  United States Court of Appeals
      for the Federal Circuit
                ______________________

    MILLENNIUM PHARMACEUTICALS, INC.,
             Plaintiff-Appellant

                           v.

   SANDOZ INC., ACCORD HEALTHCARE, INC.,
ACTAVIS LLC, MYLAN LABORATORIES LIMITED,
     AGILA SPECIALTIES INC., DR. REDDY'S
      LABORATORIES, LTD., DR. REDDY'S
 LABORATORIES, INC., SUN PHARMACEUTICAL
 INDUSTRIES LIMITED, SUN PHARMA GLOBAL
    FZE, APOTEX CORP., APOTEX INC., TEVA
   PHARMACEUTICALS USA, INC., GLENMARK
     PHARMACEUTICALS LTD., GLENMARK
  GENERICS LTD., GLENMARK GENERICS INC.,
   USA, HOSPIRA, INC., WOCKHARDT BIO AG,
            WOCKHARDT USA LLC,
              Defendants-Appellees
             ______________________

2015-2066, 2016-1008, 2016-1009, 2016-1010, 2016-1109,
           2016-1110, 2016-1283, 2016-1762
               ______________________

    Appeals from the United States District Court for the
District of Delaware in Nos. 1:12-cv-01011-GMS, 1:12-cv-
01490-GMS, 1:12-cv-01750-GMS, 1:13-cv-01874-GMS,
1:14-cv-01156-GMS, 1:15-cv-00040-GMS, 1:15-cv-00539-
GMS, 1:15-cv-00540-GMS, 1:15-cv-00804-GMS, 1:16-cv-
00034-GMS, Judge Gregory M. Sleet.
                 ______________________
2              MILLENNIUM PHARMACEUTICALS    v. SANDOZ INC.



                  Decided: July 17, 2017
                 ______________________

    WILLIAM F. LEE, Wilmer Cutler Pickering Hale and
Dorr LLP, Boston, MA, argued for plaintiff-appellant.
Also represented by MARK CHRISTOPHER FLEMING, LISA
JON PIROZZOLO, JASON H. LISS, ANNA E. LUMELSKY, TASHA
JOY BAHAL, EMILY R. WHELAN; ROBERT M. GALVIN, Palo
Alto, CA.

   THOMAS J. MELORO, Willkie Farr & Gallagher LLP,
New York, NY, argued for all defendants-appellees.
Defendant-appellee Hospira, Inc. also represented by
MICHAEL JOHNSON.

    GEORGE C. LOMBARDI, Winston & Strawn LLP, Chica-
go, IL, for defendant-appellee Sandoz Inc. Also represent-
ed by KATHLEEN BRIDGET BARRY, MAUREEN L. RURKA.

    PAUL BRAIER, Greenblum & Bernstein, P.L.C., Reston,
VA, for defendant-appellee Accord Healthcare, Inc. Also
represented by PETER BRANKO PEJIC.

    GARY EDWARD HOOD, Polsinelli PC, Chicago, IL, for
defendant-appellee Actavis LLC. Also represented by
MARK THOMAS DEMING, KHURRAM NAIK; ROBYN AST-
GMOSER, St. Louis, MO.

    TUNG ON KONG, Rhodes Attorneys at Law P.C., San
Francisco, CA, for defendants-appellees Mylan Laborato-
ries Limited, Agila Specialties Inc. Also represented by
ELHAM FIROUZI STEINER, Wilson, Sonsini, Goodrich &
Rosati, PC, San Diego, CA.

    LOUIS HARRY WEINSTEIN, Budd Larner, P.C., Short
Hills, NJ, for defendants-appellees Dr. Reddy’s Laborato-
ries, Ltd., Dr. Reddy’s Laboratories, Inc. Also represented
by ELLEN TCHORNI LOWENTHAL, STUART D. SENDER.
MILLENNIUM PHARMACEUTICALS   v. SANDOZ INC.            3




    RACHEL C. HUGHEY, Merchant & Gould P.C., Minne-
apolis, MN, for defendants-appellees Sun Pharmaceutical
Industries Limited, Sun Pharma Global FZE. Also repre-
sented by AARON M. JOHNSON, CHRISTOPHER J. SORENSON.

   WILLIAM A. RAKOCZY, Rakoczy Molino Mazzochi Siwik
LLP, Chicago, IL, for defendants-appellees Apotex Corp.,
Apotex Inc. Also represented by PETER JAMES CURTIN,
THOMAS EHRICH, LUKE TIMOTHY SHANNON.

    MARK DAVID SCHUMAN, Carlson, Caspers, Vanden-
burgh, Lindquist & Schuman, P.A., Minneapolis, MN, for
defendant-appellee Teva Pharmaceuticals USA, Inc. Also
represented by JENNELL CHRISTINE BILEK, SAMUEL T.
LOCKNER, ALEXANDRA JANE OLSON, TODD S. WERNER.

