lation of claim 1, wherein said 

solution is buffered at a pH of 5.0 :t0.5. 

7. The pham1accutical formulation of claiml, wherein said 

EDTA is in an amOtmt of0.5 mg/mL, wherein said mannitol 

25 is in an amount of 4 J .5 mglmL, wherein said solution f·urtJ1er 

comprises a citrate buffer at a concentration of20 millimolar, 

and wherein said solution is buffered at a pH of 5.0 :t0.5. 

8. A pharmaceutical single-use, unit-dose formulation for 

intravenous administration to a htunan to reduce the li.keli30 hood of cancer chemotherapy-induced nausea and vomiting, 

comprising a 5 mL sterile aqueous isotonic solution, said 

solution comprisi11g: 

35 

palonosetron hydrochloride in an amount of0.25 mg based 

on the weight of its free base; 

from 0.005 mglmL to 1.0 mglmL EDTA; and 

from 10 mglmL to 80 mglmL mannitol, wherein said formulation is stable at 18 months when stored a t room 

temperatlu·e. 

* * * * * 

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 18 of 39 PageID: 3976
EXHIBIT 2

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 19 of 39 PageID: 3977
UNITED STATES DISTRICT COURT 

DISTRICT OF NEW JERSEY 

__________________________________________ 

HELSINN HEALTHCARE S.A. and : 

ROCHE PALO ALTO LLC., : 

 : 

 Plaintiffs, : 

 : Civil Action No. 13-5815 (MLC)(DEA) 

 v. : 

 : 

DR. REDDY’S LABORATORIES, LTD., : 

DR. REDDY’S LABORATORIES, INC., :

SANDOZ INC., TEVA PHARMACEUTICALS : Hon. Mary L. Cooper, U.S.D.J. 

USA, INC., and TEVA PHARMACEUTICAL : Hon. Douglas E. Arpert, U.S.M.J. 

INDUSTRIES, LTD., : 

 : 

 Defendants. : 

 : 

DEFENDANTS’ PROPOSED CLAIM TERMS FOR CONSTRUCTION 

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 20 of 39 PageID: 3978
2 

Michael E. Patunas 

Mayra V. Tarantino 

LITE DEPALMA GREENBERG, LLC 

Two Gateway Center 

Suite 1201 

Newark, NJ 07102 

(973) 623-3000 

mpatunas@litedepalma.com 

mtarantino@litedepalma.com 

Of Counsel: 

George C. Lombardi 

Lynn MacDonald Ulrich 

Julia M. Johnson 

David Luger 

WINSTON & STRAWN LLP 

35 West Wacker Drive 

Chicago, IL 60601 

(312) 558-5600 

glombardi@winston.com 

lulrich@winston.com 

jmjohnson@winston.com 

dluger@winston.com 

Jovial Wong 

WINSTON & STRAWN LLP 

1700 K Street 

Washington, DC 20006 

(202) 282-5000 

jwong@winston.com 

Attorneys for Defendants 

Teva Pharmaceuticals USA, Inc. and Teva 

Pharmaceutical Industries Ltd.

Eric I. Abraham 

Christina Saveriano 

HILL WALLACK LLP 

202 Carnegie Center 

Princeton, NJ 08540 

(609) 924-0808 

eabraham@hillwallack.com 

csaverino@hillwallack.com 

Of Counsel: 

David Doyle 

Elizabeth Cary Miller 

MORRISON & FOERSTER LLP 

12531 High Bluff Drive, Suite 1000 

San Diego, CA 92130 

(858) 720-5100 

ddoyle@mofo.com 

emiller@mofo.com 

Matthew D’Amore 

Jayson L. Cohen 

Hui Liu 

MORRISON & FOERSTER LLP 

1290 Avenue of the Americas 

New York, NY 10104-0050 

(212) 468-8000 

mdamore@mofo.com 

jcohen@mofo.com 

hliu@mofo.com 

Attorneys for Defendant Sandoz Inc. 

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 21 of 39 PageID: 3979
3 

Stuart D. Sender 

Michael H. Imbacuan 

Stephanie L. Donahue 

H. Howard Wang 

BUDD LARNER, P.C. 

