Novo Nordisk A/S v. Caraco Pharmaceutical Laboratories, Ltd. , 719 F.3d 1346 ( 2013 )

United States Court of Appeals
for the Federal Circuit
______________________
NOVO NORDISK A/S AND NOVO NORDISK INC.,
Plaintiffs-Appellants,
v.
CARACO PHARMACEUTICAL LABORATORIES,
LTD. AND SUN PHARMACEUTICAL INDUSTRIES,
LTD.,
Defendants-Appellees.
______________________
2011-1223
______________________
Appeal from the United States District Court for the
Eastern District of Michigan in No. 05-CV-40188, Judge
Avern Cohn.
______________________
Decided: June 18, 2013
______________________
MARK A. PERRY, Gibson, Dunn & Crutcher LLP, of
Washington, DC, argued for plaintiffs-appellants. With
him on the brief were JOSH A. KREVITT, WAYNE BARSKY,
and MICHEAL A. SITZMAN. Of counsel was LUCAS C.
TOWNSEND.
JAMES F. HURST, Winston & Strawn LLP, of Chicago,
Illinois, argued for defendants-appellees. With him on the
brief were DAVID S. BLOCH, CHARLES B. KLEIN, STEFFEN
2 NOVO NORDISK A/S v. CARACO PHARMACEUTICAL
N. JOHNSON and ANDREW C. NICHOLS. Of counsel was
JOHN K. HSU.
______________________
Before NEWMAN, DYK, and PROST, Circuit Judges.
Opinion for the court filed by Circuit Judge PROST. Opin-
ion concurring in part and dissenting in part filed by
Circuit Judge NEWMAN.
PROST, Circuit Judge.
Novo Nordisk A/S and Novo Nordisk Inc. (“Novo”) ap-
peal a decision of the United States District Court for the
Eastern District of Michigan which held that claim 4 of
U.S. Patent No. 6,677,358 (“’358 patent”) was invalid as
obvious and that the ’358 patent was unenforceable due to
inequitable conduct. See Novo Nordisk A/S v. Caraco
Pharm. Labs., 775 F. Supp. 2d 985, 1025 (E.D. Mich.
2011). For the reasons set forth below, we affirm in part
and reverse in part.
I. BACKGROUND
This case, now before us for a third time, 1 concerns
pharmaceuticals used in the treatment of non-insulin
dependent diabetes mellitus (“NIDDM” or “Type II diabe-
tes”), a disease where the body secretes insufficient levels
of the hormone insulin, and/or the body is resistant to the
effects of insulin. Id. at 997. Type II diabetes can be
treated with orally administered antidiabetic drugs
(“OADs”) in the form of monotherapy (a single OAD) or
combination therapy (more than one OAD). Id. Before
the filing date for the ’358 patent, there were several
1 See Novo Nordisk A/S v. Caraco Pharm. Labs.,
Ltd., 601 F.3d 1359 (Fed. Cir. 2010), rev’d, 132 S. Ct. 1670(2012), remanded to, 688 F.3d 766 (Fed. Cir. 2012).
NOVO NORDISK A/S v. CARACO PHARMACEUTICAL 3
known classes of OADs having different chemical quali-
ties and varying mechanisms of action. This appeal
concerns two of these OAD classes: insulin secretagogues
and insulin sensitizers.
Insulin secretagogues work by stimulating insulin re-
lease from pancreatic beta cells, and they fall into two
subclasses: meglitinides and sulfonylureas. Id. at 997-98.
As of the ’358 patent’s filing date, there were five known
meglitinides and fifteen known secretagogues, but only a
handful of these were generally prescribed for treating
Type II diabetes. Id. at 997-98, 1004-06. The drug rep-
aglinide, which is a meglitinide, is the primary focus of
this appeal.
Insulin sensitizers reduce insulin resistance by acting
on the liver to reduce glucose production and thereby
improving insulin sensitivity in muscle and fat tissues.
Id. Of the known sensitizers in the relevant time frame,
the most widely-used and successful was a drug called
metformin. Id. at 1006.
This case involves a claim for treating Type II diabe-
tes with combination therapy using repaglinide and
metformin, specifically: “[a] method for treating non-
insulin dependent diabetes mellitus (NIDDM) comprising
administering to a patient in need of such treatment
repaglinide in combination with metformin.” Id. at 989.
A
Novo, a large pharmaceutical manufacturer, began
experimenting in 1990 with repaglinide’s efficacy in
monotherapy for treating Type II diabetes. Id. at 998. It
found repaglinide to be a rapid and short-acting insulin
secretagogue that was quickly eliminated from the body,
findings which corresponded to what was known about
the drug in the art. See id. at 1004-05. Shortly thereaf-
ter, a team of Novo investigators conducted a study on
Australian patients to determine whether repaglinide
4 NOVO NORDISK A/S v. CARACO PHARMACEUTICAL
might be more effective when administered in combina-
tion therapy with metformin (“Moses Study”).
In the Moses Study, patients failing on metformin
alone were given repaglinide/metformin combination
therapy. Id. at 1010. One of Dr. Moses’s test parameters,
HbA1c or glycosylated hemoglobin, measured the pa-
tient’s average glucose level in the recent past. Id. The
repaglinide/metformin combination reduced that level by
1.41%, or roughly twice what repaglinide and metformin
separately yielded in monotherapy. Id.The Moses Study also measured fasting plasma glu-
cose (“FPG”) levels, which is the glucose level after the
patient has not eaten for about eight hours. Id. Although
repaglinide was previously thought to have no effect upon
FPG due to its short-acting tendencies, the Moses Study
found that repaglinide/metformin reduced FPG to levels
more than eight times lower than what was typically
achieved by metformin alone. Id.Armed with the results from its Moses Study, Novo
filed a provisional patent application for the rep-
aglinide/metformin combination on October 29, 1997. Id.
at 999. The examiner rejected this initial application,
reasoning that it was obvious to try combining repaglinide
with metformin, and it was also predictable that the
combination would yield, at a minimum, a benefit equal to
the drugs taken separately, i.e., an “additive” effect. 2 Id.
at 999-1000.
2 Combination therapy yields an “additive” effect
when the total effect of the combination equals the sum of
the effect of each drug taken separately, and a “synergis-
tic” effect when the combination’s effect exceeds the sum
of the separately administered effects. Novo Nordisk, 775
F. Supp. 2d at 998.
NOVO NORDISK A/S v. CARACO PHARMACEUTICAL 5
Novo responded by directing the examiner’s attention
to Example 3 of its application, which contained the data
from the Moses Study, and arguing that this study yield-
ed synergistic results which no artisan would have ex-
pected. Id. at 1000. The examiner disagreed, and
continued her rejection. Id. Novo’s third and fourth office
action responses, each of which asked the examiner to
reconsider her position on the Moses Study, were both
rejected. Id.Novo then filed a fifth response, this time presenting
via declaration the results of an additional study conduct-
ed by Novo scientist Dr. Sturis (“Sturis Declaration”). Id.
at 1000-01. Dr. Sturis’s study tested the effects of met-
formin and repaglinide on the glucose levels of “Zucker
obese rats,” which are rats bred specifically for use in
pharmaceutical studies as models for obesity, diabetes
and heart disease. Id. at 1000 n.10. Dr. Sturis divided
twenty rats into four groups: the first group was given a
placebo, the second was given only metformin, the third
was given only repaglinide, and the fourth was given the
repaglinide/metformin combination therapy. J.A. 17167.
Dr. Sturis measured the blood glucose levels of these rats
at 30, 60, and 120 minutes, and then calculated the
combination’s “hypothetical additive effect” by adding the
glucose reduction found in the metformin-only rats to that
of the repaglinide-only rats. J.A. 17168. Finally, he
compared the “hypothetical additive effect” to the actual
glucose reduction found in the repaglinide/metformin
group to calculate the probability (as a “p-value” 3) that
3 The p-value is a value that statisticians use to
show the level of uncertainty in a study’s results. Novo
Nordisk, 775 F. Supp. 2d at 1018 n.20. A p-value is
“statistically significant” if it is 0.05 or less, which indi-
cates that there is 5% or less likelihood that the outcome
was the result of pure chance. Id.6 NOVO NORDISK A/S v. CARACO PHARMACEUTICAL
any glucose reduction caused by the combination therapy
might be attributable to synergistic rather than additive
effects. Id.Dr. Sturis reported his study’s results in two ways.
