  United States Court of Appeals
      for the Federal Circuit
                ______________________

    INSITE VISION INCORPORATED, INSPIRE
     PHARMACEUTICALS, INC., PFIZER INC.,
                Plaintiffs-Appellees

                           v.

                   SANDOZ, INC.,
                  Defendant-Appellant

      SANDOZ GMBH, SANDOZ INDUSTRIAL
               PRODUCTS S.A.,
                   Defendants
             ______________________

                      2014-1065
                ______________________

    Appeal from the United States District Court for the
District of New Jersey in No. 3:11-cv-03080-MLC-LHG,
Judge Mary L. Cooper.
                ______________________

                Decided: April 9, 2015
                ______________________

    DOMINICK A. CONDE, Fitzpatrick, Cella, Harper &
Scinto, New York, NY, argued for plaintiffs-appellees.
Also represented by DAVID E. DE LORENZI, Gibbons P.C.,
Newark, NJ. Plaintiffs-appellees Inspire Pharmaceuti-
cals, Inc., Pfizer Inc. also represented by MARGARET A.
SCOOLIDGE, Fitzpatrick, Cella, Harper & Scinto, New
York, NY; DENNIS C. AELING, Costa Mesa, CA.
2                 INSITE VISION INCORPORATED    v. SANDOZ, INC.



    BRIAN ROBERT MATSUI, Morrison & Foerster LLP,
Washington, DC, argued for defendant-appellant. Also
represented by DEANNE E. MAYNARD; DAVID CLARENCE
DOYLE, JAMES WEBB HUSTON, MARK ANDREW
WOODMANSEE, SAN DIEGO, CA; MATTHEW D'AMORE, NEW
YORK, NY.
               ______________________

    Before PROST, Chief Judge, NEWMAN and LINN, Circuit
                          Judges.
LINN, Circuit Judge.
     In this Hatch-Waxman Act litigation, Sandoz, Inc.
(“Sandoz”) appeals the district court’s decision in Insite
Vision, Inc. v. Sandoz, Inc, No. 11-3080, 2013 WL 5975015
(D.N.J. Oct. 4, 2013), which held that Sandoz had not
shown that the claims of U.S. Patents No. 6,861,411 (the
“’411 patent”); No. 6,239,113 (the “’113 patent”); No.
6,569,443 (the “’443 patent”); and No. 7,056,893 (the “’893
patent”) (collectively “the patents-in-suit”) asserted by
Insite Vision, Inc. (“Insite”); Inspire Pharm., Inc. (“In-
spire”); and Pfizer, Inc. (“Pfizer”) (collectively “plaintiffs”)
are invalid as obvious. This court agrees that Sandoz
failed to show that the asserted claims in the patents-in-
suit would have been obvious to a person of ordinary skill
in the art and therefore affirms.
                       I. BACKGROUND
                  A. THE PATENTS-IN-SUIT
    The ’411 patent issued from U.S. Patent Application
No. 09/200,199 (the “’119 application”), which was filed on
November 25, 1998, claiming priority to a provisional
application filed on December 2, 1997. It is owned by
Pfizer. Insite owns the ’113, ’443 and ’893 patents (the
“ISV patents”). The ISV patents claim priority to an
application filed on March 31, 1999. Inspire is the exclu-
INSITE VISION INCORPORATED   v. SANDOZ, INC.             3



sive sub-licensee of the ’411 patent and the exclusive
licensee of the ISV patents.
    The ’411 patent discloses methods of treating eye in-
fections by the topical administration of azithromycin to
the eye. ’411 patent col.1 ll.8–10. The patent states that
prior to the invention, azithromycin was commonly ad-
ministered orally for the treatment of antibacterial infec-
tions, but was not known to be effective when topically
administered to the eye. Id. at col.1 ll.22–27. Claim 1 of
the ’411 patent is representative and recites:
   1. A method of treating an ocular infection, com-
   prising topically administering to an eye of an an-
   imal in need of such treatment an ocular
   infection-treating amount of azithromycin.
    The ISV patents disclose various formulations and
methods of using topical azithromycin as a gel eyedrop for
treating eye infections. Claim 1 of the ’113 patent; claim
16 of the ’443 patent; and claim 1 of the ’893 patent are
representative and recite:
   1. A process for treating an eye, which comprises:
   topically applying an aqueous polymeric suspen-
   sion of an azalide antibiotic, wherein said suspen-
   sion comprises water, 0.01% to 1.0% of an azalide
   antibiotic, and 0.1 to 10% of a polymeric suspend-
   ing agent.
’113 patent claim 1;
   16. A topical ophthalmic composition comprising
   an aqueous polymeric suspension comprising wa-
   ter, 0.01% to 1.0% of an azalide antibiotic and 0.1
   to 10% of a polymeric suspending agent, wherein
   said topical ophthalmic composition has an osmot-
   ic pressure of from 10 to 400 mOsM and wherein
   said composition does not contain constituents
   that are physiologically or ophthalmically harmful
   to the eye.
4                INSITE VISION INCORPORATED   v. SANDOZ, INC.



