## United States Court of Appeals for the Federal Circuit

05-1396, -1429, -1430 ELI LILLY AND COMPANY and LI LLY INDUSTRIES LIMITED, Plaintiffs-Appellees,

v. ZENITH GOLDLINE PHAR MACEUTICALS, INC. (now known as Ivax Pharmaceuticals, Inc.), Defendant-Appellant, and TEVA PHARMACEUTICALS USA, INC., Defendant-Appellant, and DR. REDDY’S LABORATORIES, LTD., Defendant-Appellant.

Charles E. Lipsey , Finnegan, Henderson, Farabow, Ga rrett & Dunner, L.L.P., of Reston, Virginia, argued for plaintiffs- appellees. With him on the brief were L. Scott Burwell ; David S. Forman and Laura P. Masurovsky , of Washington, DC; Robert F. McCauley , of Palo Alto, California; and Jan M. Carroll , Barnes & Thornburg, LLP, of Indianapolis, Indiana. Of counsel on the brief were James P. Leeds , David M. Stemerick , and Robert D. Titus , Eli Lilly and Company, of Indianapolis, Indiana. William L. Mentlik , Lerner, David, Littenberg, Krumholz & Mentlik, LLP, of Westfield, New Jersey, argued for defendant-appe llant, Zenith Goldline Pharmaceuticals, Inc. (now known as Ivax Pharmaceutical s, Inc.). With him on the brief were Roy H. Wepner and Michael H. Teschner . Of counsel on the brief were Jeffrey S. Ward and Thomas P. Heneghan , Michael Best & Friedrich LLP, of Madison, Wisconsin. Joining in the brief were Steven J. Lee , Elizabeth Holland , and Patrice P. Jean , Kenyon & Kenyon, of New York, New York, for defendant-appell ant,Teva Pharmaceuticals USA, Inc.Stuart D. Sender , Budd Larner, P.C., of Short Hills, New Jersey, argued for defendant-appellant, Dr. Reddy’s Laboratories, Ltd. With him on the brief were Ellen T. Lowenthal and Michael H. Imbacuan

. Appealed from: United States District C ourt for the Southern District of Indiana Judge Richard L. Young

## United States Court of Appeals for the Federal Circuit

05-1396,-1429,-1430 ELI LILLY AND COMPANY and LI LLY INDUSTRIES LIMITED, Plaintiffs-Appellees,

v. ZENITH GOLDLINE PHAR MACEUTICA L S , INC. (now known as Ivax Pharmaceuticals, Inc.), Defendant- A ppellant, and TEVA PHARMACEUT ICALS USA, INC., Defendant- A ppellant, and DR. REDDY’S LA BORATORIES , LTD., Defendant- A ppellant.

__________________ _________ DECIDED: December 26, 2006

__________________ _________ Before RADER, SCHALL, and GAJARSA, Circuit Jud ges

. RADER, Circuit Judge

. Zenith Goldlin e Ph armaceuticals, Inc. (now known as IVAX Pharmaceuticals, Inc.) (IVAX); Dr. Reddy’s Laborat ories, Ltd. (DRL); and Teva Pharmaceuticals USA, Inc. (Teva) (defendants), filed an Ab breviated New Drug Applic ation ( A NDA). In response, the plaintiffs, Eli Lilly and Company and Lilly Indus tries Ltd. (collectivel y Lilly), filed suit against all defendants for infringement of Unit ed States Patent No. 5,229,382 (’382 05-1396,-1429,-1430 1patent). Following a t w o and on e-half week bench trial, the United States District Court for the Southern District of Indiana found the ’382 patent valid and infringed. Eli Lilly & Co. v. Zenith Goldline Pharm. , 1:01-cv-443-RLY-VSS (S.D. Ind. A p r. 14, 2005) ( Final Judgment ); Eli Lilly & Co. v. Zenith Goldline Pharm. , 1:01-cv-443-RLY-VSS (S.D. Ind. May 9, 2005) ( Amended F i nal Judgment ). In 221 pages of wr itten analy s is, the trial court documented its findings and conclusions. E li L i lly & Co. v. Ze nith Gold line Pharm. , 1:01-cv-443-RLY-VSS (S.D. Ind. Apr. 14, 2005) ( F i ndings of Fact and Conclusions of Law ). The defendants appeal the trial c ourt’s conclu sions on the validity of the ’382 patent and inequitabl e conduct. Finding no revers ible error, this court affirms.
I. The ’382 patent claims bot h olanzapine and use of the compound to treat schizophrenia. Findings of Fact and Conc lusions of Law , slip op. at 3. A Lilly research chemist first synthesized olanzapine in the United Kingdom in 1982. Id. at 12. Lilly filed the ’382 patent applic ation on M a y 22, 1992. The pat ent i ssued on July 20, 1993. The United States Food a nd Drug A d ministratio n (FDA) a p p roved o l a n zapin e , s o ld by L illy under the trademark Zyprexa®, in late 1996. Findings of Fact and Conc lus i ons of Law , slip op. at 3. By filin g an ANDA, the def endants stipulate to infringemen t if the ’382 patent is valid and enf orceable. Amended Final Judgment , slip op. at 1

. Claims 1, 2, 3, 7, 8, and 15 of the ’382 patent set forth the boundaries of the invention: 1. 2-Methyl -10-(4-methyl-1 -piper azinyl)-4H-thieno[2,3- b][1,5]benzodiazepine, or an ac id addition salt thereof.

