recro vs actavis

IN THE UNITED STATES DISTRICT COURT

FOR THE DISTRICT OF DELAWARE

RECRO GAINESVILLE LLC,

Plaintiff,

v.

ACTAVIS LABORATORIES FL, INC.,

Defendant.

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C.A. No. 14-1118 (GMS)

CONSOLIDATED

HIGHLY CONFIDENTIAL

FILED UNDER SEAL

RECRO’S PROPOSED POST-TRIAL

FINDINGS OF FACT AND CONCLUSIONS OF LAW

MORRIS, NICHOLS, ARSHT & TUNNELL LLP

Jack B. Blumenfeld (#1014)

Maryellen Noreika (#3208)

Jeremy A. Tigan (#5239)

Megan E. Dellinger (#5739)

1201 North Market Street

P.O. Box 1347

Wilmington, DE 19899-1347

(302) 658-9200

[email protected]

[email protected]

[email protected]

[email protected]

Attorneys for Recro Gainesville LLC

November 7, 2016

REDACTED - PUBLIC VERSIONFILED 11/14/2016

Case 1:14-cv-01118-GMS Document 131 Filed 11/14/16 of 43 PageID #: 2688

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TABLE OF CONTENTS

Page

TABLE OF AUTHORITIES ......................................................................................................... iii

INTRODUCTION .....................................................................................................................1 I.

PROPOSED FINDINGS OF FACT ..............................................................................................1 II.

Zohydro® ER ...........................................................................................................1 A.

POSA .......................................................................................................................3 B.

Infringement of the ’096 Patent ...............................................................................3 C.

Actavis’s Ethylcellulose-Based Coating Is Equivalent to the 1.

Claimed Polyacrylic Coatings ......................................................................5

The Inventors Did Not Dedicate Ethylcellulose to the 2.

Public ...........................................................................................................8

The Excipients Added to Actavis’s Ethylcellulose-Based 3.

Coatings Are Disclosed in the Specification and Permitted

by the Claims .............................................................................................10

Infringement of the ’742 Patent .............................................................................11 D.

Actavis’s Active-Ingredient-Containing Pellets Comprise a 1.

First and a Subsequent Population of Particles ..........................................12

Actavis’s Active-Ingredient-Containing Pellets Deliver 2.

Hydrocodone “In a Pulsatile Manner” .......................................................16

a. The “Release” of Active Ingredient from Actavis’s

ANDA Products Is Pulsatile ..........................................................16

b. The Plasma Concentration Profile Is Characterized

by Two or More Peaks Interspersed with Low

Concentration Troughs...................................................................18

The Asserted Dependent Claims Are Also Infringed ................................23 3.

PROPOSED CONCLUSIONS OF LAW .....................................................................................24 III.

Actavis Infringes Claims 1, 4, and 5 of the ’096 Patent ........................................25 A.

The Inventors Did Not Dedicate Ethylcellulose to the 1.

Public .........................................................................................................26


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Claim 1 of the ’096 Patent Does Not Foreclose the Use of 2.

the Common Excipients Actavis Included in Its

Ethylcellulose-Based Coating ....................................................................28

Actavis’s ANDA Products Infringe the Asserted Claims of the B.

’742 Patent .............................................................................................................30

Relief ......................................................................................................................35 C.


- iii -

TABLE OF AUTHORITIES

Page(s)

Cases

Abbott Labs. v. Baxter Pharm. Prods., Inc.,

334 F.3d 1274 (Fed. Cir. 2003)................................................................................................29

Abbott Labs. v. TorPharm, Inc.,

300 F.3d 1367 (Fed. Cir. 2002)................................................................................................30

Acorda Therapeutics Inc. v. Apotex Inc.,

C.A. No. 07-4937-GEB-MCA, 2011 WL 4074116 (D.N.J. Sept. 6, 2011) .............................32

Adams Respiratory Therapeutics, Inc. v. Perrigo Co.,

616 F.3d 1283 (Fed. Cir. 2010)................................................................................................30

Advanced Cardiovascular Sys., Inc. v. Scimed Life Sys., Inc.,

261 F.3d 1329 (Fed. Cir. 2001)................................................................................................24

Allergan, Inc. v. Watson Labs., Inc.-Fla.,

869 F. Supp. 2d 456 (D. Del. 2012) .........................................................................................31

Arcelormittal France v. AK Steel Corp.,

C.A. No. 10-50-SLR, 2011 WL 63417 (D. Del. Jan. 4, 2011) ................................................27

Baxter Healthcare Corp. v. Spectramed, Inc.,

49 F.3d 1575 (Fed. Cir. 1995)..................................................................................................24

Broadcom Corp. v. Emulex Corp.,

732 F.3d 1325 (Fed. Cir. 2013)................................................................................................31

E.I. Du Pont de NeMours & Co. v. Heraeus Precious Metals N. Am.

Conshohocken LLC,

No. 12-1104-HU, 2013 WL 2659533 (D. Or. June 7, 2013) ...................................................29

Eastman Kodak Co. v. Agfa Gevaert N.V.,

560 F. Supp. 2d 227 (W.D.N.Y. 2008) ..............................................................................33, 34

Eli Lilly & Co. v. Teva Pharm. USA, Inc.,

557 F.3d 1346 (Fed. Cir. 2009)................................................................................................35

Epistar Corp. v. ITC,

566 F.3d 1321 (Fed. Cir. 2009)................................................................................................34

Ferring B.V. v. Watson Labs., Inc.-Florida,

764 F.3d 1401 (Fed. Cir. 2014)................................................................................................33


- iv -

Grober v. Mako Prods., Inc.,

686 F.3d 1335 (Fed. Cir. 2012)................................................................................................34

Hoechst v. Celanese Corp. v. BP Chems. Ltd.,

78 F.3d 1575 (Fed. Cir. 1996)..................................................................................................29

i4i Ltd. P’ship v. Microsoft Corp.,

598 F.3d 831 (Fed. Cir. 2010)..................................................................................................31

Johnson & Johnston Assocs. Inc. v. R.E. Serv. Co.,

285 F.3d 1046 (Fed. Cir. 2002)................................................................................................26

LG Elec. U.S.A., Inc. v. Whirlpool Corp.,

798 F. Supp. 2d 541 (D. Del. 2011) .........................................................................................25

Lucent Techs., Inc. v. Gateway, Inc.,

580 F.3d 1301 (Fed. Cir. 2009)................................................................................................31

Michalic v. Cleveland Tankers, Inc.,

364 U.S. 325 (1960) .................................................................................................................30

Moleculon Res. Corp. v. CBS, Inc.,

793 F.2d 1261 (Fed. Cir. 1986)................................................................................................30

Norian Corp. v. Stryker Corp.,

363 F.3d 1321 (Fed. Cir. 2004)................................................................................................28

PSC Comp. Prods., Inc. v. Foxconn Int’l, Inc.,

355 F.3d 1353 (Fed. Cir. 2004)..........................................................................................26, 27

Purdue Pharm. Prods. L.P. v. Actavis Elizabeth LLC,

C.A. No. 12-5311-JLL-JAD, 2015 WL 5032650 ....................................................................31

Research Found. of SUNY v. Mylan Pharm. Inc.,

809 F. Supp. 2d 296 (D. Del. 2011) ...................................................................................31, 32

Ring & Pinion Serv. Inc. v. ARB Corp. Ltd.,

743 F.3d 831 (Fed. Cir. 2014)..................................................................................................28

Riverbed Tech., Inc. v. Silver Peak Sys., Inc.,

C.A. No. 11-484-RGA, 2014 WL 4695765 (D. Del. Sept. 12, 2014) .....................................30

SanDisk Corp. v. Kingston Tech. Co., Inc.,

695 F.3d 1348 (Fed. Cir. 2012)..........................................................................................26, 28

Tate Access Floors, Inc. v. Interface Arch. Res. Inc.,

279 F.3d 1357 (Fed. Cir. 2002)................................................................................................32


- v -

Teleflex, Inc. v. Ficosa N. Am. Corp.,

299 F.3d 1313 (Fed. Cir. 2002)................................................................................................34

Toshiba Corp. v. Imation Corp.,

681 F.3d 1358 (Fed. Cir. 2012)................................................................................................30

Tuna Processors, Inc. v. Hawaii Int’l Seafood, Inc.,

No. 05-517-BMK, 2006 WL 2989248 (D. Haw. Oct. 17, 2006) .............................................27

Warner Chilcott Co., LLC v. Zydus Pharm. (USA) Inc.,

C.A. No. 11-1105-RGA, 2013 WL 1729383 (D. Del. Apr. 22, 2013) ....................................28

Warner-Jenkinson Co. v. Hilton Davis Chem. Co.,

520 U.S. 17 (1997) .............................................................................................................24, 25

Rules and Statutes

35 U.S.C. § 271(e) .........................................................................................................................35


1

INTRODUCTION I.

The inventions of the patents in this case, U.S. Patent Nos. 9,132,096 (the “’096 patent”)

and 6,902,742 (the “’742 patent”), relate to an improved hydrocodone product to treat severe

pain. The ’742 patent covers a formulation to treat severe pain quickly, yet safely, over an

extended period of time. The’096 patent covers a product with features designed to deter abuse.

The result of the patents is Zohydro® ER, an extended-release hydrocodone product.

During the trial, Plaintiff Recro Gainesville LLC (“Recro”) proved by a preponderance of

the evidence that Defendant Actavis Laboratories FL, Inc.’s (“Actavis”) proposed generic

versions of Zohydro® ER (“ANDA products”) infringe the ’096 and ’742 patents. Recro’s

experts, Drs. Jürgen Siepmann and Lawrence Fleckenstein, relying on Actavis’s ANDA

documents, demonstrated that (1) the ethylcellulose-based coating on Actavis’s abuse-deterrent

(“placebo”) beads is equivalent to the polyacrylic coatings claimed in the ’096 patent and

(2) Actavis’s active ingredient-containing beads contain two populations of particles that deliver

hydrocodone in the “pulsatile manner” required by the Court’s claim construction. Actavis did

not dispute that the other limitations of the asserted claims are met and dropped its invalidity

case (Trial Tr. 461:21–22), leaving infringement as the only issue for the Court to decide.

