United States Court of Appeals
for the Federal Circuit
__________________________
DAIICHI SANKYO COMPANY, LTD.,
AND DAIICHI SANKYO, INC.,
Plaintiffs/Counterclaim
Defendant-Appellees,
v.
MATRIX LABORATORIES, LTD., MYLAN INC.,
MYLAN LABORATORIES, INC., AND MYLAN
PHARMACEUTICALS, INC.,
Defendants-Counterclaimant-Appellants.
__________________________
2009-1511
__________________________
Appeal from the United States District Court for the
District of New Jersey in Case No. 06-CV-03462, Judge
William J. Martini.
____________________________
Decided: September 9, 2010
____________________________
DOMINICK A. CONDE, Fitzpatrick, Cella, Harper &
Scinto, of New York, New York, argued for plain-
tiffs/counterclaim defendant-appellees. With him on the
brief were LISA B. PENSABENE and JOSHUA I. ROTHMAN.
Of counsel on the brief were HENRY B. GUTMAN, ROBERT
DAIICHI SANKYO CO v. MYLAN PHARMA 2
A. BOURQUE and NOAH M. LEIBOWITZ, Simpson Thacher &
Bartlett LLP, of New York, New York.
ROBERT L. BYER, Duane Morris LLP, of Pittsburgh,
Pennsylvania, argued for defendants/counterclaimant-
appellants. Of counsel on the brief were SHANNON M.
BLOODWORTH, Perkins Coie LLP, of Washington, DC, and
DAVID J. HARTH, The Law Office of David J. Harth, of
Madison, Wisconsin. Of counsel was DAN L. BAGATELL,
Perkins Coie Brown & Bain P.A., of Phoenix, Arizona.
__________________________
Before LOURIE, FRIEDMAN, and LINN, Circuit Judges.
LOURIE, Circuit Judge.
Matrix Laboratories, Ltd., Mylan Inc., Mylan Labora-
tories, Inc., and Mylan Pharmaceuticals, Inc. (collectively,
“Mylan”) appeal from the final decision of the United
States District Court for the District of New Jersey sus-
taining the validity of U.S. Patent 5,616,599 (“the ’599
patent”) under 35 U.S.C. § 103. We affirm.
BACKGROUND
I.
Daiichi Sankyo Company, Ltd. and Daiichi Sankyo,
Inc. (collectively, “Daiichi”) own the ’599 patent, which
claims 1-biphenylmethylimidazole compounds and their
use as angiotensin receptor blockers (“ARBs”) for the
treatment of high blood pressure. Claim 13 of the ’599
patent covers the chemical compound olmesartan me-
doxomil, an ARB approved by the Food and Drug Admini-
stration (“FDA”) and commercialized by Daiichi as the
active ingredient in Benicar®, Benicar HCT®, and Azor®.
The invention of olmesartan medoxomil as an effec-
tive ARB built on years of research beginning in the
3 DAIICHI SANKYO CO v. MYLAN PHARMA
1970s, when scientists first came to appreciate the role of
the angiotensin protein in controlling blood pressure. The
first non-protein, small molecule ARBs were developed in
the late 1970s and early 1980s by the Japanese pharma-
ceutical company Takeda Pharmaceutical Co. Ltd. (“Ta-
keda”). These compounds each comprised an imidazole
ring—a five-membered ring of the formula C3H4N2—to
which other chemical moieties were bonded at the 1-5-
positions of the ring. One Takeda compound, S-8307,
possessed a chlorophenyl group bonded through a methyl-
ene group at the 1-position, a butyl group (-C4H9) at the 2-
position, a chlorine atom (-Cl) at the 4-position, and an
acetic acid moiety (-CH2COOH) at the 5-position. The
chemical structure of S-8307 is pictured below with the
ring’s 1-position nitrogen positioned at the bottom of the
ring.
The Takeda compounds, however, bound only weakly
to the angiotensin receptor and thus were of little thera-
peutic value. Nevertheless, using Takeda’s compounds as
leads, scientists at E. I. du Pont de Nemours and Com-
pany (“DuPont”) embarked on their own ARB research
program with the aim of developing new compounds with
DAIICHI SANKYO CO v. MYLAN PHARMA 4
increased receptor-binding activity. DuPont’s research
led to the discovery of the first orally active ARB, known
as losartan, which exhibited ten-fold greater binding
affinity than the Takeda compounds. To obtain losartan,
DuPont modified Takeda’s S-8307 at the 1- and 5-
positions of the imidazole ring: At the 1-position, DuPont
added a second phenyl group with a tetrazole group
attached, generating a biphenyltetrazole substituent. At
the 5-position, DuPont replaced the acetic acid group with
a hydroxymethyl group (-CH2OH), which is metabolized to
a carboxylic acid (-COOH) in the body. The chemical
structure of losartan is depicted below.
