Petition for Writ of Certiorari — Salix Pharmaceuticals, Ltd., et al., Petitioners v. Norwich Pharmaceuticals Inc.
Supreme Court briefSep 11, 2024
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APPENDIX
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APPENDIX
TABLE OF CONTENTS
Page
Appendix A — Court of appeals opinion
(Apr. 11, 2024) ................................1a
Appendix B — District court trial opinion (Aug.
10, 2022) ........................................33a
Appendix C — District court memorandum order (May 17, 2023) ........................90a
Appendix D — Court of appeals order (June 13,
2024) ..............................................96a
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APPENDIX A
UNITED STATES COURT OF APPEALS
FOR THE FEDERAL CIRCUIT
SALIX PHARMACEUTICALS, LTD., SALIX
PHARMACEUTICALS, INC., BAUSCH HEALTH
IRELAND LTD., ALFASIGMA S.P.A.,
Plaintiffs-Appellants
v.
NORWICH PHARMACEUTICALS INC.,
Defendant-Cross-Appellant
2022-2153, 2023-1952
Appeals from the United States District Court for
the District of Delaware in No. 1:20-cv-00430-RGA,
Judge Richard G. Andrews.
Decided: April 11, 2024
WILLIAM R. PETERSON, Morgan, Lewis & Bockius
LLP, Houston, TX, argued for plaintiffs-appellants.
Also represented by MICHAEL J. ABERNATHY, KARON
NICOLE FOWLER, MICHAEL SIKORA, Chicago, IL; JULIE
S. GOLDEMBERG, Philadelphia, PA; JOSHUA DANIEL
CALABRO, SHANNON KEOUGH CLARK, STEVEN C. KLINE,
ALEXIS M. MCJOYNT, SCOTT K. REED, BECKY E. STEEPHENSON, Venable LLP, New York, NY.
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CHAD A. LANDMON, Axinn, Veltrop & Harkrider
LLP, Hartford, CT, argued for defendant-cross-appellant. Also represented by MATTHEW BECKER, REBECCA
L. CLEGG, THOMAS K. HEDEMANN, MATTHEW S. MURPHY.
IRENA ROYZMAN, Kramer Levin Naftalis &
Frankel LLP, New York, NY, for amici curiae Regeneron Pharmaceuticals, Inc., Ocular Therapeutix, Inc.
Also represented by CHRISTINE WILLGOOS; PAUL
BRZYSKI, Washington, DC.
PAUL WHITFIELD HUGHES, III, McDermott Will &
Emery LLP, Washington, DC, for amicus curiae
Vanda Pharmaceuticals Inc. Also represented by
CHRISTOPHER MICHAEL BRUNO, SARAH HOGARTH,
APRIL ELISE WEISBRUCH.
Before LOURIE, CHEN, and CUNNINGHAM, Circuit
Judges.
Opinion for the court filed by Circuit Judge LOURIE.
Opinion dissenting-in-part filed by Circuit Judge
CUNNINGHAM.
LOURIE, Circuit Judge.
Salix Pharmaceuticals, Ltd., Salix Pharmaceuticals, Inc., Bausch Health Ireland Ltd., and Alfasigma
S.P.A. (collectively, “Salix”) appeal from a final judgment of the United States District Court for the District of Delaware holding claim 2 of U.S. Patent
8,309,569, claim 3 of U.S. Patent 10,765,667, claim 4
of U.S. Patent 7,612,199, and claim 36 of U.S. Patent
7,902,206 invalid as obvious. See Salix Pharms., Ltd.
3a
v. Norwich Pharms., Inc., No. 20-cv-430, 2022 WL
3225381 (D. Del. Aug. 10, 2022) (“Decision”).
Norwich Pharmaceuticals Inc. (“Norwich”) crossappeals from an order that issued after the district
court concluded that Norwich infringed claim 8 of U.S.
Patent 8,624,573, claim 6 of U.S. Patent 9,421,195,
and claims 11 and 12 of U.S. Patent 10,335,397 and
had failed to prove that those claims were invalid.
That order, contained within the final judgment, instructed the FDA that the effective approval date of
Norwich’s Abbreviated New Drug Application
(“ANDA”) may not precede the expiration dates of
those claims. J.A. 51. Norwich also cross-appeals from
a denial of its motion to modify the final judgment. See
Salix Pharms., Ltd. v. Norwich Pharms., Inc., No. 20430, 2023 WL 3496373 (D. Del. May 17, 2023) (“Rule
60(b) Order”).
For the following reasons, we affirm.
BACKGROUND
Rifaximin, the active ingredient in Salix’s commercial product Xifaxan®, has been widely used as an
antibiotic for decades, having been first synthesized in
the early 1980s in Italy and approved there as an antibiotic in 1985. Decision at *8; J.A. 2532. The FDA
approved Xifaxan nearly 20 years later, in 2004, as
200 mg tablets for the treatment of travelers’ diarrhea. Decision at *1. The FDA subsequently approved
550 mg tablets for hepatic encephalopathy (“HE”) in
2010 and for irritable bowel syndrome with diarrhea
(“IBS-D”) in 2015. Id.
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Norwich sought to market a generic version of
rifaximin and, in 2019, filed an ANDA for 550 mg tablets with the same indications as Xifaxan, certifying
pursuant to 21 U.S.C. § 355(j)(2)(vii)(IV) that Salix’s
rifaximin patents were invalid. Salix timely sued, asserting that Norwich’s ANDA infringed dozens of
valid, Orange Book-listed patents. By the time of trial,
the case had been streamlined to three groups of patents:
the ’573, ’195, and ’397 patents, directed to
treating HE (“the HE patents”);
the ’569 and ’667 patents, directed to treating
IBS-D with 550 mg rifaximin three times a day
(1,650 mg/day) for 14 days (“the IBS-D patents”); and,
the ’199 and ’206 patents, directed to rifaximin
form β (“the polymorph patents”).
Following a bench trial, the district court held
that Norwich infringed the HE patents’ claims and
had failed to establish their invalidity. Decision at
*10-11. Norwich did not appeal those holdings. The
court also held that Norwich’s ANDA infringed the
IBS-D and polymorph patents, but that those patents’
claims would have been obvious over certain prior art.
Id. at *2-3, 16-17. Salix appealed those invalidity
holdings.
As part of the entered judgment, the district court
ordered that the effective date of a final approval of
Norwich’s ANDA should not precede October 2029,
which is the latest expiration date associated with the
HE patents. J.A. 51. Norwich then amended its ANDA
in an attempt to remove the infringing HE indication
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and moved to modify the judgment under Federal
Rule of Civil Procedure 60(b), asserting that the
amendment negated any possible infringement. The
court denied Norwich’s motion, and Norwich cross-appealed.
We have jurisdiction under 28 U.S.C. § 1295(a)(1).
DISCUSSION
Salix first contends that the district court’s conclusion that the asserted claims of the IBS-D patents
were invalid as obvious was reached in error. Subsumed within that challenge is a question of whether
or not a background reference discussed by the court
was properly established as prior art. Salix also contends that the court erred in holding that the asserted
polymorph patent claims were invalid as obvious.
Norwich’s cross-appeal asserts that the court erred in
the phrasing of its order precluding final approval of
its ANDA until expiration of the HE patents. Norwich
further asserts that the court erred in denying its motion to modify after the ANDA was amended in an attempt to avoid infringement. We address each argument in turn.
I
We turn first to Salix’s contention that the district
court erred in concluding that the asserted claims of
the IBS-D patents would have been obvious over the
asserted prior art.
Whether or not a claim would have been obvious
is a question of law, based on underlying factual determinations. Hospira, Inc. v. Fresenius Kabi USA,
LLC, 946 F.3d 1322, 1328–29 (Fed. Cir. 2020). We review the ultimate legal question of obviousness de
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novo and the underlying factual determinations for
clear error. Id. at 1328. A finding is clearly erroneous
only if we are “left with a definite and firm conviction
that the district court was in error.” Id. (citations
omitted).
The IBS-D patents are directed to treating IBS-D
with 550 mg rifaximin, thrice-daily (1,650 mg/day), for
14 days. For example, claim 2 of the ’569 patent depends from claim 1 as follows:
1. A method of providing acute treatment for diarrhea-associated Irritable Bowel Syndrome
(dIBS) comprising: administering 1650 mg/day of
rifaximin for 14 days to a subject in need thereof,
wherein removing the subject from treatment after the 14 days results in a durability of response,
wherein the durability of response comprises
about 12 weeks of adequate relief of symptoms.
2. The method of claim 1, wherein the 1650 mg
is administered at 550 mg three times per day.
’569 patent, col. 30 ll. 4–12 (emphases added); see also
’667 patent, col. 46 ll. 29–33, 39–40 (claims 1 & 3, similar). The key limitation on appeal is the dosage
amount that appears in the claims: 550 mg, three
times per day (“TID”), for a total of 1,650 mg/day.
Norwich challenged the IBS-D claims’ validity by
asserting as prior art references a clinical trial protocol that had been published on the ClinicalTrials.gov
website in 2005 (“the Protocol”)1 and a 2006 journal
ClinicalTrials.gov, History of Changes for Study:
NCT00269412, Randomized, Double Blind, Placebo-Controlled
Study to Assess the Efficacy and Safety of Three Different Doses
of Rifaximin Administered BID either Two or Four Weeks in the
1
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article (“Pimentel”).2 The Protocol describes a Phase
II study evaluating twice-daily doses of 550 mg (1,100
mg/day) and 1,100 mg (2,200 mg/day) for 14 and 28
days for the treatment of IBS-D. See J.A. 7051. Pimentel teaches administering 400 mg, TID (1,200 mg/day),
for the treatment of IBS,3 but further opines that the
“optimal dosage of rifaximin may, in fact, be higher
than that used in our study.” J.A. 4644.
The district court found that those two references
disclose each and every limitation of the challenged
IBS-D claims, and further found that a skilled artisan
would have been motivated to combine those two references to arrive at what is claimed with a reasonable
expectation of success. Decision at *17, *19–20. The
court then concluded that the challenged IBS-D
claims were invalid as obvious. Id. at *17–22. Salix
appeals, asserting that the court erred in finding that
a skilled artisan would have had a reasonable expectation of success in using the claimed 1,650 mg/day
dosage to treat IBS-D. Appellants’ Br. at 39–48.
Whether or not there would have been a reasonable
expectation of success is a question of fact, IXI IP, LLC
v. Samsung Elecs. Co., 903 F.3d 1257, 1262 (Fed. Cir.
Treatment of Patients with Diarrhea-Associated Irritable Bowel
Syndrome (December 22, 2005); J.A. 7047–55.
2 M. Pimentel et al., The Effect of a Nonabsorbed Oral Antibiotic (Rifaximin) on the Symptoms of the Irritable Bowel Syndrome, 145 ANN. INTERN. MED., 557 (2006); J.A. 4639–46.
3 Salix did not argue a difference between a motivation to use
rifaximin to treat IBS versus IBS-D. Decision at *19 n.3. It concedes on appeal that “[r]oughly one-third of IBS patients suffer
from IBS-D,” Appellants’ Br. at 6, and has not otherwise suggested that treatments for IBS would not inform treatments of
IBS-D.
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2018), which we review for clear error, Hospira, 946
F.3d at 1328.
Salix does not appear to dispute the district
court’s finding that the Protocol and Pimentel “disclose all limitations of the IBS-D claims.” See Decision
at *17. Rather, it contends that even if the asserted
combination of references effectively discloses the
claimed 1,650 mg/day dosage, there remains insufficient evidence to support a finding of a reasonable expectation of success in using that particular dosage
amount. See, e.g., Appellants’ Br. at 39–40. According
to Salix, the highest prior art dosage amount that
could have been supported with a reasonable expectation of success was the 1,200 mg/day dose evaluated
by Pimentel. Id. at 40. We disagree.
The Protocol provides an outline of a planned
Phase II clinical trial in which “three different doses
(275, 550 and 1100 mg) of rifaximin” were to be “administered BID [i.e., twice-daily] for either two or four
weeks in the treatment of patients with diarrhea-associated irritable bowel syndrome.” J.A. 7050 (cleaned
up). As an outline of that clinical trial plan, the Protocol provides only that those three specific, twice-daily
dosage regimens were to be investigated for either two
or four weeks. The Protocol does not include any efficacy or safety data, nor does it mention a 1,650 mg/day
dose or TID dosing.
Although we have rejected the idea that “efficacy
data [are] always required for a reasonable expectation of success,” OSI Pharms., LLC v. Apotex Inc., 939
F.3d 1375, 1385 (Fed. Cir. 2019), we are hesitant to
conclude as a general matter that the disclosure of a
Phase II clinical trial plan, standing alone, provides
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an expectation of success sufficient to render obvious
a dosage that was not included within the planned
clinical trial. See Appellants’ Reply Br. at 13-14. But
the Protocol was not asserted alone; it was asserted in
combination with Pimentel.
Pimentel teaches that administration of 400 mg
rifaximin, TID (1,200 mg/day), “resulted in greater
improvement in IBS symptoms” and “lower bloating
score[s] after treatment.” J.A. 4639; see also id. at
4642–43 (providing supporting data). Pimentel explains that the 400 mg TID regimen was chosen “on
the basis of a previous study that demonstrated the
efficacy of rifaximin in bacterial overgrowth.” Id. at
4640. However, Pimentel does not merely provide that
daily rifaximin doses of 1,200 mg were likely to be successful in the treatment of IBS. Pimentel further
teaches that “[r]ecent data suggest that the optimal
dosage of rifaximin may, in fact, be higher than that
used in our study.” J.A. 4644; Decision at *20 (emphases added).
The district court did not clearly err in finding
that a skilled artisan would have looked to both of
those references, considered their limits, and had a
reasonable expectation of success as to the efficacy of
550 mg TID dosing. The combined message that the
skilled artisan would have discerned from the Protocol
and Pimentel is that the optimal dosage for treating
patients suffering from IBS disorders may be higher
than 400 mg TID, and the next higher dosage unit
from the Protocol was 550 mg. We see no clear error
in the conclusion that there would have been a reasonable expectation of success in administering the
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claimed 1,650 mg/day to IBS-D patients. Indeed, certainty and absolute predictability are not required to
establish a reasonable expectation of success. See Almirall, LLC v. Amneal Pharms. LLC, 28 F.4th 265,
275 (Fed. Cir. 2022) (“A finding of a reasonable expectation of success does not require absolute predictability of success.”); Acorda Therapeutics, Inc. v. Roxane
Lab’ys, Inc., 903 F.3d 1310, 1333 (Fed. Cir. 2018)
(“This court has long rejected a requirement of conclusive proof of efficacy for obviousness.” (cleaned up)).
Moreover, references establishing the background
knowledge of a person of ordinary skill in the art are
consistent with the reasonable expectation of success
provided by the combination of the Protocol with Pimentel. For example, Cuoco4 teaches the efficacy of
1,200 mg rifaximin/day for 14 days for the treatment
of small intestinal bacterial overgrowth (“SIBO”). J.A.
4533. Salix has acknowledged that those of ordinary
skill in the art identified “bacterial alterations” as a
potential underlying cause for IBS, Appellants’ Br. at
7, and the literature5 describes SIBO as a condition
that is “highly prevalent in patients with irritable
bowel syndrome (IBS),” such that “SIBO decontamination is associated [with] a significant improvement
of IBS symptoms.” J.A. 4664. We therefore agree with
the district court that references describing the treatment of SIBO would have been pertinent to the skilled
L. Cuoco & M. Salvagnini, Small intestine bacterial overgrowth in irritable bowel syndrome: a retrospective study with
rifaximin, 52 MINERVA GASTROENTEROL. DIETOL. (2006) 89; J.A.
4533–39.
4
5 E. Scarpellini et al., High dosage rifaximin for the treatment
of small intestinal bacterial overgrowth, 25 ALIMENT. PHARMACOL. THER. 781 (2007); J.A. 4663–67 (“Scarpellini”).
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artisan’s considerations as to what treatments would
have a potential for success in treating individuals
suffering from IBS.
In addition to Cuoco, Lauritano6 teaches an increase in rifaximin efficacy for the treatment of SIBO
as doses were increased from 600 mg/day to 1,200
mg/day, providing the trend that Pimentel described
as indicating that doses higher than 1,200 mg/day
may be even more optimal for the treatment of IBS.
J.A. 7267 (“Higher doses of rifaximin lead to a significant gain in terms of therapeutic efficacy in [SIBO]
eradication without increasing the incidence of sideeffects.”); see also id. at 4644. As evidenced by Scarpellini and Lin,7 those in the art advanced on those
findings, and subsequently evaluated higher doses.
For example, Scarpellini reported that a 1,600 mg/day
dose “showed a significantly higher efficacy” compared with 1,200 mg/day for the treatment of SIBO.
J.A. 4663; see also id. at 4666 (Table 1, noting study
patients included those suffering from IBS-D); id. at
4747 (teaching that “[a]bout 400 to about 600 mg of
rifaximin may be administered TID for about 10 days”
(i.e., 1,200 mg/day to 1,800 mg/day) for the eradication
of bacterial overgrowth).
The record further supports the finding that there
would have been a reasonable expectation of success
in administering higher doses of rifaximin without an
E.C. Lauritano et al., Rifaximin dose-finding study for the
treatment of small intestinal bacterial overgrowth, 22 ALIMENT.
PHARMACOL. THER., 31 (2005); J.A. 7267–71.
6
7 International Patent Application Publication 2006/102536;
J.A. 4721–47.