PROPOSED FINDINGS OF FACT II.

1. The agreed description of the parties and Actavis’s ANDA No. 206952 is in the

Final Pretrial Order (D.I. 114), Exhibit 1 – Joint Statement of Uncontested Facts, ¶¶ 1–2, 12–17.

Zohydro® ER A.

2. Zohydro® ER extended-release capsules are “indicated for the management of

pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which

alternative treatment options are inadequate.” JTX 22 at 1.

3. The active ingredient in Zohydro® ER is hydrocodone bitartrate, an opioid that


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acts as a strong analgesic. Fleckenstein Tr. 178:11–161; JTX 22 at 4. Using the technology

disclosed in Recro’s ’742 patent (JTX 2), Zohydro® ER was designed to have a “biphasic

release profile, which following oral administration, results in initial rapid release of a proportion

of hydrocodone followed by a prolonged absorption phase resulting in sustained hydrocodone

concentrations over 12 hours.” Rekhi Tr. 530:18-531:23; JTX 105 at 19.

4. This biphasic formulation design, with a first, immediate-release (“IR”)

component and a second, extended-release (“ER”) component, provides an initial rapid release of

drug for quick pain relief, followed by an extended release of drug that permits twice-a-day

dosing and improves patient convenience and compliance. Fleckenstein Tr. 181:10–182:2,

183:20–184:2; Rekhi Tr. 521:9-16; Sidwell Tr. 498:5–20. It also prevents the plasma

concentration of drug from getting too high (because the first dose is being cleared from the body

as the second dose releases), while at the same time preventing the drug concentration from

dropping so low that the analgesic effect is lost. Fleckenstein Tr. 183:8–19.

5. Zohydro® ER also utilizes the invention of the ’096 patent (JTX 3) to reduce the

risk of drug abuse by incorporating a gelling agent (polyethylene oxide or “PEO”) that traps the

drug during attempts to misuse it by, e.g., dissolving the intact or crushed beads in a liquid.

Siepmann Tr. 95:19–96:9, 97:23–98:7, 99:15–101:12; JTX 3 at 9:50–62, 10:4–8. If used as

intended, however, the invention ensures that the release of the drug is unaffected and pain relief

is achieved. Siepmann Tr. 98:13–99:14.

6. The ’096 and ’742 patents are both listed in the FDA’s Orange Book for

Zohydro® ER. Joint Statement of Uncontested Facts, ¶¶ 8–9.

1 Citations to the transcript are in the format: [Witness Name] Tr. [Page(s)]:[Line(s)]. Photos

of Recro’s witnesses and summaries of their qualifications and testimony, are in Appendix A.


3

POSA B.

7. Recro and its experts proposed the following definition for a person of skill in the

art in this case (Siepmann Tr. 74:17-75:9; Fleckenstein Tr. 184:16–185:11):

Scientists with a background in pharmacokinetics, or an analogous field such as

pharmacy, pharmacology, or biostatistics, as well as scientists who investigate

pharmaceutical formulations and have a degree in pharmaceutical sciences or an

analogous field such as pharmaceutical chemistry, chemistry, or chemical

engineering. The pharmacokineticist(s) and formulator(s) would work together

and contribute expertise from their respective fields. A formulations POSA would

have at least a master’s degree in pharmaceutical sciences or a related field like

pharmaceutical chemistry, chemistry, or chemical engineering, and at least two

years of relevant experience. A pharmacokineticist POSA would have at least a

master’s degree in pharmacy or a related field such as pharmacology,

pharmacokinetics, or biostatistics with at least two years of relevant experience.

8. Actavis and its experts proposed a different definition, which inter alia, requires a

Ph.D. or medical degree. Felton Tr. 281:2–13; Dowling Tr. 399:21-400:9; Siepmann Tr. 75:13-

19; Fleckenstein Tr. 185:19–24. Recro disagrees. Siepmann Tr. 75:20-24; Fleckenstein Tr.

185:24–186:2. In any event, the parties’ experts agree that their opinions would not change

regardless of which definition the Court adopts. Siepmann Tr. 75:25-76:3; Fleckenstein Tr.

186:3–5; Felton Tr. 281:21–23; Dowling Tr. 400:15-17.

Infringement of the ’096 Patent C.

9. The ’096 patent, entitled “Abuse Resistant Pharmaceutical Compositions,” issued

on September 15, 2015. JTX 3 at 1. Recro asserts that Actavis’s ANDA products infringe claims

1, 4, and 5 of the ’096 patent. Siepmann Tr. 95:13–16, 115:20–116:24.

10. Actavis does not dispute that its ANDA products meet all but one of the

limitations contained in claims 1, 4 and 5 of the ’096 patent (JTX 3, claim 1):

An oral pharmaceutical composition comprising a first population of beads and a

second population of beads; said first bead population comprising a

pharmaceutically active ingredient selected from the group consisting of

hydrocodone and pharmaceutically acceptable salts thereof, wherein said first

bead population is substantially free of polyethylene oxide; and said second bead


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population comprising polyethylene oxide [PEO] and a permeable or semi-

permeable coating selected from the group consisting of an ammonio

methacrylate copolymer, a methacrylic acid copolymer and a mixture

thereof, wherein said second bead population is substantially free of any

pharmaceutically active ingredient.

11. Actavis’s ANDA products are oral pharmaceutical compositions comprising first

and second populations of beads. JTX 35 at 28; Siepmann Tr. 115:22–25.

12. The first population of beads in the ANDA products comprise hydrocodone

bitartrate as the pharmaceutically active ingredient. Felton Tr. 312:23-24; Siepmann Tr. 102:23–

25, 116:1–4; JTX 35 at 28. Hydrocodone bitartrate is a pharmaceutically acceptable salt of

hydrocodone. JTX 44 at 2; Siepmann Tr. 94:6-12.

13. The hydrocodone-containing beads in Actavis’s ANDA products do not contain

PEO and thus are substantially free of PEO. Siepmann Tr. 103:1–3; 116:5–7; JTX 35 at 28.

14. The second population of beads (the “placebo” beads) in the ANDA products

comprise PEO and an ethylcellulose-based coating. Felton Tr. 351:4-18; Siepmann Tr. 116:8–11;

JTX 35 at 28. Actavis’s ethylcellulose-based coating is equivalent to the claimed coatings

“consisting of an ammonio methacrylate copolymer, a methacrylic acid copolymer and mixtures

thereof” (collectively, “polyacrylic coatings”). Infra at ¶¶ 18–25; Siepmann Tr. 116:8–11; JTX

35 at 28. Actavis’s placebo beads have additional layers underneath the PEO. JTX 35 at 28;

Felton Tr. 294:4-295:19, 351:4-352:25; Siepmann Tr. 104:23–105:3. These additional layers are

permitted by the open-ended nature of claim 1 (i.e., “comprising”). JTX 3 at claim 1. Actavis’s

expert agreed. Felton Tr. 353:6-14.

15. The PEO-containing beads in Actavis’s ANDA products do not contain an active

ingredient and thus are substantially free of hydrocodone bitartrate or any other pharmaceutically

active ingredient. Siepmann Tr. 103:4–8, 116:13–16; JTX 35 at 28.

16. As required by claim 4 of the ’096 patent, the first bead population in Actavis’s


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ANDA products contains hydrocodone bitartrate as the pharmaceutically active ingredient.

Felton Tr. 312:23-24; Siepmann Tr. 102:23–25, 116:17–20; JTX 30 at 4.

17. As required by claim 5 of the ’096 patent, the first bead population in Actavis’s

ANDA products contains hydrocodone bitartrate in an amount of from 5 to 250 mg because

Actavis seeks approval for 10, 15, 20, 30, 40, and 50 mg dosage strengths. Siepmann Tr. 116:21–

24; JTX 35 at 5, 15; JTX 30 at 4.

Actavis’s Ethylcellulose-Based Coating Is Equivalent to the Claimed 1.

Polyacrylic Coatings

18. Actavis’s “placebo beads” contain PEO with a “release controlling polymer” coat.

Siepmann Tr. 102:17–22, 105:8–10; JTX 35 at 28. The polymer coat contains ethylcellulose,

triethyl citrate, and talc. Felton Tr. 351:10-13; Siepmann Tr. 105:15–106:5; JTX 35 at 36.

Actavis’s ethylcellulose-based coating is equivalent to the claimed permeable or semi-permeable

polyacrylic coatings in the patent. Siepmann Tr. 106:16–22; see also Sidwell Tr. 505:8–506:8.

19. According to the ’096 patent, the purpose of the coating applied to the placebo

beads is to act as a permeable or semipermeable coating. JTX 3 at 15:47–52. This coating

“provid[es] a physical barrier essentially separating or sequestering the gelling agent from the

other components of the composition [and] most important[ly] … serves to control (i.e. delay or

otherwise limit) the ingress of water … thus restraining the gelling action of the gelling agent.”

JTX 3 at 4:65–5:6.

20. Actavis’s ethylcellulose coating is a semipermeable coating. Felton Tr. 296:17-21,

355:5-18, 362:2-7. It performs substantially the same function as the claimed polyacrylic

coatings, both when the drug is used as intended or misused. Siepmann Tr. 106:23–107:10.

