Eli Lilly & Co. v. Sicor Pharmaceuticals, Inc. (705 F. Supp. 2d 971, 2010)

FINDINGS OF FACT AND CONCLUSIONS OF LAW

SARAH EVANS BARKER, District Judge.

This matter is before the Court for decision following a trial on the issues of validity, enforceability, and infringement of two patents held by Plaintiff Eli Lilly and Company (“Lilly”): United States Patent Nos. 4,808,614 (“the '614 patent”) and 5,464,826 (“the '826 patent”). The '614 patent covers the compound gemcitabine, and the '826 patent covers the method of treating susceptible neoplasms in mammals with gemcitabine. Lilly markets gemcitabine for injection under the trade-name GEMZAR®, which is approved for the treatment of ovarian, cancer, breast cancer, non-small cell lung cancer, and pancreatic cancer. (DTX 39.)

Lilly is the holder of approved New Drug Application No. 20-509 for the use of Gemzar® as a treatment for these cancers. In January 2006, Defendant Sicor Pharmaceuticals, Inc. (“Sicor”) filed two Abbreviated New Drug Applications (“ANDAs”) under the Drug Price Competition and Patent Term Restoration Act of 1984, 98 Stat. 1585 (popularly known as the HatchWaxman Act), with the Food and Drug Administration (“FDA”) seeking approval to market generic versions of Lilly’s gemcitabine product in two different dosage forms (200 mg and 1 g) prior to the expiration of the '614 and '826 patents. In August 2008, Defendant Teva Parenteral Medicines, Inc. (“Teva Parenteral”) filed a third ANDA seeking approval to market generic versions of gemcitabine in a third dosage form (2 g). Sicor’s (and Teva Parenteral’s) ANDAs included “paragraph IV certifications,” pursuant to 21 U.S.C. § 355(j)(2)(A)(vii)(IV), asserting that the claims of Lilly’s '614 and '826 patents are invalid, unenforceable, or not infringed. As required by the Hatch-Waxman Act, Sicor and Teva Parenteral sent Lilly notice of these ANDA filings and paragraph IV certifications.

On February 15, 2006, after receiving notice of Sicor’s ANDA filings and paragraph IV certification relating to the 200 mg and 1 g dosage forms, Lilly filed suit against Sicor and Teva USA alleging infringement of the '614 and '826 patents under 35 U.S.C. § 271(e)(2)(A) and 35 U.S.C. § 271(b). Within forty-five days of receiving Teva Parenteral’s notice relating to the 2 g dosage form, on September 26, 2008, Lilly filed suit against Teva Parenteral and Teva USA alleging infringement of the '614 and '826 patents. On January 15, 2009, the Court issued an order consolidating the two previously separate actions.

With the present action, Lilly seeks an order: (1) requiring the FDA to change the effective date of ANDA Nos. 77-961 and 77-983 until after the expiration of the '614 and '826 patents; (2) prohibiting the FDA from approving Teva Parenteral’s ANDA No. 090644 prior to the expiration of the patents, in accordance with 35 U.S.C. § 271(e)(4)(A); and (3) enjoining Defendants from the commercial manufacture, use, offer to sell, sale, or importation of their gemcitabine products prior to the expiration of Lilly’s exclusivity, in accordance with 35 U.S.C. § 271(e)(4)(B).

Defendants have stipulated that if Claim 12 of the '614 patent and Claim 7 of the '826 patent are valid and enforceable, then Defendants’ actions constitute infringement of those patents under 35 U.S.C. § 271(e)(2). (PTX 870, PTX 871).

Defendants challenge the validity of the '614 patent on the following grounds: anticipation under 35 U.S.C. § 102 and obviousness under 35 U.S.C. § 103. Defendants challenge the validity of the '826 patent on the following grounds: obviousness-type double patenting, anticipation under 35 U.S.C. § 102, obviousness under 35 U.S.C. § 103, and lack of enablement under 35 U.S.C. § 112. Defendants further assert that Lilly is collaterally es-topped from asserting the '826 patent against them as a result of a prior determination of invalidity in a related case brought by another pharmaceutical company against Lilly in another district court.

On the final day of trial, a post-trial briefing schedule was set for submission of the parties’ proposed findings of fact and conclusions of law, post-trial briefs, and responses. These submissions were due on or before November 30, 2009. [Docket No. 339]. Having now considered the evidence adduced at trial as well as the parties’ post-trial submissions, we hold, as detailed below, that: (1) the '614 patent is valid and enforceable and Defendants’ proposed commercial gemcitabine product infringes claim 12 of that patent; and (2) although the '826 patent is valid and enforceable in all other regards, Lilly is collaterally estopped from defending against Defendants’ claim of obviousness-type double patenting relating to that patent, pending a final determination on appeal.

Findings of Fact

The Parties

Plaintiff Eli Lilly and Company (“Lilly”) is an Indiana corporation with its principal place of business in Indianapolis, Indiana. Lilly is engaged in the business of research, development, manufacture, and sale of pharmaceutical products throughout the world.

Defendants Sicor Pharmaceuticals, Inc. (“Sicor”), now known as Teva Parenteral Medicines, Inc. (“Teva Parenteral”), and Teva Pharmaceuticals USA, Inc. (“Teva USA”) (collectively “Defendants”) are Delaware corporations. Defendants are engaged in the business of selling generic pharmaceutical products, which they distribute in Indiana and throughout the United States.

The Patents-in-Suit

The '614 patent, issued on February 28, 1989 to Lilly, names Dr. Larry W. Hertel as the sole inventor. The '826 patent, issued on November 7, 1995 to Lilly, names Dr. Larry W. Hertel and Dr. Gerald B. Grindey as joint inventors. Both patents are owned by Lilly.

The '614 patent discloses and claims a series of 2'2'-difluoronucleoside analogs, including gemcitabine. (DTX 1; D.I. 261 ¶ 23.) Claim 12, the only claim being asserted from the '614 patent, specifically claims the nucleoside analog gemcitabine. (Radtke 432:13-20.) The chemical name of gemcitabine appears as the eighth compound in a list of thirty-six potential 2'2'-difluoronucleosides. (DTX 1, col. 3, II. 55-56.) The '614 patent claims priority to U.S. Patent Application Ser. No. 473,883 (“the '883 Application”), filed on March 10, 1983.

The specification of the '614 patent details the antiviral utility of this class of nucleoside analogs. It also contains one paragraph describing the later-discovered anticancer activity of this class of nucleosides and providing specific dosages. (PTX 1 at col. 17, II. 53-68.) The '883 Application, which was the original application in this patent, does not disclose any anticancer activity in the difluoronucleoside analogs. (Radtke 475:17-19.) The anticancer disclosure of the '614 patent was added by Lilly in a continuation-in-part application (“CIP”), Ser. No. 677,146, filed on December 4, 1984 (“1984 CIP Application”). (PTX 7 at 42; D.I. 261 ¶ 30.)

Also on December 4, 1984, the same day of the filing of the 1984 CIP Application related to the '614 patent, Lilly filed a completely separate patent application, which eventually issued as the '826 patent. The '826 patent claims the benefit, under 35 U.S.C. § 120, of a series of applications, the earliest having been filed on December 4, 1984, U.S. Patent Application Ser. No. 677,783 (“the '783 Application”). (PTX 9 at 3-46.)