DuPont disclosed losartan in U.S. Patent 5,138,069
(“the ’069 patent”) along with more than four hundred
structurally related ARBs. The ’069 patent also discloses
binding affinity data, measured as IC50 values, 1 for over
two hundred compounds, including forty-two in losartan’s
biphenyltetrazole series. Chemists were able to use the
1 The half maximal inhibitory concentration, or
IC50, represents the concentration of an inhibitor that is
required for 50% inhibition of its target, and thus the
effectiveness of an inhibitor. More specifically, a lower
IC50 indicates a higher affinity binding.
5 DAIICHI SANKYO CO v. MYLAN PHARMA
data disclosed in the ’069 patent to uncover correlations
between the compounds’ structures and their binding
affinities, called “structural-activity relationships”
(“SARs”), which they could then use to guide the develop-
ment of even more potent ARBs. For example, if the
presence of a certain chemical moiety or type of chemical
moiety at a given position correlates with an increase in
binding affinity, chemists could attempt to use that
chemical moiety or type of moiety in the next generation
of ARBs, and they did.
Following losartan’s success, over twenty different
pharmaceutical companies, including Daiichi, established
research programs to develop the next generation of
ARBs. Daiichi’s program resulted in the synthesis of
olmesartan, the active metabolite of olmesartan me-
doxomil. Like losartan, olmesartan consists of an imida-
zole ring containing a biphenyltetrazole substituent at the
1-position and an alkyl group (propyl rather than butyl)
at the 2-position. At the 4-position, however, olmesartan
replaced losartan’s lipophilic, or fat-loving, chlorine atom
with its opposite, a hydrophilic, or water-loving, hydroxy-
isopropyl group (-C(CH3)2OH). 2 Of the compounds dis-
closed in DuPont’s ’069 patent, the vast majority contain a
lipophilic group at the ring’s 4-position. One compound
with a hydrophilic group is losartan’s regioisomer, 3 Ex-
ample 118, in which the 4- and 5-positions on the imida-
2 When one speaks of replacing one group with an-
other, it is understood that the “replacement” is not
accomplished merely by writing it on paper and that an
actual change from one group to another more often
occurs by a new synthesis using different starting materi-
als, i.e., a chlorine atom is not directly replaced with a
hydroxyisopropyl group.
3 A regioisomer of another compound is one in
which substituents around a ring are the same, but varied
in position.
DAIICHI SANKYO CO v. MYLAN PHARMA 6
zole ring are reversed. The transposition results in a
compound with a chlorine atom at the 5-position and a
hydrophilic hydroxymethyl group (-CH2OH) at the 4-
position, as shown below.
Olmesartan medoxomil also differs from losartan at
the 5-position. Daiichi replaced losartan’s hydroxymethyl
group with a carboxy group masked by a medoxomil
prodrug substituent to improve oral absorption. Like the
hydroxymethyl group, the medoxomil moiety is metabo-
lized to the carboxylic acid in the body. The structures of
olmesartan medoxomil and olmesartan are depicted
below.
7 DAIICHI SANKYO CO v. MYLAN PHARMA
Other second-generation ARBs, all prior art to olme-
sartan medoxomil, include DuPont’s DuP 532, in which
losartan’s chlorine at the 4-position is replaced with
multiple lipophilic fluorine atoms (-C2F5), and six com-
pounds disclosed in DuPont’s U.S. Patent 5,137,902 (“the
’902 patent”), each of which has a more lipophilic alkyl
group at the 4-position. The ARBs disclosed in DuPont’s
’902 patent (“the ’902 compounds” or “the ’902 ARBs”) are
the closest structurally to olmesartan, with Example 6
differing from olmesartan by only a single oxygen atom at
the 4-position, as depicted below
DAIICHI SANKYO CO v. MYLAN PHARMA 8
Other second-generation ARBs differ more significantly
from losartan by not containing an imidazole ring, includ-
ing Merck & Co., Inc.’s L-158,809 compound, Ciba-Geigy
Corp.’s valsartan, and Eisai Inc.’s E-4177 compound.
