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Yeda Research and Development Co. Ltd. v. Imclone Systems Inc.

September 18, 2006


The opinion of the court was delivered by: Naomi Reice Buchwald, United States District Judge


Plaintiff Yeda Research and Development Company, Ltd. ("Yeda") brought this action against defendants ImClone Systems Inc. ("ImClone") and Aventis Pharmaceuticals, Inc. ("Aventis") alleging improper inventorship of United States Patent No. 6,217,866 (the "'866 patent"). Yeda is affiliated with the Weizmann Institute of Science (the "Weizmann"), a world-renowned academic institute located in Rehobot, Israel, and exists to protect the intellectual property created at the Weizmann. Yeda is the assignee of the legal interests of three scientists employed at the Weizmann during the mid- to late- 1980s, namely Professor Michael Sela ("Sela"), Dr. Esther Aboud-Pirak ("Pirak"), and Dr. Esther Hurwitz ("Hurwitz") (collectively, the "Weizmann scientists"), who maintain that they are the true inventors of the '866 patent. The legal rights of the scientists actually named on the patent, Professor Joseph Schlessinger ("Schlessinger"), Dr. Francoise Bellot ("Bellot"), Dr. Richard Kris ("Kris"), and Dr. David Givol ("Givol") (collectively, the "named inventors"), have been assigned to defendants Aventis and ImClone. The named inventors all worked at Meloy Laboratories, Inc. ("Meloy") and its successor corporation, Rorer Biotechnology, Inc. ("Rorer"), both predecessors-in-interest to Aventis, during that same time period. ImClone is the exclusive licensee of the patent at issue.

Yeda filed its complaint on October 28, 2003, seeking joint inventorship of the '866 patent. Subsequently, the Court granted leave for Yeda to amend the complaint to seek a judgment adding the Weizmann scientists to the patent and removing the named inventors. After we denied summary judgment to defendants, see Yeda Research and Develop. Co., Ltd. v. ImClone Sys. Inc., 03 Civ. 8484(NRB), 2005 WL 2923545 (S.D.N.Y. Nov. 3, 2005), the Court held a bench trial to determine inventorship; the trial began on June 5, 2006 and concluded with oral argument on July 19, 2006.*fn1 The opinion that follows constitutes this Court's findings of fact and conclusions of law.


In the mid-1980s, Schlessinger left the Weizmann on a sabbatical, accepting a position at Meloy/Rorer. Soon thereafter, Schlessinger invited Drs. Givol, Kris, and Bellot, all colleagues from the Weizmann, to join him. Under Schlessinger's direction, the named inventors created two monoclonal antibodies*fn2 ("mAbs") for use as research tools. Subsequently, in January 1987, Schlessinger and Hurwitz had a brief discussion at the Weizmann, during which Schlessinger offered to give samples of the antibodies to the Weizmann scientists. Though both Schlessinger and Hurwitz recalled having this conversation, they provided different accounts of it during the trial. While Schlessinger offered a somewhat extended version of the conversation, Hurwitz testified that Schlessinger merely described the antibodies as "good" and did not suggest any intended uses.

The Weizmann scientists performed experiments with the antibodies for the next fourteen months. During that time, they discovered that when one of the two antibodies, known as mAb 108, was administered in vivo in a mixture with chemotherapy drugs, the effect on human tumor cells was synergistic; i.e., the combined effect exceeded the effect of the antibody alone added to the effect of the drug alone. Whether Schlessinger would have anticipated that the Weizmann scientists would conduct a mixture experiment was a matter of dispute during the trial. Schlessinger testified that he "knew" that this mixture experiment would be performed based on his knowledge of Hurwitz's prior work. Hurwitz, however, testified that most of her prior work involved testing conjugates, whereby one substance is chemically attached to another, rather than mixtures, which involve separately administering two substances that are not attached. In fact, Hurwitz testified that the Weizmann scientists only decided to conduct the mixture experiment more than a year after the research began, and only then as a result of Hurwitz's independent judgment that such an experiment might yield promising results.

Soon after the discovery of the synergistic effect, Drs. Sela and Pirak informed Schlessinger in March 1998 of their discovery of this synergy while Schlessinger was visiting the Weizmann to deliver a lecture. About a month later, Pirak sent Schlessinger a draft of a paper she was preparing summarizing the results of the experiments the Weizmann scientists' had conducted with mAb 108. Almost immediately thereafter, Meloy/Rorer began pursuing patent protection for both the antibodies themselves and for the method of administering them with chemotherapy drugs that had been developed by the Weizmann scientists. Only the scientists employed by Meloy/Rorer were included as inventors on its patent applications. The Weizmann scientists were not included as inventors, even though they had conducted all of the experiments relating to the mixture of mAb 108 and chemotherapy drugs. Moreover, Meloy/Rorer and later, ImClone, directly copied the text and figures from the paper drafted by the Weizmann scientists into their patent applications.