150 John F. Kennedy Parkway 

Short Hills, NJ 07078-0999 

(973) 379-4800 

ssender@buddlarner.com 

mimbacuan@buddlarner.com 

sdonahue@buddlarner.com 

hwang@buddlarner.com 

 

Attorneys for Defendants 

Dr. Reddy’s Laboratories, Ltd. and 

Dr. Reddy’s Laboratories, Inc. 

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 22 of 39 PageID: 3980
4 

Pursuant to the Court’s March 4, 2014 Pretrial Scheduling Order, and the parties’ 

subsequent agreement, Defendants Teva Pharmaceuticals USA, Inc. and Teva Pharmaceutical 

Industries Ltd. (“Teva”), Dr. Reddy’s Laboratories, Ltd. and Dr. Reddy’s Laboratories, Inc. 

(“DRL”), and Sandoz Inc. (“Sandoz”) (collectively, “Defendants”) hereby identify the following 

proposed terms to be construed for the asserted claims of U.S. Patent Nos. 8,518,981 (the “’981 

patent”); 8,598,218 (the “’218 patent”); and 8,598,219 (the “’219 patent”). Defendants reserve 

the right to include additional terms or withdraw terms, and Defendants will continue to evaluate 

whether constructions of any terms are appropriate based on Plaintiffs’ proposed terms and 

constructions. 

Claim Term Asserted Patents and Claims 

“filling said containers” Claim 1 of the ’981 patent 

Claims 1 and 11 of the ’218 patent 

“A method of manufacturing and terminally 

sterilizing a finished single unit dose vial of 

palonosetron or a pharmaceutically acceptable 

salt thereof comprising” 

Claim 1 of the ’981 patent 

Claims 1 and 11 of the ’218 patent 

“A pharmaceutical single-use, unit-dose 

formulation for intravenous administration to a 

human to reduce the likelihood of cancer 

chemotherapy-induced nausea and vomiting 

comprising” 

Claims 1 and 8 of the ’219 patent 

“pharmaceutically stable” Claim 1 of the ’981 patent 

Claims 1 and 11 of the ’218 patent 

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 23 of 39 PageID: 3981
5 

By: 

LITE DEPALMA GREENBERG, LLC 

Attorneys for Defendants Teva 

Pharmaceuticals USA, Inc. and Teva 

Pharmaceutical Industries, Ltd. 

By: /s/ Mayra V. Tarantino 

 Michael E. Patunas 

 Mayra V. Tarantino 

 Two Gateway Center 

 Suite 1201 

 Newark, NJ 07102 

Dated: May 5, 2014 

BUDD LARNER, P.C. 

Attorneys for Defendants Dr. Reddy’s 

Laboratories, Ltd. and Dr. Reddy’s 

Laboratories, Inc. 

By: /s/ Michael H. Imbacuan 

 Stuart D. Sender 

 Michael H. Imbacuan 

 Stephanie L. Donahue 

 H. Howard Wang 

 150 John F. Kennedy Parkway 

 Short Hills, NJ 07078-0999 

 

Dated: May 5, 2014 

HILL WALLACK LLP 

Attorneys for Defendant Sandoz Inc. 

By: /s/ Eric I. Abraham 

 Eric I. Abraham 

 202 Carnegie Center 

 Princeton, NJ 08540 

 

Dated: May 5, 2014 

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 24 of 39 PageID: 3982
EXHIBIT 3

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 25 of 39 PageID: 3983
UNITED STATES DISTRICT COURT

DISTRICT OF NEW JERSEY

__________________________________________ HELSINN HEALTHCARE S.A. and :

ROCHE PALO ALTO LLC., :

:

Plaintiffs, :

: Civil Action No. 13-5815 (MLC)(DEA)

v. :

:

DR. REDDY’S LABORATORIES, LTD., :

DR. REDDY’S LABORATORIES, INC., :

SANDOZ INC., TEVA PHARMACEUTICALS : Hon. Mary L. Cooper, U.S.D.J.

USA, INC., and TEVA PHARMACEUTICAL : Hon. Douglas E. Arpert, U.S.M.J.