II.
Mylan filed multiple Abbreviated New Drug Applica-
tions (“ANDAs”) with Paragraph IV certifications under
the Hatch-Waxman Act, 21 U.S.C. § 355, challenging the
’599 patent and seeking FDA approval to manufacture
generic olmesartan medoxomil in various dosages and
combinations. Daiichi responded by filing suit against
Mylan for patent infringement in the United States
District Court for the District of New Jersey. The parties
stipulated to infringement of claim 13, leaving only My-
lan’s counterclaim that claim 13 would have been obvious
in light of (1) the second-generation ARBs in DuPont’s
’902 patent, which Mylan alleged one of skill in the art
would have been motivated to select as lead compounds;
(2) Example 118, losartan’s regioisomer, in DuPont’s ’069
patent, which Mylan alleged would have motivated one of
skill in the art to modify the ’902 compounds’ lipophilic
alkyl groups at the 4-position with olmesartan’s hydro-
9 DAIICHI SANKYO CO v. MYLAN PHARMA
philic hydroxyalkyl group; and (3) the well-known use of
medoxomil as a prodrug.
After a ten-day bench trial, the district court held, in
a comprehensive and well-reasoned opinion, that claim 13
of the ’599 patent was not invalid as obvious. Daiichi
Sankyo Co., Ltd. v. Mylan Pharms. Inc., 670 F. Supp. 2d
359 (D.N.J. 2009). The court determined that Mylan had
failed to show by clear and convincing evidence that one
skilled in the art would have chosen the ’902 ARBs as
lead compounds over other better-studied ARBs with
greater potency and thus had failed to establish a prima
facie case of obviousness. Id. at 376-77. The district court
went on to find that, even assuming that Mylan had
shown the ’902 ARBs to be leads, the structure of the ’902
compounds differed significantly from olmesartan me-
doxomil, id. at 377-78, and that, even assuming structural
similarity, Mylan had failed to prove that one of skill in
the art would have been motivated to modify the 4- and 5-
positions of the ’902 ARBs to obtain olmesartan me-
doxomil, id. at 378-81. Regarding the 4-position, the court
found that the emphasis on lipophilicity in both the ’069
patent and the second-generation ARBs taught away from
the use of a hydrophilic group at the 4-position and from
any expectation that the use of a hydrophilic group would
generate an ARB with significantly improved biological
properties. Id. at 370-75, 378-80. Regarding the 5-
position, the court found that converting olmesartan into
a prodrug was a disfavored and unpredictable approach
and that medoxomil was a disfavored prodrug. Id. at 380.
Finally, the district court concluded that even if My-
lan had established a prima facie case of obviousness,
secondary considerations counseled against a finding of
obviousness. Id. at 381. Specifically, the court found
evidence of unexpected results in olmesartan medoxomil’s
enhanced potency and other favorable biological proper-
DAIICHI SANKYO CO v. MYLAN PHARMA 10
ties. Id. at 382-84. The court also found evidence of
commercial success based on the significant market
penetration of Benicar® despite being the seventh ARB on
the market and despite Daiichi spending roughly the
same amount in marketing as its competitors. Id. at 384-
86.
On August 6, 2009, the district court entered final
judgment and permanently enjoined Mylan’s commer-
cialization of olmesartan medoxomil until the expiration
of the ’599 patent. Mylan appealed. We have jurisdiction
pursuant to 19 U.S.C. § 1295(a)(1).
DISCUSSION
Under the Patent Act, “[a] patent may not be ob-
tained . . . if the differences between the subject matter
sought to be patented and the prior art are such that the
subject matter as a whole would have been obvious at the
time the invention was made to a person having ordinary
skill in the art to which said subject matter pertains.”
35 U.S.C. § 103(a). While the ultimate determination of
obviousness under § 103 is a question of law, it is based
on several underlying factual findings, including (1) the
scope and content of the prior art; (2) the level of ordinary
skill in the pertinent art; (3) the differences between the
claimed invention and the prior art; and (4) evidence of
secondary factors, such as commercial success, long-felt
need, and the failure of others. Graham v. John Deere
Co., 383 U.S. 1, 17-18 (1966). After a bench trial, we
review the district court’s conclusions of law de novo and
findings of fact for clear error. Golden Blount, Inc. v.
Robert H. Peterson Co., 365 F.3d 1054, 1058 (Fed. Cir.
