United States District Court, D. Delaware
FOREST LABORATORIES, LLC, FOREST LABORATORIES HOLDINGS, LTD., and ALLERGAN PHARMACEUTICALS INTERNATIONAL LTD., Plaintiffs,
SIGMAPHARM LABORATORIES, LLC, et al., Defendants.
B. Blumenfeld, Esquire and Jeremy A. Tigan, Esquire of
Morris, Nichols, Arsht & Tunnell LLP, Wilmington,
Delaware. Counsel for Plaintiffs. Of Counsel: Howard W.
Levine, Esquire, Sanya Sukduang, Esquire, Jonathan R. Davies,
Esquire, Courtney B. Casp, Esquire, Mindy L. Ehrenfried,
Esquire, and Jorge F. Gonzalez, Esquire of Finnegan,
Henderson, Farabow, Garrett & Dunner, LLP, New York, New
C. Phillips, Jr., Esquire and Megan C. Haney, Esquire of
Phillips, Goldman, McLaughlin & Hall, P.A., Wilmington,
Delaware. Counsel for Defendant Sigmapharm Laboratories, LLC.
Of Counsel: Anthony G. Simon, Esquire and Anthony R.
Friedman, Esquire of The Simon Law Firm, P.C., St. Louis,
GOLDBERG, MITCHELL S., DISTRICT JUDGE.
Hatch-Waxman patent infringement action revolves around an
Abbreviated New Drug Application (“ANDA”) filed
by Sigmapharm Laboratories, LLC (“Sigmapharm”)
seeking approval to market a generic version of Saphris®,
a sublingual asenapine maleate tablet commonly used to treat
schizophrenia and bipolar related disorders. Plaintiffs
Forest Laboratories LLC, Forest Laboratories Holdings, Ltd.,
and Allergan Pharmaceuticals International Ltd.
(collectively, “Forest”) are the assignee of U.S.
Patent Nos. 5, 763, 476 (“the '476 patent”),
7, 741, 358 (“the '358 patent”), and 8, 022,
228 (“the '228 patent”), which are listed in
the Food and Drug Administration's publication titled
Approved Drug Products with Therapeutic Equivalence
Evaluations (the “Orange Book”) as covering
Saphris®. (PTX 563).
June 18-20, 2018, I held a three-day bench trial on the only
remaining issue in this matter: Sigmapharm's alleged
infringement of claim 1 of the '476 patent. After review of
the evidence and briefing submitted by the parties, I find
that Forest has proven by a preponderance of the evidence
that Sigmapharm's ANDA infringes claim 1 of the '476
patent. Pursuant to Fed.R.Civ.P. 52(a)(1), the facts and
conclusions supporting this decision are set forth below.
Consolidation and Stay
August 7, 2014, Sigmapharm notified Forest that it had
submitted an ANDA to the FDA seeking approval of a generic
version of sublingual asenapine maleate tablets with a
Paragraph IV certification, pursuant to 21 U.S.C. §
355(j)(2)(A)(vii)(IV), stating that the patents-in-suit are
invalid and/or will not be infringed. (PTX 118). On September
3, 2014, Forest sued Sigmapharm for infringement of two of
the three patents covering Saphris®-the '476 patent
and '358 patent. (D.I. 1, C.A. No. 14-1119). Forest
brought similar suits against Hikma Pharmaceuticals, LLC,
Hikma Pharmaceuticals, PLC, and West-Ward Pharmaceutical
Corp. (collectively, “Hikma”) (see D.I. 1, C.A.
No. 14-1266); Breckenridge Pharmaceutical, Inc.
(“Breckenridge”) (see D.I. 1, C.A. No. 14-1504);
Alembic Pharmaceuticals Ltd., Alembic Global Holding S.A.,
and Alembic Pharmaceuticals, Inc. (collectively,
“Alembic”) (see D.I. 1, C.A. No. 15-0158); and
Amneal Pharmaceuticals, LLC, Amneal Pharmaceuticals of New
York, LLC, and Amneal Pharmaceuticals Co. India PVT., Ltd.