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intolerable increase in negative side effects. For example, Cuoco teaches that rifaximin was understood as
having “a low risk of causing microbial resistance,”
J.A. 4533, and that rifaximin was well known for its
“profile of tolerability and safety widely described in
the literature,” id. at 4538. Scarpellini further reported that the 1,600 mg/day dose provided a “similar
compliance and side-effect profile” compared with the
1,200 mg/day dose. Id. at 4663. As the district court
noted, the “[w]idespread off-label use” of rifaximin
also supported the conclusion that rifaximin was safe
and effective “for the treatment of IBS-D with a reasonable expectation of success.” Decision at *19; see
also Appellants’ Br. at 17 (“There is no dispute that
skilled artisans knew of the general concept of trying
off-label use of rifaximin to treat IBS-D.”).
In view of the record before us, we see no clear error in the finding that a skilled artisan would have
had a reasonable expectation of success in administering the claimed 1,650 mg/day regimen for the treatment of IBS-D. We therefore affirm the district court’s
holding that the challenged IBS-D claims would have
been obvious over the cited references. See In re Applied Materials, Inc., 692 F.3d 1289, 1295 (Fed. Cir.
2012) (“[W]here the general conditions of a claim are
disclosed in the prior art, it is not inventive to discover
the optimum or workable ranges by routine experimentation.” (citation omitted)).
Salix further contends that a Press Release8 issued by Salix in a filing with the Securities and Ex8 Salix Pharms., Ltd., Current Report (Form 8-K) (Sept. 5,
2007); J.A. 7477–82.
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change Commission less than a year before the patents’ priority date was not prior art because Norwich
failed to establish that it was “by others” as required
by pre-AIA 35 U.S.C. § 102(a). Appellants’ Br. at
30−39. According to Salix, the district court’s inclusion of that allegedly non-prior art reference in its discussion of the skilled artisan’s expectation of success
was harmful error. Id.
Although the district court cited the Press Release
in its discussion of the skilled artisan’s expectations,
it ultimately held that the “Protocol and Pimentel [ ]
disclose all limitations of the IBS-D claims” and that
a skilled artisan “would have been motivated to combine the . . . Protocol and Pimentel [ ] with a reasonable
expectation of success.” Decision at *17. We therefore
need not decide whether or not the Press Release was
prior art because, even assuming that it was not, the
Protocol and Pimentel alone established the obviousness of the claims.
We accordingly affirm the district court’s determination that Norwich established that the IBS-D
claims would have been obvious in view of the Protocol
and Pimentel.
II
We next turn to Salix’s contention that the district
court clearly erred in finding that there would have
been a reasonable expectation of success in obtaining
the rifaximin form β recited in the polymorph patents’
claims.
Whether or not there would have been a reasonable expectation of success is a question of fact, IXI IP,
LLC v. Samsung Elecs. Co., 903 F.3d 1257, 1262 (Fed.
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Cir. 2018), which we review for clear error, Hospira,
946 F.3d at 1328. We review the ultimate conclusion
of obviousness de novo. Id.
The polymorph patents are directed to rifaximin
form β. For example, claim 4 of the ’199 patent recites:
4. Rifaximin in polymorphic form β, wherein the
rifaximin has x-ray powder diffraction pattern
peaks at about 5.4°; 9.0°; and 20.9°2θ and wherein
the rifaximin has a water content of greater than
5%.
’199 patent, col. 10 ll. 24–27; see also ’206 patent, col.
11 ll. 33–37, 41–43 (claims 34 & 36, similar).
Norwich challenged the polymorph claims’ validity by asserting, inter alia, Cannata,9 which discloses
that rifaximin exists in crystalline form with “outstanding antibacterial properties.” J.A. 4528; Decision
at *6. Cannata does not discuss rifaximin’s crystal
structure in detail, but it does disclose several preparation protocols for rifaximin that include solvents
used for crystallization. J.A. 4529–31; see also id. at
3408.
The district court held that expert testimony supported a conclusion that, in view of the prior art, (1) a
skilled artisan would have had good reason to characterize the crystalline rifaximin obtained by following
the Cannata protocols, (2) that such characterization
was routine and could have been performed “in one
day,” and (3) that doing so would have led the skilled
artisan to have “detected rifaximin β.” Decision at *6–
7. The district court subsequently concluded that the
9
U.S. Patent 4,557,866; J.A. 4526−32.
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challenged polymorph claims would have been obvious over the asserted prior art in view of the common
knowledge of the skilled artisan. Id. at *7–8.
Salix first challenges the district court’s conclusion of obviousness by asserting that Grunenthal
GMBH v. Alkem Laboratories Ltd., 919 F.3d 1333
(Fed. Cir. 2019) and Pharmacyclics LLC v. Alvogen,
Inc., No. 2021-2270, 2022 WL 16943006 (Fed. Cir.
Nov. 15, 2022) compel the opposite result. Appellants’
Br. at 49–51. Salix further contends that the court
“applied the wrong test” by not following a rationale
provided in the district court opinion from Pharmacyclics. Id. at 55–57. We disagree.
In Grunenthal, we held that it was not clear error
for the district court to find that the record failed to
establish by clear and convincing evidence a reasonable expectation of success in preparing the claimed
polymorphic Form A of tapentadol hydrochloride. See
919 F.3d at 1341. In that case, the synthesis of tapentadol hydrochloride known in the prior art produced a
particular form—Form B. Id. The district court found
that there was a lack of evidence that a prior art synthesis would have resulted in the claimed Form A and
that no prior art guidance existed to establish “what
particular solvents, temperatures, agitation rates,
etc., were likely to result” in the claimed polymorph.
Id. at 1343. We found no clear error in that analysis.
Id. at 1344–45.
We also affirmed a conclusion of non-obviousness
of a claimed polymorph in our non-precedential Pharmacyclics decision, which issued after the district
court released its decision in this case. See 2022 WL
16943006, at *10–11. But the court here acted within
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its discretion when it declined to follow the district
court decision in Pharmacyclics as though it was binding precedent. See Decision at *7 n.1 (“Plaintiffs call
to my attention [the district court’s decision in] Pharmacyclics LLC v. Alvogen Pine Brook LLC. I have considered that case but I do not agree with it on this
point.”). And our later affirmance of the factual findings in Pharmacyclics did not retroactively override
the district court’s analysis here.
Moreover, a lack of clear error in Grunenthal and
Pharmacyclics does not compel a conclusion of non-obviousness here. Indeed, Grunenthal underscored the
factual nature of these types of inquiries and expressly held that it did “not rule out the possibility
that polymorph patents could be found obvious.” 919
F.3d at 1344–45. “The determination of obviousness is
dependent on the facts of each case.” SanofiSynthelabo v. Apotex, Inc., 550 F.3d 1075, 1089 (Fed.
Cir. 2008); see also Pfizer, Inc. v. Apotex, Inc., 480 F.3d
1348, 1366 (Fed. Cir. 2007). In Grunenthal and Pharmacyclics, the issue was whether a skilled artisan
would have had a reasonable expectation of success in
producing a crystalline form of a compound. See 919
F.3d at 1341–43; 2022 WL 16943006, at *10–11. Here,
the prior art included a process to produce a crystalline form of rifaximin, and the dispute centered
around characterizing the crystalline form resulting
from that process. See Decision at *13–14. These distinct factual predicates support the district courts’ factual findings in each of these three cases under the
clear error standard of review.
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In Graham v. John Deere Co. of Kansas City, 383
U.S. 1 (1966), the Supreme Court set forth the background against which obviousness is to be assessed:
“Under § 103, the scope and content of the prior art
are to be determined” and “differences between the
prior art and the claims at issue are to be ascertained.” Id. at 17. The scope and content of the prior
art here includes preparations of crystalline rifaximin, which expert testimony supports would have
yielded the β form of rifaximin. Decision at *7; J.A.
3391−92 (“[T]he as-synthesized form of rifaximin reported by Examples 1, 6, 7, and 9 [of Cannata] were
necessarily rifaximin form Beta, because of the methods used, the solvent system used, and it was later
confirmed by later work, including work from the
named inventors.”); id. at 3408−09 (similar testimony); id. at 3393–3404 (discussing the evidence of
record that supports that conclusion); id. at 4700–07,
4846–47, 5007–14 (providing supporting evidence for
that conclusion). And the parties do not dispute that
the methods for characterizing the resulting crystalline rifaximin were well known and readily available
to the skilled artisan. Decision at *3. The difference
between the prior art and the claims is thus effectively
nothing more than the performance of routine characterization to identify the polymorphic forms that result from the known Cannata processes.
In this regard, Salix does not appear to dispute
that there would have been a motivation to explore
potential polymorphic forms of rifaximin. Appellants’
Br. at 48–49. Rifaximin was, after all, a known compound with a known, useful activity. Salix further refers to the district court’s finding that “polymorph β is
a commonly produced polymorph and the most stable
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form of rifaximin” as an “undisputed” fact. Id.; see also
Decision at *7. There thus appears to be no dispute
that the claimed polymorph can be readily produced
from the crystallization conditions disclosed in Cannata and that it would have been well within the abilities of the skilled artisan to procure and characterize
the β form of rifaximin.
According to Salix, however, rifaximin’s β form
constituted a non-obvious invention because, although skilled artisans “actually succeed[ed]” in producing and characterizing it, they would not have “expect[ed] to succeed” because, as of the critical date, the
polymorphic nature of rifaximin had not yet been reported and the identity of the β form remained undisclosed. Appellants’ Br. at 49. Salix further argues that
there could have been no expectation of success because the skilled artisan would not have been able to
predict what polymorphic forms might result from following the preparation protocols disclosed in the prior
art. Id. at 20–21, 50–53. Salix’s framing of the issue
suggests that no unknown entity could ever be obvious, as one cannot reasonably expect what was hitherto unknown, which is incorrect.
Here, the district court found a reasonable expectation of success in characterizing the crystalline
product of Cannata for potential polymorphism using
routine, conventional methods and skill. Decision at
*6–7. We see no clear error in that conclusion. Indeed,
Salix has done no more than combine known elements
of the prior art to verify readily accessible information
concerning a compound already in the hands of those
of ordinary skill in the art, and such routine efforts do
not justify removing this polymorph from the public
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domain. See KSR Int’l Co. v. Teleflex Inc., 550 U.S.
398, 427 (2007); see also Pfizer, 480 F.3d at 1367–68.
To be sure, we do not hold that there is always a reasonable expectation of success in accessing or characterizing polymorphs. We are simply reviewing the district court’s decision before us as to its factual finding
of a reasonable expectation of success, and in so doing,
have not been left with a definite and firm conviction
that a mistake was made in reaching that finding. See
Scanner Techs. Corp. v. ICOS Vision Sys. Corp. N.V.,
528 F.3d 1365, 1374 (Fed. Cir. 2008).
Having found no clear error in the district court’s
fact findings as to the existence of a reasonable expectation of success, we affirm the court’s conclusion that
the polymorph patent claims were invalid as obvious.
Because we affirm the court’s holding that the polymorph patent claims would have been obvious over
the asserted prior art, we need not consider Norwich’s
separate argument that the polymorph claims would
have also been invalid as inherently anticipated.
III
On cross-appeal, Norwich raises two related but
distinct arguments that arose after the district court
held that Norwich infringed the HE patents and failed
to establish invalidity. See Decision at *10–16. Norwich first argues that, in issuing its final decision, the
district court misinterpreted 35 U.S.C. § 271(e)(4)(A),
which directs a court, following a finding of infringement, to order the FDA to defer final approval of an
ANDA until the expiration of the infringed patent. According to Norwich, that statute precludes delaying final approval of an entire ANDA, and instead requires
delaying only the approval of the infringing use.
20a
Norwich’s second argument arises from its decision to amend its ANDA to carve out the infringing
HE use after final judgment. Following that amendment, Norwich filed a motion to modify the final judgment to allow for prompt approval of the amended
ANDA that purportedly no longer sought approval for
the infringing HE use. The district court denied that
motion, and Norwich cross-appealed.
We address both of Norwich’s concerns in turn.
A.
We first address Norwich’s arguments regarding
the district court’s interpretation of 35 U.S.C. §
271(e)(4)(A) in ordering that a final approval of Norwich’s ANDA could not be effective before the HE patents expired. J.A. 50–51.
We review issues of statutory interpretation without deference to the district court’s interpretation.
Waymark Corp. v. Porta Sys. Corp., 245 F.3d 1364,
1366 (Fed. Cir. 2001). “The starting point in every
case involving construction of a statute is the language itself.” Blue Chip Stamps v. Manor Drug Stores,
421 U.S. 723, 756 (1975) (Powell, J., concurring).
Moreover, we “give effect, if possible, to every clause
and word of [the] statute.” United States v. Menasche,
348 U.S. 528, 538–39 (1955) (citation omitted). When
a statute does not define a given word or phrase, we
presume that Congress intended the word or phrase
to have its ordinary meaning. Asgrow Seed Co. v. Winterboer, 513 U.S. 179, 187 (1995). However, “[i]n expounding a statute, we must not be guided by a single
sentence or member of a sentence, but look to the provisions of the whole law, and to its object and policy.”
21a
U.S. Nat’l Bank of Or. v. Indep. Ins. Agents of Am.,
Inc., 508 U.S. 439, 455 (1993) (citation omitted).
Section 271(e)(4)(A) instructs that, following a
finding of infringement, “the court shall order the effective date of any approval of the drug or veterinary
biological product 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.” The order here instructed the FDA that “the effective date of
any final approval . . . of Norwich’s ANDA No. 214369
is to be a date not earlier than the date of expiration
of the last to expire of [the HE patents] (currently October 2, 2029).” J.A. 51.
Norwich argues that the language of § 271(e)(4)
requires courts to tie the restriction on FDA approval
to the indication for which the ANDA seeks approval
when that indication was the source of infringement.
Cross-Appellants’ Br. at 14. Norwich’s ANDA originally sought approval for the treatment of both IBS-D
and HE. Although only the HE indication was found
to infringe a valid patent, the order restricted final approval of the entire ANDA, including the non-infringing indication, until 2029. Norwich argues that the
statute requires the district court’s order “to specify
that the approval date pertains to Norwich’s ANDA
seeking approval for the infringing HE Indication.” Id.
at 18. But the district court order concerned only the
specific ANDA in question that included an infringing
use, referred to the ANDA by its number, and enjoined
the approval of that ANDA. J.A. 51. Norwich suggests
that the district court order unfairly precludes it from
22a
receiving final approval of a new non-infringing
ANDA.10 The district court did no such thing.
Section 271(e)(4)(A) describes delaying the approval of “the drug . . . involved in the infringement.”
Since the FDA does not approve drugs in the abstract,
but rather approves drugs for particular uses (indications) of that drug, the statute is appropriately construed as directed to approval of particular infringing
uses of the drug, not all uses of the drug including noninfringing uses. The statutory scheme makes clear
that it is not the potential use of Norwich’s rifaximin
for HE that constitutes the relevant infringement
here, nor is it the unpatented drug compound itself,
but rather it is the submission of the ANDA that included an infringing use. See 35 U.S.C. § 271(e)(2)(A)
(making it an “act of infringement to submit” an
ANDA “for a drug claimed in a patent or the use of
which is claimed in a patent”). That the ANDA further
recited a non-patent-protected indication does not negate the infringement resulting from the ANDA’s submission. The order thus appropriately delayed the effective final approval date of “this infringing ANDA”
submission. J.A. 48. The order appropriately said
nothing that would prevent approval of a new non-infringing ANDA.
We therefore affirm the district court’s order setting the effective approval date of Norwich’s ANDA
10 Norwich notes that on June 2, 2023, FDA tentatively approved its amended ANDA, which purportedly lacks the HE indication. Cross-Appellant’s Br. at 6. The tentative approval letter
noted, however, that “final approval cannot be granted until October 2, 2029 as specified in the court order.” Id.
23a
No. 214369 to be no earlier than the date of expiration
of the last to expire of the HE patents.
B.
Following entry of the final judgment, which included the resetting order barring final approval of
Norwich’s ANDA until 2029, Norwich amended its
ANDA in an attempt to remove the infringing HE indication. Norwich then moved to modify the judgment
under Federal Rule of Civil Procedure 60(b), asserting
that the amendment negated any possible infringement, and that the final approval date of the ANDA,
as amended, should not be tied to the HE patents. See
Cross-Appellant’s Br. at 27. The district court denied
that motion, holding that Norwich “fully litigated the
merits of its non-infringement and invalidity case,
lost, and now seeks a way around the final judgment
through Rule 60(b).” Rule 60(b) Order at *2. Norwich
cross-appealed.
“Because denial of a Rule 60(b) motion is a procedural issue not unique to patent law, we apply the rule
of the regional circuit where appeals from the district
court would normally lie,” Amstar Corp. v. Envirotech
Corp., 823 F.2d 1538, 1550 (Fed. Cir. 1987), which,
here, is the Third Circuit. The Third Circuit “review[s]
the denial of Rule 60(b) relief for an abuse of discretion.” Coltec Indus., Inc. v. Hobgood, 280 F.3d 262, 269
(3d Cir. 2002); see also Bohus v. Beloff, 950 F.2d 919,
930 (3d Cir. 1991) (noting that Rule 60(b) motions are
“extraordinary relief which should be granted only
where extraordinary justifying circumstances are present” (citation omitted)).