    JAY PHILIP LESSLER, Blank Rome LLP, New York, NY,
for defendants-appellees Glenmark Pharmaceuticals Ltd.,
Glenmark Generics Ltd., Glenmark Generics Inc., USA.
Also represented by CHRISTOPHER K. HU, PAUL M. ZAGAR;
DAVID ANTHONY DOREY, Wilmington, DE.

    KEVIN MICHAEL NELSON, Duane Morris LLP, Chicago,
IL, for defendants-appellees Wockhardt Bio AG, Wock-
hardt USA LLC. Also represented by PATRICK
GALLAGHER.
                ______________________
 Before NEWMAN, MAYER, and O’MALLEY, Circuit Judges.
NEWMAN, Circuit Judge.
    Millennium Pharmaceuticals, Inc. is the exclusive li-
censee of U.S. Patent No. 6,713,446 (“the ’446 Patent”),
issued March 30, 2004 and assigned to the United States.
Millennium developed the patented product for treatment
of oncology disease, particularly multiple myeloma and
mantle cell lymphoma. The product has the brand name
4              MILLENNIUM PHARMACEUTICALS      v. SANDOZ INC.



Velcade®. Appellees in Appeal Nos. 15-2066, 16-1008, 16-
1009, 16-1010, 16-1110, 16-1283, and 16-1762 (collective-
ly, “Sandoz”) all filed abbreviated new drug applications
(“ANDAs”), admitting infringement and seeking to invali-
date various claims of the ’446 Patent. Based on the
litigation that ensued, the district court held that claims
20, 31, 49, and 53 of the ’446 Patent were invalid, 1 leading
to this appeal.
    Millennium filed a notice of appeal in Appeal No. 16-
1109 after the district court entered final judgment
against Millennium in separate cases arising from AN-
DAs filed by Apotex and Teva, based on collateral estop-
pel arising from the district court’s judgment of invalidity
of claims 20, 31, 49, and 53 of the ’446 Patent in the
Sandoz-Millennium action. We consolidated the appeals
in the Sandoz, Apotex, and Teva actions.
     On review of the record and the applicable law, we
conclude that the district court erred in the Sandoz litiga-
tion and that invalidity was not established. We reverse
and enter judgment in favor of Millennium in the Sandoz
litigation. We also vacate the district court’s judgment in
the action between Millennium, Teva, and Apotex based
on our decision in the Sandoz litigation and remand that
action for further proceedings.
                      I. BACKGROUND
                    A. The ’446 Patent
    The ’446 Patent describes the chemical compound D-
mannitol      N-(2-pyrazine)carbonyl-L-phenylalanine-L-
leucine boronate. The compound is described as a boro-



    1  Millennium Pharm., Inc. v. Sandoz Inc., No. 12-
1011, 2015 WL 4966438 (D. Del. Aug. 20, 2015) (“Dist. Ct.
Op.”).
MILLENNIUM PHARMACEUTICALS    v. SANDOZ INC.              5



nate ester of bortezomib (a boronic acid) and D-mannitol
(a hydroxy compound) and has the following chemical
structure, with Millennium’s highlight of the bonds be-
tween the bortezomib moiety and the D-mannitol moiety:




Millennium Br. 13. The lyophilized compound is claimed
in Claim 20:
   20. The lyophilized compound D-mannitol N-(2-
   pyrazine)carbonyl-L-phenylalanine-L-leucine
   boronate.
Other asserted claims include the new compound as a
lyophilized cake, the method of preparation of the new
compound, and its reconstitution with a pharmaceutically
acceptable carrier. Dist. Ct. Op. *2.
    Bortezomib and its properties as a proteasome inhibi-
tor were previously known and are described in United
States Patent No. 5,780,454 (“the Adams Patent”). How-
ever, despite its known efficacy against various cancers,
bortezomib never achieved FDA approval and market
status because of its instability, its rapid degradation in
liquid formulations, and its insolubility. The record states
that these problems remained unsolved despite extensive
research effort by the inventor Dr. Adams and others at
Millennium and its predecessor company. Dr. Adams’
team attempted to develop a stable liquid formulation of
bortezomib, but after evaluating approximately 20 differ-
ent formulations, the team failed to develop a formulation
that was stable enough for transportation, storage, and
6              MILLENNIUM PHARMACEUTICALS     v. SANDOZ INC.



