# United States Court of Appeals **for the Federal Circuit**

______________________
MILLENNIUM PHARMACEU TICALS, INC., Plaintiff

- Appellant

v.
SANDOZ INC., ACCORD HEALTHCARE, INC., ACTAVIS LLC, MYLAN L ABORATORIES LIMITED, AGILA SPECIALTIES IN C., DR. REDDY'S LABORATORIES, LTD., DR. REDDY'S LABORATORIES, INC., SUN PHARMACEUTICAL INDUSTRIES LIMITED, SUN PHARMA GLOBAL FZE, APOTEX CORP., A POTEX INC., TEVA PHARMACEUTICALS USA, INC., GLENMARK PHARMACEUTICALS LTD. , GLENMARK GENERICS LTD., GLENM ARK 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 No s . 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

- 00 040

- 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.

______________________MILLENNIUM PHARMACEU TICALS v. SANDOZ INC

. 2

Decided: July 17, 2017

______________________
W ILLIAM F. L EE , Wilmer Cutler Pickering Hale and Dorr LLP, Boston, MA, argued for plaintiff

- appellant. Also represented by M ARK C HRISTOPHER F LEMING , L ISA J ON P IROZZOLO , J ASON H. L ISS , A NNA E. L UMELSKY , T ASHA J OY B AHAL , E MILY R. W HELAN ; R OBERT M. G ALVIN , Palo Alto, CA.

T HOMAS J. M ELORO , Willkie Farr & Gallagher LLP, New York, NY, argued for all defendants -appellees. Defendant

- appellee Hospira, Inc. also represented by M ICHAEL J OHNSON

.
G EORGE C. L OMBARDI , Winston & Strawn LLP, Chic ago, IL, for defendant

- appellee Sandoz Inc. Also represen ted by K ATHLEE N B RIDGET B ARRY , M AUREEN L. R URKA

.
P AUL B RAIER , Greenblum & Bernstein, P.L.C., Reston, VA, for defendant

- appellee Accord Healthcare, Inc. Also represented by P ETER B RANKO P EJIC

.
G ARY E DWARD H OOD , Polsinelli PC, Chicago, IL, for defendant

- appellee Actavis LLC. Also represented by M ARK T HOMAS D EMING , K HURRAM N AIK ; R OBYN A ST

G MOSER , St. Louis, MO.

T UNG O N K ONG , Rhodes Attorneys at Law P.C. , San Francisco, CA, for defendants

- appellees Mylan Laborat ories Limited, Agila Specialties Inc. Also represented by E LH AM F IROUZI S TEINER , Wilson, Sonsini, Goodrich & Rosati, PC, San Diego, CA.

L OUIS H ARRY W EINSTEIN , Budd Larner, P.C., Short Hills, NJ, for defendant s- appellee s Dr. Reddy’s Laborat ories, Ltd.
, Dr. Reddy’s Laboratories, Inc. Also represented by E LLEN T CHORNI L OWENTHAL , S TUART D. S ENDER

.MILLENNIUM PHARMACEUTICALS v. SANDOZ INC

. 3

R ACHEL C. H UGHEY , Merchant & Gould P.C., Minn eapolis, MN, for defendants

- appellees Sun Ph armaceutical Industries Limited, Sun Pharma Global FZE. Also repr esented by A ARON M. J OHNSON , C HRISTOPHER J. S ORENSON

.
W ILLIAM A. R AKOCZY , Rakoczy Molino Mazzochi Siwik LLP, Chicago, IL, for defendant s- appellee s Apotex Corp.
, Apotex Inc. Also represented by P ETER J AMES C URTIN , T HOMAS E HRICH , L UKE T IMOTHY S HANNON

.
M ARK D AVID S CHUMAN , Carlson, Caspers, Vande nburgh, Lindquist & Schuman , P.A., Minneapolis, MN, for defendant