The '826 patent discloses and claims methods of treating susceptible neoplasms with grem-difluoronucleosides, including gemcitabine. Claim 7 of the '826 patent, the only claim of that patent being asserted here, claims a method of treating susceptible neoplasms in mammals, where the susceptible neoplasm is selected from the group consisting of leukemias, sarcomas, carcinomas, and myelomas, and comprising the administration of a therapeutically effective amount of gemcitabine as treatment for human patients. (PTX 2 at col. 23, 1.42-col. 24, 1.64; Green 220:25-221:6.)

Definition of Person of Ordinary Skill in the Art for the '614 Patent

At trial, Defendants’ expert, Dr. Piet Herdewijn, and Lilly’s expert, Katherine Radtke, testified that the person of ordinary skill in the art to which the '614 patent pertains would have a Ph.D. or equivalent degree in chemistry or the pharmaceutical sciences, with additional and considerable experience designing and synthesizing nucleoside analogs for biological purposes. (Radtke 432:25-433:15; Herdewijn 980:19-982:2.) Drs. Kathlyn Parker and Larry Overman held a similar view but did not include in their definition a particular expertise in nucleoside chemistry. (Overman 599:6-17; Parker 1137:21-1138:10.) The definition of a person of ordinary skill in the art does not appear to be a matter of major dispute between the parties. We find that the definition must recognize the particular complexity of the science involved in the invention of the asserted claim, as well as the formative nature of the field of nucleoside synthesis at the time of the issuance of the patent.

Accordingly, based on the testimony of these experts, we find that a person of ordinary skill in the art for the '614 patent would have a Ph.D. in chemistry, postdoctoral training in nucleoside chemistry, and experience in the design and synthesis of nucleoside analogs for biological purposes.

Defínition of a Person of Ordinary Skill in the Art for the '826 Patent

The invention of the '826 patent relied upon clinical trial experience, and Claim 7 of the '826 patent is directed to treating cancers, which are typically treated by clinical oncologists. As Defendants’ expert, Dr. Kenneth Tew explained, in 1984, clinical oncologists administered cancer drugs to patients and were clinical trial investigators. (Tew 1273:9-19, 1277:17-20.) Because of the role of such experimentation in the development of the asserted claim, contrary to the opinion asserted by Defendants’ experts that clinical oncologist expertise would not be part of the “ordinary” knowledge in the art, the definition of a person of ordinary skill in the art must consider the role of designing, implementing, and conducting clinical trials necessary for a complete understanding of the skill required in this field. (Green 222:2-16.) Furthermore, Lilly’s expert, Dr. Mark Green, testified that the '826 patent, which is a method of use patent, does not require medicinal chemistry. (Green 222:17-21.)

Accordingly, we hold that, for the '826 patent, a person of ordinary skill in the art would have a medical degree (M.D.) or a Ph.D. degree in biology, pharmacology, or a similar degree in a related field of science, and would have experience in developing chemotherapeutic agents for the treatment of cancer. That person would have knowledge encompassing the design, implementation, and execution of clinical trials. (Green 221:21-222:10.)

Gemcitabine and Nucleoside Analogs Generally

The Food and Drug Administration (“FDA”) has approved gemcitabine, sold by Lilly as Gemzar®, for use in treating patients with neoplasms, including pancreatic, lung, ovarian, and breast cancers. (PTX 443 at 10-11.) Gemcitabine has been used to treat approximately 1.5 million patients worldwide since its first approval in 1996. (D.I. 287, Grabowski Rep. ¶ 45.) Currently, gemcitabine is the primary therapy given to patients with advanced pancreatic cancer, as experimental data indicates that it offers improved one-year survival nine times better than the previous standard of care. (Green 200:11-201:4; PTX 436 at 2403.)

Gemcitabine is a “nucleoside analog,” or a modified version of a class of compounds called nucleosides, which are the building blocks of DNA. (Shewach 770:3-14; LDX 8.24.) Nucleosides consist of a 5-member “sugar” ring joined to a “base.” (Radtke 426:14-16; LDX 7.2.) By convention, the atoms at each of the corners of the base are numbered 1 through 6, and the carbon atoms at each corner of the sugar are numbered 1' (“1 prime”) through 5’. Gemcitabine differs structurally from the natural nucleoside 2'-deoxycytidine in that it has twin fluroine atoms at the C-2' position of the sugar (hence, the “gem” in its name, which stems from “geminal,” for twin). (Radtke 433:23-434:4.)

Nucleoside analogs can be used as anticancer or antiviral agents because they are similar enough in structure to naturally occurring nucleosides that cells are tricked into accepting them, but are different enough to disrupt cell functioning and replication once inside the cell. (Rustum 1537:6-1538:6.) Because of these attributes, since at least the 1960s, chemists specializing in nucleosides have explored the implementation of structural changes to naturally occurring nucleosides in an effort to produce nucleoside analogs with therapeutic properties. (Radtke 441:15— 24; Shewach 792:19-793:2; PTX-602.) This process and the results it engenders have been regarded as highly unpredictable; as one leading researcher stated in a 1973 review article, “[0]nly Zeus sitting on top of Mount Olympus could predict which modifications would produce clinically effective antiviral agents. Unfortunately, we poor mortals are not privy to such knowledge.” (Radtke 430:15-431:15; PTX 647 at 881; see also PTX 692 at 3-5).

Even today, scientists in the field regard nucleoside analog design for therapeutic anticancer purposes as very unpredictable. (Radtke 431:12-432:5.) This unpredictability stems from the profound change in biological properties that can be created by minor changes in the structure of a nucleoside compound. Slight structural modification can drastically alter the biological activity of nucleoside analogs. This is the result of the effect structural modification typically has on the three-dimensional shape of the compound, which alters the analog’s ability to interact with biologically significant enzymes. (Radtke 427:15-430:14.) An example given in this litigation was that the building blocks of RNA and DNA, two compounds that are processed by the human body in remarkably different ways, differ physically in only one respect: that the RNA nucleosides have a hydroxyl group (OH) at the C-2' position, whereas DNA nucleosides do not. (Radtke 427:15-428:5; LDX 7.3.)

The key modification in gemcitabine involves the element fluorine. In the early 1980s, fluorine chemistry as applied to the nucleoside field was relatively new, and little was known about how one might synthesize difluorinated nucleosides. (Overman 596:7-601:17; 615:13-616:25.) Indeed, years after the invention of gemcitabine, Dr. Herdewijn wrote that “the synthesis of fluorinated nucleosides is still a difficult task.” (PTX 688 at 67.) Furthermore, the properties of fluorine, which is the most electronegative atom of all known elements, are known to lead to particularly unpredictable results, with corresponding unpredictable effects on biological activity. (Overman 615:13-616:1; Radtke 434:12-20.) Because of this electronegative potency, a geminal fluorine substitution, like the one in gemcitabine, was a particularly unpredictable addition to nucleoside analogs. (Bergstrom 935:15-936:22; PTX 533 at Bergstrom 21; see also Rustum 1605:14-22.) This unpredictability remained even after Lilly’s development of gemcitabine; as Defendants’ expert, Dr. Herdewijn wrote in a 1989 review article, “[I]t seems very difficult to predict [a] molecule’s biological behaviour when a C-H or a C-OH has been displaced by a C-F group.” (PTX 688 at 66; Herdewijn 1097:2-13.)

