Court Opinion

ID: 2678151
Source: CourtListenerOpinion
Date Created: 2014-06-12 16:00:47.133734+00
Date Added: 2024-06-11T09:37:54.975586
License: Public Domain

United States Court of Appeals
      for the Federal Circuit
                 ______________________

       BRISTOL-MYERS SQUIBB COMPANY,
               Plaintiff-Appellant,

                            v.

       TEVA PHARMACEUTICALS USA, INC.,
                Defendant-Appellee.
              ______________________

                       2013-1306
                 ______________________

    Appeal from the United States District Court for the
District of Delaware in No. 10-CV-0805, Magistrate Judge
Christopher J. Burke.
                 ______________________

                 Decided: June 12, 2014
                 ______________________

    WILLIAM F. LEE, Wilmer Cutler Pickering Hale and
Dorr LLP, of Boston, Massachusetts, argued for plaintiff-
appellant. With him on the brief were LAUREN B.
FLETCHER and ANDREW J. DANFORD; AMY K. WIGMORE and
THOMAS G. SAUNDERS, of Washington, DC. Of counsel on
the brief were PAUL BERGHOFF, ALISON J. BALDWIN, and
JOSHUA R. RICH, McDonnell Boehnen Hulbert & Berghoff
LLP, of Chicago, Illinois.

    GEORGE C. LOMBARDI, Winston & Strawn LLP, of Chi-
cago, Illinois, argued for defendant-appellee. With him on
the brief were LYNN MACDONALD ULRICH, IVAN M.
2                     BRISTOL-MYERS SQUIBB COMPANY v. TEVA
                                 PHARMACEUTICALS USA, INC.

POULLAOS, JULIA MANO JOHNSON, and WILLIAM P.
FERRANTI.
              ______________________

    Before PROST, ∗ Chief Judge, PLAGER and CHEN, Circuit
                            Judges.
CHEN, Circuit Judge.
    This patent infringement case concerns a drug for the
treatment of hepatitis B. After a four-day bench trial, the
United States District Court for the District of Delaware
found claim 8 of U.S. Patent No. 5,206,244 (’244 patent)
invalid as obvious. We affirm the district court’s invalidi-
ty judgment for the reasons that follow.
                             I.
    Appellant Bristol-Myers Squibb Co. (BMS) owns the
’244 patent. Claim 8 of the ’244 patent is directed to a
nucleoside analog composed of two regions: a carbocyclic
ring and a guanine base. Nucleoside analogs are man-
made compounds designed to mimic the activity of natu-
ral nucleosides, the building blocks of DNA and RNA.
These compounds are modified slightly from their natural
counterparts to interfere with the replication of viral
DNA—which means that they can serve as possible
antiviral compounds. Claim 8 covers one such compound,
entecavir. BMS markets entecavir as a treatment for
hepatitis B under the trade name Baraclude®.
     Entecavir is a modified version of the natural nucleo-
side 2′-deoxyguanosine (deoxyguanosine). Entecavir is
structurally identical to deoxyguanosine except for one
difference: it has a carbon-carbon double bond (also

     ∗
       Sharon Prost assumed the position of Chief Judge
on May 31, 2014.
BRISTOL-MYERS SQUIBB COMPANY     v. TEVA                 3
PHARMACEUTICALS USA, INC.

known as an exocyclic methylene group) at the 5’ position
of the carbocyclic ring where deoxyguanosine has an
oxygen atom.
    The chemical structures of entecavir and deoxyguano-
sine are illustrated below:

Appellant’s Br. 8; see also J.A. 11.
    The structures referenced throughout this opinion in-
clude a “carbocyclic ring” of carbon atoms, which is illus-
trated above as the pentagonal structure at the left of
each diagram, and a nucleoside base, which is illustrated
above as the double ring structure to the right. In both
figures above, the nucleoside base is guanine.
    Entecavir is an effective treatment for hepatitis B.
The drug is generally accepted as a safe drug, with a
broad therapeutic window for treatment, providing for a
wide gap between low doses of the drug that are effective
against disease and the high doses that could cause
unwanted toxicity. It also has a high genetic barrier to
resistance such that, if they have not previously received
a nucleoside-based treatment, few patients treated with
entecavir develop drug resistance to it.
     The appellee, Teva Pharmaceuticals USA, Inc. (Teva),
filed an abbreviated new drug application (ANDA) for a
generic version of entecavir. In support of its ANDA,
Teva filed “Paragraph IV” certifications, alleging that its
generic products would not infringe the ’244 patent,
4                     BRISTOL-MYERS SQUIBB COMPANY v. TEVA
                                 PHARMACEUTICALS USA, INC.