First, he plotted a chart showing glucose levels across
time and then calculated the “area under the curve” for
each line, thus expressing the average glucose reduction
found across the entire study for each group of rats. J.A.
17168. According to this calculation, the rats who re-
ceived the repaglinide/metformin treatment experienced a
greater average reduction in blood glucose levels than the
other three groups, and the combination therapy also
proved more effective than the “hypothetical additive
effect” of the two drugs. Id. The p-value for this finding
was 0.061. Id. Second, Dr. Sturis isolated just the glu-
cose measurements taken at the 120-minute mark, where
he found the largest disparity between rep-
aglinide/metformin and the other three groups. J.A.
18169. Using this data, he calculated a p-value of 0.02.
Id.Dr. Sturis opined that the 0.061 p-value “indicate[d]”
that repaglinide/metformin had a synergistic effect upon
blood glucose levels over the entire two-hour span, and
that the 0.02 p-value at the 120-minute mark in particu-
lar demonstrated “significant synergy.” J.A. 17168-69.
He thus concluded that repaglinide/metformin combina-
tion therapy had synergistic effects in Zucker obese rats,
and that his study together with the Moses Study “strong-
ly suggest[ed] that the combination of repaglinide and
metformin has synergistic properties in type 2 diabetic
[human] patients.” Novo Nordisk, 775 F. Supp. 2d at
1019.
Novo submitted the Sturis Declaration to the examin-
er, along with assertions from its counsel Dr. Richard
Bork that the declaration “provide[d] clear evidence of
synergy . . . in the treatment of type II diabetes,” and that
NOVO NORDISK A/S v. CARACO PHARMACEUTICAL 7
any prima facie case of obviousness was “rebutted by the
evidence of synergistic and surprising results achieved by
the claimed combined therapy in humans.” Id. at 1001.
The examiner withdrew her rejection, explaining that
her decision was “[b]ased solely upon the Declaration
submitted by Dr. Sturis and reconsideration of the syner-
gistic effects demonstrated in Example 3.” Id. at 1001.
After additional proceedings not relevant here, the ’358
patent issued on January 13, 2004. Id. Claim 4 of the
patent, which is the sole claim at issue here, was not
amended at any point during prosecution. Id.B
The present litigation arose under the Drug Price
Competition and Patent Term Restoration Act of 1984,
Pub. L. No. 98–417, 98 Stat. 1585 (1984) (codified at
21 U.S.C. §§ 355, 360cc; 35 U.S.C. §§ 156, 271), as amend-
ed by the Medicare Prescription Drug Improvement and
Modernization Act of 2003, Pub. L. No. 108–173, 117 Stat.
2066 (2003) (collectively, “Hatch-Waxman Act”). Specifi-
cally, this case stems from an Abbreviated New Drug
Application that Caraco filed in 2005 requesting approval
from the Food and Drug Administration to sell a generic
version of repaglinide, which the Orange Book associated
with Novo’s ’358 patent. 4 Caraco certified in the filing
that the ’358 patent was invalid or would not be infringed
by the sales of the generic repaglinide, and Novo respond-
ed with a patent infringement lawsuit claiming that
Caraco infringed claim 4 of the ’358 patent. Caraco
counterclaimed asserting, inter alia, obviousness and
unenforceability. Novo Nordisk, 775 F. Supp. 2d at 989.
4 For more details about the pharmaceutical appli-
cations that inspired this case, or about the history,
language, and scope of the Hatch-Waxman Act, see Cara-
co, 132 S. Ct. at 1675-80.
8 NOVO NORDISK A/S v. CARACO PHARMACEUTICAL
Following a bench trial, the district court held that
claim 4 of the ’358 patent was invalid because of obvious-
ness and that the patent was not enforceable because of
inequitable conduct. Novo appeals these rulings, and we
have jurisdiction under 28 U.S.C. §§ 1292(c)(2) and
1295(a).
II. OBVIOUSNESS
We turn first to the district court’s obviousness ruling.
The district court found, and the parties do not dispute,
that Caraco set forth a prima facie case that it was obvi-
ous to try combination therapy using metformin and
repaglinide to treat Type II diabetes. Novo Nordisk, 775
F. Supp. 2d at 1007. It was apparently well-known in the
art that two drugs having different mechanisms for
attacking diabetes may be more effective than one, and so
drugs were often tested in combination therapy after
demonstrating effectiveness in monotherapy. Id. at 1002.
Combination therapy using insulin sensitizers and insulin
secretagogues was common at the time, and metformin
was the most widely-used insulin sensitizer as of the ’358
patent’s filing date. Id.Having thus established the existence of a prima facie
case, but “[b]efore reaching the ultimate conclusion on the
issue of obviousness,” the district court undertook a
thorough analysis of “the evidence and assertions of
unexpected and surprising results, as well as synergistic
results.” Id. at 1007. The key question was whether
repaglinide/metformin proved more effective than what
would have been expected in view of the prior art, i.e.,
whether the combination yielded an unexpected synergis-
tic effect.
To undermine the examiner’s finding that the Moses
and Sturis studies had demonstrated synergy, Caraco
introduced new prior art and evidence which the examin-
er had never considered, such as testimony from expert
witnesses and Novo scientists. Id. at 1009. After review-
NOVO NORDISK A/S v. CARACO PHARMACEUTICAL 9
ing Caraco’s evidence, the district court determined that
an artisan would have expected repaglinide/metformin
would yield some synergy. Id. at 1010. The court then
considered, and rejected, the premise that Novo’s studies
had yielded an unexpected or superior level of synergy,
finding instead that Novo’s results were entirely expected
in view of the state of the art at that time. Id. at 1017.
The court thus concluded that Caraco had shown, by clear
and convincing evidence, that claim 4 of the patent was
invalid as obvious. Id. at 1018.
Novo attacks the district court’s obviousness ruling on
three grounds. First, it asserts that the district court
misallocated the burden of persuasion in this case by
forcing Novo to “overcome” Caraco’s “prima facie” case of
obviousness with evidence of unexpected results. Second,
Novo argues that even if the burdens were properly
allocated in this case, Caraco’s evidence insufficiently
supported the court’s ultimate obviousness findings.
Finally, Novo believes that the district court should have
deferred to the examiner’s original finding that the Sturis
and Moses studies demonstrated unexpected synergy.
For the reasons set forth below, we disagree with all
three of Novo’s arguments, and we therefore affirm the
district court’s conclusion that claim 4 of the ’358 patent
is invalid as obvious.
A
As its first ground for reversal, Novo contends that
the district court misallocated the burden of persuasion
during its obviousness analysis. It is black-letter law that
a patent is presumed valid under 35 U.S.C. § 282, that a
party challenging its validity bears the burden of proving
the factual elements of invalidity by clear and convincing
evidence, and that “because the presumption of validity
remains intact . . . throughout the litigation,” the burden
of persuasion never shifts to the patentee during the
10 NOVO NORDISK A/S v. CARACO PHARMACEUTICAL
course of a district court obviousness challenge. Pfizer v.
Apotex, 480 F.3d 1348, 1359-60 (Fed. Cir. 2007).
In this case, the district court recited the correct legal
standard for obviousness, stating that:
[o]nce the challenger has presented a prima facie
case of invalidity, the patent owner has the bur-
den of going forward with rebuttal evidence. This
requirement “does not in substance shift the bur-
den of persuasion, because the presumption of va-
lidity remains intact and the ultimate burden of
proving invalidity remains with the challenger
throughout the litigation.”
Novo Nordisk, 775 F. Supp. 2d at 992 (emphasis added)
(quoting Pfizer, 480 F.3d at 1359-60).
