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488 F.3d 1377, *; 2007 U.S. App. LEXIS 11886, **; PFIZER, INC., Plaintiff-Appellee, v. APOTEX, INC. (formerly known as Tor-
Pharm, Inc.) Defendant-Appellant.
2006-1261
UNITED STATES COURT OF APPEALS FOR THE FEDERAL CIRCUIT
488 F.3d 1377; 2007 U.S. App. LEXIS 11886; 82 U.S.P.Q.2D (BNA) 1852
May 21, 2007, Decided
May 21, 2007, Filed

PRIOR HISTORY: [**1] Appealed from: United
States District Court for the Northern District of Illinois. of rehearing and rehearing en banc is de- Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 2007 U.S. App. LEXIS 6623 (Fed. Cir., 2007) JUDGES: Before MICHEL, Chief Judge, NEWMAN,
MAYER, LOURIE, RADER, SCHALL, BRYSON, GA- JARSA, LINN, DYK, PROST, and MOORE, Circuit Judges. NEWMAN, LOURIE, and RADER, Circuit Judges, would rehear the appeal. NEWMAN, Circuit dissents in the denial of the petition for Judge, dissents [**3] in the denial of the petition for rehearing en banc in a separate opinion. rehearing in a separate opinion. LOURIE, Circuit Judge, dissents in the denial of the petition for rehearing in a separate opinion. RADER, Circuit Judge, dissents in the the denial of the petition for rehearing en denial of the petition for rehearing in a separate opinion. the denial of the petition for rehearing en The Appellee, Pfizer, Inc. filed a combined petition for panel rehearing and rehearing en banc, and a re- sponse thereto was invited by the court and filed by the Appellant, Apotex, Inc. The petition for rehearing was referred to the panel that heard the appeal, and thereafter the petition for rehearing en banc and response were re- ferred to the circuit judges who are authorized to request a poll whether to rehear the appeal en banc. A poll was DISSENT BY: NEWMAN; LOURIE; RADER
Apotex, Inc. moves for expedited denial of rehearing and rehearing en banc, and for expedited issuance of the NEWMAN, Circuit Judge, dissenting from the de- The court has not accepted the suggestion that this case be reviewed en banc, and the panel was unper- suaded by the argument that the decision is incorrect when the law of precedent is applied. I write separately because the panel's statement of the applicable law and its application to the facts of this case are inconsistent 488 F.3d 1377, *; 2007 U.S. App. LEXIS 11886, **; with the court's precedent. Our obligation as an appellate panel further erred in declining to give weight to these court is to assure that the law is both correctly stated and acknowledged "secondary considerations" of unexpected correctly applied. When inconsistency is raised by the results. See Richardson-Vicks, Inc. v. Upjohn Co.,122 panel's treatment, our obligation is to assure that conflicts F.3d 1476 (Fed. Cir. 1997) (evidence of unexpected re- with precedent -- whether real or apparent -- are re- sults must be considered); Ruiz v. AB Chance Co., 234 solved, as well [**5] as to assure that the law is cor- F.3d 654, 667 (Fed. Cir. 2000) ("Our precedents clearly rectly applied. From the court's denial of rehearing en hold that secondary considerations, when present, must be considered in determining obviousness.") The ruling in this case has important policy as well The panel decision changes the criteria as well as the as legal implications, as the many amici curiae point out, analysis of patentability, with results of particular sig- each side stressing a different aspect of the effect on nificance for their effect on the conduct of R&D, the commercial activity in the pharmaceutical field. Both costs of drug development, and the balance between ge- sides acknowledge that the effects of chemical changes neric access to established products and the incentive to on properties of medicinal products is not predictable; development of new products. The amici curiae on both the difference residing in the panel's acceptance of the sides of the issue stress different policy considerations: long-discredited "obvious to try" standard, on which the the pharmaceutical research companies point [**8] out panel superimposes the theory that the skill of these in- that diminished access to patenting will affect the kind ventors guided them to trial of the besylate salt (despite and direction of product development; the generic pro- the prior art's preference for the maleate salt), thereby ducers point out that the sooner they can enter the market negating patentability. The panel's application of the ob- for established drugs, the lower the consumer price. The vious-to-try standard is in direct conflict with precedent; placement of the balance in this ever-present conflict it has long been the law that "patentability shall not be between innovator and copier has long engaged the pub- negated by the manner in which the invention is made." lic and Congress, and needs must continue to do so. 35 U.S.C. § 103. In Gillette Co. v. S.C. Johnson & Son, Meanwhile, however, it is inappropriate for a panel of Inc., 919 F.2d 720, 725 (Fed. Cir. 1990) this court stated this court to make a change in the precedent by which that "we have consistently held that 'obvious to try' is not both sides of the debate have heretofore been bound. to be equated [**6] with obviousness." In In re Stability of precedent and the uniform application of Tomlinson, 53 C.C.P.A. 1421, 363 F.2d 928, 931 (CCPA correct law to achieve the correct result are the assign- 1966) the court explained that "there is usually an ele- ment of the Federal Circuit, for our rulings are of nation- ment of 'obviousness to try' in any research endeavor, wide effect. A primary purpose for which our court was that . . . is not undertaken with complete blindness but formed was to provide the judicial stability that supports rather with some semblance of a chance of success." The commercial investment -- this was a unique judicial role, amici curiae representing research pharmaceutical indus- and was adopted in recognition of the dependence of tries in this petition point out that methodical experimen- technology-based industry on an effective patent system. tation is fundamental to scientific advance, and particu- It was recognized that a nationally uniform, consistent, larly for biological and medicinal products, where small and correct patent law is an essential foundation of tech- change can produce large differences. At the trial there nological innovation, which is today the dominant con- was no contradiction to the testimony of Pfizer's expert tributor to the nation's economy. [**9] See the Report witness Dr. Anderson that "one of ordinary skill in the of the Domestic Policy Review of Industrial Innovation, art could neither draw any conclusions nor have any ex- Department of Commerce 1979 (stressing the need for pectations about the properties of amlodipine besylate judicial administration of correct and uniform patent from the properties of a besylate salt of a different com- law). In enacting the implementing statute, Congress pound." Pfizer Br. at 7. Indeed, the parties stipulated this Nor was there any evidence contradicting Pfizer's position that "the superior properties at issue were not Federal Circuit] is to resolve some of the some abstract concept of 'good' properties, but specific myriad structural administrative and pro- properties which solved both the sticking and instability problems of the [**7] prior art, while providing non- ability of our Federal courts to deal with hygroscopicity and good solubility. . . . Trade-offs in salt the vast range of controversies among our properties are the rule, and one of skill must usually ac- cept some undesirable properties [*1380] to achieve meaningfully to their demands for justice . other desirable ones. Amlodipine besylate, unlike any . . which include the inability of our pre- other amlodipine salt, presented no trade-offs." Id. The 488 F.3d 1377, *; 2007 