and/or that the patent was invalid or unenforceable. See
21 U.S.C. § 355(j)(2)(A)(vii)(IV).
    BMS sued Teva for patent infringement, claiming
that Teva’s ANDA filing infringed the ’244 patent. See 35
U.S.C. § 271(e)(2). At trial, the parties narrowed the
issues to obviousness and inequitable conduct. 1 Teva’s
obviousness argument focused on the selection of 2′-CDG
as a lead compound from the prior art.
                             A.
     2′-CDG is a potent antiviral carbocyclic nucleoside
analog that is structurally similar to the natural nucleo-
side deoxyguanosine, differing only in that it replaces an
oxygen atom with a carbon atom at the 5’ position. The
following illustrations compare the chemical structures of
2′-CDG and deoxyguanosine.

Appellant’s Br. 14; see also J.A. 11, 23.
    The earliest priority date for the ’244 patent is the
date that BMS filed the application, October 18, 1990. 2′-
CDG’s synthesis was first published in the Journal of
Medicinal Chemistry in 1984 by Dr. Y. Fulmer Shealy (the

    1
        The district court found that Teva did not demon-
strate by clear and convincing evidence that the inventor
and prosecuting attorneys committed inequitable conduct.
Teva does not raise the inequitable conduct issue on
appeal.
BRISTOL-MYERS SQUIBB COMPANY    v. TEVA                    5
PHARMACEUTICALS USA, INC.

Shealy reference) of the Southern Research Institute (the
SRI). The Shealy reference taught that 2′-CDG exhibited
better in vitro antiviral activity against the herpes virus
than the FDA-approved best-selling drug at the time, Ara-
A. Dr. Shealy obtained a patent for 2′-CDG and other
related compounds, stating that they were useful in the
treatment of viral infections. Subsequent research on 2′-
CDG by Dr. Shealy showed in vivo activity against herpes
viruses.
     After the Shealy reference was published, other re-
searchers soon began working with 2′-CDG as an antivi-
ral, including scientists at SRI, Mount Sinai School of
Medicine, GlaxoSmithKline (Glaxo), and other institu-
tions. In 1989, Dr. J.A. Montgomery of SRI published an
article summarizing the state of antiviral research at the
time and reported that 2′-CDG was “[b]y far the most
promising” antiviral against herpes. J.A. 2148. The
Montgomery reference also taught that 2′-CDG was five to
six times more potent than one of the leading drugs on the
market, acyclovir. Teva’s expert, Dr. Heathcock, stated
that the Montgomery reference was a “lamp post that
really illuminate[d] 2′-CDG as … a very exciting lead
compound to work from,” and other chemists, during the
relevant time period, were using 2′-CDG as a lead com-
pound. J.A. 27. BMS’s expert, Dr. Schneller, conceded
that he did not “completely disagree” with Dr. Heath-
cock’s opinion. J.A. 27-28. In fact, Dr. Schneller himself
published research investigating antiviral activity of
carbocyclics, including 2′-CDG, and cited to Dr. Shealy’s
article, noting the significant antiviral activity of 2′-CDG.
    Also in 1989, Peter M. Price and other researchers
with the Mount Sinai School of Medicine published the
results of testing 2′-CDG against hepatitis (the Price
reference). The Price reference disclosed that 2′-CDG
showed “excellent activity” against the hepatitis B virus
“with as little as 25 ng of 2′-CDG per ml” resulting in the
“almost complete disappearance of replicating” hepatitis
BRISTOL-MYERS SQUIBB COMPANY       v. TEVA                  7
PHARMACEUTICALS USA, INC.

