Full opinion text
DECISION AVERN COHN, District Judge. TABLE OF CONTENTS I. INTRODUCTION........................................................989 A. The Case............................................................989 B. The Decision.........................................................989 II. BACKGROUND..........................................................989 A. Overview............................................................989 B. History..............................................................989 III. THE TRIAL.............................................................990 A. Witnesses............................................................990 1. Caraco...........................................................990 2. Novo ............................................................990 B. Exhibits.............................................................991 IV. THE LAW...............................................................991 A. Anticipation..........................................................991 B. Obviousness..........................................................991 C. Inequitable Conduct...................................................995 y. THE PATENT........._..................................................997 A. Technical Overview .'..................................................997 B. Conception and Development of the Patented Combination.................998 C. Prosecution History...................................................999 VI. ANTICIPATION.......................................................'. 1001 A. Discussion..........................................................1001 B. Conclusion....................................................•......1001 VII. OBVIOUSNESS.........................................................1002 A. Discussion..........................................................1002 1. The Level of Skill in the Art.......................................1002 2. The Prior Art....................................................1002 3. Prima Facie Obviousness..........................................1006 4. Secondary Considerations.........................................1007 (a) Background and Precedents — Unexpected Results................1007 (b) The Trial Record — Unexpected Results..........................1008 (i) The Moses Study.........................................1010 (ii) The Sturis Study.........................................1013 (iii) The Pfeiffer Study........................................1014 (iv) Scope of Claim 4..........................................1015 (c) Commercial Success...........................................1017 B. Conclusion..........................................................1018 VIII. INEQUITABLE CONDUCT ................ 1018 A. Discussion..........................................................1018 1. Materiality......................................................1018 (a) The Sturis Declaration ........................................1018 (b) The Bork Representations.....................................1021 (c) Novo’s Post-Clinical Trials.....................................1022 2. Intent ..........................................................1023 B. Conclusion..........................................................1025 IX. CONCLUSION .........................................................1025 Appendix I — Reports and Articles Referenced in Decision...........................1026 Appendix II — PX 477A..........................................................1027 I. INTRODUCTION A. The Case This is a patent case undér the Hatch Waxman Act, 21 U.S.C. § 356, et seq. The patent-in-suit, U.S. Patent No. 6,677,-358B1, NIDDM REGIMEN (the '358 Patent) in the words of the abstract: ... discloses a method of achieving improvement in glycemic control by combined use of repaglinide and metformin in NIDDM patients poorly controlled on metformin alone. The patent is owned by assignment by plaintiffs Novo Nor disk A/S and Novo Nordisk, Inc. (Novo). Defendant, Caraco Pharmaceutical Laboratories, Ltd. (Cara-co) asserts that Claim 4, the claim-in-suit of the '358 patent which reads A method for treating non-insulin dependent diabetes mellitus (NIDDM) comprising administering to a patient in need of such treatment repaglinide in combination with metformin is invalid as obvious and anticipated, and is unenforceable because of inequitable conduct and patent misuse. Proceedings against defendant Sun Pharmaceutical Industries, Ltd., the second defendant of which Caraco is a partially owned subsidiary, have been stayed until further order of the Court (Doc. 346). The issues of obviousness, anticipation and inequitable conduct were tried to the Court in June and August of 2010. The issue of patent misuse is the subject of a separate proceeding before the Court. B. The Decision For the reasons which follow, which constitute the findings of fact and conclusions of law required by Fed.R.Civ.P. 52(a), the Court finds that: • The '358 Patent is not invalid because of anticipation • The '358 Patent is invalid because of obviousness • The '358 Patent is not enforceable because of inequitable conduct II. BACKGROUND A. Overview This case has a long and complicated history. It began with the filing of a complaint by Novo charging Caraco with infringement of the '358 Patent on July 21, 2005 (Doc. 1), and Caraco responding with an answer and counterclaim asserting invalidity and unenforceability of the '358 Patent (Doc. 7). Since filing, the case has generated over 500 docket entries. B. History The history of the case is generally described in the following decisions of the Court and the Court of Appeals for the Federal Circuit as follows: On August 31, 2009, the Court held that Caraco could challenge the incorrect use code narrative furnished by Novo for placement in the Orange Book maintained by the Food and Drug Administration on its application for approval of the new drug covered by the '358 Patent, and that Caraco could assert an affirmative defense to the charge of infringement because of this. Novo v. Caraco, 649 F.Supp.2d 661 (E.D.Mich.2009). On September 24, 2009, the Court found that Novo improperly filed a use code narrative in its application for approval of the. new drug. Novo v. Caraco, 656 F.Supp.2d 729 (E.D.Mich.2009). On September 25, 2009, the Court entered an Order and Injunction (Doc. 423) requiring Novo to correct the use code narrative in the Orange Book. On April 14, 2010, the Federal Circuit reversed the Order and Injunction, holding that a counterclaim such as filed by Caraco challenging the Orange Book listing was not available under Hatch Waxman. Novo v. Caraco, 601 F.3d 1359 (Fed.Cir.2010). On July 21, 2010, rehearing was denied. Novo v. Caraco, 615 F.3d 1374 (Fed.Cir. 2010). On December 23, 2010, Caraco applied to the Supreme Court for certiorari. On June 9, 2010, the Court found that the relevant date for prior art in the challenge to validity of the '359 Patent was October 29, 1996. Novo v. Caraco, 2010 WL 2403041 (E.D.Mich. June 9, 2010) On October 6, 2010, in a Memorandum and Order, the Court denied Novo’s motion to dismiss the case for lack of subject matter jurisdiction premised on the grounds that Caraco had changed the nature of its Application For A New Drug (ANDA) with the Food and Drug Administration (FDA). Novo v. Caraco, 2010 WL 3942727 (E.D.Mich. Oct. 6, 2010). On September 09, 2009, Caraco stipulated that its ANDA filed with the FDA infringed the '358 Patent (Doc. 309). On August 24, 2010, in a Notice of Lodging of Stipulation of Infringement, the stipulation was reaffirmed (Doc. 489). III. THE TRIAL On April 23, 2010, the Court entered an order (Doc. 459) reversing the order of proofs at trial. The trial extended over 11 days in June and August of 2010. A. The Witnesses Fourteen witnesses, as named in the List of Trial Witnesses (Doc. 490) filed by the parties post-trial, testified. The witnesses’ direct testimony for the most part was presented in narrative form (see Doc. 459). A brief description by name and general nature of testimony of the witness follows. 