Full opinion text
Opinion for the court filed by Circuit Judge NEWMAN, in which Circuit Judge ARCHER concurs in the judgment and joins except as to Parts I and VI. Dissenting opinion filed by Circuit Judge GAJARSA. NEWMAN, Circuit Judge. This appeal is from the grant of a preliminary injunction, pending final resolution of the several challenges raised by Sandoz, Inc. to the validity, enforceability, and infringement of the Abbott Laboratories patents in suit. We conclude that abuse of discretion has not been shown in the district court’s decision to grant the injunction pendente lite. That decision is affirmed. BACKGROUND This suit concerns two Abbott Laboratories patents on extended release formulations of the antibiotic drug clarithromycin, sold by Abbott with the brand name Biax-in®XL. The patent on clarithromycin itself expired in 2005; only extended release formulations are at issue. The purpose of the extended release formulation is to extend the period of drug effectiveness after ingestion and thereby to reduce the requisite frequency of dosage. Sandoz filed an Abbreviated New Drug Application (ANDA) for its extended release formulation of clarithromycin; the Food and Drug Administration approved the ANDA on August 25, 2005, and on September 16, 2005 Abbott filed suit in the United States District Court for the Northern District of Illinois, charging Sandoz with infringement of United States Patent No. 6,010,718 (the '718 patent) and Patent No. 6,551,616 (the '616 patent). Abbott also charged infringement of Patent No. 6,872,407, but has withdrawn this patent from suit. The '718 patent claims an extended release pharmaceutical composition comprising an erythromycin derivative and a phar-maceutically acceptable polymer, whereby after ingestion certain specified parameters of drug bioavailability are met. Claims 1, 4, and 6 of the '718 patent are in suit: 1. A pharmaceutical composition for extended release of an erythromycin derivative in the gastrointestinal environment, comprising an erythromycin derivative and from about 5 to about 50% by weight of a pharmaceutically acceptable polymer, so that when ingested orally, the composition induces statistically significantly lower mean fluctuation index in the plasma than an immediate release composition of the erythromycin derivative while maintaining bioavailability substantially equivalent to that of the immediate release composition of the er-ythromycin derivative. 4. A pharmaceutical composition for extended release of an erythromycin derivative in the gastrointestinal environment, comprising an erythromycin derivative and from about 5 to about 50% by weight of a pharmaceutically acceptable polymer, so that upon oral ingestion, maximum peak concentrations of the erythromycin derivative are lower than those produced by an immediate release pharmaceutical composition, and area under the concentration-time curve and the minimum plasma concentrations are substantially equivalent to that of the immediate release pharmaceutical composition. 6. An extended release pharmaceutical composition comprising an erythromy-cin derivative and a pharmaceutically acceptable polymer, the composition having an improved taste profile as compared to the immediate release formulation. The '616 patent is a continuation-in-part of the '718 patent, with claims directed to the method of reducing gastrointestinal side effects. Claim 2 is in suit, shown with claim 1 from which it depends: 1. A method of reducing gastrointestinal adverse side effects comprising administering an effective amount of extended release pharmaceutical composition comprising an erythromycin derivative and a pharmaceutically acceptable polymer. 2. The method according to claim 1, wherein the erythromycin derivative is clarithromycin. In response to the charge of infringement Sandoz presented the defenses of invalidity based on anticipation and obviousness, unenforceability based on inequitable conduct, and noninfringement. This appeal is from the district court’s grant of Abbott’s motion for a preliminary injunction, preserving the status quo during the pen-dency of this litigation. Sandoz challenges the district court’s rulings on all issues. I VALIDITY ISSUES The district court reviewed the factors relevant to the grant or denial of a preliminary injunction, viz., (1) likelihood of success on the merits of the underlying litigation, (2) whether irreparable harm is likely if the injunction is not granted, (3) the balance of hardships as between the litigants, and (4) factors of the public interest. See Oakley, Inc. v. Sunglass Hut Int’l, 316 F.3d 1331, 1338-39 (Fed.Cir.2003); H.H. Robertson Co. v. United Steel Deck, Inc., 820 F.2d 384, 387-88 (Fed.Cir.1987). At the stage of the preliminary injunction, before the issues of fact and law have been fully explored and finally resolved, “[t]he purpose of a preliminary injunction is merely to preserve the relative positions of the parties until a trial on the merits can be held.” University of Texas v. Camenisch, 451 U.S. 390, 395, 101 S.Ct. 1830, 68 L.Ed.2d 175 (1981). On appellate review of the grant of a preliminary injunction, the question “is simply whether the issuance of the injunction constituted an abuse of discretion.” Doran v. Salem Inn, 422 U.S. 922, 932, 95 S.Ct. 2561, 45 L.Ed.2d 648 (1975). “It is well settled that the granting of a temporary injunction, pending final hearing, is within the sound discretion of the trial court; and that, upon appeal, an order granting such an injunction will not be disturbed unless contrary to some rule of equity, or the result of improvident exercise of judicial discretion.” Deckert v. Independence Shares Corp., 311 U.S. 282, 290, 61 S.Ct. 229, 85 L.Ed. 189 (1940). Abuse of discretion is established “by showing that the court made a clear error of judgment in weighing relevant factors or exercised its discretion based upon an error of law or clearly erroneous factual findings.” Novo Nordisk of North Amer-ica, Inc. v. Genentech, Inc., 77 F.3d 1364, 1367 (Fed.Cir.1996). See Cybor Corp. v. FAS Technologies, Inc., 138 F.3d 1448, 1460 (Fed.Cir.1998) (en banc) (“A district court abuses its discretion when its decision is based on clearly erroneous findings of fact, is based on erroneous interpretations of the law, or is clearly unreasonable, arbitrary or fanciful.”). Sandoz assigns legal error to the district court’s rulings that Abbott is likely to prevail on the issues of validity, infringement, and inequitable conduct, and states that the district court abused its discretion in balancing the equities and granting the injunction. Anticipation “Anticipation” in patent usage means that the claimed invention was previously known and described in a printed publication, explicitly or inherently. Anticipation is established by documentary evidence, and requires that every claim element and limitation is set forth in a single prior art reference, in the same form and order as in the claim. See In re Omeprazole Patent Litigation, 483 F.3d 1364, 1373 (Fed.Cir.2007); Continental Can Co. v. Monsanto Co., 948 F.2d 1264, 1267 (Fed.Cir.1991). An anticipating reference must enable that which it is asserted to anticipate. Omeprazole, 483 F.3d at 1378 (“To ‘anticipate,’ the identical subject matter must not only be previously known, but the knowledge must be sufficiently enabling to place the information in the