The unpredictability in this area of chemistry is, in large part, the reason that gemcitabine remains the primary treatment for particularly intractable neoplasms. Prior to Lilly’s synthesis of this compound, no other research team had synthesized a nucleoside analog with geminal fluorine atoms. (Radtke 473:12-474:5.). Furthermore, between that synthesis and the year 2000, roughly forty similar nucleoside analogs (with geminal fluorine atoms at the 2'-position) had been reported, yet none had proved effective for treating cancer in humans. (Radtke 528:14-529:6; PTX 620 at 87-88.) More broadly, out of nearly 300,000 compounds that had been evaluated as anticancer agents by 1979, shortly before Lilly’s synthesis of gemcitabine, only forty were deemed useful in treating neoplasms. (Shewach 744:8-745:8; PTX 692 at 3.)

Nucleoside Analogs in the Prior Art

Defendants point to three compounds they contend were contained in the prior art and were significant to the development of gemcitabine: Arar-C, which has an OH group “up” at the 2' position; 2'-F-aro-C, which has one fluorine “down” at the 2' position; and 2'-F-cytidine, which has one fluorine “down” at the 2' position. These three, according to Defendants, presaged Lilly’s discovery.

In the 1970s, the first of these compounds, Arar-C, was a widely used anticancer drug. (Bobek 1300:18-13-1:3.) Although it was relatively effective, the compound was rapidly deactivated in the body by a process called “deamination.” (Bobek 1301:8-16.) Because of problems stemming from this lack of effectiveness, researchers at the Fox Laboratory at Memorial Sloan-Kettering Cancer Center (“Sloan-Kettering” or “Fox Laboratory”) and elsewhere had undertaken efforts to improve on Arar-C.

The two fluorinated nucleoside analogs, 2'-F-ar&-C and 2'-F-cytidine, had been synthesized in the 1960s by Sloan-Kettering. (Radtke 441:15-442:17; Shewach 750:20-751:6.) But neither compound was reported in the prior art to have been advanced to testing in animals, as compounds with promise for medical activity typically are. (Shewach 752:25-753:10.) Nor was either considered a lead compound for further exploration in the late 1970s and early 1980s. (Radtke 440:22-441:6.)

2'-F-cytidine was first reported in 1967 and found to be twenty times less cytotoxic in vitro than Arar-C. (Radtke 441:15-24; PTX 602.) The fact that 2'-F-eytidine did not effectively inhibit DNA synthesis in intact cells indicated that it also did not significantly inhibit the enzyme ribonucleotide reductase (“RNR”) in vivo. Moreover, although this nucleoside analog was discovered in 1967, Fox Laboratory never tested it for biological activity in animals or in the clinic, nor did any other laboratory so test it. (Shewach 752:25-753:10; Radtke 448:2-20.)

In 1970, researchers at Sloan-Kettering reported that they had synthesized 2'-F-aro-C. (Radtke 448:21-449:14; PTX 603.) However, similar to 2'-F-cytidine, this analog posed no improvement on the in vitro cytotoxicity of Arar-G, and the prior art reported no in vivo activity for 2'-F-ara-C. (Radtke 454:13-18.)

In contrast to these two compounds, which the prior art largely deemed of low antiviral and anticancer activity, two nucleoside analogs referred to as FIAC and FMAU were identified by researchers as the “most potent and selective” of the fluorinated Sloan-Kettering analogs. (Radtke 454:19-456:9; PTX 584 at 30.) Dr. Herdewijn, Defendants’ expert, noted in a 1989 review that FIAC and FMAU were “important” nucleoside analogs for further study, omitting any mention of 2'-F-cyti-dine or 2'-F-aro^C. That the FIAC and FMAU compounds were more prominent in the prior art than 2'-F-cytidine and 2'-F-ara^-C is further supported by a presentation prepared by Dr. Donald Bergstrom in 1980, which mentioned neither 2'-F-ara^C and 2'-F-cytidine but did describe FIAC. (PTX-541 at Bergstrom 3257.)

In addition to providing information regarding the properties of these compounds, the research referenced in the pri- or art indicated to those skilled in the art that a nucleoside analog’s in vitro cytotoxicity does not necessarily correlate with in vivo anticancer activity. (Shewach 795:23-797:7; PTX 725 at 1163; Rustum 1586:13-15.) Thus, any in vitro data reported for 2'-F-ara^C and 2'-F-cytidine was not necessarily indicative of how those compounds would act in vivo. (Rustum 1583:25-1584:4.) As the prior art revealed with considerable clarity, because viruses produce different enzymes than mammalian cancer cells, (Herdewijn 1105:6-15; Shewach 857:14-21; PTX 937 at 486), not all molecules exhibiting antiviral activity also have anticancer activity.

Dr. Miroslav Bobek’s Attempts to Synthesize Gemcitabine

Dr. Miroslav Bobek, now a retired medicinal chemist, spent the majority of his career developing modified nucleosides for anticancer purposes at Roswell Park in Buffalo, New York. (Bobek 1299:1-7.) In connection with this work, in June 1977, Dr. Bobek submitted a manuscript to Tetrahedron Letters setting forth proposed synthetic routes for making gemdifluorosaccharides, including a method used in his laboratory for making an intermediate of gemcitabine. (DTX 95; Bobek 1322:6-1323:8, DTX 873 at SICOR/TEVA-Bobek 472.) In March 1978, Dr. Bobek carried out a series of chemical reactions with the intention of creating gemcitabine, but he never succeeded in synthesizing the compound. (Bobek 1324:9-1330:10.)

Dr. Bobek reports that he publicly presented his work on gemcitabine in the 1970s during at least one seminar held at Roswell Park. (Bobek 1317:8-1319:25; DTX 220 at SICOR/TEVA-Bobek 133.) During that time period, Dr. Gerald Grindey, a named inventor on the '826 patent, was a colleague in the same department as Dr. Bobek. (DTX 78.) Dr. Grindey left his position with Roswell Park in December 1980 to join Lilly.

Dr. Bobek’s laboratory notebook contains a series of attempted reactions leading to an intermediate of gemcitabine, but none of them resulted, even hypothetically, in gemcitabine itself. (Bobek 1324:9-23; 1325:11-19; PTX 508 at 61.) His first relevant experiment, in which he attempted to make a difluoronucleoside using DAST, failed. (Bobek 1358:7-9, 1359:8-9; Radtke 459:12-436:3; PTX 492.) Similarly, an alternative synthesis which started with a 6-member ring sugar that was reported in his grant application was reported to have failed. (PTX 499 at Bobek 202; PTX 500 at Bobek 154.)

Although Dr. Bobek claimed at trial that his experiments and proposed reactions were capable of producing gemcitabine, no other evidence in the record supports this claim. None of Defendants’ experts testified that Dr. Bobek actually synthesized gemcitabine, or even that his synthetic route was capable of doing so. Moreover, experimental evidence demonstrated clearly that the synthetic route purportedly used by Dr. Bobek could not have produced gemcitabine. (Radtke 485:11-25; Overman 623:13-625:5; PTX 509; PTX 516.) Eventually, Dr. Bobek abandoned his attempts to synthesize the compound and focused instead on the pursuit of other nucleoside analogs. (Bobek 1330:20-25; 1394:1-6.)