When the product is used as intended, both types of coatings separate the PEO from the active

beads (id. 106:23–107:4; Felton Tr. 354:15-355:4) and restrict the ingress of water in a way that


6

does not affect the release of drug. Felton Tr. 286:8–287:18, 296:17-22, 354:15-355:18, 362:2-7;

Siepmann Tr. 98:12–99:14; see also JTX 3 at 3:7–12, 4:65-5:6; 9:30–49; JTX 35 at 5. When the

product is misused, however, such as when intact or crushed beads are dissolved, both types of

coatings permit the gelling agent to release quickly, trapping the drug. JTX 35 at 5, 37;

Siepmann Tr. 107:5–10; see also JTX 3 at 9:50–62.

21. Actavis’s ethylcellulose coating works in substantially the same way as the

claimed polyacrylic coatings. Siepmann Tr. 107:11–111:6; see also Sidwell Tr. 507:3–13. When

the product is used as intended, both types of semi-permeable coatings initially restrict the

ingress of water. Felton Tr. 355:5-18, 362:2-7; JTX 3 at 2:37–40, 5:2–6, 15:42–46. Thereafter, as

described by the ’096 patent, “the permeable or semi-permeable nature of the coating enables

some water to pass through the coating thus initiating hydration of the gelling agent.” JTX 3 at

15:47–52; see also Siepmann Tr. 107:15–20, 125:20–126:4. “When the composition is

administered intact and as intended the various beads disperse along a region of the

gastrointestinal tract. Water from the surrounding environment is absorbed through the coating

of the gelling agent-containing beads which, upon contact with the gelling agent, causes the

beads to swell.” 2

JTX 3 at 9:31–36.

22. “The beads may swell to the extent that the coating ruptures, thus allowing more

rapid ingress of water.” JTX 3 at 9:31–38; Felton Tr. 354:15-355:18, 362:2-7; Siepmann Tr.

107:21–22. Dr. Felton agreed that the claimed methacrylic acid copolymers are rupturable and

so are ethylcellulose coatings. Felton Tr. 358:14-16; 355:22-25. This conclusion is well-known

and supported in the literature. PTX 56 (describing captopril cores coated with ammonio

2 When misused, both coatings break or rupture, freeing the gelling agent to trap the drug upon

exposure to water. Siepmann Tr. 107:15–16; JTX 3 at 16:24–33, 29:62–67; JTX 35 at 36–37.


7

methacrylate copolymers as “an outer rupturable layer”); Felton Tr. 358:17-359:16; Siepmann

Tr. 109:14–111:6; PTX 68 at 5 (showing the “rupture sequence” of “pulsatile release tablets …

[with] a rupturable ethylcellulose coating”); PTX 51 at 1 (“[f]ormation of the rupturable top-

coating was successfully performed using an aqueous dispersion of ethylcellulose”); PTX 72 at 1

(pellets included “a rupturable layer of plasticized ethylcellulose”); PTX 48 at 6 (“[t]he carbon

dioxide produced upon contact with water results in rupture of the outer layer leading to drug

release”); see also Felton Tr. 356:1-357:14 (discussing the rupturable ethycellulose coating in

PTX 68).

23. Although Actavis complains that Recro did not perform tests on Actavis’ ANDA

products, no such testing is necessary. Indeed, Actavis does not dispute that its ethylcellulose

coating is a semi-permeable coating that controls ingress of water, or that ethylcellulose-based

coatings, like Actavis’s, were known to rupture when exposed to liquid – just like the claimed

polyacrylic coatings. Felton Tr. 296:17-21; 355:22-25; Siepmann Tr. 109:14–111:6.3

24. Comparison of the rupture of the methacrylate coating in PTX 56 (left) and of the

ethycellulose coating in PTX 68 (right) confirms that these coatings work in the same way:

3 Actavis’s expert, Dr. Felton, questioned the effect, if any, the triethyl citrate in the coating

might have on the mechanism of ingress – e.g., forming cracks vs pores. Felton Tr. 291:1-7, 299:16-300:5. But the patent does not require any particular mechanism. JTX 3 at 15:47–52; see also id. at 15:12–14 (explaining that, for example, pore formers may be used aid permeability). It simply states that the coating must be permeable or semi-permeable, enabling “some water to pass through.” JTX 3 at 15:47–52.


8

Both examples capture what the authors describe as the “rupture sequence” of the respective

coatings. PTX 56 at 6–7; PTX 68 at 5. In each instance, the tablet coatings were exposed to

water, leading to water ingress through the coating over time, and, eventually, “strong rupturing”

of the coating. PTX 56 at 6–7; PTX 68 at 5.

25. Finally, Actavis’s ethylcellulose-based coating and the claimed polyacrylic

coatings achieve substantially the same result. Siepmann Tr. 111:7–13. With either coating the

composition cannot be misused by dissolving the crushed or intact beads, but when used as

directed the patient “gets the same drug exposure as if the[re] were no polyethylene [oxide].” Id.;

Felton Tr. 354:15-24; JTX 44 at 28.

The Inventors Did Not Dedicate Ethylcellulose to the Public 2.

26. Actavis contends that the inventors of the ’096 patent dedicated ethylcellulose to

the public and, therefore, Actavis cannot infringe.

27. Ethylcellulose is never mentioned in the ’096 patent. Felton Tr. 365:17-19;

Siepmann Tr. 111:22–112:3, 115:7–19, 146:23–25; see JTX 3. Although “cellulosic polymers”

are referenced generally in the ’096 patent as “[s]uitable coating materials” (JTX 3 at 5:13,

14:24–26; Felton Tr. 284:15–18; Siepmann Tr. 146:20–22), “cellulosic polymers” refers to a

broad class that encompasses “many, many” polymers. Siepmann Tr. 112:18–22, 146:20–22.

28. Cellulosic polymers are derivatives of cellulose, to which many modifications can


9

be made. Siepmann Tr. 112:18–113:18. There are many thousands of “cellulosic polymers,”

including dozens that are “commonly used” in pharmaceutical formulations. Siepmann Tr.

113:19–114:18, 146:17–19; see also Felton Tr. 365:20-22.

29. Examples of cellulosic polymers that can be used as coatings in pharmaceutical

formulations include cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose

propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate,

cellulose triacetate, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose

trivalerate, cellulose trilaurate, cellulose tripalmitate, cellulose trisuccinate, cellulose

trioctanoate, acetaldehyde dimethyl cellulose acetate, cellulose acetate ethylcarbamate, cellulose

acetate methyl carbamate, and cellulose acetate dimethylaminocellulose acetate. Felton Tr.

367:8-370:2; DTX 568 at 9:50–10:45.

30. Although a POSA might recognize ethylcellulose as one choice among the

thousands of cellulosic polymers, the ’096 patent does not disclose or point to the use of

ethylcellulose. Indeed, it points away from such a use. In referencing “cellulosic polymers,” the

’096 patent divides the class into three specified sub-classes: “cellulose acetates, cellulose

alkanylates, and cellulose acrylates.” JTX 3 at 5:14–15, 14:26–27; Felton Tr. 364:8-18;

Siepmann Tr. 114:24–115:6.4 According to Actavis’ expert, however, a POSA would not

understand ethylcellulose to be included in any of these sub-classes. Felton Tr. 364:21-365:5.

31. In addition to “cellulosic polymers” and its three sub-classes, the ’096 patent

names other broad classes of materials that may be “[s]uitable coating materials[:] . . .

polyamides; polyurethanes; [and] sulfonated polystyrenes.” JTX 3 at 5:13–16, 14:24–28; Felton

4 These sub-classes include, for example, cellulose acetate, cellulose diacetate, cellulose

triacetate, and mono, di, and tricellulose alkanylates. DTX 568 at 10:15–17.


10

Tr. 365:6-10. Two specific ammonio methacrylate and methacrylic acid copolymers are included

in this list, both by chemical name and by trade name (Eu[dra]git® RS and Eudragit® L). JTX 3

at 5:16–22, 14:28–35; Felton Tr. 365:11-15. But ethylcellulose is never named (Felton Tr.

365:11-19; Siepmann Tr. 111:22–112:3, 115:7–19, 146:23–25; see JTX 3), not in the paragraphs

on coating materials or anywhere else that the ’096 patent mentions cellulose derivatives as

potential gelling agents (JTX 3 at 4:38–48, 12:22–35), binders (id. at 4:62–64, 13:20–26, 18:31–

37), pore formers (id. at 15:12–17), capsule materials (id. at 6:16), or alternatives to sugar sphere

cores (id. at 12:47–50).

The Excipients Added to Actavis’s Ethylcellulose-Based Coatings Are 3.

Disclosed in the Specification and Permitted by the Claims

32. The coating applied to Actavis’s PEO placebo beads contains ethylcellulose as the

“release controlling polymer” as well as two common excipients: triethyl citrate and talc. Felton

Tr. 360:6-24; Siepmann Tr. 105:6–106:5; JTX 35 at 5, 28. Triethyl citrate is a “plasticizer/pore

former.” Felton Tr. 360:6-16; Siepmann Tr. 106:2–3; JTX 35 at 28. Talc is a “glidant/anti-static”

that prevents the beads from sticking to one another. Siepmann Tr. 106:4–5; JTX 35 at 28.

Actavis asserts that it cannot infringe due to the presence of these excipients in its coating.

33. Many pharmaceutical coating formulations contain plasticizers, including triethyl

citrate, to impart flexibility. Felton Tr. 360:10-12. The incorporation of excipients into coatings

was well-known by persons of skill in the art. JTX 3 at 5:24–27, 15:5–11; Felton Tr. 360:2-16.

The ’096 patent specification states that “[a]s will be appreciated by the skilled person, the

coating may further comprise excipients designed to control the permeability of the coating

and/or the processing characteristics of the coating. For example, the coating may further

comprise one or more excipients selected from the group consisting of pore formers, plasticisers,

lubricants, glidants and anti-adherent agents and the like.” JTX 3 at 15:5–11.