    According to BMS’s inventor, Dr. Zahler, he was
aware of the Madhavan reference before conceiving
entecavir and testified that BMS submitted it to the
USPTO as the “most relevant” piece of prior art in the
’244 patent application. J.A. 1078, 1215, 1223. But BMS
did not submit 2′-CDG as prior art to the USPTO.
                             B.
     After a bench trial, the district court found that at the
time of BMS’s invention, 2′-CDG was a lead compound for
the development of antiviral drugs. Bristol-Myers Squibb
Co. v. Teva Pharms. USA, Inc., 923 F. Supp. 2d 602, 665
(D. Del. 2013). Based on (1) the structural similarity
between entecavir and 2′-CDG, (2) the teachings of the
Madhavan reference, (3) the finding that the exocyclic
methylene substitution would be a “small, conservative
change[]”and (4) the “totality of the prior art” on 2′-CDG,
the district court found that a skilled artisan would have
been motivated to substitute an exocyclic methylene
group at the 5’ position of 2′-CDG, with a reasonable
expectation of success of creating a compound with benefi-
cial antiviral properties. Id. at 669, 675.
     The district court also analyzed secondary considera-
tions of nonobviousness. Although the court found that
some of these considerations—commercial success, long-
felt need, and evidence of unexpected properties—cut in
favor of nonobviousness, the court ultimately concluded
that Teva proved by clear and convincing evidence that
claim 8 would have been obvious. Id. at 696. As a result,
the district court entered judgment in favor of Teva. Id.
BMS appeals the district court’s invalidity finding. We
have jurisdiction under 28 U.S.C. § 1295(a)(1).
                             II.
    The only issue for our review is the district court’s ob-
viousness ruling. Obviousness is a question of law with
underlying factual findings. Honeywell Int’l, Inc. v.
8                    BRISTOL-MYERS SQUIBB COMPANY v. TEVA
                                PHARMACEUTICALS USA, INC.

United States, 609 F.3d 1292, 1297 (Fed. Cir. 2010). We
review the conclusion of obviousness de novo, and the trial
court’s factual findings for clear error. Id.
      Obviousness requires assessing (1) the “level of ordi-
nary skill in the pertinent art,” (2) the “scope and content
of the prior art.” (3) the “differences between the prior art
and the claims at issue,” and (4) “secondary considera-
tions” of nonobviousness such as “commercial success,
long-felt but unsolved needs, failure of others, etc.” KSR
Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007) (quoting
Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966)).
     A party seeking to invalidate a patent as obvious
must demonstrate “‘by clear and convincing evidence that
a skilled artisan would have been motivated to combine
the teachings of the prior art references to achieve the
claimed invention, and that the skilled artisan would
have had a reasonable expectation of success from doing
so.’” Proctor & Gamble Co. v. Teva Pharms. USA, Inc.,
566 F.3d 989, 994 (Fed. Cir. 2009) (quoting Pfizer, Inc. v.
Apotex, Inc., 480 F.3d 1348, 1361 (Fed. Cir. 2007)).
    To establish obviousness in cases involving new chem-
ical compounds, the accused infringer must identify some
reason that would have led a chemist to modify a known
compound. Takeda Chem. Indus., Ltd. v. Alphapharm
Pty., Ltd., 492 F.3d 1350, 1357 (Fed. Cir. 2007). General-
ly, an obviousness inquiry concerning such “known com-
pounds” focuses on the identity of a “lead compound.”
Eisai Co. Ltd. v. Dr. Reddy’s Labs., Ltd., 533 F.3d 1353,
1359 (Fed. Cir. 2008).
     A lead compound is a compound in the prior art that
would be “a natural choice for further development ef-
forts.” Altana Pharma AG v. Teva Pharms. USA, Inc.,
566 F.3d 999, 1008 (Fed. Cir. 2009). The motivation to
modify that lead compound can come from any number of
sources and need not necessarily be explicit in the art.
“[I]t is sufficient to show that the claimed and prior art
BRISTOL-MYERS SQUIBB COMPANY      v. TEVA                  9
PHARMACEUTICALS USA, INC.