Dr. Donald Bergstrom’s Attempts to Synthesize Gemcitabine

Dr. Donald Bergstrom, who was, prior to March 1983, a professor at the University of North Dakota and is now a professor at Purdue University, also had proposed the synthesis of difluoronucleosides. (DTX 265; DTX 206 at SICOR/TEVA-Bergstrom 22.) However, like Dr. Bobek, Dr. Bergstrom also never successfully produced gemcitabine. (Bergstrom 920:18-20.)

Dr. Bergstrom utilized several routes in attempting to synthesize 2',2'-difluoro-2'deoxynucleosides. (Bergstrom 946:23-948:5; PTX 534.) He set forth his rationale for conducting these experiments in grant applications that he submitted to the National Institute of Health (“NIH”) in May and October of 1982. (DTX 206 at SICOR/TEVA-Bergstrom 4, 22; DTX 207 at SICOR/TEVA-Bergstrom 47. 63.) His May 1982 grant application stated that “of particular interest to us is the 2'-deoxy-2',2'-difluoro substitution pattern.” (DTX 206 at SICOR/TEVA-Bergstrom22.)

Based on this work, Dr. Bergstrom submitted an abstract entitled “Synthesis of Gem-Difluoro Substituted Nucleoside Analogs” (the “Bergstrom Abstract”) to the American Chemical Society before a March 1983 meeting at which he was scheduled to make a presentation (“1983 ACS Meeting”). (DTX 265; DTX 264 at 41.) The Bergstrom Abstract, a copy of which Dr. Hertel received on or about March 1, 1983, (PTX 6 at 52), reported that Dr. Bergstrom’s laboratory was attempting to synthesize 2' and 3' gemdifluoronucleosides, which Dr. Bergstrom anticipated would include gemcitabine. (DTX 265.) Dr. Bergstrom publicly presented his research attempts at the 1983 ACS Meeting, and the slides he used in that presentation depicted the structure of gemcitabine. (Bergstrom 914:6-9, 915:1— 917:3; DTX 455.)

Although Dr. Bergstrom made a 3’,3'-gemdifluoronucleoside, he never successfully prepared the compound gemcitabine. (Radtke 466:13-467:15; PTX 518; Bergstrom 954:5-14.) Furthermore, while Dr. Bergstrom proposed several different de novo synthetic routes, he did not utilize a Reformatsky reaction, the route utilized by Dr. Hertel to synthesize gemcitabine. Because Dr. Bergstrom was never able to synthesize either a 2',2'-difluoronucleoside or the precursor of gemcitabine, he eventually abandoned his efforts and concentrated instead on other nucleoside analogs. (Bergstrom 923:11-19, 921:25-923:7; PTX 534 at Bergstrom 68-69.)

Merrell Dow’s Synthesis of Gemcitabine

Dr. Robert Farr and Dr. Brian Metcalf at Merrell Dow Pharmaceuticals, Inc. also sought to synthesize gem-difluoronucleosides. (DTX 851, Metcalf Dep. Tr. 11:16-12:6, 16:14-18; Radtke 512:20-513:3.) Dr. Metcalfs involvement centered largely on envisioning the use of a nucleoside having a 2' gem-difluoro sugar coupled to a natural base to inhibit RNR, which he hoped would prove to have an anticancer utility. (DTX 151-153; DTX 851, Metcalf Dep. Tr. 33:11-14, 20-21, 23-4, 34:2-10; Farr Dep. Tr. 25:6-9, 11-13.) Dr. Farr, who worked under Dr. Metcalfs supervision until Dr. Metcalfs departure from Merrell Dow in December 1983, proposed a synthetic route that included a Reformatsky reaction and a Sharpless epoxidation to produce the compound. However, this route also proved unsuccessful. (PTX 552 at SA 2212-13; PTX 554 at SA 2200; Radtke 514:17-515:25, 516:3-5.)

Dr. Farr next attempted an approach derived from an article published in 1984, which also proved unsuccessful. (PTX 557 at SA 2182; PTX 566; PTX 6; Farr Dep. 47:18-51:17.) Dr. Farr did not, in fact, succeed in producing gemcitabine until, at the earliest, December 1984, and he did not test it for anticancer utility until May 1985, after a review of Dr. Hertel’s synthetic method reported in Lilly’s 1984 published British patent application. (DTX 162 at SA 2861, 2865; PTX 16; PTX 557 at SA 2185; PTX 568, 17:47-51, 18:49-30:39; PTX 16, 4:43-9:47; Farr. Dep. 59:12-17, 59:20-60:2, 91:19-93:25.) Merrell Dow filed a patent application on the use of gemcitabine as an antitumor agent in July 1985. (DTX 895.)

Lilly’s Invention of Gemcitabine and Discovery of its Utilities

I. The '61k Patent: Difluoronucleosides and Antiviral Utility

Lilly’s interest in developing nucleoside analogs as antiviral agents manifested itself in the early 1980s, when Lilly sought to obtain rights from Sloan-Kettering to develop FIAC and FMAU for antiviral utility. (Hertel 270:16-25, 271:23-272:15; PTX 22 at GM 197972.) Lilly was, however, unsuccessful in obtaining a license to these compounds. (Pearce 146:21-24, 147:13-14.) Thereafter, Dr. Larry Hertel, an employee at Lilly, became responsible for searching out ways to synthesize monofluorinated nucleoside analogs like FIAC and FMAU, in order to provide quantities of the compounds for further testing. (Hertel 271:1-13.).

Dr. Hertel proposed a new strategy called “de novo” or “total” synthesis as a method of producing the compounds, despite the fact that this method had been dismissed by other researchers as a “method of limited usefulness.” (Hertel 283:13-19, 352:25-353:24; PTX 19 at GM 153104; PTX 22 at GM 197983-84; PTX 648 at 237.) At this time, he also proposed the preparation of a “key intermediate” he believed could be used to make geminal difluoronucleosides with two fluorine atoms at the C-2' position, hoping that these new compounds would produce antiviral utility. (Hertel 273:13-275:21, PTX 19 at GM 153127; PTX 22 at GM 197985-86.)

Dr. Hertel’s synthesis of geminal difluoronucleosides was not immediately successful, as many of his attempted synthetic methods failed and he encountered unexpected impediments during his research. (Hertel 285:25-287:10; PTX 24 at GM 198006-08.) Included in his failed attempts were an intensive effort to synthesize the compounds using a “Sharpless epoxidation.” (Hertel 282:17-284-14. 287:18-288:8). Overall, Dr. Hertel spent four months (May 1981 to September 1981) attempting to prepare the necessary Sharpless intermediate. Dr. Hertel tried at least four categories of reaction to accomplish this goal, and he contacted Dr. Sharpless, a Nobel Prize-winning synthetic organic chemist, and Dr. Evans, another prominent synthetic organic chemist, for advice. (Hertel 284:12-14; 287:18-20.) Both of those prominent chemists believed the route Dr. Hertel proposed would be successful. (Hertel 283:4-284:11, 287:11-289:14; PTX-19 at GM 153104.) Nonetheless, all of these attempts failed. (Hertel 285:25-292:13, 302:24-303:8.) During the time period from July to December 1981, Dr. Hertel shifted his focus by attempting a more direct synthetic strategy using the DAST reagent. (PTX 24 at 199; Hertel 301:15-302:23.) Like the previous strategy, this attempt also failed. (Hertel 302:9-10.)