05-1396, -1429, -1430 22. A pharmaceutical c o mposition co mprising a compound according to claim 1 or a pharmaceutically acceptable ac id addition salt thereof together w i th a pharmaceutically acceptable d iluent or carrier therefor. 3. A pharmaceutical c o mposition in caps ule or tablet form comprising from 2.5 to 5 mg of the compound of clai m 1 together with a pharmaceutically acceptable diluent or carrier therefor.
* * * * 7. A method of claim 5 for treating an animal, including a human, suffering from or susceptible to schizophrenia. 8. A method of claim 7 wherein the e ffective amount is fr om 0.1 to 20 mg per day of 2-methyl-10-(4-meth yl -1-piperazinyl)-4H-thieno[2,3- b][1,5]benzodiazepine, or a pharmaceutical ly acceptable acid addition solution salt thereof.
* * * * 15. A pharmaceutical composition in capsule or tablet form compri sing from 0.1 to 20 mg of the compound of claim 1 together w i th a pharmaceutically acceptable diluent or carrier therefor. ’382 patent , col. 12, ll. 10-20, ll. 33-40, ll. 64-67. Before disc overy of olanzapine, Lilly discov e red other drugs in the same family of compounds (thienobenzodiaz epines), namely clozapine, flumezapine, ethy l flumezapine and ethyl olanzapine (a.k.a. Compound ‘222). Findings of Fac t and Conclusions of Law , slip op. at 6-8. T hese compounds share a common structural nucleus a s thienobenz odiazepines, namely a piperaz ine ring (R), a benzene ring (R1), and a thiophene ring (R2). 

### R R2 R1

05-1396, -1429, -1430 3Lilly used c l ozapine to treat some forms of schizophrenia in the lat e ‘60s and early ‘70s. Findings of Fact and Conclusions of Law , slip op. at 6. Clozapine was thus the first “atypical” antipsychot ic drug. Structurally, olanzapine diffe rs from clozapine in that olanzapine has a methyl-substituted thiop hene ring in place of the benz ene ring i n clozapine. Id. at 40. Olanz apine also has hydrogen in place of the chlorine on its benzene ring. Id. at 41. Despite its advantages, resear chers discovered in 1975 t hat clozapine c aused an often fatal blood dis o rder (agr anulocytosis) in one perc ent of patients. For that reason, Lilly withdr ew clozapine from the market. Id. Nevertheless, after a general failure to replace c l ozapine, reflected by many docum ented reports of promi s ing compounds that failed either for lack of efficacy or toxic si de-effects, the FDA, in late 1989, approved clozapine with careful blood-monitoring. Id. at 7. U n ti l di scovery of ol anzapi ne, researcher s attri buted the effi cacy of cl ozapi n e and typical antipsychotics to their “neuroleptic s ubstituent”—an elec tron-withdrawing group considered important to the antipsychotic activity of the compounds. Id. Halogen – a fluorine (F) or chlorine (Cl) atom – is such an electr on withdrawin g group. Id. at 7, 48. Olanzapine does not have a halogen atom, i.e. a fluorine (F) or chlorine ( Cl) atom. Instead, it has a hydrogen atom (H), which is not an electron withdrawing (or electronegative) group. Id. at 48.

05-1396, -1429, -1430 4The prior art to olanzapine includes et hyl flumezapine and flumezapine, both disclos ed in U.S. Patent No. 4,115,574 (’574 patent) that iss ued in 1978. The prior art also inc l udes ethyl olanzapine (a.k.a. Co mpound ‘222). Ethyl flumezapine caused wides pread blood problems in dogs. Id. at 41. Flumezapine caused extra-pyramida l symptoms (EPS) an d an incre a se in li ve r enzymes and a muscle e n zy me calle d creatine phosphok inase (CPK). Ethyl olanz apine caused a signific ant increase in cholesterol in female beagle dogs. Id. Thus, the prior art to olanzapine had sign ifican t detrimental side effects. Olanzapine differs structurally from flumezapine, by substitution of a hydrogen atom (H) for the fluorine atom (F) in flumezapine at the 7-position of the benzene ring. Id.
Olanzapine differs stru cturally from ethyl flumezapine by replac ement of the fluorine atom (F) and ethyl group (CH 2 CH 3 ) in ethyl flumezapine with a hydrogen atom (H) and methyl group (CH 3 ) respectively. Id. Olanzapine differs structurally from its ethyl analog, Co mpound ‘222 (ethyl olanzapine), by replacement of the ethyl group (CH 2 CH 3 ) with a methyl group (CH 3 ) at the 2-position of the thiophene ring. Id. ( Compound ‘222)