compounds possess a ‘sufficiently close relationship . . . to
create an expectation,’ in light of the totality of the prior
art, that the new compound will have ‘similar properties’
to the old.” Otsuka Pharm. Co., Ltd. v. Sandoz, Inc., 678
F.3d 1280, 1293 (Fed. Cir. 2012) (quoting In re Dillon, 919
F.2d 688, 692 (Fed. Cir. 1990) (en banc)). Whether a lead
compound and a claimed compound have a sufficiently
close relationship frequently turns on their “structural
similarities and differences.” Daiichi Sankyo Co. v.
Matrix Labs., Ltd., 619 F.3d 1346, 1352 (Fed. Cir. 2010).
    Based on the prior art and testimony, the district
court properly found strong evidence of obviousness,
because the record shows that a skilled artisan would
have selected 2′-CDG as a lead compound and made the
minor modification to arrive at entecavir. Moreover, we
see no clear error in the district court’s fact findings
regarding evidence of secondary considerations of nonob-
viousness.
                             A.
    BMS attacks the lower court’s obviousness determina-
tion by contending that a skilled artisan would have had
to make too many decisions to arrive at entecavir. Those
decisions include selecting (1) the class of nucleoside
analog compounds, (2) 2′-CDG as a lead compound from
the class of carbocyclics, (3) the carbocyclic ring or gua-
nine base of 2′-CDG for modification, (4) the 2’ or 5’ posi-
tion on the carbocyclic ring, (5) the specific chemical
element on the 5’ position (carbon), and (6) the type of
carbon to carbon bond (single or double). We conclude
that the district court’s analysis is well supported.
    During the relevant time period in the late 1980s,
carbocyclic analogs were generating a great deal of inter-
est among researchers searching for compounds with
antiviral activity. Both parties’ experts agree on that
point. Several research institutions—including Glaxo,
Syntex, Abbott Laboratories, and SRI— investigated and
10                   BRISTOL-MYERS SQUIBB COMPANY v. TEVA
                                PHARMACEUTICALS USA, INC.

published on antiviral activity of carbocyclic nucleosides.
Thus, the district court had sufficient evidence to conclude
that one of ordinary skill in the art during the relevant
time period would have studied carbocyclic analogs “as a
promising area” for antiviral drug discovery. J.A. 97.
    Of the carbocyclic analogs on which researchers fo-
cused in the late 1980s, 2′-CDG was a “natural choice for
further development.” Altana, 566 F.3d at 1008. The
district court observed, based on BMS’s expert’s own
testimony, that “medicinal chemists during the relevant
time frame were actually treating and using 2′-CDG as a
lead compound” in the search for new antivirals at the
time. J.A. 97 (emphasis in original). The Shealy, Mont-
gomery, and Price references collectively reinforce that
understanding of 2′-CDG.
    BMS challenges the selection of 2′-CDG as a lead
compound because it was discovered to be toxic in the
1990s. However, at the time of entecavir’s invention, the
Price reference showed that 2′-CDG was generally under-
stood to be safe and nontoxic, and other researchers were
already using it as a lead compound. As the district court
points out, in “October 1990, 2′-CDG was not yet known to
have high toxicity,” and BMS’s expert, Dr. Schneller,
agreed that researchers at the time treated 2′-CDG as a
“promising compound.” J.A. 104, 111 (emphasis in origi-
nal). Therefore, we see no error in the selection of 2′-CDG
as the lead compound here. See Velander v. Garner, 348
F.3d 1359, 1377 (Fed. Cir. 2003) (“Obviousness, and
expectation of success, are evaluated from the perspective
of a person having ordinary skill in the art at the time of
invention.” (emphasis added) (citation omitted)); see also
Eisai, 533 F.3d at 1359.
    Accordingly, we therefore agree with the district court
that those of ordinary skill in the art would have selected
2′-CDG, a carbocyclic analog, as a lead compound for
further development efforts before BMS applied for the
BRISTOL-MYERS SQUIBB COMPANY    v. TEVA                   11
PHARMACEUTICALS USA, INC.

’244 patent in October 1990. See Daiichi, 619 F.3d at
1354 (explaining that more than mere structural similari-
ty must be identified as a reason to select a compound as
a lead compound; “knowledge in the art of the functional
properties and limitations of the prior art compounds” are
also important to the analysis). 2
    After selecting a lead compound, both experts (Dr.
Schneller and Dr. Heathcock) agreed that a chemist in
drug development would seek to make small, conservative
changes to that structure. In drug development, it is
common to modify a lead compound in an effort to “obtain
a compound with better activity.” Otsuka, 678 F.3d at
1291 (quotation omitted).
     With 2′-CDG as a lead compound, the record here
amply supports the conclusion that one of ordinary skill in
the art would have had a motivation to modify 2′-CDG’s
carbocyclic ring by substituting an exocyclic methylene
group at the 5’ position to make the patented compound,
entecavir. See Otsuka, 678 F.3d at 1292; see also Takeda,
492 F.3d at 1357.