In the face of these setbacks, Dr. Hertel proposed a different de novo approach using a “Reformatsky” reaction. Applying this method, in September 1981, he succeeded in synthesizing the carbon backbone of the 2' gem-difluoro sugar, which was a precursor of gemcitabine. (Hertel 292:14-294:9, DTX-126 at 57; PTX 24 at 193.)

According to Dr. Hertel, despite this success, the process thereafter was quite rigorous and complex, consistent with what was known in the prior art about the unpredictability of fluorination:

And what we discovered very rapidly is once you introduce fluorine into an organic molecule, it significantly alters the chemistry of that molecule by deactivating some centers or activating others to reactions in that in a normal organic molecule wouldn’t be involved. And so essentially, you had to kind of learn organic chemistry all over again when you started working with a fluorinated organic.

(Hertel 297:13-20.) Dr. Hertel’s laboratory initially attempted to couple the sugar intermediate he had produced with the base thymine, rather than cytosine, the base in gemcitabine. (DTX 129, 130, 421; PTX 19, 24, 26, 31.)

In June 1982, after many more attempts, the laboratory successfully synthesized the first difluoronucleoside in the series, 2',2'-difluorothymidine. (Hertel 311:17-313:4; PTX 26 at 162, 164.) Gemcitabine was the second nucleoside analog made by Dr. Hertel’s laboratory. (PTX 31 at GM 161073, 161075; Hertel 327:17-329:7.) Lilly later tested Dr. Hertel’s difluoronucleosides, and, by June 15, 1982, the first 2',2'-difluoronucleoside had exhibited promising activity against viruses. (Hertel 316:1-319:7; PTX 26 at GM 162163; PTX 228.) Dr. Hertel’s difluoronucleosides demonstrated antiviral activity against both DNA and RNA viruses. (Hertel 316:1-319:7, 330:8-24; PTX 181 at GM 152170; PTX 228; PTX 229; PTX 242.)

On March 10, 1983, Lilly filed its original patent application related to Dr. Hertel’s difluoronucleosides, the '883 application, which listed these compounds, including the first documented reference to gemcitabine. The '883 application also described the method of manufacturing the compounds and explained their antiviral utility. (PTX 6 at 9.) Claim 12 of the patent that issued from this original application, the '614 patent, covers the nucleoside gemcitabine. (Radtke 423:13-20.)

The '614 patent is entitled “Difluoro Antivirals and Intermediate Therefor.” (PTX 1.) Consistent with its title, the patent is directed primarily to using the listed difluoronucleosides as antiviral agents. See id. However, the patent also contains a paragraph describing the later-discovered anticancer activity of these compounds. This paragraph was added on the same day that Lilly filed the original patent application ultimately leading to the '826 patent, the second patent-in-suit. Specifically, on December 4, 1984, Lilly filed the 1984 CIP Application, a continuation-in-part the '883 application that ultimately led to the issuance of the '614 patent. (PTX 7.) In accordance with the “best mode” requirement of 35 U.S.C. § 112, Lilly included in the 1984 CIP Application one paragraph discussing the later-discovered anticancer activity of the difluoronucleosides. That later discovery as contained in a separate patent application and discussed immediately below led to the issuance of the '826 patent.

II. The '826 Patent: Gemcitabine’s Anticancer Utility

Soon after he had successfully synthesized difluoronucleosides and had them tested for antiviral activity, Dr. Hertel submitted several of the compounds to Dr. Gerald Grindey, a Senior Research Scientist at Lilly, who was seeking compounds for testing in anticancer screens. (Hertel 330:25-331:20, 332:25-333:10; PTX 31 at 195; Pearce 158:9-15.)

Although few of the compounds demonstrated anticancer utility in the tests conducted by Dr. Grindey, gemcitabine exhibited significant cytotoxicity, orders of magnitude better than the other difluoronucleosides. (PTX 173 at GM 154671; PTX 181 at GM 152170.) Dr. Grindey described it as “singular among all difluoronucleosides tested to date.” (Pearce 100:9-19; PTX 179 at GM 258388.) Dr. Grindey’s laboratory first screened gemcitabine for cytotoxicity in human cancer cells on November 1, 1983. (PTX 118 at GM 157170; Hertel 334:1-21.) The compound was first tested in vivo on leukemia beginning on February 22, 1984. (Pearce 90:16-91:9; PTX 126.) Gemcitabine showed a very significant improvement in the life span of mice, used in the in vivo testing, over a very broad range of doses in a test initiated on May 9, 1984 and completed on June 6, 1984. (PTX 173 at GM 154671; Pearce 89:20-90:8, 91:22-92:5; PTX 131.)

By August 13, 1984, Dr. Grindey’s laboratory had collected and reviewed nearly all of the antitumor data for gemcitabine that appears in the '826 patent. (PTX 2; PTX 131; PTX 132; PTX 129; PTX 136; PTX 128; PTX 134; Pearce 90:16-92:5, 93:20-95:3, 104:20-105:6.) Ultimately, Dr. Grindey’s in vivo testing of gemcitabine’s antitumor activity demonstrated the compound’s activity against a wide array of solid tumors, a “very unusual feature” for a nucleoside analog and the “broadest spectrum of any agent ever tested at Lilly.” (PTX 173 at GM 154672; PTX 179 at GM 258390; Pearce 101:15-102:6.)

On December 4, 1984, based on Dr. Grindey’s findings, Lilly filed a patent application on their discovery of the anticancer utility of gemcitabine, naming Drs. Grindey and Hertel as inventors. This filing came more than twenty months after the filing of '883 application, which was the original application of the '614 patent. The '826 patent, which resulted from the '783 application, was entitled “Method of Treating Tumors in Mammals with 2',2'-Difluo-ronucleosides” and contained in vitro and in vivo experimental data supporting the method of using various difluoronucleosides, including gemcitabine, to treat susceptible neoplasms in mammals. (PTX 2.) Claim 7- of the '826 patent is limited to using gemcitabine to treat different types of cancer. (PTX 2; Green 220:25-221:6.)

The goal of the '826 patent is to treat cancer in humans. (Tew 1273:9-12.) One of ordinary skill in the art reviewing the patent and its prosecution history, along with the relevant art in 1984, would know that the claimed invention dealt with the treatment of cancer in human patients, not all mammals. The '826 patent provides extensive information as to how to make and use the claimed invention. (PTX 2.) It describes the synthesis of gemcitabine and demonstrates the compound’s cytotoxic activity in vitro and in vivo. Using standard mouse tumor model data, the patent discloses a broad range of activity, which would have led a person of ordinary skill in the art using valid methods and appropriate models to expect gemcitabine to have broad efficacy in humans against a variety of cancers. (Green 223:11-16.) Further, the patent discloses that physicians will be responsible for determining therapeutic doses of gemcitabine in humans. (PTX 2 at col. 16,11. 2-8; Green 220:6-22.)

In order to determine the types of cancers for which gemcitabine would demonstrate efficacy in humans, one skilled in the art would have understood that the compound should be tested in the clinic in phase I and/or phase II studies, which were routine to a person of ordinary skill in 1984. (Green 223:17-25, 258:25-259:7; Tew 1254:1-4.) As Defendants’ expert, Dr. Tew, explained, phase I, II, and III clinical trials are “what pharmacologists and clinical oncologists do.” (Tew 1286:6-11.) Undertaking this experimentation would have been relatively straightforward to a person of ordinary skill in the art because the approach to designing clinical trials was known and well documented. (Tew 1284:9-25,1285:1-17.)

