  United States Court of Appeals
      for the Federal Circuit
                 ______________________

       PROMETHEUS LABORATORIES, INC.,
              Plaintiff-Appellant

                            v.

   ROXANE LABORATORIES, INC., CIPLA, LTD.,
             Defendants-Appellees
            ______________________

                  2014-1634, 2014-1635
                 ______________________

    Appeals from the United States District Court for the
District of New Jersey in Nos. 2:11-cv-00230-FSH-MAH,
2:11-cv-01241-FSH-MAH, Judge Faith S. Hochberg.
                ______________________

              Decided: November 10, 2015
                ______________________

    NEAL KUMAR KATYAL, Hogan Lovells US LLP, Wash-
ington, DC, argued for plaintiff-appellant. Also represent-
ed by JACLYN DILAURO, MATTHEW A. SHAPIRO; THOMAS
SCHMIDT, New York, NY.

   HENRY C. DINGER, Goodwin Procter LLP, Boston, MA,
argued for defendants-appellees. Also represented by
KEITH A. ZULLOW, MARTA E. GROSS, MICHAEL B. COTTLER,
TIMOTHY J. DOYLE, New York, NY; WILLIAM M. JAY,
Washington, DC.
                 ______________________
2   PROMETHEUS LABORATORIES, INC.   v. ROXANE LABORATORIES,
                                                       INC.


    Before DYK, TARANTO, and HUGHES, Circuit Judges.
DYK, Circuit Judge.
    Prometheus Laboratories, Inc. (“Prometheus”) appeals
a judgment of the U.S. District Court for the District of
New Jersey holding the amended claims of U.S. Patent
No. 6,284,770 (“the ’770 patent”) invalid. The district
court found the claims would have been obvious over the
prior art or, in the alternative, invalid on grounds of
obviousness-type double patenting over U.S. Patent No.
5,360,800 (“the ’800 patent”). We affirm the district
court’s decision because the claims of the ’770 patent are
invalid as obvious over the ’800 patent and other prior
art, and do not reach the issue of double patenting.
                       BACKGROUND
    Irritable bowel syndrome (“IBS”) is a condition de-
fined and diagnosed by its constellation of symptoms.
Patients may suffer from diarrhea-predominant IBS
(“IBS-D”), constipation-predominant IBS (“IBS-C”), or,
less often, mixed IBS (“IBS-M”) or alternating IBS (“IBS-
A”). A patient’s symptoms define the type of IBS with
which a patient is diagnosed.
    In this case, Prometheus, the owner of the ’770 pa-
tent, sued Roxane Laboratories, Inc. (“Roxane”) and Cipla,
Ltd. (“Cipla”) (together “defendants”), alleging infringe-
ment of claims 5, 6, 10, 13, and 14 of the ’770 patent. As
described below, the ’770 patent claims a method of
treatment for IBS-D utilizing alosetron (known by the
brand name Lotronex). The question is whether these
claims of the ’770 patent would have been obvious over
various prior art references or are invalid for obviousness-
type double patenting over the prior ’800 patent.
    Prometheus also owns the ’800 patent, which also co-
vers the use of alosetron for treatment of IBS. The ’800
PROMETHEUS LABORATORIES, INC.    v. ROXANE LABORATORIES,     3
INC.


patent issued on November 1, 1994, and has now ex-
pired. 1 The ’800 patent is prior art to the ’770 patent
asserted here. Claim 17 of the ’800 patent is directed to
“[a] method of treating a condition [such as IBS] which is
ameliorated by antagonism of 5-HT3 receptors which
comprises administering to a patient an effective amount
of [alosetron].” ’800 patent col. 38 ll. 7–12. Claim 27 of the
’800 patent covers “[a] method according to claim 17 for
the treatment of irritable bowel syndrome.” Id. at col. 38
ll. 50–51.
    The ’770 patent, entitled “Medicaments for the
Treatment of Non-Constipated Female Irritable Bowel
Syndrome,” is also directed to a method of treating IBS
patients using alosetron. The ’770 patent has a priority
date of October 7, 1997. After the ’770 patent issued,
Prometheus initiated an ex parte reexamination of the
’770 patent, and a reexamination certificate was issued on
October 19, 2010. During reexamination, Prometheus
amended claim 5 to add new claim limitations (those new
limitations are underlined below) and added, inter alia,
claims 10 and 13.
    Reexamined claims 5, 10, and 13 provide:
    5. A method for treating a diarrhea-predominant
    female IBS patient, while excluding those with
    predominant constipation, said method compris-
    ing:
    assessing whether said diarrhea-predominant fe-
    male IBS patient has experienced symptoms for
    at least six months; and