possession of the public.”); Elan Pharmaceuticals, Inc. v. Mayo Found. for Medical Educ. & Research, 346 F.3d 1051, 1054 (Fed.Cir.2003) (same). Sandoz argued that the '718 patent is anticipated by European Patent Publication No. 0,280,571 B1 (the '571 Publication), which describes “a sustained release matrix formulation in tablet form comprising from 0.1% by weight to 90% by weight of an antimicrobial agent selected from ... erythromycin ... from 5% by weight to 29% by weight of a hydrophilic polymer, and from 0.5% by weight to 25% by weight of an acrylic polymer....” The '571 Publication states that hydrophilic polymers such as hydroxypropylmethyl cellulose (HPMC) can be used to form a hydrophilic matrix which “respond[s] to increases in pH with a corresponding increase in the permeability of the dosage form.” Sandoz argued in the district court that although the '571 Publication does not mention clar-ithromycin or the specific pharmacokinetic limitations in the '718 patent claims, the '571 Publication anticipates the '718 claims because clarithromycin is an erythromycin derivative and the claimed pharmacokinetic limitations are inherent in the extended release compositions of the '571 Publication. Sandoz also argued that enablement of the compositions in the '571 Publication must be presumed, because the compositions in the '718 patent are presumed to be enabled and, according to Sandoz, are identical. Abbott responded that the '571 Publication cannot “anticipate” because it does not show the elements of the claims of issue; it does not mention clarithromycin, it does not disclose the pharmacokinetic criteria stated in the '718 claims, and it does not enable these limitations, either expressly or inherently. Abbott argued that significant experimentation would be required to ascertain the applicability of any release agent from the large number of release agents mentioned in the '571 Publication, particularly as applied to a different biological product having different dissolution and metabolic characteristics. Thus Abbott argued that the legal criteria of “anticipation” are not met by the '571 Publication. The district court found that Sandoz did not present evidence sufficient to support its argument that “the '571 Publication’s teachings would enable Abbott to create an extended release of an erythromycin derivative drug simply based on the structural limitations.” Abbott, 500 F.Supp.2d at 840. The district court observed that the '571 Publication “does not offer any in vivo dissolution data” nor state “the pharma-cokinetic profile of its own formulations.” Id. The court concluded that Sandoz would not be likely to succeed in establishing anticipation by this reference. We discern no clear error in this conclusion, for the '571 Publication neither describes the product of the '718 claims nor enables the pharmacokinetic properties that are set forth in the '718 claims. See Elan Pharmaceuticals, 346 F.3d at 1057 (an anticipating reference must disclose every element of the claims, and place a person of ordinary skill in possession of the claimed invention). Obviousness Sandoz also argued that the claims of the '781 and '616 patents are invalid on the ground of obviousness, in view of the combination of the '571 Publication with PCT Application WO 95/30422 (the PCT or '422 Application) and United States Patent No. 5,705,190 (the '190 patent). In determining, for preliminary injunction purposes, the likelihood that patent invalidity would be established at trial, the district court evaluates the factual and legal arguments in light of the presumptions and burdens that will inhere at trial, viz., that “[a] patent shall be presumed valid.... The burden of establishing invalidity of a patent or any claim thereof shall rest on the party asserting such invalidity.” 35 U.S.C. § 282. This burden “exists at every stage of the litigation.” Canon Computer Systems, Inc. v. Nu-Kote Int’l, Inc., 134 F.3d 1085, 1088 (Fed.Cir.1998); see Sanofi-Synthelabo v. Apotex, Inc., 470 F.3d 1368, 1374 (Fed.Cir.2006) (taking into account the applicable presumptions and burdens in reviewing the grant of a preliminary injunction). Sandoz on this appeal relies on the Supreme Court’s decision in KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007), Sandoz arguing that the law of obviousness has been significantly changed, and that the district court did not give adequate recognition to the changed law. The district court had issued its initial decision granting the preliminary injunction shortly before the Court’s decision in KSR. The court then requested supplemental briefing and argument, and issued a further opinion discussing the issues in light of KSR and continuing to conclude that Abbott was likely to prevail on the merits of the question of obviousness. In its initial decision the district court discussed the references in detail. The court explained that the PCT Application, entitled “Controlled-Release Dosage Forms of Azithromycin,” describes “[a] dosage form for oral administration comprising azithromycin and a pharmaceutically acceptable carrier, which releases not more than about 10% of its incorporated azithromycin into a mammal’s stomach, and which releases not more than an additional 10% during the first 15 minutes after entering said mammal’s duodenum,” and exhibits decreased gastrointestinal side effects. The district court explained that the PCT Application shows hydroxy-propylmethylcellulose (HPMC) and other polymers as “a hydrophilic polymer sufficient to provide a useful degree of control over the azithromycin dissolution,” and contains in vitro data showing the amount and timing of dissolution of azithromycin in various conditions and sustained dosage forms. Sandoz argued that these teachings should be combined with those of the '571 Publication and the '190 patent entitled “Controlled Release Formulation for Poorly Soluble Basic Drugs,” which describes a “controlled release solid pharmaceutical composition adapted for oral administration comprising: a therapeutically effective amount of at least one basic drug having a water solubility of less than 1 part per 30 parts water ... wherein the basic drug is a macrolide” and as the release agent a water-soluble alginate salt. The '190 patent names the macrolides erythromycin, clarithromycin, dirithromycin, azithromy-cin, roxithromycin, and ABT-229 for use with the alginate salt release agent. San-doz argued that the subject matter of the '718 patent would have been obvious in view of the '571 Publication showing extended release formulations of erythromy-cin derivatives, in combination with the controlled release formulations and phar-macokinetic properties of azithromycin in the PCT Application, and the modified release alginate salt formulation of clarithro-mycin in the '190 patent. Sandoz argued that a person of ordinary skill in this field would have desired to improve the administration of clarithromycin by finding an extended release formulation having optimum release and biological properties, and would have selected and tested the HPMC from the '571 Publication, in view of the formulation of azithromycin with HPMC in the PCT Application and the '190 patent’s use of an alginate salt to modify the release of clarithromycin. Sandoz stressed that the PCT Application states the known principle of using controlled release formulations