INDUSTRIES, LTD., :

:

Defendants. :

:

DEFENDANTS’ PRELIMINARY CLAIM CONSTRUCTIONS

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 26 of 39 PageID: 3984
2

Michael E. Patunas

Mayra V. Tarantino

LITE DEPALMA GREENBERG, LLC

Two Gateway Center

Suite 1201

Newark, NJ 07102

(973) 623-3000

mpatunas@litedepalma.com

mtarantino@litedepalma.com

Of Counsel:

George C. Lombardi

Lynn MacDonald Ulrich

Julia M. Johnson

David Luger

WINSTON & STRAWN LLP

35 West Wacker Drive

Chicago, IL 60601

(312) 558-5600

glombardi@winston.com

lulrich@winston.com

jmjohnson@winston.com

dluger@winston.com

Jovial Wong

WINSTON & STRAWN LLP

1700 K Street

Washington, DC 20006

(202) 282-5000

jwong@winston.com

Attorneys for Defendants

Teva Pharmaceuticals USA, Inc. and Teva

Pharmaceutical Industries Ltd.

Eric I. Abraham

Christina Saveriano

HILL WALLACK LLP

202 Carnegie Center

Princeton, NJ 08540

(609) 924-0808

eabraham@hillwallack.com

csaverino@hillwallack.com

Of Counsel:

David Doyle

Elizabeth Cary Miller

MORRISON & FOERSTER LLP

12531 High Bluff Drive, Suite 1000

San Diego, CA 92130

(858) 720-5100

ddoyle@mofo.com

emiller@mofo.com

Matthew D’Amore

Jayson L. Cohen

Hui Liu

MORRISON & FOERSTER LLP

250 W. 55th Street

New York, NY 10019-9601

(212) 468-8000

mdamore@mofo.com

jcohen@mofo.com

hliu@mofo.com

Attorneys for Defendant Sandoz Inc.

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 27 of 39 PageID: 3985
3

Stuart D. Sender

Michael H. Imbacuan

Stephanie L. Donahue

H. Howard Wang

BUDD LARNER, P.C.

150 John F. Kennedy Parkway

Short Hills, NJ 07078-2703

(973) 379-4800

ssender@buddlarner.com

mimbacuan@buddlarner.com

sdonahue@buddlarner.com

hwang@buddlarner.com

Attorneys for Defendants

Dr. Reddy’s Laboratories, Ltd. and

Dr. Reddy’s Laboratories, Inc.

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 28 of 39 PageID: 3986
4

Pursuant to the Court’s March 4, 2014 Pretrial Scheduling Order, and the parties

subsequent agreement, Defendants Teva Pharmaceuticals USA, Inc. and Teva Pharmaceutical

Industries Ltd. (“Teva”), Dr. Reddy’s Laboratories, Ltd. and Dr. Reddy’s Laboratories, Inc.

(“DRL”), and Sandoz Inc. (“Sandoz”) (collectively, “Defendants”) hereby identify the following

preliminary constructions for each of the proposed terms to be construed for the asserted claims

of U.S. Patent Nos. 8,518,981 (the “’981 patent”); 8,598,218 (the “’218 patent”); and 8,598,219

(the “’219 patent”). Defendants further identify/designate all evidence that Defendants intend to

rely upon to support the proposed constructions. Defendants reserve the right to include

additional terms or withdraw terms, and Defendants will continue to evaluate whether

constructions of any terms are appropriate based on Plaintiffs’ proposed terms and constructions.

Claim Term Preliminary Construction Evidence

“filling said containers” Claim 1 of the ’981 patent

Claims 1 and 11 of the ’218

patent

“filling said containers in a

non-aseptic process”

The ‘981 patent, col. 1, line 10-col.

10, line 38;

The ‘218 patent, col. 1, line 10-col.

10, line 47;

U.S. Provisional Application No.

60/444,351;

Application No.

PCT/EP2004/000888;

The prosecution history of U.S.

Application No. 13/087,012

generally, including at least  Application filed 4/14/2011

 Preliminary Amendment

dated 4/14/2011

 Declaration of Valentino J.

Stella, Ph.D. dated

9/19/2007

 Declaration of Daniele

Bonadeo dated 2/9/2009

 Supplemental Declaration

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 29 of 39 PageID: 3987
5

of Daniele Bonadeo dated

6/8/2009

 Office Action dated

3/12/2012

 Amendment and Response

dated 7/2/2012

 Office Action dated

7/19/2012

 Amendment and Response

dated 7/26/2012

 Supplemental Amendment

dated 12/26/2012

 Amendment Under 37 CFR

1.312 dated 3/20/2013

 Response to Rule 312

Communication dated

4/4/2013

 Amendment to Accompany

RCE dated 5/23/2013

 Interview Summary dated

6/13/2013

 Applicant Summary of

Examiner Interview dated

6/17/2013

 Reasons for Allowance

dated 7/3/2013

 All references cited during

prosecution

The prosecution history of U.S.