2004). A factual finding is clearly erroneous if, despite
some supporting evidence, a reviewing court is left with
the definite and firm conviction that a mistake has been
11 DAIICHI SANKYO CO v. MYLAN PHARMA
made. United States v. U.S. Gypsum Co., 333 U.S. 364,
395 (1948).
When a patent claims a chemical compound, a prima
facie case of obviousness under the third Graham factor
frequently turns on the structural similarities and differ-
ences between the compounds claimed and those in the
prior art. In re Dillon, 919 F.2d 688, 692 (Fed. Cir. 1990)
(en banc) (“This court . . . reaffirms that structural simi-
larity between claimed and prior art subject matter,
proved by combining references or otherwise, where the
prior art gives reason or motivation to make the claimed
compositions, creates a prima facie case of obviousness.”);
see also Eisai Co. Ltd. v. Dr. Reddy’s Labs., Ltd., 533 F.3d
1353, 1356-57 (Fed. Cir. 2008). Proof of obviousness
based on structural similarity requires clear and convinc-
ing evidence that a medicinal chemist of ordinary skill
would have been motivated to select and then to modify a
prior art compound (e.g., a lead compound) to arrive at a
claimed compound with a reasonable expectation that the
new compound would have similar or improved properties
compared with the old. Eisai, 533 F.3d at 1357; Takeda
Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d
1350, 1356 (Fed. Cir. 2007). In keeping with the flexible
nature of the inquiry after KSR International Co. v.
Teleflex Inc., 550 U.S. 398 (2007), the motivation to select
and modify a lead compound need not be explicit in the
art. Eisai, 533 F.3d at 1357; Takeda, 492 F.3d at 1356-57.
Mylan challenges, as it must to prevail, every step in
the district court’s decision holding that Mylan failed to
establish its prima facie case that olmesartan medoxomil
would have been obvious in light of the prior art. Specifi-
cally, Mylan challenges the district court’s finding that
one of skill in the art would not have selected the six
ARBs in DuPont’s ’902 patent as lead compounds, point-
ing to evidence that the ’902 compounds are undisputedly
DAIICHI SANKYO CO v. MYLAN PHARMA 12
the closest prior art. Mylan also challenges the court’s
finding that the ’902 ARBs are not structurally similar to
olmesartan medoxomil, arguing that one of the ’902
compounds differs from olmesartan by only a single
oxygen atom. Mylan also argues that the district court
erred in finding no motivation to modify the ’902 com-
pounds at the 4- and 5-positions to arrive at olmesartan
medoxomil when the ’069 patent specifically taught a
compound with a hydroxyalkyl group at the 4-position
and the art taught medoxomil as a well-known prodrug
for improving oral activity. Finally, Mylan contends that,
contrary to the district court’s finding, one of skill in the
art would have had a reasonable expectation that modify-
ing the ’902 compounds to obtain olmesartan medoxomil
would result in a similarly effective ARB.
In response, Daiichi defends the factual findings un-
derlying the district court’s determination that claim 13 of
the ’599 patent was not invalid as obvious. Daiichi first
argues that the district court correctly found that one of
skill in the art would not have been motivated to select
the ’902 ARBs as lead compounds over other more potent
and better-studied prior art ARBs. Daiichi next asserts
that the district court correctly found no motivation to
modify the ’902 compounds to create olmesartan me-
doxomil based on the lack of structural similarity between
the ’902 ARBs and olmesartan medoxomil, the existence
of thousands of possible modifications, the illogic of select-
ing the ’902 compounds as leads only to reject their dis-
tinguishing characteristic of increased lipophilicity at the
4-position, the fact that the prior art taught away from
such an alteration at the 4-position, and the unpredict-
ability associated with the use of a prodrug in general and
medoxomil in particular. Finally, according to Daiichi,
the district court correctly found no reasonable expecta-
13 DAIICHI SANKYO CO v. MYLAN PHARMA
tion that the proposed modifications would lead to an
ARB with significantly improved activity over losartan.
We agree with Daiichi that the district court did not
err in holding that Mylan failed to establish a prima facie
case of obviousness. Specifically, we agree that Mylan
failed to show that one of ordinary skill in the art would
have been motivated to select the ’902 ARBs as lead
compounds or, even if they had, that the skilled artisan
would have been motivated to modify the ’902 compounds
to synthesize olmesartan medoxomil, the claimed inven-
tion. We address each in turn.