Novo concedes that the district court correctly sum-
marized the law of obviousness, but insists that the court
misapplied this law in practice. Novo focuses upon lan-
guage the court uses throughout its opinion, for instance,
the court’s ultimate obviousness conclusion that “[Cara-
co’s] strong prima facie case of obviousness has not been
overcome by Novo’s attempt to prove unexpected results
and commercial success.” Id. at 1018 (emphases added).
Novo cites this language as evidence that the court adopt-
ed an erroneous burden-shifting approach, similar to the
one we recently rejected in In re Cyclobenzaprine Hydro-
chloride Extended-Release Capsule Patent Litig., 676 F.3d
1063 (Fed. Cir. 2012).
In Cyclobenzaprine, we reversed and vacated a dis-
trict court decision where the court reached its ultimate
conclusion on obviousness based solely upon the prima
facie evidence. Id. at 1075 (the prematurity of the district
court’s obviousness conclusion was apparent because “[i]t
was not until after the district court found the asserted
claims obvious that it proceeded to analyze the objective
considerations”). In so doing, we reaffirmed our
NOVO NORDISK A/S v. CARACO PHARMACEUTICAL 11
longstanding precedent that it is error to find a claim
obvious “before . . . consider[ing] the objective considera-
tions,” or to shift the burden of persuasion to the patentee
at any point during its obviousness analysis. Id. at 1075.
Novo argues that just as in Cyclobenzaprine, the dis-
trict court here reached its ultimate obviousness conclu-
sion based solely upon Caraco’s prima facie evidence, then
shifted the burden of persuasion onto Novo. It believes
that this must have been so, because the court considered
whether Novo had “overcome” Caraco’s evidence by “at-
tempt[ing] to prove unexpected results.” Novo Nordisk,
775 F. Supp. 2d at 1018.
Novo misinterprets the role of the burden of persua-
sion in patent litigation. As noted above, the burden of
persuasion remains with the challenger during litigation
because every issued patent is entitled to a presumption
of validity. However, the presumption of validity does not
relieve the patentee of any responsibility to set forth
evidence in opposition to a challenger’s prima facie case
which, if left unrebutted, would be sufficient to establish
obviousness. Rather, the presumption of validity conveys
two distinct advantages upon a patentee in the litigation
context.
The patentee’s first advantage is a procedural one—he
is required to come forward with evidence of non-
obviousness only after the challenger has successfully
made his prima facie case demonstrating that the patent
might be obvious. See, e.g., Pfizer, 480 F.3d at 1360
(“[O]nce a challenger has presented a prima facie case of
invalidity, the patentee has the burden of going forward
with rebuttal evidence.”); Stratoflex, Inc. v. Aeroquip
Corp., 713 F.2d 1530, 1534 (Fed. Cir. 1983). This benefit
relates to the burden of production, which initially lies
with the challenger, then shifts to the patentee during the
course of the litigation.
12 NOVO NORDISK A/S v. CARACO PHARMACEUTICAL
The patentee’s second advantage is a substantive
one—he prevails on the issue of validity unless the chal-
lenger proves to the decisionmaker by a clear and convinc-
ing standard that, after all of the evidence has been
placed on the table for consideration, the claim is invalid.
See, e.g., Pfizer, 480 F.3d at 1360; Stratoflex, 713 F.2d at
1534. This benefit relates to the burden of persuasion,
and as we have often held (most recently in Cycloben-
zaprine), this burden never shifts during the course of the
litigation.
In this case, the court found that Caraco’s prima facie
evidence, if unrebutted, would be sufficient to establish
that the repaglinide/metformin combination was obvious
to try, and that a person of ordinary skill in the art would
have reasonably expected the combination would yield
success in the form of beneficial, and even synergistic,
results. Novo Nordisk, 775 F. Supp. 2d at 1006-07, 1010.
Having so found, it was entirely appropriate for the court
to next consider whether Novo’s countervailing secondary
consideration evidence of unexpected synergy (i.e., its
“attempt to prove unexpected results”) was sufficient to
“overcome” Caraco’s prima facie case. The mere fact that
the court conducted this analysis using terms such as
“overcome” and “prima facie” does not necessarily imply
that it shifted the burden of persuasion onto Novo. See
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 426 (2007)
(“Like the District Court, finally, we conclude Teleflex has
shown no secondary factors to dislodge the determination
that claim 4 is obvious.”) (emphasis added) (affirming
Teleflex Inc. v. KSR Int’l Co., 298 F. Supp. 2d 581, 596
(E.D. Mich. 2003) (“[T]he Court finds the evidence of
commercial success insufficient to overcome Defendant’s
clear and convincing evidence of obviousness.”) (emphasis
added)); Wm. Wrigley Jr. Co. v. Cadbury Adams USA
LLC, 683 F.3d 1356, 1365 n.5 (Fed. Cir. 2012) (“[U]se of
the terms ‘prima facie’ and ‘rebuttal’ in addressing an
invalidity challenge does not constitute reversible error as
NOVO NORDISK A/S v. CARACO PHARMACEUTICAL 13
long as the court ‘consider[s] all evidence of obviousness
and nonobviousness before reaching a determination’ and
does not shift the burden from the patent challenger.”)
(citing In re Cyclobenzaprine, 676 F.3d at 1077). Rather,
as long as the court reserved its ultimate conclusion on
validity until after it considered the evidence from both
sides, this language simply reflects the court’s shift of the
burden of production once the court determined that the
challenger has established a prima facie case of obvious-
ness.
Nothing in the court’s opinion in this case indicates
that it reached a premature conclusion on obviousness.
To the contrary, after considering the prima facie evi-
dence but “[b]efore reaching the ultimate conclusion on the
issue of obviousness,” the court thoroughly evaluated all
evidence of unexpected synergy and commercial success.
See Novo Nordisk, 775 F. Supp. 2d at 1007 (emphasis
added); id. at 1007-1017. It then concluded that, in view
of all of this evidence, Caraco had shown by clear and
convincing evidence that the combination was obvious.
Id. at 1018. Therefore, the court’s analysis was entirely
appropriate under Cyclobenzaprine and the rest of our
obviousness law.
Furthermore, and in any event, the district court did
not invalidate claim 4 due to Novo’s failure to prove
unexpected results, as Novo alleges. Instead, it found
that Caraco had established by “[c]lear and convincing
evidence . . . that the results of the claimed combination
therapy said by Novo to be unexpected and unexplainable
were, to the contrary, expected and explainable in light of
the state of the art as of the critical date.” Id. (emphasis
added). The nature of this finding further undercuts
Novo’s claim that the burden of persuasion shifted during
the course of the opinion.
14 NOVO NORDISK A/S v. CARACO PHARMACEUTICAL
We therefore reject Novo’s contention that the district
court misallocated the burden of persuasion, and decline
to reverse on this basis.
B
Novo next argues that even if the district court cor-
rectly allocated the burden of persuasion for obviousness,
the record evidence did not support a conclusion of ex-
pected results. On appeal from a bench trial on obvious-
ness, we review de novo the court’s the ultimate legal
conclusion of whether a claimed invention would have
been obvious, and review the underlying findings of fact
for clear error. See Golden Blount, Inc. v. Robert H.
Peterson Co., 365 F.3d 1054, 1058 (Fed. Cir. 2004).
At trial, Caraco contended that an artisan seeking to
predict the performance of repaglinide combined with
metformin would have considered metformin’s history in
combination therapy with other insulin secretagogues,
particularly those in the sulfonylurea class. Caraco
presented evidence, including some prior art and testimo-
ny never before the examiner, which indicated that earlier
metformin/sulfonylurea combinations were generally
understood to yield synergy. Based upon this evidence,
Caraco argued that artisans would have expected rep-
aglinide to be likewise synergistic when combined with
metformin.