’443 patent claim 16;
    1. A composition comprising water, a polymeric
    suspending agent and an azalide antibiotic,
    wherein said composition has a pH of about 6.0 to
    6.6.
’893 patent claim 1.
               B. HISTORY OF THE DISPUTE
    Inspire markets a topical azithromycin solution,
which is approved by the Food and Drug Administration
(“FDA”) and is distributed under the name “Azasite®.”
The FDA’s Approved Drug Products with Therapeutic
Equivalence Evaluations (commonly known as the “Or-
ange Book”) lists all four of the patents-in-suit for
Azasite®.
    Sandoz filed an Abbreviated New Drug Application
(“ANDA”) for its generic version of Azasite® seeking
approval prior to the expiration of the patents-in-suit.
The ANDA included a certification pursuant to 21 U.S.C.
§ 355(j)(2)(A)(vii)(IV) (2012) (commonly referred to as a
“Paragraph IV certification”) stating that the claims of the
patents-in-suit were invalid and/or not infringed. Pursu-
ant to § 355(j)(2)(B), Sandoz notified plaintiffs of the
Paragraph IV certification. In response, plaintiffs sued
Sandoz for infringing dependent claims 3 and 5 of the ’411
patent, which depend from claims 1 and 2; dependent
claims 6–9 of the ’113 patent, which depend from claims
1–3; independent claims 16 and 44 of the ’443 patent; and
dependent claims 4, 6, 7, 9–12, 30, 36 and 40 of the ’893
patent, which depend directly or indirectly from claims 1
or 23 (collectively, the “asserted claims”) under 35 U.S.C.
§ 271(e).
    After claim construction, Sandoz stipulated to in-
fringement but contested the validity of the asserted
INSITE VISION INCORPORATED   v. SANDOZ, INC.               5



claims under 35 U.S.C. § 103(a) (2006). 1 Insite, 2013 WL
5975015, at *2. Before trial, Sandoz moved to amend the
pre-trial order to include as an exhibit the file history of
the European counterpart of the ’411 patent (the “EPO
file history”). The district court denied that motion be-
cause it concluded that the late proffer was prejudicial. A
bench trial then ensued. The district court ruled that
Sandoz had failed to show by clear and convincing evi-
dence that the asserted claims would have been obvious to
a person of ordinary skill in the art and, therefore, upheld
the validity of all of the patents-in-suit. Id. at *49.
Sandoz appeals, contending that the district court “mis-
framed” the obviousness inquiry by adopting plaintiffs’
characterization of the problem facing a person of ordi-
nary skill in the art at the time of the invention as the
development of “improved topical treatments for ocular
infections,” id. at *20, rather than the narrower problem
argued by Sandoz of topically administering azithromycin
to treat conjunctivitis. Sandoz also appeals the district
court’s refusal to admit into evidence the late-proffered
EPO file history. We have jurisdiction pursuant to 28
U.S.C. § 1295(a)(1).
                      II. DISCUSSION
                 A. STANDARD OF REVIEW
   “Following a bench trial on the issue of obviousness,
we review the court’s ultimate legal conclusions de novo
and the underlying factual findings for clear error.” Tyco
Healthcare Grp. LP v. Ethicon Endo-Surgery, Inc., 774



    1   Pursuant to § 3(n)(1) of the America Invents Act
(“AIA”), Pub. L. No. 112–29, amended § 103 applies to
patent applications with claims having an effective filing
date on or after March 16, 2013. Because the applications
for the patents-in-suit were filed before that date, the pre-
AIA version of § 103 applies.
6                INSITE VISION INCORPORATED   v. SANDOZ, INC.