1. Caraco Name General Nature of Testimony Domenico Accili (Accili) Expert in the field of endocrinology and diabetes 2’esearch. Accili expressed the opinion that claim 4 of the '358 patent was invalid as obvious, and that there was a lack of unexpected results when repaglinide was combined with metformin. Marcello Pagano (Pagano) Expert in the field of biostatistics. Pagano expressed the opinion that there was a lack of statistical validity in Novo’s studies with respect to the combination of repaglinide with metformin. 2. Novo Name General Nature of Testimony Medical Director of an Australian research institute. Moses was one of the principal clinical investigators of a study of the combination of metformin and repaglinide (Moses Study) 1. His research • Robert Moses, M.D. (Moses) data and results were the foundation of the examples reported in the '358. • Peter Müller, M.D. (Müller) A research associate in Novo’s research department in Denmark. Müller is the named inventor of the '358 patent. He designed the Moses Study to test the combination of repaglinide and metformin. • Andreas Pfeiffer, M.D. (Pfeiffer) A clinical specialist in the field of endocrinology. Pfeiffer conducted clinical research on the combination of repaglinide and metformin (Pfeiffer Study). He expressed the opinion that the results of the combination were unexpected. • Jeppe Sturis, Ph.D. (Sturis) A principal scientist of Novo in Denmark. Sturis tested a combination of repaglinide and metformin in Zucker obese rats (Sturis Study). He expressed the opinion that the results of his testing were synergistic. The results were cited to the Patent Office in support of patentability of the combination of repaglinide and metformin. • Howard Thaler, Ph.D. (Thaler) An expert in biostatistics. Thaler reviewed the results of the Moses Study and the Sturis Study. He expressed the opinion that the studies showed synergistic results from the combination of repaglinide and metformin. • Peter Damsbo, M.D. (Damsbo) Novo’s chief medical advisor. Damsbo’s early work with repaglinide provided a foundation for a therapeutic approach for the combination of repaglinide and metformin. • John Miller, M.D. (Mffler) Medical director of Novo in Australia. Miller coordinated and supervised the Moses Study. He described this work and said he was surprised by the results. • Michael Mark, Ph.D. (Mark) A German scientist. Mark discovered repaglinide and attempted to commercialize it. He was involved in its transfer to Novo. • Arne Melander, M.D. (Melander) Researcher in the clinical pharmacology of diabetes. Melander expressed the opinion that repaglinide was not interchangeable with sulfonylureas, and was not thought suitable for combination therapy with metformin. • Brian Reisetter, Ph.D. (Reisetter) An expert in medical marketing. Reisetter expressed an opinion about the commercial success of the repaglinide-metformin combination therapy. • Alan Garber, M.D., Ph.D. (Garber) An expert in clinical endocrinology and biochemistry. Garber expressed the opinion that claim 4 the '358 Patent is valid as nonobvious. • Bharati Nadkarni (Nadkarni) A senior manager at Sun Pharmaceutical. Nadkarni described Sun’s activities in India and Myanmar with repaglinide and sulfonylureas. B. Exhibits Roughly over 360 exhibits were introduced in evidence at trial. A consolidated list of trial exhibits (Doc. 494) was filed by the parties post-trial. The exhibits beyond the '358 Patent (JX 1) and an abbreviated File History (JX 2A), include correspondence, chains of e-mails, articles, abstracts of articles, clinical trials reports, curriculum vitaes of scientific witnesses, data compilations and various graphic comparisons, as well as a miscellany of other written material. IV. THE LAW A. Anticipation Anticipation exists only if, within the four corners of a single prior art document, every element of the claimed invention is described, expressly or inherently, such that a person of ordinary skill in the art could practice the invention without undue experimentation. Callaway Golf Co. v. Acushnet Co., 576 F.3d 1331, 1346 (Fed.Cir.2009). B. Obviousness A patent is presumed valid, 35 U.S.C. § 282, and a party challenging its validity bears the burden of proving the factual elements of invalidity by clear and convincing evidence. Pfizer v. Apotex, 480 F.3d 1348, 1359 (Fed.Cir.2007). Once the challenger has presented a prima facie case of invalidity, the patent owner has the burden of going forward with rebuttal evidence. Id. at 1360. This requirement “does not in substance shift the burden of persuasion, because the presumption of validity remains intact and the ultimate burden of proving invalidity remains with the challenger throughout the litigation.” Id. (case citations omitted). Where the accused infringer relies only upon prior art considered by the patent examiner, the statutory presumption of validity includes deference to the examiner’s decision based upon the Patent Office’s expertise. American Hoist & Derrick Co. v. Sowa & Sons, 725 F.2d 1350, 1359-60 (Fed.Cir.1984). In the Supreme Court’s KSR decision, where the invalidity defense was based on prior art not considered by the Patent Office, the Court observed that “the rationale underlying the presumption — that the PTO, in its expertise, has approved the claim — seems much diminished here.” KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398, 426, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007). A valid patent may not be granted or upheld when “the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains.” 35 U.S.C. § 103(a). The ultimate question of patent validity is one of law, based on an underlying factual framework laid out by the Supreme Court in Graham v. John Deere Co.: Under § 103, the scope and content of the prior art are to be determined; differences between the prior art and the claims at issue are to be ascertained; and the level of ordinary skill in the pertinent art resolved. Against this background, the obviousness or nonobviousness of the subject matter is determined. Such secondary considerations as commercial success, long felt but unsolved needs, failure of others, etc., might be utilized to give light to the circumstances surrounding the origin of the subject matter sought to be patented. As indicia of obviousness or nonobviousness, these inquiries may have relevancy. 