On September 1, 1988, Meloy/Rorer filed the first application in the chain of applications that eventually led to the issuance of the '866 patent. During the patent application process, the Patent and Trademark Office (the "Patent Office" or the "PTO") repeatedly rejected claims drawn solely to the monoclonal antibodies themselves, finding them insufficiently distinct from prior art. The PTO also raised several questions about the fact that the patent application seemed to be drawn directly from work done by the Weizmann scientists. Defendants overcame this objection by suggesting that they had entirely conceived of the research conducted by the Weizmann scientists, who had simply followed their directions as to what experiments to perform. Eventually, in April 2001, the '866 patent issued.*fn3

The patent only included those claims drawn to the method of administering an antibody in a mixture with chemotherapy drugs; the PTO did not permit the antibodies themselves to be patented. In fact, the antibody that ImClone sells under the name Erbitux is not one of the antibodies created by the named inventors, but rather another member of the class of antibodies specified in the patent. This antibody was created before the named inventors created mAb 108.

Significantly, defendants did not inform either Yeda or the Weizmann scientists of their patent applications based on the work performed at the Weizmann. Yeda learned that defendants were seeking a patent in January 2000, twelve years after the initial patent application, and fourteen months before the '866 patent issued. Immediately after the patent issued, Yeda engaged in discussions with defendants in an effort to have the Weizmann scientists added to the patent. While these discussions were ongoing, ImClone obtained FDA approval for the treatment of certain types of human cancer, permitting it to distribute Erbitux under the protection of the '866 patent. As of the date of trial, ImClone had received about $900 million in revenues under a distribution agreement with Bristol Myers Squibb.

The two primary issues now before this Court are: first, which scientists invented the subject matter of the '866 patent; and second, whether the affirmative defense of laches is available to defendants. In analyzing the inventorship issue, we focus on several subsidiary issues: (1) whether Schlessinger communicated a research protocol to the Weizmann scientists before they began their research; (2) to what extent Schlessinger conceived of the invention with the requisite definiteness; (3) to what extent the Weizmann scientists' prior research was predictive of the experiments relevant to this case; (4) whether the creation of the antibodies is sufficient in and of itself to entitle the named inventors to remain on the patent; (5) whether the named inventors and the Weizmann scientists determined that mAb 108 inhibits the binding of epidermal growth factor to its receptor; and (6) whether there exists any evidence of joint inventorship between the named inventors and the Weizmann scientists. In connection with the laches defense, we focus on three issues: (1) to what extent the Weizmann scientists had knowledge that defendants were pursuing a patent; (2) whether the defendants acted deliberately in failing to disclose their actions; and (3) whether plaintiff was otherwise obligated to file its own patent application.

Having considered all of the evidence, we now find that the Weizmann scientists are entitled to sole inventorship of the '866 patent. In so holding, we make the following factual determinations, all of which are discussed at length infra: (1) Schlessinger did not give Hurwitz specific information regarding the properties of the antibodies or any intended uses; (2) Schlessinger did not specifically contemplate that the Weizmann scientists would perform the mixture experiment that forms the basis for the '866 patent; (3) the named inventors' creation of the antibodies used by the Weizmann scientists does not entitle them to inventorship; (4) the Weizmann scientists solely conceived of the idea embodied in the '866 patent; and (5) in light of the defendants' unclean hands, i.e., their copying from the Weizmann scientists' draft paper and their efforts to prevent Yeda from discovering defendants' patent applications, Yeda did not unreasonably delay asserting its rights relative to the '866 patent. Each of these conclusions is premised both on credibility determinations and the fact that while the plaintiff's version of events is strongly corroborated by contemporaneous documents, defendants' version is not.



As noted earlier, plaintiff Yeda is an independent entity affiliated with the Weizmann that exists in order to protect the intellectual property rights of the Weizmann, which Yeda accomplishes by, inter alia, seeking patents and licensing agreements. See David Mirelman ("Mirelman") Witness Statement ("WS") at ¶¶ 7-8.*fn4 As relevant here, Yeda owns any rights in the '866 patent claimed by the Weizmann scientists. See Dr. Haim Garty ("Garty") WS at ¶ 29. Under the terms of a team agreement signed in August 2002, the Weizmann scientists are entitled to forty percent of any royalties Yeda receives if it succeeds in this lawsuit. See id. at ¶ 31.

Also, as mentioned supra, defendant Aventis is the successor in interest to Meloy Laboratories, Inc. ("Meloy"), which was acquired by the Rorer Group in 1986 and became Rorer Biotechnology, Inc. ("Rorer"). See Dr. Alain Schreiber ("Schreiber") WS at ¶ 1. The named inventors of the '866 patent, Drs. Schlessinger, Bellot, Givol, and Kris,*fn5 were all employed at Meloy/Rorer during the period relevant to this case. See generally Schlessinger WS; Bellot WS; Givol WS; Kris WS. At the time that the named inventors arrived at Meloy in 1985, Meloy's biotechnology center was deeply involved in cancer research and product development. However, when the Rorer Group took over Meloy shortly thereafter, its focus shifted away from cancer research and toward developing the Rorer Group's existing products, especially Maalox, and toward research in, inter alia, cardiovascular, respiratory, and gastrointestinal therapies. See Schlessinger WS at ¶ 12. In 1990, the Rorer Group merged with the health care arm of Rhone-Poulenc, forming Rhone-Poulenc Rorer, Inc. ("RPR"). Nine years later, RPR merged with Hoechst-Marion-Roussel to form Aventis. In 2004, Aventis was acquired by Sanofi-Synthelabo, forming the sanofi-aventis Group. Defendant Aventis Pharmaceuticals is a wholly-owned subsidiary of the sanofi-aventis Group. See Schlessinger WS at ¶ 13.