F.3d 968, 974 (Fed. Cir. 2014) (citing Novo Nordisk A/S v.
Caraco Pharm. Labs., Ltd., 719 F.3d 1346, 1354 (Fed. Cir.
2013)). “A factual finding is clearly erroneous if, despite
some supporting evidence, we are left with the definite
and firm conviction that a mistake has been made.”
Ferring B.V. v. Watson Labs., Inc.-Fla., 764 F.3d 1401,
1406 (Fed. Cir. 2014) (citing United States v. U.S. Gypsum
Co., 333 U.S. 364, 395 (1948) and Alza Corp. v. Mylan
Labs., Inc., 464 F.3d 1286, 1289 (Fed. Cir. 2006)).
    “In review of an order denying a motion to amend, a
subject [that] is not unique to patent law, we look to the
law of the regional circuit court.” Optivus Tech., Inc. v.
Ion Beam Applications S.A., 469 F.3d 978, 985 (Fed. Cir.
2006) (quoting Kalman v. Berlyn Corp., 914 F.2d 1473,
1480 (Fed. Cir. 1990)). In the Third Circuit, a motion to
amend a pretrial order is reviewed for abuse of discretion.
Petree v. Victor Fluid Power, Inc., 831 F.2d 1191, 1194 (3d
Cir. 1987).
                     B. OBVIOUSNESS
    A patent is invalid “if the differences between the sub-
ject 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) (2006). As patents
are “presumed valid,” § 282, a defendant bears the burden
of proving invalidity by “clear and convincing evidence,”
Takeda Pharm. Co. v. Zydus Pharm. USA, Inc., 743 F.3d
1359, 1366 (Fed. Cir. 2014) (citing Microsoft Corp. v. i4i
Ltd., 131 S. Ct. 2238, 2242 (2011)).
    Obviousness is a question of law, based on underlying
factual determinations including: “the scope and content
of the prior art”; “differences between the prior art and
the claims at issue”; “the level of ordinary skill in the
pertinent art”; and “[s]uch secondary considerations as
commercial success, long felt but unsolved needs, failure
INSITE VISION INCORPORATED   v. SANDOZ, INC.            7



of others, etc.” Graham v. John Deere Co. of Kan. City,
383 U.S. 1, 17 (1966). “When there is a design need or
market pressure to solve a problem and there are a finite
number of identified, predictable solutions, a person of
ordinary skill has good reason to pursue the known op-
tions within his or her technical grasp.” KSR Int’l Co. v.
Teleflex Inc., 550 U.S. 398, 421 (2007).
                   1. THE ’411 PATENT
      a. The Framing of the Obviousness Question
    The district court began its obviousness analysis by
addressing a dispute between the parties regarding the
proper “framing” of the obviousness question. Insite, 2013
WL 5975015, at *19. Plaintiffs argued that the proper
question to be considered by the court was whether it
would have been obvious to a person of ordinary skill in
the art at the time of the invention to develop a topical
ophthalmic formulation containing azithromycin. Sandoz
argued for a narrower question: whether it would have
been obvious that topical azithromycin could be used to
treat conjunctivitis. The district court agreed with the
plaintiffs and found no reason to limit the question to
conjunctivitis and to azithromycin. The district court
found that there were options beyond just azithromycin
that were available to a formulator when considering
topical ophthalmic treatments, id. at *22, and that per-
sons of ordinary skill in the art would not have developed
formulations that only treated conjunctivitis and not
corneal infections, given concerns about the spread of
conjunctival infections to the cornea. Id.
    On appeal, Sandoz argues that the district court erred
as a matter of law in its framing of the obviousness in-
quiry. Sandoz contends that in broadly framing the
obviousness inquiry, the district court required Sandoz to
prove the obviousness of topical treatments of all manner
of eye infections and not merely conjunctivitis with
azithromycin. Sandoz contends that this amounts to an
8                INSITE VISION INCORPORATED   v. SANDOZ, INC.



