## United States Court of Appeals for the Federal Circuit

04-1581

NOVO NORDISK PHARMACEUTICALS, INC., and NOVO NORDISK A/S, Plaintiff-Appellee,

v.

BIO-TECHNOLOGY GENERAL CORP. and

TEVA PHARMACEUTICALS USA, INC., Defendants-Appellants.

Steven E. Lipman , Darby & Darby, P.C., of New York, New York, argued for plaintiffs-appellants. Of counsel were James Edward Hanft , Paul M. Zagar , Jay P. Lessler , Kevin L. Reiner , Robert Schaffer and Joseph R. Robinson

. John W. Bateman , Kenyon & Kenyon, of Washington, DC, argued for defendants-appellees. On the brief was Richard L. DeLucia, of New York, New York. Of counsel were Steven J. Lee , and Thomas J. Meloro , of New York, New York, and Kenneth R. Corsello , of Washington, DC. Appealed from: United States District Court for the District of Delaware

. Chief Judge Sue L. Robinson

## United States Court of Appeals for the Federal Circuit

04-1581 NOVO NORDISK PHARMACEUTICALS, INC. and NOVO NORDISK A/S,
Pl aintiffs-Appellants,

v.

BIO-TECHNOLOGY GENERAL CORP. and

TEVA PHARMACEUTICALS USA, INC., Defendants-Appellees.

__________________________ DECIDED: October 5, 2005

__________________________

Before SCHALL, Circuit Judge , ARCHER, Senior Circuit Judge , and BRYSON, Circuit Judge

. SCHALL, Circuit Judge

.

Novo Nordisk Pharmaceutical s, Inc. and Novo Nordisk A/ S (collectively, “Novo”) appeal from the final j udgment of the United St ates District Court for the District of Delaware in their suit for patent infringem ent against Bio-Technology General Corp. and Teva Pharmaceuticals USA, Inc. The district court held the two claims of Novo Nordisk A/S’s U.S. Patent No. 5,633, 352 (“the '352 patent”) invalid by reason of anticipationunder 35 U.S.C. § 102( a). The court also held th e patent unenforceable due t o inequitable conduct. Novo Nordisk Pharms., Inc. v. B i o-Technology Gen. Corp. , No. 1:02-CV-00332-SLR ( D . De l. Aug. 3, 2004) (“ Opinion ”). We affirm the judgment of invalidity with respect to claim 1 of the '352 patent, as well as the judgment that the patent is unenforceable. We va cate the judgment of invalidity wit h respect to claim 2 of the patent. BACKGROUND
I. Novo Nordisk Pharmaceuticals, Inc. and Novo Nordisk A/S are research-based pharmaceutical manufacturers. Novo Nordi sk A/S is the assignee of the '352 patent, which is entitled “Bios y nthetic Human Growth Ho rmone.” The ' 3 52 pat ent is directed to a process for producing “ripe” human growth hormone (“hGH”) protein in E.Coli bacteria through the use of recombinant DNA techniques. Novo Nord isk Pharmaceuticals, Inc. is the U.S. healthcare affilia te of Novo Nordisk A/S. The hGH protein has a specific s equence of 191 amino acids and is secreted by the anterior pituitary gl and. The protein, whic h play s a central role in cell growth and metabolism , is therapeutically us eful to treat, among other conditions, growth hormone deficienc ie s and infertility. It also is useful in wound care. Until the mid-1980’s, hGH for therapeutic purposes could be obtained only from the pi tuitar y gland of a human cadaver (known as “pituitary- derived hGH”). However, the use of pituitary-derived hG H carried a high risk of contamination and infection for the patient. Prior to the '352 patent, numerous attempts were made to produce biosynthetic hGH that would function in vivo in the same manner as pi tuitary-derived hGH. One

04-1581 2such attempt, set forth in U.S. Patent No . 4,342,832, resulted in hGH protein with 192 amino acids, instead of the 191 amino acids found in pituit ary-derived hGH. '352 patent col. 1, ll. 20-25. The addit ional amino ac id residue, me thionine, resulted in a hG H protein variant that does not function in the same way in vivo as pituitary-derived hGH. Accordingly, there was a need for a method to produce “pure” hGH, or hGH containing the 191 amino acid sequence identical to that of pituitary-derived hGH.
II. As noted, the '352 patent discloses t he production of ripe hGH protein via recombinant DNA techniques. Recombinant DNA techniques make it possible to transfer D N A segments (genes) that code fo r a human protein to bacteria, such as E. coli , for the purpose of protein synthesis. Bacteria such as E. co li normally will not recognize a human gene sequence and, thus, will not synthesize the corr esponding human protein. However, transferring the gene sequence for a “fusion protein” 1 into E. coli , in effect, “tricks” the ba cteria into synthesizing the hum an protein. The gene sequenc e for the fusion protein contains, in a side-by-side relationship: (1) the gene se quence for a bacterial protein a n d (2) the gene sequence for a human protei n, such as hGH. The E. coli recognizes the portion of the gene s equence that encodes the bacterial prot ein and, as a result, synthesizes the entire fusion protein. The fu sion protein is made up of: (1 ) the amino acid sequence for the bacterial protein and (2) the amino acid sequence for the human prot ein. In order to isolate the desired human prot ein, the bacterial amino acid sequence, or “prosequence,” must be removed from the fu sion protein. This proces s can be

04-1581 3accomplished through the us e of a proteolytic enzy m e. 2 The proteolytic enzym e cleaves the bond between the pro-sequence and the amino a c id sequence for the human protein. The '352 patent discloses a process w her eby a proteolytic enz y me, preferably the enzyme dipeptidy l aminop eptidase I (DAP I), cleaves a pre-hGH fusio n protein in order to produce “ripe” hGH protei n. '352 patent col. 1, l. 56 – col. 2, l. 2. First, the gene sequence for the hGH protein is com b ined with the gene s equence for a bacterial protein. Id. col. 4, ll. 53-67. This DNA sequence is then introduced into E. co li

. Id. col. 5, ll. 1-10. This res u lts in a pre- hGH fusion protein bei ng produced by t h e E. coli bacteria. The resulting pre-hGH fusion pr otein is made up of: (1) the 191- amino-acid sequence f o r the hGH protein; and (2) a va riable amino acid sequence with an ev en number of amino ac ids t hat is formulated to take adv ant age of the cleavage specific ity of DAP I. When DAP I is then added, it works to cleav e, or cut, the fusion protein at the junction of the two amino ac id sequences described above. Id. c o l

. 5 , l l

. 2 4

- 2 5

. T h i s results in “ r ipe” hGH protei n, or hGH protein containing the cor r ect 191 amino acid
sequence. III. The '352 patent traces priority back through a series of continuation applications to Application Ser. No. 640,081, filed on December 9, 1983, as PCT Application PCT/DK83/001118 (“the 1983 PCT applic ation”). The 1983 PCT application, in turn,
(Cont’d. . . .) 1 A “fusion protein” is coded for by genes that have been combined together in vitro fro m two or m o re sources.