11

34. Triethyl citrate is a commonly used plasticizer known to persons of skill in the art,

and is expressly listed in the ’096 patent as a “suitable plasticiser.” Felton Tr. 290:17-25;

Siepmann Tr. 147:8–10; see also JTX 35 at 32; JTX 3 at 15:29–35. The presence of triethyl

citrate does not impact release, solubility or mobility. JTX 30 at 56 (“Triethyl Citrate is used as a

plasticizer to impart flexibility to the Ethylcellulose film and its level in the formulation has a

negligible effect on drug dissolution” 5

and “both these excipients [triethyl citrate and talc] have a

negligible effect on drug dissolution”); Siepmann Tr. 127:10–128:17, 147:21–148:12, 150:13–

151:8. Rather, it is the ethylcellulose that restricts the ingress of liquid into the PEO. Felton Tr.

355:5-18, 361:7-363:25; JTX 30 at 56.

35. Talc is a commonly used glidant known to persons of skill. Siepmann Tr. 147:11–

13. Indeed, talc is used in several of the formulations disclosed in the patent examples. See, e.g.,

JTX 3 at 21:13, 21:27–28, 22:49–52, 26:58, 27:9, 27:34. Talc is used merely to prevent the beads

from sticking together during processing and does not impact the function of the coating. Felton

Tr. 297:5-10; Siepmann Tr. 106:4–5; JTX 35 at 28.

Infringement of the ’742 Patent D.

36. The ’742 patent, entitled “Multiparticulate Modified Release Composition” and

listing Dr. John G. Devane, Dr. Paul Stark, Niall M.M. Fanning, and Dr. Gurvinder Singh Rekhi

as inventors, issued on June 7, 2005. JTX 2 at 1. Recro asserts that Actavis infringes claims 1, 6,

13, 14, 16, and 19 of the ’742 patent. Siepmann Tr. 65:1-7, 92:14-94:12.

37. Actavis disputes the bolded elements of claim 1 of Recro’s ’742 patent (JTX 2):

A multiparticulate modified release composition comprising a first population

5 To the extent that Actavis asserts the quoted language refers only to the active beads,

Actavis’ documents specify that this coating layer of the placebo beads “is identical to the extended release coating of active beads containing Ethyl cellulose with Triethyl Citrate as the plasticizer and Talc.” JTX 35 at 6.


12

of active ingredient-containing particles and at least one subsequent

population of active ingredient-containing particles, the active ingredient

contained in the first population being an opiate and the active ingredient in the

subsequent population being an opiate or a non-opiate, wherein the subsequent

population of active ingredient-containing particles further comprises a modified

release coating or, alternatively or additionally, a modified release matrix

material, such that the composition following oral delivery to a subject delivers

the active ingredients of the first and subsequent populations in a pulsatile

manner.

38. Actavis also disputes that its ANDA products “in operation release[] substantially

all of the active ingredient from the first population prior to release of the active ingredient from

the subsequent population,” as required by claim 16. Actavis does not otherwise contest that the

limitations of the asserted claims are met.

39. As required by claim 1 of the ’742 patent, Actavis’s ANDA products contain an

opiate, hydrocodone. Siepmann Tr. 102:23–25, 116:1–4; JTX 35 at 28. They also comprise a

modified release coating based on ethylcellulose. Siepmann Tr. 68:25-69:17; JTX 44 at 8.

Actavis’s Active-Ingredient-Containing Pellets Comprise a First and a 1.

Subsequent Population of Particles

40. The ’742 patent defines a “particulate” as “a state of matter which is characterized

by the presence of discrete particles, pellets, beads or granules irrespective of their size.” JTX 2

at 5:53–59. The parties agree that “particles” has its plain and ordinary meaning. D.I. 62.

A POSA would understand that “particles, pellets, beads or granules” would be used

interchangeably (Felton Tr. 379:1-12, 380:6-11 (“Yes. I would use pellet and bead

interchangeably.”)), Siepmann Tr. 137:3–138:15,149:23–150:12), which is consistent with the

patent, and Actavis’s own documents (e.g., JTX 35 at 37 (using “particle,” “bead,” and “pellet”

interchangeably in Table 21); Felton Tr. 380:12-381:19).

41. Examples 1 and 2 of the patent describe the preparation of multiparticulate

compositions according to the invention in which IR particles or beads are prepared separately


13

from ER particles or beads. JTX 2 at 11:30–14:55. These beads are then placed in gelatin

capsules for administration to patients. Id. at 10:35–43, 13:38–45. Compositions made according

to the patent are not so limited, however. “A multiparticulate modified release composition

according to the present invention may be incorporated into any suitable dosage form,” including

“that of a multilayer tablet.” Id. at 10:35–38, 47–48.

42.

The outer layer is an IR

component that rapidly releases 20 percent of the total dose of the drug. Felton Tr. 370:6-371:4.

The “ER Coat” layer controls the extended release of the inner “Drug Layer.” Id. 311:15-312:5,

373:17-374:3 (discussing JTX 30 at 47). “This two-stage coating ensures immediate release of

20 percent of the dose in the stomach followed by extended release of the remaining 80 percent

in the intestine.”6 JTX 30 at 20; Felton Tr. 372:10-373:14.

43.

6 Unless specified, emphases are added, and internal citations and quotes are omitted.


14

44.

In both

cases, after the composition is swallowed and comes in contact with the aqueous media in the

gastrointestinal tract, the IR layer of hydrocodone bitartrate rapidly dissolves. Felton Tr. 371:1-7;

Fleckenstein Tr. 166:18–21. And, in both cases, an extended release of drug comes from a drug

layer surrounded by the ethylcellulose-based ER coating. Felton Tr. 373:17-374:3; Siepmann Tr.

87:11-22. That is, after the ingestion of capsules containing separate IR beads and ER beads or

multilayered beads with IR and ER layers, in either case the active drug is provided to the patient

in the same ways. That is, an IR formulation (i.e., the IR beads or IR layer) rapidly dissolves,

quickly providing active to the patient, leaving an ER component (i.e., separate ER beads or ER

beads exposed after the IR layer dissolves) that provides drug over an extended period of time.

Felton Tr. 371:1-7, 373:17-374:3; Siepmann Tr. 86:15-88:6; JTX 30 at 47; see also PDX 113.

45.


15

46.

47. This approach is very different from that disclosed in European Patent 0 274 734

(DTX 579; “La Manna”). Actavis’s expert relied on certain statements regarding La Manna

made in a communication with the Patent Office on January 11, 2007 in a subsequent related

application. DTX 519 at 1. The La Manna statements were submitted more than a year and a half

after the ’742 patent issued (June 7, 2005) with respect to a different patent application (No.

10/827,689) that was never allowed as a patent. Felton Tr. 375:25-376:14. Regardless, the

dosage form in La Manna is not a multilayered bead – it incorporates a casing using a polymer

material impermeable to and insoluble in water. Felton Tr. 377:4-378:2; DTX 579 at 2:38–39,

2:43–45, 24 (Fig. 1). Actavis’s ANDA products do not contain anything like an impermeable

casing. Felton Tr. 378:3-6. Rather, like the modified release component described in Example 1


16

of the ’742 patent (JTX 2 at 11:60–12:23), the ANDA products are comprised of a drug layer

over-coated with a modified release coating. Felton Tr. 373:17-24; Siepmann Tr. 81:11-25; JTX

44 at 7, 22. Further, the specification of the ’742 patent lists “a multilayer tablet” similar to

Actavis’s ANDA products as a “suitable dosage form” (JTX 2 at 10:47–48) and claim 23 of the

patent claims “a multilayer tablet” (JTX 2 at 17:11–15).

Actavis’s Active-Ingredient-Containing Pellets Deliver Hydrocodone 2.

“In a Pulsatile Manner”

a. The “Release” of Active Ingredient from Actavis’s ANDA

Products Is Pulsatile

48. Actavis’s own dissolution testing demonstrates that the release from its ANDA

products “provides a first pulse of an active ingredient release, followed by at least one

subsequent pulse of active ingredient release” (D.I. 69).

49. In vitro dissolution testing is the method by which POSAs “normally measure the

release of active ingredient from the dosage form itself.” Felton Tr. 328:14-17. The parties agree

that the “release” portion of the Court’s claim construction “involves in vitro release from the

dosage form.” Felton Tr. 340:8-11.

50. The ’742 patent contemplates a range of release profiles, including the

combination of an IR and a controlled (“sustained” or “extended” release) component as in

Actavis’s ANDA products. “For example, the first component may be an IR component wherein

the active ingredient is released substantially immediately upon administration. . . . The second

component may be . . . a time-delayed sustained release or extended release component in which

the active ingredient is released in a controlled fashion over an extended period of time.” JTX 2

at 8:5–16. The ’742 patent defines the number of pulses by the number of components: “The

number of pulses in the profile arising from such a composition in operation will depend on the

number of active ingredient containing components in the composition.” JTX 2 at 6:16–19.


17

51. The definition of a “pulse” applied by Actavis (“a burst, an immediate release of

active ingredient” (Felton Tr. 329:20-24) to exclude an extended release (Felton Tr. 382:15-

384:5)) is thus overly restrictive and inconsistent with the specification of the ’742 patent.

52. As Actavis’s Product Development Report explains, Actavis’s ANDA products

were designed to have two pulses of hydrocodone release: “Th[e] two-stage coating ensures

immediate release of 20% of the total dose in the stomach followed by extended release of the

remaining 80% in the intestine.” JTX 30 at 20; Felton Tr. 371:1-18, 372:18-373:14.

53. In vitro data show that the release profile of Actavis’s product matches the goal

and design of its product. That data, obtained during the development of Actavis’s ANDA

products demonstrate that Actavis’s ANDA products provide a first pulse of active ingredient

release, followed by at least one subsequent pulse of active ingredient release. There is a first,

rapid pulse of active ingredient release from the IR component that is nearly complete within

fifteen minutes (Fleckenstein Tr. 193:13–21, 194:10–12, 196:12–24, 197:16–198:7, 197:4–11;

JTX 45 at 117, 129, 141, 153, 165, 177; PDX 224, 225, 229, 230), followed after a brief lag by a

subsequent pulse of active ingredient release (Fleckenstein Tr. 192:22–193:5, 193:22–194:2,

194:13–195:18, 196:19–24, 197:12–15, 197:16–198:7; JTX 42, JTX 43, JTX 45 at 51, 54, 57,

60, 63, 66, 117, 129, 141, 153, 165, 177; PDX 224, 225, 227, 229, 230).