Novo countered that expectations for the rep-
aglinide/metformin combination would have been instead
based primarily, if not exclusively, upon repaglinide’s
known efficacy in monotherapy. Novo’s evidence indicat-
ed that repaglinide was known to be a short-acting insulin
secretagogue, different from the longer-acting sulfonylu-
reas in Caraco’s prior art. Novo specifically relied upon a
study by Wolffenbuttel which showed that repaglinide in
monotherapy had no impact upon patient FPG. Based
upon Wolffenbuttel, Novo insisted that an artisan would
have been very surprised when repaglinide/metformin
NOVO NORDISK A/S v. CARACO PHARMACEUTICAL 15
proved to be eight times more effective in reducing FPG
levels than metformin alone.
The district court agreed with Caraco, applying the
following three-step reasoning:
(1) the closest prior art [to the rep-
aglinide/metformin combination] was combination
therapy using metformin and a sulfonylurea;
(2) combination therapy using metformin and one
of the sulfonylurea class of secretagogues was well
known in the art to produce beneficial and even
synergistic results in controlling glucose levels in
Type II diabetes patients; [and]
(3) repaglinide was known as an insulin secreta-
gogue having a similar mechanism of action to the
sulfonylurea class of secretagogues.
Novo Nordisk, 775 F. Supp. 2d at 1010. We see no clear
error in these findings. Repaglinide and sulfonylureas are
both insulin secretagogues, and they therefore have a
“similar mechanism of action” in that they both treat
diabetes by stimulating the pancreas to release insulin.
Id. at 997. Metformin is an insulin sensitizer, which
treats diabetes patients using a different mechanism, i.e.,
by reducing their resistance to insulin. Id. Furthermore,
the prior art taught that metformin could be combined
with certain sulfonylureas which were, like repaglinide,
short-acting secretagogues. Id. at 1005. It is reasonable
that an artisan seeking to combine a known insulin
sensitizer (like metformin) with a new insulin secreta-
gogue (like repaglinide) would base his expectations upon
prior art sensitizer/secretagogue combinations.
In view of these findings, it was not erroneous for the
court to conclude that the prior art predicted the results
found in the Moses Study. For example, the near-term
and long-term benefits which Dr. Moses observed in his
repaglinide/metformin study were generally inferior to
16 NOVO NORDISK A/S v. CARACO PHARMACEUTICAL
the results found by prior art studies involving metformin
combined with sulfonylureas. See id. at 1011-12. Novo
argues that these studies tell only half the tale, because
they fail to account for the differences between sulfonylu-
reas and repaglinide in monotherapy. But other trial
evidence also supports the district court’s conclusion—for
instance, Dr. Sturis testified that he originally declined to
sign a declaration supporting Novo’s application because
he felt that Dr. Moses had not mathematically or scientif-
ically proven the existence of synergy. See id. at 1019.
Dr. Sturis did, of course, eventually submit a declara-
tion on Novo’s behalf. But he only did so after conducting
his own study, and even then, he went only so far as to
state that the evidence “strongly suggest[ed]” synergy. Id.It was not clearly erroneous for the district court to find
that Dr. Sturis’s results were expected, given that his
conclusions mirror the conclusions drawn in Caraco’s new
sulfonylurea prior art, which also suggested the existence
of synergy. Id. at 1009 (citing prior art reports that
metformin/sulfonylurea combinations yielded an “appar-
ent synergistic effect” and “appear[ed] to have a synergis-
tic effect”).
The only other study that supposedly demonstrated
unexpected results was a study conducted by Pfeiffer,
which compared the insulin sensitivity of eleven patients
taking only metformin with that of the same patients
after taking the repaglinide/metformin combination. Id.
at 1014. Novo argued that no ordinary artisan would
have expected the results that Pfeiffer observed, namely,
a 35% improvement in insulin sensitivity in combination
therapy over what was seen when the patients took
metformin alone. Id. But Caraco’s expert questioned that
study’s reliability due to its small sample size, and also
pointed out that Pfeiffer had himself explained away his
results in a contemporaneous report as predictable in
view of the prior art. Id.NOVO NORDISK A/S v. CARACO PHARMACEUTICAL 17
The court further noted that certain tests conducted
upon different classes of patients yielded results that
contradicted those found by Moses, Sturis, and Pfeiffer.
For instance, in one test where half of the patients were
“drug-naïve” (i.e., they had never before used any OADs),
“the synergistic effect of combination therapy observed by
Moses et al[.] was not consistently seen.” Id. at 1016. In
another study, where all of the patients involved were
drug-naïve, the combination therapy did not show statis-
tically better results than the drugs used in monotherapy.
Id.In view of all of these findings, few of which are chal-
lenged by Novo as clearly erroneous, 5 Caraco proved by
clear and convincing evidence that an artisan would have
expected the level of synergy Novo found when it com-
bined metformin and repaglinide. We therefore decline to
reverse the district court’s obviousness determination on
this basis.
5 Novo does challenge as clearly erroneous the dis-
trict court’s finding that repaglinide/metformin combina-
tion therapy had not been commercially successful, a
conclusion the court reached based upon evidence and
testimony that doctors seldom prescribe the combination
to treat Type II diabetes. Novo Nordisk, 775 F. Supp. 2d
at 1017. Novo argues that the repaglinide/metformin
combination was much more commercially successful than
repaglinide alone, and that most repaglinide sales today
are for use in combination therapy with metformin.
However, the most probative evidence of commercial
success is not overall sales, but whether those sales
represent “a substantial quantity in th[e] market.” In re
Applied Materials, Inc., 692 F.3d 1289, 1300 (Fed. Cir.
2012) (citing In re Huang, 100 F.3d 135, 140 (Fed. Cir.
1996)). Thus, the district court’s finding was not clearly
erroneous.
18 NOVO NORDISK A/S v. CARACO PHARMACEUTICAL
C
Lastly, Novo contends that the district court should
have deferred to the examiner’s finding that the Moses
and Sturis studies demonstrated synergy. Novo’s theory
cites the recent case Kappos v. Hyatt, where the Supreme
Court held that, in cases involving district court review of
U.S. Patent and Trademark Office (“PTO”) rejections
under 35 U.S.C. § 145, new evidence may be considered
and that “it makes little sense for the district court to
apply a deferential standard of review to PTO factual
findings that are contradicted by the new evidence.”
Kappos v. Hyatt, 132 S. Ct. 1690, 1696 (2012). Novo
inverts this statement, and argues that if evidence pre-
sented at trial is not new evidence then the district court
must defer to the findings of the examiner. Because Novo
believes that all of Caraco’s prior art was merely cumula-
tive of what was already before the examiner, it concludes
that de novo fact-finding was not justified in this case.
Hyatt has no relevance here. Hyatt concerned
35 U.S.C. § 145, which provides for optional review in the
Eastern District of Virginia of decisions from the PTO
rejecting patent applications in the first instance.
35 U.S.C. § 145; Hyatt, 132 S. Ct. at 1694. The present
case is a district court challenge to an issued patent
brought under the Hatch-Waxman Act, not a challenge to
a PTO rejection brought under § 145, and Hyatt is there-
fore irrelevant. But in any event, in cases such as this we
do not review the PTO’s decision. The initial determina-
tions by the PTO in determining to grant the application
are entitled to no deference as they would be in an appeal
to this court under 28 U.S.C. § 1295(4)(A) or (absent new
evidence) in a district court proceeding under
35 U.S.C. § 145. Rather, we treat the issued patent as
having a presumption of validity that must be overcome
by clear and convincing evidence. No decision of the
Supreme Court or this court has ever suggested that there
NOVO NORDISK A/S v. CARACO PHARMACEUTICAL 19
is an added burden to overcome PTO findings in district
court infringement proceedings, and we reject Novo’s
contrary assertion. Neither are we persuaded that the
presence or absence of PTO findings on particular issues
affects the basic presumption of validity.
III. INEQUITABLE CONDUCT
We next address the district court’s determination
that the ’358 patent was unenforceable due to inequitable
conduct. We review the district court’s ultimate finding of
inequitable conduct for abuse of discretion, and review the
underlying findings of materiality and intent for clear
error. Therasense, Inc. v. Becton, Dickinson & Co., 649
F.3d 1276, 1291 (Fed. Cir. 2011) (en banc); In re Omepra-
zole Patent Litig., 483 F.3d 1364, 1374-76 (Fed. Cir. 2007).