Defendant ImClone is a corporation organized under the laws of Delaware that maintains its principal place of business in New York. Stipulated Facts ("SF") at ¶ 3. ImClone is the exclusive licensee of the '866 Patent pursuant to an agreement with RPR signed in June 1994. As part of that agreement, ImClone agreed to take over the prosecution of RPR's pending patent applications relating to the subject matter of this case, which eventually culminated in the '866 patent. See Thomas C. Gallagher ("Gallagher") WS at ¶¶ 4-5. Pursuant to the protection offered by the '866 patent, ImClone now sells Erbitux, a drug approved by the Food and Drug Administration ("FDA") for use in cancer therapy. See Ronald A. Martell ("Martell") WS at ¶ 3. Currently, Erbitux is ImClone's only commercially available drug. See id. at ¶ 16.


Although many of the underlying facts in this case are not disputed, the Court was nonetheless compelled to make many findings of fact that hinge in large part on credibility findings. Having carefully considered all of the testimony and evidence, we have concluded that the plaintiff's witnesses were, as a whole, far more credible than the defendant's witnesses.*fn6

We emphasize that our credibility findings are in no way intended to impugn the professional reputations of the extraordinary scientists who testified at trial.*fn7 We also note that, although the Weizmann scientists have a financial interest in the outcome of this case, while the named inventors do not,*fn8 all the scientists who claim inventorship of the '866 patent seemed entirely motivated by their desire to be recognized for their professional accomplishments, rather than by any financial interest.*fn9 Our bases for finding certain witnesses credible and others not are discussed throughout the opinion.

A. Terms and Definitions

1. Antibodies

Before proceeding with a detailed discussion of the events underlying this lawsuit, a brief summary of the relevant terms and definitions is appropriate.*fn10 First, an antibody is a "protein produced by the immune system of humans and other higher animals in response to the introduction into the body of a foreign antigen, which is almost always a protein." Expert Report of Dr. Marc E. Lippmann, M.D. ("Lippmann Report") at 4. Antibodies consist of four polypeptides, or chains of amino acids: two long polypeptides (the "heavy chain") form a Y-shape, while two short polypeptides (the "light chain") attach to the heavy chain, forming the structure depicted below. See id. Each branch of the "Y" contains a specific site where the antibody recognizes its corresponding antigen. These antigen recognition sites vary from antibody to antibody, and are thus referred to as the "variable region." See id. On the other hand, the base of the "Y" is the same for each class of antibodies and is referred to as the "constant region." See id.

The blood of humans and other animals "contains innumerous antibodies circulating, each recognizing the various antigens that have invaded the body." Lippmann Report at 6. In order to create antibodies for use in their research, scientists inject immunized animals with an antigen, triggering the animal to produce antibodies against the antigen. See id. Scientists then draw the animal's antibody-rich blood, which is referred to as antiserum. See id. The antibodies harvested in this manner are referred to as polyclonal antibodies. See id. at 6-7. Polyclonal antibodies have long been considered valuable research tools, limited by two factors: first, antisera contain antibodies specific to the injected antigen as well as antibodies that are not antigen-specific;*fn11 second, polyclonal antibodies cannot be reproduced indefinitely, as antisera must be drawn from the blood of a live animal. See id. at 7.

The limitations of polyclonal antibodies were overcome in 1975, when Georges Köhler ("Köhler") and Cesar Milstein ("Milstein") developed technology for creating antibodies that are both antigen-specific and can be indefinitely reproduced, a discovery for which they were awarded the Nobel Prize in Medicine in 1984. See Lippmann Report at 7. These antibodies, known as monoclonal antibodies ("mAbs" or "monoclonals"), are created by immunizing a "nude" mouse*fn12 with a particular antigen, against which the mouse will generate antibodies. See id. at 8. The researcher then collects the B lymphocytes, which are the immune cells that produce antibodies, from the mouse's spleen. See id. In order to immortalize*fn13 these immune cells, the researcher fuses them with immortalized lymphocyte tumor cells. See id. The resultant cells, known as hybridomas, will produce a single type of antibody that will recognize only the antigen of choice and can be reproduced indefinitely. See id. The Köhler/Milstein method of creating monoclonal antibodies is discussed further infra.

2. EGF and EGFR

Epidermal growth factor ("EGF") is "a small protein which functions to stimulate the growth and maturation of various organs in the body," including the lungs and kidneys. Lippmann Report at 5. The cells forming these various organs produce and excrete EGF into the body, where it binds to the epidermal growth factor receptors ("EGFR") found on the surfaces of some types of cells. See id. at 6. EGFR is a protein that spans the cell membrane, meaning that it has both an intracellular and an extracellular domain, as well as a portion that actually crosses the cell membrane. When EGF binds to EGFR, the EGFR's structure changes, inducing a series of signals to be sent to the cell nucleus that result in the cell proliferating. See id. at 6. This signaling mechanism is regulated in normal, healthy cells, such that the signaling will cease when the cell has sufficiently proliferated. However, in cancer cells, this mechanism is often damaged, resulting in uncontrolled cell growth. See id.