- appellee Teva Pharmaceuticals USA, Inc. Also represented by J ENNELL C HRISTINE B ILEK , S AMUEL T. L OCKNER , A LEXANDRA J ANE O LSON , T ODD S. W ERNER

.
J AY P HILIP L ESSLER , Blank Rome LLP, New York, NY, for defendant s- appellee s Glenmark Pharmaceuticals Ltd.
, Glenmark Generics Ltd., G lenmark Generics Inc., USA. Also represented by C HRISTOPHER K. H U , P AUL M. Z AGAR ; D AVID A NTHONY D OREY , Wilmington, DE

.
K EVIN M ICHAEL N ELSON , Duane Morris LLP, Chicago, IL, for defendant s- appellee s W ockhardt Bio AG, Woc khardt USA LLC. Also represented by P ATRICK G ALLAGHER

.

______________________

Before N EWMAN , M AYER , and O’M ALLEY , Circuit Judges.

N EWMAN , Circuit Judge

. Millen n ium Pharmaceuticals, Inc. is the exclusive l icensee of U.S. Patent No. 6,713,446 ( “t he ’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 nameMILLENNIUM PHARMACEU TICALS v. SANDOZ INC

. 4

Ve lcade®. Appellees in Appeal Nos. 15

- 2066, 16

- 1008, 16

- 1009, 16

- 1010, 16

- 1110, 16

- 1283, and 16

- 1762 (collectiv ely, “Sandoz”) all filed abbreviated new drug applications (“ ANDA s” )
, admitting infringement and seeking to inval idate various claims of the ’ 446 P atent

. Based on the litigation that ensued, t he 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 A NDAs filed by Apotex and Teva, based on collateral esto ppel 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 litig ation and that invalidity was not established

. We reverse and enter judgment in favor of Millen nium 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

a ction for further proceedi ngs. I. B ACKGROUND
A. The ’446 Patent
The ’ 446 P atent describes the chemical compound Dmannitol N- (2

- pyrazine)carbonyl -L- phenylalanine -Lleucine boronate

. The compound is described as a bor o-

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 hy droxy compound) and has the following chemical structure , with Millennium ’ s highlight of the bond s between the bortezomib moiety and the D

- mannitol moiety :

Millen n ium 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 inhib itor were previously known and are described in United States Patent No. 5,780,454 (“ the Adams Paten t” ) . Ho wever, despite its known efficacy against various cancers, bortezomib never achieve d FDA approval and market status because of its instability
, its rapid degradation in liquid formulations
, and its insolubility . T he record states that these problem s remained unsolved despite extensive research effort by the inventor Dr. Ad ams and others at Millennium and its predecessor company

. Dr. Adams’ team attempted to develop a stable liquid formulation of borte zomib, but after evaluating approximately 20 diffe rent formulations
, the team failed to develop a formulation that was stabl e enough for transportation, storage, andMILLENNIUM PHARMACEU TICALS v. SANDOZ INC

. 6

administration to patients under conditions of clinical use and distribution

. The inventor of the ’446 Patent w as associated with the National Cancer Institute and the University of Kansas, and w as consulted by Dr. Adams after years of unsuccessful attempts to solve formulation and stability problems with bortezomib. Despite preparing approx imately twenty

- five different liquid formulations, the se efforts encountered the same stability and solubilit y problems as had other researchers att empting 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
, researc hers produced a promising lyophilized formulation usi ng mannitol , a known bulking agent. It was discovered that the reason for the dramatic improvement in dissolution and stability for this formulation was the format ion of a

new chemical compound during lyophilization : the claimed ester of bortezomib and ma nnitol. The mannitol ester of bortezomib acts as a “prodrug,” a compound that converts to or releases the active pharmaceutical ingred ient upon administration to a patient. T his discovery is described and claimed in the ’ 446 Patent

. T he ensuing drug product ( Velcade ®) became “ a ca ncer tre atment that changed the decades

- old standard of care for multiple myeloma and has saved thousands of li v es. The FDA approved Velcade ® in record time, despite its novel structure and mechanism of action. ” Millennium Br. 1