54. In concluding that Actavis’s dissolution data did not show pulsatile release, in

addition to applying an overly restrictive definition of “pulse,” Actavis’s expert looked only at

dissolution tests that began sampling at the one hour time point (Felton Tr. 334:10-20 (referring

to JTX 45 at 52), 384:8-385:6), long after release of the active ingredient from the IR

component. JTX 30 at 46 (the IR component of Actavis’s ANDA products was designed such

that “[w]hen these pellets come in contact with the [aqueous] medium, the Hydrocodone over-


18

coat rapidly dissolves”); Felton Tr. 371:1-18, 372:18-373:14; Fleckenstein Tr. 192:4–21,

193:16–194:2; JTX 30 at 4 (hydrocodone is “a highly soluble . . . molecule”). Dissolution testing

conducted during development of the ANDA products demonstrates that the IR coat of

hydrocodone bitartrate is substantially completely dissolved within 15 minutes – long before the

one-hour time point considered by Dr. Felton. Fleckenstein Tr. 193:6–21, 196:10–24; JTX 45 at

117, 129, 141, 153, 165, 177.

55. In distinguishing the Paradissis reference during the prosecution of the parent of

the ’742 patent, the applicants argued only that Paradissis discloses pharmaceutical compositions

with a flat (constant) “zero order release” profile, not a pulsatile profile. DTX 512 at 5. The

applicants did not otherwise characterize Paradissis. Id. Further, the word “negligible” –

mentioned by the applicants (DTX 512 at 5) and relied on by Actavis’s expert (Felton Tr.

338:10-339:24) – is not included in the Court’s construction of “pulsatile.” Felton Tr. 381:20-

382:7; D.I. 69.

b. The Plasma Concentration Profile Is Characterized by Two or

More Peaks Interspersed with Low Concentration Troughs

56. Claim 1 of the ’742 patent refers to “oral delivery to a subject.” JTX 2, claim 1.

The Court’s construction of “pulsatile” adopted the plain and ordinary meaning of “a subject.”

D.I. 69. The plain and ordinary meaning of “a” is “one or more.”

57. Pharmacokineticists look at both individual and mean data, and individual data is

“very important.” Dowling Tr. 480:10-24; Fleckenstein Tr. 204:2–13. Because Actavis’s

formulation is designed to provide an initial, rapid release from the dosage form, it is important

to look at individual data plots because, as Dr. Fleckenstein explained, the use of mean values

would “average [] out” the variability and smooth out the profiles.” Fleckenstein Tr. 204:14–

205:2. For example, two different subjects can both have pulsatile plasma curves but have


19

different curve shapes such that averaging their data would hide the peaks and low concentration

troughs. Fleckenstein Tr. 271:19–272:10, 220:23–221:5.

58. The invention of the ’742 patent was intended to be flexible in its application so

that it can be tailored to obtain the desired plasma concentration curve shape. Fleckenstein Tr.

162:25–171:18, 173:12–15; JTX 2 at 7:30–8:34; supra ¶ 50. Thus, a “pulsatile” plasma

concentration curve can have various different shapes depending on factors such as the time

between release from different components, the particular active pharmaceutical ingredient(s)

used, and the proportion of the dose in each component. Dowling Tr. 468:5-21, 472:7-21,

481:13-482:5; Fleckenstein Tr. 169:7–24, 171:3–18, 173:3–15, 174:17–25; JTX 2 at 7:30–32,

8:1–34. Even the two preferred embodiments A and B depicted in Figure 1 of the ’742 patent

have different curve shapes, with different peak heights and different trough depths. Dowling Tr.

484:10-25, 485:6-19; JTX 2, Fig. 1.

59. No particular trough depth or breadth is required by the ’742 patent. See generally

JTX 2; Fleckenstein Tr. 174:17–25. A low concentration trough is a “minimum or nadir that

would follow [] the first peak and prior to the input from the second component, where there

would be a second peak.” Fleckenstein Tr. 167:8–11; Sidwell Tr. 490:12-17 (“[M]y

understanding is that that would be . . . some concentration had been achieved and then at some

later point that concentration was lower and then at some still later . . . time point that

concentration was again higher.”). Even Actavis’s expert agreed that “in general” in

pharmacokinetics, a trough is “the lowest concentration that is measured after a dose is given.”

Dowling Tr. 485:1-5.

60. Nor is there any requirement in the Court’s claim construction that a trough

persist for a particular number of sampling points. See D.I. 69. Indeed, the number of sampling


20

time points included in a trough is determined by the sampling design of the study. Cf. Dowling

Tr. 473:25-474:16 (agreeing that “the intervals between sampling times can impact the shape of

a plasma concentration curve”).

61. Nor does Claim 1 require the pulsatile plasma concentration to “mimic” two IR

doses; indeed, “mimicking” two IR doses is an additional limitation found in two (unasserted)

dependent claims. JTX 2, claims 17, 18; Dowling Tr. 474:17-475:24. Thus, Actavis’s expert’s

requirement that low concentration troughs mimic the trough characteristic of the preferred

embodiment depicted in Figure 1 of the ’742 patent (e.g. Dowling Tr. 416:8-11, 417:7-16,

419:23-420:5) is overly restrictive and imports limitations not found in the asserted claims.

Dowling Tr. 463:15–22 (agreeing that formulations A & B are “preferred embodiments”).

62. Indeed, the examples A & B in Figure 1 of the ’742 patent are not covered by the

asserted claims because the only active ingredient is methylphenidate, which is not an opiate.

Dowling Tr. 466:7–13.

63. Similarly, a “wash out” period is a preferred embodiment, not a requirement, of

the ’742 patent. JTX 2 at 6:25–28, 11:6–9. Indeed, a POSA would understand that although a

pulsatile profile can have benefits for an extended release pain medication (supra ¶¶ 3–4), a

wash out period is not desirable, because pain relief must be relatively constant to prevent

“breakthrough pain.” See Rekhi Tr. 521:4-522:17. The reference to a wash out with respect to the

“Giunchedi” article in the Description of the Prior Art in the ’742 patent merely notes that

Giunchedi does not disclose this type of embodiment and that the peak-to-trough variation is

“small” (JTX 2 at 2:47–58); it does not disavow any scope of claim 1.

64. Actavis only conducted one clinical study (ACT-15030) on the product it intends

to market. Dowling Tr. 476:17-478:1; Fleckenstein Tr. 268:8–25.


21

65. Actavis’s ANDA products were designed to release hydrocodone in two separate

pulses in two separate locations in the gastrointestinal tract: “[t]h[e] two-stage coating ensures

immediate release of 20% of the total dose in the stomach followed by extended release of the

remaining 80% in the intestine.” JTX 30 at 20; Felton Tr. 371:1-18, 372:18-373:14.

66. At least seven individuals in the ACT-15030 study had observed low

concentration troughs in their plasma profiles in the one to four hour range: subjects 1012, 1018,

1022, 1024, 1028, 1029, and 1036. Fleckenstein Tr. 205:15–207:21, 212:25–213:15; JTX 41 at

2–7. The low concentration trough is expected to occur in this time period based on the

combination of the in vitro dissolution data (which demonstrated a rapid release from the IR

component), the formulation goals described by Actavis (a release of 20% of the dose in the

stomach followed by an extended release of the other 80% in the intestine), Actavis’s

formulation designed to reach those goals (an IR layer to quickly release drug followed by an

extended release layer to slowly release drug over time), and a pharmacokinetic model of the

reference listed drug Actavis was trying to match. Fleckenstein Tr. 202:15–203:4, 209:5–210:21,

211:3–212:5; JTX 10; cf. Fleckenstein Tr. 208:3–209:4.

67. Actavis’s own ANDA documents show that the accuracy of the assay it employed

in testing the plasma profiles of the subjects in ACT-15030 was quite good – with at most

between three and five percent error. Fleckenstein Tr. 265:19–266:10, 272:21–275:17; JTX 33

at 22. The effects observed in individual plasma concentration profiles are thus real and cannot

be the result of assay error. Fleckenstein Tr. 265:19–266:10, 272:21–275:17; JTX 33 at 22.

68. The 20 percent of the dose in Actavis’s ANDA products that releases immediately

in the stomach releases very rapidly – indeed, release of this entire component is complete within

about fifteen minutes. JTX 30 at 4, 46; Felton Tr. 371:1-18, 372:18-373:14; Fleckenstein Tr.


22

192:4–21, 193:16–21. The ER component of Actavis’s ANDA products then begins to release

after a short delay. Supra ¶ 53.

69. Actavis’s clinical study was designed to show bioequivalence to Zohydro® ER,

not to capture the pulsatile nature of the plasma profile; as such, the sampling times in the one to

four hour window were insufficiently frequent to capture the rapid changes in plasma

concentration during this timeframe. Fleckenstein Tr. 215:18–216:22.

70. Other factors, including individual variability, the disproportionate division of the

dose (the peak from the 80% of the dose in the second component overwhelms the peak from

and trough occurring after the 20% of the dose in the first component), and the administration of

the narcotic antagonist naltrexone to subjects in ACT-15030 for safety purposes (which tends to

pull the second peak in closer to the first peak), can also obscure low concentration troughs.

Fleckenstein Tr. 217:18–219:17, 220:23–221:5, 222:3–224:10; JTX 21 at 17, 46; PTX 74 at 6.