B. The Named Inventors

Before analyzing the putative contributions of the scientists claiming inventorship, we review their backgrounds for two purposes: first, to determine the extent to which the subject matter of the '866 patent seems aligned with their prior research; and second, in light of Schlessinger's suggestion that he "knew" the Weizmann scientists' research protocol, we review some of their prior published works in order to evaluate whether Schlessinger could have predicted the course of their experimentation. We begin by reviewing the professional accomplishments and interests of the named inventors.

Dr. Schlessinger received a Bachelors Degree in Chemistry and Physics and a Masters Degree in Chemistry from Hebrew University in Jerusalem. Schlessinger WS at ¶ 2. In 1974, he obtained his Ph.D. from the Weizmann after completing a thesis entitled "Study of Chemical and Biological Systems by Circular Polarization of Fluorescence." Id. at ¶ 3. After several years working at a variety of institutions, including Cornell University and the National Cancer Institute ("NCI") of the United States National Institutes of Health ("NIH"), see id. at ¶¶ 4, 11, Schlessinger returned to the Weizmann in 1978, eventually becoming a professor in the Department of Chemical Immunology. Id. at ¶ 12. Schlessinger's work at the Weizmann focused on EGF and EGFR, and the mechanisms by which EGF signals various cell responses. Id. at 27. Among the honors Schlessinger has received during his career is the Dan David Prize.*fn14 Schlessinger has also been elected to, inter alia, the American Academy of Arts and Sciences, the National Academy of Sciences, and the Institute of Medicine of the National Academies. Schlessinger WS at ¶ 22.

In late September 1985, while still employed at the Weizmann, Schlessinger accepted a job offer to serve as a Research Director at Meloy. See Trial Tr. ("Tr.") 572, line 22 to 573, line 4; see also PTX020.*fn15 By the end of November 1985, Schlessinger's visa permitting him to work at Meloy had been approved, and he had begun working at Meloy. See Tr. 586, line 20 to 587, line 5; see also PTX023. However, Schlessinger did not apply for a sabbatical from the Weizmann until January 1986, and his application was not approved until March 4, 1986. See Tr. 575, lines 3-7. Schlessinger acknowledges that until March 4, 1986, "at least as far as the Weizmann was concerned, [he was] still on the books as a full-time Professor who had not gone on sabbatical . . . ." Tr. 574, line 24 to 575, line 2. Moreover, Schlessinger acknowledges that under his agreement with the Weizmann in place at the time, "there was absolutely no doubt that if [he] made an invention" during the period from November 1985 through March 4, 1986, "it would belong to the Weizmann." Tr. 576, lines 15-18.

Among Schlessinger's responsibilities as Research Director at Meloy/Rorer was hiring staff. See Schlessinger WS at ¶ 36. As relevant here, Schlessinger initially hired two colleagues from the Weizmann, Drs. Kris and Bellot. See id. Schlessinger subsequently hired Dr. Givol, another Weizmann scientist, who established a separate laboratory within Schlessinger's department at Meloy/Rorer, as did Kris. See id.; see also Givol WS at ¶ 15. Dr. Kris holds a Ph.D. from the University of Florida in immunology/medical microbiology; his thesis involved the role of antibodies in fighting influenza. See Kris WS at ¶ 2. Dr. Givol received his Ph.D. from the Weizmann in 1964, having completed a thesis entitled "Studies of Structure and Activity of Antibodies to Natural and Synthetic Antigens." See Givol WS at ¶ 2. Dr. Bellot earned a Ph.D. from the Université de Provence in 1984 for a thesis about monitoring the cellular proliferation of colon cancer cells. See Bellot WS at ¶¶ 3-4.

After leaving Rorer in 1990, Schlessinger accepted an appointment at New York University, where he subsequently became Chairman of the Department of Pharmacology. See Schlessinger WS at ¶ 14. Subsequently, Schlessinger became Chairman of the Department of Pharmacology at the Yale University School of Medicine. See id. Since his time at Rorer, Schlessinger has also co-founded two biotechnology companies, SUGEN, Inc. ("SUGEN") and Plexxikon Inc. ("Plexxikon"), both of which are involved in developing anti-cancer drugs. See id. at ¶¶ 15-18.

1. Prior Research of the Named Inventors

According to Scientist magazine, Dr. Schlessinger's publications are among the most-cited papers in the world. See Schlessinger WS at ¶ 20; DTX930. Schlessinger has a long history of researching human cells and, particularly, cell surface receptors. See Schlessinger WS at ¶ 18. In 1978, while at the Weizmann Institute, Schlessinger demonstrated that EGF controls EGFR signaling by what he terms "control receptor dimerization." Schlessinger WS at ¶ 19. Dimerization describes the manner in which two EGF receptors move laterally on the cell surface such that they both attach to the same EGF molecule, initiating the cell signaling process. See id.; see also PTX240 (DVD provided by Dr. Lippmann, demonstrating dimerization). In 1984, Schlessinger and two other scientists, Michael Waterfield and Axel Ullrich, discovered that a virus causing leukemia in chickens contained v-erb-B, a cancer gene. Schlessinger WS at ¶ 20. Moreover, they discovered a "close similarity between epidermal growth factor receptor and the protein sequences encoded by the v-erb-B cancer gene." Id. This discovery was published in Nature, a preeminent scientific journal. See id.