383 U.S. 1, 17-18, 86 S.Ct. 684, 15 L.Ed.2d 545 (1966). Often, as here, it is necessary to utilize this framework to determine whether a patent claiming a combination of elements known in the prior art was obvious at the time of the claimed invention. Over the years, the Federal Circuit created and applied a test known as the “teaching, suggestion or motivation” (TSM) test. Under this test, a patent claim is proved obvious only if a motivation or suggestion to combine the prior art teachings can be found in the prior art. The Supreme Court in KSR held that the TSM test can provide a “helpful insight,” but noted that [ojften, it will be necessary for a court to look to interrelated teachings of multiple patents; the effects of demands known to the design community or present in the marketplace; and the background knowledge possessed by a person having ordinary skill in the art, all in order to determine whether there was an apparent reason to combine the known elements in the fashion claimed by the patent at issue.... As our precedents make clear, however, the analysis need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ. Continuing: The obviousness analysis cannot be confined by a formalistic conception of the words, teaching, suggestion, and motivation, or by overemphasis on the importance of published articles and the explicit content of issued patents. The diversity of inventive pursuits and of modern technology counsels against limiting the analysis in this way. In many fields it may be that there is little discussion of obvious techniques or combinations, and it often may be the case that market demand, rather than scientific literature, will drive design trends. 550 U.S. at 418-19, 127 S.Ct. 1727. Known disadvantages of prior art elements that might have taught away from the claimed combination may be taken into account in determining obviousness. Id. at 416, 127 S.Ct. 1727, citing United States v. Adams, 383 U.S. 39, 51-52, 86 S.Ct. 708, 15 L.Ed.2d 572 (1966). In another step applicable here, KSR approved the selective use of the “obvious to try” test that had long been rejected by the Federal Circuit: 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. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103. 550 U.S. at 421, 127 S.Ct. 1727. The Federal Circuit subsequently elaborated on the obvious-to-try “rule of thumb,” identifying two factual situations where it was inappropriate: First, an invention would not have been obvious to try when the inventor would have had to try all possibilities in a field unreduced by direction of the prior art. When “what would have been ‘obvious to try’ would have been to vary all parameters or try each of numerous possible choices until one possibly arrived at a successful result, where the prior art gave either no indication of which parameters were critical or no direction as to which ■ of many possible choices is likely to be successful” an invention would not have been obvious. [In re] O’Farrell, 853 F.2d [894] at 903 [(Fed.Cir.1988)]. This is another way to express the KSR prong requiring the field of search to be among a “finite number of identified” solutions. 550 U.S. at 421, 127 S.Ct. 1727; see also Procter & Gamble [Co. v. Teva Pharms. USA, Inc.], 566 F.3d [989] at 996 [(Fed.Cir.2009)]; Kubin, 561 F.3d at 1359. It is also consistent with our interpretation that KSR requires the number of options to be “small or easily traversed.” Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc., 520 F.3d 1358, 1364 (Fed.Cir.2008). Second, an invention is not obvious to try where vague prior art does not guide an inventor toward a particular solution. A finding of obviousness 'would not obtain where “what was ‘obvious to try’ was to explore a new technology or general approach that seemed to be a promising field of experimentation, where the prior art gave only general guidance as to the particular form of the claimed invention or how to achieve it.” O’Farrell, 853 F.2d at 903. This expresses the same idea as the KSR requirement that the identified solutions be “predictable.” 550 U.S. at 421, 127 S.Ct. 1727; see also Procter & Gamble, 566 F.3d at 996-97; Kubin, 561 F.3d at 1359-60. Bayer Schering Pharma AG v. Barr Labs., Inc., 575 F.3d 1341, 1347 (Fed.Cir. 2009). The Federal Circuit has declined to “cabin” the “obvious to try standard” to the “predictable arts” (as opposed to the relatively unpredictable biotechnology arts). In re Kubin, 561 F.3d 1351, 1360 (Fed.Cir.2009). Where, as here, all the elements of the claimed invention are found in a combination of prior art references, the party challenging validity must show by clear and convincing evidence (1) that a skilled artisan would have had a reason or motivation to combine the teachings of the prior art to achieve the claimed invention combination, or would have found it obvious to try the claimed combination, and (2) that such person would have had a reasonable expectation of success in doing so. Pfizer v. Apotex, 480 F.3d 1348, 1361 (Fed.Cir. 2007); KSR, 550 U.S. at 421, 127 S.Ct. 1727. cour(. jn pfizer elaborated on the “reasonable expectation of success:” [C]ase law is clear that obviousness cannot be avoided simply by a showing of some degree of unpredictability in the art so long as there was a reasonable probability of success.....[T]he expectation of success need only be reasonable, not absolute. Id. at 1364. A case of prima facie obviousness can be rebutted by “unexpected results,” but “the results must be shown to be unexpected compared with the closest prior art.” Id. at 1370. “[I]n order to properly evaluate whether a superior property was unexpected, the court should have considered what properties were expected.” Id. at 1371. But even unexpectedly superior results may not be sufficient to overcome a strong prima facie case of obviousness. Id. at 1372. See also, Wyers v. Master Lock Co., 616 F.3d 1231, 1246 (Fed.Cir.2010). A strongly contested legal issue here is the relevance and meaning of Asyst Techs. v. Emtrak, Inc., 544 F.3d 1310, 1316 (Fed.Cir.2008), which Caraco relies upon for its holding that.“objective evidence of non-obviousness [e.g., unexpected results and commercial success] must be commensurate in scope with the claims which the evidence is offered to support.” Evidence of unexpected results, though based upon subject matter that lies within the scope of a patent claim, will not support the unobviousness of a claim whose breadth extends far beyond that evidence unless “the probative value of a narrow range of data can be reasonably extended to prove the unobviousness of a broader claimed range.” In re Clemens, 622 F.2d 1029, 1036 (CCPA 1980); see also the MPEP § 716.02(d), which cites Clemens; In re Grasselli, 713 F.2d 731, 743 (Fed.Cir.1983) (cited in Asyst); In re Tiffin, 58 C.C.P.A. 1420, 448 F.2d 791, 792 (1971) (cited in Asyst). Prima facie obviousness can also be rebutted by evidence of commercial success of the claimed invention. Graham, supra, 383 U.S. at 17-18, 86 S.Ct. 684. C. Inequitable Conduct The overall contours of the defense of patent unenforceability due to inequitable conduct have been summarized by Judge (now Chief Judge) Rader as follows: Applicants for patents have a duty to prosecute patent applications in the Patent Office with candor, good faith, and honesty; see also 37 C.F.R. § 1.56. A breach of this duty — including affirmative misrepresentations of material facts, failure to disclose material information, or submission of false material information — coupled with an intent to deceive, constitutes inequitable conduct. In determining whether inequitable conduct occurred, a