to reduce the dosing frequency for short half-life compounds. Sandoz argued that no more than routine experimentation was needed to find a controlled release formulation that would meet the pharma-cokinetic requirements stated in the '718 claims. Sandoz applied similar arguments to the claims of the '616 patent, stating that the PCT Application teaches that control of azithromycin release reduces gastrointestinal side effects, and that the '190 patent shows the interchangeability of azithromy-cin and clarithromycin in the formulation using an alginate salt. Sandoz argued that this combination of references renders obvious a clarithromycin formulation with reduced gastrointestinal side effects as claimed in the '616 patent. In its supplemental argument based on KSR, Sandoz argued that Abbott merely “pursue[d] known options” for both the '718 and '616 patents, based on the Court’s exposition that: “When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp.” KSR, 127 S.Ct. at 1742. In the district court Abbott disputed the premises presented by Sandoz, challenged the analysis of the content and significance of the references, and argued that KSR did not hold, as Sandoz proposed, that the recognition of a problem of itself renders the solution obvious. Abbott argued that more is needed than recognizing the problem, as this court discussed in Cardiac Pacemakers, Inc. v. St. Jude Medical, Inc., 381 F.3d 1371, 1377 (Fed.Cir.2004) (“Recognition of a need does not render obvious the achievement that meets that need.... Recognition of an unsolved problem does not render the solution obvious.”) Abbott pointed out that the Court qualified its discussion by explaining that the “problem” should have “a finite number of identified, predictable solutions,” KSR, 127 S.Ct. at 1742, to expose its eventual solution to unpatentability as “obvious to try.” Id. Abbott stressed the difference between new biological compositions whose performance and effectiveness in combination cannot be confidently predicted but must be made and evaluated, and new mechanical combinations of known elements each of which predictably performs its known function in the combination. Abbott stressed that its choice of extended release components is not shown or suggested by the prior art to produce the pharmacokinetic properties of Abbott’s claims. The Court recognized in Dennison Mfg. Co. v. Panduit Corp., 475 U.S. 809, 106 S.Ct. 1578, 89 L.Ed.2d 817 (1986) that the district court is not to rely on hindsight, and that “in addressing the question of obviousness a judge must not pick and choose isolated elements from the prior art and combine them so as to yield the invention in question if such a combination would not have been obvious at the time of the invention.” 475 U.S. at 810, 106 S.Ct. 1578. In Graham v. John Deere Co., 383 U.S. 1, 86 S.Ct. 684, 15 L.Ed.2d 545 (1966) the Court recognized that the obviousness inquiry must “guard against slipping into use of hindsight and to resist the temptation to read into the prior art the teachings of the invention in issue.” Id. at 36, 86 S.Ct. 684. Abbott agreed that the basic principles of pharmacokinetics were known, but argued that the limitations in the '718 claims, whereby the bioavailability of the product was characterized, were not shown as achieved in any reference or any combination of references. Abbott pointed out that the PCT Application is directed specifically to azithromycin and shows “scores” of possible formulations, all using in vitro data, and does not contemplate metabolite activity in vivo as is manifested for chlorithromycin. Abbott stated that “the '422 publication discloses more than a dozen possible classes of delivery devices,” Abbott Brief at 42, that “the '422 publication merely provides in vitro dissolution data for a subset of its disclosed compositions,” and that the formulation in the PCT Application “did not even have equivalent bioavailability as IR [immediate release] azithromycin.” Id. at 41, 86 S.Ct. 684. Abbott described in the '718 and '616 specifications that the '190 patent reference presents “C max values [that] are not statistically significantly different from those of the IR formulation.” '718 patent, col. 2, lines 11-12; '616 patent, col. 2, lines 13-14 (referring to Ser. No. 08/574,877, the '190 patent). Abbott stated that Sandoz concedes that the '190 patent does not describe pharmacokinetic limitations based on clarithromycin plasma concentrations, and that neither the PCT Application nor the '190 patent discloses the pharmacoki-netic limitations and properties set forth in the '718 and '616 claims, and that neither the PCT Application nor any other reference provides guidance as to which formulation would provide the pharmacokinetic characteristics required by the '718 claims. Thus Abbott argued in the district court that a skilled artisan would not have known the effect of substituting clarithro-mycin for azithromycin in any specific formulation that might be selected from the PCT Application, for it is undisputed that there are significant differences among er-ythromycin derivatives. Abbott presented evidence to the district court that azithro-mycin and clarithromycin exhibit different properties in four biological processes of relevance to oral drug administration: absorption, distribution, metabolism, and excretion. These differences were tabulated by Abbott’s expert, Professor Stanley S. Davis, as follows: _Azithromycin Clarithromycin Absolute About 34% About 50% from Bioavailability from 600 mg 250 mg dose _dose_ Pharmacokinetics Linear_Non-linear_ Active Metabolite None reported 14-hydroxy in the clarithromycin Physicians Desk _Reference_ Metabolism Metabolites Extensively possess little or metabolized to an no activity active _metabolite_ About 70 hours 3-4 hours for 250 mg IR dose (14— OH metabolite, _5-6 hours)_ Elimination Half Life First Pass Effect Not significant Extensive_ Volume of Large-2200 250 litre Distribution litre Supplemental Declaration of Dr. Davis, February 7, 2007. The parties do not dispute that the PCT Application describes only in vitro data, and that in vitro data are not predictably transferable to in vivo conditions. Dr. Davis testified that “it simply isn’t the case that in vitro controlled release data will automatically correlate with the pharmacokinetic parameters in vivo, and in fact, for many of the formulations of the '422 application, they affirmatively do not so correlate.” Id. The district court concluded that a person of ordinary skill in this field would not have predicted which formulation, that might be selected from the prior art, would provide the required pharmacokinetics. The district court referred to the dissimilarities in the pharmacokinetic properties for azithromycin as shown in the PCT Application, considered the content of the '190 patent, and concluded that the bioa-vailability of the formulations claimed in the '718 patent were not predictable from these references. The court referred to the testimony of another Abbott expert, Dr. Daniel Weiner, that “the '190 patent does not disclose any clarithromycin-spe-cific PK [pharmacokinetic] data” or “any DFL [degree of fluctuation] values at all.” Declaration of Daniel Weiner, Ph.D., January 9, 2007. Dr. Weiner explained that the pK values reported in the '190 patent are based on total antibiotic activity, which consists of the