04-1581 4traces priority back to a 1 982 Danish patent application fi led on December 10, 1982. The 1983 PCT applic ation was directed to “A Process for Preparing Ripe Pr oteins from Fusion Proteins, Synthesized in Pro- or Eukaryotic Cells.” Unlike t he '352 patent, which disclos es the use of the proteoly t ic en zyme DAP I, the 1983 PCT applic ation disclos es leucine am inopeptidas e (LAP) as the preferred cleavage enzyme t o produce ripe hGH protein from a pre- hGH fusion protein. On November 12, 1992, Novo filed U. S. Applic ation No. 07/959,856 (“the '856 application” ), directed to “A Pr ocess for Preparing a Des i red Protein.” The '856 application discloses a proce ss for producing hGH protein fr om a fusion protein us ing the DAP I enzyme. The '856 a pplic ation was the first in a series of applications that claimed a priority date of De cember 10, 1982, based on the 1983 PCT application. The final application in t he chain was U.S. Application Ser. No. 402,286 (“the ''286 application” ), filed on March 10, 1995. The '352 patent issued from the '286 application on May 27, 1997. The '352 patent has two claims: 1. Biosynthetic ripe human growth hormone free of contaminant s from pituitary derived human growth hormone.

2. Biosy n thetic ripe hum an growth hormone produced by express i ng an amino terminal extended human growth hormone fusion prot ein in a microorganism capable of such expression, enzymatically c l eaving the amino te rminal extension and recovering the biosynthetically produced ripe human growth hormone.

(Cont’d. . . .) 2 Proteolytic enzymes are unique prot eins that catalyze the cleavage of peptide bonds (the bonds link i ng the chains of amino acids that make up proteins). Many proteolytic enzy m es exhibit specificity wit h respect to the bonds that they cleave.

04-1581 5IV. On July 7, 2000, the Board of Patent Appeals and Int e rferences (“Board”) of the United States Patent and Trademark Office (“PTO”) decla red an interference inv o lving Novo’s '352 patent and Bio- Tec hnology General Corp.’s 3 U.S. Application Ser. No

. 09/023,248 (“the '248 application”). Blum berg v. Dalbøge , Interference No. 104,422 (Bd. Pat. A pp. Int. Mar. 12, 2002) (“ Board Decision ”). The '248 application is directed to a biosynthetic hGH pr otein produced via rec o mbinant DNA techniques. In declaring the interference, the Boar d accorded the '352 patent the benefit of priority of the August 8, 1984 filing date of U.S. Patent Application Ser. No. 06/640,081 (“the '081 application”). 4 In due course, Novo filed a preliminary motion in t he interference seeking the benefit, for purposes of priority, of the filing date of the 1983 PCT application. Board Opinion , s l ip op. at 9. Bio-Tec h nology Genera l Corp., in turn, moved to deny Novo the benefit of the filin g da te of the 1983 PCT a pplic ation, as well as the benefit of the filing date of the '081 application. It argued that DAP I was not disclosed in the 1983 PCT application, and that the L AP enzyme that was disclosed in the application was not effective to produce ripe hGH protein. Board Decis i on , slip op. at 11. On March 12, 2002, the Board is sued its fina l decis ion, awarding priority to Novo. The Board noted that dur ing prosecution of its applic ati ons resulting in the ' 3 52 patent, Novo had made contradictor y statements regardi ng whether the 1983 PCT application enabled the production of ripe hG H protein. However, the Board concluded: “[W]e do not find the evidence relied upon by [Bio-Tec hnology General Corp.] . . . to establish

3 Bio-Technology General Corp. dev elops, manufactures, and markets biopharmaceutical products.

04-1581 6that pure LAP would not work to produce ripe hGH in the methods described in the '081 and [1983] PCT applic ations to be convincing.” Board Decis i on , slip op. at 33. On April 1, 2002, pursuant to 35 U.S. C. § 146, Bio-Technology General Corp. appealed t he final decision of the Board to the United St ates District Court for the District of Dela ware . The district cour t eventually reversed the Board’s dec i sion awarding Novo priority with respect to t he invention claimed in the '352 patent. Bio

Technology Gen. Corp. v. Novo Nordisk A/S , No. 02-235-SLR, slip op. at 59 (D. Del. Aug. 3, 2004) (“ Priority Decision ”). In doing so, the cour t ruled that the 1983 PCT application was not enabled becau se one of ordinary skill in the art would not have been able to pr oduce ripe hGH protein at the ti me the application was filed using the information disclosed in the application. Id. at 49. The court based this determination, in part, on a finding t hat No vo itself had been unable to synthesize ripe hGH protein using the disclosure of t he 1983 PCT applic ation. Id. at 56. The court remanded the case to the Board for consideration of two preliminary motions by Novo that the Board had dismis sed as moot. 5
V. On April 30, 2002, Novo filed a c o mplaint in the District of Delawa re against BioTechnology General Corp. and Teva Pharmac euticals USA, Inc. (collectively, “BioTechnology”) for infringement of the '352 pat ent and f o r injunctiv e relief to prevent the

(Cont’d. . . .) 4 The '081 applic ation is the U.S. c ounterpart of the 1983 PCT application. As far as this appeal is concerned, it is ident ical in substance to that application. 5 As of the time of this appeal, re mand proc eedings before the Board still are pending.