trial court must determine whether the party asserting the inequitable conduct defense has shown by clear and convincing evidence that the alleged nondisclosure or misrepresentation occurred, that the nondisclosure or misrepresentation was material, and that the patent applicant acted with the intent to deceive the United States Patent and Trademark Office. The nondisclosure or misrepresentation must meet threshold levels of both materiality and intent. Once the threshold levels of materiality and intent have been established, the trial court must weigh materiality and intent to determine whether the equities warrant a conclusion that inequitable conduct occurred. The more material the information misrepresented or withheld by the applicant, the less evidence of intent will be required in order to find inequitable conduct. Honeywell Int’l Inc. v. Universal Avionics Sys. Corp., 488 F.3d 982, 999 (Fed.Cir. 2007) (internal citations omitted). Even if a threshold level of both materiality and intent to deceive are proven by clear and convincing evidence, a court may still decline to render the patent unenforceable. Star Scientific, Inc. v. R.J. Reynolds Tobacco Co., 537 F.3d 1357, 1365 (Fed.Cir.2008). The applicable definitions of materiality and intent, however, are less settled. “Materiality” is defined by the Patent Office’s current rule as follows: (b) Under this section, information is material to patentability when it is not cumulative to information already of record or being made of record in the application, and (1) It establishes, by itself or in combination with other information, a prima facie case of unpatentability of a claim; or (2) It refutes, or is inconsistent with, a position the applicant takes in: (i) Opposing an argument of unpatentability relied on by the office, or (ii) Asserting an argument of patentability. A prima facie case of unpatqntability is established when the information compels a conclusion that a claim is unpatentable under the preponderance of evidence, burden-of-proof standard, giving each term in the claim its broadest reasonable construction consistent with the specification, and before any consideration is given to evidence which may be submitted in an attempt to establish a contrary conclusion of patentability. 37 C.F.R. § 1.56(b) (2009). The Federal Circuit has held that this current version, effective since 1992, was not intended to supplant the earlier “reasonable examine” standard or the ease law interpreting it. Digital Control v. Charles Machine Works, 437 F.3d 1309, 1316 (Fed. Cir.2006). The court further held that if a misstatement or omission is material under either test, or even under other previously applied tests, such as the “but for” test (the misrepresentation caused the examiner to approve claims he or she would not otherwise have approved) or the “but it may have” test (the misrepresentation may have influenced the examiner), then it is material. Id. at 1315-16. “To the extent that one standard requires a higher showing of materiality than another standard, the requisite finding of intent may be lower.” Id. In fact, recent Federal Circuit decisions have applied the definition from the earlier version of 37 C.F.R. § 1.56, namely, information is material “where there is a substantial likelihood that a reasonable examiner would consider it important in deciding whether to allow the application to issue as a patent.” Some decisions have found it appropriate, when weighing inferences relevant to intent, to consider plausible reasons for the withholding of material information: The intent element of the offense is ... in the main proven by inferences drawn from facts, with the collection of inferences permitting a confident judgment that deceit has occurred.... however, inequitable conduct requires not intent to withhold, but rather intent to deceive. Intent to deceive cannot be inferred simply from the decision to withhold [information] where the reasons given for the withholding are plausible. McKesson Information Solutions, Inc. v. Bridge Medical, Inc., 487 F.3d 897, 913 (Fed.Cir.2007) (reasons for withholding prior art patent and information from related applications held insufficient to negate inference of deceptive intent). An inference of intent to deceive is generally appropriate, however, when (1) highly material information is withheld; (2) “the applicant knew of the information [and] ... knew or should have known of the materiality of the information; and (3) the applicant has not provided a credible explanation for the withholding.” Praxair, Inc. v. ATMI, Inc., 543 F.3d 1306, 1313-14 (Fed.Cir.2008) (no good faith explanation given for failure to disclose material prior art). Another 2008 decision of the Federal Circuit raises an additional hurdle for inferring deceptive intent when alternative inferences can be drawn from the evidence. We have also held that because direct evidence of deceptive intent is rarely available, such intent can be inferred from indirect and circumstantial evidence. But such evidence must still be clear and convincing, and inferences drawn from lesser evidence cannot satisfy the deceptive intent requirement. Further the inference must not only be based on sufficient evidence and be reasonable in light of that evidence, but it must also be the single most reasonable inference able to be drawn from the evidence to meet the clear and convincing standard, [internal cites omitted] Star Scientific, supra, 537 F.3d at 1365 (emphasis added) (no deceptive intent found; withheld document found to be cumulative, and therefore not material). See also, Advanced Magnetic Closures, supra, 607 F.3d at 829. In Star Scientific, the Federal Circuit held that the existence of a reasonable alternative explanation completely precludes an inference of deceptive intent. A contemporaneous decision, however, gave the district court broad discretion to weigh the patentee’s alternative explanations against the inference of deceptive intent, affirming a finding of deceptive intent, without imposing the “single most reasonable inference” standard. Aventis Pharma S.A. v. Amphastar Pharmaceuticals, Inc., 525 F.3d 1334, 1344 (Fed.Cir.2008) (failure to disclose that half life studies were done at different doses). V. THE PATENT A. Technical Overview For ease of reference, in Parts V through VIII the paragraphs are numbered. 1. This overview is essentially based on the Glossary of Terms lodged with the Court on June 20, 2010 by the parties. This overview is a brief tutorial of the underlying technology. 2. One of the byproducts of the body’s digestion of food is glucose (sugar), which enters the bloodstream. A persistently too high level of bloodstream glucose is termed hyperglycemia, while a persistently too low glucose level is called hypoglycemia. Insulin is a hormone produced by beta cells in the pancreas, where it is stored until rising blood glucose levels cause it to be released. Insulin instructs the body’s cells to take up glucose from the blood for .use as an energy source, and also instructs the liver to stop producing glucose and to instead take up glucose from the blood and store it as glycogen until needed by the body. 3. Diabetes is a glucose metabolism disorder characterized by hyperglycemia after meals and in the fasting state. About 24 million people in the United States have diabetes. Type I diabetes, represented by five percent of the diabetic population, occurs when the pancreas’ beta cells fail to manufacture and secrete insulin in response to elevated blood glucose levels. The only therapy is treatment with exogenous (externally originated) insulin. 