“A district court may reconsider its own finding of
infringement in light of an amended ANDA,” but the
24a
court need not do so. Ferring B.V. v. Watson Lab’ys,
Inc. Fla., 764 F.3d 1382, 1391 (Fed. Cir. 2014). Rather,
“[a]llowing an amendment is within the discretion of
the district court, guided by principles of fairness and
prejudice to the patent-holder.” Id. Here, the court
reasonably held that consideration of the amended
ANDA would be inequitable and inappropriate. Rule
60(b) Order at *2. The court noted that “[i]t is not a
simple matter to determine whether an ANDA applicant has successfully carved out language from a label
to turn infringement into non-infringement” and that
what Norwich sought in its Rule 60(b) motion “would
essentially be a second litigation” following final judgment. Id. (noting also that, other than simply asserting that it carved out the HE indication and providing
the court with the amended label, Norwich “ha[d] presented no evidence in support of its assertion” that the
amended ANDA would no longer infringe the HE patents).
Norwich nevertheless argues that the amended
ANDA satisfies the judgment by not seeking approval
for the infringing use and that, in view of the amendment, it is no longer equitable to apply the judgment
prospectively. But Rule 60(b) is permissive, holding
only that the court “may relieve a party or its legal
representative from a final judgment, order, or proceeding” under various circumstances. That is—a district court has the discretion, not the obligation, to
modify a final judgment in view of a post-judgment
ANDA amendment. And as the district court held,
simply asserting that a patented indication has been
carved out of an ANDA application does not necessarily satisfy the judgment or entitle the applicant to
direct entry to the market. See Rule 60(b) Order at *2.
25a
We see no abuse of discretion in the district court
reaching that conclusion or in subsequently denying
the motion.
Norwich further argues that the district court
erred by not explicitly discussing Rule 60(b)(6), which
provides that a court may relieve a party from a final
judgment for “any other reason that justifies relief.”
We disagree that the district court so erred. The
court’s Memorandum Order thoroughly discussed the
law, the equities, the record, and the arguments before it. In so doing, the court implicitly found no additional reason that justified the relief that Norwich
sought.
We therefore affirm the district court’s denial of
the motion to modify the final judgment.
CONCLUSION
We have considered both parties remaining arguments and find them unpersuasive. For the foregoing
reasons, we affirm (1) the district court’s holding that
claim 2 of the ’569 patent, claim 3 of the ’667 patent,
claim 4 of the ’199 patent, and claim 36 of the ’206 patent would have been invalid as obvious, (2) the district court’s order setting the effective approval date
of Norwich’s ANDA to be no earlier than the date of
expiration of the last to expire of the HE patents, and
(3) the district court’s denial of the motion to modify
the final judgment.
AFFIRMED
COSTS
No costs.
26a
UNITED STATES COURT OF APPEALS
FOR THE FEDERAL CIRCUIT
SALIX PHARMACEUTICALS, LTD., SALIX
PHARMACEUTICALS, INC., BAUSCH HEALTH
IRELAND LTD., ALFASIGMA S.P.A.,
Plaintiffs-Appellants
v.
NORWICH PHARMACEUTICALS INC.,
Defendant-Cross-Appellant
2022-2153, 2023-1952
Appeals from the United States District Court for
the District of Delaware in No. 1:20-cv-00430-RGA,
Judge Richard G. Andrews.
CUNNINGHAM, Circuit Judge, dissenting in part.
I join most of the majority’s opinion, but I respectfully dissent from the majority’s opinion concerning
U.S. Patent Nos. 8,309,569 and 10,765,667 (the “IBSD patents”). I would vacate the district court’s judgment that the asserted claims of the IBS-D patents
are obvious and remand for further proceedings.
I
The district court found that “[t]he asserted IBSD claims describe a dosing regimen within the known
range” and that “[a] POSA would have been motivated
27a
to combine the RFIB 2001 Protocol1 and Pimentel
20062 with a reasonable expectation of success.” Salix
Pharms., Ltd. v. Norwich Pharms., Inc., No. 20-430RGA, 2022 WL 3225381, at *17 (D. Del. Aug. 10, 2022)
(“Decision”) (footnotes added). Based on these findings
of fact, the court concluded that “Pimentel 2006 in
light of the RFIB 2001 Protocol renders the asserted
claims of the IBS-D patents obvious.” Id. at *18. After
reviewing the evidence relied on by the district court,
applying a clear error standard, I am “left with the
definite and firm conviction that a mistake has been
committed” regarding these findings. Pfizer, Inc. v.
Apotex, Inc., 480 F.3d 1348, 1359 (Fed. Cir. 2007)
(quoting United States v. U.S. Gypsum Co., 333 U.S.
364, 395 (1948)).
The evidence cited by the district court does not
support its finding that a skilled artisan would have a
reasonable expectation of success for the claimed dosage. See Decision at *17, *19. “The reasonable-expectation-of-success analysis must be tied to the scope of
the claimed invention”––here, the claimed 1,650
mg/day (550 mg TID3) dosage for treating IBS-D. Teva
Pharms. USA, Inc. v. Corcept Therapeutics, Inc., 18
ClinicalTrials.gov, History of Changes for Study:
NCT00269412, Randomized, Double Blind, Placebo-Controlled
Study to Assess the Efficacy and Safety of Three Different Doses
of Rifaximin Administered BID Either Two or Four Weeks in the
Treatment of Patients with Diarrhea-Associated Irritable Bowel
Syndrome (December 22, 2005); J.A. 7048–55.
1
M. Pimentel et al., The Effect of a Nonabsorbed Oral Antibiotic (Rifaximin) on the Symptoms of the Irritable Bowel Syndrome, 145 ANNALS INTERN. MED. 557 (2006); J.A. 4639–46. The
majority refers to this reference as Pimentel.
2
3
TID stands for three times per day.
28a
F.4th 1377, 1381 (Fed. Cir. 2021). The district court
mainly relied on the results of the RFIB 2001 trial disclosed in the RFIB 2001 Press Release4 in arriving at
this conclusion. Decision at *19. However, there is no
reason that a skilled artisan “would have known
about the successful RFIB 2001 Protocol results,” id.,
as to the claimed 1,650 mg/day (550 mg TID) dosage
because the RFIB 2001 Press Release only discloses
an improvement in the 550 mg twice-a-day group. J.A.
7480; see Decision at *19. In fact, evidence in the record suggests the opposite—that a skilled artisan
might have understood the absence of discussions of
the 1,100 mg twice-a-day group to imply that higher
dosage did not lead to similar successful results. See
J.A. 3313–14. Indeed, the 2,200 mg/day dosage “did
not achieve more responders compared to the placebo
for adequate relief.”5 J.A. 3042. Thus, the court’s reliance on the RFIB 2001 Press Release to establish a
reasonable expectation of success was erroneous.6
Salix Pharms., Ltd., Current Report (Form 8-K) (Sept. 5,
2007); J.A. 7477–82.
4
5 Although the evidence that the 2,200 mg/day dosage did not
achieve adequate relief post-dates the priority date of the patent,
it clarifies what a skilled artisan would have understood from the
RFIB 2001 Press Release. See Syntex (U.S.A.) LLC v. Apotex,
Inc., 407 F.3d 1371, 1379 (Fed. Cir. 2005) (holding district court
erred in not considering a reference that post-dates the priority
date when it is relevant to what “was known in the art at the
relevant time”).
6 Salix also challenges the district court’s finding that the
RFIB 2001 Press Release was prior art. Appellant’s Br. 30–39;
Decision at *20. I agree with the majority that we do not need to
reach this issue.
29a
The district court’s citations to other references do
not cure this error. Cuoco7 discloses a total dose of
1,200 mg/day for 14 days, and Barrett8 similarly discloses 400 mg TID for a total dosage of 1,200 mg/day.
Decision at *19; see also J.A. 4536; J.A. 4800. The district court did not explain why these references would
give rise to a reasonable expectation of success for a
dosage that is almost 40% higher. The reference by
the district court to the “[w]idespread off-label use” of
rifaximin was also unaccompanied by any discussion
of dosages or citations to the record. Decision at *19.
Likewise, it discussed market research that shows
many physicians prescribe rifaximin for IBS without
discussing their prescribed dosages. Decision at *20
(citing J.A. 7186). The cited research does not show
that physicians prescribe at the 1,650 mg/day (550
mg/TID) dosage. J.A. 7186.
Although “efficacy data is [not] always required
for a reasonable expectation of success,” OSI Pharms.,
LLC v. Apotex Inc., 939 F.3d 1375, 1385 (Fed. Cir.
2019), the analysis must still be tied to the scope of
the claims—here, the 1,650 mg/day dosage. See Teva,
18 F.4th at 1381; see also In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Pat. Litig., 676
F.3d 1063, 1070–72 (Fed. Cir. 2012) (finding no reasonable expectation of success when the court “cited
no evidence specifically indicating that a [drug with a
L. Cuoco & M. Salvagnini, Small intestine bacterial overgrowth in irritable bowel syndrome: a retrospective study with
rifaximin, 52 MINERVA GASTROENTEROL. DIETOL. 89 (2006); J.A.
4533–39.
7
8 G. Barrett, Abstract, Benefits of the Antibiotic Rifaximin as
Empiric Therapy in Patients with Irritable Bowel Syndrome, 101
AM. J. GASTROENTEROL. S479 (2006); J.A. 4799–4800.
30a
pK profile disclosed in the prior art] would be expected
to yield the same therapeutic effect as [a different pK
profile as claimed]”); Ferring B.V. v. Watson Lab’ys,
Inc.-Fla., 764 F.3d 1401, 1407 (Fed. Cir. 2014) (finding
asserted claims not to be invalid for obviousness when
prior art references “disclose 500 mg [ ] formulations,
but no higher tablet strengths, and particularly not
the claimed 650 mg formulation”). Aside from its erroneous reliance on the RFIB 2001 Press Release, the
district court failed to tie its reasonable expectation of
success analysis to the claimed dosage. Therefore, I
would find that it clearly erred in its reasonable expectation of success analysis.
In sum, the district court clearly erred in relying
on the RFIB 2001 Press Release and other references
that do not teach the claimed dosage. For these reasons, I would have found the district court’s finding to
be clearly erroneous and would vacate the district
court’s judgment that the IBS-D claims were invalid
as obvious.
II
In affirming the district court’s judgment of obviousness, the majority relies on one additional sentence in Pimentel 2006 regarding the reasonable expectation of success analysis: “Recent data suggest
that the optimal dosage of rifaximin may, in fact, be
higher than that used in our study.” J.A. 4644; see
Maj. Op. 8. But the lack of discussion of any actual
dosage that may be optimal, the use of the word
“may,” and the fact that the RFIB 2001 Protocol discloses a specific dosing regimen of 2,200 mg/day rather than 1,650 mg/day all call into question the majority’s finding. Indeed, the district court only relied
31a
on this sentence in its motivation to combine analysis
and did not rely on this sentence in its reasonable expectation of success analysis. See Decision at *18–20.
The parties never made this argument before us.
Therefore, I disagree that this additional sentence,
when considered together with the RFIB 2001 Protocol, would give rise to a reasonable expectation of success for the claimed dosage.
The majority also discusses references not relied
on by the district court in its reasonable expectation
of success analysis, including Lauritano9, Scarpellini10, and Lin.11 Maj. Op. 9–10. But the district court
did not make any findings on what these references
teach, other than finding that the references were
prior art. See Decision at *17–22. Nor are the majority’s conclusions regarding these references uncontested. For example, Salix argues that Scarpellini and
Lauritano are both directed to the treatment of small
intestinal bacterial overgrowth (SIBO), not to the
treatment of IBS or IBS-D, and therefore cannot establish a reasonable expectation of success. Appellant’s Reply Br. 18. Although the majority may be
right that Lauritano’s and Scarpellini’s disclosures on
treating SIBO also support finding a reasonable expectation of success for treating IBS-D, see Maj. Op.
9–10, the district court never made this finding. See
E.C. Lauritano et al., Rifaximin dose-finding study for the
treatment of small intestinal bacterial overgrowth, 22 ALIMENT.
PHARMACOL. THER. 31 (2005); J.A. 7267–71.
9
10 E. Scarpellini et al., High dosage rifaximin for the treatment
of small intestinal bacterial overgrowth, 25 ALIMENT. PHARMACOL. THER. 781 (2007); J.A. 4663–67.
11 International Patent Application Publication No. WO
2006/102536; J.A. 4721–47.
32a
Golden Bridge Tech., Inc. v. Nokia, Inc., 527 F.3d
1318, 1323 (Fed. Cir. 2008) (declining to find what a
prior art reference teaches in the first instance). It
merely found that “[t]he relationship between IBS and
SIBO was actively being explored,” and that certain
prior art references “do not teach away from using
rifaximin to treat IBS.” Decision at *21. I would not
make such fact-findings about Scarpellini and Lauritano in the first instance.
In summary, I would vacate the district court’s
judgment that the asserted claims of the IBS-D patents were obvious and remand for further proceedings. On remand, I would order the district court to
consider in the first instance the teachings in the additional prior art references. See ACS Hosp. Sys., Inc.
v. Montefiore Hosp., 732 F.2d 1572, 1578 (Fed. Cir.
1984) (“Where the trial court fails to make findings,
the judgment will normally be vacated and the action
remanded for appropriate findings to be made.”). Accordingly, I respectfully dissent in part.
33a
APPENDIX B
IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF DELAWARE
SALIX PHARMACEUTICALS, LTD.; SALIX PHARMACEUTICALS, INC.; BAUSCH HEALTH IRELAND LTD.; ALFASIGMA S.P.A.,
Plaintiffs,
v.
NORWICH PHARMACEUTICALS, INC.,
Defendant.
Civil Action No. 20-430-RGA
Filed: August 10, 2022
TRIAL OPINION
Jack B. Blumenfeld, Karen Jacobs, Cameron P. Clark,
MORRIS, NICHOLS, ARSHT & TUNNELL LLP, Wilmington, DE; Scott K. Reed, Steven C. Kline, Shannon K.
Clark, Daniel A. Apgar, Alexis M. McJoynt, Damien
N. Dombrowski, Becky E. Steephenson, VENABLE
LLP, New York, NY.
Attorneys for Plaintiffs.
Karen E. Keller, Nathan R. Hoeschen, SHAW KELLER
LLP, Wilmington, DE; Matthew J. Becker, Stacie L.
34a
Ropka, Matthew S. Murphy, Chad A. Landmon, Rebecca L. Clegg, AXINN, VELTROP & HARKRIDER LLP,
Hartford, CT; Aziz Burgy, AXINN, VELTROP &
HARKRIDER LLP, Washington, DC; Richardo S. Camposanto, AXINN, VELTROP & HARKRIDER LLP, San Francisco, CA.
Attorneys for Defendant.
August 10, 2022
/s/ RICHARD G. ANDREWS
ANDREWS, U.S. DISTRICT JUDGE:
Salix sued Norwich for infringement of twenty-six
patents that cover Salix’s branded Xifaxan (rifaximin)
550 mg tablets. (D.I. 59 ¶¶ 12, 41). Before trial, Salix
narrowed its case to U.S. Patent Nos. 7,612,199,
7,902,206 (“the Polymorph Patents”), 8,642,573,
9,421,195, 10,335,397 (“the HE Patents”), 8,309,569,
and 10,765,667 (“the IBS-D Patents”). In March 2022,
I held a four-day bench trial. (D.I. 168-172, hereinafter “Tr.”).
I.
BACKGROUND
Norwich submitted an Abbreviated New Drug Application (ANDA) to the Food and Drug Administration (FDA) for approval to market a generic version of
Xifaxan.
Salix
alleges
infringement
under
§ 271(e)(2)(A) of the Patent Act. 35 U.S.C.
§271(e)(2)(A). Norwich counters that the asserted patents are invalid.
In 2004, the FDA approved Xifaxan (rifaximin)
200 mg tablets to treat travelers’ diarrhea. (D.I. 155
¶ 9). On March 24, 2010, the FDA approved Xifaxan
35a
(rifaximin) 550 mg tablets to reduce the risk of overt
hepatic encephalopathy (“HE”) recurrence in adults.
(Id. ¶10). On May 27, 2015, the 550 mg tablets were
approved to treat irritable bowel syndrome with diarrhea (“IBS-D”) in adults. (Id. ¶11). The asserted patents cover a polymorphic form of rifaximin and methods of treating HE and IBS-D in adults.
II. LEGAL STANDARD
A. Infringement
A patent is directly infringed when a person “without authority makes, uses, offers to sell, or sells any
patented invention, within the United States . . . during the term of the patent . . . .” 35 U.S.C. § 271(a). A
two-step analysis is employed in making an infringement determination. See Markman v. Westview Instruments, Inc., 52 F.3d 967, 976 (Fed. Cir. 1995) (en
banc), aff’d, 517 U.S. 370 (1996). First, the court must
construe the asserted claims to ascertain their meaning and scope. See id. The trier of fact must then compare the properly construed claims with the accused
infringing product. See id. This second step is a question of fact. See Bai v. L & L Wings, Inc., 160 F.3d
1350, 1353 (Fed. Cir. 1998).
“Under § 271(b), whoever actively induces infringement of a patent shall be liable as an infringer.”
Warner-Lambert Co. v. Apotex Corp., 316 F.3d 1348,
1363 (Fed. Cir. 2003). To prevail on a theory of induced infringement, a plaintiff must prove (1) direct
infringement and (2) “that the defendant possessed
specific intent to encourage another’s infringement
and not merely that the defendant had knowledge of
the acts alleged to constitute infringement.” Vanda
Pharm. Inc. v. West-Ward Pharm. Int’l Ltd., 887 F.3d
36a
1117, 1129 (Fed. Cir. 2019) (quoting DSU Med. Corp.
v. JMA Co., 471 F.3d 1293, 1306 (Fed. Cir. 2006)).