III. The Unexpected Properties of Gemcitabine

Gemcitabine exhibited a number of properties that would have been unexpected to the person of ordinary skill in the art, including a unique mechanism of action, broad activity in treating susceptible neoplasms, and increased survival and higher clinical benefit response in the treatment of pancreatic cancer when compared to 5-fluorouracil (“5-FU”).

A number of gemcitabine’s mechanistic properties would have been unexpected, such as greater transport into cells and higher accumulation and retention inside cells, both of which provide an improved capacity to kill cancer cells over Ara-C. (Shewach 754:4-755:14, 759:12-763:18, 764:2-6; PTX 695 at 4028, PTX 696 at 100; LDX 8.7-8.8, 8.13-8.16.) Gemcitabine also proved to have superior effects on DNA synthesis, increased incorporation into DNA, and remarkable ability to inactivate the enzyme RNR. (Shewach 754:4-755:14, 763:19-768:21, 769:15-781:11; PTX 712 at 6110, 6116; PTX 705 at 567, 571; PTX 703 at 3220; LDX 8.21-8.29.)

As a result of these properties, gemcitabine exhibited unprecedented activity against a broad spectrum of cancers. (Shewach 754:21-23.) Gemcitabine’s activity against tumors, including solid tumors, was unexpected in view of and in comparison to the compounds in the prior art. (Pearce 95:22-96:14; Green 178:16-22, 217:5-19.) Furthermore, at least one study concluded that patients with advanced pancreatic cancer treated with gemcitabine alone demonstrated a statistically significant, unexpected survival advantage and higher clinical benefit response when compared to those treated with 5-FU. (Green 178:5-15, 200:11-201:4; PTX 436 at 2403, 2406, 2409, 2412; LDX 5.12-5.13.)

TV. Gemcitabine’s Impact on the Market

For decades prior to the development of gemcitabine, researchers experienced significant difficulty developing effective treatments for solid tumors, despite success in treating other forms of cancer. (PTX 460 at 12; PTX 461 at IV-50; Rustum 1581:15-21; Pearce 81:15-82:1.) During this period, patients suffering from advanced pancreatic cancer consistently faced a particularly negative prognosis because no chemotherapy was available that was effective as a treatment. (Green 183:19-184:5; PTX 452 at 2061.) Prior to gemcitabine, only two drugs had been approved by the FDA for use in patients with this disease: 5-FU and mitomycin. (Green 182:25-183:18.) 5-FU in particular held some promise for survival benefit, based on early stage studies, but it did not ultimately demonstrate a significant increase in survival or pain relief. (Green 184:6-21,202:13-23; PTX 452; PTX 455 at 1033; PTX 436 at 2403.)

Thus, despite the existence of 5-FU, the need for more effective chemotherapeutic agents for the treatment of solid tumors like those present in pancreatic cancer still existed in the early 1980s, at the time of the invention of gemcitabine and its anticancer utility. The use of gemcitabine to treat patients with advanced pancreatic cancer therefore satisfied this need and, although not a cure, became the accepted standard of care, which it remains today. (Green 178:23-179:11, 204:25-205:17, 205:18-23.)

Because of this effectiveness, gemcitabine, marketed as the commercial product Gemzar®, which embodies the inventions disclosed and claimed in the patents-in-suit, became and remains a commercial success. Gemzar® is now Lilly’s fourth-largest selling product worldwide, with net sales growing from $175 million in 1997 to $1,592 billion in 2007. (Grabowski Rep. ¶¶ 14, 35, Ex. 2.) The evidence adduced at trial indicates that Lilly’s marketing expenditures for Gemzar® equal about one-half of one percent of the net sales of Gemzar®, which is a marketing-to sales ratio lower than the average ratio for Gemzar®’s direct competitors as well as other relevant oncology drugs. (Id. at ¶¶ 18, 48-50, Ex. 6A-6B.)

Conclusions of Law

I. Standard of Review

Federal Circuit precedent governs matters of substantive patent law in this Court pursuant to 28 U.S.C. § 1295(a). Southwire Co. v. Essex Group, Inc., 220 U.S.P.Q. 1053, 1056 n. 6 (N.D.Ill.1983) (“The law that controls this action ... is that law of the Federal Circuit[, which] has declared that the patent decisions of [the C.C.P.A.] will be considered binding ....”) (citing S. Corp. v. United States, 690 F.2d 1368, 1370 (Fed.Cir.1982) (en banc)).

Patents are presumed to be valid. Moreover, each claim within a patent is independently presumed to be valid, even if other claims within that patent are held invalid. 35 U.S.C. § 282. Accordingly, the burden of proving invalidity rests with the patent challenger, here, Defendants, who must prove invalidity by clear and convincing evidence. Id.; Golden Blount, Inc. v. Robert H. Peterson Co., 365 F.3d 1054, 1061-62 (Fed.Cir.2004). This burden “is constant and remains throughout the suit on the challenger” and “does not shift at any time to the patent owner.” TP Labs., Inc. v. Prof'l Positioners, Inc., 724 F.2d 965, 971 (Fed.Cir.1984). Pursuant to Defendants’ obligation to carry this burden, “if the fact trier of the issue is left uncertain, the party with the burden loses.” Tech. Licensing Corp. v. Videotek, Inc., 545 F.3d 1316, 1327 (Fed.Cir.2008) (citation omitted).

If the patent challenger alleges invalidity based on prior art that was considered by the U.S. Patent and Trademark Office (“PTO”) during the prosecution of the patent, the challenger has the “added burden of overcoming the deference that is due to a qualified government agency presumed to have properly done its job.” Ultra-Tex Surfaces, Inc. v. Hill Bros. Chem. Co., 204 F.3d 1360, 1367 (Fed.Cir.2000) (quoting Am. Hoist & Derrick Co. v. Sowa & Sons, 725 F.2d 1350, 1359 (Fed.Cir.1984)); see also Impax Labs., Inc. v. Aventis Pharms., Inc., 468 F.3d 1366, 1378 (Fed.Cir.2006) (“When the prior art was before the examiner during prosecution of the application, there is a particularly heavy burden in establishing invalidity.”) (citation omitted). The rationale underlying the presumption of validity is, however, “much diminished” when the prior art relied upon was not considered by the PTO during prosecution. KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398, 426, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007). That said, if a reference was not before the PTO examiner but was cumulative of others that were before the examiner, the heavy burden of proof nonetheless applies. Metabolite Labs., Inc. v. Lab. Corp. of Am. Holdings, 370 F.3d 1354, 1368 (Fed.Cir.2004).

II. Effective Filing Dates of the Patents

Under 35 U.S.C. § 120:

An application for patent for an invention disclosed in the manner provided by the first paragraph of section 112 of this title in an application previously filed in the United States, ... which is filed by an inventor or inventors named in the previously filed application shall have the same effect, as to such invention, as though filed on the date of the prior application, if filed before the patenting or abandonment of or termination of proceedings on the first application or on an application similarly entitled to the benefit of the filing date of the first application and if it contains or is amended to contain a specific reference to the earlier filed application....

35 U.S.C. § 112, in turn, provides:

The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.