Application No. 13/901,288

generally, including at least  Application filed 5/23/2013

 Preliminary Amendment

dated 5/23/2013

 Applicant Summary of

Examiner Interview dated

6/17/2013

 Interview Summary dated

8/22/2013

 Reasons for Allowance

dated 9/6/2013

 All references cited during

prosecution

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 30 of 39 PageID: 3988
6

Remington, The Science and

Practice of Pharmacy, 20th ed.

(2000), Chapters 40-42 and 52.

Pharmaceutical Dosage Forms:

Parenteral Medications, Volume 1,

Ch. 4 (Kenneth E. Avis et al., ed.)

(Marcel Dekker Inc. 2d ed. 1992).

“A method of manufacturing

and terminally sterilizing a

finished single unit dose vial

of palonosetron or a

pharmaceutically acceptable

salt thereof comprising”

Claim 1 of the ’981 patent

Claims 1 and 11 of the ’218

patent

Defendants do not believe

that this term is a limitation

of the asserted claims. If

the Court finds that this

term is a limitation and

should be construed, it

should be construed as:

“A method of

manufacturing using non- aseptic processes and

terminally sterilizing a

finished single unit dose

vial of palonosetron or a

pharmaceutically

acceptable salt thereof

comprising”

Am. Med. Sys. v. Biolitec, Inc., 618

F.3d 1354 (Fed. Cir. 2010);

Symantex Corp. v. Computer

Assocs. Int’l, Inc., 522 F.3d 1279

(Fed. Cir. 2008); Catalina

Marketing Int’l v.

Coolsavings.com, 289 F.3d 801

(Fed. Cir. 2002); Bristol-Myers

Squibb Co. v. Ben Venue Labs.,

Inc., 246 F.3d 1368 (Fed. Cir.

2001); IMS Tech, Inc. v. Haas

Automation, Inc., 206 F.3d 1422,

(Fed. Cir. 2000); STX LLC v.

Brine, Inc., 211 F.3d 588 (Fed Cir.

2000); Pitney Bowes, Inc. v.

Hewlett-Packard Co., 182 F.3d

1298 (Fed. Cir. 1999); Rowe v.

Dror, 112 F.3d 473 (Fed. Cir.

1997). The ‘981 patent, col. 1, line 10-col.

10, line 38;

The ‘218 patent, col. 1, line 10-col.

10, line 47;

U.S. Provisional Application No.

60/444,351;

Application No.

PCT/EP2004/000888;

The prosecution history of U.S.

Application No. 13/087,012

generally, including at least  Application filed 4/14/2011

 Preliminary Amendment

dated 4/14/2011

 Declaration of Valentino J.

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 31 of 39 PageID: 3989
7

Stella, Ph.D. dated

9/19/2007

 Declaration of Daniele

Bonadeo dated 2/9/2009

 Supplemental Declaration

of Daniele Bonadeo dated

6/8/2009

 Office Action dated

3/12/2012

 Amendment and Response

dated 7/2/2012

 Office Action dated

7/19/2012

 Amendment and Response

dated 7/26/2012

 Supplemental Amendment

dated 12/26/2012

 Amendment Under 37 CFR

1.312 dated 3/20/2013

 Response to Rule 312

Communication dated

4/4/2013

 Amendment to Accompany

RCE dated 5/23/2013

 Interview Summary dated

6/13/2013

 Applicant Summary of

Examiner Interview dated

6/17/2013

 Reasons for Allowance

dated 7/3/2013

 All references cited during

prosecution

The prosecution history of U.S.

Application No. 13/901,288

generally, including at least  Application filed 5/23/2013

 Preliminary Amendment

dated 5/23/2013

 Applicant Summary of

Examiner Interview dated

6/17/2013

 Interview Summary dated

8/22/2013

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 32 of 39 PageID: 3990
8

 Reasons for Allowance

dated 9/6/2013

 All references cited during

prosecution

Remington, The Science and

Practice of Pharmacy, 20th ed.

(2000), Chapters 40-42 and 52.