In a Hatch-Waxman case, a plaintiff “can satisfy
its burden to prove the predicate direct infringement
by showing that if the proposed ANDA product were
marketed, it would infringe the [asserted patent].”
Vanda, 887 F.3d at 1130. For method-of-treatment patents, if an ANDA applicant’s “proposed label instructs users to perform the patented method . . . , the
proposed label may provide evidence of [the ANDA applicant’s] affirmative intent to induce infringement.”
AstraZeneca LP v. Apotex, Inc., 633 F.3d 1042, 1060
(Fed. Cir. 2010). “When proof of specific intent depends on the label accompanying the marketing of a
drug inducing infringement by physicians, the label
must encourage, recommend, or promote infringement.” Vanda, 887 F.3d at 1129 (cleaned up).
B. Obviousness
A patent is invalid as obvious under 35 U.S.C.
§ 103 if “the claimed invention as a whole would have
been obvious to a person of ordinary skill in the art at
the time the invention was made.” Kahn v. Gen. Motors Corp., 135 F.3d 1472, 1479 (Fed. Cir. 1998). “Obviousness is a question of law based on underlying factual findings: (1) the scope and content of the prior
art; (2) the differences between the claims and the
prior art; (3) the level of ordinary skill in the art; and
(4) objective considerations of nonobviousness.” In re
Morsa, 713 F.3d 104, 109 (Fed. Cir. 2013) (citations
omitted).
To show a patent is obvious, a party “must demonstrate by clear and convincing evidence that a skilled
artisan would have been motivated to combine the
37a
teachings of the prior art references to achieve the
claimed invention, and that the skilled artisan would
have had a reasonable expectation of success in doing
so.” InTouch Techs., Inc. v. VGO Commc’ns, Inc., 751
F.3d 1327, 1347 (Fed. Cir. 2014) (cleaned up). The
overall inquiry into obviousness, though, must be “expansive and flexible.” KSR Int’l Co. v. Teleflex, Inc.,
550 U.S. 398, 415 (2007). In conducting the obviousness analysis, “a court can take account of the inferences and creative steps that a person of ordinary skill
in the art would employ.” Id. at 418.
C. Written Description
The written description “must clearly allow persons of ordinary skill in the art to recognize that the
inventor invented what is claimed.” Ariad Pharm.,
Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351
(Fed.Cir.2010) (en banc) (cleaned up). The test is
whether the disclosure “conveys to those skilled in the
art that the inventor had possession of the claimed
subject matter as of the filing date.” Id. This requires
an “objective inquiry into the four corners of the specification from the perspective of a person of ordinary
skill in the art.” Id.
D. Indefiniteness
35 U.S.C. § 112 requires that claims “particularly
point[ ] out and distinctly claim[ ] the subject matter.”
The claims, viewed in light of the specification and
prosecution history, must “inform those skilled in the
art about the scope of the invention with reasonable
certainty.” Nautilus, Inc. v. Biosig Instruments, Inc.,
572 U.S. 898, 910 (2014). “While a claim employing a
term of degree may be definite where it provides
enough certainty to one of skill in the art when read
38a
in the context of the invention, a term of degree that
is purely subjective and depends on the unpredictable
vagaries of any one person’s opinion is indefinite.” Intell. Ventures I LLC v. T-Mobile USA, Inc., 902 F.3d
1372, 1381 (Fed. Cir. 2018) (cleaned up).
III. THE POLYMORPH PATENTS
The Polymorph Patents claim polymorphic forms
of rifaximin. Plaintiffs assert two such claims. Asserted Claim 4 of the ’199 patent states:
4. Rifaximin in polymorphic form β, wherein the
rifaximin has x-ray powder diffraction pattern
peaks at about 5.4°; 9.0°; and 20.9° 2θ and
wherein the rifaximin has a water content of
greater than 5%.
Asserted Claim 36 of the ’206 patent depends on
claim 34:
34. A solid pharmaceutical composition comprising rifaximin in polymorphic Form β and a pharmaceutically acceptable excipient or carrier,
wherein the rifaximin Form β has x-ray powder
diffraction pattern peaks at about 5.4°; 9.0°; and
20.9° 2-θ.
36. The pharmaceutical composition of claim 34,
wherein the rifaximin Form β has a water content
of between about 4.5% to about 40%.
A. Findings of Fact
1.
If approved, Norwich’s ANDA product will infringe the asserted claims of the Polymorph Patents.
39a
2.
The priority date of the asserted polymorph
claims is November 7, 2003.
3.
A person of skill in the art (a “POSA”) would have
had a B.S. in chemistry, chemical engineering, or
a related discipline with at least 3 years’ experience in the pharmaceutical industry related to
API manufacturing, crystallization, characterization, or evaluation of solid state forms. Or a POSA
would have had an advanced degree with less or
no experience.
4.
The ’199 patent is a continuation of, and contains
substantially the same disclosures as, the ’206 patent.
5.
Rifaximin exists in polymorphic forms. Norwich’s
ANDA product comprises polymorphic form β.
6.
X-ray powder diffraction (XRPD) peaks are an inherent characteristic of a polymorph. Each peak
in an XRPD diffractogram is a structural element
of that form. XRPD was routine as of the priority
date.
7.
A crystalline form of a known compound can be
characterized by a subset of XRPD peaks. The
subset of XRPD peaks at about 5.4°, 9.0°, and
20.9° 2θ was sufficient as of the priority date to
distinguish rifaximin β from the other known
rifaximin polymorphs.
8.
Water content is an inherent characteristic of a
crystal form that can be determined by routine
testing methods such as Karl Fischer (KF) or thermogravimetric analysis (TGA).
40a
9.
Cannata, Marchi, and the Normix Label are prior
art.
10. Cannata disclosed crystalline rifaximin, methods
of making it, and that it had antibacterial properties.
11. The four post-filing references relied upon by Defendant’s expert, Dr. Zaworotko, do not show that
any of the Cannata methods produces rifaximin β
every time.
12. Cannata does not inherently anticipate the asserted polymorph claims.
13. Marchi disclosed methods of preparing crystalline
rifaximin, rifaximin’s antibacterial properties,
and that it could be used in pharmaceutical compositions with conventional pharmaceutically acceptable excipients or carriers.
14. The Normix Label describes the use of rifaximin
as a pharmaceutical.
15. Cannata in view of common knowledge discloses
each and every limitation of claim 4 of the ’199 patent.
16. A POSA would have had a motivation to combine
Cannata with commonly known testing techniques XRPD and KF or TGA because regulatory
bodies instructed applicants to characterize the
solubility, stability, and bioavailability of drug
candidates.
17. A POSA would have had a reasonable expectation
of success at characterizing the rifaximin β polymorph and arriving at the claimed XRPD peaks at
41a
about 5.4°, 9.0°, and 20.9° 2θ and water content of
greater than 5%.
18. Marchi in view of Cannata and common
knowledge discloses each and every limitation of
claim 36 of the ’206 patent.
19. A POSA would have had a motivation to combine
Cannata with Marchi in light of common
knowledge.
20. A POSA would have had a reasonable expectation
of success at achieving a pharmaceutical composition comprising rifaximin β and a pharmaceutically acceptable excipient or carrier.
21. All rifaximin β claim limitations are expressly disclosed in the specifications of the Polymorph Patents.
B. Infringement
Norwich admits that its ANDA Product, if approved, will infringe claim 4 of the ’199 patent and
claim 36 of the ’206 patent. (D.I. 148, Ex. 1, ¶¶ 126,
127).
C. Invalidity
1.
Inherent Anticipation
Each expert asserts that his validity analysis is
not impacted by which definition of a POSA I use. (Tr.
860:7-861:8; Tr. 936:21-937:13). In view of Defendant’s burden to prove invalidity by clear and convincing evidence, I will adopt Plaintiffs’ definition of a
POSA.
42a
Norwich argues that U.S. Patent No. 4,557,866
(the “Cannata” reference) (JTX-37) inherently anticipates claim 4 of the ’199 patent because it discloses a
process that necessarily produces the claimed rifaximin β. (D.I. 176 at 32). “[A] prior art reference may
anticipate without disclosing a feature of the claimed
invention if that missing characteristic is necessarily
present, or inherent, in the single anticipating reference.” Schering Corp. v. Geneva Pharms., Inc., 339
F.3d 1373, 1377 (Fed. Cir. 2003). A disclosed process
may anticipate “if it discloses in an enabling manner
the production” of the claimed polymorph. SmithKline
Beecham Corp. v. Apotex Corp., 403 F.3d 1331, 1344
(Fed. Cir. 2005).
Here, the issue is whether the process disclosed by
Cannata invariably produces rifaximin β. Norwich
has presented the following evidence in support:
The “Viscomi Declaration,” a declaration to the
PTO stating that samples of batches produced
according to Cannata “are composed either of
mixture of polymorph (alpha and beta, and in
some case alpha and epsilon) or different polymorphs.” (JTX 80 ¶ 7).
The “Viscomi 2008” article, which Norwich’s expert Dr. Zaworotko testified shows that rifaximin β is a necessary precursor to the formation
of rifaximin α, δ, and ε. (JTX 65; Tr. 880:20881:1, 921:24-922:6).
The “Braga 2012” article, which describes the
inherent properties of rifaximin β. (JTX 105).
43a
The “Bacchi 2008” article, which described
rifaximin beta 4 (“RX4”), a substance the author concluded was “the so-called beta rifaximin of the literature.” (DTX 43; Tr. 882:14–24).
The article describes slow evaporation as the
method of preparation. From this article,
Dr. Zaworotko concluded, “Examples 1 and 7,
at the very least, of Cannata would have . . .
necessarily afforded rifaximin Beta because of
the solvent system used, the method used of
controlled crystallization, and the lack of drying or lack of aggressive drying.” (Tr. 883:6–10).
According to this evidence, Norwich argues, “Cannata
inherently produced rifaximin β every time, either directly or as a necessary precursor to the α, δ, and ε
forms and mixtures disclosed in the Viscomi Declaration.” (D.I. 185 at 9).
I do not think this evidence amounts to clear and
convincing evidence that Claim 4 is inherently anticipated by Cannata. Norwich could have shown anticipation either because (1) as a law of nature, rifaximin
α, δ, and ε cannot exist without having been derived
from rifaximin β, or (2) a method disclosed in Cannata
produces rifaximin β each and every time it is practiced. Dr. Zaworotko’s testimony did not prove either.
Dr. Zaworotko’s opinion does not clearly support
the conclusion that, as a law of nature, rifaximin β is
a necessary precursor to rifaximin α, δ, and ε. For one
thing, had that been his opinion, he could have clearly
stated that, and I do not think he did. (See Tr. at 870884). I think Dr. Zaworotko’s opinion was relying
upon the Viscomi 2008 article:
44a
Q: Would rifaximin Beta form as a precursor to
any polymorph listed in the Viscomi declaration
listed at paragraph 7?
A: Yes, based upon the Viscomi 2008 article,
where the effect of moisture on rifaximin crystal
forms was studied and based upon the diagram
[derived from Viscomi 2008] it’s clear that Beta
has to be the precursor for any of the other crystal
forms with lower water content.
(Tr. 921:25–922:1). This opinion appears to be based
on Dr. Zaworotko’s reading of Viscomi 2008, and not a
conclusion that rifaximin α, δ, and ε cannot exist in
the world without having first been rifaximin β. I
think Dr. Zaworotko stated his opinion the way he did
because the “diagram” to which Dr. Zawortko refers,
which is based on Figure 4 (“The relationship between
the various crystal forms of rifaximin”), was not the
main point of the article. The article’s purpose, consistent with its title (“Crystal forms of rifaximin and
their effect on pharmaceutical properties”) was to report on a “study [ ] to identify the presence of crystal
forms of rifaximin and to assess their impact on parameters such as solubility, intrinsic dissolution and
bioavailability.” (JTX-65 at 1074). The paper concluded, “The unexpected outcome of this study is that
we have found that some crystal forms of rifaximin are
significantly absorbed, while it was previously considered a non-absorbable drug. These finding[s] indicate
the need of putting appropriate manufacturing and
analytical procedures in place to consistently yield
rifaximin of the appropriate crystalline structure.”
(Id. at 1080). Thus, to the extent Dr. Zaworotko was
offering an opinion that Viscomi 2008 is conclusive
45a
proof that rifaximin α, δ, and ε are necessarily derived
from rifaximin β, I do not find that conclusion to be
well-supported. It is not clear and convincing proof.
Thus, to show that Cannata inherently anticipates Claim 4, Norwich would need to show that every
time Cannata is performed, rifaximin β is produced.
Norwich has not done so.
The Viscomi Declaration does not help Norwich. It
stated that among “samples of batches” produced according to Cannata, when retested in 2006, there were
four batches with no rifaximin β. The four batches consisted of (1) only the “delta polymorph,” (2) only of the
“epsilon form,” (3) a mixture of “the alpha and epsilon
form,” and (4) a mixture of the “alpha and delta
forms,” respectively. (JTX-80, ¶7; see Tr. 949:8-12).
Although Viscomi 2008 states that the “method of
production of rifaximin” was disclosed in European
Patent No. 161534, the counterpart to Cannata, Salix
has persuasively argued that Viscomi 2008 discloses
steps that are more specific than what Cannata describes. (See JTX 105 at 6404 n.3; JTX 65 at 1074 &
1074 n.29; Tr. 874:16-25).
In Viscomi 2008, the reaction step for preparing
wet rifaximin describes (1) heating the reaction mixture to 50°C for 5 hours, then cooling it to 20°C;
(2) adding a mixture of 0.1 moles of ascorbic acid and
2.5 moles of concentrated hydrochloric acid in 220 mL
of 58% ethyl alcohol in water over 30 minutes; and
(3) adding concentrated hydrochloric acid dropwise
until pH 2.0 is reached. (Tr. 951:8-13; JTX 65 at 1074).
Cannata has none of these details. (Tr. 951:13-17).
The crystallization step in Viscomi is also described
46a
with more precision than in Cannata. (Tr. 951:18–
952:2).
Similarly, Bacchi 2008 discloses a process that
does not precisely match Cannata’s examples 1 and 7.
Bacchi describes using a “slow evaporation” process
while Cannata does not mention evaporation. (DTX 43
at 1734; Tr. 949:20-22). Furthermore, the Cannata examples crystallize rifaximin from a 7:3 ethanol to water mixture, whereas Bacchi does not disclose any ethanol to water ratio. (Tr. 949:15-23; Tr. 953:2-954:3).
Ultimately, it appears that Cannata left certain
steps up to the discretion of the chemist preparing the
rifaximin. To show that Cannata invariably produces
rifaximin β, Norwich would have needed to show that,
no matter how the chemist exercised his or her discretion, rifaximin β would be produced. I do not think
Norwich has done so. “Experiments that do not follow
the prior art procedure alleged to inherently anticipate cannot show inherent anticipation.” Merck & Cie
v. Watson Lab’ys, Inc., 125 F. Supp. 3d 503, 513 (D.
Del. 2015) (cleaned up), rev’d on other grounds, 822
F.3d 1347 (Fed. Cir. 2016).
Thus, I find that Norwich has not shown by clear
and convincing evidence that claim 4 of the ’199 patent is inherently anticipated by Cannata.
2.
Obviousness
Norwich contends that claim 4 of the ’199 patent
is obvious over Cannata in view of common
knowledge. (D.I. 176 at 34–35). Norwich contends that
claim 36 of the ’206 patent is obvious over Cannata in
view of the Normix Label and common knowledge or
47a
over Marchi in view of Cannata and common
knowledge. (Id. at 35).
A POSA would have understood from Cannata
that rifaximin exists in crystalline form and that
rifaximin has “outstanding antibacterial properties.”
(JTX 37 at 3:10-16, 5:21–36). Norwich argues this
knowledge would motivate a POSA to “identify the
characteristics of the obtained rifaximin” using “routine methods.” (D.I. 176 at 35). Furthermore, Norwich
argues that a POSA would recognize “that the crystallization solvent used by Cannata included water,
which could lead to hydrate formation, and thus [the
POSA] would have been motivated to analyze the effect of water on the crystalline form using conventional methods.” (Id.). A POSA could have performed
a “routine humidity experiment . . . in one day and detected rifaximin β.” (Id.).
The Court of Appeals considered the obviousness
of a polymorph patent in Grunenthal GmbH v. Alkem
Labs. Ltd., 919 F.3d 1333, 1336 (Fed. Cir. 2019). The
Grunenthal patent claimed Form A of tapentadol hydrochloride characterized by its XRPD peaks. Id. The
Grunenthal defendant, Alkem, argued that the claim
was obvious in light of prior art that disclosed a Form
B of tapentadol hydrochloride. Id. at 1337.
Alkem’s prior art references included (1) the prior
art patent that described a crystalline form of tapentadol hydrochloride (later called “Form B”) and (2) an
article that “outlines a number of variables that may
be adjusted during the recrystallization process to determine whether polymorphism occurs in a compound.” Id. at 1337, 1341. The “polymorphism of
tapentadol hydrochloride was unknown at the time of
48a
filing the [asserted patent],” and “Form B was the only
crystal structure . . . known in the art at the time.” Id.
at 1341.
The Court of Appeals found that the article did not
provide “guidelines regarding which [variables] are
likely to result in polymorphs of particular compounds.” Id. at 1342. Thus, the article did little more
than tell a POSA to “vary all parameters or try each
of numerous possible choices until one possibly arrived at a successful result,” which does not provide a
reasonable expectation of success. Id. (quoting Pfizer,
Inc. v. Apotex, Inc., 480 F.3d 1348,1365 (Fed. Cir.
2007)).