At trial, Caraco alleged that the Sturis Declaration, as
well as the representations made by Dr. Bork during
prosecution of the ’358 patent, constituted inequitable
conduct. In particular, Caraco challenged: (a) Dr. Sturis’s
omission of certain opinions regarding his own study and
the Moses Study, as well as his failure to tell the PTO
that certain of his reported results had not been part of
his original test protocol; and (b) Dr. Bork’s assertion that
Dr. Sturis’s data provided “clear evidence of synergy,” and
his failure to disclose certain e-mails that allegedly refut-
ed this statement. Novo Nordisk, 775 F. Supp. 2d at
1019, 1021. These actions were particularly troubling,
Caraco contended, because the examiner withdrew her
rejection “[b]ased solely upon the Declaration submitted
by Dr. Sturis and reconsideration of the synergistic ef-
fects.” Id. at 1001.
The district court issued its opinion after we agreed to
hear Therasense en banc, but before we reached our
decision in that case. Therefore, it applied both the pre-
Therasense and post-Therasense tests for materiality and
intent, and found that under either standard, Sturis and
Bork had intentionally withheld material information
20 NOVO NORDISK A/S v. CARACO PHARMACEUTICAL
from the PTO. See id. at 995, 1021-22. Accordingly, the
court concluded that the ’358 patent was unenforceable
due to inequitable conduct. Id. at 1024.
Novo argues that the district court clearly erred in
finding that Sturis’s and Bork’s representations and
omissions were material and intentional under The-
rasense. We agree with Novo on the issue of materiality,
and so for the reasons outlined below, we reverse the
district court’s conclusion on inequitable conduct.
A
Caraco’s inequitable conduct case against Dr. Sturis
was based upon his trial testimony, wherein he conceded
certain facts that were never submitted to the PTO. For
instance, Dr. Sturis testified that when he first conducted
his study, he had planned to calculate only one p-value
based upon the “area under the curve” data, which result-
ed in a p-value of 0.061. But after conducting his test, he
decided to calculate and submit the second p-value (i.e.,
the 0.02 p-value) using the isolated data from the 120-
minute interval. See id. at 1019-20. Dr. Sturis’s Declara-
tion did not indicate to the PTO that his original test
protocol called for calculating only the less favorable of
the two p-values he ultimately presented.
Dr. Sturis also testified that his rat study, having
been conducted on animals, could not alone establish that
the combination had a synergistic effect on humans. Id.
at 1021. He further told the court that he held reserva-
tions, both before and after submitting his Declaration,
about whether the Moses Study alone, or even taken
together with the results of his rat study, could affirma-
tively prove synergy in humans. Id. at 1020-21.
Based upon this testimony, the district court found
that Dr. Sturis had omitted material information from his
Declaration, namely:
NOVO NORDISK A/S v. CARACO PHARMACEUTICAL 21
the facts that the two-hour data point was not
part of the test protocol, and that a correction fac-
tor had not been applied to that p-value. That da-
ta point was the only one in his rat test that
appeared to produce a statistically significant p-
value of less than 0.05. Also undisclosed were
Sturis’ opinions . . . that, by his own standards re-
quiring mathematical proof, neither his rat study
nor the Moses Study alone proved synergy in hu-
mans.
Id. at 1020. The omissions were material under the pre-
Therasense standard, the court found, “because they
refuted or were inconsistent with the opinions expressed
in his Declaration in support of patentability” and be-
cause “[a] reasonable examiner, focused on the issue of
synergism as was the examiner here, would have wanted
to consider any qualifications or reservations held by
Sturis concerning the conclusions he expressed in his
Declaration.” Id. at 1021. The court further found that
“the examiner’s explicit reliance on the Sturis Declaration
warrants the conclusion that the Declaration satisfied the
[post-Therasense] ‘but for’ materiality test.” Id.We reject the district court’s materiality finding as
clearly erroneous, because we fail to see how Dr. Sturis’s
omissions qualify as “but for” material. For instance, any
reasonable examiner would have understood that Dr.
Sturis’s rat study was conducted on animals, and there-
fore could not definitively prove synergy in humans.
Moreover, Dr. Sturis’s declaration, which stated only that
his results “indicated” and “strongly suggest[ed]” synergy,
was generally consistent with his trial testimony that
synergy was not affirmatively proven and that “neither
his rat study nor the Moses Study alone proved synergy in
humans.” Id. at 1020.
While Dr. Sturis’s decision to omit his original test
protocol from the Declaration is slightly more troubling, it
22 NOVO NORDISK A/S v. CARACO PHARMACEUTICAL
similarly fails the “but for” materiality test. This is not a
case where a declarant hid adverse test results from the
PTO in favor of more promising data selected post hoc.
Here, Dr. Sturis disclosed the results of his original
protocol to the examiner, allowing her the opportunity to
weigh the significance of the different p-values he calcu-
lated. Nor is this a case where the declarant’s omission
expressly undermined his stated opinion. To the contra-
ry, even after taking the omitted test protocol into ac-
count, the court specifically found that Dr. Sturis’s
conclusions on synergy had not been shown to be false.
See id. (“[Dr. Sturis’s ‘strongly suggests’ qualified conclu-
sion] has not been shown by clear and convincing evidence
to be false.”)
Instead, Dr. Sturis stands accused of inequitable con-
duct because he failed to notify the PTO that the 0.02 p-
value calculated at 120 minutes, while probative of syner-
gy, was not called for in his original test plan. Although
this information ideally would have been disclosed to the
PTO, it is nevertheless a non-material omission because it
can “be rendered irrelevant in light of subsequent argu-
ment or explanation by the patentee.” See Therasense,
649 F.3d at 1294. For instance, at trial, Dr. Sturis justi-
fied his deviation from protocol by testifying that he saw
surprisingly high levels of glucose reduction at 120
minutes, and he felt it would have been scientifically
irresponsible for him not to investigate and report those
findings. In view of this reasonable explanation, and the
fact that he disclosed the results of his original test proto-
col to the PTO, we do not believe that his omitted test
protocol was “but for” material.
NOVO NORDISK A/S v. CARACO PHARMACEUTICAL 23
B
Caraco’s inequitable conduct case against Dr. Bork fo-
cused primarily upon the following statements he made in
support of the Sturis Declaration:
the data presented in the Declaration of Dr.
Sturis, provides clear evidence of synergy for the
use of the claimed combination of repaglinide and
metformin in the treatment of type II diabetes.
. . . prima facie case [of obviousness] is rebutted by
the evidence of synergistic and surprising results
achieved by the claimed combination therapy in
humans (Example application) and in Zucker
obese rats (Sturis’ Declaration).
Novo Nordisk, 775 F. Supp. 2d at 1021 (alteration in
original). The district court found that this statement
was material because it went beyond Sturis’s “strongly
suggests” language by indicating that “clear evidence” of
“synergistic and surprising results” in humans had been
“achieved.”
Caraco also alleged that Dr. Bork should have provid-
ed the PTO with an e-mail he received from Dr. Sturis
after making the above representations, wherein Dr.
Sturis stated that “[t]he presence of greater-than-additive
effects may be of relevance to the clinical efficacy of the
[repaglinide/metformin] combination.” Id. at 1022 (em-
phasis added). The court found that Bork should have
understood that the word “may” contradicted his prior
representation that “clear evidence” of synergy in humans
had been “achieved,” and that this triggered his duty to
disclose the e-mail.
The court deemed Bork’s representations material
under the pre-Therasense standard because his unquali-
fied statements contradicted with what he knew about the
Sturis Declaration, i.e., that it did not definitively prove
synergy. Id. The district court addressed the post-
24 NOVO NORDISK A/S v. CARACO PHARMACEUTICAL
Therasense test only briefly, stating that “[a]s in the case
of the Sturis Declaration, [Dr. Bork’s representations] also
satisfy the alternative ‘but for’ materiality test.” Id.As with Dr. Sturis’s omissions, we believe that the
statements and omissions by Dr. Bork are troubling, but
not material. Dr. Bork’s characterization of the Sturis
Declaration employed carefully-chosen language which
tracked the qualified nature of Dr. Sturis’s opinions. For
instance, whereas Dr. Sturis said his results “indicated”
and “strongly suggest[ed]” synergy, Dr. Bork referred to
Sturis’s test results as “evidence” rather than “proof” of
synergy. These statements are also generally consistent
with Dr. Sturis’s e-mail, and its use of the word “may.”