Shortly after this discovery, Schlessinger, along with Kris and others, demonstrated that EGFR is over-expressed in malignant brain tumors. See id. at ¶ 21. This discovery indicated that the EGF-EGFR signaling mechanism might play a role in human cancer. See id.

While conducting his post-doctoral research at the NIH in 1964-65, Givol isolated and characterized an enzyme known as Protein Disulphide Isomerase, which, inter alia, "protects brain cells from misfolded proteins and guards them against Alzheimer's and Parkinson's disease." Givol WS at ¶ 9. Subsequently, while at the Weizmann in 1972-73, Givol and other researchers "discovered the smallest active antibody fragment that retains full binding capacity of the original antibody," which he named the "Fragment variable" ("Fv"). Id. at ¶ 10. Givol's team determined that the Fv is the "variable region of the antibody that differs among antibodies and determines the antigen to which the antibody binds." Id. Moreover, Givol and his team found "that by creating an antibody with only the Fv portion, it was less likely that the body's own immune system would rebel against its introduction into the system." Id. Givol describes the discovery and characterization of the Fv as "one of the most known contributions of the Weizmann Institute to immunology." Id. About ten years after this discovery, in 1982 or 1983, Givol and other scientists at the Weizmann cloned and sequenced a gene known as "tumor protein 53" ("tp53"). See id. at ¶ 11. Givol and his fellow researchers determined that tp53 "regulates the cell cycle and controls the mechanism for apoptosis (a mechanism of programmed cell death)." Id. The scientists' work with tp53 "paved the way to study the molecular genetics of cancer." Id. Thus, Givol, like Schlessinger, has a long history of research at the molecular level relating to "basic biological problems," see Givol WS at ¶ 12, some of which eventually has proven to have therapeutic applications. See id. at ¶ 11 (describing how tp53 is now being developed for clinical use by biotechnology companies). Givol explains that Schlessinger invited him to come to Meloy/Rorer because he "had experience in researching monoclonal antibodies, and in molecular biology, genetic engineering, DNA sequencing and Fv fragments." Id. at ¶ 15.

Kris worked a great deal with EGFR while he was a postdoctoral fellow in Schlessinger's laboratory, beginning in 1983, in particular working with polyclonal antibodies against the EGF receptor.*fn16 Specifically, Kris was involved with Schlessinger's research relating to the cell signaling function of the v-erb-B protein, discussed supra. See Kris WS at ¶ 10. In February 1985, Schlessinger, Kris, and others published an article in Biotechnology, a scientific journal, in which they discussed the potential role of the EGF-EGFR signaling mechanism in cancer, observing that "[r]ecent studies indicate that oncogenes are linked to growth factors and to growth factor receptors, suggesting that these molecules participate in the proliferation of normal and neoplastic cells." Kris WS at ¶ 12; DTX915 at 135.

Dr. Bellot joined Schlessinger's laboratory at the Weizmann in 1985 after working at Immunotech, a French company where Bellot "made monoclonal antibodies against various proteins . . . ." Bellot WS at ¶¶ 5, 7. Bellot sought to work with Schlessinger after "learn[ing] of his work with growth factors from the published literature" while preparing her thesis. Id. at ¶ 6. Because Bellot was working at a private company before joining the Weizmann, and very soon thereafter left to join Schlessinger at Meloy/Rorer, she does not have as extensive a list of published research papers as her colleagues, though the record clearly reflects her skill in producing monoclonal antibodies according to the Köhler/Milstein method.

C. The Weizmann Scientists

Professor Sela received his Ph.D. from the Hebrew University in 1954 for research he conducted at the Weizmann's Department of Biophysics. See Sela WS at ¶ 4. Currently, Sela is the Institute Professor of Immunology at the Weizmann, only the second person to be given the title of Institute Professor.*fn17

See id. at ¶ 5. From 1975 to 1985, Sela served as the President of the Weizmann, during which time he was elected to be a Foreign Associate of the National Academy of Sciences. See id. at ¶¶ 7, 10. Sela's research throughout his career has focused on therapies for cancer and Multiple Sclerosis ("MS"). See id. at ¶ 14. Sela, along with collaborators, invented Copaxone, a drug that helps prevent relapses and new brain lesion development in about 100,000 American MS patients. See id. at ¶ 15.

Hurwitz retired from the Department of Chemical Immunology at the Weizmann in July 1999. See Hurwitz WS at ¶ 1. Hurwitz began working at the Weizmann in 1963 under Dr. Sela, and earned her Ph.D. from the Weizmann in 1974. See id. at ¶ 4. After spending a year engaged in post-doctoral research at the NIH, Hurwitz returned to the Weizmann, where she continued to work with Sela for the remainder of her career. See id. at ¶¶ 4-5. From 1975 until her retirement, Hurwitz held the title of "Engineer," placing her in charge of certain specialized technical work in Sela's laboratory. See id. at ¶ 5. Her position also enabled her to perform some independent research. See id. at ¶ 6.