administration to patients under conditions of clinical use
and distribution.
    The inventor of the ’446 Patent was associated with
the National Cancer Institute and the University of
Kansas, and was consulted by Dr. Adams after years of
unsuccessful attempts to solve formulation and stability
problems with bortezomib. Despite preparing approxi-
mately twenty-five different liquid formulations, these
efforts encountered the same stability and solubility
problems as had other researchers attempting to solve
this problem.
    After failing to develop a viable liquid formulation, re-
searchers began work on a lyophilized formulation for
injection. The process of lyophilization (freeze-drying) is
not intended to change the chemical structure of the
active pharmaceutical ingredient. After experimenting
with multiple variables that affect the lyophilization
process, including solvents and bulking agents, research-
ers produced a promising lyophilized formulation using
mannitol, a known bulking agent. It was discovered that
the reason for the dramatic improvement in dissolution
and stability for this formulation was the formation of a
new chemical compound during lyophilization: the
claimed ester of bortezomib and mannitol. The mannitol
ester of bortezomib acts as a “prodrug,” a compound that
converts to or releases the active pharmaceutical ingredi-
ent upon administration to a patient. This discovery is
described and claimed in the ’446 Patent.
     The ensuing drug product (Velcade®) became “a can-
cer treatment that changed the decades-old standard of
care for multiple myeloma and has saved thousands of
lives. The FDA approved Velcade® in record time, despite
its novel structure and mechanism of action.” Millennium
Br. 1.
MILLENNIUM PHARMACEUTICALS    v. SANDOZ INC.             7



           B. Proceedings in Sandoz Litigation
    After the Sandoz defendants each filed an ANDA
seeking FDA approval for the commercial manufacture,
use, and sale of generic counterparts of Velcade®, Millen-
nium filed patent infringement suits alleging that the
products infringe at least claims 20, 31, 49, and 53 of the
’446 Patent. The defendants stipulated to infringement of
all asserted claims, and raised the defense of patent
invalidity based on obviousness.
    The district court held that the claims were obvious
because they were the inherent result of an allegedly
obvious process, viz., lyophilizing bortezomib in the pres-
ence of the bulking agent mannitol. Millennium argued
that a person of ordinary skill would avoid lyophilization
in developing a formulation involving bortezomib because
“bortezomib was known to be unstable even in the dry
state as a freestanding solid compound.” Dist. Ct. Op. *6.
The court was not persuaded by this argument and in-
stead relied on the testimony of Sandoz’s witness, Dr.
Repta, to find that, as of the ’446 Patent’s priority date,
lyophilization “was well-known in the field of formulation”
and that it was considered an obvious alternative “when a
liquid formulation provided limited success.” Id.
    The district court did not find that the prior art
taught or suggested that the claimed new compound
would be formed, or taught or suggested making the
claimed new compound by any method, or taught or
suggested that this new compound would have the prop-
erties of stability, solubility, and dissociability that it
exhibited. No reference taught or suggested reacting
bortezomib with mannitol, and no reference hinted that
such an esterification reaction might occur during lyophi-
lization. No reference taught or suggested that the prod-
uct of such lyophilization would be a new chemical
compound that would solve the problems that had inhib-
ited development of bortezomib in oncology. However, the
8              MILLENNIUM PHARMACEUTICALS    v. SANDOZ INC.



district court concluded that lyophilizing bortezomib with
mannitol was an obvious option “from which the prior art
did not teach away.” Id. at *7. The district court found
that the Adams Patent “pointed directly to mannitol”
despite the Adams Patent’s failure to mention mannitol.
Id.
     The district court received testimony from the inven-
tor and others that the formation of this new compound
was not expected or intended when they conducted the
lyophilization. There was no contrary evidence. Nonethe-
less, the district court held the claims invalid on the
ground of obviousness, agreeing with Sandoz that “Mil-
lennium conceded as a matter of law that the ester is the
‘natural result’ of freeze-drying bortezomib with manni-
tol.” Id. at *8. The court reasoned that the “natural
result” of a chemical procedure is inherent in the proce-
dure, and thus the product thereof “would have been
obvious to a person of ordinary skill,” in the words of
§ 103.
    On the evidence of objective indicia of obviousness,
the district court found that Millennium did not establish
unexpected results because it did not compare the claimed
invention to a glycerol ester of bortezomib. Id. at *9. The
court also rejected long-felt need as objective evidence of
non-obviousness, stating that “the lyophilized mannitol
ester of bortezomib did not solve any problem having
persisted over a long period of time without resolution by
the prior art.” Id. at *10 (quoting Hitachi Koki Co. v.
Doll, 620 F. Supp. 2d 4, 30 (D.D.C. 2009)).
     C. Proceedings in Apotex and Teva Litigations
    Millennium also filed suit against Appellees Apotex
and Teva after each filed an ANDA seeking approval for
the commercial manufacture, use, and sale of a generic
MILLENNIUM PHARMACEUTICALS     v. SANDOZ INC.              9