4. In Type II diabetes, representing the remaining 95 percent of the diabetic population, the beta cells fail to secrete sufficient insulin, and/or the body is resistant to the effects of insulin. Type II diabetes is also known as non-insulin dependent diabetes (NIDDM). It can be treated with orally administered antidiabetic drugs (OADs) in the form of monotherapy (a single OAD) or combination therapy (more than one OAD). Insulin resistance is a characteristic of Type II diabetes in which the cells and the liver are insensitive to the presence of insulin, and do not respond to the chemical message carried by insulin. 5. There are several groups of OADs. The two groups which are the primary focus of this lawsuit are insulin secretagogues and insulin sensitizers. The secretagogues stimulate insulin release from the pancreas’ beta cells. Sensitizers reduce insulin resistance by acting on the liver to reduce glucose production from glycogen stored there, and improve insulin sensitivity in muscle and fat tissues. 6. Repaglinide, one of the two ingredients specified in Claim 4 of the '358 Patent, is an insulin secretagogue. It is one of five members of the meglitinide class of secretagogues, only one other of which (nateglinide or A-4166) has been approved by the FDA. A second class of secretagogue consists of thirteen sulfonylureas. 7. Metformin, the other claimed ingredient in Claim 4, is an insulin sensitizer. It is the only one of three members of the biguanide class that has been approved by the FDA. A second class of sensitizer, the thiazolidinediones (“TZDs”), consists of five drugs. 8. Two measures of glucose control have been referred to in this lawsuit. The first is HbAlc or glycosylated hemoglobin, a form of hemoglobin to which glucose in the blood binds. The glucose remains attached for the life of the hemoglobin cell (about four months). This parameter is not influenced by daily fluctuations in blood glucose, and shows the average glucose level in the recent past. It is therefore used to monitor the effect of diet, exercise and drug therapy on blood glucose. The second measure is FPG or fasting plasma (blood) glucose. This measurement is taken after a patient has not eaten for about eight hours (e.g., overnight). , High levels of FPG can be caused by increased glucose production from glycogen stored in the liver, resulting from impaired insulin action in the liver. 9. As will be amplified below, combination therapy-using any two drugs having different mechanisms of action — will generally be more effective than monotherapy — using just one of those drugs. If monotherapy with a drug proves successful, a logical testing progression was to test that drug in combination therapy. Combination therapy using an insulin sensitizer and an insulin secretagogue was a well-known successful technique for treating Type II diabetes long before the invention claimed in the '358 Patent. 10. A combination of drugs is said to have an additive effect when the total effect equals the sum of the effect of each drug taken separately (e.g., Drugs A and B each reduce hypertension by 10% when administered separately, and reduce hypertension by 20% if administered together). If the combined effect exceeds the sum of the separately administered effects, the effect is' said to be greater-than-additive or synergistic (e.g., Drugs A and B in the above example yield a 25% reduction in hypertension when administered together). If Drug B inhibits or counteracts the effect of Drug A, the drugs are said to be antagonistic (e.g., the combination of the same Drugs A and B reduce hypertension by only 5%). B. Conception and Development of the Patented Combination 11. Novo is a large producer of drugs used to treat diabetes. In November, 1990, it acquired license rights to repaglinide, a known but still unapproved insulin secretagogue. Development of repaglinide became the exclusive focus of Muller, who joined Novo in Denmark as a clinical researcher in 1989. He is the patentee of the '358 Patent. During 1991-92,. he treated Type II patients with repaglinide to determine proper dosages and prove its efficacy and safety. He also compared its performance with sulfonylureas, a well-known class Of insulin secretagogues. 6/7/10 Tr. at 186-95 (Müller). 12. As Müller- explained, in that time period there were sulfonylureas (secretagogues) and metformin, an iiisulin sensitizer that had been around for many years. He conceived the repaglinide/metformin combination at an unknown date before June of 1994, and did not study any other repaglinide combinations. Id. 192, 198. He thought “it would make more sense” to combine repaglinide with metformin than with sulfonylureas, because of metformin’s complementary mechanism of action. “That’s why my thought was a good idea to combine those two.” Id. at 192-93. Relative to patients whose glucose levels were not adequately controlled on metformin alone, he therefore “expected some additional improvements in the glucose control of the patients treated with the combination.” 6/8/10 Tr. at 18 (Müller) 13. Damsbo, who worked with Müller, testified that metformin was the first drug they tested in combination with repaglinide because repaglinide “was a natural thing to combine with a sensitizer ... it’s not more complicated than that.” 8/5/10 Tr. at 49 (Damsbo). That combination “was the only relevant other angle for treating Type II diabetes ... apart from the sulfonylureas.” Id. at 52. The sensitizer metformin was chosen because, by attacking the disease from different angles, “you might get a better effect, a synergistic effect.” Id. at 54 (emphasis added). 14. Müller had another reason for studying the effect of the repaglinide/metformin combination on patients that were not adequately controlled on metformin alone. While monotherapy with a new drug is necessary for regulatory review: you also try to keep a focus on how you can prove something new and exciting, not least for your marketing colleagues when they have to go out and sell your product after approval ... [T]his would be an obvious — not obvious, but a good idea of where to expand your market .... It would be a scientifically sound thing to do. It would not cannibalize on the markets we were already looking for. So in that respect, I think it made sense. 6/8/10 Tr. at 13-14 (Müller). 15. The protocol for a clinical trial of the repaglinide/metformin combination on patients failing on metformin alone was developed under Müller’s direction. Id. at 22. The study was conducted in Australia during 1995-96 by a team of investigators led by Moses. 8/5/10 Tr. at 201 (Miller). 16. On June 13, 1997, Novo filed a patent application on this combination therapy in Denmark, and filed a provisional application in the United States on October 29, 1997. The '358 patent was granted on January 13, 2004. The critical date for prior art under 35 U.S.C. § 102(b) is therefore October 29, 1996. The same critical date applies to prior art under § 102(b)/103. See Memorandum of June 9, 2010 (Doc. 417). 