combined concentrations of clarithromycin and its active metabolite, while the pharmacokinetic elements of the '718 patent relate specifically to clarithromycin plasma concentrations. Dr. Weiner concluded, and the district court agreed, that a skilled artisan would not have had a reasonable expectation of producing effective compositions based on the mention of clarithromycin along with azithromycin in the '190 patent, because of their different mechanisms of antibiotic activity and the effect of this activity on pharmacokinetic behavior. The district court observed that the in vivo azithromycin controlled release formulations in the PCT Application have less total bioavailability than their immediate release counterparts, supporting Abbott’s argument that the behavior of differing biological systems, even when structurally similar, is not predictable. See Alza Corp. v. Mylan Laboratories, 464 F.3d 1286, 1297 (Fed.Cir.2006) (“Alza’s evidence of in vitro dissolution rates is irrelevant absent evidence demonstrating that the in vitro system is a good model of actual in vivo behavior.”). The district court concluded that the in vivo extended release properties claimed in the '718 patent are sufficiently dissimilar to or unpredictable from the in vitro controlled release data for azithromycin in the PCT Application that a person of ordinary skill in the field of the invention would not have had the degree of confidence of success in transferring the PCT Application’s azithromycin formulation to the different metabolic and solubility systems of clari-thromycin as would render the '718 claimed invention unpatentable on the ground of obviousness. In reaching these conclusions, the district court relied on the Federal Circuit’s decision on the same patents in Abbott Laboratories v. Andrx Pharmaceuticals, Inc., 473 F.3d 1196 (Fed.Cir.2007) (herein “Andrx”). This court, sustaining the district court’s grant of a preliminary injunction, had concluded that obviousness was not likely to be established, reversing this court’s prior ruling reversing the grant of a preliminary injunction in Abbott Laboratories v. Andrx Pharmaceuticals, Inc., 452 F.3d 1331 (Fed.Cir.2006) (herein “Teva”). Sandoz argued to the district court that the Federal Circuit’s ruling in Andrx is incorrect, and on this appeal Sandoz urges us to reject Andrx and reinstate Teva. In Teva a panel of this court held that the claims of the '718 patent were likely to be held not infringed. This court also stated that there was a substantial likelihood that claim 4 of the '718 patent would be held invalid for obviousness based on the PCT Application together with the '190 patent. This court held that the preliminary injunction should be denied, although the panel cautioned that its ruling “in no way resolves the ultimate question of invalidity.” Teva, 452 F.3d at 1347. In Andrx a later panel of this court, on an enlarged record, rejected the invalidity ruling in Teva and held that the '718 claims were likely to withstand the attack on validity. Andrx, 473 F.3d at 1203-07. Reviewing this history as applied to San-doz’ arguments herein, the district court explained that this court in Teva had not been made aware of the differences between the pharmacokinetic criteria described in the '190 patent and those of the '718 patent. The district court explained that the pharmacokinetic data in the '190 patent were based on measurements of total antibiotic activity in the body, which includes both clarithromycin and its active metabolite formed after ingestion, whereas the data in the '718 patent are specific to clarithromycin alone. The court found that “Abbott has shown ... that the PK profile of the clarithromycin-metabolite data of the '190 patent formulation was not the same as the PK profile of the clarithro-mycin-only data utilized by the '718 patent,” Abbott, 500 F.Supp.2d at 841. Sandoz argued, in its supplemental briefing in the district court after the KSR decision, that this court’s decision in Andrx does not survive scrutiny under the principles set forth in KSR, and stressed that application of KSR renders it “obvious to try” the various release agents in the PCT Application, such that any successful composition would be unpatentable, whether or not the results were predictable. Sandoz argued that the '190 patent shows that clarithromycin and azithromycin have similarities as well as differences, and that it would be obvious to experiment to determine which formulations were effective in view of these differences and similarities. Sandoz stressed that the Abbott scientists had knowledge of the prior art including the PCT Application, and that they developed the Abbott formulation in only one month of research effort. Sandoz quoted the Court’s admonition in KSR that a court “can take account of the inferences and creative steps that a person of ordinary skill in the art would employ,” 127 S.Ct. at 1741, and that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” Id. at 1739. The district court, applying KSR, reconsidered its prior determination and framed the question as “whether an ordinary person skilled in the art would have seen a benefit to combining an erythromycin derivative with a polymer with the same PK [pharmacokinetic] limitations as embodied in claims 1 and 4 of the '718 patent given the state of the pharmaceutical industry at the time.” Abbott, 500 F.Supp.2d at 851. The court concluded: “Based upon what evidence and argument Sandoz offered, the answer was and remains no.” Id. The district court explained that “this Court’s preliminary factual findings ... found that Sandoz had not produced evidence indicating that the PK limitations were disclosed in the prior art or were inherent to the structural limitations of the prior art compositions.” Id. at 852. The district court observed that “[t]he KSR opinion only focused on the Federal Circuit’s strict use of the TSM [teaching, suggestion, motivation] test in performing the obviousness analysis; it did not mention or affect the requirement that each and every claim limitation be found present in the combination of the prior art references before the analysis proceeds.” Id. at 852. We agree that the obviousness of selection of components, when there is no prediction in the prior art as to the results obtainable from a selected component, differs from the issue in KSR, where the Court provided guidance that “a court must ask whether the improvement is more than the predictable use of prior art elements according to their established functions.” 127 S.Ct. at 1740. The Court explained the conditions in which “obvious to try” may negate patentability, depending on the relation of the prior art teaching to the later-developed technology. The Court explained that when the problem is known, the possible approaches to solving the problem are known and finite, and the solution is predictable through use of a known option, then the pursuit of the known option may be obvious even absent a “teaching, suggestion, or motivation” concerning that option. Then, “if this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.” 