    1  Prometheus acquired the ’770 and ’800 patents,
along with other rights relating to the Lotronex franchise,
from Glaxo Group Ltd. in 2007.
4   PROMETHEUS LABORATORIES, INC.   v. ROXANE LABORATORIES,
                                                       INC.


    administering an effective amount of alosetron or
    a pharmaceutically acceptable derivative thereof
    to said patient who has experienced symptoms for
    at least six months, wherein said effective amount
    is dependent on the condition of the patient and is
    at the discretion of the attendant physician.
    10. The method for treating according to claim 5,
    further comprising assessing whether said female
    IBS patient has experienced at least moderate
    pain prior to administration of alosetron.
    13. A method for treating a diarrhea-predominant
    female IBS patient, while excluding those with
    predominant constipation, said method compris-
    ing:
    assessing whether said diarrhea-predominant fe-
    male IBS patient has experienced symptoms for
    at least six months;
    assessing whether said nonconstipated female
    IBS patient experiences at least moderate base-
    line pain from IBS; and
    administering an effective amount of alosetron or
    a pharmaceutically acceptable derivative thereof
    to said patient who has experienced symptoms for
    at least six months and who experiences at least
    moderate baseline pain from IBS, wherein said ef-
    fective amount is dependent on the condition of
    the patient and is at the discretion of the at-
    tendant physician.
Ex Parte Reexamination Certificate, ’770 patent. Claims 6
and 14, which depend from claims 5 and 13, respectively,
limit alosetron to its hydrochloride salt form. Id.
    Some background information on the history of Lo-
tronex is helpful to understanding the issues here. Shortly
before the issuance of the ’770 patent, Lotronex was
PROMETHEUS LABORATORIES, INC.   v. ROXANE LABORATORIES,    5
INC.


approved by the FDA as a treatment for IBS and was
launched in 2000. That same year, the drug had to be
taken off the market because of serious side effects,
including death. The drug was re-launched in 2002, with
a new, more restrictive label, new warnings about side
effects, and a risk management program. After reintro-
duction, the label specified that Lotronex is indicated only
for women with severe IBS-D who have, inter alia, chronic
symptoms generally lasting six months or longer, and
should not be used on patients with constipation—
indications that correspond to the limitations of the
amended ’770 patent claims. The label also included so-
called “black box” warnings regarding the potential for
serious side effects and repeated that Lotronex should
only be prescribed to women with severe diarrhea-
predominant IBS who have not responded adequately to
conventional therapy.
    Following reintroduction, the number of severe inci-
dents associated with Lotronex dropped, but the rate of
adverse events did not change. The district court found
that “[l]imiting the patient population to women with
severe IBS-D did not change the risk profile for Lotronex.
Even when limited to that cohort of the patient popula-
tion, Lotronex’s incidence of complications did not de-
crease.” J.A. 12. The district court also found that the
decrease in the number of severe incidents is less likely
due to the more restrictive label, and:
    more likely attributable to other changes in how
    Lotronex is prescribed. For example, Lotronex can
    only be prescribed pursuant to a REMS (Risk
    Evaluation and Mitigation Strategies), which re-
    quires patients and doctors to complete a form
    that highlights the risks; Lotronex’s label now has
    “black box” warnings about the drug’s potential
    side effects and instructs doctors that it should
    only be prescribed to patients with severe IBS-D
    who have not responded to conventional therapy;
6   PROMETHEUS LABORATORIES, INC.   v. ROXANE LABORATORIES,
                                                       INC.