04-1581 7sale of Tev

- Tropin®, a recombinant hGH protein produc t. 6 On June 7, 2002, the district court issued a preliminary inj unction, which was vacated by this court on November 26,
2002. Novo Nordisk A/S v. Bi o-Technology Gen. Corp. , No. 02-1447, 52 Fed. Appx. 142 (Fed. Cir. Nov. 26, 2002). On June 12, 2002, Bio-Technology filed its answer to the complaint and assert ed a counterclaim for a dec laratory judgment that the '352 patent i s invalid and unenforceable. Prior to trial, Bio-Technology admitted infr ingement of claim 1 of the '352 patent. Opinion , slip op. at 5. Thereafter, from Augus t 4, 2003, to August 8, 2003, the district court construed the claims of the '352 paten t and held a bench trial on the is sues of: (1) invalidity of claim 1 of the '352 patent by reason of anticipation; and (2) unenforceability of the '352 patent due to inequitable conduct

. Following the trial, the dist rict court found that clai m 1 of the '352 patent was anticipated by a December 1981 article by George N. Pavlak is, pub lis hed in the journal Biochem istry and entit led “Expres s ion of two hum an gr owth hormone genes in monke y cells infect ed by simian virus 40 recombi nants” (“the 1981 Pavl ak is article”). Opinion , slip op. at 80. Bas e d upon t hat finding, the court ruled clai ms 1 and 2 inva lid under 35 U.S.C. § 102(a). Id. In addition, the court held that the '352 patent was unenforceable based on inequitable conduct during prosecuti on of the '856 application and during the interference proceeding before the Board. Id.

6 Teva Phar maceuticals USA, Inc. develops, manufactures and markets generic pharmaceutical produc ts. It has entered into an agreement with BioTechnology General Corp. to market and sell Bio-Technology General Corp.’s biosynthetic hGH protein in the Unit ed States under the name Tev-Tropin®.

04-1581 8Novo now appeals the district c ourt’s decis ion. We ha ve jurisdic tion pursuant to 35 U.S.C. § 1295(a)(1). DISCUSSI ON
I. We review a district court’s decision foll owing a bench trial for errors of law and clearly erroneous findings of fact. SmithKline Beecham Co rp. v. Apotex Corp. , 403 F.3d 1331, 1337 (Fed. Cir . 2005) (citing Allen Eng’g Corp. v. Bartell Indus., Inc. , 299 F.3d 1336, 1343-44 (Fed. Cir. 2002)). “A factual fi nding is c l early erroneous when, ‘although there is evidence to support [the finding], the reviewing court on the entire evidenc e is left with the definite and firm conviction that a mistak e has b een committed.’” Tegal Corp. v. Tokyo Electron Am., Inc. , 257 F.3d 1331, 1338-39 (F ed. Cir. 2001) (quoting United Sta t es v. Unit ed States Gypsum Co. , 333 U. S. 364, 395 (1948)). Howev e r, “[w]here the record v i ewed in it s entirety renders the district c ourt’s account of the evidenc e plausible or disclos es two permiss ible readings of the e v idence, the fact-finder has committed no clear error.” King Instruments Corp. v. Perego , 65 F.3d 941, 943 (Fed. Cir. 1995) (citation omitted). On appeal, Novo challenges the district court’s rulings with respect to both validity and inequit able conduct. We address its cont entions in turn, starti ng with the validity issue.
II.
A. As noted above, the district court ruled t hat the '352 pat ent was inv a lid by reason of anticipation based upon the 19 81 Pav l akis article. In the article, Pavlak is describes a

04-1581 9method of producing hGH protein with monkey kidney cells using what is known as the secretion approach. 7 The article discusses using the secretion approac h with two different hGH genes, identifi ed as hGH1 and hGH2. T he hGH1 gene encodes for the 191 amino acid sequence of pituitary-derived hGH. The hGH2 gene is a variant of the hGH1 gene, containing fourt een amino acid substitutions. The article describes a variety of tests performed on the two resulti ng proteins , using (1) gel electrophoresis; (2) isoelectric focusing and nonequ ilibrium pH gradient electrophor etic gels; and (3) cell surface receptor binding studies invo lving IM-9 culture human lymphocytes and pregnant rabbit liver membranes. 8 Based on these tests, Pavlakis comes to the conclus i on that the “hGH 1 protein, as predicted fr om the DNA sequenc e, appears identical in all respects to the major form of pituitary hGH. In cont rast, the hGH2 protein differs from authentic hGH both in its behav ior on isoelectric focusing gels and in its low immunoreactivity, yet it binds to hGH receptors quite effi ciently.” In its anticipation analysis, the district court constr ued the term “ripe” hGH in claim 1 of the '352 pat ent to mean “a prot ein produced by recombinant DNA t e chniques composed of a 191 amino acid sequence ident ical to that of hGH produced by the human pituitary gland wit h the full biologic al activity of hGH produced by the human pituitary gland, and free of the contaminant s present in hGH produced by the human

7 The secretion approac h, based on re combinant DNA techniques, involves the steps of transforming a host organism (suc h as a monkey kidney cell) to express a pre-protein consisting of the desired protein and a “leader” or “signal” sequence. The leader sequence causes the pre-protein to be transported across the cell membrane. In the process of transport across the cell me mbrane, a specialized enzyme clips off the leader s e quence. As a resul t, the des ired protein is secr eted from the cell of the hos t organism. 8 An understanding of the details of these tests is not neces sary for purposes of this appeal.

04-1581 10pituitary gland.” Opinion , slip op. at 45. The court det ermined that the 1981 Pavlak is article disc loses each limitation of claim 1 of the '352 patent. Id. at 64. The court stated: First, the Pavlak is article descr ibes a method to pr oduce hGH . . . using . . . recombi nant DNA techniques. Second, the Pavlak is 1981 article spec if ic ally discus s es experimental tests used to characterize the hGH product. Gel electrophor esis, isoelectric focusing, and nonequilibrium pH gradient electrophoresis analyses all revealed that the hGH product was indistinguishable from pituitary-derived hGH.