    2   BMS asserts that the district court erroneously
failed to consider other nucleoside analogs as potential
lead compounds. We disagree. The district court as-
sessed all three classes of nucleosides (furanosides, acy-
clics, and carbocyclics) but explained that the field for
furanosides and acyclics, compared to carbocyclics, was
“crowded” and “fairly well developed” to the point that one
would have a “hard time finding [a furanoside or acyclic
that] someone else hadn’t already tried.” J.A. 19, 94.
This is in marked contrast to the “fertile” field of research
in carbocyclics. Id.
12                   BRISTOL-MYERS SQUIBB COMPANY v. TEVA
                                PHARMACEUTICALS USA, INC.

     In choosing whether to modify 2′-CDG’s carbocyclic
ring or its guanine base, BMS’s expert, Dr. Schneller,
initially testified that he would “retain the [carbocyclic]
portion,” J.A. 114, but he acknowledged on cross-
examination that other chemists were making changes to
the carbocyclic portion. JA 1307-08. Teva’s expert, Dr.
Heathcock, also testified that changing the carbocyclic
portion resulted in greater activity than changes to the
guanine ring. Accordingly, this was a natural decision
because the goal was to develop antivirals with improved
activity.
     Unrefuted expert testimony also explained how the
next obvious choice for modification would have been
either the 2’ or 5’ position on the carbocyclic ring, because
only at these locations could small changes easily be made
to the molecule. Both experts agreed that a skilled arti-
san would focus on the smallest elements on the top row
of the periodic table, including carbon and fluorine. For a
specific element, BMS’s expert, Dr. Schneller, testified in
his deposition that he would “rule out everything but the
carbon” and that carbon was “the only one that sticks
out.” J.A. 1304. Teva’s expert, Dr. Heathcock, also ex-
plained that the choice to have an exocyclic methylene
(carbon-to-carbon double bond) over a methyl group
(carbon-to-carbon single bond) would be a more conserva-
tive choice, because a methyl group is bigger and longer
than an exocyclic methylene group, and the easiest way to
synthesize a methyl group would be to make methylene
first. J.A. 117-118, 1053, 1306.
    Futhermore, the Madhavan reference demonstrated
that adding an exocyclic methylene group to a carbocyclic
nucleoside analog can result in a lead compound with
improved antiviral activity. Specifically, it teaches that
aristeromycin and Madhavan 30 were two compounds
that differed only in the presence of an exocyclic meth-
ylene substitution at the 5’ position; that modification
resulted in the formation of a much more potent antiviral.
BRISTOL-MYERS SQUIBB COMPANY    v. TEVA                   13
PHARMACEUTICALS USA, INC.

    Teva’s expert, Dr. Heathcock, testified that the substi-
tution was an “obvious modification” in light of the prior
art “because there were other [antiviral] compounds like
that that had already been made” and a chemist would
expect the nucleoside analog “to have similar biological
properties of [2′-]CDG itself, which were good properties.”
J.A. 44. During prosecution of the ’244 patent, BMS
presented the Madhavan reference as containing the
closest piece of prior art to entecavir. BMS’s expert, Dr.
Schneller, does not directly state that entecavir was
obvious. But, on cross examination, Dr. Schneller stated
that the Madhavan reference “would not dissuade” a
chemist from adding the exocyclic methylene to form an
antiviral drug. And even though the Madhavan com-
pound was more toxic than the underlying lead com-
pound, aristeromycin, (which itself was cytotoxic), Dr.
Schneller admitted that the combination of features
reported in the Madhavan and Shealy references “could
have led” a person of skill in the art to seek new antivi-
rals. J.A. 1311-12.
     Based on the record, we see no clear error in the dis-
trict court’s finding that the modification required to
transform 2′-CDG into the structurally similar entecavir
is a minor one: the addition of a single carbon atom to
form an exocyclic methylene with the already-present
carbon atom at the 5’ position of the carbocyclic ring of 2′-
CDG to create entecavir. See supra at 6. Upon selecting
2′-CDG as the lead compound, the steps of deciding which
bond to modify and how to modify that bond “equate to a
small, finite number of changes to try to [arrive at] the
lead compound.” J.A. 117. See In re Cyclobenzaprine
Hydrochloride Patent Litig., 676 F.3d 1063, 1072 (Fed.
Cir. 2012) (“Evidence of obviousness . . . is insufficient
unless it indicates that the possible options skilled arti-
sans would have encountered were ‘finite,’ ‘small,’ or
‘easily traversed,’ and that skilled artisans would have
14                    BRISTOL-MYERS SQUIBB COMPANY v. TEVA
                                 PHARMACEUTICALS USA, INC.