U.S. App. LEXIS 11886, **; tive answer to legal questions of nation- can remedy panel lapses, if indeed this decision repre- sents such a lapse, or uniformly adopt panel advances in the law, if indeed this decision represents such an ad- vance. From the court's decision to decline this review, I S. Comm. on the Judiciary, Federal Courts Improvement Act of 1981, S. Rep. No. 97-275, at 1 (1981). LOURIE, Circuit Judge, dissenting from the denial When conflicts arise between panel decisions of the Federal Circuit the ensuing uncertainty is of national I respectfully dissent from the court's decision not to scope, contravening the purpose of establishing this rehear this case en banc. At bottom, I consider that the court. This adds weight to our obligation to undertake en decision of the panel was incorrect. But, we do not re- banc review, both to reestablish consistency in the law hear appeals simply because a non-panel member dis- and to correct errors in panel decisions. In 1998, in a agrees with its result. See Amgen Inc. v. Hoechst Marion letter to the Commission on Structural [**10] Alterna- Roussel, Inc., 469 F.3d 1039, 1043 (Fed. Cir. 2006) tives for the Federal Courts of Appeals, Justice Scalia (Lourie, J., concurring) [**12] ("I do not believe that every error by a panel is enbancable. A panel is entitled to err without the full court descending upon it."). [T]he function of en banc hearings . . . is Federal Rule of Appellate Procedure 35(a) provides that "[a]n en banc hearing or rehearing is not favored and flicts, [*1381] but also to correct and de- ordinarily will not be ordered unless: (1) en banc consid- ter panel opinions that are pretty clearly eration is necessary to secure or maintain uniformity of wrong . . . . The disproportionate segment the court's decisions; or (2) the proceeding involves a question of exceptional importance." Our Internal Oper- docket that is consistently devoted to re- ating Procedures ("IOPs") state that "[a]mong the reasons for en banc actions are: (1) necessity of securing or maintaining uniformity of decision; (2) involvement of a question of exceptional importance; (3) necessity of reduction function is not being performed overruling a prior holding of this or a predecessor court expressed in an opinion having precedential status; or (4) the initiation, continuation, or resolution of a conflict Letter dated Aug. 21, 1998, Hearing before the S. Sub-comm. on Administrative Oversight and the Courts of However, consistent with those established criteria the S. Comm. on the Judiciary, 106th Cong. 72 (1999). for taking a case en banc, I consider that the panel erred in its legal determinations, and that those errors will con- It is important to the federal system as a fuse the law relating to rebuttal of a prima facie case of whole that the Courts of Appeals utilize obviousness of a chemical compound. [**13] Thus, an en banc hearing is warranted in this case in order to within the circuit that are likely to other- maintain uniformity of the court's decisions and [*1382] because it presents questions of exceptional importance. The panel reversed the district court's decision that claims relating to amlodipine besylate (the active ingre- dient in the hypertension drug Norvasc (R)) were valid For the Federal Circuit, it was intended and expected and nonobvious after a bench trial. Pfizer, Inc. v. Apotex, that this court would provide uniform national law in all Inc., 480 F.3d 1348 (Fed. Cir. 2007). In my view, several of the fields assigned to our exclusive jurisdiction; not legal errors were made in this decision, and improper only in patent [**11] law. Our cases are rarely factually deference was given to fact-findings of the district court. simple, and when there arise apparently divergent panel First, the panel failed to defer to fact-findings made statements of the law and its application, the responsibil- by the district court that were not clearly erroneous re- ity for en banc review looms large. The goal of judging garding the unexpected properties of amlodipine besy- is "full, equal and exact" enforcement of the law. See late. Evidence in the record, including trial testimony of Roscoe Pound, "The Etiquette of Justice," 3 Proceedings experts and Pfizer scientists, internal research and devel- Neb. St. Bar Assn. 231 (1909) ("full, equal and exact opment documents, and a scientific article, supported the enforcement of substantive law is the end" of the judicial district court's finding that "the besylate salt clearly and process). Through the system of en banc review, courts unexpectedly exhibited a superior combination of prop- 488 F.3d 1377, *; 2007 U.S. App. LEXIS 11886, **; erties when compared to what was suggested in the pre- fore was not patentable. See Pfizer, 480 F.3d at 1367 ferred preparation." District Court Oral Op. Tr. at 23:13- (emphases added) (stating that the "type of experiments 15; see Pet. for Reh'g en banc at 5-6. The panel [**14] used by Pfizer's scientists to verify the physicochemical disregarded that express finding of fact, holding that characteristics of each salt are not equivalent to the trial "Pfizer has simply failed to prove that the results are un- and error procedures often employed to discover a new expected." Pfizer, 480 F.3d at 1371. Moreover, relying compound where the prior art gave no motivation or on the testimony of both parties' experts, the district suggestion to make the new compound nor a reasonable court found that there was no reasonable expectation of expectation of success"). That conclusion conflicts with success with regard to using the besylate salt form of the statutory requirement that "[p]atentability shall not be amlodipine. District Court Oral Op. Tr. at 23:1-9. How- negatived by the manner in which the invention was ever, rather than give deference to the district court's made." 35 U.S.C. § 103(a). Moreover, the conclusion fact-findings, the panel substituted its own finding that a contradicts the district court's supported findings that the reasonable expectation of success existed in the art. See results were unexpected, and that the experiments led to Pfizer, 480 F.3d at 1361, 1364-65 ("The record also sat- showing the totality of the [**17] properties of the in- isfies us that, contrary to the district court's finding, a vention, see Papesch, 50 C.C.P.A. 1084, 315 F.2d 381, reasonable fact-finder could only conclude that the 1963 Dec. Comm'r Pat. 334, which makes the compound skilled artisan would have had a reasonable expectation nonobvious, not merely to the verification of results. of success with the besylate salt form of amlodipine."). In addition, holding an inventor's expectations of Much public discussion has occurred, and even judicial success against the objective unexpectedness of the comments in opinions, that we should defer to district properties of the compound unfairly suggests that an court judges concerning certain aspects of claim con- inventor should try only that which he doubts will work. struction, which we have held is a matter of law. Be that See Pfizer, 480 F.3d at 1371 ("Dr. Wells' testimony re- as it may, it is undisputed that we must defer to fact- flects the fact that he believed that amlodipine besylate findings by a district court, unless they are [**15] would solve the problems of amlodipine maleate."). In- clearly erroneous, and I do not believe that they were ventors generally are optimistic about what they choose to experiment with, but that does not necessarily suggest In addition, the panel improperly placed greater im- portance on the therapeutic value of a claimed compound These issues are of exceptional importance. Chemi- over the value of its physical properties. The panel con- cal and pharmaceutical compounds often can be found to cluded that the improvement of the invention, which be prima facie