. . . This collective data establishes that the hG H product necessarily must be composed of the same 191 amino acid residues as the pitu itary-derived hGH. Third, the Pavlak is 1981 article disclos es through receptor binding assay data that the hGH1 product exhibited the same receptor binding affinity as pi tuitary-derived hGH in both the human lymphocyte line IM-9 an d the pregnant rabbit liver membranes. From this, the c ourt concludes that the hGH1 product has the full biological activity of hGH produced by the human pituitary gland. Fi nally, the aforementioned data inherently establishes that the hGH product is free of contaminants present in hGH produced by the human pituitary gland. Accordingly, the court concludes that the 1981 Pav l akis article clearly and convinc i ngly discloses all of the limitations of claim 1 of the '352 patent. Id. at 64-65. The court also determined t hat the Pavlakis article was enabled. Id.
B. On appeal, Novo argues that the 1981 Pavl akis article cannot ant icipate c l aim 1 of the '352 patent because the article does not disclos e the second and third limitations of the claim (a protein that is composed of a 191- amino acid s e quence identical to that of pituitary-derived hG H and that has the full biological activi ty of pituitary-derived hGH). Novo argues that the test results di sclosed in the article do not demonstrate conclus i vely that the hGH1 pr otein disc uss ed is identical in thes e respects to pituitaryderived hGH.

04-1581 11Novo also argues that the di strict court committed reversib le error when it stated that “[p]rior art references are presumed to be enabling,” Opinion , slip op. at 66, given that the 1981 Pavlakis article is a non-patent publication. Novo acknowledges our decision in Amgen Inc. v. Hoechst Marion Roussel, Inc. , 314 F.3d 1313, 1355 ( F ed. Cir. 2003), in which we held that “a presumption arises that both t he claimed and unclaimed disclos ures in a prior art patent are enabled,” but in whic h we did not decide whether the presumption applies to non-patent public ations. See id. at 1355 n.22 (“We note that by logic a l extension, our reasoning here might also apply to prior art printed public ations a s well, but as Sugimoto is a patent we nee d not and do not so decide today.”). Novo argues that, in the case of a non-patent prior art refer ence, however, the burden of proving enablement of the prio r art reference by clear and convincing ev idence should remain on an alleged infringer. Bio-Technology responds that the distri ct court correctly determined that the 1981 Pav l akis article disclos es each limitati on of claim 1. Bio-Technology also argues that the district court correct ly held that the 1981 Pavlakis article is pres umed to be enabled. Lastly, Bio-Technology urges that even if the ar ticle is not presumptively enabled, the district court hel d on separate grounds that it enabled the subject matter of claim 1. C. A patent claim is invalid by reason of antic ipation if “the invention was known or used by others in this country, or patented or de scribed in a printed publ ication in this or a foreign country, before the invention thereof by the applicant for patent . . . .” 35 U.S.C. § 102(a). Anticipation based on a printed public ation und er section 102(a)

04-1581 12requires the presenc e in the p ublic ation of each and every limitation of the cla i m e d invention. Advanced Display Sy s., In c. v. Kent State Univ. , 212 F.3d 1272, 1282 (Fed. Cir. 2000) (citation omitted). However, “a prior art refe rence may anticipate without disclos ing a feature of the cl aimed invention if that mi ssing feature is necessarily present, or inherent, in the si ngle anticipating reference.” SmithKline Beecham , 403 F.3d at 1343 (quoting Schering Corp. v. Geneva Pharms., Inc. , 339 F.3d 1373, 1377 (Fed. Cir. 2003)). “What a prio r art reference discloses in an anticipation analys is is a factual determination that we review under the clearly erroneous standard.” Tegal Corp. , 257 F.3d at 1345-46 (citing In re Graves , 69 F.3d 1147, 1151 (Fed. Cir. 1995)). In order to anticipate, a pr ior art disclos ure must also be enabling, such that one of ordinary skill in the art c ould practice the invention wit hout un due e x perimentation. SmithKline Beecham , 403 F.3d at 1342. The standard for enablement of a prior art reference for purposes of anticipation unde r section 102 differs from the enablement standard under 35 U. S.C. § 112. Rasmusson v. SmithKline Beecham Corp. , 413 F.3d 1318, 1325 (Fed. Cir . 2005) (citat ion omitted). While sect ion 112 “provides that the specification must enable one skilled in the art to ‘use’ the invention,” id. (quoting In re Hafner , 410 F.2d 1403, 1405 (CCPA 1969) ), “sec tion 102 makes no such requirement as to an anticipatory disclosure,” id. Signific antly, we have stated that “anticipation does not require actual performance of suggestions in a disc losure. Rather, anticipation only requires that those suggestions be enabl e d to one of skill in the art.” Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc. , 246 F.3d 1368, 1379 (Fed. Cir. 2001) (citing In re Donhue , 766 F.2d 531, 533 (Fed. Cir. 1985) (“It is not, however, necessary that an invention disclosed in a publication shall hav e actually been made in order to satisfy the

04-1581 13enablement requirement.”)). “Whet her a prior art reference is enabling is a question of law bas ed upon underlying factual findings.” SmithKline Beecham , 403 F.3d at 1342-43 (citation omitted).
D. We see no error in the district court’ s finding that t he 198 1 Pavlakis article disclos es the second and thir d limitations of claim 1 of the ' 3 52 patent. These limitations require that t he hGH protein be composed of a 191-amino acid sequence identical to that of pituit ary-derived hGH and t hat the protein have the full biologica l activity of pituitary-derived hG H. In that regard, the arti cle states that “[t]he hGH1 protein, as predicted fr om the DNA sequence, appears identical in all respects to the major form of pituitary hGH .” (emphasis added). Further, the article discuss es experimental tests used to characterize t he hGH product. These tests were designe d in order to determine whether t he hGH1 protein had the same amino acid sequence and biological activity as pituitar y-derived hGH. The article’s di scuss ion of the tests provides strong support for the district court’s conclusion that the 1981 Pavlakis article disc loses the subject matter of claim 1. Gel elec trophoresis tests repor ted in the article demonstrated that the hGH1 prot ein c o -migrat ed with pituitary-derived hGH on the ge l and that hGH1 thus was of the same overall si z e as pituitary-derived hGH. At the same time, the results from tests using isoelec tric focusing and nonequilibrium pH gradient electrophor esis gels s howed that the hGH1 protein co-migrated wit h pituitary-derived hGH on a pH gradient and that it thus had the same charge as pituitary-derived hGH. Finally, the results of radiorecept or a ssays with both t he human lymphocyte IM-9 line and pregnant rabbit liver membranes showed that hGH1 was indistinguis hable from