    and its prior removal from the market caused doc-
    tors to be more vigilant with respect to complica-
    tions. These cautionary steps are not claimed in
    the ’770 patent.
J.A. 13 (citations omitted).
    In 2009, Roxane filed an Abbreviated New Drug Ap-
plication (“ANDA”) with the Food and Drug Administra-
tion (“FDA”) seeking approval to commercially market a
generic version of Lotronex prior to the expiration of the
’770 patent. In 2010, following the relisting in the Orange
Book of the ’770 patent after its reexamination, Roxane
submitted to the FDA a paragraph IV certification that
the patent was non-infringed or invalid.
    In 2011, Prometheus filed suit against defendants al-
leging infringement of reexamined claims 5, 6, 10, 13, and
14 of the ’770 patent based on the filing of the ANDA, an
artificial act of infringement. See 35 U.S.C. § 271(e)(2).
Prometheus alleged, inter alia, that Roxane’s label would
encourage doctors to prescribe alosetron in a manner that
infringes the claims. Cipla, a defendant-appellee, manu-
factures the active pharmaceutical ingredient, alosetron
hydrochloride, used in Roxane’s ANDA products.
     After a bench trial, the district court held that the as-
serted claims of the ’770 patent would have been obvious
when considering the prior art and secondary considera-
tions of nonobviousness. The district court found that “the
elements of the ’770 patent were present in the prior art,
and the differences between the prior art and the claims
of the ’770 patent are insubstantial . . . [as] some of the
prior art is virtually identical to the claimed inventions.”
J.A. 44. The district court also found that the asserted
claims of the ’770 patent would have been obvious in light
of secondary considerations. The district court found that
it was not unexpected for alosetron to exhibit greater
efficacy in IBS-D patients, who have exhibited symptoms
for greater than six months, and who have experienced at
PROMETHEUS LABORATORIES, INC.    v. ROXANE LABORATORIES,     7
INC.


least moderate pain. The district court held that the
limited evidence at trial did not establish that there is an
unexpected result of greater efficacy in women. The
district court concluded that, “[a]t best, the claims at issue
are a combination of known elements, combined in a
known way, to produce expected results.” J.A. 47. As
noted above, the district court found that the clinical
improvement of reintroduced Lotronex was due to factors
other than the ’770 patent. Moreover, the district court
found that any commercial success of reintroduced Lo-
tronex could not be attributed to the method claimed in
the ’770 patent, but rather was due to Prometheus’ mar-
keting and sales practices. Finally, the district court
found that the method claimed in the ’770 patent did not
satisfy a long-felt but unmet need. Thus, “[a]fter consider-
ing the knowledge of one of ordinary skill in the art, the
scope and content of the prior art compared to the claimed
invention, and the objective considerations of nonobvious-
ness,” the district court held that “the claims of ’770
patent, considered as a whole, are obvious.” J.A. 44. In the
alternative, the district court held that the claims were
invalid for obviousness-type double patenting in light of
the claims of the ’800 patent. 2 Given its invalidity rulings,
the district court did not reach the issue of infringement.
    Prometheus appeals. We have jurisdiction pursuant to
28 U.S.C. § 1295(a)(1). “On appeal from a bench trial, this
court reviews the district court’s conclusions of law de
novo and findings of fact for clear error.” MeadWestVaco



    2   The parties stipulated below that if the district
court found independent claim 5 of the ’770 patent invalid
due to, inter alia, obviousness or obviousness-type double
patenting, then dependent claims 6, 11, and 12 would be
invalid for the same reason. The same stipulation was
entered with respect to independent claim 13 and de-
pendent claims 14, 15, and 16.
8   PROMETHEUS LABORATORIES, INC.   v. ROXANE LABORATORIES,
                                                       INC.