I
05-1396,-1429,-1430 5The trial c ourt found that the defendants did not prov e by clear and conv incing evidenc e that claims 1, 2, 3, 7, 8, and 15 of the ’382 patent were invalid a s anticipat ed under 35 U.S.C. § 102. Findings of Fact and Conc lusio n s of Law , slip op. at 212. The primary reference the defendants cited for ant icipation of these claims is an article entitled “4-Piperaz inyl-10 H -thieno[2,3- b ][1,5]benzodiaz epines as Po tential Neuroleptics ” from the Journal of Medi cinal Chemistry in 1980 ( Chakrabarti 1980a ). Jiban K. Chakrabarti, Linda Horsman, et al., 4-Piperazinyl-10 H -thieno[2,3- b

][1,5]benzodiazepines as Potential Neuroleptics , 23 J. Med. Chem. 8 (1980). Anticipation is a ques tion of fact, inc l uding whether or not an el ement is inh e rent in the prior art. See I n re Schreiber , 128 F.3d 1473, 1477 (Fed. Cir . 1997). Therefore, this court reviews a finding of anticipatio n under the clearly erroneous stand a rd. Atla s Powder Co. v. lreco, Inc. , 190 F.3d 1342, 1346 (F ed. Cir. 1999). To ant ic ipate, a prior art reference must place the inv entive co m pound or composition in the pos session of the public. In re Brown , 329 F.2d 1006, 1011 (C. C .P.A. 1964). Thus, the prior art reference must disclose each and every feature of the claimed inv ention, eith er exp lic itly or inherently. Glaxo Inc. v. Novopharm Ltd. , 52 F.3d 1043, 1047 (Fed. Cir. 1995). Pointing to In re Petering , 301 F

. 2d 676 (C. C .P.A. 1962) and In r e Schaumann , 572 F.2d 312 (C.C.P.A. 1987), IVAX asserts that Chakrabarti 1980a anticipated claim 1 of the ’382 patent because it identified com pounds from the same fa mily of compounds (thienobenzodiazepines). Indeed, in Petering , the Board of Patent Appeals affirmed the examiner’s rejection of clai ms 1, 2, 4, 5, 7, and 10- 12 of the patent applic ant’s application on “isoalloxazines.” 301 F.2d at 677. However, in contrast to this case, the prior art in Petering did more than make a broad generic disclos ure. In Pe tering , the

05-1396, -1429, -1430 6prior art disclosed a limited num ber of specific preferences from a specific ally defined group of is oalloxazines. Id. A s a r e s u l t , Petering actually disclos ed to one sk illed in the art a limited class of only “s ome 20 c o m pounds, ” including “6, 7-dimethyl-9-(Bmonohydroxyethyl)-isoalloxazine.” Schaumann , 572 F.2d 315 (citing Petering , 301 F.2d at 682). Similarly, the prior art in Schaumann dis c losed 14 compounds, later further narrowed t o 7, cons idering express preferences . Additionally, the structural formula of this prior ar t contained but a single va riable. 572 F.2d at 314. Thus, in S c haumann , the prior art patent embraced a very limited number of closely related compounds and specifically described the clai med compound. 572 F.2d at 316. Thus, unlik e this case, the prior art in both Petering and Schaumann expressly spelled out a definite an d limited c l as s of compounds that enabled a person of ordinary ski ll in the art to at once envisage each member of this limited clas s. Schaumann , 572 F.2d at 315; Peterin g , 301 F.2d at 681-82. By contrast, the number of compounds actu ally disclos ed by Chakrabarti 1980a numbers in the million s (includin g all propo sed alternative substituents). Chakrabarti
1980a examined forty-five specific compounds (as opp osed to a genus of c o mpounds) in the 4-piperazinyl-10H-t hieno[2,3-b][1,5]benzodiazepi ne family and fourteen analogous 5-piperazinyl-substi tuted 4H-thieno[2,3-b][1,4 ]benzodiazepines, which were created to compare activity. Findings of F a ct and Conclusions of Law , slip op. at 43. Indeed, Chakrabarti 1980a listed several pr eferred compounds and substituents, none of which resemble olanzapine: for R - a methyl, hydroxyeth y l , or hydroxypr opyl; for R1 - a fl uorine, chlori ne, or 7, 8, di-fluoro [no hydrogen] ; and

05-1396, -1429, -1430 7for R2 - a methyl, 2-e t hyl, or 2-isopropyl group. Id. at 43. Five of the preferred individual c o m pounds (9, 12, 17, 29, and 34) are more potent than clozapi ne (scoring a 3 CAR 1 or higher) and have c l ozapine-like effect. For those five preferred compounds, the Chakrabarti 1980a authors expressed a preference for specific, complete compounds without any va riation of the individual su bstituents on those molecules. Chakrabarti 1980a al so al w a ys ex pressed a preference for halogencontaining compounds (fluorine or chlorine), not hydrogen. Id. at 8-9. Fu rthermore, compounds 9, 12, 17, and 29 all have fluorine at the 7-position of the benzene rin g