Here, the prior art includes Cannata, which discloses processes for preparing a crystalline form of
rifaximin. As in Grunenthal, rifaximin’s polymorphism was unknown as of the priority date. In
Grunenthal, however, the prior art patent was known
to produce a particular form—Form B—of tapentadol
hydrochloride. Here, by contrast, no rifaximin had
been publicly characterized as a particular form as of
the priority date.
I think the evidence is clear and convincing that a
POSA would have been motivated to characterize the
rifaximin produced by the Cannata processes. Cannata disclosed that rifaximin had strong antibacterial
properties and low bioavailability, motivating a POSA
to evaluate the substance as a potential drug candidate. (JTX 37 at 3:10-16; JTX 94 at 6-7; Tr. 869:16–
870:4; Tr. 891:16-892:12). The FDA encouraged, if not
required, that the solid forms of a drug substance be
well-characterized during drug development, includ-
49a
ing as to the properties of solubility, stability, and bioavailability. (DTX 315-35; Tr. 892:13-894:7). XRPD
profiling was the predominant method for identifying
crystalline materials. (DTX 315-38; Tr. 894:23895:12). FDA guidance required “appropriate manufacturing and control procedures” when manufacturing and storing the drug substance could result in a
hydrated drug substance. (DTX 315-39; Tr. 895:13–
24). Because the Cannata process for preparing rifaximin used water, a POSA would know about the potential for a hydrate to form, and be motivated to perform routine testing (e.g., KF or TGA) for water content and hydration formation. (DTX 317-19; JTX 54 at
182; Tr. 888:3-890:5; DTX 315-39).
I think the evidence shows that a POSA would
have a reasonable expectation of success in characterizing the polymorph β, as opposed to the other forms
of rifaximin. Although Norwich’s evidence failed to
show that β was produced each and every time rifaximin was prepared according to Cannata, it did
strongly suggest that polymorph β is a commonly produced polymorph and the most stable form of rifaximin.
The Viscomi Declaration stated that rifaximin
prepared according to Cannata yielded β along with
other polymorphs. (JTX 80 at ¶ 7). Dr. Zaworotko explained that β is the most stable form. Tr. 877:17-18.
(“[B]eta is the winner in terms of stability under normal conditions of temperature and humidity.”).
Dr. Myerson’s critiques of Dr. Zaworotko’s testimony
do not have the same force in the context of obviousness as they did in the context of inherent anticipation. While Viscomi 2008’s increased specificity in the
50a
method of preparation suffices to suggest that Cannata may not produce rifaximin β each and every time
(as would be required for inherent anticipation), the
standard for obviousness is a reasonable expectation
of success. See Medichem, S.A. v. Rolabo, S.L., 437
F.3d 1157, 1165 (Fed. Cir. 2006) (“While the definition
of ‘reasonable expectation’ is somewhat vague, our
case law makes clear that it does not require a certainty of success.”).
I reject Salix’s argument that a POSA would not
have been able to predict the precise peaks that characterize rifaximin β, and accordingly a POSA would
not have had a reasonable expectation of success. The
Federal Circuit has held, “[A] rule of law equating unpredictability to patentability, applied in this case,
would mean that any new salt . . . would be separately
patentable, simply because the formation and properties of each salt must be verified through testing. This
cannot be the proper standard since the expectation of
success need only be reasonable, not absolute.” Pfizer,
Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir.
2007). I think the same is true in this context. I credit
the testimony of Dr. Zaworotko that the XRPD peaks
and water content are “inherent” properties of a crystal form that can be tested using routine methods. (Tr.
871:20–872:5; 884:2–13; 895:8–12). Thus, a POSA
would have a reasonable expectation of success at
characterizing the polymorph and arriving at the
claimed XRPD peaks and water contents.1
1 Plaintiffs call to my attention Pharmacyclics LLC v. Alvogen
Pine Brook LLC, 556 F. Supp. 3d 377, 412 (D. Del. 2021), app.
filed, No. 21-2270 (Fed. Cir. Aug. 31, 2021). (D.I. 181 at 37). I
have considered that case but I do not agree with it on this point.
51a
There is no evidence of secondary considerations
of nonobviousness for the Polymorph Patents. (See
D.I. 174 at 15–18).
Thus, I find by clear and convincing evidence that
claim 4 of the ’199 patent is obvious in light of Cannata in view of common knowledge.
Claim 36 of the ’206 patent claims a pharmaceutical composition comprising (1) rifaximin β with the
claimed XRPD peaks and a water content between
about 4.5% to 40% and (2) a pharmaceutically acceptable excipient or carrier.
Norwich argues that rifaximin had previously
been formulated as a pharmaceutical composition
comprising pharmaceutically acceptable excipients or
carriers. (D.I. 176 at 37). Marchi in 1982 and the
Normix Label in 2001 each taught “pharmaceutical
compositions” comprising rifaximin. (Id.). Marchi disclosed that rifaximin can be used as an “antibacterial
agent[ ]” in pharmaceutical compositions with conventional pharmaceutically acceptable excipients or carriers. (JTX 48 at 4:27-33, 4:67-5:4, 5:14-40, 60-62, 6:631, Cls. 10–11; Tr. 865:10-866:12, 868:20-869:3). The
Normix Label disclosed that rifaximin was an approved antibacterial drug in Italy in 1985 as a coated
tablet comprising 200 mg of rifaximin and pharmaceutically acceptable excipients. (JTX 94 at 5, 7-8; Tr.
867:13-17, 869:10-870:4, 903:3-9).
Norwich further argues that rifaximin’s antibacterial properties were known. Cannata taught that
rifaximin has outstanding antibiotic properties and
has poor absorption, which indicates to a POSA that
it could be used for GI treatments. (Tr. 862:22–24;
52a
863:14–18). Marchi also disclosed “remarkable” antibacterial properties. (JTX 48 at 4:27-33, 4:67-5:4,
5:14-40, 5:60-62, 6:6-31, Cls. 10–11; Tr. 865:10-866:12,
868:20-869:3).
Salix did not respond to these arguments. (See D.I.
181 at 37–39).
The only difference between the previous pharmaceutical compositions of rifaximin and claim 36 is that
claim 36 characterizes rifaximin as polymorphic form
β. Rifaximin β is obvious over Cannata in view of common knowledge, for the same reasons as previously
stated in connection with asserted claim 4 of the ‘199
patent. Accordingly, I find that a POSA would have
had the motivation to combine the prior art references
of Cannata, the Normix Label, or Marchi and Cannata, in view of the commonly known testing techniques, with a reasonable expectation of success in doing so. Salix offers no evidence or arguments to the
contrary. Thus, Norwich has proved by clear and convincing evidence that claim 36 of the ’206 patent is invalid as obvious.
3.
Written Description
The asserted claims describe rifaximin β as having XRPD peaks “at about 5.4°, 9.0°, and 20.9° 2θ.”
’199 Patent, Cl. 4, ’206 Patent, Cl. 36. The specification states that rifaximin β is “characterized . . . by a
powder X-ray diffractogram (reported in FIG. 2) which
shows peaks at the values of the diffraction angles 2θ
of 5.4°; 6.4°; 7.0; 7.8°; 9.0°; 10.4°; 13.1; 14.4°; 17.1;
17.90°; 18.30°; 20.9°.” ’199 Patent 5:64–6:3. Norwich
argues that the polymorph patents improperly claim
a genus, whereas the specification recites only a species. (D.I. 176 at 37–38).
53a
Salix responds that (1) the claims, on their face,
are limited to the specific polymorphic form rifaximin
, rendering Norwich’s genus characterization inaccurate, and (2) even if Norwich is right, the claims identify structural features common to the genus as required by the caselaw. (D.I. 181 at 39–42). I agree with
Salix on the first point, and accordingly will not address Salix’s second argument.
The evidence shows that a subset of XRPD peaks
can identify the polymorph. The “normal practice at
the USPTO” is to claim a polymorphic form using “at
least three powder diffraction pattern peaks.” (Tr.
965:11–17; JTX 28 at XIFAX_NOR_0002208). Dr. Zaworotko’s own patent explains, “For XRPD data
herein, each composition of the present invention[, a
new crystalline form of a known compound,] may be
characterized by any one, any two, any three, any
four, any five, any six, any seven, or any eight or more
the 2θ angle peaks.” (Tr. 916:17–917:18, PTX 707 at
15:36–39). I do not think the asserted claims claim a
genus. They claim only rifaximin β, a polymorphic
form which can be identified using the three peaks recited in the claims.
Thus, I reject Norwich’s written description challenge.
I.
THE METHOD PATENTS
A. Inducement
1.
Findings of Fact
1. At least some physicians will review Norwich’s
label.
54a
2. Physicians will instruct patients to take rifaximin according to the instructions on the label.
2.
Infringement
Before turning to a limitation-by-limitation infringement analysis for the method patents, I will address an underlying dispute regarding induced infringement when the patient is the one performing the
patented method. Inducement requires direct infringement. Salix argues that either (1) the patients,
in taking rifaximin, will directly infringe “because patients will read and follow the instructions in Norwich’s Label (with or without the help of their physician),” or (2) physicians and patients will jointly infringe based on the label. (D.I. 174 at 4). I do not think
there is joint infringement. I find that Plaintiffs have
not shown that doctors condition the patient’s receipt
of a rifaximin prescription on the performance of particular steps in the way contemplated by Akamai. See
Akamai Techs., Inc. v. Limelight Networks, Inc., 797
F.3d 1020, 1023 (Fed. Cir. 2015) (en banc). Rather, the
patients directly infringe.
According to Norwich, “Because patients will not
take rifaximin correctly without physician instruction, the Norwich Label does not induce patients and
cannot be the basis for finding specific intent.” (D.I.
183 at 3–4 (citation omitted)). Essentially, because
there is another party involved in the inducement
(physicians), the “chain of events leading to infringement is . . . too attenuated to prove specific intent.”
(D.I. 183 at 6–7). I disagree. The Court of Appeals has
long held, “the sale of a product specifically labeled for
use in a patented method constitutes inducement to
55a
infringe that patent[.]” Eli Lilly & Co. v. Actavis Elizabeth LLC, 435 F. App’x 917, 926 (Fed. Cir. 2011). In
the context of a prescription medication, physicians
have a particularly important role in conveying essential information to patients. The evidence in this case
bears this out. (See Tr. 66:22-69:20; Tr. 119:5-120:16
(describing the process of prescribing rifaximin to patients)). Other areas of law, such as the learned intermediary doctrine, recognize the physician’s essential
role in communicating information about a medication to the patient. See Reyes v. Wyeth Lab’ys, 498 F.
2d 1264,1276 (5th Cir. 1974). A pharmaceutical company, such as Norwich, is well aware of how doctors
prescribe medications to patients. Thus, if there will
be direct infringement, then Norwich will have the
specific intent to induce patients’ direct infringement.
B. The HE Patents
HE is a liver disease that affects the brain. (Tr.
41:15-21; 48:10-16). For patients with HE, the liver
does not properly filter toxins from the blood. These
toxins can cause changes to the patient’s mental state.
(Id.) Physicians grade HE severity using the Conn
score, which ranges from 0 to 4. (Tr. 45:14–47:4). Conn
scores of 0 or 1 reflect a normal or near-normal mental
state. A Conn score of 2 or higher reflects more serious
symptoms, from obvious personality changes to stupor
or even coma. (Tr. 46:6-11, 14-15). Conn scores of 0
and 1 cannot be detected in a routine physical exam.
(Tr. 45:20–21; 46:4–5). Physicians also assess HE severity using an asterixis score. (Tr. 346:5–8). Asterixis
occurs when a patient cycles between lower and
higher levels of consciousness and can be measured by
56a
tremors in a patient’s outstretched hand. (Tr. 46:16–
47:4).
HE can be either episodic or persistent. (Tr.
44:13–25). Persistent HE is characterized by a Conn
score that remains at 2 or above. (Tr. 44:24–25). Patients with episodic HE have periods of remission
punctuated by episodes of breakthrough overt HE.
(Tr. 44:13–25; 45:14–46:15). An episode of “breakthrough overt HE” is an increase in the patient’s Conn
score to grade 2 or higher (e.g., going from 0 or 1 to 2
or more), or an increase in the patient’s Conn and asterixis scores of one grade each with a baseline Conn
Score of 0. (D.I. 149, Ex. 1 ¶ 81). Patients with a history of overt HE who are not currently having an overt
HE episode are in “remission of HE.” (Id. ¶ 81; Tr.
48:2–6). Thus, patients with a Conn score of 0 or 1 and
no asterixis are in remission. (Tr. 48:2–6). After a first
overt HE episode, only about half of patients will live
one year. (Tr. 50:6–19).
Plaintiff asserts four method claims in connection
with the HE patents.
Asserted Claim 6 of the ’195 patent is a dependent
claim with three elements: (1) reducing the risk of HE
recurrence, (2) by orally administering about 550 mg
of rifaximin twice daily (BID) to the adult subject,
(3) for a period of 12 months or longer.
Asserted Claim 8 of the ’573 patent is a dependent
claim with three elements: (1) maintaining remission
of HE, wherein remission is defined as a Conn score of
0 or 1, (2) by administering 550 mg of rifaximin to the
subject BID, (3) for a period of 12 months or longer.
57a
Asserted Claim 11 of the ’397 patent is a dependent claim with four elements: (1) reducing a subject’s
risk of experiencing a breakthrough overt HE episode,
(2) by orally administering to the subject 550 mg of
rifaximin BID, (3) for a period of about 12 months or
longer, (4) to a subject with a Conn score of 0 or 1.
Asserted Claim 12 of the ’397 patent is a dependent claim with five elements: (1) reducing a subject’s
risk of experiencing a breakthrough overt HE episode,
(2) by orally administering to the subject between
about 1000 mg to about 1200 mg of rifaximin daily,
(3) for a period of about 12 months or longer, (4) to a
subject with a Conn score of 0 or 1, (5) “further comprising administering lactulose.”
1.
Findings of Fact
1.
Norwich has knowledge of the HE patents.
2.
Norwich’s label will encourage administration
of rifaximin for 12 months or longer.
3.
Norwich’s label will encourage administration
of rifaximin for the “reduction in risk of overt
hepatic encephalopathy (HE) recurrence in
adults.”
4.
Norwich’s label will encourage administration
in patients having a Conn score of 0 or 1.
5.
Norwich’s label will encourage at least some
physicians to co-administer rifaximin and lactulose.
6.
Patients will take rifaximin according to the
instructions on the label and will directly infringe the asserted HE claims.
58a
7.
Norwich’s label will induce infringement of the
asserted HE claims.
8.
The priority date of the asserted claims is October 2, 2008.
9.
A POSA would have had a Ph.D. in pharmacology, biology, biomedical sciences, microbiology and/or an M.D. with board certification in
gastroenterology. He or she would have had
training in or experience with liver and GI disorder research. If needed, a POSA would have
collaborated with others having ordinary skill
in areas relevant to the claimed subject matter, including infectious diseases and microbiology.
10. The Salix Presentation was not publicly accessible as of the priority date and is not prior art.
11. Leevy 2007 does not disclose a method of administering rifaximin to maintain remission.
12. As of the priority date, a 12-month duration for
the administration of rifaximin was not within
the common knowledge of a POSA.
13. The claimed method met a long-felt need of reducing the risk of HE recurrence and maintaining remission.
14. There was skepticism in the industry regarding the long-term use of antibiotics to maintain
remission in HE patients.
15. The HE patents are not invalid as obvious.
16. The specification describes using rifaximin
with or without lactulose.
59a
17. A POSA would recognize that the inventors
had possession of the claimed method.
2.
Infringement
i.
Administering for 12 Months or
Longer (All Claims)
It is more likely than not that Norwich’s Label will
encourage administration of the ANDA product for 12
months or longer in at least some patients, and that
Norwich knows and specifically intends for this period
of administration. Norwich’s product is indicated for
reducing overt HE recurrence. (JTX 73 § 1.2). HE is
chronic. It must be managed until the patient gets a
liver transplant or dies. I credit the testimony of
Drs. Mahl and Brown that they have had HE patients
maintain remission of HE for 12 months while on
rifaximin 550 mg BID. (Tr. 120:21–24; Tr. 55:3–11).
The label has no recommendation as to duration of administration. The label further describes a study in
which some patients used the product for 12 months
or longer. Taken together, this evidence demonstrates
by a preponderance of the evidence that Norwich’s label would encourage administering rifaximin for at
least 12 months.
ii. Maintaining Remission (’573 Patent, Claim 8)
I find that Salix has proved by a preponderance of
the evidence that Norwich’s label instructs as to
“maintaining remission of HE” as required by the asserted claims. Norwich’s label is indicated for the “reduction in risk of overt hepatic encephalopathy (HE)
recurrence in adults.” (JTX 73 § 1.2). The experts described “reducing the risk of overt HE recurrence” and
60a
“maintaining remission of HE” as “basically synonymous” or a “continuum of the same thing.” (Tr.
249:23–250:18, 252:9–18; Tr. 51:21–52:19). Remission
is binary—either a patient is in remission or the patient is not. An overt HE recurrence ends remission.
Thus, to maintain remission, a patient must avoid
overt HE recurrence.
iii. Conn Score of 0 or 1 (’397 Patent,
Claims 11 and 12)
Norwich’s label will more likely than not induce
use of rifaximin in patients with a Conn score of 0 or
1. The label encourages use to prevent an overt HE
recurrence, which as I have found, means maintaining
remission. The evidence shows that patients in remission of HE have a Conn score of 0 or 1. Thus, the label
will encourage the use of rifaximin in patients who
have a Conn score of 0 or 1. This conclusion is bolstered by the Clinical Studies section, which describes
a clinical study in which the patients were “defined as
being in remission (Conn score of 0 or 1) from hepatic
encephalopathy.” (JTX 73 § 14.2).