Corp. v. Rexam Beauty & Closures, Inc., 731 F.3d 1258,
1266 (Fed. Cir. 2013). Both obviousness and double pa-
tenting are questions of law based on underlying facts.
Power Integrations v. Fairchild Semiconductor Int’l, Inc.,
711 F.3d 1348, 1355–56 (Fed. Cir. 2013) (obviousness);
AbbVie Inc. v. Mathilda & Terence Kennedy Inst. of
Rheumatology Tr., 764 F.3d 1366, 1372 (Fed. Cir. 2014)
(double patenting).
                        DISCUSSION
     We conclude that the asserted claims of the ’770 pa-
tent are invalid as obvious under 35 U.S.C. § 103. A
patent would have been obvious “if the differences be-
tween the claimed invention and the prior art are such
that the claimed invention as a whole would have been
obvious before the effective filing date of the claimed
invention to a person having ordinary skill in the art to
which the claimed invention pertains.” Id. Obviousness is
based on underlying factual findings, including: (1) the
level of ordinary skill in the art; (2) the scope and content
of the prior art; (3) the differences between the claims and
the prior art; and (4) secondary considerations of nonobvi-
ousness, such as commercial success, long-felt but unmet
needs, failure of others, and unexpected results. See KSR
Int’l Co. v. Teleflex, Inc., 550 U.S. 398, 406 (2007); Gra-
ham v. John Deere Co., 383 U.S. 1, 17–18 (1966).
     The primary prior art reference relied on by the dis-
trict court was the ’800 patent. In addition to the ’800
patent, the district court relied on a number of research
publications that predated the October 7, 1997, priority
date of the ’770 patent as prior art references.
    The district court determined, and the parties agreed,
that the relevant person of ordinary skill in the art is a
gastroenterologist with three years of experience. The
district court also found, and Prometheus and defendants
agreed, that the claims of the ’770 patent recite a species
of the genus method claimed in the ’800 prior art patent.
PROMETHEUS LABORATORIES, INC.   v. ROXANE LABORATORIES,   9
INC.


The ’800 patent claims the use of alosetron to treat pa-
tients suffering from IBS. The ’770 patent claims treating
a subset of those IBS patients—those who (1) are women
(2) with IBS-D (3) who have experienced symptoms for at
least six months and (4) who have had moderate pain.
While the parties dispute whether the claims of the ’770
patent operate as exclusions defining patient categories
that should not be treated with alosetron, we need not
decide this question. Even treating the limitations of the
’770 claims as exclusions, we conclude that before October
7, 1997, it would have been obvious to a person of ordi-
nary skill to treat those sub-species claimed here.
    To be sure, “[i]t is well-settled that a narrow species
can be non-obvious and patent eligible despite a patent on
its genus.” AbbVie, 764 F.3d at 1379. An “earlier disclo-
sure of a genus does not necessarily prevent patenting a
species member of the genus.” Eli Lilly & Co. v. Bd. of
Regents of Univ. of Wash., 334 F.3d 1264, 1270 (Fed. Cir.
2003).
     The genus-species distinction may have particular
relevance in the field of personalized medicine, where, for
example, a particular treatment may be effective with
respect to one subset of patients and ineffective (and even
harmful) to another subset of patients. See, e.g., Margaret
A. Hamburg & Francis S. Collins, The Path to Personal-
ized Medicine, 363 New Eng. J. Med. 301, 301 (2010).
Singling out a particular subset of patients for treatment
(for example, patients with a particular gene) may reflect
a new and useful invention that is patent eligible despite
the existence of prior art or a prior art patent disclosing
the treatment method to patients generally. An obvious-
ness rejection likely would not be appropriate where the
new patient subset displayed unexpected results.
    But that is not the situation here. In this case, the
district court’s factual findings make clear that, at the
time of the ’770 patent, it would have been obvious for a
10 PROMETHEUS LABORATORIES, INC. v. ROXANE LABORATORIES,
                                                    INC.


person skilled in the art to have separately treated the
limited subset claimed in the ’770 patent with alosetron,
and that any unexpected results were attributable to
factors exogenous to the ’770 patent.
    The first limitation of asserted claim 5 of the ’770 pa-
tent pertains to treating women. Prometheus argues that
the district court erred in framing its inquiry as whether
alosetron was administered to women with IBS-D in the
prior art, rather than as whether it was obvious to focus
on treating women rather than men. It is not disputed
that it was well known in 1997 that a majority of IBS
patients were women. As the district court found, it was
well known that “approximately 75% to 80% of IBS-D
patients . . . have always been[] women.” 3 J.A. 9. For
example, the 1992 Thompson article reported that female
IBS patients predominate in Western countries. Even if
the claims should be read as focusing treatment on wom-
en, as Prometheus urges, the district court found the prior
art taught precisely that. The Hysu study (1995) taught
that females taking alosetron “had higher concentrations
of alosetron in their blood and total amount of the drug
absorbed compared to [males taking alosetron]” and the
district court found that “[t]his could reasonably suggest
that women would have a greater response to the drug
than men.” J.A. 25. At the time of the ’770 patent’s priori-
ty date, it would have been obvious to a person having
ordinary skill in the art to treat women as a separate
group of IBS patients.
    The next claim limitation in asserted claim 5 of the
’770 patent pertains to only treating patients suffering
from IBS-D. The district court concluded that several pre-