. And though Compound 34 does have hydr ogen at the 7-position of the benz ene ring, it has a hydr oxyethy l on its pipe razine ring, unlik e olanzapine. Id. In sum, Chakrabar t i 1980a disc loses nothing close to the claimed invention. Chakrabarti 1980a does provide a general struct ural formula with p o s s ible substituents of “R,” “R1,” and “R2,” but it does not define them at all. Findings of Fact and Conc lusions of Law , slip op. at 161. No possible combinat ion of those preferred substituents would lead to the component s that make up olanz apine, bec ause each would cont ain a fluorine or a chlo rine. T o make olanzapine from Chakrab a rti 1980a , one would have to depart from the teaching of the article and recombine the component s of the specific illus t rati ve compounds wit h hinds ight . Thus, Chakrabarti
1980a does not anticipate because: (1) the ar ticle prefers complete compounds, not indiv i dual substituents, (2) the article disc loses no gener ic disc losure enc ompassing

1 Conditioned Avoidance Response (CAR): The CAR test evaluates the inhibition of a behavioral response in rats. The CAR test was the only measure of potential antipsychotic activity, and if t he compound did not achieve a CAR score of three or four at a dose of less than 30 mg/kg, it was not considered active.

05-1396, -1429, -1430 8olanzapine or even stating that subs tituents on different compounds were interchangeable, and (3) the article does not suggest transforming unpreferred compound 7 2 into a preferred compound. Thus, Chakrabarti 1980a did not place olanzapine in the possession of the public. Ther efore, this court det ects no clear error in the trial court’s finding of no anticipation.
II The trial c ourt found that the defendants did not prov e by clear and conv incing evidenc e that claims 1, 2, 3, 7, 8, and 15 of t he ’382 patent were invalid as obvious under 35 U.S.C. § 103. Findings of Fact and Conclus i ons of Law , slip op. at 212. On
appea l, IVAX argues that the dist rict court erred by erecting “a threshold requiremen t that defendants establish a teachi ng or incentive to treat t he closest prior art (i.e., Compound ‘222) as a ‘lea d co mpound.’” IVAX als o charges that the district court disregarded (1) the s t ructural characteristic of olanza p ine as the adjacent homolog of Compound ‘222, (2) the sugges tions to delet e fluorine from the prior art compound flumezapine, and (3) the observ a tion that Co mpound ‘222 and flumezapine “bracket” olanzapine. This court reviews obviousness without deference as a legal conclus i on with underlying factual determinations whic h are reviewed f o r clear error. Medichem, S.A. v. Rolabo, S.L. , 437 F.3d 1157, 1164 (Fed. Cir. 2006). The factual underpinnings are: (1) the scope and content of the prior art, (2) the differenc es between the prior art and the claimed inv ention at the time of invention, (3) the level of or dinary s k ill in the ar t, and (4)

2 Furthermore, compound 7 (lik e co mpound ‘222) lacks the electron withdrawing “neuroleptic substi tuent” believed at that time to be nec e ssary for antipsychot ic efficacy.
05-1396, -1429, -1430 9the objective indic i a of nonobviousness. See Graham v. John Deere Co. , 383 U.S. 1, 17 (1966); Panduit Corp. v. Dennison Mfg. , 810 F.2d 1561, 1566- 67 (Fed. Cir. 1987). For a chemical compound, a prima facie ca se of obviousness requires “structural similarity between claimed and prior art subjec t matter . . . where the prior art gives reason or motivation to make the claimed compositions.” In re Dillon , 919 F.2d 688, 692 (Fed. Cir. 1990) (en banc). “[A] reasonable expectati on of success, not absolute predictabilit y” supports a c onclus i on of obviousness. In re Longi , 759 F.2d 887, 896 (Fed. Cir. 1985). For the following reas ons, the district court did not err in reaching its conc lus i on. As succinctly stated by the district court: 175. In light of the general stat e of the art, including the teachings of the ’574 patent and Chakr abarti 1980a , Chakrabarti 1982 , and Chakrabarti 1989 , one of ordinary skill in the art would h a ve expected that replacing the fluorine atom wit h a hydrogen atom would pr oduce a compound without sufficient antipsychotic activity. Nichols Tr. 2776:5-11. 176. While Chakrabarti 1980a suggests that a chlorine atom in place of the fluorine atom would al so enhance the com pound’s ac tivity, it does not s pecifically suggest that t he same result could be obtained with a hydrogen atom. Nichols Tr. 2779: 17-24; TX 3465 at 879, col. 2. Nor does anything in Su lliv an and Fra n k lin s uggest the des irability of using a hydrogen atom at this pos ition. Nichols 2776:5-11; TX 3161; Findings of Fact § IV. B.I.d. lf one were looking to repl ace the fluorine, one woul d replace the fluorine with other el ectronegative groups, not hydrogen . TX 1315 at 3172; LaVoie Tr. 1572:12- 1573: 18. Indeed, the art as a whole teaches directly away from using hy drogen becaus e it is not an electronwithdrawing substituent. Findings of Fact and Conclusions of Law , slip op. at 48 (emphases added). Though the ’574 patent disclosed Compound ‘222, the patent expressed a preference for haloge n containing compounds and spec ifically those with a hal ogenated substituent on the benzene ring in a loc a tion analogous to the chlorine in clozapine. Findings of Fact and Conclusions of Law , slip op. at 36. These teachi ngs do not suggest or make obvious,