Norwich argues that (1) doctors do not calculate a
Conn score for their patients before prescribing rifaximin, and (2) the Indications section does not reference the Clinical Studies section and thus it “merely
describe[es] a parameter of the study, rather than actually encouraging, recommending, or promoting” the
infringing use. (D.I. 183 at 10). I find these arguments
unpersuasive.
The expert testimony shows that at least some
physicians use Conn scores in clinical practice. (Tr.
154:2–22; 264:6–7). Defendant’s expert, Dr. Mahl, testified that he does not calculate Conn scores but does
61a
record the “elements that might go into a Conn score.”
(Tr. 114:16–20). The patents do not require the calculation of a Conn score. Rather, they require use in patients with a Conn score of 0 or 1, which can be present
regardless of whether it has been calculated. On this
testimony, it seems likely that Norwich’s ANDA product will be used in at least some patients who have a
calculated Conn score of 0 or 1 as well as patients
whose Conn scores would be a 0 or 1, if calculated,
based on the symptoms observed by their physicians.
Regarding the Clinical Studies section, the law
does not require the indication section of a label to
specifically direct the reader to look at other sections
in order for those other sections to be considered. The
Court of Appeals has held, “The jury was entitled to
credit expert testimony regarding the label’s instructions on who should take what drug, when, why, and
how, and to reject the argument that certain portions
of the label were disjointed from others.” GlaxoSmithKline LLC v. Teva Pharms. USA Inc., 7 F.4th
1320, 1329 (Fed. Cir. 2021), petition for cert. filed,
No. 22-37 (July 11, 2022). I credit the testimony of
Dr. Brown that physicians commonly read the Clinical Studies section. (Tr. 67:24–68:8). The “Hepatic Encephalopathy” subsection starts with the sentence:
“The efficacy of rifaximin tablets 550 mg taken orally
two times a day was evaluated in a randomized, placebo-controlled, double-blind, multi-center 6-month
trial of adult subjects from the U.S., Canada, and Russia who were defined as being in remission (Conn
score of 0 or 1) from hepatic encephalopathy (HE).”
(JTX 73 § 14.2). Accordingly, I find that the label will
induce use in patients with a Conn score of 0 or 1.
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iv. Administration with Lactulose
(’397 Patent, Claim 12)
Norwich’s label will encourage co-administration
with lactulose. In the Indications and the Clinical
Studies section, the label notes that 91% of patients
took rifaximin and lactulose concomitantly, and that
lactulose did not alter the treatment effect of rifaximin. (JTX 73 §§ 1.2, 14.2). This strongly suggests that
taking lactulose concomitantly is safe and effective,
and it will likely encourage some physicians to administer rifaximin in conjunction with lactulose as required by the claims. I reject Norwich’s comparison to
Shire LLC v. Amneal Pharmaceuticals, which held
that label indicating that a drug could be taken “with
or without” food was “indifferent” as to which option
was select and thus not an instruction to infringe.
2014 WL 2861430, at *5 (D.N.J. June 23, 2014), aff’d
in part, rev’d on other grounds, 802 F.3d 1301 (Fed.
Cir. 2015). The high percentage of patients who took
lactulose concomitantly, and the fact that this information was included in the Indications section, encourages physicians to prescribe the two concomitantly.
I credit the testimony of Dr. Brown, who stated
that the label, by citing the 91 percent figure, “makes
clear that you can – you can and probably should use
Lactulose in the majority of your subjects.” (Tr. 76: 5–
7). I further credit Dr. Brown’s testimony, “Whenever
possible, I use the combination of Lactulose and rifaximin because that’s where the bulk of the data is.” (Tr.
at 76:12–13). I find that a physician reading the Norwich label and considering a study in which 91% of the
patients were administered lactulose concomitantly
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will be inclined to do so likewise “because that’s where
the bulk of the data” showing the efficacy of rifaximin
is.
v. Substantial Noninfringing Use
(All Claims)
Norwich argues that its ANDA product has substantial noninfringing uses, which is relevant to intent to induce. (D.I. 183 at 11–12). Most HE patients
live less than 12 months after their first overt HE episode. Thus, a substantial number of patients taking
Norwich’s ANDA as directed will not take rifaximin
for 12 months or more, and these uses will not meet
the 12-month-or-more claim limitation. Norwich
points to Warner-Lambert Co. v. Apotex Corp., 316
F.3d 1348,1363–66 (Fed. Cir. 2003) in support of this
argument.
The Federal Circuit has distinguished WarnerLambert, where the infringing use would be off-label
use of the defendant’s ANDA product and encompass
only a small number of sales, and cases where “the
proposed label itself recommends infringing acts.”
Vanda Pharms. Inc. v. West-Ward Pharms. Int’l Ltd.,
887 F.3d 1117,1132–33 (Fed. Cir. 2018). Here, since I
find that the label itself recommends infringement,
the potential for substantial non-infringing uses does
not negate Norwich’s intent to induce infringement.
3.
Invalidity
The parties agree that the definition of a POSA is
not outcome determinative. (D.I. 176 at 2; D.I. 181 at
1). I adopt Plaintiffs’ definition of a POSA.
64a
Norwich argues that as of 2008, it was widely
known that rifaximin was safe and effective for treating HE. (D.I. 176 at 3). Rifaximin was indicated
abroad for HE in 2000. (JTX 94 at 5, 9). In 2004, the
FDA approved Salix’s Xifaxan for traveler’s diarrhea.
From that time, there is evidence of widespread offlabel use of Xifaxan by physicians to treat patients
with HE. Market research conducted by Salix shows
that, by January 2007, 77% of physicians who treated
HE patients had prescribed Xifaxan for HE. (DTX
349-16).
The prior art described the use of rifaximin in HE
patients. For instance, a 1993 article (“Festi”) described one open study and two randomized, controlled, comparative studies. The three studies “confirm[ed] the usefulness of rifaximin in the management of cirrhotic patients with mild HE.” (JTX 42 at
607; Tr. 165:11-166:5). A 2000 article (“Williams
2000”) described a study confirming that 1200 and
2400 mg doses of rifaximin showed significant improvement “in reducing objective parameters of HE in
cirrhotic patients,” and “treatment with rifaximin
1200 mg/day may be considered as an adjuvant or an
alternative” to lactulose, with no adverse effects. (JTX
66 at 203-4, 207). Lactulose was the “mainstay” for HE
therapy at the time. (See Tr. 203:17–204:5). In 2004,
doctors at a Salix-hosted conference on hepatology reported being “very happy with [rifaximin’s] results”
and that rifaximin had “excellent” tolerability with
“no significant side effects.” (Tr. 172:10–18; 174:8-22;
DTX 584-1, 3). A 2007 retrospective chart review
(“Leevy 2007”) showed better treatment outcomes for
patients on rifaximin than on lactulose. (DTX 390-3;
Tr. 204:6-16).
65a
Norwich also points to retrospective chart reviews
published after the priority date that show use of
rifaximin for HE before the priority date. (See D.I. 176
at 9–10 (citing JTX 111, JTX 109)). I do not think
these uses are in the prior art because there is no evidence that a POSA would have known about them.
They do provide evidence of a POSA’s state of mind,
since the physicians prescribing Xifaxan off-label
meet both parties’ definition of a POSA. (See D.I. 182
¶ 121; D.I. 177 ¶ 1). See In Re: Copaxone Consol.
Cases, 906 F.3d 1013, 1025 (Fed. Cir. 2018) (holding,
“The district court . . . properly relied on [a reference]
not as statutory prior art, but for the fact that
[POSAs] were interested in pursuing less frequent
dosing regimens.”).
i.
Prior Art Combinations
Norwich presents two obviousness combinations
for the asserted HE claims: the Bausch HE Study in
light of the Salix Presentation, and Leevy 2007 in
light of common knowledge. I will consider each in
turn.
The Bausch HE Study is the protocol for the clinical trial that ultimately led to the approval of rifaximin for HE. It disclosed the method, dosage, lactulose,
and Conn score limitations of the asserted claims. The
Salix Presentation was a presentation given by
Dr. Leevy at a Salix shareholder’s meeting in which
Dr. Leevy described using rifaximin to treat HE. (DTX
52-4). Dr. Leevy described the duration limitation. Between the two, all claim limitations are disclosed.
Salix argues that the Salix Presentation was not
in the prior art because it was not accessible. (D.I. 181
at 4). Salix tried to exclude the evidence before trial.
66a
(D.I. 150). I denied Salix’s motion without prejudice to
evaluating its prior art status based on a complete understanding of the record. (D.I. 161 at 28:9–18). Norwich’s response to the motion in limine relied on evidence that Norwich did not present at trial. (See D.I.
150 at 9 of 18 (describing a Salix press release announcing the conference)). Accordingly, I will reconsider the question in light of the evidence presented at
trial.
At trial, Defendant offered the transcript of the
Salix Presentation and expert testimony regarding
the presentation. (DTX 660; Tr. 175:20–176:22). Defendant’s expert, Dr. Berg, testified that the Salix
presentation was publicly available online at the SEC
and that a POSA would be motivated to find it because
Salix was the only company selling rifaximin in the
United States at the time. (Tr. 175:22–24; 176:15–22).
Salix responds that this testimony is unsupported by
explanation or evidence. (D.I. 181 at 4–5). While I
credit Dr. Berg’s assertions regarding a POSA’s motivation to look for and methods of finding such a document, I do not credit his testimony regarding the
availability of the Salix Presentation online before the
priority date. I do not think a medical doctor’s expertise is a basis for opining on what the SEC had available online more than a decade ago. Dr. Berg’s opinion
is not supported by independent evidence. “At this
critical point in the determination of obviousness,
there must be factual support for an expert’s conclusory opinion.” Upjohn Co. v. Mova Pharm. Corp., 225
F.3d 1306, 1311 (Fed. Cir. 2000). Without evidence of
online accessibility, and without evidence that the
meeting was attended by interested POSAs (or even
directed to POSAs, rather than investors), I find that
67a
Defendant has not shown by clear and convincing evidence that the Salix Presentation is prior art.
Norwich’s second prior art combination is Leevy
2007 and common knowledge. Norwich argues, “Leevy
2007 disclosed the method, dosage, and Conn score
limitations.” (D.I. 176 at 8). Norwich argues that common knowledge supplies the missing limitations of duration (of 12 months or more) and lactulose. (Id. at 9).
Upon review of the evidence, I find that Leevy
2007 does not describe the method limitation. Independently, common knowledge cannot supply the duration limitation. I will address each in turn.
The claims are directed to maintaining remission
or reducing the risk of breakthrough overt HE. Leevy
2007 concluded that HE hospitalizations were less frequent and shorter for patients on rifaximin than for
patients on lactulose. Norwich argues that these hospitalizations are a metric for breakthrough overt HE
and therefore Leevy 2007 discloses the method limitation. (D.I. 176 at 8). But Norwich’s argument is not
supported by the record. Norwich’s expert, Dr. Berg,
testified as to Leevy 2007’s disclosure of rifaximin’s
ability “to treat HE” or as “therapy for HE.” (E.g., Tr.
181:9–18; 206:2–10). He did not characterize it as disclosing prevention or the like. I see no testimony linking Leevy’s reduction in hospitalizations with the
claimed method of preventing breakthrough overt HE.
Furthermore, Leevy 2007 did not track Conn
scores throughout the study. As Salix argues, “a POSA
would not have been able to determine whether subjects who had a Conn score of 1 at the beginning of the
rifaximin phase maintained that Conn score throughout the 6 months.” (D.I. 181 at 5). I credit Dr. Brown’s
68a
testimony, “You cannot interpret the natural course of
these patients’ HE through the six-month period
based on the data provided.” (Tr. 393:4–6). Leevy 2007
does not teach the maintaining remission limitation.
Thus, Leevy 2007 cannot supply the limitations
required for the asserted claims, whether it is maintaining remission of HE or reducing the risk for breakthrough overt HE. On that basis alone, Defendant
fails to prove obviousness.
There is a second, independent basis to reject the
prior art combination of Leevy 2007 and common
knowledge. I do not think that a POSA would have a
reasoned basis to resort to the “common sense” that
rifaximin could be used for 12 months or longer. Common sense can supply a limitation missing from the
prior art if a “searching” review of the prior art provides a “reasoned basis for resort to common sense.”
Arendi S.A.R.L. v. Apple Inc., 832 F.3d 1355, 1363
(Fed. Cir. 2016).
Many of the sources Norwich relies upon to show
long-term administration are not prior art. (See D.I.
176 at 9–10 (citing retrospectives published after the
priority date and the Salix Presentation)). They were
not, at that point, in the common knowledge of the
field.
Administration of rifaximin for 12 months or more
suggests prevention (i.e., maintaining remission or reducing the risk of overt HE recurrence), not mere
treatment. Norwich argues, “[T]he record is replete
with prior art disclosing the use of rifaximin in patients in remission from HE (i.e., having a Conn score
of 0 or 1).” (D.I. 185 at 5–6). It is true that some of the
studies included patients with Conn scores of 0 or 1.
69a
(JTX 66 at 205; JTX 42 at 607.) Many of these patients
would have been in remission, but the sources discuss
HE “treatment,” not prevention or maintenance of remission. The Bausch HE study was the first prior art
source to clearly articulate a desire to prevent hepatic
encephalopathy. (DTX 52-4). As of the priority date,
the Bausch Study did not have any results. Accordingly, I do not think that a 12-month treatment period
was within the common knowledge as of the priority
date.
Furthermore, Salix has presented evidence that a
POSA would have known that long-term administration of rifaximin, an antibiotic, was risky. Not only
could long-term use of antibiotics lead to a superinfection, which could kill the patient, but, “A POSA would
have been concerned that if an HE patient developed
clinical resistance to rifaximin, [the POSA] would not
be able to administer rifaximin the next time the patient experienced an HE episode.” (D.I. 181 at 11; Tr.
388:3–9). The parties’ experts disagreed about the
level of risk associated with long-term administration
of rifaximin and how a POSA would consider that risk.
I credit Dr. DuPont’s testimony that without further
studies, a POSA would have been reluctant to administer rifaximin long-term. (Tr. 467:7–12). Thus, I
think that the prior art does not provide enough of a
reasoned basis for supplying the duration limitation.
Finally, Salix has presented evidence of secondary
considerations of nonobviousness that weigh in favor
of finding the HE patents nonobvious. The claimed
HE methods met a long-felt need for maintaining remission and reducing the risk of breakthrough overt
HE episodes. Salix argues, “As of October 2008, no
70a
drug had been approved for HE in over 30 years, and
no drug had ever been approved to prevent HE recurrence.” (D.I. 174 at 17). Norwich’s expert responded
that there was no need because physicians were already using a combination of rifaximin and lactulose
to treat HE. (Tr. 222:7–20). As Salix points out, however, “Short-term, off-label use of rifaximin to treat
HE did not meet a long-felt need for long-term prevention of HE recurrence.” (D.I. 186 at 10).
There was also some skepticism in the industry.
Salix points to comments from the FDA advisory committee expressing the concern “that indefinite use of
rifaximin could change the gut flora and cause antibiotic resistance.” (D.I. 174 at 17). Norwich argues that
the FDA statements lack a nexus to the asserted
claims. I disagree. “Where the offered secondary consideration actually results from something other than
what is both claimed and novel in the claim, there is
no nexus to the merits of the claimed invention.” Novartis AG v. Torrent Pharm. Ltd., 853 F.3d 1316, 1330
(Fed. Cir. 2017) (citation omitted). But here, the potential antibiotic resistance would have resulted from
the claimed method of treatment. Accordingly, I give
some weight to the FDA comments as evidence of
skepticism.
Ultimately, I find that Norwich has not shown by
clear and convincing evidence that the asserted HE
claims are invalid as obvious.
ii. Written Description
Norwich argues, “Claim 8 of the ’573 patent,
claim 6 of the ’195 patent, and claim 11 of the ’397 patent are invalid for lack of written description because
the specifications of the patents fail to show that the
71a
administration of rifaximin alone (i.e., in the absence
of concomitant administration of lactulose) achieves
the claimed effects.” (D.I. 181 at 16). Norwich’s argument seems to be that the specifications lack data supporting the efficacy of rifaximin alone. (See id.). This
is not the standard for written description. The specifications all describe using rifaximin with or without
lactulose. (JTX 19 at 16:62-17:3 (“This method includes: administering rifaximin to a subject daily that
is being treated with lactulose, and tapering lactulose
consumption . . . . In one embodiment, the baseline use
of lactulose is no use.”); JTX 11 at 16:62-17:3; JTX 22
at 10:49-57). I therefore find that Norwich has not
shown a lack of adequate written description by clear
and convincing evidence.
C. THE IBS-D PATENTS
Irritable bowel syndrome (“IBS”) is characterized
by symptoms including abdominal pain, bloating, frequency, urgency, gas, and changed bowel habits, such
as diarrhea, constipation, or alternating diarrhea and
constipation. (E.g., Tr. 618:23–620:2). Subtypes of IBS
include IBS with diarrhea (IBS-D), IBS with constipation (IBS-C), or IBS with alternating diarrhea and
constipation (IBS-A). (Tr. 622:9–623:1). The IBS-D
subtype comprises about one-third of IBS patients.
(Tr. 622:21–623:1). IBS may be caused, for example,
by abnormal motility, abnormal muscular coordination, changes in the microbiome in the colon or small
intestine, intolerance to certain foods, or psychological
factors. (Tr. 618:23–620:2).