(collectively, “Amneal”) (see D.I. 1, C.A. No.
15-0430). These cases were initially overseen by the
Honorable Sue L. Robinson, now retired, and consolidated
under Civil Action No. 14-1119. (D.I. 21; D.I. 35; D.I. 70).
10, 2015, Sigmapharm filed counterclaims seeking a
declaratory judgment of invalidity and non-infringement for
all three patents covering Saphris®-i.e., the '476
patent, the '358 patent, and the '228 patent. (D.I.
43). On April 15, 2016, Judge Robinson entered the following
judgments pursuant to a stipulation by the parties: (i) in
favor of Sigmapharm for Forest's claim of infringement of
the '358 patent; (ii) in favor of Sigmapharm for
Sigmapharm's counterclaim of non-infringement of the
'358 patent; and (iii) in favor of Sigmapharm for
Sigmapharm's counterclaim of non-infringement of the
'228 patent. (D.I. 181 at ¶ 1(a-c)). Also by
stipulation of the parties, Judge Robinson dismissed without
prejudice, Sigmapharm's counterclaims seeking a
declaration that the '358 patent and '228 patent were
invalid. (Id.). As a result, the only remaining
claim and counterclaim between Forest and Sigmapharm related
to the infringement and validity of the '476 patent.
October 13, 2016, Judge Robinson ordered that all issues
relating to Sigmapharm's infringement of the '476
patent be stayed and that the 30-month stay of FDA approval
of Sigmapharm's ANDA be tolled until the stay was lifted.
(D.I. 278). Judge Robinson further ordered that she would
proceed to trial with the remaining four defendants (Hikma,
Breckenridge, Alembic, and Amneal) to determine, among other
things, the validity of the '476 patent. (Id.).
Pursuant to that order, Sigmapharm would be bound by any
final judgment concerning the validity of the '476
Robinson held a bench trial with the remaining four
defendants between October 24, 2016 and November 3, 2016 and
issued an opinion and order on June 30, 2017. (D.I. 322; D.I.
323). A final judgment was entered on July 11, 2017. (D.I.
325). All four trial defendants stipulated to infringement of
claims 1, 2, 5, and 6 of the '476 patent. (D.I. 323). Two
of the four defendants (Hikma and Amneal) also stipulated to
infringement of claims 4, 9, and 10 of the '476 patent.
(Id.). The other two defendants (Alembic and
Breckenridge) were found not to infringe claims 4, 9, and 10
of the '476 patent. (Id.). Finally, Judge
Robinson held that the '476 patent was valid and entered
judgment on that issue in favor of Forest and against all
defendants, including Sigmapharm. (D.I. 325).
four trial defendants have appealed Judge Robinson's
decision finding the asserted claims of the '476 patent
valid, and Forest has cross-appealed Judge Robinson's
decision that Alembic and Breckenridge did not infringe
claims 4, 9, and 10 of the '476 patent. (D.I. 326; D.I.
327; D.I. 328; D.I. 329; D.I. 334). That appeal is pending
before the Court of Appeals for the Federal Circuit. (See
Lead No. 17-2369; Cross Appeal Nos. 17-2436, 17-2441).
25, 2017, the case was reassigned to my docket. On February
9, 2018, I lifted Judge Robinson's stay on Sigmapharm.
(D.I. 358). On June 21, 2018, the 30-month stay of FDA
approval of Sigmapharm's ANDA expired. (D.I. 362 at 2).
Effective July 17, 2018, the FDA approved Sigmapharm's
ANDA No. 206107, for Asenapine Sublingual Tablets, 5 mg and
10 mg. (D.I. 398 at 1 n. 1).