version of Velcade®. 2 After the district court invalidated
claims 20, 31, 49, and 53 of the ‘446 Patent in the Sandoz
litigation, Apotex moved to dismiss Millennium’s in-
fringement claims, arguing that the district court’s opin-
ion created collateral estoppel barring Millennium from
re-litigating the validity of the asserted claims. Eventual-
ly the parties stipulated that collateral estoppel warrant-
ed entry of judgment and dismissal in favor of Apotex and
Teva.
                      II. DISCUSSION
                   A. Sandoz Litigation
     In this Hatch-Waxman litigation, the district court
invalidated the ’446 patent on the ground of obviousness.
The determination of obviousness under 35 U.S.C. § 103
is a legal conclusion based on underlying facts. Graham
v. John Deere Co. of Kansas City, 383 U.S. 1, 17 (1966).
After a bench trial, appellate review of the district court’s
factual findings is for clear error, and conclusions of law
receive de novo review. Allergan, Inc. v. Sandoz Inc., 726
F.3d 1286, 1290 (Fed. Cir. 2013) (citation omitted). Inva-
lidity of an issued patent must be shown by clear and
convincing evidence. Microsoft Corp. v. i4i Ltd. P'ship,
564 U.S. 91, 95 (2011). “While we afford deference to a
district court's factual findings, however, we retain plena-
ry review to determine whether, as a legal matter, the
evidence satisfies the clear-and-convincing standard of
proof.” In re Cyclobenzaprine Hydrochloride Extended-
Release Capsule Patent Litig., 676 F.3d 1063, 1069 (Fed.
Cir. 2012) (citing Procter & Gamble Co. v. Teva Pharm.
USA, Inc., 566 F.3d 989, 993-94 (Fed. Cir. 2009)).




    2   The district court consolidated Millennium’s liti-
gation against Teva and Apotex.
10             MILLENNIUM PHARMACEUTICALS      v. SANDOZ INC.



                             1.
     Recognizing our obligation to give deference to a dis-
trict court’s greater familiarity with the record and au-
thority to reach factual conclusions therefrom, we
conclude that the district court erred in its evaluation of
obviousness. See KSR Int’l Co. v. Teleflex Inc., 550 U.S.
398, 419-20 (2007) (the question of law is whether the
prior art rendered the invention obvious). In the case at
bar, the question is whether a person of ordinary skill,
seeking to remedy the known instability and insolubility
and to produce an efficacious formulation of bortezomib,
would obviously produce the D-mannitol ester of borte-
zomib, a previously unknown compound.
    The prior art contains no teaching or suggestion of
this new compound, or that it would form during lyophi-
lization. Sandoz identifies no reference or combination of
references that shows or suggests a reason to make the
claimed compound. No reference teaches or suggests that
such a new compound would have the long-sought proper-
ties of stability and solubility, and sufficiently dissociate
to release bortezomib at an effective rate in the blood-
stream, all critical to effective use for treating multiple
myeloma.
    The D-mannitol ester of bortezomib is a new com-
pound with distinct chemical properties. We consider
whether the prior art “would have supplied one of ordi-
nary skill in the art with a reason or motivation to modify
a lead compound to make the claimed compound with a
reasonable expectation of success.” Otsuka Pharm. Co.,
Ltd. v. Sandoz, Inc., 678 F.3d 1280, 1292 (Fed. Cir. 2012);
see also Bristol-Myers Squibb Co. v. Teva Pharm. USA,
Inc., 752 F.3d 967, 973 (Fed. Cir. 2014) (“To establish
obviousness in cases involving new chemical compounds,
the accused infringer must identify some reason that
would have led a chemist to modify a known compound.”);
In re Rosuvastatin Calcium Patent Litig., 703 F.3d 511,
MILLENNIUM PHARMACEUTICALS     v. SANDOZ INC.              11



518 (Fed. Cir. 2012) (affirming district court conclusion
that “the Defendants did not demonstrate the required
motivation for selecting Sandoz Compound 1b as a lead
compound”). The parties agree that bortezomib is the
proper lead compound for this analysis. It is not disputed
that the Velcade® compound provided unexpected proper-
ties, solving the problems that accompanied bortezomib.
    The district court clearly erred in its obviousness
analysis. There is no teaching or suggestion in the refer-
ences to produce the claimed mannitol ester. No reference
shows or suggests ester formation at freeze-drying condi-
tions, or that any such ester might solve the problems of
instability and insolubility of the free acid while dissociat-
ing rapidly in the bloodstream. No reference provides a
reason to make the mannitol ester of bortezomib.
    Sandoz argues that lyophilization was generally
known in formulating pharmaceutical products. It states
that bulking agents were known for use in lyophilization,
and that mannitol was a known bulking agent. All true.
However, the prior art does not teach or suggest that
lyophilization of bortezomib in the presence of mannitol
would produce a chemical reaction and form a new chemi-
cal compound, or provide a reason to make this specific
new chemical compound, or that this new compound
would solve the previously intractable problems of borte-
zomib formulation. Although mannitol was a known
bulking agent, and lyophilization was a known method of
drug formulation, nothing on the record teaches or sug-
gests that a person of ordinary skill should have used
mannitol as part of a synthetic reaction to make an ester
through lyophilization. A result is obvious when it is “the
natural result flowing from the operation as taught,” or a
“property that is necessarily present” when applying a
process disclosed in the prior art. Par Pharm., Inc. v. TWI
Pharm., Inc., 773 F.3d 1186, 1195 (Fed. Cir. 2014) (em-
phasis omitted) (first quoting In re Oelrich, 666 F.2d 578,
581 (CCPA 1981); then quoting Alcon Research, Ltd. v.
12             MILLENNIUM PHARMACEUTICALS     v. SANDOZ INC.