In accordance with these statutory provisions, the effective filing date of the '614 patent is March 10, 1983, the filing date of Dr. Hertel’s original patent application containing a description of gemcitabine and a disclosure of a method of utility. (PTX 1.) The effective filing date of the '826 patent is December 4, 1984, the filing date of Dr. Hertel’s and Dr. Grindey’s original patent application containing a description of a method of using gemcitabine to treat susceptible neoplasms. (PTX 2.)

III. Defendants’ Claim of Double Patenting

In August 2009, summary judgment was entered against Lilly in the Eastern District of Michigan, in a factually similar case to the case before this Court, in which it was held that obviousness-type double patenting rendered the '826 patent invalid. Sun Pharm. Indus., Ltd. v. Eli Lilly & Co., 647 F.Supp.2d 820 (E.D.Mich.2009). In handing down that ruling, the court addressed and resolved the exact same double patenting issue presented to us here. Defendants, accordingly, contend that Lilly is estopped from asserting in this litigation that the doctrine of obviousness-type double patenting does not apply.

Defendants invoke the rule promulgated by the Supreme Court in Blonder-Tongue v. University Foundation, 402 U.S. 313, 91 S.Ct. 1434, 28 L.Ed.2d 788 (1971), which bars Plaintiff from relitigating the validity of the '826 patent. The Blonder-Tongue Court held that once a court determines that a patent is invalid in a proceeding where the patent owner had a full and fair opportunity to adjudicate the issue, the patent owner is collaterally estopped from relitigating the issue in a future case. Blonder-Tongue, 402 U.S. 313, 91 S.Ct. 1434. Collateral estoppel limits patent owners to “one full and fair opportunity for judicial resolution of the same [invalidity] issue.” Id. at 328, 91 S.Ct. 1434. Blonder-Tongue also held that the application of collateral estoppel is governed by “the trial courts’ sense of justice and equity.” Id. at 334, 91 S.Ct. 1434.

Whether collateral estoppel applies is determined in accordance with Seventh Circuit precedent, rather than the Federal Circuit precedent which ordinarily controls in patent cases. Bayer AG. v. Biovail Corp., 279 F.3d 1340, 1345 (Fed.Cir.2002). Thus, under Seventh Circuit precedent, for collateral estoppel to apply, “four elements must be met: ‘(1) the issue sought to be precluded must be the same as that involved in the prior litigation, (2) the issue must have been actually litigated, (3) the determination of the issue must have been essential to the final judgment, and (4) the party against whom estoppel is invoked must be fully represented in the prior action.’ ” Meyer v. Rigdon, 36 F.3d 1375, 1379 (7th Cir.1994).

Further, “[c]laim preclusion (res judicata), as Rule 8(c) of the Federal Rules of Civil Procedure makes clear, is an affirmative defense,” Rivet v. Regions Bank of Louisiana, 522 U.S. 470, 476, 118 S.Ct. 921, 139 L.Ed.2d 912 (1998), which “must be pleaded.” Blonder-Tongue, 402 U.S. at 350, 91 S.Ct. 1434. “The purpose of such pleading is to give the opposing party notice of the plea of estoppel and a chance to argue, if he can, why the imposition of estoppel would be inappropriate.” Id.

We recognize that, in this case, Defendants did not plead collateral estoppel as an affirmative defense. However, it is equally clear that the likely reason for this deficiency is that the Eastern District of Michigan decision subjecting the issue of double patenting as it relates to the '826 patent to collateral estoppel was handed down a mere month prior to the trial in the case at bar. Therefore, Defendants had no meaningful opportunity to plead it. Lilly contends that the pleading requirement is essential and must be upheld because Lilly was not given sufficient notice of the res judicata defense; however, Lilly’s contention has been undermined by the fact that Lilly availed itself of an opportunity, in post-trial briefing of the issues before the Court, to argue at length why estoppel should not apply. Accordingly, rigid enforcement of the typical pleading requirement would serve only to undermine “justice and equity” in this case. Blonder-Tongue, 402 U.S. at 334, 91 S.Ct. 1434.

Upon review of the parties’ arguments for and against the application of res judicata, we conclude that the four elements of collateral estoppel are clearly met here. Lilly implicitly concedes the first three elements of the collateral estoppel standard have been satisfied: (1) the double patenting issue presented is exactly the same; (2) the issue was actually litigated before the Sun Pharmaceutical Court; (3) final judgment was entered in Sun Pharmaceutical, based on the double-patenting issue. As to the fourth element, Lilly argues only that it was denied a full and fair opportunity to litigate the double patenting issue at trial because the Michigan court’s summary judgment decision was “facially and indisputably wrong as a matter of law.” (Pl.’s Tr. Br. at 36.) Although we do not here reject Lilly’s arguments related to the merits of the Sun Pharmaceutical decision, we do hold that simply disagreeing with the result at the summary judgment phase, which resulted in a final judgment for collateral estoppel purposes, see Smith v. City of Chicago, 820 F.2d 916 (7th Cir.1987), is insufficient to demonstrate the lack of a full and fair representation in the prior litigation. Therefore, Lilly is estopped in this action from defending against Defendants’ claim that the '826 patent is invalid for obviousness-type double patenting.

IV. Anticipation

A patent claim is invalid under 35 U.S.C. § 102(a) if “the invention was known or used by others in this country, or patented or described in a printed publication in this or a foreign country, before the invention thereof by the applicant for patent.” 35 U.S.C. § 102(a). Pursuant to 35 U.S.C. § 102, anticipation requires “the presence in a single prior art disclosure of all elements of a claimed invention arranged as in that claim.” Carella v. Starlight Archery & Pro Line Co., 804 F.2d 135, 138 (Fed.Cir.1986) (citation omitted).

Defendants, as challengers of the patents’ validity, bear the burden of proving by clear and convincing evidence that the references relied upon to demonstrate anticipation are, in fact, prior art. Norian Corp. v. Stryker Corp., 363 F.3d 1321, 1330 (Fed.Cir.2004). To determine what constitutes prior art for invalidity analysis, the Court must consider the “invention date” for the asserted claim. 35 U.S.C. § 102(a); Mahurkar v. C.R. Bard, Inc., 79 F.3d 1572, 1576 (Fed.Cir.1996). Documents that are not prior art cannot anticipate a patent claim. IMX, Inc. v. LendingTree, LLC, 2006 WL 47066, at *1 (D.Del. Jan. 10, 2006). In showing that all elements of an invention were anticipated, the challenging party may not rely upon the knowledge of one skilled in the art of the disclosure of another reference to supply missing elements. Structural Rubber Prods. Co. v. Park Rubber Co., 749 F.2d 707, 715 (Fed.Cir.1984).

A. Dr. Bobek’s Slides

Defendants attempted at trial to show that a group of slides (“Bobek Slides”) produced by Dr. Bobek anticipated the asserted claims of the '614 and '826 patents because those slides contained a drawing of the chemical structure of gemcitabine. (DTX 220 at Bobek 133.) We thus must first determine if these slides did in fact constitute prior art for invalidity purposes. Norian, 363 F.3d at 1330.