71. Seventeen additional individuals showed evidence of infringement in the form of

a region of flat concentration indicative of a low concentration trough (or a peak) that was not

captured: subjects 1003, 1004, 1005, 1007, 1013, 1014, 1017, 1019, 1020, 1021, 1023, 1025,

1026, 1033, 1034, 1035, and 1037. Fleckenstein Tr. 213:23–215:8, 220:8–11, 225:19–226:2;

JTX 41 at 2–7.

72. It would have been unethical for Recro to conduct clinical testing of an

unapproved Schedule II narcotic on healthy human volunteers solely for the purposes of patent

litigation. Fleckenstein Tr. 221:15–25, 271:11–15.

73. Although Actavis only conducted clinical testing on its 10 mg product, the results

of this testing – which demonstrate that the plasma concentration profile is characterized by two

or more peaks interspersed with low concentration troughs – equally apply to the 15, 20, 30, 40,


23

and 50 mg dosage strengths. That is because Actavis requested a biowaiver from the FDA,

seeking approval of those additional dosage strengths without additional in vivo bioequivalence

studies. PTX 175 at 3–4; Fleckenstein Tr. 188:5–189:3. That is, Actavis has certified to the FDA

that the in vivo behavior of its other dosage strengths of its ANDA products is the same as the in

vivo behavior of the tested 10 mg dose. PTX 175 at 3–4; Fleckenstein Tr. 188:5–189:3.

74. The Alza reference mentioned in the Description of the Prior Art section of the

’742 patent (JTX 2 at 2:11–26) does not depict either actual in vivo data or even simulations of in

vivo data but only an idealized and speculative version of what the applicant hoped might occur.

Fleckenstein Tr. 254:25–256:2; DTX 812. Such a profile could only be obtained with an

intravenous infusion where the rate of administration was gradually increased. Fleckenstein Tr.

255:9–13, 255:21–256:2. Thus, it is not a depiction, even a hypothetical one, of a region of flat

concentration disguising a missing low concentration trough. Id. Further, the ’742 patent

describes the Alza reference as “administering methylphenidate in a sustained and constantly

ascending rate.” JTX 2 at 2:12–13. Administering hydrocodone at a “constantly ascending rate”

would be dangerous, as it would put patients at risk of overdose; the pulsatile design of

Zohydro® ER, the reference listed drug for Actavis’s ANDA products, provides rapid analgesia

from the first, IR pulse, but avoids excessive drug levels because the first input is already being

cleared from the body as the second, extended release begins. Supra, ¶¶ 3–4.

The Asserted Dependent Claims Are Also Infringed 3.

75. As required by claim 6, the subsequent population in Actavis’s ANDA products

comprises opiate-containing particles. Siepmann Tr. 102:23–25, 116:1–4; JTX 35 at 28.

76. As required by claim 13, “at least one of the active ingredients of the first and

subsequent populations comprises hydrocodone or a pharmaceutically acceptable salt thereof.”

Siepmann Tr. 102:23–25, 116:1–4; JTX 35 at 28.


24

77. As required by claim 14, the first (immediate release) and subsequent (extended

release) populations of Actavis’s ANDA products have different in vitro dissolution profiles. The

IR population dissolves rapidly such that it is substantially dissolved within fifteen minutes,

whereas the ER population releases gradually over about twelve hours. Fleckenstein Tr. 193:6–

194:14, 196:2–197:15, 198:9–17; PDX 224, 225, 229, 230; JTX 45 at 51, 54, 57, 60, 63, 66, 117,

129, 141, 153, 165, 177.

78. As required by claim 16, the first population of IR particles in the ANDA

products releases substantially all of the active ingredient prior to the release of the active from

the subsequent, modified-release particles. Fleckenstein Tr. 196:2–197:15, 198:18–199:3; PDX

229, 230; JTX 45 at 51, 54, 57, 60, 63, 66, 117, 129, 141, 153, 165, 177.

79. As required by claim 19, the mean in vitro dissolution data for the first

(immediate release) population is such that substantially all of the active ingredient is released

within two hours—in fact, Actavis’s dissolution testing demonstrates that substantially all of the

active ingredient is released from the IR population within about 15 minutes. Fleckenstein Tr.

193:13–21, 194:4–14, 196:12–24, 197:7–11, 199:4–12; JTX 45 at 117, 129, 141, 153, 165, 177.

PROPOSED CONCLUSIONS OF LAW III.

80. The patent holder bears the burden of proving infringement by a preponderance of

the evidence. See Advanced Cardiovascular Sys., Inc. v. Scimed Life Sys., Inc., 261 F.3d 1329,

1336 (Fed. Cir. 2001). A product literally infringes a claim if it meets each and every limitation

of the claim. Baxter Healthcare Corp. v. Spectramed, Inc., 49 F.3d 1575, 1582 (Fed. Cir. 1995).

“[A] product or process that does not literally infringe upon the express terms of a patent claim

may nonetheless be found to infringe if there is ‘equivalence’ between the elements of the

accused product or process and the claimed elements of the patented invention.” Warner-

Jenkinson Co. v. Hilton Davis Chem. Co., 520 U.S. 17, 21 (1997).


25

81. There are two tests that can be applied to determine whether an element is met

under the doctrine of equivalents:

Under the insubstantial differences test, “[a]n element in the accused

device is equivalent to a claim limitation if the only differences between

the two are insubstantial.” Under the function-way-result test, the

insubstantiality of an alleged equivalent is determined by asking whether

an element in the accused device “performs substantially the same

function in substantially the same way to obtain the same result” as the

claim limitation.

LG Elec. U.S.A., Inc. v. Whirlpool Corp., 798 F. Supp. 2d 541, 554 (D. Del. 2011). When

performing an equivalents analysis, it is appropriate to consider whether a POSA would consider

the element of the accused product to be substantially similar to the element recited in the claim.

Warner-Jenkinson, 520 U.S. at 36, 37. The doctrine of equivalents is not applied to the accused

product or process as a whole, but rather to individual claim elements. Id. at 29.

Actavis Infringes Claims 1, 4, and 5 of the ’096 Patent A.

82. Actavis does not dispute that its ANDA products meet each and every limitation

of claims 1, 4, and 5 of the ’096 patent, with one exception: Actavis denies that the

ethylcellulose-based coating on its placebo beads is substantially similar to the polyacrylic

coatings listed in claim 1.

83. Substantial evidence demonstrates that Actavis’s ethylcellulose-based coating

performs the same function as the claimed polyacrylic coatings in that both separate the gelling

agent from aqueous media when the compositions are used as directed. Findings of Fact (“FF”)

¶¶ 19–20. Similarly, when the compositions are misused, both types of coatings permit release of

the gelling agent, trapping the drug. Id.

84. There is also substantial evidence – expert testimony (from both parties’ experts

(FF ¶¶ 21–23)), literature in the field (FF ¶¶ 22, 24), and guidance in the ’096 patent (FF ¶ 21–

22) – that both types of coatings work in substantially the same way. Both coatings allow ingress


26

of water, causing the gelling agent to swell, eventually rupturing the coatings. FF ¶¶ 21–25.

85. Finally, there is no dispute that the ethylcellulose-based and polyacrylic-based

coatings achieve substantially the same result. FF ¶ 25. Accordingly, the coating limitation in

claim 1 is met under the doctrine of equivalents and because Actavis does not contest that its

ANDA products meet the other limitations contained in claims 1, 4, and 5 of the ’096 patent,

those claims are infringed as well.

The Inventors Did Not Dedicate Ethylcellulose to the Public 1.

86. The disclosure-dedication doctrine does not limit the application of the doctrine of

equivalents to Actavis’s ANDA products that use ethylcellulose as “a permeable or semi-

permeable coating” on the placebo beads. “Whether the disclosure-dedication rule prevents a

patentee from pursuing a doctrine of equivalents infringement theory is a question of law . . . .”

SanDisk Corp. v. Kingston Tech. Co., 695 F.3d 1348, 1364 (Fed. Cir. 2012). The doctrine of

dedication to the public applies when a patentee discloses subject matter in the specification of a

patent but does not claim it. Johnson & Johnston Assocs. v. R.E. Serv. Co., 285 F.3d 1046, 1054

(Fed. Cir. 2002). Disclosures have been found sufficient to dedicate unclaimed subject matter to

the public where there was a “clear, precise disclosure” of “explicit alternatives to the inventions

claimed.” PSC Comp. Prods., Inc. v. Foxconn Int’l, Inc., 355 F.3d 1353, 1358 (Fed. Cir. 2004).

87. “[T]he [disclosure-dedication doctrine] ‘does not mean that any generic reference

in a written specification necessarily dedicates all members of that particular genus to the

public.’ Rather, ‘the disclosure must be of such specificity that one of ordinary skill in the art

could identify the subject matter that had been disclosed and not claimed.’” SanDisk, 695 F.3d at

1363 (quoting PSC, 355 F.3d at 1360). Thus, a generic disclosure like “other resilient materials

may be suitable for the strap” does not dedicate all unclaimed resilient materials to the public,

even if those materials were known in the art. PSC, 355 F.3d at 1360.


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88. On this basis, the disclosure-dedication rule did not apply to preclude a plaintiff

from asserting the doctrine of equivalents where the claim covered only “an ultimate tensile

strength of 1500 MPa or greater” and the defendants’ products used tensile strengths of 1414

MPa and 1470 MPa because “the specification [wa]s imprecise with respect to the range of

thermal treatments that can be applied to the claimed compositions; the disclosure [was] not of

‘such specificity’ that one of ordinary skill in the art could identify the precise tensile strength

ranges disclosed but not claimed.” Arcelormittal France v. AK Steel Corp., C.A. No. 10-50-SLR,

2011 WL 63417, at *1 (D. Del. Jan. 4, 2011). Similarly, where a patent on a method for smoking

meat claimed a 250–400 °C temperature range, but disclosed text and figures demonstrating that

smoke can be generated at temperatures from 200–1000 °C, the patentee did not dedicate all

temperatures over 400 °C to the public because the “disclosure of the volume of gas released at

various temperatures is too generic” for “a person of ordinary skill to identify any disclosed but

unclaimed alternative optimal or beneficial smoking temperature.” Tuna Processors, Inc. v.