Plaintiffs assert two claims in connection with the
IBS-D patents.
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Asserted Claim 3 of the ’667 patent is a dependent
claim that has three elements: (1) administering
550 mg of rifaximin three times a day (TID) for 14
days; (2) to treat one or more symptoms of IBS-D;
(3) in a subject 65 years of age or older.
Asserted Claim 2 of the ’569 patent is a dependent
claim with two elements: (1) administering 550 mg of
rifaximin TID for 14 days; and (2) after stopping rifaximin, achieving a durability of response that comprises about 12 weeks of adequate relief of symptoms.
1.
Findings of Fact
1.
Norwich is aware of the IBS-D patents.
2.
Norwich’s label will encourage administering
rifaximin to adults aged 65 years or older with
IBS-D.
3.
Norwich’s label will encourage administration
of “one 550 mg tablet taken orally three times
a day for 14 days” for the treatment of IBS-D,
which inevitably will result in at least some
patients having a durability of response comprising about 12 weeks of adequate relief after
stopping rifaximin.
4.
Patients will take rifaximin according to the
label and will directly infringe the asserted
IBS-D claims.
5.
Norwich’s label will induce infringement of the
asserted IBS-D claims.
6.
The priority date for the IBS-D claims is February 26, 2008.
73a
7.
A person of skill in the art would have had a
medical degree with training in gastroenterology or have been a practicing physician, such
as an internist, with experience in treating
IBS.
8.
The prior art includes the ’608 patent (JTX
132), the Pimentel Book (PTX 752), Yang (DTX
892), the RFIB 2001 Press Release (DTX 657),
Pimentel 2006 (JTX 53), the RFIB 2001 Protocol (DTX 340), Cuoco (JTX 38), Barrett (JTX
71), Viscomi 2005 (JTX 64), Lin 2006 (JTX 69),
Lauritano (DTX 384), and Scarpellini (JTX
60).
9.
The RFIB 2001 Protocol and Pimentel 2006
disclose all limitations of the IBS-D claims.
10. A POSA would have been motivated to combine the RFIB 2001 Protocol and Pimentel
2006 with a reasonable expectation of success.
11. As of the priority date, the prior art disclosed
positive results in using rifaximin to treat IBSD for a range of doses. The asserted IBS-D
claims describe a dosing regimen within the
known range.
12. A POSA would have had motivation to treat
IBS-D patients 65 years of age or older with
rifaximin. A POSA would have had a reasonable expectation of success in treating this patient group with rifaximin.
13. The prior art did not teach away from using
rifaximin to treat IBS-D according to the
claimed methods.
74a
14. There was some skepticism in the literature.
15. The asserted IBS-D claims are invalid as obvious.
16. The specification describes “durability of response” as including adequate relief from
symptoms for 12 weeks.
17. A POSA would recognize that the inventor possessed the claimed durability of response.
18. A POSA would have reasonable certainty regarding the meaning of “adequate relief” and
“durability of response.”
2.
Infringement
i.
Age 65 and Over (‘667 Patent,
Claim 3)
Claim 3 of the ’667 patent requires administration
of rifaximin to patients who are 65 years and older. I
find that Norwich’s label will induce administration to
this patient population. Norwich’s ANDA product is
indicated for “adults.” (JTX 73 § 1.3). “Adults” include
people who are 65 years and older. The label’s “Use in
Special Populations” section describes “Geriatric
Use.” (JTX 73 § 8.5). The label states, “No overall differences in safety or effectiveness were observed between these subjects [aged 65 and over] and younger
subjects for either indication.” (Id.)
Accordingly, Norwich knows and specifically intends that its ANDA product will be used to treat IBSD in patients who are 65 and older.
75a
ii. 12 Week Durability of Response
(’569 Patent, Claim 2)
Claim 2 of the ’569 patent requires a “durability of
response [that] comprises about 12 weeks of adequate
relief.” I find that Norwich’s label will induce such a
response in at least some patients. Salix argues, “By
following [the dosing] instructions [on the label], some
patients will inevitably have a durability of response
comprising about 12 weeks of adequate relief” (D.I.
174 at 14). Salix’s expert testified to this, and Norwich’s expert admitted as much. (Tr. 537:12–540:4,
581:16–22 (agreeing that at least some patients “will
experience adequate relief of their IBS-D symptoms
for 12 weeks after taking rifaximin 550 milligrams
three times a day for 14 days”)). “[A]n accused product
that sometimes, but not always, embodies a claimed
method nonetheless infringes.” Bell Commc’ns Rsch.,
Inc. v. Vitalink Commc’ns Corp., 55 F.3d 615, 622–23
(Fed. Cir. 1995).
Norwich’s label supports a finding of inducement.
The product is indicated “for the treatment of irritable
bowel syndrome with diarrhea.” (JTX 73 § 1.3). The
Clinical Studies section states, “The efficacy of rifaximin tablets for the treatment of IBS-D was established in 3 randomized, multi-center, double-blind,
placebo-controlled trials in adult patients.” (JTX 73
§ 14.3). The third study, TARGET 3, tracked longterm response to treatment. In it, “382 [patients] experienced a period of symptom inactivity or decrease
that did not require repeat treatment by the time they
discontinued, including patients who completed the
22 weeks after initial treatment with rifaximin.” (Id.).
Norwich argues that TARGET 3 only measured two
76a
symptoms of IBS-D, rather than the claimed “adequate relief” of IBS-D symptoms, and that it reported
“time to recurrence” rather than the claimed “durability of response.” (D.I. 183 at 14). Even when a proposed label does not exactly track the claim language,
a package insert containing directives that will “inevitably lead some consumers to practice the claimed
method” provides sufficient evidence for a finding of
specific intent. See AstraZeneca LP v. Apotex, Inc., 633
F.3d 1042, 1060 (Fed. Cir. 2010). Accordingly, I find
that Norwich’s label will induce some patients to experience a 12-week durability of response as required
by the patents and that Norwich will have the specific
intent to induce infringement.
3.
Obviousness
Salix asserts that the definition of a POSA is not
outcome determinative. (D.I. 181 at 16). Noriwch has
proposed that a POSA would have had a medical degree with training in gastroenterology or have been a
practicing physician, such as an internist, with experience in treating IBS. (D.I. 181 at 17). I adopt Norwich’s definition of a POSA.
Norwich argues that, as of the priority date, rifaximin was known to be safe and effective in treating
IBS-D. Prior to February 2008, there was widespread
off-label use of Xifaxan to treat IBS in the United
States. As of January 2008, 74% of gastroenterologists
polled by Salix had prescribed Xifaxan for IBS. (DTX
349-130). Prescription data showed that 27.7% of Xifaxan 200 mg tablet uses in November 2007 had been
for IBS. (DTX 349-89; Tr. 832:2-833:23).
The prior art also discussed using rifaximin to
treat IBS. In 1999, Dr. Pimentel applied for patents
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on the use of rifaximin to treat IBS. (JTX 132; JTX
133; Tr. 617:1-21). The ‘608 patent claims a method of
“treating a subject suffering from [IBS], comprising
administering rifaximin to the subject . . .” (JTX 132
at cl. 1; Tr. 620:3-621:9).2 At a 2005 conference hosted
by Salix, Dr. Pimentel disclosed that his practice
group had used rifaximin to treat about 900 patients.
(Tr. 627:7-628:5; DTX 582-4, 5). In 2006, Dr. Pimentel
published a book titled A New IBS Solution, Bacteria
– the Missing Link in Treating Irritable Bowel Syndrome, which recommended the use of rifaximin as a
safe and effective way to treat IBS-D. (PTX 752; Tr.
623:25-624:21).
In 2006, three studies were published on the use
of rifaximin to treat IBS. A randomized, double-blind,
placebo-controlled study found rifaximin to be more
effective than placebo in improving IBS. (“Pimentel
2006,” JTX 53). A retrospective chart review of IBS
patients who had tested positive for small intestine
bacterial overgrowth (“SIBO”) reported a significant
reduction in the number of patients having IBS symptoms 4-5 months after treatment, and that 12 of 23
patients had “complete resolution of IBS symptoms.”
(“Cuoco,” JTX 38 at 94). Another retrospective chart
review of 8 patients disclosed, “rifaximin use resulted
in complete resolution of clinical symptoms in 4 patients, with no IBS relapse (follow-up, 1 to 6 months),”
and “partial symptom improvement was observed in 4
patients, 3 of whom were treated for an additional 2
months with rifaximin 400 mg three times daily cycle
2 The ’608 patent issued in 2010 but the parties agree that it
was publicly accessible before the priority date. (D.I. 149, Ex. 1 ¶
136).
78a
therapy (2 weeks on / 1 week off [ ]) which resulted in
a 50% to 70% improvement from baseline.” (“Barrett,”
JTX 71; Tr. 639:9-640:5).
Norwich proposes three prior art combinations involving three pieces of prior art. Because I agree that
Pimentel 2006 in light of the RFIB 2001 Protocol renders the asserted claims of the IBS-D patents obvious,
I will not address the other two combinations.
Pimentel 2006 administered rifaximin, 400 mg
TID for 10 days, to treat IBS patients aged 18-65. Pimentel 2006 taught, “rifaximin resulted in statistically greater global improvement in IBS than placebo,” and “[i]mprovements were sustained through
10 weeks of follow-up” after 10 days of treatment.
(JTX 53 at 562).
The “RFIB 2001 Protocol” (DTX 340) was a Phase
II trial designed to administer rifaximin to patients
aged 18 and over, 550-2,220 mg per day for 14 days for
the treatment of IBS-D. The protocol included the outcome measures of providing adequate relief of symptoms and evaluating a durability of response over a
12-week post–treatment period. Salix announced the
successful completion of this study on September 5,
2007 (the “RFIB 2001 Press Release”) and disclosed,
“Top-line results of this study demonstrate that . . . a
14-day course of rifaximin at 550 mg twice-a-day, provides a statistically significant improvement in both
adequate relief of IBS symptoms and adequate relief
of bloating, compared to placebo.” (DTX 657-4; Tr.
656:12-657:10).
The RFIB 2001 Protocol and Pimentel 2006 disclose all limitations of the asserted IBS-D claims.
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I find that a POSA would have been motivated to
combine Pimentel 2006 with the RFIB 2001 Protocol
and would have had a reasonable expectation of success. Pimentel 2006 reported sustained improvement
in IBS symptoms for patients aged 18-65 for at least
10 weeks on a 400 mg TID, 10-day regimen. The RFIB
2001 Protocol included no upper age limit, a 14-day
dosing regimen of 550 to 2200 mg per day, and the
treatment of patients with IBS-D in particular. As of
the priority date, a POSA would have known about
the successful RFIB 2001 Protocol results. Widespread off-label use reflects a motivation to use rifaximin for the treatment of IBS-D with a reasonable expectation of success. As described above, several
pieces of prior art reported success in treating IBS
with rifaximin. The caselaw does not require “conclusive proof of efficacy.” Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014). Rifaximin had been shown to be effective in treating IBS in
Pimentel 2006 and IBS-D in the RFIB 2001 Protocol,
which were randomized, placebo-controlled clinical
trials. Together, I think this is strong evidence that a
POSA would have a motivation to use rifaximin for
the treatment of IBS-D.3
3 The parties do not discuss whether there is any difference
between the motivation to use rifaximin to treat IBS and to treat
IBS-D. I think a POSA would have been motivated to treat IBSD and would have had a reasonable expectation of success in doing so, even though much of the prior art describes the treatment
of “IBS.” About one third of IBS patients have IBS-D, and there
is no evidence in the record that a POSA would expect an IBS-D
patient to respond differently to treatment than a patient with
another form of IBS. (Tr. 622:21-623:1).
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I also find that a POSA would have had the motivation to select an optimal dosing regimen from
within the known range. The prior art describes positive results from a range of doses. Pimentel 2006 used
400 mg of rifaximin TID for 10 days and reported
“global improvement in IBS.” (JTX 53 at 558). Cuoco
disclosed a total dose of 1200 mg for 14 days and reported significant reduction in the number of patients
having IBS symptoms. (JTX 38 at 91). Barrett disclosed 400 mg TID for 1-5 months. (JTX 71). In 2007,
Quigley explained, “Antibiotic dose and duration of
therapy have not been established. All studies to date
have used different doses and antibiotic regimens; the
optimal approach needs to be established in a prospective, placebo-controlled, dose-ranging study.” (PTX
692 at 1142). The RFIB 2001 Protocol taught a range
from 1100 mg to 2200 mg per day for 10-14 days. (Tr.
655:20-656:11). The RFIB 2001 Press Release reported that a “14-day course of rifaximin at 550 mg
twice-a-day” dosage saw effective results. (DTX 6574). The claimed dose is 550 mg of rifaximin TID for 14
days.
“Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover
the optimum or working ranges by routine experimentation.” In re Applied Materials, Inc., 692 F.3d 1289,
1295 (Fed. Cir. 2012) (cleaned up). Here, a POSA
would have been motivated to combine the prior art to
achieve a dosage regimen within the known range. Salix’s market research showed that 56% of physicians
who prescribed Xifaxan for IBS used TID dosing and
62% had prescribed the drug to be taken for 10-14
days. (DTX 349-131). This market research is not
prior art because it was not publicly available as of the
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priority date, but it reflects a POSA’s state of mind.
Pimentel 2006 taught, “Recent data suggest that the
optimal dosage of rifaximin may, in fact, be higher
than that used in our study.” (JTX 53 at 562). A POSA
would have been motivated to use TID dosing to maintain an effective concentration of rifaximin in the
small intestine to control bacteria levels. (Tr. 672:423). Finally, a POSA would have been motivated to
improve the use of rifaximin to treat IBS by using a
larger tablet to reduce patients’ pill burden and improve compliance. (Tr. 674:1-16.).4
I further find that a POSA would have had the
motivation to treat patients 65 years of age or older
with a reasonable expectation of success. The prior art
described rifaximin use to treat symptoms of IBS-D
patients 65 years or older. (JTX 71 at 1-2; DTX 340-7;
DTX 657-4). A POSA would have expected the effect
observed in Pimentel 2006 to apply to older patients
too. (Tr. 679:12-16).
Salix attacks Norwich’s obviousness case on several fronts.
4 Salix argues that Dr. Harary undermined his own testimony on the pill burden. Dr. Harary testified, “I don’t think going
from two pills to one pill would make a big difference, but if you
have a larger number of pills, then going to one pill would be –
would be convenient and the patients would be more comfortable
taking them.” (Tr. 674:12–16). As of the priority date, only
200 mg pills were available. I take Dr. Harary’s testimony to be
saying that three 200 mg pills would be needed to achieve a similar dose (600 mg, as opposed to the claimed 550 mg), and that
three pills are more inconvenient than one pill. Accordingly, I do
not see how Dr. Harary undermined his own testimony regarding pill burden.
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Salix argues that a POSA would recognize these
prior art sources as flawed. Cuoco, for instance, is
based on the unproven premise that SIBO contributed
to IBS-D. Furthermore, its methodology was poor.
(D.I. 181 at 19). Barrett was a retrospective chart review of only 8 patients and concluded that more research was needed. (Id.). Pimentel 2006 did not find
an improvement in the symptoms of abdominal pain
and diarrhea. (JTX 53 at 561). An editorial by
Dr. Drossman noted that Pimentel 2006’s limitations
made its “findings inconclusive and raise[d] questions
about the clinical significance of the results.” (PTX
457 at 627; Tr. 767:11-18, 770:10-19). Finally, Salix
argues that the RFIB 2001 Protocol did not disclose
results, and “it was unrebutted that a POSA would
not have reasonably expected RFIB2001 would be successful simply because the trial had begun.” (D.I. 181
at 19–20).
I am unpersuaded by these arguments. It is fair to
critique sources, and a POSA would take a source’s
shortcomings into consideration when evaluating the
evidence. Obviousness does not require perfect evidence, however, and the available evidence persuaded
a significant number of doctors who would have been
qualified as POSAs to use rifaximin to treat IBS. Regarding Pimentel 2006’s failure to find an improvement in abdominal pain and diarrhea, the patents are
not directed to specific symptoms but to “adequate relief.” There are many symptoms of IBS-D. The patents
themselves do not claim relief from every symptom.
Finally, I find that Salix’s press release disclosing
success in the RFIB 2001 Protocol study is prior art,
and thus a POSA would have known about the RFIB
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2001 top-line results as of the priority date. Salix argues that the press release was derived from the inventor’s work and thus cannot be prior art. (D.I. 181
at 20 (citing Invitrogen Corp. v. Biocrest Mfg., L.P.,
424 F.3d 1374, 1380-81 (Fed. Cir. 2005))). Norwich argues that Salix has waived this contention by failing
to raise it in the Pretrial Order. (D.I. 185 at 8). Upon
review of the Pretrial Order and its Exhibits (D.I. 147149), I see Plaintiffs’ acknowledgement that Norwich
is asserting the press release as prior art (D.I. 149, Ex.
4, at 5 n.2), and I see a list of items the prior art status
of which Plaintiffs contest, which does not include the
press release (id. at 6 ¶28), and I do not see any discussion of derivation, so the argument is likely
waived. But I do not need to decide waiver, however,
because there is no evidence upon which to make a
factual finding that the press release was derived
from the inventor’s work. “Since appellees have produced no evidence—unsurprising given their belated
recourse to this argument—and provided no supported explanation demonstrating that the Brandt
references were in fact printed publications authored
by Dr. VanDenburgh for the purposes of § 102(a), we
see no reason to remand to make further findings on
this issue.” Allergan, Inc. v. Apotex Inc., 754 F.3d 952,
969 (Fed. Cir. 2014). The Allergan Court thus concluded that the printed publications at issue were
prior art. Id. at 969–70). The press release is therefore
prior art. Its disclosure of positive results would give
a POSA a reasonable expectation of success in using
rifaximin to treat IBS-D.