We therefore reverse the district court’s materiality
and inequitable conduct findings as to both Dr. Sturis and
Dr. Bork. We need not reach the issue of intent.
IV. CONCLUSION
For the reasons set forth above, we affirm the district
court’s determination that claim 4 of the ’358 patent was
invalid as obvious, but reverse the district court’s deter-
mination that the ’358 patent was unenforceable due to
inequitable conduct.
AFFIRMED IN PART AND REVERSED IN PART
United States Court of Appeals
for the Federal Circuit
______________________
NOVO NORDISK A/S AND NOVO NORDISK INC.,
Plaintiffs-Appellants,
v.
CARACO PHARMACEUTICAL LABORATORIES,
LTD. AND SUN PHARMACEUTICAL INDUSTRIES,
LTD.,
Defendants-Appellees.
______________________
2011-1223
______________________
Appeal from the United States District Court for the
Eastern District of Michigan in No. 05-CV-40188, Judge
Avern Cohn.
NEWMAN, Circuit Judge, concurring in part, dissenting in
part.
I agree that neither Dr. Sturis nor Dr. Bork engaged
in inequitable conduct, and concur in the judgment re-
versing the district court’s ruling in that respect. Howev-
er, Novo’s discovery of the synergistic combination of
metformin and repaglinide meets the criteria of patenta-
bility, and was incorrectly held to be unpatentable on the
ground of obviousness, 35 U.S.C. §103.
The section 103 determination in this case relates to a
synergistic combination of two diabetes drugs. The com-
bination described and claimed in the patent in suit, U.S.
Patent No. 6,677,358 (“the ’358 patent”), is eight-fold
2 NOVO NORDISK A/S v. CARACO PHARMACEUTICAL
more effective than the additive properties, and is now
apparently a treatment of choice for persons whose Type
II diabetes had previously been untreatable. It is a life-
saving combination for such persons, and is valuable to
other diabetics, for it permits a more flexible treatment
regimen than prior products. The Novo inventors pur-
sued this combination despite the advice of other “ex-
perts” that they were wasting time and money.
Nonetheless the district court, and now my colleagues on
this panel, find the combination obvious to them, and
invalidate the patent. I respectfully dissent.
DISCUSSION
“Real world considerations provide . . . a solid eviden-
tiary foundation on which to rest a nonobviousness de-
termination.” Minn. Mining & Mfg. Co. v. Johnson &
Johnson Orthopaedics, Inc., 976 F.2d 1559, 1575 (Fed.
Cir. 1992). These “real world considerations” include the
realities and challenges of discovering a new medicinal
product. The panel majority discards this principle in
concluding that the synergistic combination of metformin
and repaglinide would have been obvious to a person of
ordinary skill.
The question is not whether it would have been obvi-
ous to look for synergistic combinations; the question is
whether it was obvious that the combination of metformin
and repaglinide would exhibit synergism and that the
combination would be 800% more effective than the
additive effect of the components separately.
My colleagues reason that because synergism is un-
predictable, then if it is found, it is obvious. Maj. Op. at 8.
(“It was apparently well-known in the art that two drugs
having different mechanisms for attacking diabetes may
be more effective than one, and so drugs were often tested
in combination.”). That is not the meaning of “obvious to
try.” A new composition is “obvious to try” when it is
reasonable to expect that the trial will produce a predict-
NOVO NORDISK A/S v. CARACO PHARMACEUTICAL 3
able result. See KSR Int’l Co. v. Teleflex Inc., 550 U.S.
398, 421 (2007) (“[T]he fact that a combination was obvi-
ous to try might show that it was obvious under § 103” if,
among other things, “there are a finite number of identi-
fied, predictable solutions”). That situation did not here
exist. See Eisai Co. v. Dr. Reddy’s Labs., Ltd., 533 F.3d
1353, 1359 (Fed. Cir. 2008) (“To the extent an art is
unpredictable, as the chemical arts often are, KSR’s focus
on these ‘identified, predictable solutions’ may present a
difficult hurdle because potential solutions are less likely
to be genuinely predictable.”).
It was known that a combination of metformin and a
sulfonylurea—a class of compounds that does not include
repaglinide—may or may not have a synergistic effect on
blood sugar control, for only some sulfonylureas showed
such effect. Repaglinide is not chemically similar to the
sulfonylureas. It was known at the time of Novo’s inven-
tion that repaglinide “differs from the sulfonylureas in its
molecular structure, profile of action, and excretion mech-
anism.” B.H.R. Wolffenbuttel et al., Effects of a new oral
hypoglycaemic agent, repaglinide, on metabolic control in
sulphonylurea-treated patients with NIDDM, Eur. J. Clin.
Pharmacol. 45, 1993, at 113. The existence of synergy in
some metformin-sulfonylurea combinations is not predic-
tive of synergy in the combination of metformin with
repaglinide.
The defendants deposed the inventors, who explained
their thought processes in experimenting with this com-
bination. The district court, and now my colleagues on
this panel, cite the testimony of the inventors, who suc-
cessfully pursued this unpromising combination, and hold
that since the inventors pursued this combination and
found the observed synergism, the synergism was obvious.
The court uses the inventors’ exceptional intellect against
them, rather than the knowledge of the person of ordinary
skill.
4 NOVO NORDISK A/S v. CARACO PHARMACEUTICAL
The district court held that since these inventors pur-
sued this combination, it was obvious to do so. The court
stated that the PTO examiner, in granting the patent on
the basis of unpredictable synergy, “did not have the
benefit of the testimony of Müller [the inventor] and
Damsbo [his colleague] as to the results they expected.”
Novo Nordisk A/S v. Caraco Pharm. Labs., 775 F. Supp.
2d 985, 1009 (E.D. Mich. 2011). This is a misunderstand-
ing of the law, for “[o]bviousness may not be established
using hindsight or in view of the teachings or suggestions
of the inventor.” Para-Ordnance Mfg., Inc. v. SGS Im-
porters Int’l, Inc., 73 F.3d 1085, 1087 (Fed. Cir. 1995); see
Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1296
(Fed. Cir. 2012) (“The inventor’s own path itself never
leads to a conclusion of obviousness; that is hindsight.
What matters is the path that the person of ordinary skill
in the art would have followed.”).
My colleagues adopt the district court’s reasoning, ig-
noring the wisdom counseled by precedent. My colleagues
appear to hold that because these Novo scientists studied
this combination, it was obvious to try this combination.
Such a thesis would expunge patentability for all except
random observations. All scientific experiments are
conducted with a purpose of inquiry, and all experiment-
ers have a theory of possible outcomes. Such experiments
may partake of varying degrees of vision, hope, or expec-
tation on the part of the experimenter, but these are not
criteria of patentability.
Patentability is determined not from the position of
the inventor, but from the knowledge of the person of
ordinary skill. See Standard Oil Co. v. Am. Cyanamid
Co., 774 F.2d 448, 454 (Fed. Cir. 1985) (“Inventors, as a
class, according to the concepts underlying the Constitu-
tion and the statutes that have created the patent system,
possess something . . . which sets them apart from the
workers of ordinary skill, and one should not go about
determining obviousness under § 103 by inquiring into
NOVO NORDISK A/S v. CARACO PHARMACEUTICAL 5
what patentees (i.e., inventors) would have known or
would likely have done.”) (emphases in original).