17. Claim 4, the only claim in suit, reads as follows: 4. A method for treating non-insulin dependent diabetes mellitus (NIDDM) comprising administering to a patient in need of such treatment repaglinide in combination with metformin. C. Prosecution History 18. The patent examiner issued four successive rejections of Müller’s application as obvious over the prior art. The first.rejection was based upon a 1996 written by one of Novo’s expert witnesses, Melander. (Melander Article). The examiner stated: Melander teaches combination therapy as a rational approach to the treatment of NIDDM comprising administering agents that have different mechanisms of action and different side-effect profiles .... One skilled in the diabetes art would have been motivated to combine two hypoglycemic agents as one pharmaceutical composition to treat NIDDM based on their onsets and durations of action in view of the teaching of Melander. Such would have been obvious in the absence of evidence to the contrary because it would have been reasonable to expect clinical efficacy to be additive, while dosage and side-effect profiles could be decreased, following the administration of clinically effective agents that demonstrate different modes of action. JX 2A, Tab 3 at C0172889-90, Office Action dated 10/19/2000. 19. In response, Novo’s’ argument included reliance on Example 3 of the application, which contains the data from the Moses Study, as demonstrating an unexpected “synergistic effect.” Id. at Tab 4, C0172904-05, Amendment and Response filed 1 /15/2002. 20. The examiner then repeated her obviousness rejection based upon the Melander Article and made the rejection Final. Id. at Tab 6, C0172930-31, dated 3/15/2001. 21. Novo’s next Amendment and Response argued that the Melander Article did not suggest the specific combination of repaglinide and metformin; that “obvious to try” is not a proper basis for rejection (KSR’s endorsement of that basis had not yet occurred); and again argued that Example 3 in the application demonstrated an unexpected synergistic effect. . Id. at Tab 8, C0172937-39, dated 7/6/2001. 22. The examiner withdrew the Final Rejection because she entered an additional ground of rejection, not here relevant. She further stated that the claims failed to recite a synergistic effect in quantitative terms, and repeated her position that Me-lander’s teaching made the claimed combination obvious. Id. at Tab 9, C0172944-45, dated 7/23/2001. 23. Novo then repeated its earlier arguments, adding that the law does not require that the improved or unexpected properties relied upon be included in the claims. Id. at Tab 11, C0172955-57, dated 1/15/2002. 24. A fourth and final obviousness rejection of all claims followed: The prior art is replete with examples of combination therapy wherein side-effects are minimized, dosages are reduced and a more clinically beneficial outcome is observed as compared with monotherapy [additional prior art publications omitted]. One skilled in the diabetic art would have been motivated to combine metformin for its longer acting effects and its ability to reduce blood glucose levels with a shorter acting, insulin-releasing agent having a rapid onset of action, in view of the teachings of Melander. Repaglinide and A-4166, which are more rapid in their onset of action and are shorter-acting, and are specifically disclosed by Melander, would have reasonably been preferable to the older sulfonylureas. Id. at Tab 13, C0173001-02, dated 4/16/2002. 25. Novo’s next Amendment and Response reiterated its “unexpected and synergistic effect” arguments, and submitted a Declaration of Sturis (Sturis Declaration, PX 233). The Sturis Declaration reported the results of his study of the repaglinide/metformin combination on Zucker obese rats, and concluded that his data showed: ... synergistic effects on glucose tolerance in Zucker obese rats and that this data, taken together with the data presented in Example 3 of the present application, strongly suggests that the combination of repaglinide and metformin has synergistic properties in type 2 diabetic patients. Id. at Tab 14, C0173015,10/16/2002. 26. Although the Sturis Declaration did not itself conclude that the test results were either unexpected or surprising, the accompanying Remarks of Novo’s attorney, Dr. Richard Bork (Bork), asserted that the data contained in the application and in the Declaration “provides clear evidence of synergy ... in the treatment of type II diabetes,” and that any prima facie case of obviousness “is rebutted by the evidence of synergistic and surprising results achieved by the claimed combined therapy in humans.” Id. at Tab 14, C0173010. 27. These submissions caused the examiner to withdraw her rejection of claims to the repaghnide/metformin combination. She unequivocally stated her reason: Based solely on the Declaration submitted by Dr. Sturis and reconsideration of the synergistic effects demonstrated in Example 3, pages 11-12 of the specification, and Table I, page 14, which are limited to the combination of metformin and repaglinide, this rejection of record is withdrawn for claims 25-29 and 31-33. Neither the Declaration nor the showing in the specification is directed to an unexpected synergistic effect resulting from the combination of compound AY4166 [nateglinide] and metformin. For the reasons of record, the rejection of record under 35 U.S.C. 103 is maintained with respect to claim 30. Id. at Tab 17, C0173146. Although the examiner’s first sentence is clear enough, the second sentence confirms that it was the presence or .absence of evidence of the “unexpected synergistic effect” that was the sole basis of her decision. Although the examiner’s first rejection opined that it was “reasonable to expect clinical efficacy to be additive” when drugs having differing modes of action were combined, the examiner cited no prior art describing or predicting synergistic (i.e., more than additive) results. 28. Additional Patent Office proceedings, not relevant to the issue of validity of Claim 4 in suit, followed the examiner’s withdrawal of the rejection, and the '358 Patent issued on January 13, 2004. (JX 1). Claim 4 corresponds to application claim 29. which was never amended during the prosecution of the application. VI. ANTICIPATION A. Discussion 29. Caraco contends that Claim 4 is anticipated by the Rachman’s 1995 article (Rachman). The article teaches the benefits of combination therapy for treatment of Type II diabetes, using insulin sensitizers and insulin secretagogues. It specifically identifies metformin as one of the first group and repaglinide as one of the second. Novo’s expert, Garber, conceded that Rachman “suggests that metformin combined with repaglinide will give you additive effects [in diabetes patients]” 8/11/10 Tr. at 87 (Garber). 30. However, Rachman does not specifically describe the metformin/repaglinide combination in its listing of many individual drugs and drug types. The article also states that it is “uncertain” whether repaglinide will have clinical advantages, “and initial studies do not indicate a major effect” (Rachman at 471). Also, Rachman is listed in the '358 Patent as a reference that was considered by the examiner. B. Conclusion 31. In sum, Rachman, though strongly probative on the issue of obviousness, does not fairly or directly teach the claimed metformin/repaglinide combination of Claim 4, and therefore does not anticipate Claim 4; the '358 patent is not invalid on grounds of anticipation. VII. OBVIOUSNESS A. Discussion 1. The Level of Skill in the Art 32. A person of ordinary skill in the art is a person having a medical degree with training in endocrinology and three years of clinical experience or laboratory research in the field of diabetes treatment. 