Pharmaceutical Dosage Forms:

Parenteral Medications, Volume 1,

Ch. 4 (Kenneth E. Avis et al., ed.)

(Marcel Dekker Inc. 2d ed. 1992). “A pharmaceutical single- use, unit-dose formulation

for intravenous

administration to a human to

reduce the likelihood of

cancer chemotherapyinduced nausea and vomiting

comprising” Claims 1 and 8 of the ’219

patent

Defendants do not believe

that this term is a limitation

of the asserted claims. If

the Court finds that this

term is a limitation and

should be construed, it

should be construed as: “A pharmaceutical single- use, unit-dose formulation

comprising”

Am. Med. Sys. v. Biolitec, Inc., 618

F.3d 1354 (Fed. Cir. 2010);

Symantex Corp. v. Computer

Assocs. Int’l, Inc., 522 F.3d 1279

(Fed. Cir. 2008); Catalina

Marketing Int’l v.

Coolsavings.com, 289 F.3d 801

(Fed. Cir. 2002); Bristol-Myers

Squibb Co. v. Ben Venue Labs.,

Inc., 246 F.3d 1368 (Fed. Cir.

2001); IMS Tech, Inc. v. Haas

Automation, Inc., 206 F.3d 1422,

(Fed. Cir. 2000); STX LLC v.

Brine, Inc., 211 F.3d 588 (Fed Cir.

2000); Pitney Bowes, Inc. v.

Hewlett-Packard Co., 182 F.3d

1298 (Fed. Cir. 1999); Rowe v.

Dror, 112 F.3d 473 (Fed. Cir.

1997). The ‘219 patent, col. 1, line 10-col.

10, line 38;

U.S. Provisional Application No.

60/444,351;

Application No.

PCT/EP2004/000888;

The prosecution history of U.S.

Application No. 11/186,311

generally;

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 33 of 39 PageID: 3991
9

The prosecution history of U.S.

Application No. 11/388,268

generally;

The prosecution history of U.S.

Application No. 11/388,269

generally;

The prosecution history of U.S.

Application No. 11/388,270

generally;

The prosecution history of U.S.

Application No. 13/087,012

generally, including at least  Application filed 4/14/2011

 Preliminary Amendment

dated 4/14/2011

 Declaration of Valentino J.

Stella, Ph.D. dated

9/19/2007

 Declaration of Daniele

Bonadeo dated 2/9/2009

 Supplemental Declaration

of Daniele Bonadeo dated

6/8/2009

 Office Action dated

3/12/2012

 Amendment and Response

dated 7/2/2012

 Office Action dated

7/19/2012

 Amendment and Response

dated 7/26/2012

 Supplemental Amendment

dated 12/26/2012

 Amendment Under 37 CFR

1.312 dated 3/20/2013

 Response to Rule 312

Communication dated

4/4/2013

 Amendment to Accompany

RCE dated 5/23/2013

 Interview Summary dated

6/13/2013

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 34 of 39 PageID: 3992
10

 Applicant Summary of

Examiner Interview dated

6/17/2013

 Reasons for Allowance

dated 7/3/2013

 All references cited during

prosecution

The prosecution history of U.S.

Application No. 13/901,288

generally, including at least  Application filed 5/23/2013

 Preliminary Amendment

dated 5/23/2013

 Applicant Summary of

Examiner Interview dated

6/17/2013

 Interview Summary dated

8/22/2013

 Reasons for Allowance

dated 9/6/2013

 All references cited during

prosecution

The prosecution history of U.S.

Application No. 13/901,437

generally, including at least  Application filed 5/23/2013

 Applicant Summary of

Examiner Interview dated

6/17/2013

 Interview Summary dated

7/11/2013

 Office Action dated

7/12/2013

 Interview Summary dated

7/22/2013

 Office Action dated

7/24/2013

 Office Action dated

7/29/2013

 Amendment and Response

dated 7/30/2013

 Interview Summary dated

9/30/2013

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 35 of 39 PageID: 3993
11

 Reasons for Allowance

dated 9/30/2013

 All references cited during

prosecution

“pharmaceutically stable”

Claim 1 of the ’981 patent

Claims 1 and 11 of the ’218

patent

“without significant change

in chemical or physical

integrity for

pharmaceutical use”

The ‘981 patent, col. 1, line 10-col.