obvious, as they are based on prior work related to drug formulation, viz., increased stability and that could reasonably suggest them, see KSR Int'l Co. v. decreased stickiness, was "insufficient" to meet the stan- Teleflex Inc., 127 S. Ct. 1727, 167 L. Ed. 2d 705, 2007 dards of patentability. Id. at 1368 (emphases added) WL 1237837 (2007), but commercialization of such ("[W]e hold that the optimization of the acid addition salt compounds may depend on their possession of unex- formulation for an active pharmaceutical ingredient pected properties. Such properties may be biological or would have been obvious where as here the acid addition physical. A failure to recognize all such properties that salt formulation has no effect on the therapeutic effec- [**18] may be relevant to the value of such a compound tiveness of the active ingredient and the prior art heavily may doom the compound to being poured down the drain suggests the particular anion used to form the salt."). I rather than becoming an important therapeutic. The gen- read that conclusion as improperly requiring a compound eral public, innovative companies, and, ultimately, ge- to possess a specific type of improvement over the prior neric companies, depend upon faithful adherence to this art--in this case, improved therapeutic properties--to be principle. In addition, our cases hold that unexpected patentable, negating other important properties, a conclu- properties make for non-obviousness, see Papesch, 50 sion that is not compelled by our case law and not sound. C.C.P.A. 1084, 315 F.2d 381, 1963 Dec. Comm'r Pat. Any useful and unexpected property should be eligible to 334, and this decision disdains such properties if they are overcome a prima facie obviousness determination. not biological. That is a conflict with our precedent that [**16] See In re Papesch, 50 C.C.P.A. 1084, 315 F.2d 381, 391, 1963 Dec. Comm'r Pat. 334 (CCPA 1963) ("From the standpoint of patent law, a compound and all Not least, the question of deference to district courts, of its properties are inseparable; they are one and the at least on fact issues, needs reaffirming. We must not same thing. . . . There is no basis in law for ignoring any shy away from reversing fact-findings that truly are property in making such a comparison."). clearly erroneous, as we do encounter them from time to time, but this case does not present them. [*1383] Third, the panel also found that the inven- tion was the result of routine experimentation, and there- 488 F.3d 1377, *; 2007 U.S. App. LEXIS 11886, **; Thus, I would rehear this case, and I dissent from the cerned a reasonable expectation of success by giving undue emphasis to the inventor's subjective hopes for the outcome of his experiments. RADER, Circuit Judge, dissenting from the denial The panel also mistakenly determined that the supe- rior properties of the besylate did not overcome a prima I respectfully dissent from the decision to deny re- facie case of obviousness because they showed no supe- rior therapeutic value--the maleate salt form of amlodip- In this case, the trial court made the factual determi- ine worked just as well as the besylate form in clinical nation that the besylate salt form of amlodipine had un- trials. Therapeutic value, however, is just one property of expected superior properties over the [**19] closest a pharmaceutical. Other properties, such as solubility, prior art. Accordingly, the underlying patent ('303) was stability, hygroscopicity, and processability, must also valid and nonobvious. Three separate district courts held play a role in the analysis of advantages. The superior trials involving the '303 patent. Indeed, each of those properties of the besylate salt form of amlodipine, over- three different district court judges came to the same came the stability and stickiness problems that existed [*1384] factual conclusion regarding the nonobvious- with the maleate salt form and created a superior formu- ness of amlodipine besylate. Because the factual deter- lation. Although the maleate salt [**21] form was also minations in the case below were not clearly erroneous, therapeutically effective, the besylate form was still a this court should have deferred to the district court's fac- significant improvement because it overcame the stabil- ity and processing problems that could have prevented successful commercial marketing. As the testimony indicated, the properties of new pharmaceutical salt forms are entirely unpredictable. The panel also found that amlodipine besylate was Even the Berge reference on which the panel relied not patentable since it was made by a routine testing or a clearly states: "Unfortunately there is no reliable way of "well known problem solving strategy." This clearly vio- predicting the influence of a particular salt species on the lates the statutory mandate that "patentability shall not be behavior of the parent compound." The district court negatived by manner in which the invention was made." agreed and made the factual determination that the supe- 35 U.S.C. 103(a). Many if not most pharmaceutical in- rior properties of amlodipine besylate over the prior art ventions are discovered through a routine screening pro- (increased stability and decreased stickiness) were in- tocol or through an established trial and error process. deed unexpected--a finding that deserved deference. Pharmaceutical inventions discovered by these routine screening methods include not only new formulations Furthermore 'obvious to try' jurisprudence has a very and salt forms, but also include the active pharmaceutical limited application in cases of this nature. With unpre- compounds themselves. Thus, this decision calls into dictable pharmaceutical inventions, this court more question countless pharmaceutical patents, which in turn wisely employs a reasonable expectation [**20] of suc- could have a profoundly negative effect on investments cess analysis. In this case, salt selection is unpredictable, into the design and development of new life-saving thus rebutting, as most other courts found, any reason- pharmaceuticals. With many questions about this case, I able expectation of success. Although the panel gives "lip service" to the principle that 'obvious to try' does not work in this field, it nonetheless appears to be the basis for its decision in this case. In addition, the panel dis- Citation #3
2007 U.S. App. LEXIS 15349
TAKEDA CHEMICAL INDUSTRIES, LTD. and TAKEDA PHARMACEUTI-
CALS NORTH AMERICA, INC., Plaintiffs-Appellees, v. ALPHAPHARM PTY.,
LTD. and GENPHARM, INC., Defendants-Appellants.
UNITED STATES COURT OF APPEALS FOR THE FEDERAL CIRCUIT
492 F.3d 1350; 2007 U.S. App. LEXIS 15349; 83 U.S.P.Q.2D (BNA) 1169
June 28, 2007, Decided

SUBSEQUENT HISTORY: Later proceeding at
similarly structured compounds exhibited negative side Takeda Chem. Indus. v. Ranbaxy Labs., Ltd., 2007 U.S. effects, while other compounds were more promising at App. LEXIS 15883 (Fed. Cir., June 28, 2007) the time of invention. The court of appeals concluded US Supreme Court certiorari denied by Alphapharm Pty that the district court did not err in determining that the v. Takeda Chem. Indus., 2008 U.S. LEXIS 3015 (U.S., claimed compounds would not have been obvious in light of the prior art, and that the patent had not been shown to be invalid. The trial also did not err in holding PRIOR HISTORY: [**1]
that the generic manufacturer failed to establish a prima Appealed from: United States District Court for the facie case of obviousness. Because the district court's Southern District of New York Judge Denise Cote. conclusions were not clearly erroneous and were sup- Takeda Chem. Indus. v. Mylan Labs., Inc., 417 F. Supp. ported by the record evidence, there was no basis to dis- 2d 341, 2006 U.S. Dist. LEXIS 6710 (S.D.N.Y., 2006) DISPOSITION: AFFIRMED.