.MILLENNIUM PHARMACEUTICALS v. SANDOZ INC

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B. Proceedings in Sandoz Litigation
After the Sandoz defendants each filed an ANDA seeking FDA approval for the commercial manufacture, use, and sale of gener ic counterparts of Velcade® , Mille nnium filed patent infringement suit s alleging that the products infringe at least claims 20, 31, 49, and 53 of the ’446 P atent. 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 claim s w ere obvio us because they were the inherent result of an allegedly obvious process, viz ., lyophilizing bortezomib in the pre sence of the bulking agent mannitol. Millennium argued tha t a person of ordinary skill would avoid lyophiliza tion in develop ing 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. T he court was not persuaded by this argument and i nstead relied on the testimony of Sandoz’s witne ss, 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 pro perties of stability, s olubility, and dissociability that it exhibited. N o reference taught or suggested reacting bortezomib with mannitol, and no reference hinted that such an esterification reaction might occur during lyoph ilization. No reference taught or suggested that the pro duct of such lyophilization would be a new chemical compound that would solve the problems that had inhi bited development of bortezomib in oncology. However, theMILLENNIUM PHARMACEU TICALS v. SANDOZ INC

. 8

district court concluded that lyophilizing bortezomib with mannitol was an obvious option “f rom which the prior art did not teach away.” Id. at *7. The district court found that the Adams P atent “pointed directly to mannitol” despite the Adams P atent’s failure to mention mannitol. Id. The district court received testimony from the inve ntor and others that the formation of this new compound was not expected or intended when they conducted the lyophilization. There was no contrary evidence. Noneth eless, the district court held the claims invalid on the ground of obviousness, agreeing with Sa ndoz that “ Mi llennium conceded as a matter of law that the ester is the ‘natural result’ of freeze

- drying bortezomib with mann itol.” Id. at *8. The court reasoned that the “natural result” of a chemical procedure is inherent in the proc edure, and thus th e 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 Litigation s 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 ge nericMILLENNIUM PHARMACEUTICALS v. SANDOZ INC

. 9

version of V elcade®

. 2 After the district court i nvalidat ed claims 20, 31, 49, and 53 of the ‘446 Patent in the Sandoz litigation , Apotex moved to dismiss Millennium’s i nfringement claims , arguing that the district court’s opi nion created collateral estoppel barring Millennium from

re

- litigating the validity of the asserted claims. Even tua lly the parties stipulated that collateral estoppel warran ted entry of judgment and dismissal in favor of Apotex and Teva.
II. D ISCUSSION
A. S andoz 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)

. Inv alidity 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 plen ary 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 T he district court consolidated Millennium’s lit igation against Teva and Apotex

.MILLENNIUM PHARMACEU TICALS v. SANDOZ INC

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1. Recognizing our obligation to give deference to a di strict court’s greater familiarity with the record and a uthority to reach factual conclusions therefrom, we conclude that t he distr ict court erred in its evaluation of obviousness. See KSR Int ’ l Co. v. Teleflex Inc ., 550 U.S. 398, 4 19

- 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 ordin ary 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 bort ezomib, a previous ly unknown compound.
The prior art contains no teaching or su ggestion of this new compound, or that it would form during lyoph ilization. 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 prope rties of stability and solubility, and sufficiently dissociate to release bortezomib at an effective rate in the bloo dstream, all critical to effective use for treating multiple myeloma.
T he D

- mannitol ester of bortezomib is a new co mpound with distinct chemical properties . W e consider whether the prior art “would have supplied one of ord inary 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 bortezom ib is the proper lead compound for this analysis. It is not disputed that the Velcade® compound provided unexpected prope rties, solving the proble ms that accompanied bortezomib.
T he district court clearly erred in its obviousness analysis

. There is no teaching or suggestion in the refe rences to produce the claimed mannitol ester. No reference shows or suggests ester formation at freeze