Pirak obtained her Ph.D. in biochemistry and cancer sciences in 1984 from the Universite Catholique de Louvain la Neuve in Belgium, where she carried out research for Professor Christian de Dube, a Nobel Prize winner in Medicine and Physiology. See Pirak WS at ¶¶ 5-6. As part of the research for her thesis, Pirak applied the Köhler/Milstein method for creating monoclonal antibodies. See id. at ¶ 19. From 1984 to 1992, Pirak served as a research scientist at the Weizmann. See id. at ¶ 3. She currently serves as Vice President of Technologies at Meytav Technological Incubator Ltd., an Israeli biotechnology company. See id. at ¶ 1.

1. Prior Research of the Weizmann Scientists

Professor Sela has spent most of the past fifty years at the Weizmann, where he has focused a great deal of his research on targeting cancer cells with anti-cancer drugs. See Sela WS at ¶¶ 6, 17-19. In the 1970s, Sela and other scientists at the Weizmann pioneered the "guided missile" approach to cancer therapy, whereby researchers seek to deliver anti-cancer drugs to cancer cells while minimizing harm to noncancerous cells. See id. at ¶ 17. This "guided missile" approach is driven by the fact that anti-cancer drugs are generally toxic both to cancerous and noncancerous cells, causing the harmful side effects of chemotherapy. See id. at ¶ 18. Sela's laboratory thus sought ways to target cancer cells by conjugating, or chemically attaching, anti-cancer drugs to substances that would seek out and deliver the drugs only to cancer cells. See id. at ¶ 19. Sela's extensive research into the targeting of cancer cells is reflected in the list of published papers attached to his curriculum vitae. See generally PTX169; see especially DTX521, DTX243, PTX172, PTX175.

As mentioned supra, Pirak's thesis involved preparing and purifying monoclonal antibodies. See Pirak WS at ¶ 18. Her specific objective was to bind anti-cancer drugs "through a suitable linkage to specific antibodies [that] are capable of killing selectively breast cancer cells." Id. For her thesis research, Pirak and a colleague prepared conjugates of monoclonal antibodies and daunomycin and doxorubicin.*fn18 See id. at ¶ 20. Pirak's thesis also discussed using membrane receptors, including EGFR, as sites through which anti-cancer drugs could be delivered to tumor cells. See id. at ¶ 22. Moreover, in order to obtain her Ph.D., Pirak was required to submit a theoretical research project as part of an "annex thesis," which involved giving a lecture in addition to submitting a paper. See id. at ¶ 23. Pirak lectured on oncogenes, including ErbB 2, which is structurally related to EGFR. See id. As Pirak explains, "[t]hrough this work, I became even more familiar with the role that EGF and EGFreceptors had in cancer." Id. at ¶ 23. In 1984, shortly after presenting her thesis, Pirak was invited by Sela to join his laboratory at the Weizmann as a Research Fellow. See id. at ¶ 25.

Before retiring in 1999, Hurwitz spent several decades in Sela's laboratory at the Weizmann involved in research in the fields of immunochemistry and immunotherapy; in particular, she worked on a large number of conjugate and targeting studies related to Sela's "guided missile" approach to treating disease. See Hurwitz WS at ¶¶ 4-6, 11-12. Hurwitz explains that she and Sela hypothesized "that antibodies which could either recognize cancer cells specifically or at a higher affinity than normal cells could be used to target anti-cancer drugs directly to such cells. We were therefore looking for an effective combination of an anti-cancer drug with a carrier that would have strong affinity for cancerous cells." Id. at ¶ 14.

In 1975, Hurwitz co-authored a paper with Sela and others entitled "The Specific Cytotoxic Effects of Daunomycin Conjugated to Antitumor Antibodies." See DTX521. This paper described a research project in which Sela's laboratory employed a mixture of polyclonal antibodies and the free drug as a control to the titular experiment. As discussed infra, it is significant that Sela's laboratory had not yet begun using polymer bridges in creating their conjugates. See id.; see also Hurwitz WS at ¶ 19. Moreover, the mixture tested in this experiment did not exhibit a cytotoxic effect, let alone the synergy*fn19 that would later be observed in the experiments performed with mAb 108, one of the two monoclonal antibodies Schlessinger provided to the Weizmann scientists. See DTX521; see also Hurwitz WS at ¶ 19. Three years later, Hurwitz, Sela, and others published a paper in the International Journal of Cancer in which a mixture of an anti-cancer drug and a polyclonal antibody was used as a control to an experiment focusing on the use of conjugates that were not bound by polymer bridges. See PTX172. In this case, however, the results from the mixture experiments did indicate a potential therapeutic effect. See Hurwitz WS at ¶ 20; PTX172.

Subsequently, in 1982, Hurwitz and Sela collaborated with scientists from the Hokkaido University School of Medicine (the "Hokkaido") in Japan on research that eventually led to the publication of a paper entitled "Effect of a conjugate of daunomycin and antibodies to rat α-fetoprotein on the growth of α-fetoprotein-producing tumor cells." See DTX722. Here, Hurwitz prepared conjugates of polyclonal antibodies at the Weizmann, using a polymer bridge to load daunomycin onto the antibodies. See id.; see also Hurwitz WS at ¶ 21. However, Hurwitz did not participate in the actual in vivo experiments described in the paper, as they were conducted at the Hokkaido. See Hurwitz WS at ¶ 21. This is the only example of a published paper on which Hurwitz was a co-author where a mixture of free drug and antibody was used as a control to an experiment testing a conjugate of drug and antibody bound by a polymer bridge.*fn20 As noted earlier, Hurwitz did not perform the mixture experiments and the antibodies used were polyclonal, rather than monoclonal. See id.

