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-cv01490-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-cv00034-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, Chicago, IL, for defendant-appellee Sandoz Inc. Also represented 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 ASTGMOSER, St. Louis, MO.

TUNG ON KONG, Rhodes Attorneys at Law P.C., San 

Francisco, CA, for defendants-appellees Mylan Laboratories 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 Laboratories, 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., Minneapolis, MN, for defendants-appellees Sun Pharmaceutical 

Industries Limited, Sun Pharma Global FZE. Also represented 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, Vandenburgh, 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, Wockhardt USA LLC. Also represented by PATRICK 

GALLAGHER. 

______________________ 

Before NEWMAN, MAYER, and O’MALLEY, Circuit Judges.

NEWMAN, Circuit Judge. 

Millennium Pharmaceuticals, Inc. is the exclusive licensee 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 (collectively, “Sandoz”) all filed abbreviated new drug applications 

(“ANDAs”), admitting infringement and seeking to invalidate 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 ANDAs filed by Apotex and Teva, based on collateral estoppel 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 litigation 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 Dmannitol N-(2-pyrazine)carbonyl-L-phenylalanine-Lleucine 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 between 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 inhibitor were previously known and are described in United 

States Patent No. 5,780,454 (“the Adams Patent”). However, 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 different 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 approximately 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, researchers 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, researchers 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 ingredient upon administration to a patient. This discovery is 

described and claimed in the ’446 Patent. 

The ensuing drug product (Velcade®) became “a cancer 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®, Millennium 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 presence 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 instead 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 properties 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 lyophilization. No reference taught or suggested that the product of such lyophilization would be a new chemical 

compound that would solve the problems that had inhibited 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 inventor and others that the formation of this new compound 

was not expected or intended when they conducted the 

lyophilization. There was no contrary evidence. Nonetheless, the district court held the claims invalid on the 

ground of obviousness, agreeing with Sandoz that “Millennium conceded as a matter of law that the ester is the 

‘natural result’ of freeze-drying bortezomib with mannitol.” Id. at *8. The court reasoned that the “natural 

result” of a chemical procedure is inherent in the procedure, 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 infringement claims, arguing that the district court’s opinion created collateral estoppel barring Millennium from 

re-litigating the validity of the asserted claims. Eventually the parties stipulated that collateral estoppel warranted 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). Invalidity 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 plenary review to determine whether, as a legal matter, the 

evidence satisfies the clear-and-convincing standard of 

proof.” In re Cyclobenzaprine Hydrochloride ExtendedRelease 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 litigation against Teva and Apotex. 
10 MILLENNIUM PHARMACEUTICALS v. SANDOZ INC. 

1. 

Recognizing our obligation to give deference to a district court’s greater familiarity with the record and authority 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 bortezomib, a previously unknown compound.

The prior art contains no teaching or suggestion of 

this new compound, or that it would form during lyophilization. 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 properties of stability and solubility, and sufficiently dissociate

to release bortezomib at an effective rate in the bloodstream, all critical to effective use for treating multiple 

myeloma. 

The D-mannitol ester of bortezomib is a new compound with distinct chemical properties. We consider 

whether the prior art “would have supplied one of ordinary 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 properties, solving the problems that accompanied bortezomib.

The district court clearly erred in its obviousness

analysis. There is no teaching or suggestion in the references to produce the claimed mannitol ester. No reference 

shows or suggests ester formation at freeze-drying conditions, or that any such ester might solve the problems of 

instability and insolubility of the free acid while dissociating 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 chemical compound, or provide a reason to make this specific 

new chemical compound, or that this new compound 

would solve the previously intractable problems of bortezomib formulation. Although mannitol was a known

bulking agent, and lyophilization was a known method of 

drug formulation, nothing on the record teaches or suggests 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) (emphasis 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. Mannitol 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 defendants stated that they were aware of prior art to fill any of 

the gaps in teaching or suggestion of the Velcade® product—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 experiments 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 proposes lyophilization in the presence of mannitol to produce 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 reference3

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 motivation 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 Approaching 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 producing 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 stabilized 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 mannitol 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 person 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 bulking 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 determination 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 effectively 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 dissociates in the bloodstream at a rate of pharmaceutical efficacy, 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 dissociation 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 consideration 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 inherent. 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 matters 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 unexpected results and long-felt need. All of the Graham

factors must be considered, including the objective indicia

when present, before any conclusion regarding obviousness 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 probative evidence of nonobviousness in the record,” and objective 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 obviousness.

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 results 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 lyophilized 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 disclosed, prepared, or tested in the Adams Patent. Although Sandoz now argues that the bortezomib glycerol 

ester is “generically” encompassed by the Adams Patent, 

Sandoz has not argued that any glycerol ester is specifically 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 invention would have been obvious if the prior art were different than it actually was.”).

We conclude that the district court should have treated bortezomib as the closest prior art compound, and 

acknowledged the unrebutted evidence that the Dmannitol ester of bortezomib exhibited unexpected results

compared with bortezomib, including unexpectedly superior 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 nonobviousness 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 approval.

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 successful results, for the D-mannitol ester is necessary to provide the required solubility and stability.

 

5 Sandoz argues that there was no “failure of others” 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. Although “[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 judgment in the Sandoz litigation, we vacate and remand the 

Apotex and Teva litigation to the district court for appropriate 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 defendants. 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.