Hawaii Int’l Seafood, Inc., No. 05-517-BMK, 2006 WL 2989248, at *4 (D. Haw. Oct. 17, 2006).

89. Here, “ethylcellulose” is not mentioned in the ’096 patent. FF ¶¶ 27, 31. The ’096

patent mentions the generic category of “cellulosic polymers.” FF ¶¶ 27–31. “Cellulosic

polymers” is a broad genus that encompasses many thousands of polymers, at least dozens of

which are commonly used as pharmaceutical coating materials. FF ¶¶ 28–29. “Cellulosic

polymers” is not a “clear, precise disclosure” of ethylcellulose of such “specificity that one of

ordinary skill in the art could identify the subject matter that had been disclosed and not

claimed.” PSC, 355 F.3d at 1358, 1360. Indeed, the ’096 patent further describes “cellulosic

polymers” as comprising three sub-classes (cellulose acetates, cellulosic alkanylates, and

cellulose acrylates), but as Actavis’s expert agreed, ethylcellulose is not an example of any these


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three identified sub-classes. FF ¶ 30.

90. It is irrelevant that ethylcellulose was a known cellulosic polymer where it was

not specifically identified but only generically included in a broad category – “[w]hether a

person of ordinary skill ultimately could employ the disclosures of the patent to implement a

purported equivalent does not amount to actually disclosing to one of ordinary skill that

equivalent as an alternative to a claim limitation.” SanDisk Corp., 695 F.3d at 1364. Nor does

foreseeability of an alternative bar application of the doctrine of equivalents – indeed, “[i]t has

long been clear that known interchangeability weighs in favor of finding infringement under the

doctrine of equivalents.” Ring & Pinion Serv. Inc. v. ARB Corp. Ltd., 743 F.3d 831, 834 (Fed.

Cir. 2014) (“[t]here is not, nor has there ever been, a foreseeability limitation on the application

of the doctrine of equivalents” and collecting cases).

Claim 1 of the ’096 Patent Does Not Foreclose the Use of the Common 2.

Excipients Actavis Included in Its Ethylcellulose-Based Coating

91. The disputed limitation in claim 1 of the ’096 patent is a Markush-style element

requiring “a permeable or semi-permeable coating selected from the group consisting of an

ammonio methacrylate copolymer, a methacrylic acid copolymer and a mixture thereof.” JTX 3.

Actavis contends that this language “do[es] not allow any of ethylcellulose, triethylcitrate or talc

in a coating of a second bead population.” D.I. 114, Ex. 13, ¶ 494. That is not the law.

92. The transitional term “consisting of” is understood to be a limitation on permitted

elements under the claim, but it is not “absolutely restrictive.” Warner Chilcott Co., LLC v.

Zydus Pharm. (USA) Inc., C.A. No. 11-1105-RGA, 2013 WL 1729383, at *5 (D. Del. Apr. 22,

2013). An exception to the “closed” nature of Markush claiming applies for “unrecited

element[s] . . . ‘unrelated to the invention.’” Id. (citing Norian Corp. v. Stryker Corp., 363 F.3d

1321, 1331–32 (Fed. Cir. 2004)). For example, “[t]he presence of excipients can [] be


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understood to be unrelated to the actual invention,” and, therefore, not excluded from the

Markush group. Id. (declining to construe a Markush group to exclude pharmaceutical excipients

where “portions of the specification [] clearly show[ed] ‘inner coating layers’ formed by a

polymer with additional excipients, solvents, or plasticizers” and noting that “[t]he Federal

Circuit has stated that ‘it is unlikely that an inventor would define the invention in a way that

excluded the preferred embodiments, or that persons of skill in this field would read the

specification in such a way.’” (quoting Hoechst v. Celanese Corp. v. BP Chems. Ltd., 78 F.3d

1575, 1580 (Fed. Cir. 1996))).

93. The use of Markush language does not preclude application of the doctrine of

equivalents. “A Markush group is a listing of specified alternatives of a group in a patent claim,

typically expressed in the form: a member selected from the group consisting of A, B, and C. . . .

It is well known that members of the Markush group are . . . alternatively usable for the purposes

of the invention.” Abbott Labs. v. Baxter Pharm. Prods., Inc., 334 F.3d 1274, 1280 (Fed. Cir.

2003). Even where a claim element is crafted in Markush format:

The proper inquiry for the court is to apply the doctrine of equivalents, asking

whether an asserted equivalent represents an “insubstantial difference” from the

claimed element, or “whether the substitute element matches the function, way,

and result of the claimed element.” . . . Courts should be cautious not to shortcut

this inquiry by identifying a “binary” choice in which an element is either present

or not present.

E.I. Du Pont de NeMours & Co. v. Heraeus Precious Metals N. Am. Conshohocken LLC, No. 12-

1104-HU, 2013 WL 2659533, at *4 (D. Or. June 7, 2013) (recognizing that “the doctrine of

equivalents, by definition, recognizes that an element is missing that must be supplied by the

equivalent substitute”).

94. Triethyl citrate and talc are common excipients disclosed in the specification and

incorporated into preferred embodiments. FF ¶¶ 32–35. These excipients are unrelated to the


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purpose of the invention, as they do not play any substantial role in the ingress of water into the

PEO-containing core of Actavis’s placebo beads, nor in the swelling of the PEO and the

rupturing of the ethylcellulose coating, as confirmed by Actavis’s own documents. Id.

Accordingly, these common excipients are not excluded by the Markush-style claim element and

Actavis’s ANDA products infringe the asserted claims of the ’096 patent.

Actavis’s ANDA Products Infringe the Asserted Claims of the ’742 Patent B.

95. In a Hatch-Waxman case, the patentee must show that it is more likely than not

that the ANDA product would, if commercially marketed, meet the claim limitations of the

patents-in-suit. Adams Respiratory Therapeutics, Inc. v. Perrigo Co., 616 F.3d 1283, 1287 (Fed.

Cir. 2010); Abbott Labs. v. TorPharm, Inc., 300 F.3d 1367, 1373 (Fed. Cir. 2002).

96. For the reasons explained in paragraphs 40–47 above, Actavis’s ANDA products

meet the populations of particles limitations of the asserted claims of the ’742 patent, either

literally or under the doctrine of equivalents.

97. A patentee is not required to show that the defendant’s product will meet the

claims “9 times out of 10,” but, instead, that the product will more likely than not infringe.

Adams Respiratory Therapeutics, 616 F. 3d at 1287.

98. Infringement may be shown through circumstantial, as well as direct, evidence.

“It is hornbook law that direct evidence of a fact is not necessary.” Moleculon Res. Corp. v. CBS,

Inc., 793 F.2d 1261, 1272 (Fed. Cir. 1986), abrogated on other grounds by Egyptian Goddess,

Inc. v. Swisa, Inc., 543 F.3d 665 (Fed. Cir. 2008) (en banc). “Circumstantial evidence is not only

sufficient, but may also be more certain, satisfying and persuasive than direct evidence.” Id. at

1272 (quoting Michalic v. Cleveland Tankers, Inc., 364 U.S. 325, 330 (1960)). “‘Direct

infringement can be proven by circumstantial evidence.’ . . . Circumstantial evidence must show

that at least one person directly infringed an asserted claim during the relevant time period.”


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Toshiba Corp. v. Imation Corp., 681 F.3d 1358, 1364 (Fed. Cir. 2012); see also Riverbed Tech.,

Inc. v. Silver Peak Sys., Inc., C.A. No. 11-484-RGA, 2014 WL 4695765, at *6 (D. Del. Sept. 12,

2014) (“Taken together, this circumstantial evidence is sufficient to permit a jury to reasonably

conclude that sometime during the relevant period [], more likely than not one person

somewhere in the United States performed the claimed method using the [accused] products.”).

99. Thus, it is not required that a patentee test the accused product to show

infringement. Here, where the active ingredient in the ANDA product is a Schedule II narcotic, it

would not only be impractical but unethical to conduct testing in humans with unapproved

products for the sole purpose of obtaining direct evidence for patent litigation. FF ¶ 72; Purdue

Pharm. Prods. L.P. v. Actavis Elizabeth LLC, C.A. No. 12-5311-JLL-JAD, 2015 WL 5032650,

at *18 & *18 n.9 (D.N.J. Aug. 25, 2015) (“Throughout trial, Defendants have persistently

criticized Plaintiffs for failing to test Defendants’ respective ANDA products. However, the

Court will not overlook the implications of such unapproved testing. Indeed, it would be highly

unethical to have testing performed on humans (i.e. in vivo) for unapproved products particularly

for the limited purpose of patent litigation as Defendants[] appear to suggest.” (citing Allergan,

Inc. v. Watson Labs., Inc.-Fla., 869 F. Supp. 2d 456, 500 (D. Del. 2012))).

100. Moreover, there is no requirement that a substantial number or even a majority of

products or uses infringe. “[A] finding of infringement can rest on as little as one instance of the

claimed method being performed during the pertinent time period.” Lucent Techs., Inc. v.

Gateway, Inc., 580 F.3d 1301, 1317–18 (Fed. Cir. 2009); see also i4i Ltd. P’ship v. Microsoft

Corp., 598 F.3d 831, 850 (Fed. Cir. 2010). Further, it is well-established that an accused device

that “sometimes, but not always, embodies a claim nonetheless infringes.” Broadcom Corp. v.

Emulex Corp., 732 F.3d 1325, 1333 (Fed. Cir. 2013).