04-1581 14pituitary-derived hGH, indic a ting that hGH1 had an identical abil ity to bind to cell surfac e receptors. Thus, the test re sults disclosed in the Pavlakis article indicat ed that the hGH1 protein had the same structure and c hemic al properties as pituitary-derived hGH. In other words, the test resu lts indicated that the hGH1 protein contained the same 191 amino ac id sequence and bi ological activ i ty as pituitary

- de rived hGH. Accor d ingly, we hold that the article discl oses a ripe hGH protein. As far as enablement is conc er ned, in our view, a fair reading of the dis t rict court’s opinion is that the cour t did not rely solely on t he Amgen presumption in finding that the 1981 Pavlakis article was enabled. See Koito Mfg. v. Turn Key Tech. , 381 F.3d 1142, 1151 (Fed. Cir. 2004) (“At trial, [the declarat o ry judgment plaintif f (potential infringer)] . . . failed to provide any testimony or other evidence that would demonstrate . . . how that reference [JP ' 082, a Japanes e unexamined applic ation] met the limitations of the claim in the '2 68 patent or how the reference enabled on e of ordina ry skill in the art to practice the claimed invention.”). In that regard, the cour t determined that BioTechnology affirmatively estab lis hed enablement of the 1981 Pavl akis article. The co urt stated: Moreover, the Pav l akis 1981 article offers particular materials and methodology to produce hG H. The c o urt has no reason to doubt that this information will not lead to the successful production of hGH. Indeed, Dr. Pavlak is actually made the subject matter of claim 1 using the dis c losed materials and methodology set forth in t he Pav l ak is 1981 article. Opinion , slip op. at 67-68. The critical inquiry is w hether the 1981 Pavlakis article disclos es in an enabling manner the production of ripe hG H. See S m ithKlin e , 403 F.3d at 1344 (“Thus, whether

04-1581 15it was actually possible to make pure PCH anhy drate before the critical date of the '723 patent is irrelevant. The '196 patent suffices as an anticipatory prior art reference if it disclos es in an enabling manner the production of PHC hemihydrate.”); see als o Rasmusson , 413 F.3d at 1326; Bristol-Myers Squibb , 246 F.3d at 1379; In re Donhue , 766 F.2d at 533. The 1981 Pav l akis article di scloses the production of ripe hGH protein in an enabling manner because it disc usse s particular materials and a particular methodology (the sec r etion appr oach) to pr oduce the hGH protein. In other words, the article relies on standard rec o mbinant DNA techniques that would have be en understood by one of ordi nary sk ill in the art at the time of its publicati on. We see no reason to disturb t he district court’s c onc lus i on that the 1981 Pavlakis article is sufficiently enabling t o serve as an anticipating reference. We therefore affirm the district court’s ruling t hat claim 1 of the '3 52 patent is anticipated by the 1981 Pavlak is article. 9
The district court’s or der, dated August 3, 2004, states that “[t he '352 patent] is invalid under 35 U.S.C. § 102.” Howev e r, as Novo points ou t, the validity of claim 2 was not litigate d at trial. According l y, we va c a te the portion of the district court’s order relating to claim 2 of the '352 patent.

9 Because we affirm the district court’s ruling that claim 1 of the '352 patent is invalid as anticipated by the 1981 Pavlakis artic l e, we need not address BioTechnology’s alternative argument s that the district court e rred in construing claim 1, and that under Bio-T e chnology’s proposed construction, U.S. Patent No. 4,775,622 to Hitzeman would antic ipate claim 1.

04-1581 16III.
A.
W e t u r n n e x t t o N o v o ’ s a r gument that the district cour t erred in holding the '352 patent unenforceable due to inequitable conduct during pr osecution of the '85 6 application and during the inte rference proceedings before the Board. T h e following additional facts relating to prosecution of the '856 application are relevant to the inequitable conduct issue: As noted above, the '352 patent claims priority based on the 1983 PCT application. The 1983 PCT application, in turn , claims priority to the Danish Patent application filed on De cember 10, 1982. The 1983 PCT applic ation di sc loses the us e of the LA P enzyme to produce ripe hGH from a pre-hGH fusion protein. Ex ample 1 of the application des cribes the production, purification, and eval uation of a fusion protein. It also describes treatment of the fusion protein with the LAP enzyme in or d e r t o o b t a i n r i p e h G H

. F i n a l l y , E x a m p l e 1 states that standard tests indicated that the disclos ed methodology produced ripe hGH protein that was 98% pure. Speak ing in the pas t tense, the example states that “[t]he fusion product was purified from this extract,” 1983 PCT applic ation at 10 (emphasis added), that “[t] he purified fusion protein was evaluated to be more than 98% pure,” id. (emphasis added), and that “[t]his . . . product was then treated with leuc ine aminopeptidase,” id. (emphasis added). The district court found, however, and it is undisputed, that when the 1983 PCT application was filed on December 10, 1983, the inventors had not successfull y prepared hGH with LAP us ing r e combinant DNA technology. Priority Dec i s i on , sli p op.

04-1581 17at 20. For five months after the 1983 PC T application was filed, Novo’s scientists attempted unsuccessfully to us e LAP enzy me to synthesize hG H. Finally, on March 7, 1984, Nov o successf ully sy nthesized hGH using commercial LAP purchased from a company called Sigm a. Id. at 21. However, unbeknownst to Novo at the time, the particular batch of LAP cont ained the DAP I enzym e. Id. at 22. At a meeting on October 18, 1984, Novo scientist s concluded that “the active component in Sigma LAP presumably is not LAP but a ‘c ontaminating’ substance.” Id. at 23. The discovery that this “contaminating” substance was DAP I led to the filing, on February 6, 1986, of PCT/DK86/00014 (“the 1986 PCT app lication”). The 1986 PCT application, entitled “A Process for Producing Human Growth Ho rmone,” disclosed a process for producin g hGH from a fusion protein using the DAP I enzyme. Id. On October 3, 1986, Novo fi led U.S. Patent Applic atio n Ser. No. 06/910,230 (“the '230 applic ation”), entitled “Proc e ss fo r Producing Human Growth Hormone.” Priority Decis i on , s lip op. at 24. The ' 2 30 applicat ion did not claim priority to the 1983 PCT application, but instead claimed priority to the 1986 PCT app lication. During prosecution of the '230 applicat ion, the originally filed claims were rejected under 35 U.S.C. § 103 as obv ious over U.S. Patent No. 4,532,207 to Brewer 10 i n v i e w o f U

. S

. Patent No. 4,543,329 to Daum. 11 On April 11, 1990, in a respons e to a final rejection,

10 The applic ation that re sulted in the Brewer '207 patent was filed on Marc h 3, 1983. Its European counterpart was published on September 28, 1983. The examiner read the Br ewer paten t as disclos ing a method of producing a protein using a sequence of charged amino acid s and a cleavage enzy m e. 11 The applic ation that resulted in the Daum '329 patent was filed on July 6, 1982, claiming priority to an applic ation f iled on May 29, 1980. The Daum paten t disclos es the use of LAP enzyme to cleave a fu sion protein. '329 patent col. 9, ll. 60-62.