Issues and Asserted Claims for Trial
asserts that Sigmapharm infringes claims 1-2, 4-6, and 9-10
of the '476 patent. (D.I. 384-1, Ex. 4). The parties
agree that Sigmapharm's infringement of claims 2, 5, and
6 rises and falls with infringement of claim 1. (D.I. 362 at
¶ 3). The parties further agree that Sigmapharm's
infringement of claims 4, 9, and 10 will depend on the
outcome of the appeal pending before the Federal Circuit,
because any finding as to infringement of those claims by
Alembic and Breckenridge will apply with equal force to
Sigmapharm. (Id. at ¶ 4). Given these
agreements, the sole issue before me is whether Sigmapharm
infringes claim 1 of the '476 patent either literally or
under the doctrine of equivalents. (Id. at ¶
FINDINGS OF FACT
'476 patent, entitled “Sublingual or Buccal
Pharmaceutical Composition, ” was issued from the
United States Patent and Trademark Office on June 9, 1998.
(D.I. 384, Ex. 1 at ¶ 5). Claim 1 of the '476 patent
is a composition claim and recites:
A pharmaceutical composition comprising as a medically active
compound: trans-5-chloro-2-methyl-2, 3, 3a,
12b-tetrahydro-1H-dibenz[2, 3:6, 7]oxepino-[4, 5-c] pyrrole
or a pharmaceutically acceptable salt thereof; wherein the
composition is a solid composition and disintegrates within
30 seconds in water at 37° C.
(Id. at ¶ 15). No. terms from claim 1 were
construed in the only claim construction order issued in this
case. (See D.I. 133). Judge Robinson did, however, construe
claim 1 in her June 2017 trial opinion. She found claim 1
“limited to sublingual or buccal compositions.”
(D.I. 322 at 18). For sublingual tablets, the patient places
the formulation under the tongue and waits for it to
dissolve. (Id. at 2). For buccal tablets, the
formulation is placed in the pouch of the cheek.
(Id. at 12).
experts testified at trial. Forest presented the expert
testimony of Dr. Adam Myers (“Dr. Myers”) and Dr.
Lisbeth Illum (“Dr. Illum”) and Sigmapharm
stipulated to their qualification as experts. (D.I. 386 at
82:8-22; D.I. 388 at 29:10-21). Dr. Myers is a PhD organic
chemist. (D.I. 386 at 36:4-7, 85:1-8). He performed testing
on samples of Sigmapharm's product and was generally
offered as an expert in disintegration testing,
pharmaceutical analysis, and U.S. Pharmacopeia, Chapter
<701> (“USP <701>”). (D.I. 386 at
89:23-90:2). Dr. Illum has a PhD and DSc in pharmacy. (D.I.
388 at 28:1-25). She was generally offered as an expert in
drug delivery systems, transmucosal drug delivery, and
disintegration testing. (D.I. 388 at 34:22-25). Sigmapharm
presented the expert testimony of Dr. Thomas Kupiec
(“Dr. Kupiec”) and Dr. Harry Brittain (“Dr.
Brittain”). Dr. Kupiec has a PhD in pharmaceutical
sciences. He performed testing on samples of Sigmapharm's
product and was generally offered as an expert on
disintegration testing and USP <701>. (D.I. 390 at
4:25-5:3). Dr. Kupiec was found to be qualified as an expert.
(Id. at 39:24-25). Dr. Brittain is a pharmaceutical
scientist with a PhD in physical chemistry. (D.I. 391 at
4:22-25). He was generally offered as an expert on USP
<701> and Forest stipulated to his qualification as an
expert. (Id. at 4:22-5:22). Finally, Sigmapharm
offered the testimony of Dr. Spiridon Spireas (“Dr.
Spireas”), the CEO of Sigmapharm, but did not seek to
have him qualified as an expert. (D.I. 386 at 9:18-14:1).
U.S. Pharmacopeia, Chapter <701>
determination of whether Sigmapharm's accused product
infringes claim 1 of the '476 patent depends on one
issue: does the accused product “disintegrate within
30 seconds in water at 37° C.” The parties agree
that USP <701> is the proper method for measuring
disintegration. (D.I. 386 at 33:16-22, 59:17-60:11; D.I. 388
at 46:15-47:16; D.I. 398 at 3; D.I. 400 at 3). Because Forest
relies on USP <701> to prove infringement and the
parties criticize how the opposing experts conducted their
tests, it is useful to first understand the purpose of the
test, the testing procedures prescribed by USP <701>,
and the possible test outcomes.