had a reason to select the route that produced the claimed
invention.”) (citations omitted).
    Further, the skilled artisan’s reasonable expectation
of success is measured “as of the date of the invention.”
Amgen Inc., v. Hoffman-LaRoche, 580 F.3d 1340, 1362
(Fed. Cir. 2009). The Madhavan reference’s teachings of
improved potency with an exocyclic methylene at the 5’
position supports the expectation that the same substitu-
tion to 2′-CDG would reasonably lead to similar proper-
ties. As explained above, 2′-CDG and entecavir are very
structurally similar, and it is well settled that structural-
ly similar compounds often have similar properties. See
Takeda, 492 F.3d at 1356; Altana, 566 F.3d at 1007; In re
Soni, 54 F.3d 746, 750 (Fed. Cir. 1995) (“[T]he presump-
tion [is] that similar compositions have similar proper-
ties.”).
    BMS fails to establish any clear error in the district
court’s factual determinations, which are based on the
prior art and expert testimony. In light of those factual
findings, we agree with the district court that Teva pro-
vided strong evidence of obviousness, given the use of 2′-
CDG as a lead compound during the relevant time period,
the “totality of the prior art,” and the structural similarity
between entecavir and 2′-CDG suggesting similar proper-
ties. J.A. 128, 131.
    BMS also argues that a new chemical entity, as a
matter of law, cannot be obvious when the claimed inven-
tion possesses unexpected properties. Specifically, BMS
argues that the existence of unexpected properties fore-
closes a finding of a reasonable expectation of success. We
have already rejected this argument en banc in Dillon,
explaining that an unexpected result or property does not
by itself support a finding of nonobviousness. Dillon, 919
F.2d at 693, 697. In Dillon, we held that the expected
properties of a claimed compound may be sufficient to
lead to a reasonable expectation of success in modifying a
BRISTOL-MYERS SQUIBB COMPANY     v. TEVA                 15
PHARMACEUTICALS USA, INC.

prior art compound to make that claimed compound. Id.
at 697.
    As here, Dillon’s claimed compound demonstrated
both expected and additional, unexpected properties.
Those additional unexpected properties, however, did not
upset an already established motivation to modify a prior
art compound based on the expected properties of the
resulting compound. Id. at 693. We therefore upheld the
finding of obviousness despite Dillon’s arguments of
unexpected properties.
    Contrary to BMS’s argument, unexpected results do
not per se defeat, or prevent, the finding that a modifica-
tion to a lead compound will yield expected, beneficial
properties. 3  Rather, as secondary considerations of
nonobviousness, they come into play in determining “the
ultimate question of patentability.” Dillon, 919 F.2d at
692-93; Procter & Gamble, 566 F.3d at 997-98 (citing to
Dillon and finding evidence of superior properties such as
potency and safety that were “unexpected and could not
have been predicted” could outweigh evidence of obvious-
ness).
                            B.
    Secondary considerations of nonobviousness “must
always when present be considered,” and can serve as an
important check against hindsight bias. See Cycloben-
zaprine, 676 F.3d at 1075-76, 1079 (quoting Stratoflex,
Inc. v. Aeroquip Corp, 713 F.2d 1530, 1538-39 (Fed. Cir.
1983)). While secondary considerations must be taken

   3    We have held an invention to be obvious despite
findings of unexpected results. See, e.g., Allergan, Inc. v.
Sandoz Inc., 726 F.3d 1286, 1293 (Fed. Cir. 2013); Alcon
Research, Ltd. v. Apotex, Inc., 687 F.3d 1362, 1365, 1369-
70 (Fed. Cir. 2012); Pfizer, 480 F.3d at 1372.
16                   BRISTOL-MYERS SQUIBB COMPANY v. TEVA
                                PHARMACEUTICALS USA, INC.