OUTCOME: The judgment of the district court was
CASE SUMMARY:
JUDGES: Before LOURIE, BRYSON, and DYK, Cir-
PROCEDURAL POSTURE: Defendant, the manufac-
cuit Judges. Opinion for the court filed by Circuit Judge turer of a generic version of pioglitazone, a compound LOURIE. Concurring opinion filed by Circuit Judge successful in anti-diabetic treatment, appealed from a holding of the United States District Court for the South- ern District of New York that the generic manufacturer OPINION BY: LOURIE
failed to prove by clear and convincing evidence that the patent claims asserted by plaintiff patent holder were invalid as obvious under 35 U.S.C.S. § 103, at the time Alphapharm Pty., Ltd. and Genpharm, Inc. (collec- OVERVIEW: The generic manufacturer filed an abbre-
tively "Alphapharm") appeal from the decision of the viated new drug application seeking U.S. Food and Drug United States District Court for the Southern District of Administration approval to market its generic product New York, following a bench trial, that U.S. Patent under 21 U.S.C.S. § 355(j) et seq. The district court re- 4,687,777 was not shown to be invalid under 35 U.S.C. § jected the obviousness argument, because the closest 103. Takeda Chem. Indus., Ltd. v. Mylan Labs., 417 F. prior art compound exhibited negative properties that Supp. 2d 341 (S.D.N.Y. 2006). Because we conclude would have directed one of ordinary skill in the art away [**2] that the district court did not err in determining that from the compound that was eventually patented as the the claimed compounds would not have been obvious in lead compound for anti-diabetic treatment. The most 492 F.3d 1350, *; 2007 U.S. App. LEXIS 15349, **; light of the prior art, and hence that the patent has not Diabetes is a disease that is characterized by the body's inability to regulate blood sugar. It is generally caused by inadequate levels of insulin--a hormone pro- duced in the pancreas. Insulin allows blood sugar or glu- consists essentially of a compound of the cose, which is derived from food, to enter into the body's cells and be converted into energy. There are two types of diabetes, known as Type 1 and Type 2. In Type 1 dia- betes, the pancreas fails to produce insulin, and individu- als suffering from this type of diabetes must regularly salt thereof, in association with a pharma- receive insulin from an external source. In contrast, Type cologically acceptable carrier, excipient or 2 diabetic individuals produce insulin. However, their bodies are unable to effectively use the insulin that is produced. This is also referred to as insulin resistance. As a result, glucose is unable to enter the cells, thereby depriving the body of its main source of energy. Type 2 diabetes is the most common form of diabetes--affecting For purposes of this appeal, the critical portion of the compound structure is the left moiety of the mole-cule, namely, the ethyl-substituted pyridyl ring. 1 That In the 1990s, a class of drugs known as thiazolidin- chemical structure, which has an ethyl substituent ediones [**3] ("TZDs") was introduced on the market as (C[2]H[5]) pictorially drawn to the center of the pyridyl a treatment for Type 2 diabetes. Takeda Chemical Indus- ring, indicates that the structure covers four possible tries, Ltd., and Takeda Pharmaceuticals North America, compounds, [**5] viz., compounds with an ethyl sub- Inc. (collectively "Takeda") first invented certain TZDs stituent located at the four available positions on the in the 1970s. Takeda's research revealed that TZDs acted pyridyl ring. Takeda, 417 F. Supp. 2d at 360. The for- as insulin sensitizers, i.e., compounds that ameliorate mula includes the 3-ethyl compound, 4-ethyl compound, insulin resistance. Although the function of TZDs was 5-ethyl compound (pioglitazone), and 6-ethyl compound. not completely understood, TZDs appeared to lower blood glucose levels by binding to a molecule in the nu- [*1354] Claim 2 of the '777 patent covers the sin- cleus of the cell known as PPAR-gamma, which acti- gle compound pioglitazone. That claim, which depends vates insulin receptors and stimulates the production of glucose transporters. Takeda, 417 F. Supp. 2d at 348-49. The transporters then travel to the cellular surface and enable glucose to enter the cell from the bloodstream. Id. wherein the compound is 5-4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl-2,4- Takeda developed the drug ACTOS (R), which is used to control blood sugar in patients who suffer from Type 2 diabetes. ACTOS (R) has enjoyed substantial commercial success since its launch in 1999. By [*1353] '777 patent, claim 2. Pioglitazone is referred to as the 5- 2003, it held 47% of the TZD market, and gross sales for ethyl compound because the ethyl substituent is attached that year exceeded $ 1.7 billion. Id. at 386. The active to the 5-position on the pyridyl ring. That portion of the ingredient in ACTOS (R) is the TZD compound pioglita- zone, a compound claimed in the patent in suit. Takeda owns U.S. Patent 4,687,777 [**4] (the "'777 patent") entitled "Thiazolidinedione Derivatives, Useful 1 Pyridine is a "six-membered carbon- As Antidiabetic Agents." The patent is directed to "com- containing ring with one carbon replaced by a ni- pounds which can be practically used as antidiabetic trogen." Takeda, 417 F. Supp. 2d at 351. agents having a broad safety margin between pharmacol-ogical effect and toxicity or unfavorable side reactions." Alphapharm, a generic drug manufacturer, filed an '777 patent col.1 ll.34-37. The asserted claims are claims Abbreviated New Drug Application ("ANDA") pursuant 1, 2, and 5. Claim 1 claims a genus of compounds. Claim to the Hatch-Waxman Act seeking U.S. Food and Drug 5 claims pharmaceutical compositions containing that Administration ("FDA") approval under 21 U.S.C. § genus of compounds. Those claims read as follows: 355(j) et seq. to manufacture and sell a generic version of 492 F.3d 1350, *; 2007 U.S. App. LEXIS 15349, **; pioglitazone. Alphapharm filed a Paragraph IV certifica- are [**8] such that the subject matter as a whole would tion with its ANDA pursuant to § 505(j)(2)(B)(ii), [**6] have been obvious at the time the invention was made to asserting that the '777 patent is invalid as obvious under a person having ordinary skill in the art." 35 U.S.C. § 35 U.S.C. § 103. In response, Takeda sued Alphapharm, 103(a). [HN2]Because a patent is presumed to be valid, along with three other generic drug manufacturers who 35 U.S.C. § 282, the evidentiary burden to show facts also sought FDA approval to market generic pioglita- supporting a conclusion of invalidity, which rests on the zone, alleging that the defendants have infringed or will accused infringer, is one of clear and convincing evi- dence. AK Steel Corp. v. Sollac & Ugine, 344 F.3d 1234, 1238-39 (Fed. Cir. 2003). Whether an invention would On January 17, 2006, the district court commenced a have been obvious under 35 U.S.C. § 103 is a "question bench trial solely on the issues of validity and enforce- of law, reviewed de novo, based upon underlying factual ability of the '777 patent. Alphapharm advanced its inva- questions which are reviewed for clear error following a lidity argument, asserting that the claimed compounds bench trial." Alza Corp. v. Mylan Labs., Inc., 464 F.3d would have been obvious at the time of the alleged in- vention. Alphapharm's obviousness contention rested entirely on a prior art TZD compound that is referenced in Table 1 of the '777 patent as compound b. The left moiety of compound b consists of a pyridyl ring with a Alphapharm raises three main arguments in support methyl (CH[3]) group attached to the 6-position of the of its contention that the claims would have been obvi- ring. That portion of its chemical structure is illustrated ous. First, Alphapharm asserts that the district court mis- applied the law, particularly the law governing obvious-ness in the context of structurally similar chemical com- pounds. According to Alphapharm, the record estab- Alphapharm asserted that the claimed compounds lished that compound b was the most effective antidia- would have been obvious over compound b. betic compound in the prior art, and thus the court erred by failing to apply [**9] a presumption that one of ordi- The district court found that Alphapharm failed to nary skill in the art would have been motivated to make prove by clear and convincing evidence that the asserted the claimed compounds. Alphapharm asserts that such a claims were invalid as obvious under 35 U.S.C. § 103. conclusion is mandated by our case law, including our en The court first [**7] concluded that there was no moti- banc decision in In re