The Purpose of the USP <701> Test
is a standardized test used in the United States to determine
whether tablets disintegrate within the time prescribed.
(D.I. 384, Ex. 1 at ¶ 39). USP<701> is most
commonly used by manufacturers to test whether a batch of
tablets is in compliance with a disintegration specification
before a product is released for use or sale. (D.I. 387 at
59:13-22; D.I. 390 at 13:24-14:3). For example, if a
disintegration specification requires the tablets to
disintegrate in 30 seconds in water at 37° C, then USP
<701> is used to confirm that a batch of tablets will
perform as required before being released. The test is
conducted on a representative sample of tablets from a drug
product batch. (D.I. 391 at 15:12-16). Then, the results of a
single USP <701> disintegration test are imputed to the
entire batch. (D.I. 387 at 73:10-19; D.I. 389 at 40:12-19).
Thus, in the case of Sigmapharm, the characteristics of
anywhere between 6 and 18 sample tablets are imputed onto a
batch of 150, 000 tablets. (PTX 679 at 1).
<701> requires a basket-rack assembly with six
open-ended transparent tubes held in a vertical
position. (PTX 631 at 3; PTX 592). The bottom of
each tube is a stainless-steel wire screen. (PTX 631 at 3;
DTX 29 at SIGMA111656, SIGMA112023-SIGMA112024). An apparatus
is used to raise and lower the basket in an immersion fluid,
such as water, at a constant frequency rate. (PTX 631 at 3;
PTX 594; DTX 29 at SIGMA111806; D.I. 386 at 110:23-24).
“Dips per minute” refers to the rate at which the
apparatus moves the basket up and down in the water, which
the experts here set at 30 per minute. (D.I. 386 at 109:6-7).
To conduct the test, one tablet is placed in each of the six
tubes and a plastic cylindrical disk is added above the
tablet. (PTX 631 at 4). After loading the tablets into the
tubes, the apparatus is operated for the time specified.
(Id.). Here, the time specified by the '476
patent is 30 seconds. (PTX 1 at 6:2-3).
operating the apparatus for the time specified, one must
determine if “complete disintegration” has
occurred. Under USP <701>, complete disintegration
“does not imply complete solution of the [tablet] or
even of its active constituent.” (PTX 631 at 3).
Instead, “complete disintegration” is defined as
“that state in which any residue of the [tablet],
except fragments of insoluble coating or capsule shell,
remaining on the screen of the [basket-rack assembly] or
adhering to the lower surface of the disk is a soft mass
having no palpably firm core.” (Id.).
Therefore, a tablet is considered to have completely
disintegrated under USP <701> even if some part of the
tablet remains at the end of the time specified, as long as
the remaining pieces are “fragments of insoluble
coating or capsule shell” or “a soft mass having
no palpably firm core.” (D.I. 386 at 102:8-24). The
experts agree “palpably firm core” means that any
remaining mass should be probed or palpated, typically with a
spatula, to determine if it is soft or hard. (Id.;
D.I. 391 at 64:1-4).
Possible Test Outcomes
has two stages of testing. In stage one, a run of 6 tablets
is tested. (PTX 631 at 4). If all 6 tablets (written by the
parties as 6/6) completely disintegrate within 30 seconds,
testing stops because the results are conclusive: The batch
from which the sample tablets were taken will disintegrate
within 30 seconds. (Id.; D.I. 386 at 106:4-11). If 3
or fewer tablets (1/6, 2/6, or 3/6) completely disintegrate
within 30 seconds, then testing stops and the product cannot
be released because the batch is not “in control,
” meaning the tablets are not uniformly performing
within the required specifications. (D.I. 386 at
105:18-106:3; D.I. 390 at 13:24-14:3; D.I. 391 ...