05-1396, -1429, -1430 10among other things, olanzapine’s hydrogen com ponent . The prior art references at the time of this invention taught away fr om using a non-halog enated compound as a substituent in the benzene ring, exactly where olanzapine has a hydrogen atom. Furthermore, the trial court found that a person of ordinary skill in the art would not have c hosen Compound ‘222 as the beginning compound because it contained a hydrogen atom instead of a halogen atom, which again is not a preferred substituent. Findings of Fact and Conclusions of Law , slip op. at 46. In addition, th e prior art supplied no motivation to chan ge the 2-ethyl in Comp ound ‘222 t o a 2-methyl. The prior art would have instead suggested modificati on by adding a halogen atom to supply the neuroleptic substituent as a trigger for antipsychotic ac tivity. Id. The district court found that, at the relevant time, a person with ordinary skill in the art would not have expected any reasonable chanc e of success with other clozapine-like compounds. Id. at 49-51. And though olanzapine is also t he adjacent homolog of Compound ‘2 22, patentability for a chemical compound does not depend only on structural similarit y

. Comm’r of Patents v. Deut sche Gold-und-Silber-Schei deanstalt Vormals Roessler , 397 F.2d 656 (D.C. Cir. 1968). This court will not i gnore a relevant property of a compound in the obv iousness calculus. In r e Lalu , 747 F.2d 703 ( F ed. Cir. 1984). When claimed properties differ from the prior ar t, those di fferences, if unexpected and significant, may lead to nonobvious nes s. In re Me hta , 347 F.2d 859 (C. C .P.A. 1965); In re Gr abiak , 769 F.2d 729 ( F ed. Cir. 1985). In this case, the tria l court noted som e structural similarity of olanzapine and the prior art, but also accoun ted for the unexpected benefic ial properties in olanz apine.

05-1396, -1429, -1430 11This case is similar in many respects to Yamanouchi Pharm. Co., Ltd. v. Danbury Pharmacal, Inc. , 231 F.3d 1339, 1344 (Fed. Cir. 2000). In Yamanouchi , this court held that the ANDA filer did not show obv iousness of the famotidine com pound: [The ANDA filer] did not show sufficient mo tivation for one of ord i nary skill in t h e art at the time of invention to take any one of the following steps, let alone the entire complex combination: (1) selecti ng example 44 as a lead compound, (2) combining the polar tail from example 44 with the substituted heterocycle from tiotidine, and (3) substituting the car bamoyl (CONH2) group in the intermediate compound with a sulfamoyl group (SO2 NH2) to create famotidine. Id. Likewise, in this case, the defendant s have not shown that a person ordinarily skilled in this art would have selected Com pound ‘222 as a le ad compound because it contained hydrogen rather t han fluorine or c h lorine. At the ti me of invention, the state of the art would h a ve directed the person of ordin a ry skill in the art away from unfluorinat ed compounds like Compound ‘222. After all, t he pr imary example of th e state of the art at that time, the ’574 pat ent, did not provide any biologic al data for compound ‘222, suggested a preference for halogen-cont aining compounds, and identified a fluorine-c ontaining c o mpound, ethyl flumezapine, as “particularly active.” Findings of Fact and Conclusions of Law , slip op. at p. 170. Moreover, as the trial court detailed, Chakrabarti 1980a expr essly taught that the addi tion of a fluorine or chlorine enhanced anti-psychotic activity. It also taught that the unflu orinated Com pound ‘222 was less active than the benchm ark compound, clozapine. Id. Thus, rather than providing t he requisit e motivation, the prio r art taught away from selectin g Compound ‘222 as a lead compound for further development. Nevertheless, citing to an article entitled “ In Vitro Thiomethylation: Studies with Flumezapine,” written by H.R. Sullivan and R.B. Franklin ( S&F article ) , IVAX argues that removal of fluorine from flumezapine would have resulted in a default to a hydroge n

05-1396, -1429, -1430 12atom. H.R. Sullivan and R.B. Franklin, In Vitro Thiomethylation: Studies with Flumezapine , 13 Drug & Metabolism Dis position 276 (1985). To the contrary, however, the S&F article says nothing whats oever about removal of fluo rine. Spec ifically, the article disc usses the metabolism of flumez apine in dogs that produces methylthio metabolite. Id. T h e S&F article does not stat e that flumezapine is toxic or that the methylthio metabolite could be avoided by r eplacement of fluorine with hy drogen. As noted by the district court, the S&F article “does not teach t hat replacing the fluorine with a hydr ogen atom would stop the formation of the methylthio metabolit e. Indeed, acetaminophen (Tylenol®), a non-fluorinat ed compound, also forms methylthio metabolite.” Findings of Fact and Conc lusions of Law , slip op. at 39. The trial court correctly concluded t hat nothing in the S&F article suggested “that a hydrogen atom in place of the fluorine atom . . . would be des irable . . . or that to ma ke such a substitution would avoid the formation of the methylthio metabolite.” Id. Beyond the nonobv ious selectio n step, the prior art al so did not suggest any of the other modifications necess a ry to reach olanzapine. Thus, even if the S&F article taught wha t IVAX claims, the skilled artisa n would still need to c o mbine thos e teachin g s with compound 34 in Chakrabarti 1980a to r each olanz apine. As t aught by Yamanouchi Pharm. Co. and other precedent, mere identificati on in the prior art of each component of a composition does not s how that the combination as a whole lacks the necessary attributes for patentability, i.e. is obvious. In re Kahn , 441 F.3d 977, 98 6 (Fed. Cir. 2006) (citing In re Rouffet , 149 F.3d 1350, 1355 (Fed. Cir. 1998)). Rather, to establish a prima facie case of obviousness based on a comb ination of elements in the prior art, the law requires a motivation to select the refer ences and to combine them in the particular