   3   The district court also found that “the limited evi-
dence at trial . . . did not actually show that there is a
greater efficacy [of alosetron] in women compared to
men.” J.A. 40.
PROMETHEUS LABORATORIES, INC.   v. ROXANE LABORATORIES, 11
INC.


1997 publications taught that “alosetron and other 5-HT3
antagonists slow colonic transit” and “taught that
alosetron would be beneficial to prescribe to those with
IBS-D and potentially harmful to those with IBS-C.” J.A.
30. For instance, the district court found that the Talley
study (1992) “taught that 5-HT3 antagonists slowed
colonic transit and would be helpful in treating IBS-D and
harmful in treating IBS-C.” J.A. 30. The district court
found that the Sanger study (1996) taught that “5-HT3
antagonists have the potential to treat diarrhea and
recommends that they only be used with severe patients
because of the potential to cause constipation.” J.A. 22.
    Prometheus’ basic objection is that the district court
simply relied on studies suggesting that the class of 5-HT3
antagonist drugs, of which alosetron is a part, should be
used to treat IBS-D and not IBS-C. While those studies
were not focused on alosetron, but the class of drugs,
there is ample testimony that a person of ordinary skill
would have understood the studies as equally applicable
to alosetron. See, e.g., J.A. 1747–51, 1760. We do not think
the district court clearly erred in concluding that the
lessons drawn with regard to a class of drugs (5-HT3
antagonists) are applicable to a species (alosetron) within
that class.
     Prometheus submits that the district court relied on
references in which alosetron was administered to healthy
volunteers instead of IBS patients, and that studies that
did test alosetron in IBS patients suggested only that
alosetron would be helpful in treating IBS generally. But
the district court did not extrapolate those study results
on its own; rather, this conclusion was informed by expert
testimony. E.g., J.A. 1763. And the studies cited by Pro-
metheus specifically state that alosetron delays colonic
transfer. J.A. 866, 868. We see no clear error in the dis-
trict court’s conclusion that it would have been obvious to
a person of ordinary skill in the art reading the claims of
12 PROMETHEUS LABORATORIES, INC. v. ROXANE LABORATORIES,
                                                    INC.


the ’800 patent and the prior art to limit treatment to
patients suffering from IBS-D.
    As to the claim limitation requiring symptoms for “at
least six months” before administering alosetron, J.A. 71,
it was common practice at the time of the ’800 patent to
determine whether a patient had suffered symptoms for
longer than six months. Dr. Lucak, Prometheus’ own
expert, testified that the benefit of the six-month limita-
tion was having “a greater confidence in the diagnosis.”
J.A. 1372. Pre-October 1997 studies suggest using a six-
month standard for the diagnosis of IBS. The so-called
Manning criteria (named after a 1978 study) call for
symptoms lasting at least 6 months. The Kruis study
(1984) “specifically teaches using the existence of symp-
toms for over two years as a basis for increasing the
confidence in a diagnosis of IBS.” J.A. 20. The Francis
paper (February 1997) “discloses the use of a 6-month
duration criterion to reduce the margin of error” in diag-
nosing IBS. J.A. 21. In fact, the district court found that
“most IBS-D patients will have symptoms for more than 6
months” and “it has always been true that waiting a
longer period of time to observe a patient’s symptoms
decreases the likelihood of a false positive.” J.A. 9. In
1997, it would have been obvious for a person having skill
in the art to treat patients displaying IBS symptoms for
more than six months as a separate group. Although
Prometheus argues that three months was the diagnostic
standard in 1997, the district court’s finding as to the six-
month standard is amply supported by the record and is
not clearly erroneous.
    Regarding the limitation directed to at least moderate
pain, at the time the ’800 patent issued, it was well-
known to evaluate patients for pain in order to diagnose
PROMETHEUS LABORATORIES, INC.   v. ROXANE LABORATORIES, 13
INC.