For questions of biological synergism, predictability is
notoriously difficult. In re Luvisi, 342 F.2d 102, 109–10
(CCPA 1965) (“We do not accept the notion that every
suggestion of synergism in the art coupled with a finding
of synergism in the practice of the invention automatical-
ly compels a conclusion of obviousness . . . . [S]ome prior
art compositions may show little synergism and others
show considerable synergistic effects, with the net result
that predictability is impossible save the fact that a
synergistic result of some kind will probably be found.”);
see also Allergan, Inc. v. Sandoz, Inc., ___ F.3d ___, No.
2011-1619, 2013 WL 1810852, at *7 (Fed. Cir. May 1,
2013) (holding combination unobvious because there is
“no reason why the success of unrelated drugs would
make it obvious to one of ordinary skill that a fixed com-
bination of brimonidine and timolol could be dosed twice
per day without loss of efficacy”). My colleagues contra-
vene precedent, and hold that because some synergism
has been observed in some combinations with metformin,
any discovery of a unique synergistic combination with
unusual properties would have been obvious.
The PTO granted this patent based on the synergistic
effect that these inventors discovered and established.
This activity was not suggested in the prior art, was not
predictable, and was not obvious. The court errs in hold-
ing otherwise.
A. The Evidence
There was evidence at trial that repaglinide was not
successful as an antidiabetic drug:
Most companies believed that there was no com-
mercial use or value for repaglinide given its
pharmacodynamic profile when compared to long-
er-acting sulfonylureas already on the market or
6 NOVO NORDISK A/S v. CARACO PHARMACEUTICAL
other antidiabetics in development. More general-
ly, no one was willing to go to the expense of doing
clinical trials for regulatory approval if the drug
had no commercial value.
Trial Tr. vol. 9, 14, Aug. 9, 2010 (testimony of Dr. Michael
Mark, Novo scientist who conducted research on rep-
aglinide).
Dr. Peter Müller, the inventor of the patent in suit,
pressed for clinical trials despite the skepticism of the
clinical investigators. Dr. John Miller, Medical Director
of Novo in Australia, who coordinated and supervised the
Australian study, testified as follows:
Given that repaglinide was such a short-acting
compound that had no effect on FPG [fasting
plasma glucose], the investigators tried to explain
to the clinical development staff that it made no
sense to use fasting glucose as a measurement
[because FPG measures] the amount of glucose in
blood plasma after the patient has not eaten for
about eight hours (i.e., overnight).
Trial Tr. vol. 8, 121–22, Aug. 5, 2010.
The Australian study was conducted with patients
with poorly controlled diabetes, who were treated with
metformin alone, repaglinide alone, or a combination of
metformin and repaglinide. ’358 patent col.7 l.61 – col.10
l.40. The patients receiving the combination exhibited
markedly better control of blood sugar than either the
patients on metformin monotherapy or those on rep-
aglinide monotherapy. Id. col.9 ll.37–58. The claimed
drug combination’s ability to control blood sugar, accord-
ing to fasting plasma glucose (FPG) and glycosylated
hemoglobin (HbA1c) measurements, was substantially
better than the additive effects of metformin and rep-
aglinide. Id. For example, the combination lowered FPG
by 2.18 mmol/l, which was over eight times the efficacy
NOVO NORDISK A/S v. CARACO PHARMACEUTICAL 7
observed in patients on metformin alone (0.25 mmol/l).
Id. col.9 ll.45–58. Repaglinide monotherapy actually
increased the patients’ FPG levels by 0.49 mmol/l, con-
tributing to the problem instead of curing it. Id.Novo scientists were concerned that the Australian
study did not prove synergy to a statistical certainty
because the study lacked a placebo group. The district
court understood that “ethical reasons precluded remov-
ing the sick patients from all therapy.” Novo, 775 F.
Supp. 2d at 1010. When the patent examiner criticized
Novo’s quantification of synergy, Novo conducted the rat
study to include untreated controls; the results showed a
statistically significant synergistic effect between met-
formin and repaglinide, corroborating the results of the
Australian human study.
The PTO issued the ’358 patent on the basis of these
studies, stating that “[t]he combined administration of
repaglinide and metformin resulted in an unexpected
synergistic effect on blood glucose levels.” ’358 patent
“Reasons for Allowance” (May 31, 2003). See Quad Envtl.
Techs. Corp. v. Union Sanitary Dist., 946 F.2d 870, 876
(Fed. Cir. 1991) (“[C]ourts may take cognizance of, and
benefit from, the proceedings before the patent examiner,”
although “the question [of validity] is ultimately for the
courts to decide, without deference to the rulings of the
patent examiner”).
The record shows that defendant Sun Pharmaceutical
Industries1 advertises its repaglinide product as synergis-
tic when combined with metformin:
1 Sun is the corporate parent of codefendant Caraco
Pharmaceutical Laboratories.
8 NOVO NORDISK A/S v. CARACO PHARMACEUTICAL
Repaglinide in combination with metformin . . .,
 Produced a greater improvement in glycemic
control than that seen by the sum of the
changes with the two agents alone.
Undated Advertisement for Rapilin, Sun’s Repaglinide
Product. This is the benefit that Sun told the district
court did not exist. This benefit was unknown until
discovered by Novo scientists, and unavailable to public
benefit until federally approved at Novo’s initiative and
expense.
B. Analysis
My colleagues misunderstand and misapply the “obvi-
ous to try” criterion of obviousness. The motivation to
develop a new pharmaceutical “is not abstract, but practi-
cal, and is always related to the properties or uses one
skilled in the art would expect the compound to have, if
made.” In re Gyurik, 596 F.2d 1012, 1018 (CCPA 1979).
This expectation must be rooted in the prior art and in
the person of ordinary skill, not in the ingenuity or crea-
tivity of the inventor.
The district court reasoned that since metformin was
known to form synergistic combinations with some sul-
fonylureas, it would be obvious to expect synergism of
metformin and repaglinide, for although repaglinide is
not a sulfonylurea, it was believed to have a similar
mechanism of action as a secretagogue. This analysis is
supported only by hindsight, for the record reflects a more
complicated reality. It was known that synergy is not
exhibited by all sulfonylurea secretagogues, and the
district court agreed that one skilled in the art would
“perhaps” have expected synergistic results from the
metformin-repaglinide combination. “Perhaps” is not
clear and convincing evidence of obviousness of the unu-
sually efficacious results that were obtained. See Mi-
NOVO NORDISK A/S v. CARACO PHARMACEUTICAL 9
crosoft Corp. v. i4i Ltd. P’ship, 131 S. Ct. 2238, 2242
(2011) (holding that invalidity must be proved by clear
and convincing evidence).
The panel majority offers the generalization that “ear-
lier metformin/sulfonylurea combinations were generally
understood to yield synergy.” Maj. Op. at 14. This is
inaccurate, for only some sulfonylureas formed synergistic
combinations. Synergism was not a general property of
such combinations. The particular metformin-
sulfonylurea combination relied on by the district court to
invalidate the ’358 patent is metformin-glyburide.2 The
district court observed that both glyburide and rep-
aglinide are “insulin secretagogues” because they stimu-
late the secretion of insulin. Indeed, this is how most
diabetes treatments work. However, it was well-known
that not all insulin stimulants form synergistic combina-
tions with metformin.
There are significant differences between glyburide
and repaglinide, in structure and in properties. The
compounds are structurally quite different:
Glyburide
2 Glyburide is also known as glibenclamide.
10 NOVO NORDISK A/S v. CARACO PHARMACEUTICAL
Repaglinide
Glyburide is “long-acting,” having a biological half-life of
between ten and twenty hours. Repaglinide is “short-
acting,” with a half-life of about one hour. The record
repeatedly states that the short life of repaglinide de-
terred interest in this compound for treatment of diabetes.
The only prior art of record comparing repaglinide to
glyburide, the 1993 Wolffenbuttel article cited supra,
described the dissimilar effects of the two drugs on blood
sugar control in diabetics:
After 12 weeks glibenclamide [glyburide] had re-
duced fasting blood glucose levels without any ef-
fect on postprandial blood glucose, whereas
repaglinide had significantly lowered postprandial
blood glucose, but with no effect on fasting blood
glucose.