05-1396, -1429, -1430 13claimed manner to reach t he claimed invention. Id. In conclus i on, because flumezapin e caused EPS in two patients, elevatio ns in CPK a nd a varie t y of live r enzymes in a number of patients, substant ial evidence supports the trial court’s conclus i on that the S&F article would not have led a person of ordinary skill in the art to believe that flumezapine could be successf ully modified with a hydrogen atom. Th e district court correctly conc luded that nothing in the S&F article and Chakrabarti 1980a made the combination reached in olanzapine obvious. Nonethe les s , IVAX also cites to In re Payne , 606 F.2d 303 (C. C .P.A 1979) to argue that Compound ‘222 an d flumezapine “bracket,” and ther eby make olanzapine prima facie obvious. To the contrary, Payne did not feature prior art that taught away from making the structural alterations as in t h is case. I n this case, the prior art would have direc t ed one o f skill a w ay from making flu m ezapine and ethyl- olanza p in e (Compound ‘222). T he “bracket” notion from Payne s i mply characterized the structural similarity in that case, which this cour t has noted does not control this case. Furthermore, Lilly ov ercame any prima facie case of obvi ousness. Among other things, Lilly proved ext ensive s e c ondary considerations to rebut obviousness . The trial court found the evidence clear ly establis hed four of the five proffered secondar y considerations. Findings of Fac t and Conc lusions of Law , slip op. at 52-101, 173-87. Lilly established (1) a long- felt and unm et need; ( 2 ) failure of others; (3) industry acclaim; and (4) unexpected res u lts. Id. The record s hows a lo ng-felt need for a safer, less toxic, and more effective clozapine-lik e dr ug; a decade (or more) of failure to find a replacement for clozapine; a reasonable amount of commercial success for olanzap i ne; and a num ber of awards for olanzapine as indicators of industry acclaim. Id

. at 52-54.

05-1396, -1429, -1430 14Specifically , the trial court noted a “long-felt but unsolv ed need for a safe atypica l antipsychot ic from 1975 until 1990,” as well as extensiv e evidenc e supporting the other objective c r iteria. Id. at 8-11, 174-75. The trial c our t also disc ussed the unexpected differences between t he clos est analog, Com pound ‘222 and olanzapine, most of whic h focused on olanz apine not rais ing cholestero l levels in dogs, and a comparis on of some humans tests with other simila r drugs that raised CPK. Id. at 55-100. In sum, these objective criteria buttressed the tri a l court’s conclus i on of nonobviousness.
III The trial c o urt concluded that Lilly ’s clinica l trials of olanzapine wer e not a public, but an experimental, use that negated any section 102 bar. Findings of Fact and Conclusions of Law , slip op. at 192-93. Under sect ion 102, a person is entitled to a patent, unless “the invention was . . . in public use . . . in this country, more than one year prior to the date of the application for patent in t he Un ited States.” 35 U.S.C. § 102(b) (2000). Public use inc l udes “any [publ ic] use of [the claimed] inv ention by a person other than the inventor who is under no limitation, re striction or obligation of secrecy to the inventor.” In re Smith , 714 F.2d 1127, 1134 (Fed. Cir. 1983) (citing Egbert v. Lippmann , 104 U.S. 333, 336 (1881)). In considering whether a particular use wa s “ public” within the meaning of section 102(b), this court considers t he polic ies underlying the bar. Tone Bros., Inc. v. Sysco Corp. , 28 F.3d 1192, 1198 (Fed. Cir. 1994), cert. denied , 514 U.S. 1015 (1995). In assessing this case, the trial court found that Lilly p e rsonnel c onducted the HGAA, HGAB, and HGAC P h ase I clin ic al trials of olanzapine in the Lilly clin ic. Findings of Fac t and Conclusions of Law , slip op. at 189. In all three st ages, Lilly restricted access to the