IBS. The Rome criteria 4 for diagnosing IBS are standard
criteria used to diagnose IBS and inquire into pain and its
severity. Pain is in fact a main symptom of IBS (along
with diarrhea and constipation). The Manning study
(1978) states that “[a]bdominal pain, constipation, and
diarrhoea are the main symptoms [of IBS].” J.A. 822. The
Kruis study (1984) defines IBS as “a cluster of chronic
symptoms that include abdominal pain.” J.A. 815. The
Steadman study (1992) states that “[c]linically, patients
with IBS experience fluctuations in bowel habit, ab-
dominal pain, and other symptoms.” J.A. 839. And the
Talley study (1992) states that “[p]atients with irritable
bowel syndrome typically have a chronic but erratic
disturbance of defecation and associated abdominal pain.”
J.A. 855. In the Manning study, all but one of the thirty-
two patients diagnosed with IBS had pain. In the Kruis
study, 96% of patients diagnosed with IBS had abdominal
pain.
    Prometheus concedes that doctors commonly assess
IBS patients for pain, and does not dispute that it would
have been obvious to use alosetron to treat pain. Instead,
Prometheus argues that it would not have been obvious to
administer alosetron only to patients suffering from at
least moderate pain. But as the district court noted,
Prometheus’ own expert, Dr. Lembo, testified that be-
cause a candidate for Lotronex was a patient with severe
IBS, “it’s pretty obvious that [a physician] will assess for
at least moderate pain.” J.A. 1303. The expert testimony
also shows that a person of ordinary skill would have
adopted a conservative approach in treating IBS patients,
and avoided drug intervention for a patient with mild
symptoms. The district court did not err in finding that it
would have been obvious for a person having skill in the



   4    According to the district court, the Rome criteria
are described in the Thompson reference (1992).
14 PROMETHEUS LABORATORIES, INC. v. ROXANE LABORATORIES,
                                                    INC.


art to single out IBS patients displaying at least moderate
pain.
    Relevant here is our decision in AbbVie. There, a prior
art genus patent claimed a method of co-administering
two drugs to treat rheumatoid arthritis. AbbVie, 764 F.3d.
at 1378–79. The later patent contained a species claim
limiting the prior art genus to a more specific patient
group: individuals with “active disease.” AbbVie, 764 F.3d
at 1378–79. Borrowing from “the law of obviousness
generally,” we noted that “if the later expiring patent is
merely an obvious variation of an invention disclosed and
claimed in the reference patent, the later expiring patent
is invalid.” Id. at 1378–79 (quotation marks and citation
omitted). This case is analogous. Here, it would have been
obvious for a person having ordinary skill in the art
reading the ’800 patent to treat female patients with IBS-
D who had symptoms for at least six months and who had
experienced at least moderate pain. As discussed above,
these limitations are directed to a known type of IBS, to
treating the gender that predominantly experiences IBS,
to treating patients with a characteristic that is always or
almost always evaluated in establishing IBS, and to
assessing symptoms for a duration of time that was
common in diagnosing patients with IBS.
    While this case, unlike AbbVie, involves a few differ-
ent variables, the district court found that it would have
been obvious to combine the teachings of the prior art in
the form of the ’770 patent. The record contains abundant
evidence that there was a limited number of known
parameters and it would have been obvious to combine
the teachings as to each parameter.
    Finally, the district court carefully considered second-
ary considerations of nonobviousness as required by our
precedent, In re Cyclobenzaprine Hydrochloride Extended-
Release Capsule Patent Litig., 676 F.3d 1063, 1079 (Fed.
Cir. 2012), and found that the secondary considerations
PROMETHEUS LABORATORIES, INC.   v. ROXANE LABORATORIES, 15
INC.