6/1/10 Tr. at 100 (Accili). This definition, based on Accili’s definition, is similar to Garber’s except that the latter’s definition would require that the three years of experience be in clinical treatment of diabetes. 8/10/10 Tr. at 109 (Garber). The inclusion of the alternative laboratory research experience is appropriate because excellent diabetes research on OADs has been done by laboratory researchers without clinical experience but having familiarity with OAD uses and combinations. 6/1/10 Tr. at 100 (Accili). 2. The Prior Art 33. The critical date for prior art under 35 U.S.C. § 102(b)/103 is October 29, 1996. See, ¶ 16, supra. 34. Garber testified that the prior art taught “two drugs are better than one” when they have “different mechanisms of actions” and attack diabetes from different angles. 8/11/10 Tr. at 51 (Garber). In response to the Court’s question, Garber also agreed that “in general any two drugs which have different mechanisms of action are better than one.” Id. at 53. Melander testified that the logical progression in testing new diabetes drugs is to test it in monotherapy, including comparison with other monotherapy drugs; then, if successful in monotherapy, in most cases the “next logical step” is to test the drug in combination therapy. 8/9/10 Tr. at 183 (Melander). 35. The “most widely used and most extensively studied” OAD combination as of the critical date was metformin (an insulin sensitizer) combined with a sulfonylurea (a class of insulin secretagogues). (Consensus Statement at 1517); see also 6/1/10 Tr. at 125-26 (Accili). “[D]octors have been treating diabetes patients with combinations of metformin with secretagogues for about a half of a century.” 8/11/10 Tr. at 44 (Garber). This combination had been prescribed both as separate and as co-formulated tablets. 6/1/10 Tr. at 128 (Accili); 8/11/10 Tr. at 44 (Garber). 36. The rationale for the metformin/secretagogue combination therapy is well summarized in the Melander Article and was further explained by Accili at trial. Insulin secretagogues are OADs that act upon the pancreas’ beta-cells to stimulate insulin secretion, thereby lowering blood glucose. OADs that reduce insulin resistance are “insulin sensitizers,” because they increase receptivity of muscle and fat tissue to insulin’s action. Thus, sensitizers improve glucose utilization by the body, and act on the liver to reduce glucose production there. 6/1/10 Tr. at 114-16 (Accili). Melander taught that if monotherapy with either of these types of drugs does not result in near-normal glucose levels: [C]ombination treatment seems rational for a number of reasons. These agents have different mechanism of action and different side-effects; hence the clinical efficacy would be additive while dosage and side-effects could be minimized. (Melander Article at 146). 37. Other prior art reported the beneficial effect of combination therapy using the sensitizer metformin with secretagogues such as the sulfonylureas, because of their different mechanisms of action. A 1965 article stated that “[t]he two drugs thus act synergistically, the sulphonylureas to augment release and plasma activity of insulin, and the diguanides [biguanides, such as metformin] to potentiate its effect on the tissues.... The apparent synergistic effect of the sulphonylureas and diguanides is probably due to their different modes of hypoglycaemic action.” (Clarke at 1251) (emphasis added); 6/1/10 Tr. at 127 (Accili). 38. In 1995, the Consensus Statement reported that “the availability of agents that act by differing mechanisms or may have differing side effects permits the design of individualized regimens that address the heterogeneity of the pathophysiology of NIDDM.” (Consensus Statement at 1515). After discussing sulfonylureas and metformin, the Consensus Statement observed that where glycemic goals are not maintained with an initial medication, “in most patients, it is reasonable to consider combination therapy.” Id. at 1517. Further, “[t]he most widely used and most extensively studied combinations are a sulfonylurea plus metformin or a sulfonylurea plus insulin.” Id. See also, 6/1/10 Tr. at 125-26 and 148 (Accili). 39. Metformin is a member of the biguanide class, the oldest class of insulin sensitizers. Of the three members of that class known before the critical date, it was the only one currently available for clinical practice in most countries, the other two either haying been withdrawn or never approved because of safety issues. 6/1/10 Tr. at 116 (Accili); Melander Article at 145. Metformin was approved by the FDA in 1995, and quickly became popular in the United States, both in monotherapy and combination therapy. 6/1/10 Tr. at 119 (Accili). 40. Two classes of insulin secretagogues were known before the critical sulfonylureas (used since the 1950s) and meglitinides (repaglinide and netaglinide). At that time, only the sulfonylureas were approved by a regulatory body for treatment of NIDDM. The Mfelander Article identified two new non-sulfonylurea “insulin-releasing drugs,” then under study: repaglinide and A-4166 (netaglinide, repaglinide’s sister meglitinide). He described them as having similar action to sulfonylureas, though absorbed and eliminated more quickly. Although they had not yet been approved, Melander said they “look very promising” because possibly less likely than sulfonylureas to cause dangerously low blood sugar levels. (Melander Article at 145). See also, 6/1/10 Tr. at 114-15 (Accili); 8/9/10 Tr. at 145 (Melander). Me-lander himself admitted at trial that his article would have encouraged a person of ordinary skill in the art to scientifically study the combination of repaglinide with metformin. 8/9/10 Tr. at 197 (Melander). 41. A 1995 article also encouraged combining OADs having different mechanisms of action, because “the limited efficacy of sulphonylureas and metformin on their own ... make polypharmacy inevitable in many cases.” (Rachman at 474). He added that it was “likely” that such therapy “will have additive effect.” Id. at 467. The article specifically described repaglinide as a “non-sulphonylurea secretagogue.” Id. at 471. Although Rachman did not specifically describe the repaglinide/metformin combination, Garber conceded that Rachman “suggests that metformin combined with repaglinide will give you additive effects [in diabetes patients].” 8/11/10 Tr. at 87 (Garber). 42. Further evidence of the state of the art as of the October 29, 1996 critical date is found in a November 12, 1996 publication (Kaku). Although published two weeks after the critical date, Garber agreed that the article was “just recapping the prior art” and that it had been written and submitted for publication 2-6 months earlier. 8/11/10 Tr. at 78, 83-84 (Garber). Kaku described repaglinide as a “new insulin secretagogue” that is rapid and short-acting, and stated that “it is expected to be used” to improve postprandial hyperglycemia and to reduce delayed hypoglycemia (Kaku at NOVO-6741638). He also stated that that “combination therapy using these agents will be performed largely, because these agents have individual unique characteristics” Id. at NOVO6741641, Figure 2 of the article displayed seeretagogues as being combined with biguanide sensitizers (such as metformin). Id. at NOVO-6741644. 