into account, they do not necessarily control the obvious-
ness determination. Pfizer, 480 F.3d at 1372; see also
KSR, 550 U.S. at 426. Here, the district court found
evidence of some secondary considerations of nonobvious-
ness, including commercial success, long-felt need, and
unexpected results. On appeal, BMS focuses primarily on
unexpected results.
                             i.
    To be particularly probative, evidence of unexpected
results must establish that there is a difference between
the results obtained and those of the closest prior art, and
that the difference would not have been expected by one of
ordinary skill in the art at the time of the invention. Kao
Corp. v. Unilever U.S., Inc., 441 F.3d 963, 970 (Fed. Cir.
2006); see also Pfizer, 480 F.3d at 1371. Unexpected
properties, however, do not necessarily guarantee that a
new compound is nonobvious. While a “marked superiori-
ty” in an expected property may be enough in some cir-
cumstances to render a compound patentable, a “mere
difference in degree” is insufficient. In re Papesch, 315
F.2d 381, 392 (CCPA 1963); In re Hoch, 428 F.2d 1341,
1344 n.5 (CCPA 1970) (explaining that unexpected “dif-
ferences in properties” can mean “significant difference in
degree of the same property” amounting to a “marked
superiority” for purposes of evaluating unexpected re-
sults) (quotation omitted).
    And “differences in degree” of a known and expected
property are not as persuasive in rebutting obviousness as
differences in “kind”—i.e., a new property dissimilar to
the known property. Compare In re Merck, 800 F.2d
1091, 1099 (Fed. Cir. 1986) (finding evidence that the new
drug was a more potent sedative and stronger anticholin-
ergic effect than the prior art was insufficient to outweigh
the evidence of obviousness), with In re Albrecht, 514 F.2d
1389, 1396 (CCPA 1975) (reversing an obviousness rejec-
tion based on evidence of additional antiviral activity
BRISTOL-MYERS SQUIBB COMPANY      v. TEVA                17
PHARMACEUTICALS USA, INC.

“totally dissimilar to any activity previously disclosed for
prior art”). When assessing unexpected properties, there-
fore, we must evaluate the significance and “kind” of
expected results along with the unexpected results. See
Hoffmann-La Roche Inc. v. Apotex Inc., --- F.3d ---, 2014
WL 1394948, at *7 (Fed. Cir. Apr. 11, 2014) (“The evi-
dence of superior efficacy does nothing to undercut the
showing that there was a reasonable expectation of suc-
cess with the 150 mg monthly dose, even if the level of
success may have turned out to be somewhat greater than
would have been expected.”); In re Eli Lilly & Co., 902
F.2d 943, 948 (Fed. Cir. 1990) (finding claims obvious
when “[patentee] has not shown that a significant aspect
of his claimed invention is unexpected in light of the prior
art”).
                            ii.
    BMS primarily relies on three contentions for unex-
pected properties: (1) high potency against hepatitis B, (2)
a larger than expected therapeutic window, and (3) a high
genetic barrier to resistance. J.A. 150-51. The antiviral
activity of entecavir, however, was not entirely unex-
pected because, as the district court found, it was already
known in the prior art that 2′-CDG was effective against
hepatitis B. J.A. 150. Specifically, the Price reference
suggested that the structurally similar entecavir would
likely have excellent antiviral activity against hepatitis B
because 2′-CDG already demonstrated “excellent activity”
against the virus. J.A. 2086. Moreover, the Price refer-
ence also suggested—and Teva’s expert, Dr. Heathcock,
testified—that 2′-CDG was known to have a good thera-
peutic window. Thus, while the district court found that
entecavir’s degree of effectiveness was unexpected, it also
noted that entecavir’s “effectiveness against hepatitis B
without known toxicity issues” was “not unexpected” in
light of the structurally similar 2′-CDG. J.A. 150 (empha-
sis added). As for the high genetic barrier to resistance,
the district court properly credited this attribute as an
18                   BRISTOL-MYERS SQUIBB COMPANY v. TEVA
                                PHARMACEUTICALS USA, INC.