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101. This concept holds true in the Hatch-Waxman context. In Research Found. of

SUNY v. Mylan Pharm. Inc., 809 F. Supp. 2d 296, 330–31 (D. Del. 2011), aff’d in part, vacated

in part (on validity of other patents), 531 F. App’x 1008 (Fed. Cir. 2013), the Court found

infringement where, without rounding, one patient had plasma concentration levels that met the

requirements of the asserted claims and, with rounding, a total of three (out of thirty-one)

patients’ plasma levels met the claim elements. There the generic company argued that the mean

Cmin value was well outside the claimed range. Id. at 330. The Court noted that the asserted

claims “are not directed to mean values across a large population; neither claim mentions ‘mean’

values whatsoever. . . . Hence, in the context of the [patent], even if only 1 of 31 subjects in the

pivotal pK study had a Cmin of 0.3 to 0.6 μg/mL, this is a sufficient basis from which to find

infringement.” Id. at 330–31; accord Acorda Therapeutics Inc. v. Apotex Inc., C.A. No. 07-4937-

GEB-MCA, 2011 WL 4074116, at *12–13 (D.N.J. Sept. 6, 2011) (finding that plaintiff had

shown sufficient evidence from which the court could infer that some patients will meet the

claim limitation and noting that “the question is not whether there is a statistically significant

number of patients whose Cmax and somnolence are reduced. . . . [I]f a single patient attains a

reduced Cmax from [defendant’s] product, the product infringes.”).

102. Here, the ’742 patent claims reinforce that it is individuals – not mean data or a

percentage of the population – who infringe: claim 1 of the ’742 patent is directed to “a subject,”

which, under the claim construction, carries its plain and ordinary meaning: one or more

subjects. E.g., Tate Access Floors, Inc. v. Interface Arch. Res. Inc., 279 F.3d 1357, 1360 (Fed.

Cir. 2002).

103. That only some individuals, or as in the Research Foundation case, only one

individual, may be found to infringe is not the same as having an “anomalous” result as the only


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evidence of infringement. Here, not only has Dr. Fleckenstein identified multiple individuals

whose plasma concentration data is pulsatile (FF ¶ 66), but this data was demonstrated to be

quite accurate – with errors of at most three to five percent – by Actavis’s own assay accuracy

calculations. FF ¶ 67. Dr. Fleckenstein also explained that at least another seventeen individuals

demonstrated circumstantial evidence of peaks and troughs that were not captured due to the

infrequent sampling times employed in Actavis’s clinical study (which was designed to

demonstrate bioequivalence to Zohydro® ER, not to demonstrate pulsatile plasma

concentrations), or other factors that conceal the peaks and troughs. FF ¶¶ 68–71.

104. This is different from situations like those in Ferring B.V. v. Watson Labs., Inc.-

Florida, 764 F.3d 1401, 1409 (Fed. Cir. 2014), where the district court found no infringement

when only four out of nearly 200 tablets met the claim limitations of an in vitro dissolution test.

There, the expert testified that there was obviously something wrong with the few samples that

met the claim limitations: “there was something incomplete about the coating. It lacked coating

integrity. The coating on the tablet sort of came apart and opened up. It was very atypical and

aberrant relative to all of the other 176 tablets that were examined.” Id. at 1409. Similarly, in

Eastman Kodak Co. v. Agfa Gevaert N.V., 560 F. Supp. 2d 227, 277–80 (W.D.N.Y. 2008), the

court concluded that infringement had not been established for one product where samples taken

from the same batches had different thicknesses and aspect ratios (id. at 278) but did find

infringement for another product where there was more internal consistency amongst the results.

Id. at 279–80. In doing so, the court there did not apply an arbitrary percentage for infringing

samples, noting that “[t]he extent of infringement, i.e., the percentage of the [accused product]

which infringes the [asserted patent] has yet to be determined . . . .” Id. at 280.

105. Here, Actavis’s own in vitro dissolution data for its ANDA products demonstrates


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consistent release (FF ¶ 53), and its in vivo assay accuracy calculations (FF ¶ 67) demonstrate

that the observation that some individuals in the ACT-15030 study had low concentration

troughs in their plasma concentration curves is real and not a result of abnormalities in the

capsules or errors in blood plasma concentration measurements. Id.

106. Neither the in vitro release patterns nor the shapes of the plasma curves of

Actavis’s ANDA products were disavowed by the patentee during prosecution or in the

specification. For the in vitro release, the patentee distinguished the Paradissis reference solely

based on Paradissis’s teaching of “approaching a zero order release rate.” FF ¶ 55 (emphasis in

original). There was no discussion or distinction made over specific release profiles. Id. A

disavowal of claim scope must be “unambiguous” and “clearly and unmistakably disclaim[]

claim scope or meaning.” Grober v. Mako Prods., Inc., 686 F.3d 1335, 1342 (Fed. Cir. 2012).

107. Similarly, disavowal of claim scope in the specification requires “expressions of

manifest exclusion or restriction, representing a clear disavowal of claim scope.” Epistar Corp.

v. ITC, 566 F.3d 1321, 1335 (Fed. Cir. 2009) (quoting Teleflex, Inc. v. Ficosa N. Am. Corp., 299

F.3d 1313, 1325 (Fed. Cir. 2002)). “[D]isparaging comments alone do not necessarily show a

manifest or express disavowal of the criticized subject matter.” Id. at 1336.

108. The reference to “Giunchedi” in the Description of the Prior Art in the ’742 patent

describes that article as lacking the preferred “well defined wash out period” and notes that the

peak to trough variations are “small” (JTX 2 at 2:47–59); such a description of the prior art is not

a “clear disavowal” or “manifest restriction.” Nor does the ’742 patent’s note that an object of

the “Alza” reference is to avoid uneven blood levels (JTX 2 at 2:11–26) disavow coverage of the

dosage forms with overlapping peaks and shallower troughs that are expressly contemplated by

the specification (JTX 2 at 8:17–34). (Alza does not describe oral dosage forms where a trough


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occurs but is concealed due to infrequent sampling times but rather a dosage with constantly

ascending plasma levels only achievable with constant intravenous infusion. FF ¶ 74.)

109. For the reasons above, Actavis’s ANDA products literally meet the pulsatile

limitations of the asserted claims. Because all elements of the asserted claims of the ’742 patent

are met, Actavis’s ANDA products infringe the asserted claims of the ’742 patent.

Relief C.

110. Under 35 U.S.C. § 271(e)(2), a generic drug manufacturer infringes a patent by

filing an ANDA to obtain approval for a generic drug product covered by a valid and unexpired

patent. Eli Lilly & Co. v. Teva Pharm. USA, Inc., 557 F.3d 1346, 1348 (Fed. Cir. 2009).

111. Section 271(e)(4)(A) provides that for an act of infringement under § 271(e)(2),

“the court shall order the effective date of any approval of the drug . . . involved in the

infringement to be a date which is not earlier than the date of the expiration of the patent which

has been infringed.” 35 U.S.C. § 271(e)(4)(A).

112. Section 271(e)(4)(B) provides that for an act of infringement under § 271(e)(2),

“injunctive relief may be granted against an infringer to prevent the commercial manufacture,

use, offer to sell, or sale within the United States or importation into the United States of an

approved drug.”

113. As the ’096 and ’742 patents are valid and have not expired, Recro requests the

Court order that the effective date of any final approval of Actavis’s ANDA shall not be earlier

than the last to expire of the ’096 and ’742 patents, including any extensions and marketing

exclusivities, pursuant to 35 U.S.C. § 271(e)(4)(A). Recro also requests that Actavis be enjoined

from commercially manufacturing, using, offering for sale, selling, or importing its proposed

generic version of Zohydro® ER prior to the patents’ expiration, including any extensions and

marketing exclusivities.


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MORRIS, NICHOLS, ARSHT & TUNNELL LLP

/s/ Jeremy A. Tigan Jack B. Blumenfeld (#1014)

Maryellen Noreika (#3208)

Jeremy A. Tigan (#5239)

Megan E. Dellinger (#5739)

1201 North Market Street

P.O. Box 1347

Wilmington, DE 19899-1347

(302) 658-9200

[email protected]

[email protected]

[email protected]

[email protected]

Attorneys for Recro Gainesville LLC

November 7, 2016 10555837


APPENDIX A

RECRO GAINESVILLE LLC’S WITNESSES

Dr. Lawrence Fleckenstein

Dr. Fleckenstein, an expert in the field of

pharmacokinetics, is professor emeritus at the

University of Iowa, College of Pharmacy, in the

Department of Pharmaceutical Sciences and

Experimental Therapeutics, in the Division of

Pharmaceutics and Translational Therapeutics.

Dr. Fleckenstein’s research is focused on the

pharmacokinetics of new drugs in human

subjects. He has taught extensively in the field of

clinical pharmacokinetics for 24 years and has

extensive experience designing, conducting, and

analyzing clinical research.

At trial, Dr. Fleckenstein testified about the in

vitro and in vivo properties of Actavis’s ANDA

products, concluding that those products meet the

“pulsatile” limitation of claim 1 of the ’742 patent

and the additional limitations present in claims

14, 16, and 19 of that patent. Fleckenstein Tr.

151:13–275:21.

Dr. Jürgen Siepmann

Dr. Siepmann, an expert in the field of

pharmaceutical formulation, is a full professor of

pharmaceutical technology at the University of

Lille in Lille, France. Dr. Siepmann’s research is

focused on drug formulation development, and he

has extensive experience in the fields of coated

dosage forms and controlled-release drug delivery

systems, in particular polymer-coated pellets

releasing drugs in a controlled manner in the

gastrointestinal tract.

At trial, Dr. Siepmann testified about the

formulation aspects of Actavis’s ANDA products,

concluding that those products infringe claims 1,

4, and 5 of the ’096 patent; claims 6 and 13 of the

’742 patent, and satisfy the formulation

limitations in claim 1 of that patent. Siepmann Tr.

55:14–151:11.


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