- drying cond itions, or that any such ester might solve the problems of instability and insolubility of the free acid whil e dissocia ting 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 chem ical compound, or provide a reason to make this specific new chemical compound, or that this new compound would solve the previously intractable problems of bort ezomib formulation. A lthough mannitol wa s a known bulking agent
, and lyophilization wa s a known method of drug formulation, nothing on the record teach es or su ggest s that a person of ordinary skill should have use d mannitol as part of a synthet ic 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) (e mphasis omitted) (first quoting In re Oelrich , 666 F.2d 578, 581 (CCPA 1981); then quoting Alcon Research, Ltd. v.MILLENNIUM PHARMACEU TICALS v. SANDOZ INC

. 12

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 te aching or suggestion. The first group shows that lyophilization is a known technique to prepar e pharmaceutical formulations
, although no reference shows lyophilization of bortezomib. The second group shows that mannitol is a known inert bulking agent, al though 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 Paten t. None of these references, alone or in combination, suggests or teaches that the solution to th e problem s 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 este rs may be made, and it lists ten alcohols for this purpose. Adams Patent, col. 10, ll. 15

– 18. Mann itol 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 bor tezomib. None of the experts presented by the many defen dants stated that they were aware of prior art to fill any of the gaps in teaching or suggestion of the Velcade® pro duct

— although they variously opined that this long

- sought discovery was obvious. Sa ndoz’s expert Dr. Repta, who offered an opinion of obviousness, conceded that he hadMILLENNIUM PHARMACEUTICALS v. SANDOZ INC

. 13

“ never worked with any boronic acid compound and has not performed or supervised any lyophilization exper iments since 1983.” Repta Dep. Tr. at 190, l. 10

– 192, l. 8. Dr. Repta cited seventeen references, none of which teach es or suggest s the claimed new compound, or pr opose s lyophilization in the presence of mannitol to pr oduce a new compound, or suggest s that such new compound should be prepared in order to obtain the

nec essary stability
, solubility , and dissociability for treatment of multiple myeloma.
Sandoz argues i n 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, s cheme 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 th e stability of any ester, i d. 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 mot ivation 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. O RGANIC C H EMISTRY 4526 (1986).MILLENNIUM PHARMACEU TICALS v. SANDOZ INC

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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 pr oduci ng 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. McCub bin’s testimony in another case, for Sandoz does not mention that he also testified that Millennium could not have predicted that bortezomib would be stab ilized by forming the mannitol ester. See McCubbin Dep. Tr. at 333, l. 24

– 334, l.4 (“But for any spec ific 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 anal ysis that one has to do to really justify its stability difference.”)

. The sole reason Sandoz provides for choosing mann itol 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 pe rson 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 bul king agent in lyophilization, and he also explained th at 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.
T he district court also clearly erred in its determin ation that lyophilizing bortezomib with mannitol to form an ester was a “suitable option from which the prior artMILLENNIUM PHARMACEUTICALS v. SANDOZ INC

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did not teach away .” Dist. Ct. Op. *7 (citing P ar 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) (quoti ng 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 s kill for fear of disturbing the chemical properties whereby bort ezomib function s effe ctively 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 dissoc iate s in the bloodstream at a rate of pharmaceutical effic acy , 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, a nd is not supported by the Adams P atent , which does not discuss the dissoci ation 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. Ad ams 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 consider ation 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.” P ar Pharm
., 77 3 F.3d at 1195 –96. “The mereMILLENNIUM PHARMACEU TICALS v. SANDOZ INC

. 16

fact that a certain thing may result from a given set of circumstances is not sufficient” to render the result inhe rent. 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 ma tters 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.”
S ee 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 isMILLENNIUM 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. 19 85)

. 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 une xpected results and long

- felt need. All of the Graham factors must be considered, including the objective indicia whe n present , before any conclusion regarding obviou sness 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 in dicia are “ not just a cumulative or confirmatory part of the obviousness calculus but consti tute[] independent evidence of nonobviousness”)