I. Selection of a Lead Compound
In rejecting the ’902 ARBs as lead compounds, the
district court accepted as true all of Mylan’s evidence on
the ’902 compounds, including that they represented a
continuation of DuPont’s work on the ARBs disclosed in
the ’069 patent, including losartan, and thus could take
advantage of the ’069 patent’s SAR data, and that the
preferred ’902 compounds “exhibit[ed] remarkable and
unexpected potency as antihypertensives” with “oral
antihypertensive activity approximately 2 to 4 fold higher
than the most active compounds [of the ’069 patent] which
have been tested.” Daiichi Sankyo, 670 F. Supp. 2d at
376 (alternations in original). Nevertheless, the court
found that a medicinal chemist of ordinary skill would not
have been motivated to select the ’902 compounds over
other second-generation ARBs, including L-158,809, DuP
532, the Eisai compounds, and valsartan, because many of
the latter ARBs demonstrated greater potency and all had
been more thoroughly studied than the ’902 ARBs. Spe-
cifically, the court found that L-158,809 had 180 times,
Example 7 of the Eisai compounds had 100 times, and
DuP 532 had seven times the potency of losartan. Id.
The court also found that while the ’902 patent disclosed
DAIICHI SANKYO CO v. MYLAN PHARMA 14
in vivo oral activity, the prior art included not only data
on oral activity for all but the Eisai compounds, but also
data on the binding affinity and intravenous activity for
L-158,809, the Eisai compounds, DuP 532, and valsartan
as well as selectivity data for L-158,809 and DuP 532. Id.
Finally, the court found that DuP 532, which shared
losartan’s imidazole-biphenyltetrazole backbone, could
also benefit from the ’069 patent’s SAR data. Id. We see
no clear error in the court’s findings.
Mylan argues that because the ’902 ARBs are undis-
putedly the closest prior art, that “should have been
dispositive of the lead compound issue.” Appellant Prin-
cipal Br. 25. That argument runs contrary to our case
law. In Takeda, we upheld a district court’s finding that
one of skill in the art would not have chosen the structur-
ally closest prior art compound, compound b, as the lead
compound in light of other compounds with more favor-
able characteristics. 492 F.3d at 1357-59. We reached
the same result in Eli Lilly & Co. v. Zenith Goldline
Pharmaceuticals, Inc., 471 F.3d 1369, 1377-79 (Fed. Cir.
2006). These cases illustrate that it is the possession of
promising useful properties in a lead compound that
motivates a chemist to make structurally similar com-
pounds. Yet the attribution of a compound as a lead
compound after the fact must avoid hindsight bias; it
must look at the state of the art at the time the invention
was made to find a motivation to select and then modify a
lead compound to arrive at the claimed invention. See
Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc., 520 F.3d
1358, 1364 (Fed. Cir. 2008). Accordingly, proving a rea-
son to select a compound as a lead compound depends on
more than just structural similarity, but also knowledge
in the art of the functional properties and limitations of
the prior art compounds. See Eli Lilly, 471 F.3d at 1377-
15 DAIICHI SANKYO CO v. MYLAN PHARMA
79. Potent and promising activity in the prior art trumps
mere structural relationships.
Mylan further faults the district court for not follow-
ing this court’s “clarification that a ‘lead compound’
analysis does not require identification of a single, best,
compound as a starting point” but “the prior art may
point to more than a ‘single lead compound for further
development efforts.’” Appellant Principal Br. 24 (quoting
Altana Pharma AG v. Teva Pharms. USA, Inc., 566 F.3d
999, 1008 (Fed. Cir. 2009)). But that misinterprets the
district court’s decision. As described above, the district
court selected multiple compounds as leads, just not the
compounds disclosed in the ’902 patent. Daiichi, 670 F.
Supp. 2d at 376. Contradicting itself, Mylan also faults
the district court for selecting only five potential leads
and for not including the ’902 compounds among that
finite number. While the lead compound analysis must,
in keeping with KSR, not rigidly focus on the selection of
a single, best lead compound, see Altana Pharma, 566
F.3d at 1008, the analysis still requires the challenger to
demonstrate by clear and convincing evidence that one of
ordinary skill in the art would have had a reason to select
a proposed lead compound or compounds over other
compounds in the prior art. Here, the district court did
not commit error, let alone clear error, in finding that
Mylan failed to meet that burden.