04-1581 18Novo argued that the Daum pat ent was distinguishable from the invention in the ' 2 30 application. Novo stated: Daum mentions . . . that with LAP it is p o ssible to “split off N- terminal methioni ne from foreign p r oteins[.]” Although applic ants have tested LAP with bacterially produced HGH, LAP has been shown not to be effective. The effectiveness of LAP seem s to disappear as soon as peptides gr eater than about 50 amino acids are involved. (emphasis in original). In addition, on September 12, 1990, Novo filed a declaration on behalf of Jorli Ringsted, J ohn Pendersen, and T horkild Christensen, all of whom are named inv e ntors on the '352 patent (the “1990 decl aration”). The 1990 declara tion described the ability of the LAP enzyme to remove a pro-sequenc e from a fusion protein to pr oduce hG H. After describing an experiment in whic h the scientists c o m pared LAP preparations from several different suppliers, the inventors stated: It is shown that es sentially only LAP-preparations from Sigma contain enzym atic activi ty able to convert Ala-GluhGH to mature hGH. LAP-prep arations from Merck, Serva, and Worthington did not contain su ch enzy m atic activity at all. It is thus likely that an en zymatic activity different from LAP-activit y is contained in the Sigma preparations . . . , which can convert Ala-Glu-hGH to mature hGH. The Novo s c ientists went on to conclude: The experiments show clearly that a pure LAP-preparation will not convert amino extended hGH to mature hGH. Only LAP-prepar ations with relev ant impurities will have some effect depending upon the nature and amount of the impurity and of course this can lead to misunderstanding about the effect o f LAP.

04-1581 19Thus, during prosecution of t he '230 application, Novo s ought to overcome the prior art rejection based upon Daum by arguing that t he LAP enzyme disclosed in Daum was not effective in the production of hGH protein. Unable to overcome the examiner’s rejections under section 103, Novo eventually abandoned the ' 230 applic ation. Over the next sever a l years, Novo filed a number of U.S. applic ations des cribing the use of the DAP I enzyme to produce ripe hGH and c l aiming priority to the 1986 PCT application. Then, on Novemb er 12, 1992, Novo filed t he '856 applicati on, directed to “A Process for Preparing a Desir e d Protein. ” As seen above, the '856 applic ation disc lo sed a pr ocess for producing hGH from a fusion protein using the DAP I enzyme. In a preliminary amendment, filed on October 13, 1992, Novo amended the spec ification of the '856 applic at ion to indic a te that the application was entitled to a priority date of December 10, 1982, based upon the 1983 PCT applic ation claiming priority back to the 1982 Danish application. Novo specifica lly pointed out that the Decem ber 10, 1982 priority date of the 1983 PCT a p plic ation— based upon that application ’s claim of priority to the prio rity date of the 1982 Danis h patent application—pr eceded the 1983 priority date of the Brewer patent. The examiner did not immediately acce pt the new priority claim, and on September 22, 1993, rejected t he two pending claims as obvi ous under 35 U. S.C. § 103
in v i ew of several ref e rences, including th e Brewer patent. On January 7, 1994, the examiner held a personal inte rvie w with Ch e r yl Agris, a Novo in-house patent attorney, Poul Eisten Petterson, a Novo in-house pat ent advis or, and Thorkild Christensen an d Henrik Dalbøge, two of the named inventor s on the '856 application. The examin er’s interview-s u mmary record indicates that the Brewer patent was one of the prior art

04-1581 20items that was disc us sed at the conference and states in re lev a nt part: “The priority date should be 1982 . [Cheryl Agris] will point out where in p r iority documents the enablement is present.” Novo followed up the interview with an am endment, on Januar y 20, 1994, whic h addressed the issue of whether the 1983 PCT application was enabled. The issue of whether the 1983 PCT applic ation was enabled was critical to the prosecution becaus e, if the applic ation was not enabled, Novo would not be able to rely upon the application’s priority date to overcome the Brewer paten t. Nov o pointed to the 1983 PCT application as providing “the general concept of addi ng an amino-termi nal extension with a n aminopeptidase, and isolat ion of mature hGH.” Novo also pointed to Example 1 of the 1983 PCT application as being “spec ifically directed to hGH.” Novo was ultimately abl e to claim priority to the 1983 PCT application. Upon allow ance, the examiner stated: [T]he amendment of abandoned files to recite additional parent history places the effect i v e filing date of the instant invention to December 9, 198 3, and for e ign priorit y to December 10, 1982. T herefore, the Brewer et al. reference, published September 28, 1983, does not appear to be prior art against the invention. As seen, t he '352 patent issued on May 27 , 1997 from the '286 appl ication, the final application in the chain of applicat ions that resulted in the patent.
B. Inequitable conduct occurs when a patent applicant breaches his or her “duty of candor and good faith” to the PT O. 37 C.F.R. § 1.56(a) (2004); Bruno Indep. Living Aids, Inc. v. Acorn Mobility S e rvs., Ltd. , 394 F.3d 1348, 1351 (Fed. Cir. 2005). Inequitable conduct includes “affirmative misrepres entation of a material fact, failure to disclos e material infor m ation, or submission of false material infor m ation, coupled wit h