Salix also points to skepticism in the literature regarding the connection between SIBO and IBS and
whether to use antibiotics to treat IBS-D. Drossman
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criticized the Pimentel 2006 methodology, as discussed above. A 2007 Education Practice note by
Eamonn M.M. Quigley stated, “sound rationale for antibiotic therapy ha[d] not been established because
the issue of SIBO in IBS ha[d] not been resolved.”
(PTX 692 at 1142; Tr. 777:20–21). Indeed, Salix argues, using antibiotics would have drawbacks: antibiotics could “exacerbate symptoms” or “lead to antibiotic resistance and opportunistic infections” like c. difficile. (PTX 664 at 1780; PTX 692 at 1142). A February
4, 2008 article by Vanner considered the evidence and
concluded that there was insufficient evidence to recommend the use of antibiotics to treat IBS. (Tr. 779:3–
8). Accordingly, Salix argues that the off-label use is
best understood as physicians acting out of “desperation, not because they expected it to work.” (D.I. 181
at 17).
Upon review of the evidence, it appears that IBS
is a complex disease and the pathogenesis was unknown as of the priority date. The relationship between IBS and SIBO was actively being explored, provoking a debate within the field. Quigley, Vanner, and
Drossman do not teach away from using rifaximin to
treat IBS, and Salix does not argue that they do.
Based on the evidence, I do not think a POSA would
elevate these sources above the other prior art available. The RFIB 2001 Press Release—which was not
cited by Quigley, Vanner, or Drossman—states, “The
belief that bacteria in the small bowel may play a role
in the symptoms of IBS gains additional evidence with
this large, multicenter trial.” (DTX 657-4). I do not
think a POSA would have discounted prior art sources
that were based upon the theory that SIBO contributed to IBS because studies such as the RFIB 2001
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Protocol were testing that hypothesis at the time.
More importantly, a POSA would look to the top-line
results from the RFIB 2001 Protocol as evidence that
rifaximin could be effective in treating IBS-D, regardless of whether the results were based upon a link between IBS-D and SIBO.
Regarding the concerns of bacterial resistance, expert testimony shows that short-term administration
did not raise resistance concerns. (Tr. 493:15-494:20).
Furthermore, in 2007, a retrospective study of 84 IBS
patients who were retreated with rifaximin noted that
69% of patients had a “clinical response” to rifaximin
and that retreatment did not result in clinically relevant antibiotic resistance. (DTX 892-2, 5; Tr. 630:5-19,
631:9-18).
Accordingly, I do not think these concerns would
dissuade a POSA from exploring the use of rifaximin
in treating IBS-D. The 74% of gastroenterologists who
had reported using rifaximin for IBS-D patients is
real world evidence supporting the conclusion that
there was a motivation to explore this treatment, despite the potential risks.
Regarding secondary considerations, Salix argues
that there was skepticism that the claimed dosing regimen could safely and effectively treat IBS-D. (D.I.
174 at 17). Salix points to statements in Quigley,
Drossman, and Vanner such as, “A sound rationale for
antibiotic therapy has not been established . . . . ,” and,
“There is insufficient evidence to recommend antibiotics for the treatment of [IBS] at present.” (PTX 692 at
1142; PTX 693 at 1319). Furthermore, experts on the
FDA advisory committee stated that using rifaximin
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550 TID for 14 days was “a completely different paradigm and a different treatment structure,” and that
Salix had proposed to “treat[ ] a disease which we
know nothing or very little about with a drug that we
know little or nothing about.” (PTX 535 at 302, 307).
The FDA advisory committee also expressed concern
about antibiotic resistance. (Id. at 137).
Norwich responds that Salix’s evidence of skepticism “fails” because rifaximin had already been used
to safely and effectively treat IBS-D before 2008. (D.I.
183 at 18). I do not think this negates Salix’s evidence
of skepticism.
Regarding skepticism in the literature, Norwich
argues that one of the articles was published before
Yang and the RFIB 2001 Press Release, and the other
two articles did not cite those references. (Id. at 20). I
agree that evidence of skepticism is not as powerful
when the skepticism is expressed by a source unfamiliar with the “prior art references that laid the groundwork for the inventors’ experiments.” PharmaStem
Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1365
(Fed. Cir. 2007). I still give some weight to these articles, especially Vanner, which was published less than
a month before the priority date.
Regarding the FDA advisory committee, Norwich
argues, “The cited passages from the 2011 FDA advisory committee meeting regarding the IBS-D indication did not criticize the safety or effectiveness of
rifaximin to treat IBS-D in at least some patients.”
(Id. at 19). Norwich’s expert did not address the FDA
statements. I decline to adopt attorney argument in
place of expert testimony.
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Ultimately, I give some weight to Salix’s evidence
of skepticism from the literature and the FDA’s statements. I do not think these experts “expressed disbelief,” United States v. Adams, 383 U.S. 39, 52 (1966),
but there is a “range of third-party opinion that can
constitute skepticism.” Neptune Generics, LLC v. Eli
Lilly & Co., 921 F.3d 1372, 1378 (Fed. Cir. 2019). Ultimately, Salix has shown a small amount of skepticism but not enough to change the outcome of the obviousness analysis.
I find that the asserted IBS-D claims are invalid
as obvious.
4.
Written Description
Norwich argues that asserted claim 2 of the ‘569
patent lacks written description because it fails to
show possession of the claimed “durability of response
compris[ing] about 12 weeks of adequate relief of
symptoms.” (D.I. 176 at 30). The specification explains:
As used herein, ‘durability of response’ includes
for example, adequate relief of symptoms after removal of treatment, continuous adequate relief of
symptoms after removal of treatment, or response
that is greater than or superior to placebo response. . . . The duration of response, may be, for
example, 2 days, 7 days, two weeks, 3 weeks, 4
weeks, 12 weeks, between about 1 week and about
24 weeks or longer.
’569 Patent at 11:44–53. The specification also discloses a proposed study design in Figure 3 “to show
durability of response.” Id. at 6:10–12. Figure 3 shows
a “4 Week Treatment Period” follow by a 12 week
88a
“Post-Treatment Phase.” Id. at Fig. 3, 25:55–59. I
think this is enough to show possession of the claimed
12-week durability of response.
Norwich argues that the disclosure is “effectively
unlimited in time.” (D.I. 176 at 31). “[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the
claims and on the complexity and predictability of the
relevant technology.” Ariad Pharm., Inc. v. Eli Lilly &
Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010). Here, the
evidence shows that IBS-D is a complex disease and
that not all patients achieve a 12-week durability of
response. A POSA would recognize that the inventor
adequately described a range of possibilities for the
durability of response and was in possession of the
claimed 12-week period.
5.
Indefiniteness
Norwich argues that asserted claim 2 of the ’569
patent is invalid as indefinite. (D.I. 176 at 28). As
noted, Claim 2 includes the limitation, “durability of
response compris[ing] about 12 weeks of adequate relief of symptoms.” Norwich argues that “adequate relief of symptoms” is subjective opinion. (Id.). Salix responds that “adequate relief” and “durability of response” have accepted meanings to a POSA. (D.I. 181
at 31). IBS-D is a collection of symptoms and there is
no biomarker to determine a successful overall treatment of IBS-D. (Tr. 507:24-508:7). I credit Dr. Schoenfeld’s testimony that patient-reported “adequate relief” is used to determine IBS-D treatment success in
the field. (Tr. 519:15-22; 821:9-822:1). Thus, I reject
Norwich’s argument that claim 2 of the ’569 patent is
invalid as indefinite.
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V. CONCLUSION
For the foregoing reasons, Norwich’s ANDA will
induce infringement of the HE, IBS-D, and Polymorph
patent claims. The HE claims are nonobvious and
Norwich has failed to show a lack of adequate written
description. The asserted Polymorph and IBS-D
claims are invalid as obvious.
I will enter a final judgment in accord with the
conclusions of this opinion.
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APPENDIX C
IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF DELAWARE
SALIX PHARMACEUTICALS, LTD.; SALIX PHARMACEUTICALS, INC.; BAUSCH HEALTH IRELAND LTD.; ALFASIGMA S.P.A.,
Plaintiffs,
v.
NORWICH PHARMACEUTICALS, INC.,
Defendant.
Civil Action No. 20-430-RGA
Filed: May 17, 2023
MEMORANDUM ORDER
I filed a final judgment in this case. (D.I. 193).
Shortly thereafter, Defendant filed a motion to modify
that judgment pursuant to Federal Rule of Civil Procedure 60(b). (D.I. 205). Subsequent briefing made
clear that Defendant was primarily relying upon Rule
60(b)(5), which provides: “On motion and just terms,
the court may relieve a party . . . from a final judgment, order, or proceeding for the following reasons: . . . (5) the judgment has been satisfied, released,
or discharged; it is based on an earlier judgment that
has been reversed or vacated; or applying it prospectively is no longer equitable.” Plaintiffs oppose the motion. (D.I. 213).
91a
The background to the pending motion is that Defendant filed an ANDA seeking to make and market a
drug for two different methods of treatment—the IBSD indication and the HE indication. I had a bench
trial. After trial, I ruled in Defendant’s favor on the
IBS-D indication (as well as the composition claims),
finding all patent claims asserted in relation to those
two issues to be invalid. I ruled in Plaintiffs’ favor only
on the HE indication, finding all claims asserted in relation to that issue to be infringed and not invalid. In
the final judgment, I ordered the FDA not to approve
the ANDA before the latest expiration (in about 2029)
of the patents on which Plaintiffs won. About a month
after entry of the final judgment, Defendant filed an
amended ANDA that purports to carve out everything
relating to the HE indication. Defendant says, if the
FDA approves the amended ANDA, Defendant would
not be inducing infringement by marketing the pharmaceutical with the amended label. Other than
providing the proposed label, Defendant has refused
to provide any other information about the amended
ANDA, including its status with the FDA or anything
else.
I do not think Defendant’s request fits in comfortably with the requirements of Rule 60(b)(5), and I do
not think, even if it did, that it could be resolved in the
summary fashion that Defendant seems to think it
should be.
First, the Rule. Defendant says the judgment has
been “satisfied,” but I think it is pretty clear that the
“satisfied, released, or discharged” language is talking
about money, and is therefore inapplicable. Defendant
says the injunction prohibiting FDA approval before
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2029 is “no longer equitable” because Defendant no
longer seeks to do the act that was the basis for the
injunction. The case law says that Rule 60(b)(5) is for
a significant change in circumstances. See Rufo v. Inmates of Suffolk Cnty. Jail, 502 U.S. 367, 383 (1992).
While such a change in circumstances does not have
to be entirely unforeseeable, a “modification should
not be granted where a party relies upon events that
actually were anticipated at the time” the final judgment was entered. Id. at 385. I do not think “changed
circumstances” applies here. The case was tried as essentially three independent up-or-down decisions. In
my experience with ANDAs, it is common, and certainly not rare, to have split decisions. ANDA practitioners and pharmaceutical companies surely know
this. Thus, there were a limited number of possible
outcomes at trial. But, of course, the trial results are
not the changed circumstances, as the actual outcomes were previewed two weeks before the final
judgment (D.I. 189) and disclosed at the same time as
the final judgment. The only changed circumstance is
that Defendant decided to amend its ANDA, which it
filed on September 6, 2022 (D.I. 206 at 2), nearly one
month after the final judgment. The changed circumstance is simply a voluntary decision of the trial loser
to change course, which is neither unanticipated nor
unforeseeable.
I also wonder about “equitableness” generally. Defendant made various strategic choices along the way,
but now does not want to live with the consequences
of those choices.1 Defendant says that it is now worse
I was assigned one related ANDA, where Defendant was
only seeking approval to market the IBS-D indication, and not
1
93a
off than other generics that settled with Plaintiffs and
apparently can launch in 2028. While true, Defendant
does not argue that it could not have settled and gotten the same deal as the other generics. Defendant
says that it has gone to the effort of proving the asserted composition and IBS-D patent claims invalid,
so other generics will be able to enter the market a lot
sooner than 2028 by taking advantage of Defendant’s
accomplishments.2 Defendant suggests this is inequitable (and perhaps it is), but the inequity does not exist between Plaintiffs and Defendant. To the extent
there is inequity, it is between Defendant and other
generics. Defendant says that the public will be
harmed because Plaintiffs will not have any generic
competition (with attendant lower costs) on the IBSD treatment method for some period of time, even
though Plaintiffs have no right to a monopoly on that
treatment method. This is a bit speculative, since
there is no information about if or when the FDA
might approve the amended ANDA.
Second, the record. It is not a simple matter to determine whether an ANDA applicant has successfully
carved out language from a label to turn infringement
into non-infringement.3 Defendant, other than saying
the HE indication. Salix Pharms., Ltd. v. Sun Pharms. Inds.,
LTD, No. 19-734-RGA (D.Del. filed April 24, 2019). That Defendant quickly resolved its case with Plaintiffs.
This may be a bit speculative too, because Plaintiffs have
lots of relevant patents and patent claims, and, while presumably they advanced their best claims at the trial in this case, I
would expect they have more listed in the Orange Book to assert
against the next generic to file an ANDA.
2
I had an ANDA trial in January 2023 where one of the issues
is whether the carve out has been successful. The issue is hotly
3
94a
it has successfully carved out the HE indication, and
providing me the label, has presented no evidence in
support of its assertion. Further, Rule 60(b) “does not
allow relitigation of issues that have been resolved by
the judgment.” 11 WRIGHT, MILLER, & KANE, FEDERAL
PRACTICE AND PROCEDURE § 2863, at 459 (3d ed.
2012). Defendant presents no facts indicating that it
could not have litigated the carve-out or that it was
denied a full and fair opportunity to do so. Allergan,
Inc. v. Sandoz Inc., 2013 WL 6253669, at *3 (E.D. Tex.
Dec. 3, 2013), aff’d, 587 F. App’x 657 (Fed. Cir. 2014).
As in Allergan, Defendant fully litigated the merits of
its non-infringement and invalidity case, lost, and
now seeks a way around the final judgment through
Rule 60(b) that “is tantamount to seeking summary
judgment premised on new allegations that only came
to exist after the final judgment was rendered . . . .” Id.
Defendant states that Plaintiffs have not tried to
state a claim against the carve out, and therefore, they
cannot. I am unpersuaded that Plaintiffs have some
duty now to state a claim on something that Defendant never raised as an issue before entry of final judgment. It is not surprising that Defendant has cited no
case that requires a plaintiff to be able to state a claim
on a new issue after judgment. What Defendant wants
would essentially be a second litigation.
Third, the law. Plaintiffs say, and Defendant does
not present any argument to the contrary, that what
Defendant seeks is unprecedented in an ANDA case.
disputed. See Sanofi-Aventis U.S. LLC v. Sandoz, Inc., No. 20804-RGA, D.I. 355 at 2 (D.De1. Feb. 17, 2023) (arguing non-infringement because Sandoz removed certain information from its
proposed label).
95a
I am hesitant to be the first, because it just seems
wrong to me that Defendant can litigate a case
through trial and final judgment based on a particular
ANDA, and then, after final judgment, change the
ANDA to what it wishes it had started with, and win
in a summary proceeding.
Thus, I DENY Defendant’s Rule 60(b) motion.
(D.I. 205).
IT IS SO ORDERED this 17th day of May, 2023.
/s/ RICHARD G. ANDREWS
United States District Judge
96a
APPENDIX D
NOTE: This order is nonprecedential.
UNITED STATES COURT OF APPEALS
FOR THE FEDERAL CIRCUIT
SALIX PHARMACEUTICALS, LTD., SALIX
PHARMACEUTICALS, INC., BAUSCH HEALTH
IRELAND LTD., ALFASIGMA S.P.A.,
Plaintiffs-Appellants
v.
NORWICH PHARMACEUTICALS INC.,
Defendant-Cross-Appellant
2022-2153, 2023-1952
Appeals from the United States District Court for
the District of Delaware in No. 1:20-cv-00430-RGA,
Judge Richard G. Andrews.
Filed: June 13, 2024
ON PETITION FOR PANEL REHEARING AND
REHEARING EN BANC
97a
Before Moore, Chief Judge, Lourie, Dyk, Prost,
Reyna, Taranto, Chen, Hughes, Stoll, and Cunningham, Circuit Judges.1
PER CURIAM.
ORDER
Salix Pharmaceuticals, Ltd., Salix Pharmaceuticals, Inc., Bausch Health Ireland Ltd., and Alfasigma
S.p.A filed a combined petition for panel rehearing
and rehearing en banc.
Norwich Pharmaceuticals Inc. also filed a combined petition for panel rehearing and rehearing en
banc.
The petitions were referred as petitions to the
panel that heard the appeal, and thereafter the petitions were referred to the circuit judges who are in
regular active service.
Upon consideration thereof,
IT IS ORDERED THAT:
The petitions for panel rehearing are denied.
The petitions for rehearing en banc are denied.
The mandate of the court will issue June 20, 2024.
FOR THE COURT
June 13, 2024
Date
/s/ Jarrett B. Perlow
Jarrett B. Perlow
Clerk of Court
1 Circuit Judge Newman and Circuit Judge Stark did not participate.
This is a copy of a public record, reproduced as it was published. It is not legal advice, and it may not be the version a court would rely on. Check the official source before you cite it.