Eur. J. Clin. Pharmacol. 45, at 115. This observation was
explained by repaglinide’s “mode of action and short
plasma half-life.” Id.
Caraco’s expert Dr. Accili conceded at trial that rep-
aglinide would have been expected to have “at best a
small impact on fasting plasma glucose.” Trial Tr. vol. 4,
52–53, June 7, 2010. This is in contrast to long-acting
sulfonylureas such as glyburide, which were known to
reduce fasting plasma glucose even absent combination
with metformin.
NOVO NORDISK A/S v. CARACO PHARMACEUTICAL 11
The structural and functional disparities between
repaglinide and glyburide render it unreasonable to
expect the repaglinide-metformin combination to have
synergistic properties superior to the prior art combina-
tion of glyburide and metformin. See In re Lalu, 747 F.2d
703, 707 (Fed. Cir. 1984) (“[A] relevant property of a
compound cannot be ignored in the determination of non-
obviousness.”). As Dr. Accili acknowledged, “[a]ny time
multiple things are used [in combination therapy], the
potential for error increases.” Trial Tr. vol. 3, 37, June 3,
2010.
The district court did not address the known differ-
ences between repaglinide and the sulfonylureas, includ-
ing glyburide. The court did not mention the
Wolffenbuttel article, although it was the only reference
to compare repaglinide and a sulfonylurea. In the search
for scientific truth “[o]ne cannot . . . pick and choose
among isolated disclosures in the prior art to deprecate
the claimed invention.” In re Fine, 837 F.2d 1071, 1075
(Fed. Cir. 1988); it is necessary to consider prior art that
supports unobviousness of the claimed invention, as well
as that which weighs against it. In re Young, 927 F.2d
588, 591 (Fed. Cir. 1991).
The district court’s obviousness determination was
based on the court’s finding that two prior art studies on
the metformin-glyburide combination “reported greater
reductions in HbA1c and FPG than those of the [Australi-
an] Study.” The district court stated that these studies
represented the “closest prior art,” and invalidated the
’358 patent because “[t]he evidence does not establish that
the claimed combination therapy produces clinical results
superior to those produced by the closest prior art.” Novo,
775 F. Supp. 2d at 1011–12. That is, the district court
held that because the metformin-glyburide combination
appeared to control diabetes as well as the metformin-
repaglinide combination, the patent was invalid for obvi-
ousness. That is not the law of obviousness. See In re
12 NOVO NORDISK A/S v. CARACO PHARMACEUTICAL
Chupp, 816 F.2d 643, 646 (Fed. Cir. 1987) (“To be patent-
able, a compound need not excel over prior art compounds
in all common properties.”). Further, the district court
did not discuss the evidence of effectiveness in difficult-to-
treat cases of Type II diabetes, or other differences that
were not predictable from prior art.
The question is whether it would have been obvious
that this particular combination would produce results
superior to the additive effect of the components separate-
ly. It was not shown that because glyburide was an
effective synergist, the different compound repaglinide
would be expected to be an effective synergist.
The expert witnesses for both sides testified as to the
uncertainties of predicting synergistic action. It was not
shown that the prior art metformin-glyburide combina-
tion predicted the claimed invention, for the differences
between glyburide and repaglinide were well-recognized.
Glyburide is one of the longer-acting sulfonylureas, a poor
comparator for short-acting repaglinide. A more reasona-
ble analysis would consider metformin in combination
with nateglinide, which is structurally similar to rep-
aglinide, or a shorter-acting sulfonylurea such as glipiz-
ide.
My colleagues state that “the prior art taught that
metformin could be combined with certain sulfonylureas
which were, like repaglinide, short-acting secretagogues.”
Maj. Op. at 15. However, the record discussing these
short-acting sulfonylurea combinations does not state that
their synergy with metformin was known or existed. The
“closest prior art” is the reference having the most “in
common” with the claimed invention, not the reference
that happens to describe the most impressive results. In
re Merchant, 575 F.2d 865, 868–69 (CCPA 1978); see KSR,
550 U.S. at 421 (“A factfinder should be aware, of course,
of the distortion caused by hindsight bias and must be
cautious of arguments reliant upon ex post reasoning.”).
NOVO NORDISK A/S v. CARACO PHARMACEUTICAL 13
The purpose of our patent system is a practical one:
“To promote the Progress of Science and useful Arts.”
U.S. Const. art. I, §8, cl. 8. Consistent with this “constitu-
tional command,” Graham v. John Deere Co., 383 U.S. 1, 6
(1966), the Supreme Court, and this court, have recog-
nized that the statutory requirement of non-obviousness
is a “practical test of patentability,” id. at 17. Section 103
must be “followed realistically,” id., if the law is to sup-
port innovation as it is manifested in the pragmatic world
of technologic advance and commercial investment. See
KSR, 550 U.S. at 415 (summarizing the Court’s “function-
al approach” to obviousness); In re Kahn, 441 F.3d 977,
986 (Fed. Cir. 2006) (in enacting §103, Congress created
“a more practical . . . test for patentability”); Rosemount,
Inc. v. Beckman Instruments, Inc., 727 F.2d 1540, 1546
(Fed. Cir. 1984) (“the facts of real-world experience”
inform the obviousness analysis); In re Lunsford, 357 F.2d
385, 391–92 (CCPA 1966) (“The provisions of section 103
must be followed realistically to develop the factual
background against which the section 103 determination
must be made.”).
The synergy demonstrated by Novo for the metformin-
repaglinide combination therapy was not predicted or
predictable, and was not obvious.
C. Claim Scope
The district court faulted the Australian study as too
narrow to support claims that state that the metformin-
repaglinide combination is administered “to a patient in
need,” a broader class of diabetics than patients whose
diabetes is poorly controlled on metformin monotherapy.
The district court stated that “Novo presented no evidence
that the claimed combination therapy produced unex-
14 NOVO NORDISK A/S v. CARACO PHARMACEUTICAL
pected or synergistic results in drug-naïve patients.”3 The
court concluded that the Australian clinical study and Dr.
Sturis’ rat study were not probative of synergy “in ‘all
instances.’” Novo, 775 F. Supp. 2d at 1015–17.
Novo’s experimentation was objective and substantial.
The Australian study was conducted with over eighty
persons whose diabetes was poorly controlled on metfor-
min alone, and thus were not “drug naïve.” Diabetes is
typically treated with a single drug first; if monotherapy
does not work, or stops working after a period of time,
combination therapy is prescribed. It was reasonable for
Novo to test the metformin-repaglinide combination on
patients who responded poorly to metformin monothera-
py.
Dr. Sturis’ rat study corroborated the observed syner-
gism. The district court acknowledged that the Zucker
obese rats studied by Dr. Sturis “are an accepted animal
model with excellent predictive capabilities for humans
with Type II diabetes.” Novo, 775 F. Supp. 2d at 1013.
Novo “demonstrate[d] that an embodiment has an unex-
pected result and provide[d] an adequate basis to support
the conclusion that other embodiments falling within the
claim will behave in the same manner, [which] will gen-
erally establish that the evidence is commensurate with
[the] scope of the claims.” In re Kao, 639 F.3d 1057, 1068
(Fed. Cir. 2011).
The Australian study tested, and demonstrated, the
efficacy of the metformin-repaglinide combination in a
patient population with difficult-to-control Type II diabe-
tes, those who would most benefit from the combination.
It was not necessary for Novo to prove synergy in patients
for whom combination therapy is not needed, in order to
3 In this context, “drug naïve” refers to a person
whose diabetes has not yet been treated pharmaceutical-
ly.
NOVO NORDISK A/S v. CARACO PHARMACEUTICAL 15
claim administering the combination of metformin and
repaglinide to “a patient in need.” See In re Chupp, 816
F.2d at 646 (to be patentable, a compound need not “pro-
duce superior results in every environment in which the
compound may be used”); In re Kao, 639 F.3d at 1068 (a
patentee is not obligated “to test every embodiment
within the scope of the claims”).
From my colleagues’ erroneous view of the evidence
and incorrect application of the law of obviousness, I
respectfully dissent.