error of law contrary to bedrock legal principles that
“‘[c]laims which are broad enough to read on obvious
subject matter are unpatentable even though they also
read on nonobvious subject matter.’” Muniauction, Inc. v.
Thomson Corp., 532 F.3d 1318, 1328 n.4 (Fed. Cir. 2008)
(alteration in original) (quoting In re Lintner, 458 F.2d
1013, 1015 (C.C.P.A. 1972)). Sandoz also relies heavily on
Alcon Research, Ltd. v. Apotex Inc., in which this court
held that courts should “look at any motivation [for com-
bining references, even] beyond that articulated by the
patent.” 687 F.3d 1362, 1368 (Fed. Cir. 2012).
    Plaintiffs respond that identifying the problem faced
by a person of skill in the art is a factual question, on
which the district court properly ruled. Plaintiffs contend
that nothing in the district court’s framing of the issue
precluded Sandoz from proving that topical treatment of
conjunctivitis would have been obvious, but that Sandoz
simply failed to carry its burden—a factual issue not a
legal question.
    The district court did not clearly err in framing the
obviousness inquiry as it did, based on its understanding
of the problem facing those skilled in the art at the time
the invention was made. Moreover, the district court, in
framing the question, did not foreclose Sandoz from
attempting to prove that the claims would have been
obvious based on the treatment of conjunctivitis by the
topical administration of azithromycin.
    The obviousness inquiry entails consideration of
whether a person of ordinary skill in the art “would have
been motivated to combine the teachings of the prior art
references to achieve the claimed invention, and . . . would
have had a reasonable expectation of success in doing so.”
Proctor & Gamble Co. v. Teva Pharm. USA, Inc., 566 F.3d
989, 994 (Fed. Cir. 2009) (internal quotation mark omit-
ted) (quoting Pfizer, Inc. v. Apotex, Inc., 490 F.3d 1348,
1361 (Fed. Cir. 2007)); see also Bayer Schering Pharma
INSITE VISION INCORPORATED   v. SANDOZ, INC.             9



AG v. Barr Labs, Inc., 575 F.3d 1341, 1347 (Fed. Cir.
2009). “In considering motivation in the obviousness
analysis, the problem examined is not the specific prob-
lem solved by the invention.” In re Kahn, 441 F.3d 977,
988 (Fed. Cir. 2006). “Defining the problem in terms of its
solution reveals improper hindsight in the selection of the
prior art relevant to obviousness.” Monarch Knitting
Mach. Corp. v. Sulzer Morat GmbH, 139 F.3d 877, 881
(Fed. Cir. 1998). And, here, the district court recognized
that an overly narrow “statement of the problem [can]
represent[] a form of prohibited reliance on hindsight,
[because] [o]ften the inventive contribution lies in defin-
ing the problem in a new revelatory way.” Mintz v. Dietz
& Watson, Inc., 679 F.3d 1372, 1377 (Fed. Cir. 2012).
    Whether a person of ordinary skill in the art would
narrow the research focus to lead to the invention de-
pends on the facts. Alcon is not to the contrary. Alcon
merely holds that if the prior art would motivate a person
of skill in the art to make the claimed invention, even if
that was not based on “the same motivation that the
patentee had,” the patent would have been obvious. 687
F.3d at 1368. But whether the prior art would so moti-
vate a skilled artisan is a question of fact. Cf. PAR
Pharm., Inc. v. TWI Pharm., Inc., 773 F.3d 1186, 1196
(Fed. Cir. 2014) (“‘The presence or absence of a motivation
to combine references in an obviousness determination is
a pure question of fact.’” (quoting Alza Corp. v. Mylan
Labs., Inc., 464 F.3d 1286, 1289 (Fed. Cir. 2006))).
    Here, the district court did not clearly err in finding
that the problem faced by one skilled in the art was
broader than merely seeking to use azithromycin to treat
conjunctivitis. The district court found that azithromy-
cin’s characteristics—including that molecules in its class
were “known to be bacteriostatic, to have a limited spec-
trum of activity, and to require multiple doses per day to
penetrate tissue,” Insite, 2013 WL 5975015, at *19—
would make it a poor choice for treating ocular infections.
10               INSITE VISION INCORPORATED   v. SANDOZ, INC.