05-1396, -1429, -1430 15facility and provided full-time se curity. Id. Lilly clos ely monitor ed and c o nfined the movements of the volunteers, who were h ealthy and not suffering from schizophrenia, for the duration of the study. Id. Visitors to the volunteers di d not interrupt the control or confidentiality of the study. Id. Moreover, as the trial court noted, the clin ic al trials did not use the drugs to treat sch izophrenic patients, but merely to test the safety and efficacy of the drug. Findings of Fact and Conclusions of Law , at 190-91. Beyond this convinc i ng record evidenc e, the experimental character of these tests negated any statutory bar. Even a us e that occurs in the open may not invoke a bar when undertaken to experiment on or with the claim ed invention. TP Labs., Inc

. v. Prof’l Positioners, Inc. , 724 F.2d 965, 971, (Fed. Cir. 1984), cert. denied , 469 U.S. 826 (1984). In the words of the Supreme Court, “ [t]he use of an inventio n by the inventor himself, or of any other person under his direct ion, by way of experiment, and in order to bring the invention to perfection, has never been regarded as [a public] use.” City of Eliza beth v

. Am. Nic holson Pavement Co. , 97 U.S. 126, 134 (1877). Several indicia may show the negating experimental character of a use, including (1) the length of the test period, (2) any confi dentiality agreement, (3) any records of testing, (4) any monitoring and control of the test results, (5) the number of tests, and (6) the length of the test period in relation to tests of similar inventions

. TP Labs. , 724 F.2d at 971-72; see also In re Brigance , 792 F.2d 1103, 1108 (Fed. Cir. 1986). In this case, Lilly tailored its tests to their experimental drug safety and efficacy purpose, adequately monitored for results, and maintained conf identiality throughout the duration of the study. The trial court did not err i n finding no public us e.

05-1396, -1429, -1430 16IV DRL argues that the district court e rred in not finding inequitable conduc t because if it had look ed at the totality of the circumstances, the evidenc e would hav e shown that Lilly intentionally made per se material statements that misled the exam iner

. “Inequitable conduct occurs when a patentee br eaches his or her dut y to the United States Patent and Trademark Office (PT O ) of ‘candor, good faith, and honesty.’” Warner-Lambert Co. v. Teva Pharms. USA, Inc. , 418 F.3d 1326, 1342 (Fed. Cir. 2005) (quoting M o lins PL C v. Textron, Inc. , 48 F.3d 1172, 1178 (Fed. Cir. 1995)). Inequitab l e conduct includes affirmative misrepresentations of material facts, non-disclosure of material inf o rmation, or submission of false material inf o rmation, coupled with an intent to deceive. See Nobelpharma AB v. Implant Innovations, Inc. , 141 F.3d 1059, 1068-71 (Fed. Cir. 1998) (citing Molins , 48 F.3d at 1178). To assess inequitable conduct, the trial court must determine w hether the withheld reference meet s a threshold level of materiality. Dayco Prods., Inc. v. Total Containment , Inc. , 329 F.3d 135 8 , 1362-63 (Fed. Cir. 2003) (quoting Purdue Pharma L.P. v. Boehringer Ingelheim GMBH , 237 F.3d 1359, 1366 (Fed. Cir . 2001)). Then, the trial court must also det ermine whether the evidenc e s hows a thr e shold lev e l of intent to mislead the PTO. See Hallib urton Co. v. Schlumber ger Tech. Corp. , 925 F.2d 1435, 1439 (Fed. Cir. 1991). After finding the threshold levels of materiality and intent, the trial court then bal ances those factors. See Molins , 48 F.3d at 1178. Gross negligence alone is insufficient to ju stify an inference of intent to deceive the PTO. See Kings down Med. Consultants, Ltd. v. Hollister, Inc. , 863 F.2d 867, 876 (Fed. Cir. 1988); FMC Corp. v. Manitowo c Co. , 835 F.2d 141 1, 1415 n. 9 (Fed. Cir

.

05-1396, -1429, -1430 171987). In a case inv o lving an omission of a material reference to the PTO, the record must contain clear and convincing ev idenc e that the applic ant made a deliberate decision to withhold a know n material reference. See Molins , 48 F.3d at 1181. Bey o nd that, the applic ant must have withheld the material subjec t matter with the intent to deceive. F e rring B.V. v. Barr Lab s., Inc. , 437 F.3d 1181, 1190 (Fed. Cir. 2006). “Intent to deceive cannot be inferred simply from the decision to withhold the reference wher e the reasons given for the withholding are plausible.” Dayco Prods. , 329 F.3d at 1368. B e fore the S w edi s h B oard, Lilly noted idiosyncratic blood toxic i ty problem s in isolated do gs at 10 mg/kg, and DRL cla i ms Lilly ’s failure to mention this to the PTO is inequitable conduct. However, the PTO had questions only about blood cholesterol levels. Be fore the S w edis h Bo ard, Lilly n e ver commented about cholesterol levels. Indeed, Lilly’s statements to t he Swedish Board about the idiosyncratic blood toxicit y resulted from Lilly’s desire to conduct hum an clinical studies of olanzapine in Scandinavia. Findings of Fact and Conc lus i ons of Law , slip op. at 105. Before allowing human clinical studies , the Swedish Board requi red Lilly to respond to concerns about the toxic effects of olanzapine on blood cells and bone marrow in dogs during the D07290 Dog Study. Id. at 205. Lilly repli ed that these findings of hematotoxicity “were believed not to have clinical relevance to humans since the effects occurred at large multiples o f the clinic al dose.” Id. at 105. These statement s to the Swedish Board discounted the result s of the blood studies by reference to idiosyncratic hematoxic i ty, not cholest e rol problems. Thus, Lilly did not fail to disclose information or contradict its later patentability arguments.