Hurwitz also published a paper in 1986, entitled "A Synergistic Effect between Anti-Idiotype Antibodies and Anti-neoplastic Drugs in the Therapy of a Murine B-cell Tumor," in collaboration with Professor J. Haimovich ("Haimovich") of Tel Aviv University, where all the research for the paper occurred.*fn21

See PTX188. Hurwitz and Haimovich tested mixtures of polyclonal antibodies and anti-cancer drugs for this paper; they did not test any conjugates, using the free drug and the free antibody as their two controls. See id.; see also Hurwitz WS at ¶ 22. Hurwitz and Haimovich observed a synergistic effect when the mixture was administered in vivo.*fn22 See PTX188. This represents the only instance where Hurwitz published a paper reporting an observed synergistic effect in an experiment involving a mixture of an antibody and an anti-cancer drug.

D. The Creation of Monoclonal Antibodies 96 and 108

In the spring of 1986, Schlessinger, Bellot and Kris, who were by then all working at Meloy, began developing monoclonal antibodies directed against EGFR. See Bellot WS at ¶ 15. Although the actual creation of the relevant antibodies occurred in 1986, the genesis of the project occurred in October 1984, when Schlessinger, who was then still at the Weizmann full-time, applied for a grant from the US-Israel Binational Science Foundation ("BSF") in order to, inter alia, generate antibodies "for structural and functional studies of EGF-receptor and Verb-B protein." PTX016-002. Under the heading "Objectives and expected significance of the research," Schlessinger stated that "[t]he major objective of the proposed research is to understand the mechanism of epidermal growth factor (EGF) and its membrane receptor in normal growth and in neoplasma." PTX016-014. Schlessinger's proposal continues by noting that he plans to generate antibodies "as a diagnostic tool to explore structure/function relationships in the EGF-receptor and the Verb-B protein." PTX016-015. Significantly, the grant application does not suggest the use of the antibodies as anything other than a research tool; Schlessinger did not state that he anticipated using the antibodies for cancer therapy. See PTX016.

The work that was done under the BSF grant began at the Weizmann, though Schlessinger is unclear to what extent the same research was continued at Meloy/Rorer. See Tr. 605 lines 24-25 ("People may have moved back and forth and -- but probably -- I would guess that most of it was done at the Weizmann."). In any event, pursuant to the BSF grant, Dr. Etta Livneh ("Livneh") created CH-71 cells, which are Chinese Hamster Ovary cells genetically engineered to express the extracellular portion of human EGFR. See Bellot WS at ¶ 17. These CH-71 cells had been created by Livneh at the Weizmann before Schlessinger and his colleagues went to Meloy/Rorer. See, e.g., Tr. 400 lines 4-5.

Bellot testified that by the mid-1980s, when she created the antibodies relevant to this case in Schlessinger's laboratory at Meloy, the Köhler/Milstein process for producing monoclonal antibodies was a "matter of routine . . . for anybody who was working in the field," although the process was still "laborious." Tr. 417 line 12 to 418 line 1. In order to create the monoclonal antibodies pursuant to the Köhler/Milstein process, Bellot began by immunizing mice with the CH-71 cells obtained from the Weizmann. See Bellot WS at ¶ 17. Schlessinger's laboratory "did not get permission to take" the CH-71 cells from the Weizmann, despite the fact that Schlessinger was on sabbatical from the Weizmann and working at Meloy at the time he procured them. See Tr. 664 line 2.*fn23

Bellot used the CH-71 cells taken from the Weizmann for several reasons: first, because Schlessinger desired to study the EGFR signaling mechanism, CH-71 cells were ideal because they expressed the extracellular domain of EGFR as the antigen;*fn24 second, CH-71 cells express large numbers of EGF receptors on their surface, again making them ideal for developing antibodies against EGFR; and third, CH-71 cells do not contain A-431 carbohydrate chains attached to the extracellular domain, such that the antibodies generated would bind to the protein, rather than the carbohydrate portion, of the EGFR extracellular domain. See Bellot WS at ¶ 17. After Bellot oversaw the immunization of eight mice, four of which were immunized with CH-71 cells and four of which were immunized with CH-71 cell membranes, Bellot performed tests on the sera, i.e., the fluid portion of an animal's blood, of seven of the mice in order to determine whether the sera contained antibodies that bound to EGFR. See id. at ¶ 22.*fn25 Bellot recorded all of the testing relevant to the instant dispute on loose sheets of paper, which were stored in folders, despite a Meloy company policy of recording all scientific data in signed, dated laboratory notebooks. See, e.g., Tr. 403 line 25 to 406 line 12. Bellot's initial testing revealed that all seven mice whose sera she tested were producing antibodies that bound to EGFR. See Bellot WS at ¶ 23.