Dillon, 919 F.2d 688 (Fed. Cir. vation in the prior art to select compound b as the lead 1990). Second, Alphapharm argues that the court erred in compound for antidiabetic research, and that the prior art determining the scope and content of the prior art, in taught away from its use. As such, the court concluded particular, whether to include the prosecution history of that Alphapharm failed to make a prima facie case of the prior '779 patent. Lastly, Alphapharm assigns error to obviousness. The court continued its analysis and found numerous legal and factual determinations and certain that even if Alphapharm succeeded in making a prima evidentiary rulings that the court made during the course facie showing, Takeda would still prevail because any prima facie case of obviousness was rebutted by the un-expected results of pioglitazone's nontoxicity. The court Takeda responds that the district court correctly de- then rendered judgment in favor of Takeda. The district termined that Alphapharm failed to prove by clear and court also held that the '777 patent had not been procured convincing evidence that the asserted claims are invalid though inequitable conduct. That decision has been sepa- as obvious. Takeda contends that there was overwhelm- rately appealed and has been affirmed in a decision is- ing evidence presented at trial to support the court's con- clusion that no motivation existed in the prior art for one of ordinary skill in the art to select compound b as a lead Alphapharm timely appealed. We have jurisdiction compound, and even if there was, that the unexpected results of pioglitazone's improved toxicity would have rebutted any prima facie showing of obviousness. Ta- keda further argues that all of Alphapharm's [**10] re- maining challenges to the district court's legal and factual rulings are simply without merit. In this appeal, we are presented with one issue, namely, whether the asserted [*1355] claims of the '777 We agree with Takeda that the district court did not patent would have been obvious under 35 U.S.C. § 103 err in concluding that the asserted claims of the '777 pat- at the time the invention was made. [HN1]An invention ent would not have been obvious. The Supreme Court is not patentable, inter alia, "if the differences between recently addressed the issue of obviousness in KSR In- the subject matter sought to be patented and the prior art ternational Co. v. Teleflex Inc., 127 S. Ct. 1727, 167 L. 492 F.3d 1350, *; 2007 U.S. App. LEXIS 15349, **; Ed. 2d 705 (2007). The Court stated that[HN3] the fied, however, that in order to find a prima facie case of Graham v. John Deere Co. of Kansas City, 383 U.S. 1, unpatentability in such instances, a showing that the 86 S. Ct. 684, 15 L. Ed. 2d 545 (1966), factors still con- "prior art would have suggested making the specific mo- trol an obviousness inquiry. Those factors are: 1) "the lecular modifications necessary to achieve the claimed scope and content of the prior art"; 2) the "differences invention" was also required. Id. (citing In re Jones, 958 between the prior art and the claims"; 3) "the level of F.2d 347 (Fed. Cir. 1992); Dillon, 919 F.2d 688; ordinary skill in the pertinent art"; and 4) objective evi- Grabiak, 769 F.2d 729; In re Lalu, 747 F.2d 703 (Fed. dence of nonobviousness. KSR, 127 S. Ct. at 1734 (quot- That test for prima facie obviousness for chemical In a thorough and well-reasoned opinion, albeit ren- compounds is consistent with the legal principles enunci- dered before KSR was decided [*1356] by the Supreme ated in KSR. 2 While the KSR Court rejected a rigid ap- Court, the district court made extensive findings of fact plication of the teaching, suggestion, or motivation and conclusions of law as to the four Graham factors. ("TSM") test in an obviousness [**13] inquiry, the Alphapharm's arguments challenge the court's determina- Court acknowledged the importance of identifying "a tions with respect to certain of these factors, which we reason that would have prompted a person of ordinary skill in the relevant field to combine [*1357] the ele-ments in the way the claimed new invention does" in an 1. Differences Between the Prior Art and the Claims obviousness determination. KSR, 127 S. Ct. at 1731. a. Selection of Compound b as Lead [**11] Com- Moreover, the Court indicated that there is "no necessary inconsistency between the idea underlying the TSM test and the Graham analysis." Id. As long as the test is not Alphapharm's first argument challenges the court's applied as a "rigid and mandatory" formula, that test can determination with regard to the "differences between the provide "helpful insight" to an obviousness inquiry. Id. prior art and the claims." Alphapharm contends that the Thus, in cases involving new chemical compounds, it court erred as a matter of law in holding that the ethyl- remains necessary to identify some reason that would substituted TZDs were nonobvious in light of the closest have led a chemist to modify a known compound in a prior art compound, compound b, by misapplying the particular manner to establish prima facie obviousness of law relating to obviousness of chemical compounds. We disagree. Our case law concerning prima facie obviousness of structurally similar compounds is well- 2 We note that the Supreme Court in its KSR established. We have held that [HN4]"structural similar- opinion referred to the issue as whether claimed ity between claimed and prior art subject matter, proved subject matter "was" or "was not" obvious. Since by combining references or otherwise, where the prior art 35 U.S.C. § 103 uses the language "would have gives reason or motivation to make the claimed composi- been obvious," and the Supreme Court in KSR tions, creates a prima facie case of obviousness." Dillon, did consider the particular time at which obvi- 919 F.2d at 692. In addition to structural similarity be- ousness is determined, we consider that[HN7] the tween the compounds, a prima facie case of obviousness Court did not in KSR reject the standard statutory also requires a showing of "adequate support in the prior formulation of the inquiry whether [**14] the art" for the change in structure. In re Grabiak, 769 F.2d claimed subject matter "would have been obvious at the time the invention was made." 35 U.S.C. § 103. Hence, we will continue to use the statutory We elaborated on this requirement in the case of In re Deuel, 51 F.3d 1552, 1558 (Fed. Cir. 1995), where we stated that[HN5] "[n]ormally a prima facie case of obvi- We agree with Takeda and the district court that Al- ousness is based [**12] upon structural similarity, i.e., phapharm failed to make that showing here. Alphapharm an established structural relationship between a prior art argues that the prior art would have led one of ordinary compound and the claimed compound." That is so be- skill in the art to select compound b as a lead compound. cause close or established "[s]tructural relationships may By "lead compound," we understand Alphapharm to re- provide the requisite motivation or suggestion to modify fer to a compound in the prior art that would be most known compounds to obtain new compounds." Id. promising to modify in order to improve upon its [HN6]A known compound may suggest its homolog, antidiabetic activity and obtain a compound with better analog, or isomer because such compounds "often have activity. 3 Upon selecting that compound for antidiabetic similar properties and therefore chemists of ordinary skill research, Alphapharm asserts that one of ordinary skill in would ordinarily contemplate making them to try to ob- the art would have made two obvious chemical changes: tain compounds with improved properties." Id. We clari- first, homologation, i.e., replacing the methyl group with 492 F.3d 1350, *; 2007 U.S. App. LEXIS 15349, **; an ethyl group, which would have resulted in a 6-ethyl rivatives" ("Sodha II"). The Sodha II reference disclosed compound; and second, "ring-walking," or moving the data relating to hypoglycemic activity and plasma ethyl substituent to another position on the ring, the 5- triglyceride lowering activity for 101 TZD compounds. position, thereby leading to the discovery of pioglita- [**17] Those compounds did not include pioglitazone, zone. Thus, Alphapharm's obviousness argument clearly but included compound b. Significantly, Sodha II identi- depends on a preliminary finding that one of ordinary fied three specific compounds that were deemed most skill in the art would have selected [**15] compound b favorable in terms of toxicity and activity. Notably, compound b was not identified as one of the three most favorable compounds. On the contrary, compound b, was 