05-1396, -1429, -1430 18Furthermore, contrary to DRL’s argument, Dr. David Scruby’s dec laration did n o t create a “false” impression t hat the D07290 Dog Study cholesterol findings could be extrapolate d to humans. Dr . S c ruby had been a staff physician at Lilly since 1983

. Findings of Fact and Conclusions of Law , slip op. at 121. This court acknowledges that Rohm & Haas, Co. v. Crystal Chem. Co., 722 F.2d 1556, 1571 ( F ed. Cir. 1983) states: “[T]here is no room to argue that submission of false affidavits is not material.” In this case, however, the record shows that Dr. Scruby’s affidavit was not false. Dr. Scruby’s affidavit could only be cons idered false if read to suggest that Dr. Scruby wa s tellin g the examiner to extrapo la te point-by-point to humans olanzapine’s improved cholesterol levels in dogs as compared to Compound ‘222. Dr. Scruby’s affidavit does not suggest su ch an extrapolation of the benefit s of olanzapine from dogs to humans. Dr. Scruby, in fact, separates into different paragraphs his discussions of olanzapine’s benefits for cholesterol levels in humans and the effe cts of Compound ‘222 for dogs. F u rthermore, he expres sly relies on the dec larations of Dr. Jeffrey Means and Dr. James Symanowski as “the basis for my clinic al statements concerning the dog toxicology studies.” Dr. Means is a pharmacologist an d toxicologist; and Dr. Symanows k i is a statistician. Findings of Fact and Conclusions of Law , slip op. at 20. Dr. Scruby’s affidavit appears in the pr osecution his t ory as a Respons e After Final ( Res ponse ) for the following propositions: (1) th at “cholesterol is recognized as a factor in coronary artery disease; ” (2) that the Framingham Study “i ndicated that a 1% reduction in the cholesterol level results in a 2% reduction in cor onary artery diseas e;” and (3) that “there is overwhel ming evidenc e in the literature that seru m cholesterol in

excess of 240 mg/dL is a s i gnificant contri butor to the genesis of atherosclerosis.”

05-1396, -1429, -1430 19These statements are not false. The trial court did not err in discerning no clear and convinc i ng evidence that Dr . Scruby misrepresented or wit hheld information from the PTO with an intent to deceive. Id. , at 124. Lilly’s Res ponse did not intentionally blur t he distinctions between humans and dogs. Rather, Lilly’s Respons e express l y replied to the examiner’s request for human clinical comparisons of olanzapi ne and Compound ‘222 by stating: Applicants maintain t hat the Examiner ’s request for human clinical com paris on of olanz api ne and com pound ‘222 is inappropriate . . . . In light of serious cons equences associat ed with artificially altering the balanc e of cholesterol synthesis, Applicants assert that human clinic a l trials with ‘222 would be unethic a l and well as unreasonable

. Respons e , at p. 11 (emphases adde d). Lilly made clear t hat it bas e d none of its statements about the effe cts of either olanz apine or Co mpound ‘222 on human testing. Furthermore, the examiner al so understood that t he cholesterol data was based on the D07290 Dog Study because he asked about those results without any reference to cholesterol benefits for humans. Findings of Fact and Conclusions of Law , slip op. a t
121. In addition, on a s eparate inequitable c ondu ct question, the trial c ourt concluded that Lilly did not omit materi al su bject matter from its In formation Disclosure Statement in Apr il 1 9 9 1 , which did not disc lose the ’574 patent and Chakrabarti 1980a

. Id. at 199. The trial court also found no clear and conv incing ev i dence that Li lly withheld Chakrabarti 1980a or the ’574 patent with an in tent to deceive the PTO. Id. at 199-200. The trial co urt noted that Lilly did disclos e U. S. Patent No . 4,115,568 (’568 p a tent) to the PTO, and specifically explained that “[t]he reference fails to disclose the compound which is now claimed, but does describe the adjacent homologue [ C ompound ‘222].” Id.

05-1396, -1429, -1430 20at 148. It also noted that the technical disclosures of the ’574 and ’568 patents are identical and each disclos es the genus of compounds that generically includes olanza p ine. Moreover, Lilly cited the Britis h counterpart of the ’574 and ’568 p a tents in the olanzapine patent application. In add ition, the examiner found and relied on Chakrabarti 1980a during prosecution. As a result, the trial court did not err in its conclus i on that nondisclosure of Chakrabarti 1980a or the ’574 patent was neither a material omission nor done with an intent to deceive. V In conclus i on, this court affirms the tr ial court on anticipation, obviousness , and public use questions. Because the parties do not dispute the facts, this court also affirms the trial court’s legal conclusions on inequitable conduc t finding no abuse of discretion therein. COSTS Each party shall bear its own costs. AFFIRMED

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