Furthermore, the district court found “the unique balance
of log P, molecular weight, solubility, and charge,” also
made it “not a good candidate.” Id. The district court also
credited the testimony of plaintiffs’ expert, Dr. Asbell,
that, desirably, effective treatment of conjunctivitis would
include penetration of the cornea as well as the conjuncti-
va because of the potential that a conjunctival infection
could spread to the cornea. Id. at *7–8. These factual
findings provide sufficient support for the district court’s
framing of the relevant question.
    And the district court’s framing of the question did
not prevent Sandoz from attempting to invalidate the
asserted claims, which were not limited to the cure of
conjunctivitis, by proving that it would have been obvious
to use azithromycin in a topical treatment to cure that
one infection. The problem for Sandoz, as we will next
address, is that its proofs simply failed to carry the day in
satisfying its clear and convincing burden.
     b. The Merits of the Obviousness Determination
     Sandoz claims that the ’411 patent is an obvious mod-
ification of Ilotycin®—a topical formulation of erythromy-
cin (an active ingredient similar to azithromycin)—and
Zithromax®, an oral azithromycin formulation used to
treat conjunctivitis. Sandoz argues that in light of the
teachings of the prior art, it would have been obvious to
try azithromycin as a topical treatment of bacterial con-
junctivitis, with a reasonable expectation of success. It
relies on the testimony of Dr. Reed that azithromycin was
the “newer iteration” of erythromycin, with remarkably
effective properties and contends that it would have been
common sense to substitute a new and improved antibi-
otic for the antibiotic present in Ilotycin®. Id. at *14
(quoting the trial testimony of Dr. Reed).
    Sandoz also contends that persons of ordinary skill in
the art would have been motivated to use azithromycin in
a topical treatment given that it was well known, accord-
INSITE VISION INCORPORATED   v. SANDOZ, INC.             11



ing to Sandoz’s expert, Dr. Goren, that topical treatments
are generally more effective than oral treatments. It also
asserts that while oral use of azithromycin worked
through a unique process called phagocytosis, that process
was not the only process at work in delivering the drug to
infected tissue and persons of ordinary skill in the art
would not have been deterred from investigating the
topical administration of azithromycin. Finally, Sandoz
relies on proposals for the topical use of azithromycin in
the treatment of trachoma allegedly made at a 1997
World Health Organization meeting that occurred in
Geneva (the “Geneva meeting”) and contends that the
district court was wrong to disregard and discount this
evidence.
    Plaintiffs counter by arguing that the district court’s
factual findings were well-supported and not clearly
erroneous. They argue that the district court considered
all of the potential drug options and correctly concluded
that those options would have directed persons of ordi-
nary skill in the art away from the topical administration
of azithromycin. They also assert that there is no correla-
tion between oral and topical ophthalmic drug penetra-
tion.      Finally, they point to Sandoz’s expert’s
contemporaneous failure to use azithromycin topically
prior to the ’411 invention as evidence of non-obviousness.
    The district court concluded that it would not have
been obvious to a person of ordinary skill in the art to
formulate a topical azithromycin formulation for oph-
thalmic treatment of any infection as recited in the as-
serted claims of the ’411 patent. The district court
thoroughly and properly considered all of the evidence
presented and the various arguments raised by the par-
ties in ruling the asserted claims to be not invalid. We
agree.
    First, the district court did not clearly err in finding
that there were “innumerable” options for ophthalmic
12               INSITE VISION INCORPORATED   v. SANDOZ, INC.



treatments, including fluoroquinolones.         Id. at *22.
Fluoroquinolones “were known to be a better option than
azithromycin,” because they “were bactericidal[,] could act
on a broad range of bacteria [and] were known to pene-
trate ocular tissue.” Id. at *21, *22. Furthermore, the
district court did not clearly err in determining that those
of skill in the art would have been concerned that
azithromycin might not penetrate ocular tissue based on
its high molecular weight, charge and insolubility in
water. Id. at *22. Even Sandoz’s expert, Dr. Reed, admit-
ted that compounds with high molecular weights and
charged compounds might not penetrate ocular tissue.
See id. at *13.
    The district court also did not clearly err in crediting
Dr. Asbell’s testimony that a person of ordinary skill in
the art “would not assume that delivering high concentra-
tions of a drug to the eye topically would ensure that the
drug would penetrate the ocular tissue simply because the
drug was successful when administered systemically.” Id.
at *8. Dr. Asbell’s testimony is supported by the fact that
oral azithromycin was delivered to the eye at least in part
through phagocytosis—a bloodstream dependent pro-
cess—which would not occur when azithromycin was
administered topically. See id. at *11, *21.
    The district court did not clearly err in discounting
the relevance of Ilotycin®, given that there was conflicting
expert testimony on whether it had fallen out of favor by
1996. See id. at *9–10. The district court also did not
clearly err in discounting Dr. Reed’s testimony that
erythromycin formulations would make azithromycin
formulations obvious, given that Dr. Reed’s own 1994
patent for topical ophthalmic treatments listed 24 poten-
tial antibiotics, including erythromycin, but did not list
azithromycin. See id. at *18.
   For all of the above reasons, this court concludes that
Sandoz has not met its clear and convincing burden and
INSITE VISION INCORPORATED   v. SANDOZ, INC.            13