3 The parties do not dispute that compound b singled out as causing "considerable increases in body was the closest prior art compound. Thus, the le- gal question is whether or not the claimed subject The court also considered Takeda's '779 patent. That matter would have been obvious over that com- patent covers a subset of compounds originally included pound. We will, however, use Alphapharm's ter- in the '200 patent application, namely, TZD compounds minology of "lead compound" in this opinion, de- "where the pyridyl or thiazolyl groups may be substi- ciding the appeal as it has been argued. tuted." Id. at 353. The broadest claim of the '779 patent The district court found, however, that one of ordi- covers over one million compounds. Id. at 378. Com- nary skill in the art would not have selected compound b pound b was specifically claimed in claim 4 of the pat- as the lead compound. In reaching its determination, the ent. The court noted that a preliminary amendment in the court first considered Takeda's U.S. Patent 4,287,200 prosecution history of the patent contained a statement (the "'200 patent"), which was issued on September 1, that "the compounds in which these heterocyclic rings 1981, and its prosecution history. The court found that are substituted have become important, especially [com- the '200 patent "discloses hundreds of millions of TZD compounds." 4 Takeda, 417 F. Supp. 2d at 378. The pat- Based on the prior art as a whole, however, the court ent specifically identified fifty-four compounds, includ- found that a person of ordinary skill in the art would not ing compound b, that were synthesized according to the have selected compound b as a lead compound for procedures described in the patent, but did not disclose antidiabetic treatment. Although [**18] the prosecution experimental data or test results for any of those com- history of the '779 patent included the statement that pounds. The prosecution history, however, disclosed test characterized compound b as "especially important," the results for nine specific compounds, including compound court found that any suggestion to select compound b b. That information was provided to the examiner in re- was essentially negated by the disclosure of the Sodha II sponse to a rejection in [**16] order to show that the reference. The court reasoned that one of ordinary skill claimed compounds of the '200 patent were superior to in the art would not have chosen compound b, notwith- the known compounds that were disclosed in a cited ref- standing the statement in the '779 patent prosecution his- erence. The court, however, found nothing in the '200 tory, "given the more exhaustive and reliable scientific patent, or in its file history, to suggest to one of ordinary analysis presented by Sodha II, which taught away from skill in the art that those nine compounds, out of the compound b, and the evidence from all of the TZD pat- hundreds of millions of compounds covered by the pat- ents that Takeda filed contemporaneously with the '779 ent application, were the best performing compounds as [p]atent showing that there were many promising, broad antidiabetics, and hence targets for modification to seek avenues for further research." Id. at 380. The court found that the three compounds that the 4 Three divisional applications derive from the Sodha II reference identified as "most favorable" and '200 patent. Those applications matured into U.S. "valuable for the treatment of maturity-onset diabetes," Patent 4,340,605, U.S. Patent 4,438,141, and U.S. not compound b, would have served as the best "starting Patent No. 4,444,779 (the "'779 Patent"). The point for further investigation" to a person of ordinary '779 patent is of particular relevance in this ap- skill in the art. Id. at 376. Because diabetes is a chronic peal and is discussed below. Takeda, 417 F. disease and thus would require long term treatment, the court reasoned that researchers would have been dis-suaded from selecting a lead compound that [**19] ex- [*1358] The court next considered an article that hibited negative effects, such as toxicity, or other adverse was published the following year in 1982 by T. Sodha et side effects, especially one that causes "considerable al. entitled "Studies on Antidiabetic Agents. II. Synthesis increases in body weight and brown fat weight." Id. at 376-77. Thus, the court determined that the prior art did benzyl]thiazolidine-2,4-dione (ADD-3878) and Its De- not suggest to one of ordinary skill in the art that com- 492 F.3d 1350, *; 2007 U.S. App. LEXIS 15349, **; pound b would be the best candidate as the lead com- closed a broad selection of compounds any one of which could have been selected as a lead compound for further investigation. Significantly, the closest prior art com- Admissions from Alphapharm witnesses further but- pound (compound b, the 6-methyl) exhibited negative tressed the court's conclusion. Dr. Rosenberg, head of properties that would have directed one of ordinary skill Alphapharm's intellectual property department, testified in the art away from that compound. Thus, this case fails as a 30(b)(6) witness on behalf of Alphapharm. In dis- to present the type of situation contemplated by the Court cussing Sodha II, Dr. Rosenberg admitted that there was when it stated that an invention may be deemed obvious nothing in [*1359] the article that would recommend if it was "obvious to try." The evidence showed that it that a person of ordinary skill in the art choose com- pound b over other compounds in the article that had the same efficacy rating. Dr. Rosenberg, acknowledging that Similarly, Alphapharm's reliance on Pfizer fares no compound b had the negative side effects of increased better. [**22] In Pfizer, we held that certain claims cov- body weight and brown fat, also admitted that a com- ering the besylate salt of amlodipine would have been pound with such side effects would "presumably not" be obvious. The prior art included a reference, referred to as a suitable candidate compound for treatment of Type II the Berge reference, that disclosed a genus of pharma- diabetes. Alphapharm's expert, Dr. Mosberg, concurred ceutically acceptable anions that could be used to form in that view at his deposition when he admitted that a pharmaceutically acceptable acid addition salts, as well medicinal chemist would find [**20] such side effects as other publications that disclosed the chemical charac- teristics of the besylate salt. Pfizer, 480 F.3d at 1363. Noting that our conclusion was based on the "particular- Moreover, another Alphapharm 30(b)(6) witness, ized facts of this case," we found that the prior art pro- Barry Spencer, testified at his deposition that in review- vided [*1360] "ample motivation to narrow the genus ing the prior art, one of ordinary skill in the art would of 53 pharmaceutically-acceptable anions disclosed by have chosen three compounds in Sodha II as lead com- Berge to a few, including benzene sulphonate." Id. at pounds for research, not solely compound b. In addition, 1363, 1367. Here, the court found nothing in the prior art Takeda's witness, Dr. Morton, testified that at the time to narrow the possibilities of a lead compound to com- Sodha II was published, it was known that obesity con- pound b. In contrast, the court found that one of ordinary tributed to insulin resistance and Type 2 diabetes. Thus, skill in the art would have chosen one of the many com- one of ordinary skill in the art would have concluded that pounds disclosed in Sodha II, of which there were over Sodha II taught away from pyridyl compounds because it ninety, that "did not disclose the existence of toxicity or associated adverse side effects with compound b. side effects, and to engage in research to increase the We do not accept Alphapharm's assertion that KSR, efficacy and confirm the absence of toxicity of those as well as another case recently decided by this court, compounds, rather than to choose as a starting point Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir. [**23] a compound with identified adverse effects." 