Apotex Inc., 687 F.3d 1362, 1369 (Fed. Cir. 2012), and In
re Kubin, 561 F.3d 1351, 1357 (Fed. Cir. 2009)). Sandoz
failed to show that it was obvious to use mannitol to make
an ester during lyophilization, or that the ester would
solve the problems experienced with bortezomib.
    Sandoz defends the district court’s ruling by citing
three groups of references that purportedly provide the
required teaching or suggestion. The first group shows
that lyophilization is a known technique to prepare
pharmaceutical formulations, although no reference
shows lyophilization of bortezomib. The second group
shows that mannitol is a known inert bulking agent,
although no reference shows mannitol as a bulking agent
for bortezomib. The third group starts from the Adams
Patent that states that boronic acids can form esters,
although mannitol is not included in the ester-forming
alcohols mentioned in the Adams Patent. None of these
references, alone or in combination, suggests or teaches
that the solution to the problems of creating an efficacious
formulation of bortezomib lay in freeze-drying bortezomib
with mannitol to form an ester having the necessary
properties for stability, storage, and treatment.
     Nor does the Adams Patent provide the requisite
teaching. As noted, bortezomib is described in the Adams
Patent. That reference states that bortezomib is a boronic
acid and that esters may be made, and it lists ten alcohols
for this purpose. Adams Patent, col. 10, ll. 15–18. Manni-
tol is not mentioned. Nor does the Adams Patent teach or
suggest that the esters provide a solution to the problems
of instability and insolubility of bortezomib.
    None of the experts presented by the many defend-
ants stated that they were aware of prior art to fill any of
the gaps in teaching or suggestion of the Velcade® prod-
uct—although they variously opined that this long-sought
discovery was obvious. Sandoz’s expert Dr. Repta, who
offered an opinion of obviousness, conceded that he had
MILLENNIUM PHARMACEUTICALS     v. SANDOZ INC.             13



“never worked with any boronic acid compound and has
not performed or supervised any lyophilization experi-
ments since 1983.” Repta Dep. Tr. at 190, l. 10–192, l. 8.
Dr. Repta cited seventeen references, none of which
teaches or suggests the claimed new compound, or pro-
poses lyophilization in the presence of mannitol to pro-
duce a new compound, or suggests that such new
compound should be prepared in order to obtain the
necessary stability, solubility, and dissociability for
treatment of multiple myeloma.
    Sandoz argues in this appeal that a Brown reference 3
and the Adams Patent teach that esters are more stable
to oxidation than boronic acids. Sandoz Br. 33 (citing
Adams, scheme 1, col. 29–30; Brown at 4526). However,
Sandoz’s witness Dr. Repta testified that (1) he could not
identify any portion of the Brown reference making this
point, Repta Dep. Tr. at 291, l. 18-292, l. 16, and (2) the
Adams Patent says nothing about the stability of any
ester, id. at 214, ll. 5–12. In Pfizer, Inc. v. Apotex, Inc.,
480 F.3d 1348, 1361 (Fed. Cir. 2007), the court held that,
in determining obviousness, the challenger bears the
burden of establishing 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 in doing so.” Here, neither the requisite moti-
vation nor expectation of success is found in the prior art.




    3  Herbert C. Brown and J.V.N. Vara Prasad, Chiral
Synthesis via Organoboranes. 9. Crystalline “Chelates”
from Borinic and Boronic Esters. A Simple Procedure for
Upgrading Borinates and Boronates to Materials Ap-
proaching 100% Optical Purity, 51 J. ORGANIC CHEMISTRY
4526 (1986).
14             MILLENNIUM PHARMACEUTICALS      v. SANDOZ INC.