therefore affirms the district court’s determination that
the asserted claims of the ’411 patent are not invalid.
                   2. THE ISV PATENTS
    The ISV patents disclose various formulations and
methods of using topical azithromycin as a gel eyedrop for
treating eye infections. The claims essentially call for
azalide (azithromycin) in a polymeric suspending agent
for topical ophthalmic use. The district court concluded
that none of the asserted claims of the ISV patents would
have been obvious based on its finding that persons of
ordinary skill in the art would not have been motivated to
use the water-based polymeric solutions of the prior art in
an azithromycin formulation because azithromycin was
considered insoluble and unstable in water. See id. at
*47. In addition, it found that were one to make a topical,
water-based azithromycin formulation, one of skill in the
art would not use polycarbophil, a gelling polymer, but
would instead use a colloidal system. See id. The district
court also found that many of the other limitations pre-
sent in the claims were separately not obvious. See id. at
*48. Finally, the district court found that the secondary
considerations of unexpected results and long-felt need
favored plaintiffs. Id. at *49.
    On appeal, Sandoz repeats its “framing of the obvi-
ousness question” argument and contends that it would
have been obvious to use azithromycin to treat conjuncti-
vitis and to formulate that treatment using DuraSite®, a
commercial embodiment of Insite’s U.S. Patent No.
5,192,535 (the “’535 patent”), which lists a number of
active ingredients, including erythromycin. According to
Sandoz, it would have been obvious to replace erythromy-
cin with azithromycin. It also contends that the ’411
patent itself is prior art to the ISV patents and that
14               INSITE VISION INCORPORATED   v. SANDOZ, INC.



Example 5 of the ’411 patent 2 discloses a water-based
azithromycin formulation that renders the asserted
claims obvious.
    Plaintiffs repeat their argument regarding the fram-
ing of the obviousness question and contend that the
district properly determined that the ISV patents were
not obvious. They argue that the ’535 patent is too gen-
eral and lacked sufficient data to motivate a person of
skill in the art to combine azithromycin with polycarbo-
phil. They further contend that the expert testimony
presented at trial supports the district court’s conclusion
that the prior art taught away from the use of an aqueous
polymer with azithromycin as recited in the asserted
claims of the ISV patents. Plaintiffs also argue that
Sandoz failed to show that a person of ordinary skill in
the art would have been motivated to select a polymeric
solution from among the number of choices available or
would have had a reasonable expectation of success in
making such a selection. Finally, Plaintiffs argue that the
district court correctly held the asserted claims of the ISV
patents are not invalidated by the ’411 patent.
    We have already addressed the framing of the obvi-
ousness question in connection with our treatment of
the ’411 patent, supra at 7–10. On the merits, we agree
with the district court that Sandoz has not clearly and
convincingly shown that the asserted claims of the ISV
patents would have been obvious. Sandoz relies on
the ’535 patent, which mentions the possibility that
erythromycin could be combined with polycarbophil. The
district court found, however, that the ’535 patent disclos-
es a “laundry list of active ingredients” and credited the
testimony of Dr. Lee that a researcher would focus on the