127 S.Ct. at 1742. Abbott argued that the “known options” in the prior art were not “finite, identified, and predictable,” the words of KSR, and are identified only with hindsight knowledge of Abbott’s new formulation and its pharmacokinetic properties. Abbott pointed to the discussion in the PCT Application of over a dozen possible drug delivery modes, including matrix systems, membrane-moderated or reservoir systems, osmotic pumps, coated hydrogel tablets and multi particulates, sustained release compositions with delayed-release layers, pH-dependent coated tablets, bursting osmotic core devices, bursting coated swelling core devices, pH-triggered bursting osmotic core devices, pH-triggered bursting coated swelling core devices, enzyme-triggered supported liquid membrane devices, bac-terially degradable coating devices, and swelling plug devices, all classes of controlled release for drug delivery systems, each containing sub-classes and variations. PCT App. at 8-38. The expert witnesses pointed out the difficulties in predicting the behavior of any composition in any specific biological system. The evaluation of the choices made by a skilled scientist, when such choices lead to the desired result, is a challenge to judicial understanding of how technical advance is achieved in the particular field of science or technology. Such understanding is critical to judicial implementation of the national policy embodied in the patent statute. In Publication of Tomlinson, 53 C.C.P.A. 1421, 363 F.2d 928 (1966) our predecessor court discussed the role of “obvious to try” in scientific and technologic research and in patentability: Slight reflection suggests, we think, that there is usually an element of “obviousness to try” in any research endeavor, that is not undertaken with complete blindness but rather with some semblance of a chance of success, and that patentability determinations based on that as the test would not only be contrary to statute but result in a marked deterioration of the entire patent system as an incentive to invest in those efforts and attempts which go by the name of “research.” Id. at 931. The Court in KSR did not create a presumption that all experimentation in fields where there is already a background of useful knowledge is “obvious to try,” without considering the nature of the science or technology. The methodology of science and the advance of technology are founded on the investigator’s educated application of what is known, to intelligent exploration of what is not known. Each case must be decided in its particular context, including the characteristics of the science or technology, its state of advance, the nature of the known choices, the specificity or generality of the prior art, and the predictability of results in the area of interest. The district court discussed the differences between the pharmacokinetic properties shown in the '190 patent reference and the properties in the '718 patent claims, the differences in the chemical and biological properties of azithromycin and clarithromycin, the differences between in vitro and in vivo data, and the differences between azithromycin and clarithromycin. For example, Abbott’s expert Dr. Davis stated that “the absorption of clarithromy-cin is affected by a phenomenon know as the ‘first pass effect’ which does not occur for azithromycin,” and that azithromycin’s “metabolism occurs only post-absorption.” Dr. Davis also stated that “the half-life for azithromycin is about 70 hours, whereas that for clarithromycin is about 3-^4 hours at low IR doses.” First-pass metabolism was explained as meaning that a significant amount of the drug is metabolized and converted into another compound before it enters the circulation; Dr. Davis stated that a person of skill in this field, having this knowledge, would not have assumed that the two drugs would exhibit similar behavior if placed in the same formulation. The district court concluded that it was not predictable, from the in vitro behavior of azithromycin, how any specific clarithromycin extended release formulation would perform in vivo. Sandoz presented other arguments, for example, that the FDA regulations state the requirements for approval of extended release formulations, thereby rendering obvious a formulation that meets these requirements. However, knowledge of the goal does not render its achievement obvious. The district court appropriately applied the KSR standard of whether the patents in suit represented an “identified, predictable solution” and “anticipated success,” the words of KSR, to the problem of producing extended release formulations having the pharmacokinetic properties in the claims. On the record of the preliminary injunction proceedings, and considering this court’s ruling in Andrx and the guidance of the Court in KSR, we do not discern reversible error in the district court’s ruling that Abbott is likely to prevail on the issues of patent validity based on anticipation and obviousness. II INEQUITABLE CONDUCT Sandoz also argued that the '718 and '616 patents are unenforceable due to Abbott’s “inequitable conduct” in the Patent and Trademark Office. Sandoz stated that Abbott submitted a false declaration to the PTO, and also that Abbott withheld from the examiner the results of certain tests after the patent applications were filed and that were inconsistent with information in the patent applications. The district court found that there was no intent to deceive the examiner, and that the criticized activity did not constitute inequitable conduct. The evidentiary standard for determining whether there was inequitable conduct in obtaining a patent that is otherwise valid was set forth by this court, sitting en banc for the purpose, in Kingsdown Medical Consultants, Ltd. v. Hollister Inc., 863 F.2d 867 (Fed.Cir.1988). The court explained that “[t]o be guilty of inequitable conduct, one must have intended to act inequitably,” and held: “Inequitable conduct resides in failure to disclose material information, or submission of false material information, with an intent to deceive, and those two elements, materiality and intent, must be proven by clear and convincing evidence.” Id. at 872. Mistake or negligence, even gross negligence, does not support a ruling of inequitable conduct. The court held: We adopt the view that a finding that particular conduct amounts to “gross negligence” does not of itself justify an inference of intent to deceive; the involved conduct, viewed in light of all the evidence, including evidence indicative of good faith, must indicate sufficient culpability to require a finding of intent to deceive. Id. at 876. When both materiality and deceptive intent have been established the district court determines, in the court’s discretion, whether inequitable conduct has occurred; appellate review is on this basis. See id. at 876 (“As an equitable issue, inequitable conduct is committed to the discretion of the trial court and is reviewed by this court under an abuse of discretion standard. We, accordingly, will not simply substitute our judgment for that of the trial court in relation to inequitable conduct.”). The '718 patent Sandoz first challenges the district court’s findings with respect to a declaration by an inventor, Dr. Linda Gustavson, comparing the products of the pending '718 application with the products in a prior art Abbott patent, U.S. Patent No. 4,808,411, directed to a pediatric clarithromycin suspension that is administered twice daily. Dr. Gustavson submitted data to the PTO comparing the '718 and the '411 formulations, and stated that “the ER [extended release] formulation as