2007), mandates reversal. Relying on KSR, Alphapharm Thus, Pfizer does not control this case. argues that the claimed compounds would have been Based on the record before us, we conclude that the obvious because the prior art compound fell within "the district court's fact-findings were not clearly erroneous objective reach of the claim," and the evidence demon- and were supported by evidence in the record. Moreover, strated that using the techniques of homologation and we reject the assertion that the court failed to correctly ring-walking would have been "obvious to try." Addi- apply the law relating to prima facie obviousness of tionally, Alphapharm argues that our holding in Pfizer, chemical compounds. Because Alphapharm's obvious- where we found obvious certain claims [**21] covering ness argument rested entirely on the court making a pre- a particular acid-addition salt, directly supports its posi- liminary finding that the prior art would have led to the selection of compound b as the lead compound, and Al- We disagree. The KSR Court recognized that[HN8] phapharm failed to prove that assertion, the court did not "[w]hen there is a design need or market pressure to commit reversible error by failing to apply a presumption solve a problem and there are a finite number of identi- of motivation. We thus conclude that the court did not err fied, predictable solutions, a person of ordinary skill has in holding that Alphapharm failed to establish a prima good reason to pursue the known options within his or facie case of obviousness. See Eli Lilly & Co. v. Zenith her technical grasp." KSR, 127 S. Ct. at 1732. In such Goldline Pharms., 471 F.3d 1369 (Fed. Cir. 2006) (af- circumstances, "the fact that a combination was obvious firming the district court's finding of nonobviousness to try might show that it was obvious under § 103." Id. upon concluding, in part, that the prior art compound That is not the case here. Rather than identify predictable would not have been chosen as a lead compound). solutions for antidiabetic treatment, the prior art dis- b. Choice of the Claimed Compounds 492 F.3d 1350, *; 2007 U.S. App. LEXIS 15349, **; Even if Alphapharm had established that preliminary data insufficient to show that the same effects would finding, and we have concluded that it did [**24] not, the record demonstrates that Alphapharm's obviousness Alphapharm relies on In re Wilder, 563 F.2d 457 argument fails on a second ground. The district court (CCPA 1977), for the proposition that differences in a found nothing in the prior art to suggest making the spe- chemical compound's properties, resulting from a small cific molecular modifications to compound b that are change made to the molecule, are reasonably expected to necessary to achieve the claimed compounds. In reaching vary by degree and thus are insufficient to rebut a prima that conclusion, the court first found that the process of facie case of obviousness. In Wilder, our predecessor modifying lead compounds was not routine at the time of court affirmed the Board's holding that a claimed com- the invention. Takeda, 417 F. Supp. 2d at 380. Dr. Mos- pound, which was discovered to be useful as a rubber berg opined that the steps of homologation and ring- antidegradant and was also shown to be nontoxic to hu- walking were "routine steps in the drug optimization man skin, would have been obvious in light of its ho- process," but the court found that testimony unavailing in molog and isomer that were disclosed in the prior art. light of the contrary, more credible, testimony offered by The evidence showed that the homolog was similarly Takeda's experts. Id. at 381. In addition, the court relied nontoxic to the human skin, whereas the isomer was on Dr. Rosenberg's admission that a person of ordinary toxic. [**27] The court held that [HN9]"one who claims skill in the art would "look at a host of substituents, such a compound, per se, which is structurally similar to a as chlorides, halides and others, not just methyls" in prior art compound must rebut the presumed expectation that the structurally similar compounds have similar Pioglitazone differs from compound b in two re- properties." Id. at 460. While recognizing that the differ- spects, and one would have to both homologate the ence between the isomer's toxicity and the nontoxicity of methyl group of compound b and move the resulting the homolog and claimed compound "indicate[d] some ethyl group to the 5-position on the pyridyl ring in order degree of unpredictability," the court found that the ap- to obtain pioglitazone. With regard to homologation, the pellant failed to "point out a single actual difference in court [**25] found nothing in the prior art to provide a properties between the claimed compound and the homo- reasonable expectation that adding a methyl group to logue," and thus failed to rebut the presumption. Wilder, compound b would reduce or eliminate its toxicity. Based on the test results of the numerous compounds We would note that since our Wilder decision, we disclosed in Sodha II, the court concluded that "homolo- have cautioned "that [HN10]generalization should be gation had no tendency to decrease unwanted side ef- avoided insofar as specific chemical structures are al- fects" and thus researchers would have been inclined "to leged to be prima facie obvious one from the other," focus research efforts elsewhere." Id. at 383. Indeed, Grabiak, 769 F.2d at 731. In addition to this caution, the several other compounds exhibited similar or better po- facts of the present case differ significantly from the tency than compound b, and one compound in particular, facts of Wilder. Here, the court found that pioglitazone compound 99, that had no identified problems differed exhibited unexpectedly superior properties over the prior significantly [*1361] from compound b in structure. Id. art compound b. Takeda, 417 F. Supp. 2d at 385. The at 376 n.51. Moreover, Dr. Mosberg agreed with Ta- court considered a report entitled "Preliminary Studies keda's expert, Dr. Danishefsky, that the biological activi- on Toxicological Effects of Ciglitazone-Related Com- ties of various substituents were "unpredictable" based pounds [**28] in the Rats" that was presented in Febru- on the disclosure of Sodha II. Id. at 384-85. The court ary 1984 by Dr. Takeshi Fujita, then-Chief Scientist of also found nothing in the '200 and '779 patents to suggest Takeda's Biology Research Lab and co-inventor of the to one of ordinary skill in the art that homologation '777 patent. That report contained results of preliminary would bring about a reasonable expectation of success. toxicity studies that involved selected compounds, in- As for ring-walking, the court found that there was cluding pioglitazone and compound b. Compound b was no reasonable expectation in the art that changing the shown to be "toxic to the liver, heart and erythrocytes, positions of a substituent on a pyridyl ring would result among other things," whereas pioglitazone was "com- in beneficial changes. [**26] Dr. Mosberg opined that paratively potent" and "showed no statistically signifi- the process of ring-walking was "known" to Takeda, but cant toxicity." Id. at 356-57. During the following the court found that testimony inapt as it failed to support months, Takeda performed [*1362] additional toxicity a reasonable expectation to one of ordinary skill in the studies on fifty compounds that had been already synthe- art that performing that chemical change would cause a sized and researched by Takeda, including pioglitazone. compound to be more efficacious or less toxic. Id. at 382. The compounds were tested for potency and toxicity. Moreover, Dr. Mosberg relied on the efficacy data of The results were presented in another report by Fujita phenyl compounds in Sodha II, but the court found those entitled "Pharmacological and Toxicological Studies of 492 F.3d 1350, *; 2007 U.S. App. LEXIS 15349, **; Ciglitazone and Its Analogues." Pioglitazone was shown steps of homologation and ring-walking, to synthesize to be the only compound that exhibited no toxicity, al- the claimed compounds. Because the court's conclusions though many of the other compounds were found to be are not clearly erroneous and are supported by the record evidence, we find no basis to disturb them. Thus, the court found that there was no reasonable The court properly concluded that Alphapharm did expectation that pioglitazone would possess the desirable not make out a prima facie case of obviousness because property of nontoxicity, particularly in light of the toxic- Alphapharm [*1363] failed to adduce evidence that ity [**29] of compound b. The court's characterization compound b would have been selected as the lead com- of pioglitazone's unexpected results is not clearly errone- pound and, even if that preliminary showing had been ous. As such, Wilder does not aid Alphapharm because, made, it failed to show that there existed a reason, based unlike the homolog and claimed compound in Wilder on what was known at the time of the invention, to per- that shared similar properties, pioglitazone was shown to form the chemical modifications necessary to achieve the differ significantly from compound b, of which it was not a homolog, in