10, line 38;

The ‘218 patent, col. 1, line 10-col.

10, line 47;

U.S. Provisional Application No.

60/444,351;

Application No.

PCT/EP2004/000888;

The prosecution history of U.S.

Application No. 11/186,311

generally;

The prosecution history of U.S.

Application No. 11/388,268

generally;

The prosecution history of U.S.

Application No. 11/388,269

generally;

The prosecution history of U.S.

Application No. 11/388,270

generally;

The prosecution history of U.S.

Application No. 13/087,012

generally, including at least  Application filed 4/14/2011

 Preliminary Amendment

dated 4/14/2011

 Declaration of Valentino J.

Stella, Ph.D. dated

9/19/2007

 Declaration of Daniele

Bonadeo dated 2/9/2009

 Supplemental Declaration

of Daniele Bonadeo dated

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 36 of 39 PageID: 3994
12

6/8/2009

 Office Action dated

3/12/2012

 Amendment and Response

dated 7/2/2012

 Office Action dated

7/19/2012

 Amendment and Response

dated 7/26/2012

 Supplemental Amendment

dated 12/26/2012

 Amendment Under 37 CFR

1.312 dated 3/20/2013

 Response to Rule 312

Communication dated

4/4/2013

 Amendment to Accompany

RCE dated 5/23/2013

 Interview Summary dated

6/13/2013

 Applicant Summary of

Examiner Interview dated

6/17/2013

 Reasons for Allowance

dated 7/3/2013

 All references cited during

prosecution

The prosecution history of U.S.

Application No. 13/901,288

generally, including at least  Application filed 5/23/2013

 Preliminary Amendment

dated 5/23/2013

 Applicant Summary of

Examiner Interview dated

6/17/2013

 Interview Summary dated

8/22/2013

 Reasons for Allowance

dated 9/6/2013

 All references cited during

prosecution

The United States Pharmacopeia

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 37 of 39 PageID: 3995
13

USP 25, General Information,

<1151> Pharmaceutical Dosage

Forms (2002);

Guidance for Industry, Q1A (R2)

Stability Testing of New Drug

Substances and Products, USFDA,

2003 (Revision 2);

ICH Harmonised Tripartite

Guideline, Stability Testing of

New Drug Substances and

Products Q1A (R2)(2003);

ICH Harmonised Tripartite

Guideline, Stability Testing of

New Drug Substances and

Products Q1A (1993);

P. P. DeLuca and J.C. Boylan,

Formulation of Small Volume

Parenterals, in Pharmaceutical

Dosage Forms: Parenteral

Medications, Volume 1, Chapter 5,

173-248 (Kenneth E. Avis et al.

eds., Marcel Dekker Inc., 2d ed.

1992).

Remington, The Science and

Practice of Pharmacy, 20th ed.

(2000), Chapters 41, 42 and 52.

The parties’ claim construction

briefing and related materials in

Case No. 3:11-03962 concerning

“pharmaceutically stable.”

1

1 Defendants are amenable to construing this term at trial rather than briefing this term for a

second time, as per the Court’s guidance in Case No. 3:11-03962.

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 38 of 39 PageID: 3996
14

By:

LITE DEPALMA GREENBERG, LLC

Attorneys for Defendants Teva

Pharmaceuticals USA, Inc. and Teva

Pharmaceutical Industries, Ltd.

By: /s/ Mayra V. Tarantino

Michael E. Patunas

Mayra V. Tarantino

Two Gateway Center

Suite 1201

Newark, NJ 07102

Dated: May 12, 2014

BUDD LARNER, P.C.

Attorneys for Defendants Dr. Reddy’s

Laboratories, Ltd. and Dr. Reddy’s

Laboratories, Inc.

By: /s/ Michael H. Imbacuan

Stuart D. Sender

Michael H. Imbacuan

Stephanie L. Donahue

H. Howard Wang

150 John F. Kennedy Parkway

Short Hills, NJ 07078-2703

Dated: May 12, 2014

HILL WALLACK LLP

Attorneys for Defendant Sandoz Inc.

By: /s/ Eric I. Abraham

Eric I. Abraham

Christina Saveriano

202 Carnegie Center

Princeton, NJ 08540

Dated: May 12, 2014

Case 3:11-cv-03962-MLC-DEA Document 178 Filed 06/20/14 Page 39 of 39 PageID: 3997