claimed, is supported by the above results, namely, Cmax of clarithromycin in plasma is statistically significantly lower than that for IR [immediate release] formulation given twice daily.” The declaration also stated that “AUC is maintained over 24 hours; and Cmin is substantially equivalent to that of the IR suspension”. However, in this litigation Dr. Gustavson testified that she had not analyzed statistical significance, and that “it could not definitively be concluded from the data that the difference between the ER Cmax and the Cmax for a twiee-a-day dosed suspension would have been statistically significantly different.” Based on this admission, Sandoz argued that the Gustavson submission to the PTO was a material misrepresentation, that intent to deceive is presumed, and that inequitable conduct was thereby established. Abbott did not dispute that Dr. Gustav-son did not analyze statistical significance, but argued that it was not material to patentability and that a reasonable examiner would not have found otherwise. Abbott pointed out that the actual data were before the PTO, and that the results did show a numerically lower Cmax value. San-doz pointed out to the district court that Abbott’s patent attorney argued nonobvi-ousness to the PTO based on the Gustav-son declaration, and Abbott responded that the declaration correctly stated that the pharmacokinetic properties of the product in the '411 patent are markedly different from those of the product of the '718 patent. We have been directed to no evidence of deceptive intent, or “bad faith or intentional misconduct”, in the words of PTO Rule 56; on this appeal Sandoz repeats that deceptive intent should be inferred from the misstatement. The district court cited Impax Labs., Inc. v. Aventis Pharm., Inc., 468 F.3d 1366, 1374 (Fed.Cir.2006) for its summary that a ruling of inequitable conduct requires clear and convincing evidence that the applicant while prosecuting the patent “(1) made an affirmative misrepresentation of material fact, failed to disclose material information, or submitted false material information, and (2) intended to deceive the [PTO].” In determining materiality, the district court applied the standard that “[undisclosed information is material if it satisfies 37 C.F.R. § 1.56 and if there is a substantial likelihood that a reasonable examiner would have considered the undisclosed information important in deciding whether to allow the patent to issue.” Although the Federal Circuit has not always been consistent in defining “materiality” in accordance with the PTO Rules, the principles are consistently directed to deceptive actions by patent applicants. In Digital Control, Inc. v. Charles Machine Works, 437 F.3d 1309 (Fed.Cir.2006) the court observed that four separate tests have been applied for materiality. The district court, applying the tests of materiality to the Gustavson statement about statistical significance, stated that it was “obviously troublesome that Gustav-son made her assertion without having actually performed the statistical test.” The district court concluded that the Gustavson statement was not material to patentability, “despite the fact that it satisfies the definition of ‘material’ provided by 37 C.F.R. § 1.56(b).” The court stated that: Since 1) no claim of the '718 patent requires the extended release formulation to have a statistically significant lower Cmax than the immediate release formulation; 2) the data in fact shows the Cmax of the extended release formulation to be lower (albeit not statistically significantly lower) than the Cmax of the immediate release formulation; and 3) the extended release formulation was in fact pharmacokinetically different from the immediate release suspension formulation, it is more likely than not that the PTO would not have found the “statistically significantly lower” statement to be important. 500 F.Supp.2d at 822. Relevant is the ruling in Regents of the Univ. of Cal. v. Eli Lilly & Co., 119 F.3d 1559, 1570 (Fed.Cir.1997) (that “Information is material if a reasonable examiner would have considered it important to the patentability of a claim”). The district court also found that there was no evidence of intent to deceive the examiner. The court rejected Sandoz’s argument that deceptive intent is inferred from materiality alone, for precedent requires independent proof of deceptive intent. See Kingsdown, 863 F.2d at 872 (intent to deceive the examiner into granting the patent is a separate and essential element of inequitable conduct in the PTO); Baker Oil Tools, Inc. v. Geo Vann, Inc., 828 F.2d 1558, 1565 (Fed.Cir.1987) (“The material facts upon which a holding of inequitable conduct rests relate to both the intent of the actor and the materiality of the information.”). Weighing the materiality of the statement and the absence of evidence of intent to deceive, we do not discern an abuse of discretion in the district court’s conclusion that inequitable conduct was not established by the statement concerning statistical significance. Sandoz next challenged the fact that Abbott did not provide to the patent examiner the results of some clinical tests conducted after the '718 patent application was filed, that were reported to the FDA and included on the Biaxin® XL product label. The test results relate to taste perversion results in a later clinical trial, and a study comparing clarithromycin with azi-thromycin. Sandoz stated that Abbott should have provided the patent examiners with these results and the product label, which report tests wherein the immediate release formulation has a lower incidence of taste perversion than the extended release formulation, contrary to the information in the '718 patent. Sandoz argued that the inventors knew or should have known of this discrepancy, and thus that intent to deceive is established. Abbott responded that the challenged taste tests were from dosages that were not directly comparable, and that they did not change the correctness of the data in the patent application. Abbott presented the expert testimony of Dr. Davis that “the comparison between the taste perversion incidence rate for Biaxin® IR and Biaxin® XL in the label does not relate to the invention disclosed and claimed in the '407 patent, which is for a reduction in taste perversion for the same total dose.” Supplemental Declaration of Professor Stanley S. Davis, February 7, 2007(emphases in original). The district court concluded that the taste results met the materiality criteria of Rule 56 but that a reasonable examiner would not consider the information important in deciding whether to grant the patent. The court explained that a reasonable examiner would compare data at comparable dosages, and that the data were not comparable. Although Abbott and Sandoz argued about whether the inventors knew or should have known of this discrepancy between this taste data from the Phase III clinical trial, and the taste data in the patent application, the district court observed that there was no evidence of deliberate withholding of this information in order to deceive the patent examiner. “Intent to deceive can not be inferred solely from the fact that information was not disclosed; there must be a factual basis for a finding of deceptive intent.” Hebert v. Lisle Corp., 99 F.3d 1109, 1115, 1116 (Fed.Cir.1996) (“To establish inequitable conduct