43. Garber acknowledged that, before the critical date, one of ordinary skill in the art “may” have considered repaglinide an appropriate candidate for combination therapy for at least some patient populations (namely, those whose “post-prandial,” or after-meal, glucose levels were not under control.) 8/11/10 Tr. at 94 (Garber). 44. As part of the argument that it would not have been obvious to try combining repaglinide with metformin, Novo asserted that in 1996 there were at least 44 known OADs that provide at least 900 possible two-drug OAD combinations. See PX 477. This list includes seven insulin sensitizers (one biguanide, i.e., metformin and six TZDs), twenty insulin seeretagogues (fifteen sulfonylureas and five meglitinides, including repaglinide), five glucose absorption inhibitors, six gluconeogenesis inhibitors and six weight-loss agents. Appropriately, Novo listed but did not count among the 44 OADs two other biguanides that were widely recognized as unsafe. 45. Accili, however, disagreed that each of these 44 OADs was appropriate for treatment of Type II diabetes. He considered the list “the proverbial kitchen sink,” including drugs whose use would be considered malpractice. He named seven of the 44 that he could not in good conscience prescribe to anyone. 6/3/10 Tr. at 21 (Accili). In response to the Court’s questions, Accili stated that Novo’s expanded list included drugs that had been considered as potential OADs at some time before 1996, but had been “totally discredited” by 1996. Id. at 21-22. He gave specific reasons, such as limited efficacy, discontinued availability, toxicity or other concerns for long-term safety. Id. at 8-13, 18, 24. Even Garber admitted that there were “no reputable weight-loss agents” due to “either limited efficacy or ... concerns about their long-term safety.” 8/11/10 Tr. at 75 (Garber). Similarly, he, admitted that development of gluconeogenesis inhibitors “had been hampered by toxicity,” and that none had reached the market even as of today. Id. 46. Later, again in response to the Court’s questions, Accili stated that Novo’s expanded list was the “potential universe” but it would have to be modified to show the “effective universe.” 6/7/10 Tr. at 22-23 (Accili). At the Court’s request, Accili prepared a chart showing the effective universe of OAD drugs. PX 477A, a copy of which is found in Appendix II. The chart lists (1) five sensitizers, including one biguanide (metformin) and four TZDs; (2) nine insulin seeretagogues, including seven sulfonylureas and two meglitinides (repaglinide and nateglinide); and two glucose absorption inhibitors. As of the critical date, the TZDs were still in the testing stage, some having been withdrawn. Only two were considered viable, and none was approved by the FDA until 1997. 6/1/10 Tr. at 119 (Accili). Glucose absorption inhibitors interfere with the conversion of carbohydrates to glucose in the small intestine. As of the critical date it was known that this class of drugs does not directly treat either of the two causes of NIDDM, i.e., decreased insulin secretion or impaired insulin action. One of these, acerbose, was used before the critical date, but was known to have a modest effect relative to metformin and the sulfonylureas. 6/1/10 Tr. at 119-20 (Accili). 47. According to the Consensus Statement, the metformin/sulfonylurea combinations had already been widely studied and used, and several other potential combinations had been examined and used to a lesser extent. Consensus Statement at 1517. Thus, the untested candidates for combination the'rapy represented only a fraction of the seventeen OADs comprising the effective universe charted on PX 477A. Melander explained that it would have been “more interesting scientifically and clinically to examine combination therapies with metformin and repaglinide,” as well as some others, than the already studied combinations of metformin and sulfonylureas. 8/9/10 Tr. at 195-96 (Melander). 48. Accili’s testimony regarding the effective universe of candidates for combination therapy was credible. As of the critical date, this universe of potential or previously combined OADs included a “finite number of identified, predictable solutions.” KSR, supra. The guidance provided by the prior art’s teaching of the benefits of combining insulin secretagogues and insulin sensitizers created a reasonable expectation of success in achieving at least additive results from combination of these candidate OADs. See Bayer Schering and Pfizer, supra. In other words, the Court is not persuaded by Novo’s argument that it was not obvious by the prior art to try combining repaglinide and metformin. Indeed, as explained above and below, quite the opposite was true. 49. Novo also asserts that prima facie obviousness is precluded because the prior art taught away from the claimed combination. Specifically, repaglinide was known to have a small impact on fasting plasma glucose (FPG) due to its short biological activity life. 50. According to Melander because repaglinide was quick-acting and quickly eliminated from the body, it was viewed as a “niche compound” useful for only a “narrow and very specific patient population.” 8/9/10 Tr. at 84 (Melander). However, Melander’s own article, after citing these properties, stated that repaglinide would lessen certain risks and looked “very promising.” (Melander Article at 145). He also admitted that his article taught that a short-acting sulfonylurea (glipizide) could be combined with metformin in some circumstances, without problem; that all sulfonylureas, in principle, achieve the same results; that “sulfonylurea and repaglinide are alternatives if you’re looking for an insulin seeretagogue;” and that the article encouraged a person of ordinary skill to study the metformin/repaglinide combination. 8/9/10 Tr. at 177-78, 182, 193-94, 197-98 (Melander); see also 8/11/10 Tr. at 64-66 (Garber). And Garber admitted that even if repaglinide were not beneficial for high-FPG patients, Rachman still suggested that its combination with metformin could produce additive effects and be useful for patients with elevated post-prandial glucose. Id. at 87, 94 (Garber); Rachman. 51. The examiner, as more fully quoted above (¶¶ 18, 24), also cited the Melander Article to support her view that rapid and short-acting repaglinide “would have reasonably been preferable to the older sulfonylureas” for combination with longer-acting metformin. PX 2A at Tab 13, C0173001-02, dated 4/16/2002. 52. In sum, the prior art as a whole did not teach away from combining repaglinide with metformin, even if beneficial results might not be obtained for all Type II diabetes patients. 3. Prima Facie Obviousness 53. As presented in detail above, the record clearly and convincingly establishes that the prior art supplied the teaching, suggestion and motivation to combine repaglinide with metformin as combination therapy for Type II diabetes. The prior art taught that two drugs having different mechanisms of action in treating Type II diabetes are better than one. 54. The combination of metformin (an insulin sensitizer) and a sulfonylurea (