did not support a conclusion of nonobviousness. Prome-
theus first argued that the reintroduced Lotronex’s com-
mercial success can be attributed directly to the ’770
patent, noting that from 2003 to 2007, net sales of Lo-
tronex increased each year and the original patent owner
was able to sell the Lotronex franchise to Prometheus for
$120 million. The district court recognized that sales
revenue of Lotronex increased from the time of its rein-
troduction into the market in 2002 until 2012, but ob-
served that “by 2011, there were just over 42,000
prescriptions of Lotronex written per year for about
10,000 patients. This was only about 2,100 more prescrip-
tions compared to its peak year of sales with [the original
patent owner].” J.A. 14. The district court determined
that the ’770 patent was not responsible for the commer-
cial success of reintroduced Lotronex, but instead that the
evidence showed “the growth in revenue [since Lotronex’s
reintroduction into the market] is due to Prometheus’s
actions in marketing, increasing the price of Lotronex,
and introducing a series of rebates to stimulate sales of
the drug, rather than from the treatment method claimed
in the ’770 patent.” J.A. 15. The district court was not
persuaded by Prometheus’ evidence relating the commer-
cial success of Lotronex to the ’770 patent, because Pro-
metheus did not submit an analysis that would show the
commercial success for the ’770 patent on its own merits,
“control[ling] for other variables and separat[ing] the
treatment instructions from the drug compound and the
method in the ’800 patent that already existed, nor any
analysis to control for other changing variables, such as
marketing campaigns, new drug warnings, pricing chang-
es, etc.” J.A. 41.
    Prometheus argues that the district court erred by
placing the burden of proof on Prometheus to demonstrate
the nexus between Lotronex’s commercial success and the
’770 patent. The party challenging the validity of a patent
always has the burden of persuading the trial court of
16 PROMETHEUS LABORATORIES, INC. v. ROXANE LABORATORIES,
                                                    INC.


invalidity. Microsoft Corp. v. i4i Ltd. P’ship, 131 S. Ct.
2238, 2242–43 (2011). However, “once a challenger has
presented a prima facie case of invalidity, the patentee
has the burden of going forward with rebuttal evidence.
But, all that means is that even though a patentee never
must submit evidence to support a conclusion by a judge
or jury that a patent remains valid, once a challenger
introduces evidence that might lead to a conclusion of
invalidity—what we call a prima facie case—the patentee
would be well advised to introduce evidence sufficient to
rebut that of the challenger.” Pfizer, Inc. v. Apotex, Inc.,
480 F.3d 1348, 1360 (Fed. Cir. 2007) (quotation marks
and citations omitted).
     We do not find that the district court improperly
shifted the burden of proof as to commercial success.
Although the district court described and rejected Prome-
theus’ attempts to “prove commercial success of Lotronex
and that [Lotronex] fulfilled a long-felt but unmet need,”
J.A. 41, we understand those statements to be in refer-
ence to Prometheus’ burden of production. We have found
that similar imperfect language is not grounds for rever-
sal. Optivus Tech., Inc. v. Ion Beam Applications S.A., 469
F.3d 978, 991 (Fed. Cir. 2006) (citation and quotation
marks omitted) (affirming the district court’s holding of
invalidity despite the court’s statement that “[t]here is no
indication that the [motivation to combine] was non-
obvious,” because the district court’s opinion as a whole
indicated it “correctly allocated the burden of proof”). The
district court opinion clearly states the correct standard in
finding the claims of the ’770 obvious by clear and con-
vincing evidence. J.A. 44.
    Prometheus next argued that the ’770 patent met a
long-felt but unmet need and created an unexpected
result by improving the safety and risk-benefit profiles of
alosetron. The district court rejected these contentions.
The district court was not persuaded that any long-felt
need was satisfied by the instructions claimed in the ’770
PROMETHEUS LABORATORIES, INC.   v. ROXANE LABORATORIES, 17
INC.


patent “as distinguished from . . . the drug itself, which is
covered by the ’800 patent.” J.A. 41. It found that “it is
clear that many of the benefits touted by Prometheus
were attributable to the compound itself rather than the
’770 patent’s method of treatment.” J.A. 16. The district
court further found that “any praise or reduction in the
severity of side effects is more likely attributable to ele-
ments from the ’800 patent, the new safety precautions,
heightened awareness, and warnings issued after Lo-
tronex’s reintroduction.” J.A. 44. We find no clear error in
the district court’s factual conclusions in this respect.
    We affirm the district court’s holding that the chal-
lenged claims of the ’770 patent would have been obvious
over the ’800 patent and other prior art.
                          AFFIRMED
                            COSTS
    Costs to appellees.