    No reference supports the district court’s conclusion
that “skilled formulators would be motivated to create a
mannitol ester to improve bortezomib’s stability and
solubility.” Dist. Ct. Op. *8. No reference suggests pro-
ducing this ester for this purpose. The undisputed facts
are of failed attempts to achieve a stable formulation with
the necessary properties of solubility and dissolution in
the bloodstream.
     We take note of Sandoz’s reliance on selected portions
of Dr. McCubbin’s testimony in another case, for Sandoz
does not mention that he also testified that Millennium
could not have predicted that bortezomib would be stabi-
lized by forming the mannitol ester. See McCubbin Dep.
Tr. at 333, l. 24–334, l.4 (“But for any specific compound,
you don’t know what that stability is or whether it truly
stabilizes it. There’s examples where you can’t form that
ester or you form the ester, but it’s not particularly stable.
There – It’s very mixed. It’s a very compound-specific
analysis that one has to do to really justify its stability
difference.”).
     The sole reason Sandoz provides for choosing manni-
tol to make a new ester of bortezomib is because mannitol
is one of a relatively small number of bulking agents used
in lyophilization. Sandoz provides no reason why a per-
son of ordinary skill who is seeking to make esters of
bortezomib would look to lyophilization bulking agents.
Dr. Anderson explained that mannitol is used as a bulk-
ing agent in lyophilization, and he also explained that
persons experienced with bortezomib would know of
crystallization-and boroxine-related concerns, but would
not expect the bulking agent to react with the bortezomib
to form a new compound.
                              2.
    The district court also clearly erred in its determina-
tion that lyophilizing bortezomib with mannitol to form
an ester was a “suitable option from which the prior art
MILLENNIUM PHARMACEUTICALS    v. SANDOZ INC.            15



did not teach away.” Dist. Ct. Op. *7 (citing Par Pharm.,
773 F.3d at 1198). “A reference may be said to teach
away when a person of ordinary skill, upon reading the
reference, would be discouraged from following the path
set out in the reference, or would be led in a direction
divergent from the path that was taken by the applicant.”
In re Urbanski, 809 F.3d 1237, 1244 (Fed. Cir. 2016)
(quoting In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994)).
Millennium offered persuasive evidence that the chemical
modification of bortezomib would have been unattractive
to a person of ordinary skill for fear of disturbing the
chemical properties whereby bortezomib functions effec-
tively as an anti-cancer agent; in particular, a person of
ordinary skill would have noted that the ester blocks a
portion of the bortezomib molecule.          Without the
knowledge that the D-mannitol bortezomib ester dissoci-
ates in the bloodstream at a rate of pharmaceutical effica-
cy, a person of ordinary skill would not have been led to
create the ester. Dr. Repta’s testimony that dissociation
of boronic esters would be “virtually instantaneous” was
contradicted on cross-examination, and is not supported
by the Adams Patent, which does not discuss the dissocia-
tion or stability of the esters.
    We agree with Millennium that a person of ordinary
skill would have avoided creating an ester with mannitol
because several different esters, each with different
chemical and possibly biological properties, could have
formed. Dr. Adams testified that he was surprised when
he learned that such a multiplicity of mannitol esters did
not form with bortezomib.
                            3.
    The district court also clearly erred in its considera-
tion of inherency. “A party must . . . meet a high standard
in order to rely on inherency to establish the existence of
a claim limitation in the prior art in an obviousness
analysis.” Par Pharm., 773 F.3d at 1195–96. “The mere
16             MILLENNIUM PHARMACEUTICALS      v. SANDOZ INC.



fact that a certain thing may result from a given set of
circumstances is not sufficient” to render the result inher-
ent. In re Oelrich, 666 F.2d at 581 (quoting Hansgirg v.
Kemmer, 102 F.2d 212, 214 (CCPA 1939)).
    The district court stated that Millennium “conceded
as a matter of law that the ester is the ‘natural result’ of
freeze-drying bortezomib with mannitol.” Dist. Ct. Op. *8.
However, “[t]he inventor’s own path itself never leads to a
conclusion of obviousness; that is hindsight. What mat-
ters is the path that the person of ordinary skill in the art
would have followed, as evidenced by the pertinent prior
art.” Otsuka, 678 F.3d at 1296. This oft-cited principle is
explained in, for example, In re Kratz, 592 F.2d 1169,
1175 (CCPA 1979):
     However, making weight of the method appellant
     used in finding the invention is beside the point.
     The last sentence of 35 U.S.C. § 103, with great
     clarity, excludes such methodology in stating that
     “(p)atentability shall not be negatived by the
     manner in which the invention was made.”
See also, e.g., Life Techs., Inc. v. Clontech Labs., Inc., 224
F.3d 1320, 1325 (Fed. Cir. 2000) (“[T]he path that leads
an inventor to the invention is expressly made irrelevant
to patentability by statute.”).
    Sandoz argues that although lyophilization in the
presence of mannitol produced an unexpected result, the
result was “inevitable” and thus “inherent,” and thus not
“inventive.” Sandoz Br. at 1, 12-17. However, invention
is not a matter of what the inventor intended when the
experiment was performed; obviousness is measured
objectively in light of the prior art, as viewed by a person
of ordinary skill in the field of the invention. “Those
charged with determining compliance with 35 U.S.C.
§ 103 are required to place themselves in the minds of
those of ordinary skill in the relevant art at the time the
invention was made, to determine whether that which is
MILLENNIUM PHARMACEUTICALS       v. SANDOZ INC.         17