the information that is known to the applicant and not provided to the PTO must be both material to patentability, and withheld in order to deceive or mislead the examiner.”); Molins PLC v. Textron, Inc., 48 F.3d 1172, 1181 (Fed.Cir.1995) (“While intent to deceive the PTO may be found as a matter of inference from circumstantial evidence, circumstantial evidence cannot indicate merely gross negligence.”). Materiality is not evidence of intent, which must be established as a separate factual element of a discretionary ruling of inequitable conduct. The district court finding that the factual premises of both materiality and intent to deceive were not established in connection with the taste data, did not abuse its discretion in declining to find inequitable conduct on this ground. Finally, Sandoz criticized Abbott’s failure to provide the PTO with a study designated W98-268, done after the patent application was filed, which compared the pharmacokinetic values of clarithromycin upon administration under various conditions. The district court described the issue as: “Abbott claimed that the mean DFL values for a modified release version of clarithromycin claimed by a prior patent, the '190 patent, were substantially equal to the mean DFL values for the immediate release version of clarithromy-cin” but “[t]he final report of Study W98-268 states that the modified release formulation exhibited a statistically significantly lower mean DFL than that for the immediate release formulation.” 500 F.Supp.2d at 823. Sandoz stated that Abbott committed inequitable conduct by failing to disclose these results to the PTO. Dr. Weiner stated in his January 9 Declaration that “the '190 patent does not disclose any clarithromycin-specific PK data,” and “the '190 patent does not disclose any DFL values at all,” and explained that “subsequent studies conducted by Abbott indicate that the commercial embodiment of the invention of the '190 patent does not have a statistically significantly lower DFL than the IR formulation .... Before the present litigation, Abbott had conducted five crossover studies in which the pharmacokinetic parameters for clarithromycin (i.e., clarithromycin specifically, not clarithromycin combined with its metabolite) were measured for both the MR [modified release] and IR formulations: W95-914, W95-195, W95-197, W98-268 [the study that Sandoz accuses Abbott of withholding], and TAI-99-001.” The mean DFL values in Table VII in the '718 patent are based on Study W95-195. See Supplemental Declaration of Dr. Ronald Sawchuk, February 7, 2007 (“Table VII reflects data from a multiple dose study involving MR formulation and an IR formulation that was conducted in Germany in 1995. See Ex. 12, Study W95-195.”). The studies conducted before the '718 patent application was filed showed the data reported in the specification. Many details were explained to the district court, as to all the studies, their context, and their relationship. The district court found that “contrary to Sandoz’s assertion, Study W98-268 does not demonstrate that the prior art MR formulation has the same PK properties as that claimed for the ER formulation. Therefore, Study W98-268 is not material to the patentability of the '718 patent.” Abbott, 500 F.Supp.2d at 824. The district court found that the '718 patent “speaks of the PK relationship of extended release and immediate release formulations, not of modified release and immediate release formulations .... [and] there is no evidence showing the DFL of the ER formulation to be anything but consistently statistically significantly lower than the DFL of the IR formulation.” Id. The district court found that the W98-268 study was not material under either Rule 56 or the reasonable examiner standard. Clear error has not been shown in this finding. On the preliminary injunction record, the district court did not abuse its discretion in ruling that Sandoz was not likely to succeed in establishing inequitable conduct in Abbott’s prosecution of the '718 patent application. We agree with the district court that the scales do not “tilt towards finding inequitable conduct.” Id. at 829. The '616patent Sandoz argued that inequitable conduct as to the taste perversion claim in the '718 patent taints the '616 patent because a taste perversion claim was included in the '616 application when it was filed, although that claim was cancelled before any PTO examination on the merits. The district court declined to hold the '616 patent unenforceable based on a withdrawn claim, citing 37 C.F.R. § 1.56(a): Rule 56(a). The duty to disclose information exists with respect to each pending claim until the claim is cancelled or withdrawn from consideration, or the application becomes abandoned. Information material to the patentability of a claim that is cancelled or withdrawn from consideration need not be submitted if the information is not material to the patentability of any claim remaining under consideration in the application. The district court deemed it “wholly inequitable to hold a patent to be invalid for fraudulent conduct in the prosecution of a claim that was withdrawn before actual prosecution had even begun.” Abbott, 500 F.Supp.2d at 829. This court held in Scripps Clinic & Research Found. v. Genentech, Inc., 927 F.2d 1565, 1583 (Fed.Cir.1991) that “[a] reference that is material only to withdrawn claims can not be the basis of a holding of inequitable conduct.” Rule 56 is in accord. Sandoz also argued as to the '616 patent that Abbott did not report to the PTO the results of clinical trials conducted before the continuation in-part '616 application was filed. Sandoz’ expert Dr. Marcello Pagano, in his Declaration dated January 25, 2007, stated: “I have reviewed the bronchitis and sinusitis studies [and] the claims of the '616 patent for a method of reducing gastrointestinal adverse side effects are not supported by the data from those two clinical studies.” The results of these studies were provided to the FDA, but not to the PTO. Dr. Pagano stated: “Since neither the sinusitis nor the bronchitis studies produced favorable results to support a claimed reduction in gastrointestinal adverse side effects, Abbott had to manipulate its data and report the number of discontinuations due to gastrointestinal adverse side effects to the PTO ...” The district court found that the information from these clinical trials was not material to patentability, stating that: “it is clear from both Table VI and Table VIII [of the '616 patent] that some data demonstrating no change in the subcategories of GI adverse side effects of abdominal pain, constipation, diarrhea, dyspepsia, flatulence and nausea were in fact disclosed to the PTO.” Abbott, 500 F.Supp.2d at 828. These findings have not been shown to be clearly erroneous. There was no evidence of intent to deceive with respect to the results of these clinical trials. Materiality, even if found, does not establish intent. This is not a case of new information that affects the fundamental invention; this is a case of challenging every action or inaction of the “conduct” of patent solicitation, although patentability is unaffected. The purpose of Kingsdown was to bring patent practice into the mainstream of the law and administrative practice. The law severely punishes fraudulent practices, and the patent practice includes recognition that the