As a general matter, public presentations qualify as prior art under 35 U.S.C. § 102(a) and (b). See Ecolochem, Inc. v. S. Cal. Edison Co., 227 F.3d 1361, 1369-70 (Fed.Cir.2000); Mass. Inst. of Tech. v. AB Fortia, 774 F.2d 1104, 1108 (Fed.Cir.1985) (finding that a paper that was presented to persons in the relevant field qualified as a “printed publication” under § 102(b)). Defendants contend that Dr. Bobek’s presentations were public, citing Dr. Bobek’s testimony to that effect. (Bobek 1318:13-1319:25.) Aside from his testimony, however, no other evidence in the record supports Defendants’ contention that these slides were ever disclosed or otherwise made known publicly. In fact, Dr. Rustum and Dr. Bernacki stated that they had no recollection of being present at any meeting where Dr. Bobek purportedly made a presentation disclosing his work on gemdifluoronucleosides, despite being Dr. Bobek’s departmental colleagues during that period. (Rustum 1589:21-1590:2; Bernacki Dep. 51:16-23, 52:13-18.) Therefore, Dr. Bobek’s testimony on this point is uncorroborated.

Defendants argue that his uncorroborated testimony is sufficient to establish that the public display of the presentation actually occurred, citing Thomson S.A. v. Quixote Corp., 166 F.3d 1172 (Fed.Cir.1999). The rule of Thomson — that the testimony of a “disinterested” witness need not be corroborated in certain circumstances — does not, however, apply to the present facts. Not only was Dr. Bobek a paid consultant of Defendants, but his testimony revealed his disappointment and resultant emotional reaction to his not having discovered and invented gemcitabine prior to Lilly’s doing so. (Cf. Hertel 325:20-326:3; Farr Dep. 56:20-57:6.) Further, since deciding Thomson, the Federal Circuit has reiterated that “corroboration is required of any witness whose testimony alone is asserted to invalidate a patent, regardless of his or her level of interest.” Finnigan Corp. v. Int’l Trade Comm’n, 180 F.3d 1354, 1369 (Fed.Cir.1999); see also Adenta GmbH v. OrthoArm, Inc., 501 F.3d 1364, 1371 (Fed.Cir.2007). Accordingly, because the evidence in the record is insufficient to support a finding that the Bobek Slides were presented publicly in the form advanced by Defendants, we conclude that they do not qualify as prior art by virtue of their public presentation.

Assuming arguendo that Dr. Bobek’s uncorroborated testimony established that the presentation was public and thus prior art, the Bobek Slides nonetheless constitute such limited a disclosure as to be entirely inadequate for a showing of anticipation. Regents of Univ. of Cal. v. Howmedica, Inc., 530 F.Supp. 846, 860 (D.N.J.1981), aff'd, 676 F.2d 687 (3d Cir.1982) (“[T]he projection of the slides at the lecture was limited in duration and could not disclose the invention to the extent necessary to enable a person of ordinary skill in the art to make or use the invention.”). Furthermore, Dr. Bobek’s presentations were and are insufficient to anticipate the asserted claims because of their scant content. They do not contain any information about antitumor activity, nor are they capable of enabling a person of skill in the art to synthesize gemcitabine. “In order to anticipate a claimed invention, a prior art reference must enable one of ordinary skill in the art to make the invention without undue experimentation.” Impax Laboratories, Inc. v. Aventis Pharmaceuticals, Inc., 545 F.3d 1312, 1314 (Fed.Cir.2008).

Defendants contend that Dr. Bobek invented gemcitabine prior to Lilly, but the record before the Court clearly shows that Dr. Bobek never, in fact, invented gemcitabine. Dr. Bobek admitted that he never isolated, characterized, or analyzed any product from the reaction that he asserts resulted in gemcitabine. (Bobek 1324:9-23, 1325:11-19, 1358:7-9, 1359:8-9; Radtke 459:12-463:3; PTX 499 at Bobek 202; PTX 508 at 61.) Moreover, Dr. Bobek never demonstrated any utility for gemcitabine, and therefore never actually reduced the compound he conceptualized in his slides to a practical invention. Dr. Bobek did not disclose his alleged invention of gemcitabine in a patent application, describe it in a published document, or use it publicly, and he eventually abandoned his work on the compound. For these reasons, Dr. Bobek’s work cannot be treated as prior art; it cannot support Defendants’ theory of prior invention; and it falls far short of anticipating the asserted claims. See Mahurkar v. C.R. Bard, Inc., 79 F.3d 1572, 1577 (Fed.Cir.1996); Lutzker v. Plet, 843 F.2d 1364, 1366-67 (Fed.Cir.1988).

Defendants also contend that Lilly was able to invent gemcitabine only because of information garnered from Dr. Bobek’s work. They assert that Dr. Bobek communicated information relating to gemcitabine, in particular its capacity to function as an anticancer agent, to Dr. Grindey, a named inventor of the '826 patent, while both were employed at Roswell Park. A claim of derivation “requires a showing of both (1) prior conception of the invention by another and (2) communication of that conception to the patentee that is ‘sufficient to enable [him] to construct and successfully operate the invention.’ ” Int’l Rectifier Corp. v. IXYS Corp., 361 F.3d 1363, 1376 (Fed.Cir.2004).

For all of the reasons previously discussed, it is abundantly clear that Dr. Bobek did not conceive of gemcitabine and its utility prior to Lilly’s having done so. “Conception requires both the idea of the invention’s structure and possession of an operative method of making it.” Amgen, Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 1206 (Fed.Cir.1991). Although Dr. Bobek’s slides contained a depiction of the structure of gemcitabine, he never devised a successful method for synthesizing the compound. Accordingly, Defendants have failed to prove by clear and convincing evidence that Lilly derived the invention of the '826 patent from Dr. Bobek’s work.

Defendants also failed at trial to prove the “communication” required for a derivation claim. The only evidence Defendants offered to support this contention was Dr. Bobek’s uncorroborated testimony that he communicated his idea for using gemcitabine as an anticancer agent to Dr. Grindey. (Bobek 1311:11-1312:14.) In addition to being uncorroborated, Dr. Bobek’s testimony is unconvincing because of its intrinsic inconsistency. At his deposition, Dr. Bobek alleged that Dr. Grindey had reviewed his 1975 grant proposal related to gemcitabine when Dr. Grindey acted as a grant reviewer for the American Cancer Society. (Bobek 1398:8-1399:5.) By contrast, when the veracity of this assertion was challenged at trial, Dr. Bobek testified that Dr. Grindey reviewed the grant as an in vivo tester at Roswell Park. Given the inconsistencies inherent in this testimony and the evidence in the record clearly refuting Dr. Bobek’s assertion that he communicated his ideas to Dr. Grindey, Defendants also cannot establish the second element of their derivation claim.

The derivation claim advanced by Defendants, which rests entirely on the uncorroborated testimony of Dr. Bobek, is reminiscent of an early observation by the Supreme Court:

The very fact, which courts as well as the public have not failed to recognize, that almost every important patent ... has been attacked by the testimony of witnesses who imagined they had made similar discoveries long before the patentee had claimed to have invented his device, has tended to throw a certain amount of discredit upon all that class of evidence, and to demand that it be subjected to the closest scrutiny.

Barbed Wire Patent Case, 143 U.S. 275, 284-85, 12 S.Ct. 443, 36 L.Ed. 154 (1892). Dr. Bobek’s testimony regarding his earlier conception of gemcitabine and its anticancer utility simply cannot withstand this sort of heightened scrutiny.

For all of these reasons, we hold that Defendants have failed to prove by clear and convincing evidence that Dr. Bobek’s work anticipated that patents at issue in this