now plainly at hand would have been obvious at such
earlier time.” Interconnect Planning Corp. v. Feil, 774
F.2d 1132, 1138 (Fed. Cir. 1985). No expert testified that
they foresaw, or expected, or would have intended, the
reaction between bortezomib and mannitol, or that the
resulting ester would have the long-sought properties and
advantages.
                            4.
    We conclude finally that the district court clearly
erred in its examination of the objective indicia of unex-
pected results and long-felt need. All of the Graham
factors must be considered, including the objective indicia
when present, before any conclusion regarding obvious-
ness is reached. In re Cyclobenzaprine, 676 F.3d at 1075–
76 (citation omitted); Gambro Lundia AB v. Baxter
Healthcare Corp., 110 F.3d 1573, 1579 (Fed. Cir. 1997);
see Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc., 520
F.3d 1358, 1365 (Fed. Cir. 2008) (stating that objective
indicia are “not just a cumulative or confirmatory part of
the obviousness calculus but constitute[] independent
evidence of nonobviousness”).
    Evidence of objective indicia “can be the most proba-
tive evidence of nonobviousness in the record,” and objec-
tive indicia enable “the court to avert the trap of
hindsight.” Leo Pharm. Prods., Ltd. v. Rea, 726 F.3d
1346, 1358 (Fed. Cir. 2013) (quoting Crocs, Inc. v. Int’l
Trade Comm’n, 598 F.3d 1294, 1310 (Fed. Cir. 2010)).
These indicia cannot be set aside in the analysis of obvi-
ousness.
                            i.
    “Unexpected results are useful to show the improved
properties provided by the claimed compositions are much
greater than would have been predicted.” Leo Pharm.,
726 F.3d at 1358 (quoting In re Soni, 54 F.3d 746, 751
(Fed. Cir. 1995) (internal quotation marks omitted)).
18              MILLENNIUM PHARMACEUTICALS    v. SANDOZ INC.



Nonobviousness may be established when an invention
“yield[ed] more than predictable results.” Crocs, Inc., 598
F.3d at 1309; see also In re Soni, 54 F.3d at 750–51; In re
Chupp, 816 F.2d 643, 646–47 (Fed. Cir. 1987) (considering
improved properties as selective herbicide); In re May, 574
F.2d 1082, 1093 (CCPA 1978) (considering non-addictive
property of analgesic compound). “[W]hen unexpected
results are used as evidence of nonobviousness, the re-
sults must be shown to be unexpected compared with the
closest prior art.” Kao Corp. v. Unilever U.S., Inc., 441
F.3d 963, 970 (Fed. Cir. 2006) (quotation and citation
omitted); Pfizer, 480 F.3d at 1370–71 (quoting same).
    Millennium presented expert testimony that the ly-
ophilized mannitol ester of bortezomib yielded unexpected
results as compared to bortezomib, viz., greatly improved
stability, solubility, and dissolution. However, the district
court ruled that bortezomib itself was not the closest prior
art, and declined to consider the advantages and benefits
of the Velcade® product. The district court’s error stems
from its determination that Millennium should have
compared the glycerol bortezomib ester, for the Adams
Patent included glycerol as one of ten “[p]referred . . .
dihydroxy compounds” 4 for “boronate esters.” Adams
Patent, col. 10, ll. 11-18.
     The bortezomib glycerol ester was not specifically dis-
closed, prepared, or tested in the Adams Patent. Alt-
hough Sandoz now argues that the bortezomib glycerol
ester is “generically” encompassed by the Adams Patent,
Sandoz has not argued that any glycerol ester is specifi-
cally disclosed or actually identified in the Adams Patent
(or in any other reference).