. Evidence of objective indicia “can be the most prob ative evidence of nonobviousness in the record, ” and obje ctive indicia enable “the court to avert the trap of hindsight.” Leo Pharm. Prods., Ltd. v. Rea, 726 F.3 d 1346, 1358 (Fed. Cir. 2013) (quoting Crocs, Inc. v. Int’l Trade Comm’n , 598 F.3d 1294, 1310 (Fed. Cir. 2010)). Th ese indicia cannot be set aside in the an alysis of obv iousness. i. “Unexpected results are useful to show the improved properties provided by the claimed compositions are much greater than would ha ve been predicted. ” Leo Pharm.
, 726 F.3d at 1358 (quoting In re Soni , 54 F.3d 746, 751 (Fed. Cir. 1 995) (internal quotation marks omitted) ).MILLENNIUM PHARMACEU TICALS v. SANDOZ INC

. 18

Non obviousness 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 non obviousness, the r esults 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 pr esented expert testimony that the l yophilized 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 no t 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 include d glycerol as one of ten “ [p]referred

. . . dihydroxy compounds” 4 for “boronate esters.” Adams Patent, col. 10, ll. 11

- 18.
T he bortezomib glycerol ester was not specifically di sclosed, prepared, or tested in the Adams P atent. Al though Sandoz now argues th at the bortezomib glycerol ester is “ generically ” encompassed by the Adams P atent, Sandoz has not argued that any glycerol ester is specifically disclosed or actually identified in the Adams P atent (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. U nexpected 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 inve nti on would have been obvious if the prior art were diffe rent than it actually was

. ”).
W e conclude that the district court should have trea ted 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 sup erior 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 –8 3 (“ [W] here

. . . the obviousness determination turns on whether

. . . a particular formulation of [a drug] would be [a] successful

. . . [or] effective treatment[,] objective indi cia of

. . . longfelt need [is] particularly telling

. ”). E vidence of long

- felt need is “particularly
p robative of obviousness when it demonstrates both that a demand existed for the pate nted invention, and that others tried but failed to satisfy that dema nd.” Id. at 1082

– 83 (citing In re Piasecki , 745 F.2d 1468, 1475 (Fed. Cir. 1984) ; Alco Standard Corp. v. T enn. V alley A uth.
, 808 F.2d 1490, 1500 (Fed. Cir. 1986) (finding nonobviou sne ss where the relevant industry had searched for aMILLENNIUM PHARMACEU TICALS v. SANDOZ INC

. 20

solution, and major manufacturer s 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, bortezomi b alone is not an available product. Sandoz offered no evidence of successful solution of the problems that had barred bortezomib from clinical a pproval. 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 succes sful result s, for the D

- mannitol ester is necessary to pr ovide the required solubility an d stability.

5 Sandoz argues that there was no “failure of ot hers” because the Adams Patent blocked others from bringing a bortezomib formulation to market until patent expiration in 2017. This question is not before us. W e 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. a t 17

- 18. Al though “[e]vidence is particularly probative of obviousness when it demonstrates both that a demand existed for the
pa tented invention, and that others tried but failed to sati s fy 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 unexpected ly produced new compound, and the ensuing pharmaceutical efficacy and benefit, negate the district court's ruling of obviousness

. We therefore reverse the district co urt’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 jud gment in the Sandoz litigation, we vacate and remand the Apotex and Teva litigation to the district court for appr opriate further proceedings

. III. C ONCLUSION
We concl ude that the Sandoz group of defendants did not establish the obviousness of the asserted claims of the ’446 Patent by clear and convincin g evidenc e . The district court’ s judgment of invalidity is reversed , and judgment is entered in favor of Millennium as to the Sandoz defen dants . We remand for any appropriate further proceedings in that action

. T he judgment between Millen n ium 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

- PARTMILLENNIUM PHARMACEU TICALS v. SANDOZ INC

. 22

C OSTS
C osts 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.