inventor usually knows more about the field than does the “expert” patent examiner. However, routine actions that do not affect patentability and that are devoid of fraudulent intent are not subject to a different standard than other inquiries into fraudulent procurement. The Administrative Procedure Act governs patent examination, See Dickinson v. Zurko, 527 U.S. 150, 119 S.Ct. 1816, 144 L.Ed.2d 143 (1999), and actions of patent examiners are reviewed with recognition of examiner expertise so well as recognition of the occasionally imperfect examination process. “It was to mitigate the ‘plague’ whereby every patentee’s imperfections were promoted to ‘inequitable conduct’ that this court reaffirmed that both materiality and culpable intent must be established.” Allied Colloids, Inc. v. American Cyanamid Co., 64 F.3d 1570, 1578 (Fed.Cir.1995). We conclude that the district court did not abuse its discretion in holding that the '718 and '616 patents were not likely to be held unenforceable based on inequitable conduct in obtaining the patents. Ill INFRINGEMENT The first step in most infringement suits is the procedure called “claim construction,” where the scope of the claim is defined by the court. At the preliminary injunction stage the district court’s claim construction is reviewed, as for other legal issues, for the likelihood of correctness of the ruling. This likelihood is based on the underlying facts as found at this stage of the proceedings, recognizing that “the burdens at the preliminary injunction stage track the burdens at trial.” Gonzales v. O Centro Espirita Beneficente Uniao do Vegetal, 546 U.S. 418, 429, 126 S.Ct. 1211, 163 L.Ed.2d 1017 (2006). For the patents here in suit, the issue of infringement was resolved, at this preliminary injunction stage, as a matter of claim construction. The dispositive question was whether the term “pharmaceutically acceptable polymer” is limited to the polymers named in the specification, or can include other pharmaceutically acceptable polymers. If so limited, it is likely that there would not be literal infringement; if not so limited, then literal infringement would be possible. (Infringement under the doctrine of equivalents was not addressed by the district court, although Sandoz argues the issue “in an abundance of caution.”). The meaning and scope of “pharmaceuti-cally acceptable polymer” as used in these patents has been litigated in other cases, none of which had been finally decided, but some of which had been appealed to the Federal Circuit based on the grant of a preliminary injunction. The district court now construed “pharmaceutically acceptable polymer” in accordance with the construction by the Federal Circuit in Andrx, supra. Sandoz argues on this appeal that the correct construction is that of the Federal Circuit’s earlier decision in Teva, supra. Sandoz argues that because Teva was the earlier ruling, it could not be overturned by the later Andrx panel, citing Newell Cos., Inc. v. Kenney Mfg. Co., 864 F.2d 757, 765 (Fed.Cir.1988) (“Where there is a direct conflict [between Federal Circuit panels], the precedential decision is the first.”). Abbott responds that the decision in Andrx was properly followed by this district court, for in Teva the “construction” of “pharmaceutically acceptable polymer” was not at issue, and this court’s comment thereon was dictum. The court in Andrx recognized the non-binding nature of that comment in Teva. Indeed, the district court in Teva had stated that “[a]t this early stage of the proceedings, the parties have raised no issue as to claim construction”. Abbott Laboratories v. Andrx Pharmaceuticals, Inc., No. 05 C 1490, 2005 WL 1323435, at *3, *4 (N.D.Ill. June 03, 2005) (Teva conceding literal infringement but challenging validity). The panel in Andrx decided the questions now raised by Sandoz concerning the “construction” of “pharmaceutically acceptable polymer” and the pharmacokinetic requirements in the claims. The Andrx panel also explained its departure from the panel decision in Teva. The district court herein, applying Andrx, held that a person of ordinary skill in this field would interpret “pharmaceutically acceptable polymer” in terms of the following description in the '718 specification: “Pharmaceutically acceptable” as used herein, means those compounds, which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, in keeping with a reasonable benefit/risk ratio, and effective for their intended use in the chemotherapy and prophylaxis of antimicrobial infections. '718 patent, col. 3 lines 40-47. The district court referred to the '718 specification’s listing of pharmaceutically acceptable polymers, but applied the Andrx ruling that the polymers are not limited to those that are named in the following paragraph: The pharmaceutically acceptable polymer is a water-soluble hydrophilic polymer selected from the group consisting of polyvinylpyrrolidine, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, vinyl acetate/cro-tonic acid copolymers, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers and derivatives and mixtures thereof. ’718 patent, col. 3 line 65 to col. 4 line 4. The district court construed “pharmaceuti-cally acceptable polymer” as: [A]ny polymer, which within the scope of sound medical judgment is suitable for use in pharmaceutical compositions for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, in keeping with a reasonable benefit/risk ratio, and effective for their intended use in the chemotherapy and prophylaxis of antimicrobial infections, and is capable of forming a matrix to extend drug release into the bloodstream. Such a “pharmaceutically acceptable polymer” must constitute 5 to 50% by weight of the product. Abbott, 500 F.Supp.2d at 834. The district court, following Andrx, held that the usage “from the group consisting of’ in the specification is not exclusive, as it would be in a Markush-form claim, and did not negate the broader description that is also contained in the specification, as quoted above. This aspect was debated in the district court, and again on this appeal. Sandoz argues that since “pharmaceutically acceptable polymer” is limited by the specification to water-soluble hydrophilic polymers, and that since the listed methacrylic acid copolymers are known to include water-insoluble as well as water-soluble polymers, the term “pharmaceutically acceptable polymer” must be construed to mean that the formulation cannot include any water-insoluble methacrylic acid or other polymer. The district court, receiving this argument, reasoned that “the existence of water-insoluble polymers from the specifically-mentioned methacrylic acid co-polymer subset actually militates towards a broader construction urged by Abbott that would encompass water-insoluble metha-crylic acid co-polymers.” Abbott, 500 F.Supp.2d at 834. Sandoz argues that this reasoning is flawed, and that this court in Andrx erred in rejecting this argument. However, we are not persuaded that the Andrx panel’s ruling warrants rejection on this argument, for we agree with the district court that the fact that some metha-crylic acid copolymers are water-insoluble does not require limiting “pharmaceutically acceptable polymer” to the named polymers. We conclude that the district court’s claim construction, which is that of Andrx, is correct, and that the district court properly