     4   Glycerol is a trihydroxy compound.
MILLENNIUM PHARMACEUTICALS    v. SANDOZ INC.            19



    Nor does the Adams Patent disclose the stability or
solubility of any ester compound. Unexpected results are
shown in comparison to what was known, not what was
unknown. See Pfizer, 480 F.3d at 1370–71; see also Kao,
441 F.3d at 970. Millennium was not required to create
the glycerol ester, when the product had not been created
in the prior art. See In re Geiger, 815 F.2d 686, 690 (Fed.
Cir. 1987) (Newman, J., concurring) (“The applicant is not
required to create prior art, nor to prove that his inven-
tion would have been obvious if the prior art were differ-
ent than it actually was.”).
    We conclude that the district court should have treat-
ed bortezomib as the closest prior art compound, and
acknowledged the unrebutted evidence that the D-
mannitol ester of bortezomib exhibited unexpected results
compared with bortezomib, including unexpectedly supe-
rior stability, solubility, and dissolution.
                            ii.
     The existence of a long-felt but unsolved need that is
met by the claimed invention is further objective evidence
of non-obviousness. See In re Cyclobenzaprine, 676 F.3d
at 1081–83 (“[W]here . . . the obviousness determination
turns on whether . . . a particular formulation of [a drug]
would be [a] successful . . . [or] effective treatment[,]
objective indicia of . . . longfelt need [is] particularly
telling.”). Evidence of long-felt need is “particularly
probative of obviousness when it demonstrates both that a
demand existed for the patented invention, and that
others tried but failed to satisfy that demand.” Id. at
1082–83 (citing In re Piasecki, 745 F.2d 1468, 1475 (Fed.
Cir. 1984); Alco Standard Corp. v. Tenn. Valley Auth.,
808 F.2d 1490, 1500 (Fed. Cir. 1986) (finding nonobvious-
ness where the relevant industry had searched for a
20             MILLENNIUM PHARMACEUTICALS    v. SANDOZ INC.



solution, and major manufacturers tried but failed to
develop a reliable solution)). 5
    The district court’s conclusion that the lyophilized
mannitol ester of bortezomib did not meet a long-felt need
was both perfunctory and clearly erroneous. There is no
dispute that there was a long-felt need for a product to
treat multiple myeloma, for treatments prior to Velcade®
gave poor remission and low survival rates. Although it is
agreed that bortezomib is the effective product in the
body, bortezomib alone is not an available product.
Sandoz offered no evidence of successful solution of the
problems that had barred bortezomib from clinical ap-
proval.
    The district court clearly erred in attributing
Velcade®’s commercial success to bortezomib alone, as
bortezomib is not a viable commercial product and had
been denied FDA approval because of its instability. The
D-mannitol ester was responsible for Velcade®’s success-
ful results, for the D-mannitol ester is necessary to pro-
vide the required solubility and stability.


     5  Sandoz argues that there was no “failure of oth-
ers” because the Adams Patent blocked others from
bringing a bortezomib formulation to market until patent
expiration in 2017. This question is not before us. We
have noted that, although long-felt need is closely related
to failure of others, these considerations are distinct and
we treat each separately. See, e.g., In re Cyclobenzaprine,
676 F.3d at 1081–83; Graham, 383 U.S. at 17-18. Alt-
hough “[e]vidence is particularly probative of obviousness
when it demonstrates both that a demand existed for the
patented invention, and that others tried but failed to
satisfy that demand,” a patent owner may establish a
long-felt need without presenting evidence of failure of
others. In re Cyclobenzaprine, 676 F.3d at 1082.
MILLENNIUM PHARMACEUTICALS    v. SANDOZ INC.            21



    On the entirety of the record, we conclude that the
district court clearly erred in finding that a person of
ordinary skill would obviously make the D-mannitol ester
in order to solve the problem of providing an effective
form of bortezomib. The unexpected properties of an
unexpectedly produced new compound, and the ensuing
pharmaceutical efficacy and benefit, negate the district
court's ruling of obviousness. We therefore reverse the
district court’s invalidity determination.
             B. Apotex and Teva Litigation
    Apotex, Teva, and Millennium agree that, if the
judgment in the Sandoz case is reversed, the dismissal of
the litigation between Millennium and Apotex and Teva
should be vacated and remanded, so that Apotex and Teva
have the opportunity to present their case. Apotex Br. 18;
Millennium Reply Br. 31. Because we reverse the judg-
ment in the Sandoz litigation, we vacate and remand the
Apotex and Teva litigation to the district court for appro-
priate further proceedings.
                     III. CONCLUSION
    We conclude that the Sandoz group of defendants did
not establish the obviousness of the asserted claims of the
’446 Patent by clear and convincing evidence. The district
court’s judgment of invalidity is reversed, and judgment is
entered in favor of Millennium as to the Sandoz defend-
ants. We remand for any appropriate further proceedings
in that action.
    The judgment between Millennium and Apotex and
Teva is vacated, and remanded for further proceedings in
those actions.
 REVERSED-IN-PART AND REMANDED-IN-PART;
  VACATED-IN-PART AND REMANDED-IN-PART
22             MILLENNIUM PHARMACEUTICALS   v. SANDOZ INC.



                          COSTS
    Costs to Millennium in Case Nos. 15-2066, 16-1008,
16-1009, 16-1010, 16-1110, 16-1283, and 16-1762.
     No costs in Case No. 16-1109.
