IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE RECRO GAINESVILLE LLC, Plaintiff, v. ACTAVIS LABORATORIES FL, INC., Defendant. ) ) ) ) ) ) ) ) ) C.A. No. 14-1118 (GMS) CONSOLIDATED 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 VERSION FILED 11/14/2016 Case 1:14-cv-01118-GMS Document 131 Filed 11/14/16 Page 1 of 43 PageID #: 2688
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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.
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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
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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.
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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.
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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
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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
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.
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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.
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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.
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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
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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.
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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.
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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
Case 1:14-cv-01118-GMS Document 131 Filed 11/14/16 Page 21 of 43 PageID #: 2708
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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).