II. Motivation to Modify
The district court next found that, even accepting the
’902 compounds as lead compounds, one of skill in the art
would not have been motivated to modify the ARBs dis-
closed in the ’902 patent to obtain olmesartan medoxomil.
Specifically, the court found that the prior art as a whole
taught away from the use of a hydrophilic substitute at
the 4-position of the imidazole ring, relying on, inter alia,
DAIICHI SANKYO CO v. MYLAN PHARMA 16
the structural-activity relationship (“SAR”) data in the
’069 patent and the use of lipophilic groups at the 4-
position in other second-generation compounds, including
DuPont’s ’902 compounds. Daiichi, 670 F. Supp. 2d at
369-75. Accordingly, the district court also found that the
prior art provided no motivation to modify the ’902 com-
pounds’ lipophilic alkyls at the 4-position to the hydro-
philic hydroxyisopropyl group of olmesartan. Id. at 378-
80. Again we find no error in the district court’s findings.
The ’069 patent reveals a clear preference for lipo-
philic groups at the 4-position of the imidazole ring. The
vast majority of the ’069 compounds contain a lipophilic
group at this position, as do twenty-seven of the thirty
most active compounds, with two containing a neutral
group and only one, Example 342, containing a hydro-
philic group. J.A. 13717. This preference extends to the
forty-two compounds in losartan’s biphenyltetrazole
series. Again, the vast majority, thirty-six out of forty-
two compounds, have a lipophilic group at the 4-position
and only four compounds, Examples 342, 329, 118, and
335, have a hydrophilic group. Id. at 7715. The few
compounds with hydrophilic groups at the 4-position are
drowned out by the sea of 4-lipophilic compounds, which
are the essence of what the ’069 patent teaches.
Three subseries analyses comparing the binding affin-
ity of ’069 patent compounds that vary only at the imida-
zole ring’s 4-position confirm the preference for
lipophilicity at the 4-position. In the series of compounds
with a biphenyltetrazole substitutent at the 1-position, a
propyl group at the 2-position, and a hydroxymethyl
group at the 5-position (1) three out of four compounds
with a lipophilic group at the 4-position exhibit higher
affinity binding, measured as a lower IC50, than Example
334 with a neutral group, and (2) all four compounds with
a lipophilic group exhibit higher affinity binding than
17 DAIICHI SANKYO CO v. MYLAN PHARMA
Example 335 with a hydrophilic group. Specifically,
Examples 124F, 124D, 124K, and 113 with lipophilic
groups at the 4-position have IC50 values of 0.001 μM,
0.006 μM, 0.013 μM, and 0.020 μM, respectively, com-
pared to an IC50 of 0.015 μM for Example 334, which has
the highest binding affinity of any compound with a non-
lipophilic group, and an IC50 of 0.26 μM for Example 335.
Id. at 13721.
Similarly, in the series of compounds with a bi-
phenyltetrazole substitutent at the 1-position, a propyl
group at the 2-position, and a carboxylic acid at the 5-
position, two out of three compounds with a lipophilic
group at the 4-position exhibit higher affinity binding
than Example 329 with a hydrophilic group. Specifically,
Examples 265C (DuPont’s DuP 532) and 251A have IC50
values of 0.003 μM and 0.045 μM compared to an IC50 of
0.076 for Example 329. Id. at 13720. Finally, Example
342, described above as the compound with the highest
binding affinity of any compound with a hydrophilic group
at the 4-position, has a lower binding affinity, higher IC50,
than Example 140J, which differs only by the substitution
of a lipophilic group at the 4-position. Id. at 13725. Thus,
the compounds in the prior art, including the parties’
proposed lead compounds, favor lipophilic 4-substitutents
rather than the 4-hydrophilic group of olmesartan me-
doxomil.
An analysis of regioisomer pairs in which the 4- and
5-positions are transposed provides even further confir-
mation. For all eight regioisomer pairs, the regioisomer
with a lipophilic group at the 4-position has higher bind-
ing affinity than the regioisomer with a hydrophilic group
at that position. Id. at 13713-16. In the 6155 series, for
example, two compounds with lipophilic chlorine atoms at
the 4-position exhibit ten-fold and 100-fold better binding
than compounds with a hydrophilic acetic acid or hy-
DAIICHI SANKYO CO v. MYLAN PHARMA 18
droxymethyl group, respectively. Id. at 13713. And in the
biphenyltetrazole series, losartan with a chlorine at the 4-
position has two-fold higher binding affinity than its
regioisomer, Example 118, with a hydrophilic hydroxy-
methyl group. Id. at 13716.