04-1581 21an intent to deceive.” CFMT, Inc. v. YieldUp Int’l Corp. , 349 F.3d 1333, 1340 (Fed. Cir. 2003) (quoting Molins PLC v. T e xtron, Inc. , 48 F.3d 1172, 1178 (Fed. Cir. 1995)). Materiality and intent must be establis hed by clear and convincing evidence. Id. Once materiality and intent have been established, the distric t c ourt must weigh these factors in light of all of the circ umstances to determine whether a finding that inequitable conduct oc curred is warranted. Dayco Prods., Inc. v. Total Containment, Inc. , 329 F.3d 1358, 1363 (Fed. Cir. 2003) (citing Purdue Pharma L.P. v. Boehringer Ingelhe im GMBH , 237 F.3d 1359, 1366 (Fed. Cir. 2001)). We have stated that “when balanc ed against high materiality, the showing of intent can be proportionally less.” Bristol-Myers Squib b Co. v. Rhone-Poulenc Rorer, Inc. , 326 F.3d 1226, 1234 (Fed. Cir. 2003) (citation omitted). We review the district court’ s factual findings with respect to materi ality and int ent for clear error. Perspective Biosystems, Inc. v. Pharmacia Biotech, Inc. , 225 F.3d 1315, 1319 (Fed. Cir. 2000) (citation om itted). We review the ultimate determination of inequitable conduct, however, under an abuse of discretion standard. Id. (citation s omitted). Thus, we may reverse a district c ourt’s decision on inequit able conduct only if the decision is based upon “clear ly erroneous findi ngs of fact or on a misapplication or misinterpretation of applicable law, or evidences a clear e rror of judgment on the part of the . . . court.” Elk Corp. of Dallas v. GAF Bldg. Materials Corp. , 168 F.3d 28, 30 (Fed. Cir. 1999) (citation omitted). The distric t court based its finding of inequitable conduct with respect to prosecution of the ' 856 applic ation on Novo’s failure to dis c lose to the PTO that Example 1 of the 1983 PCT application had never act ually been performed. Id. at 76.

04-1581 22Referring to Example 1 being worded in the pas t tense, the court found that “Novo did not alert the examiner that the cleavage and pur ification steps had not been performed or that the purity result was merely a prediction.” Id. The district court found the requirement of materi ality satisfied becaus e the examiner relied upon Example 1 in deciding whether the 1983 PCT application enabled th e inv ent ion of the '856 application and thus was entitled to a priority date earlier than that of the Brewer patent. Id. Next, the court found the inequitable c onduct intent requirement satisfied because “Novo, nine years after it first subm itted Example 1 to t he PTO, knew or should have known that the examiner would hav e c onsidered t he fact that Example 1 contained prophetic data important in evaluating whether t he [’081 application, the U.S. counterpart of the 1983 PCT applic ation,] enabled the inventio n of the '856 applic ation, particularly in light of the fa ct that Novo never successfully produced ripe hGH using the methodology described in Example 1.” Priority Decision , slip op. at 76. The distric t court found inequit able c ond uct with respect to the interference proceedings before the Board ba sed again upon Nov o ’s failure to inform the Board that it was ultimately unable to produce ripe hGH using the methodology described in Example 1 of the 1983 PCT application. Priority De cision , slip op. at 79. First, the district court found the materiality elem ent satisfied because the Board “looked to Example 1 and reviewed expert testimony relat ed to . . . whether the steps described therein enabled one of ordinary s k ill in the ar t to produc e ripe hGH.” Id. With respect to the intent element, the court noted that, bef ore the Board, Novo presented extensiv e exp e rt testimony from Dr. V illa-Romaroff about Example 1, knowin g that Exa m ple 1 had never been successfully performed. The c ourt found that “Novo knew or should hav e

04-1581 23known that the Board would consider both Example 1 and Dr. Villa Romaroff’s expert opinion material to the question of enablement, particularly since t h is questio n was the sole focus of the interference.” Id. at 80. Moreover, the c ourt found that following the interference proceeding, Novo failed to offe r any explanation for its silence, merely asserting that “it was not required to provi de the PTO with a running update of its efforts to make h G H.” Id. C. On appeal, Novo argues that the district court’s finding that Novo was unable to make ripe hGH according to the methodology of Example 1 is clearly erroneous

. Pointing to the exper iment performed on March 7, 1984, during whic h Novo used commercial grade LAP enzyme purchased from the Sigma company in order to produce ripe hGH, Novo as serts that it was abl e to produce ripe hGH according to the methodology of Example 1. T hus, Novo argues, because the methodology did work, there can be no culpable failure to say that it did not work. The district court did not commit clear e rror in determining that Novo was unable to make ripe hGH acc o rding to the methodology of Example 1. It is undisputed that on March 7, 1984, Nov o unintentionally used LAP from the Sigma company whic h happened to be “contami nated” with DAP I. Priorit y Decis i on , slip op. at 56-57. Moreover, at oral argument, counsel for Novo conceded that Novo was never able to produce ripe hGH through the us e of “pure” LAP enzy m e. Ex ample 1 is dir e cted to the production of ripe hG H through the use of L AP enzyme. We are not prepar ed to acc e pt the proposition that simply because fate in terceded and Novo scientists unintentionally

04-1581 24used LAP “contaminated” with DAP I, Novo produced ripe hGH according to the methodology of Example 1. Novo also assigns error to the district court’s find ing that Novo acte d with deceptive intent in failing to disclose the pr ophetic nature of Example 1 to t he PTO or the Board. According to Novo, the distri ct court never made a fi nding that anyone ha d actual knowledge that Example 1 of the PCT applic ation was pr ophetic and that Novo

never succ essfully pr oduced ripe hGH us ing the met hodology described in Example 1. Specifically , Novo c o ntends that there is no ev idenc e that Dr. Christensen, the coinventor who wrote Example 1, subsequently learned that the drafting of a prophetic example in the past tense was not a good proc edure at the PTO, or that he subsequently told any of Novo’s a ttorneys that Example 1 was prophetic. 12 Thus, Nov o asserts, because it is impossible to disclose the unknown, the district court’s finding of inequitable conduct is reversible error under FMC Corp. v. M anitowoc Co., Inc. , 835 F.2d 1411, 1415 (Fed. Cir. 1987) (stating that an “[a]pplic ant must be chargeable with knowledge of the existenc e of the prior art or information, for it is impossible t o disclos e the unknown”). Novo also asse rts that the district court’s finding of inequitable conduct amounts to a finding of misc onduct based on an imputation of gross negligenc e , contrary to our holding in Kings down Medical Consu l tants, Ltd. v. Hollister, Inc. , 863 F.2d 867, 876 (Fed. Cir. 1988) (“ We adopt the view tha t a finding t hat particular conduct

12 The district court found that, at the ti me of filing the '0 81 app licat ion, Dr. Christensen did not intentional ly breach his duty of candor and good faith. Rather, the court concluded “that Mr. Christensen’s use of past tense was m e rely an ov ersight on his part, likely due to the fact that Dr. Chri stensen is trained as a scientist, not as a patent attorney familiar with the teachings of the MPEP.” Priority Decision , slip op. at 75. However, the district court did not extend this findi ng to actions tak e n by Dr. Christensen during prosecution of the ' 856 applic ation a nd thereafter.