     2  The heading for Example 5 is missing in the speci-
fication of the ’411 patent. Example 5 is described from
column 3 line 57 to column 4 line 2.
INSITE VISION INCORPORATED   v. SANDOZ, INC.              15



patent’s examples, none of which mention erythromycin.
See Insite, 2013 WL 5975015, at *37. We see no clear
error in the district court’s findings. See ’535 patent col.8
l.64–col.9 l.25 (listing numerous potential active ingredi-
ents).
    Sandoz argues that the district court’s treatment of
the ’535 patent is inconsistent with Merck & Co., Inc. v.
Biocraft Labs., Inc., which held that just because a “pa-
tent discloses a multitude of effective combinations does
not render any particular formulation less obvious.” 874
F.2d 804, 807 (Fed. Cir. 1989). Sandoz overreads Merck.
In Merck, one reference expressly taught the combination
of the compounds claimed in the patent. Id. Here, by
contrast, selecting from the laundry list of potential active
ingredients listed in the ’535 patent at best teaches that
polycarbophil can be combined with erythromycin.
The ’535 patent does not mention azithromycin. Thus,
the skilled artisan would still need to modify that combi-
nation by changing erythromycin to azithromycin. More-
over, as noted above, those of skill in the art would have
been concerned about azithromycin’s solubility and stabil-
ity in water, so the modification from erythromycin to
azithromycin would be even less obvious.
    As for the admissibility of the ’411 patent as a refer-
ence against the ISV patents, we note that the ’119 appli-
cation (which issued as the ’411 patent) was filed in 1998,
before the earliest priority date of the ISV patents.
The ’411 patent is assigned to Pfizer, while the ISV pa-
tents are assigned to Insite. The patents are not common-
ly owned or subject to a duty to assign to a common
owner. Accordingly, the ’411 patent qualifies as prior art
to the ISV patents under 35 U.S.C. §§ 102(e) and 103(c)
(2006). The significance of the fact that these patents are
not commonly owned, despite their being licensed to
Inspire and listed in the Orange Book, may not have been
fully appreciated by Sandoz’s expert, Dr. Reed, who said
he was not basing his opinions on any post-1996 refer-
16                INSITE VISION INCORPORATED   v. SANDOZ, INC.



ences. Insite, 2013 WL 5975015, at *24. Be that as it
may, the district court’s ruling that Dr. Reed was preclud-
ed from relying on the ’411 patent should not preclude
Sandoz from relying on the ’411 patent itself as a refer-
ence, as it was listed by Sandoz in its pre-trial submis-
sion. And the district court, anticipating the possibility of
appeal, took the precaution of analyzing whether the ISV
patents were obvious over the ’411 patent. Id. It found
that even in light of the ’411 patent, the claims of the ISV
patents were not obvious. Id. at *46. We agree. The
district court found the water-based examples of the ’411
patent to fall far short of satisfying Sandoz’s burden and
found persuasive the testimony of Drs. Lee and Ahmed
that the examples disclosing azithromycin and water-
based polymers raised concerns as to stability. The
district court also found persuasive the testimony of Drs.
Reed and Lee that there were significant differences
between Carbopol disclosed in the ’411 patent and the
polycarbophil of the ISV patents. We find no clear error
in the district court’s fact-finding or the legal conclusion it
drew therefrom on the obviousness question.
     Finally, we cannot say that the district court clearly
erred in finding that there were meaningful secondary
considerations. The district court found that a 60-fold
increase in the concentration of azithromycin when dosed
topically as opposed to orally was unexpected and also
found that Azasite® met a long-felt need. Insite, 2013 WL
5975015, at *49, *50. Sandoz argues that some increase
in concentration was to be expected. See Appellant’s Br.
at 50. Even if true, Sandoz has not shown that a 60-fold
increase was expected. Sandoz also offers nothing to
rebut the district court’s finding that Azasite® met a long-
felt need.
   In sum, we find that Sandoz has failed to clearly and
convincingly show that the claims of the ISV patents
would have been obvious.
INSITE VISION INCORPORATED   v. SANDOZ, INC.             17