terms of toxicity. Consequently, Ta- In light of our conclusion that Alphapharm failed to keda rebutted any presumed expectation that compound prove that the claimed compounds would have been b and pioglitazone would share similar properties. prima facie obvious, we need not consider any objective Alphapharm also points to a statement Takeda made during the prosecution of the '779 patent as evidence that there was a reasonable expectation that making changes 5 The concurrence, while agreeing that the ques- to the pyridyl region of compound b would lead to "bet- tion of the "overbreadth" of claims 1 and 5 has ter toxicity than the prior art." During prosecution of the been waived, states further that the 6-ethyl com- '779 patent, in response to an enablement rejection, Ta- pound, which is within the scope of claims 1 and keda stated that "there should be no reason in the instant 5, has not been [**32] shown to possess unex- case for the Examiner to doubt that the claimed com- pected results sufficient to overcome a prima fa- pounds having the specified substituent would function cie case of obviousness, and hence claims 1 and 5 as a hypolipidemic and hypoglycemic agent as specified are likely invalid as obvious. Since waiver is suf- in the instant disclosure." That statement, however, indi- ficient to answer the point being raised, no further cates only that changes to the left moiety of a lead com- comment need be made concerning its substance. pound would create compounds with the same properties 2. Scope and Content of the Prior Art as the [**30] compounds of the prior art; it does not represent that lower toxicity would result. And even if Alphapharm also assigns error to the district court's the statement did so represent, it does not refer to any determination regarding the scope and content of the specific substituent at any specific position of TZD's left prior art. Alphapharm asserts that the court excluded the moiety as particularly promising. As the court correctly prosecution history of the '779 patent from the scope of noted, the compounds disclosed in the '779 patent in- the prior art after wrongly concluding that it was not ac- cluded a variety of substituents, including lower alkyls, cessible to the public. Takeda responds that the court halogens, and hydroxyl groups, attached to a pyridyl or clearly considered the '779 patent prosecution history, thiazolyl group. As discussed supra, the district court which was admitted into evidence on the first day of tes- found that the claims encompassed over one million timony. Takeda urges that the court's consideration of the compounds. Thus, we disagree with Alphapharm that prosecution history is apparent based on its extensive that statement provided a reasonable expectation to one analysis of the '779 patent and the file history that ap- of ordinary skill in the art that performing the specific steps of replacing the methyl group of the 6-methyl com- We agree with Takeda that the district court did not pound with an ethyl group, and moving that substituent err in its consideration of the scope of the prior art. As to the 5-position of the ring, would have provided a discussed above, the court considered the prosecution broad safety margin, particularly in light of the district history, and even expressly considered one of the key court's substantiated findings to the contrary. statements in the prosecution [**33] history upon which We thus conclude that Alphapharm's challenges fail Alphapharm relies in support of its position that com- to identify grounds for reversible error. The court prop- pound b would have been chosen as the lead compound. erly considered the teachings of the prior art and made Takeda, 417 F. Supp. 2d at 378. In considering the credibility determinations regarding the witnesses at trial. prosecution history of the '779 patent, the court noted [**31] We do not see any error in the district court's de- that Takeda filed a preliminary amendment on March 15, termination that one of ordinary skill in the art would not 1983, in which its prosecuting attorney stated that "the have been prompted to modify compound b, using the compounds in which these heterocyclic rings are substi- 492 F.3d 1350, *; 2007 U.S. App. LEXIS 15349, **; tuted have become important, especially [the 6-methyl ent No. 4,287,200 ("'200 patent"). Unfortunately our law compound]." Id. The court rejected Alphapharm's asser- concerning when a species [**35] is patentable over a tion that that statement supported the conclusion that genus claimed in the prior art is less than clear. It is, of compound b would have been selected as a lead com- course, well established that a claim to a genus does not pound. Rather, the court found that viewing the prior art necessarily render invalid a later claim to a species as a whole, the prior art showed "that Takeda was ac- within that genus. See Eli Lilly & Co. v. Bd. of Regents of tively conducting research in many directions, and had Univ. of Wash., 334 F.3d 1264, 1270 (Fed. Cir. 2003). In not narrowed its focus to compound b." Id. at 379. Thus, my view a species should be patentable over a genus while the district court may have incorrectly implied that claimed in the prior art only if unexpected results have prosecution histories are not accessible to the public, see been established. Our case law recognizes the vital im- id. at n.59, see also Custom Accessories, Inc. v. Jeffrey- portance of a finding of unexpected results, both in this Allan Indus., 807 F.2d 955 (Fed. Cir. 1986) context and in the closely related context where a prior ([HN11]"[t]he person of ordinary skill is a hypothetical art patent discloses a numerical range and the patentee person who is presumed to be aware of all the pertinent seeks to claim a subset of that range. See Application of prior art"), the court nonetheless considered [**34] the Petering, 301 F.2d 676, 683, 49 C.C.P.A. 993, 1962 Dec. prosecution history of the '779 patent in its obviousness Comm'r Pat. 232 (C.C.P.A. 1962) (species found pat- analysis and accorded proper weight to the statements entable when genus claimed in prior art because unex- contained therein. Thus, any error committed by the pected properties of the species were shown); see also court in this regard was harmless error. Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1371 (Fed. Cir. 2007) (relying on lack of unexpected results in de- We have considered Alphapharm's remaining argu- termining that species claim was obvious in view of prior ments and find none that warrant reversal of the district art genus claim); In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990) (when applicant claims a subset of a range disclosed in a prior art patent, the applicant [**36] must generally show that "the claimed range achieves We affirm the district court's determination that unexpected results relative to the prior art range."). claims 1, 2, and 5 of the '777 patent have not been shown to have been obvious and hence invalid. While the 5-ethyl compound (pioglitazone) is within the scope of the '200 patent, there is clear evidence, as the majority correctly finds, of unexpected results re- garding that compound, and therefore its validity is not CONCUR BY: DYK
in question on this ground. However, at oral argument the patentee admitted that the prior art '200 patent also generically covers the 6-ethyl compound, which is within the scope of claims 1 and 5 of the '777 patent, and admit-ted that there is no evidence of unexpected results for the I join the opinion of the court insofar as it upholds 6-ethyl compound. Under such circumstances, I believe the district court judgment based on a determination that that the 6-ethyl is likely obvious, and consequently a claim to pioglitazone (the 5-ethyl compound) would be claims 1 and 5 are likely invalid for obviousness. How- non-obvious over the prior art. The problem is that only ever, the argument as to the overbreadth of claims 1 and one of the three claims involved here--claim 2--is limited 5 has been waived, because it was not raised in the open- to pioglitazone. In my view, the breadth of the other two ing brief. In any event, as a practical matter, the judg- claims, claims 1 and 5 of U.S. Patent No. 4,867,777 ment finding that the appellants' filing of the ANDA for ("'777 patent")--which are also referenced in the judg- pioglitazone is an infringement and barring the making of pioglitazone is supported by the finding that claim 2 All of the compounds claimed in claims 1, 2 and 5 standing alone is not invalid and is infringed. were included in generic claims in the prior art U.S. Pat-

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