04-1581 25amounts to ‘gross negligence’ does not of itself justify an infer enc e of intent to deceive; the involved conduct, viewed in light of all the evidence, incl uding evidenc e in dicative o f good faith, must indicate sufficient culpability to require a finding of int ent to deceive.”). Bio-Technology responds that Dr. Chri stensen was aware that Example 1 was prophetic, and because “knowledge of the law is chargeable t o the inventor,” and “inventors represented by couns el are pres umed to know the law,” the district court’s inference of deceptive intent was not clearly erroneous. See Bras seler, U.S.A. I, L.P. v. Stryker Sales Corp. , 267 F.3d 1370 (Fed. Cir. 2001). We agree with Bio-Technology. It is undisputed that Dr. Christensen was a w ar e that Exam ple 1 was prophetic and that Novo never successfully produced ripe hG H through the use of “pure LAP” enzyme. It al so is undis puted that, during pros ecution of the '856 applic ation, Dr. Ch ristensen was one of four Novo representatives present during the January 7, 1994 interv iew with the examin er, during which on e of t he issues addressed was enablement of the 1983 PCT applica t ion, of which the ’081 applic ation was the U.S. counterpart. As noted, other representatives included Novo’s in-house patent attorney and in-house patent advisor. Thus, Novo asks us to hold, on the one hand, that the failure of Dr. Christensen and his co-inventors to disclose the truth about Example 1 to Novo’s attorneys absolves them of their duty to disclose this information to the PTO or the Board, because wi thout their attorney’s consultation, they could not hav e known that this information was material. At the same time, Novo asks us to hold that its counsel’s failure t o disc lose the trut h about Example 1 to t he PTO or Board is

excus ed because the inventors failed to fu lly inform them of the details s u rrounding Example 1. As we have done in similar situat ions in the past, w e reject the “circular

04-1581 26logic” of this request. See Brasseler , 267 F.3d at 1 380 (“We refuse to pursue the circular logic of Brassele r’s request and decline t o carve out an exc e ption to the inequitable conduct law to shield those guilt y of inequit able c onduct from responsibility for their actions.”); see also Molins , 48 F.3d at 1178 (stating that the knowledge and actions of an applicant’s representatives are chargeable to t he applicant (citing FMC Corp. , 835 F.2d at 1415 n.8)). Acco rdingly, the district court correctly concluded that Novo knew or should have known that the PTO and t he Bo ard would hav e considered the information relating to Example 1 im port ant in evaluating w hether the 1983 PCT application was enabled. Finally, Novo argues that the withheld information about Example 1 c annot be material as a matter of law because it was cumulative of what w a s already before the examiner, or becaus e it is les s rele vant than information about the Example 1 methodology that was disclosed. See Reg ents of Univ. of Cal. v. Eli Lilly & Co. , 119 F.3d 1559, 1574-75 (Fed. Cir. 1997) (“[E]ven where an applican t fails to disclos e an otherwise material prior art reference, that failure will not support a finding of inequitable conduct if the reference is ‘simply cumulativ e to other references,’ i.e., if the referenc e teaches no more than what a re asonable examiner would cons ider to be taught by the prior art already bef ore the PTO.”) (citing Scripps Clinic & Research Found. v

. Genentech, Inc. , 927 F.2d 1565, 1582 (F ed. Cir. 1991) (“A reference that is simply cumulative to other references does not m eet the threshold of materi ality that is predicate to a holding of inequitable conduc t

. ”) (citation omitted)). In making t h is argument, Novo points to the 1990 dec laration, which it describes as showing that pure LAP enz y m e did not work, while comme rcial LAP from Sigma did

04-1581 27work. However, the withhe ld information concerning Example 1 was not merely cumulative of information al ready before the examiner; nor was the withheld information less relevant than information already before t he examiner. First, the testing condition s in Example 1 of the 1983 PCT applic ation diffe r from the testing conditio n s used in the examples in the 1990 declaration. The 1990 declarat i on does not indicate that pure LAP enzy m e is not effective to produce ripe hGH under the me thodology and testing conditions of Example 1 of the 1983 PCT applic ation. In addition, an inventor’s failed attempts to practice an invention ar e relevant evidenc e of non-enablement. See AK Steel Cor p . v. Sollac , 344 F.3d 1234, 1244-45 (Fed. Cir. 2003) (“[G]iven th e specification’s teaching away from the s ubject matter that was eventually claimed a nd AK Steel’s own failures to make and use the la ter claimed invent ion at the time of the application, the distric t court correctly c onc luded that there wa s no genuine issue of material fact relating to undue experiment ation as it relates to enablement.”); Enzo Biochem, Inc. v. Calgene, Inc. , 188 F.3d 1362, 1372 (Fed. Cir. 1999) (“The court noted that the record is r eplete wit h the inv e nt or’s own failed attempts to control the
express i on of other genes in pr okaryotes or eukaryotes usin g antisense technology.”). We see no error in the district court’s fi nding that the withheld information concernin g Example 1 was material. We therefore affirm the district court’s ruling that the '352 patent is unenforceable due to inequitable conduct. CONCLUS ION In sum, we affirm the district c ourt’s hol ding that cla i m 1 of the '352 pat ent is invalid bas ed on anticipation un der 35 U.S.C. § 102(a), as we ll as its holding that the '352 patent is unenforceable du e to inequitable conduct. However, we vacate the

04-1581 28court’s ruling that claim 2 of the '352 paten t is invalid based on anticipation under 35 U.S.C. § 102(a). COSTS Each party shall bear its own costs.

AFFIRMED-IN-PART and VACATED-IN-PART

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