unexpected property. All taken together, the district
court found that the proffered evidence of unexpected
properties provided “some support to BMS’s argument as
to nonobviousness,” but did not find it sufficient. J.A.
151-53.
    We give deference to a lower court’s factual findings
regarding evidence of secondary considerations. See In re
Inland Steel Co., 265 F.3d 1354, 1366 (Fed. Cir. 2001)
(“An examination for unexpected results ‘is a factual,
evidentiary inquiry,’ … and we give the [fact-finding
tribunal] broad deference in its weighing of the evidence
before it.”); Santarus, Inc. v. Par Pharma., Inc., 694 F.3d
1344, 1358 (Fed. Cir. 2012) (“The district court’s findings
of fact are entitled to deference, and [Patentee] failed to
show that they are clearly erroneous.”) (citation omitted).
Accordingly, we defer to the district court’s finding on
unexpected results.
     BMS’s remaining arguments regarding unexpected
results are that the district court committed legal error by
(1) comparing entecavir to another hepatitis B drug on the
market instead of the closest prior art, 2′-CDG; and (2)
inappropriately looked to what the inventor knew at the
time of the invention—instead of one of ordinary skill in
the art—to determine what was expected. BMS is correct
on both counts. See Kao, 441 F.3d at 970 (explaining that
when unexpected results are used as evidence of patent’s
nonobviousness, results must be shown to be unexpected
compared with closest prior art); Standard Oil Co. v. Am.
Cyanamid Co., 774 F.2d 448, 454 (Fed. Cir. 1985) (holding
that “obviousness is determined entirely with reference to
a hypothetical ‘person having ordinary skill in the art’”
and the “actual inventor’s skill is irrelevant” to the obvi-
ousness inquiry) (emphasis omitted). However, both
errors were harmless. The district court ultimately made
the correct direct comparison of the patented compound to
2′-CDG, noting that prior art compounds, “including 2′-
CDG,” “showed effectiveness against hepatitis B without
BRISTOL-MYERS SQUIBB COMPANY        v. TEVA                19
PHARMACEUTICALS USA, INC.

known toxicity issues.” J.A. 150 (emphasis added). And
regardless of what the district court determined the
inventor may have known, the prior art, the trial record,
and the district court’s findings reflect that one of skill in
the art would have expected entecavir’s hepatitis B’s
efficacy, safety, and therapeutic window based on one’s
knowledge of 2′-CDG.
                             iii.
     As for BMS’s arguments regarding evidence of com-
mercial success and long-felt need, we find no clear error
with the district court’s factual findings. The district
court found that Baraclude® achieved commercial success
based on sales and market share, but it was “less dynam-
ic” than BMS represented. J.A. 138. Baraclude®’s market
share built up gradually over four years and it ultimately
held onto the top spot for less than a year. Evidence also
showed that two other competitors were able to gain
market share more quickly at launch than Baraclude®.
J.A. 54, 137. Even BMS’s internal documents viewed
Baraclude®’s market performance as “sub optimal.” J.A.
136-38.
     On long-felt need, three other drugs for treating hepa-
titis B were invented before the filing date of entecavir.
J.A. 147. These three drugs also gained FDA approval
before entecavir. Finally, entecavir’s inventors did not
know about its hepatitis B properties until four years
after the filing date, and by then the first FDA-approved
hepatitis B treatment was launched. J.A. 147-48. There-
fore, we agree with the district court that the evidence of
long-felt need is of limited value to BMS.
    Finally, BMS argues that the district court improper-
ly compared the weight of the different secondary consid-
erations against each other when it summarized that the
factors were “mixed.” J.A. 152. We understand the
district court to be noting that some categories of evidence
simply were not as helpful to BMS’s case as others. We
20                  BRISTOL-MYERS SQUIBB COMPANY v. TEVA
                               PHARMACEUTICALS USA, INC.

do not read the opinion as suggesting that unhelpful
evidence somehow diminished the strength of the more
persuasive forms of evidence.
                           III.
    We agree with the factual findings on secondary con-
siderations and find no clear error. As stated previously,
we also agree with the district court’s finding that the
record demonstrates strong evidence of obviousness.
After considering all of the findings for and against obvi-
ousness, as well as Teva’s burden of proof, we see no basis
to disturb the district court’s ultimate legal conclusion,
and we affirm the judgment that claim 8 of the ’244
patent is invalid as obvious.
                      AFFIRMED
                          COSTS
     No costs.