DuPont’s second-generation ARBs repeat and enhance
the preference for lipophilicity at the 4-position. Specifi-
cally, DuPont’s DuP 532 replaces losartan’s chlorine atom
with a more lipophilic multiple fluorine group (-C2F5), and
the six ’902 compounds replace the chlorine with more
lipophilic alkyl groups. No other second-generation ARB
but olmesartan medoxomil has a hydrophilic group at the
4-position. Id. at 13722. Altogether, the ’069 patent’s
SAR data and the structure of other second-generation
ARBs counter any notion that one of skill in the art would
have been motivated to modify the ’902 compounds’
lipophilic alkyl groups to a hydrophilic group. Such a
holding would have been based on hindsight.
Mylan argues that the motivation to modify comes di-
rectly from the ’069 patent and specifically from Example
118, losartan’s regioisomer, with its hydrophilic hydroxy-
methyl group at the 4-position. According to Mylan, the
parties’ experts agreed that Example 118 is one of the
more potent and important of the compounds disclosed in
the ’069 patent, and thus, Mylan argues, although Exam-
ple 118 is slightly less potent than losartan, it would have
motivated one of skill in the art to alter the ’902 com-
pounds’ alkyl groups to a hydrophilic group. Alterna-
tively, Mylan argues, even without the benefit of Example
118, one of skill in the art would have been motivated to
make the “minor” modification of hydroxylation of the
19 DAIICHI SANKYO CO v. MYLAN PHARMA
’902 compounds’ alkyls to produce a hydroxyisopropyl. 4
We disagree.
First, the SAR data in the ’069 patent, described in
detail above, contradict Mylan’s arguments. Example 118
may be one of the more potent biphenyltetrazole com-
pounds disclosed in the ’069 patent, but it is one of only
four to contain a hydrophilic group at the 4-position and
one of only six to have a non-lipophilic group at that
position. Furthermore its regioisomer, losartan, displays
greater binding affinity as do all the disclosed regioisom-
ers with a lipophilic group compared to a hydrophilic
group at the 4-position. And while the ’069 patent’s SAR
data do not make available a subseries analysis for Ex-
ample 118, all available subseries, as described above,
demonstrate a clear preference for lipophilic groups over
hydrophilic ones.
Second, Mylan’s argument relies on first selecting the
’902 compounds, which improved on losartan by using
even more lipophilic alkyl groups at the 4-position, only to
reject that very feature to obtain olmesartan medoxomil.
See Eisai, 533 F.3d at 1358 (affirming a holding of non-
obviousness based in part on a finding that the record
“show[ed] no discernible reason for a skilled artisan to
begin with lansoprazole only to drop the very fea-
ture . . . that gave [it an] advantageous property”). As the
district court in this case put it, “a person of ordinary skill
in the art would not select the ’902 patent compounds as
leads only to disregard one of their distinguishing charac-
teristics, specifically their increased lipophilicity at the 4-
position.” Daiichi, 670 F. Supp. 2d at 379.
4 In fact, a difference of only a single oxygen atom
between Example 6 of the ’902 patent and olmesartan, as
noted by Mylan, is of greater significance than it superfi-
cially appears, as it is the difference between functional
groups, specifically an isopropyl and a hydroxyisopropyl.
DAIICHI SANKYO CO v. MYLAN PHARMA 20
Finally, even crediting Mylan’s argument that the
’069 patent does not teach away from a hydrophilic group
at the 4-position, the ’069 patent simply does not provide
a reason to make such a modification. We thus affirm the
district court’s decision holding that one of skill in the art
would not have been motivated to modify the ’902 com-
pounds at the 4-position to obtain a compound with a
hydrophilic hydroxyalkyl group.
Because we affirm the district court’s findings that
Mylan failed to establish either that one of skill in the art
would have selected the ’902 ARBs as leads or that one of
skill in the art would have modified the ’902 ARBs at the
4-position of the imidazole ring to obtain olmesartan
medoxomil, we need not address the district court’s alter-
native grounds for holding that Mylan failed to establish
a prima facie case of obviousness or the court’s findings on
secondary considerations.
CONCLUSION
For the foregoing reasons, we affirm the district
court’s decision holding that claim 13 of the ’599 patent
was not shown to be invalid as obvious.
AFFIRMED