        3. The Exclusion of the EPO File History
    Sandoz sought to introduce into evidence the EPO file
history, which allegedly chronicled some of the discus-
sions held at the Geneva meeting. Sandoz did not list this
document in its original exhibit list. It only sought to
amend the exhibit list after the pretrial conference and
after briefing and supplemental briefing on the various
motions in limine were complete.
    In an oral order, the district court refused to allow
Sandoz to introduce the EPO file history into evidence.
The district court based its decision on several grounds,
remarking that Sandoz’s attempt to introduce the evi-
dence was “an eleventh hour proffer”; that it would take
plaintiffs “quite a bit of preparation” to deal with these
documents; that it was “told” but did not know that Euro-
pean patent law would regard oral presentations and
accompanying documentation, even if not widely availa-
ble, as prior art; and that the file contained attorney
arguments and not factual statements. The district court
acknowledged that, as parties to the original proceedings,
plaintiffs were aware of these documents and that “[s]ome
courts might consider th[e] [European proceedings] to be
pretty powerful evidence.”
    Sandoz argues that the district court abused its dis-
cretion in precluding it from amending the exhibit list.
According to Sandoz, the EPO file history contains factual
admissions about the date and content of the Geneva
meeting relevant to its obviousness case. Sandoz further
contends that there was no finding of bad faith or improp-
er tactics in the filing of its motion to amend and that the
prejudice to plaintiffs of allowing this evidence would
have been minimal. Plaintiffs counter that the district
court’s basis for excluding this document was sufficient
and did not amount to an abuse of discretion.
    Federal Rule of Civil Procedure 16(e) states that a
“court may modify the order issued after a final pretrial
18                 INSITE VISION INCORPORATED   v. SANDOZ, INC.



conference only to prevent manifest injustice.” The Third
Circuit considers five Pennypack factors in determining
whether a district court abused its discretion in excluding
evidence:
     (1) “the prejudice or surprise in fact of the party
     against whom the excluded witnesses would have
     testified” or the excluded evidence would have
     been offered; (2) “the ability of that party to cure
     the prejudice”; (3) the extent to which allowing
     such witnesses or evidence would “disrupt the or-
     derly and efficient trial of the case or of other cas-
     es in the court”; (4) any “bad faith or willfulness in
     failing to comply with the court’s order”; and (5)
     the importance of the excluded evidence.
ZF Meritor, LLC v. Eaton Corp., 696 F.3d 254, 298 (3d
Cir. 2012) (quoting Pennypack Woods Home Ownership
Ass’n, 559 F.2d 894, 904–05 (3d Cir. 1977)). “The im-
portance of the evidence is often the most significant
factor.” Id. (citing Sowell v. Butcher & Singer, Inc., 926
F.2d 289, 302 (3d Cir. 1991) and Pennypack, 559 F.2d at
904). A decision to exclude testimony should be disturbed
only if there is “‘a definite and firm conviction that the
court below committed a clear error of judgment.’” Id. at
293 (quoting In re TMI Litig., 193 F.3d 613, 666 (3d Cir.
1999)).
    Here, we do not have such a definite and firm convic-
tion for several reasons. We agree with the district court’s
assessment of the relevant Pennypack factors as being
either neutral or favoring plaintiffs. The district court
had ample basis to find prejudice to the plaintiffs as
plaintiffs, on the eve of trial, would have had to prepare
arguments explaining the differences between European
and United States’ patent law and the significance of the
statements in the prior proceedings. There is also no
indication of how plaintiffs would have been able to cure
that prejudice. Thus, the first two factors favor plaintiffs.
INSITE VISION INCORPORATED   v. SANDOZ, INC.               19



    The third factor, disruption of trial, is neutral at best.
Likewise, the fourth factor, bad faith, is neutral, given the
fact that the district court made no finding either way on
the question of bad faith. “Making no finding on the
question of bad faith (which is what the district court did)
is quite different from finding that there was no bad
faith.” Konstantopoulos v. Westvaco Corp., 112 F.3d 710,
720 n.7 (3d Cir. 1997). As for the fifth factor, relating to
the importance of the excluded evidence, the district court
was correct to at least question the relevance and proba-
tive value of the EPO file history under United States
law. The situation here is thus notably different from the
facts of ZF Meritor, where the exclusion of testimony
“clear[ly]” foreclosed plaintiffs’ suit, despite the fact that
they had won at the liability stage. 696 F.3d at 299. This
factor, like the others, does not favor Sandoz.
    In view of the totality of evidence, we do not have a
definite and firm conviction that the district court abused
its discretion and have no reason to disturb the district
court’s decision to exclude the EPO file history.
                      III. CONCLUSION
    For the foregoing reasons, we affirm the district
court’s determination that the asserted claims have not
been shown to be invalid.
                        AFFIRMED