After running several additional tests on the sera, Bellot removed spleen cells from two of the mice, labeled 3A and 6A, which were then fused to myeloma cells to make hybridomas, which are immortalized cells with the capacity to proliferate indefinitely. See id. at ¶¶ 18-21, 28; Lippmann Report at 8. This last step occurred on August 23, 1986. See id. at ¶ 21. Cells generated from mixtures of spleen cells, myeloma cells, and hybridoma cells were then diluted in Hypoxanthin-Azaserin selection medium, enabling the hybridoma cells, but not the myeloma cells, to grow (the spleen cells die in the culture) before being placed into twenty-four plates, each containing ninety-six wells. See id. at ¶ 29. Each well was then assigned a number, from 1 through 2304, and was observed for cell growth; those wells exhibiting a high level of growth were then tested for monoclonal antibodies that bound to human EGFR. See id. at ¶¶ 30-31. Eventually, Bellot focused on eleven of the wells indicating the presence of such antibodies. See id. at ¶ 36. All of these test results are found in the loose papers Bellot kept in folders, though she acknowledges that she does not recognize the handwriting on some of the documents.*fn26 See id. at ¶ 37.

After determining which of the eleven antibodies were the most promising, Bellot proceeded to make sub-clones of the hybridomas that produced mAbs 42, 80, 96, 108, 123, and 224.*fn27

See id. at ¶¶ 38-39. Subsequently, Bellot asked Meloy technicians in Springfield, Virginia to make ascites*fn28 for several of the sub-clones, including sub-clones of mAbs 96 and 108. See id. at ¶ 41. Bellot then performed further tests to determine whether the mAbs she had created inhibited the growth of cells that are mitogenically stimulated by EGF.*fn29 See id. at ¶ 52. Although the handwriting on the relevant documents is not Bellot's, and, as before, the results appear on loose sheets of paper instead of in signed, dated notebooks, see id. at ¶ 54, plaintiff does not apparently dispute that someone in Schlessinger's laboratory at Meloy performed tests during this time period to determine whether certain of the mAbs Bellot generated inhibited cell growth. Importantly, the type of cells Bellot tested were normal, noncancerous human foreskin fibroblast ("HFF") cells, not cancer cells. Tr. 438 lines 2-11. These tests were conducted with HFF cells despite the fact that Bellot's laboratory at Meloy had "many examples of human tumor cells," Tr. 438 line 13, including KB cancer cells, which are mitogenically stimulated by EGF. See, e.g., Pirak WS at ¶ 61.

One test on the HFF cells, dated December 12, 1986, indicates that sub-clones of mAbs 96 and 108 inhibited the growth of these HFF cells, while three of the other mAbs tested did not. See Bellot WS at ¶ 53; DTX933: RPR 10946-47. Again, these documents are not in Bellot's handwriting despite being found in her folder. Significantly, mAb 96 is an IgM antibody, meaning that it is a pentameter comprised of five antibody units, and is thus considered to be too large to be used for therapeutic purposes. See Pirak WS at ¶ 74; see also Tr. 549 lines 6-11 (Schlessinger testifying that "I never thought that this antibody [mAb 96] will be a candidate [for cancer therapy] because of its size."). MAb 108, however, is an IgG antibody, which contains only a single Y-shaped structure, rather than five such structures linked together. See Tr. 282 lines 14-18. Schlessinger agrees with the plaintiff that only IgG antibodies are useful in cancer therapy, as IgM antibodies "are too bulky and too large, and they are not easily produced and handled."*fn30

Tr. 506 lines 19-20.

All of the tests Schlessinger oversaw at Meloy/Rorer were performed in vitro, i.e., in a controlled laboratory setting in cultures. Dr. Alain Schreiber ("Schreiber"), who worked at Meloy/Rorer during the relevant time period, testified that it would have been difficult to perform in vivo tests, i.e., testing on live animals, at Meloy/Rorer because of the "significant financial resources" that would have to be expended to obtain necessary "bureaucratic approvals." Schreiber WS at ¶ 16. Consequently, Schreiber believed that "it was more expedient to have the [in vivo] tests run in laboratories that were continuously using animal experiments for cancer research," such as the Weizmann.*fn31 Id. at ¶ 16.

1. Additional Characterization of mAbs 96 and 108

One of the issues most hotly disputed among the parties is the extent to which each set of purported inventors had demonstrated that mAb 108 inhibited the binding of EGF to EGFR, which is required by element (iii) of Claim 1 of the patent ("Element (iii)"). The named inventors claim that the experiments conducted by Bellot clearly demonstrate that they had conceived of Element (iii) prior to the research conducted at the Weizmann. Although we need not decide which of the purported inventors conceived of this element, for reasons described infra, we nonetheless discuss the arguments presented by both sides as to why the experiments they conducted did or did not demonstrate that mAb 108 inhibits the binding of EGF to EGFR.

Bellot alleges that tests she performed between late 1986 and early 1987 conclusively demonstrate that she appreciated Element (iii). See Bellot WS at ¶ 43. As noted earlier, the documents describing the relevant experiments she performed were kept on loose sheets of paper in three folders. See DTX931; DTX932; DTX933. Some of these documents do suggest that the named inventors appreciated Element (iii), at least in part. For instance, one document contains a chart entitled "Inhibition of I-M-EGF Binding by Monoclonal Antibodies from R. Kris," which appears to show that mAb 108 inhibited between 50% and 57.3% of EGF's capacity to bind to EGFR on the surface of HFF cells and between 40.2% and 44.6% of binding to EGFR expressed by HFL1 cells, another human cell line that expresses EGFR. See DTX933: RPR10948-10949. This document, whose handwriting Bellot did not recognize, see WS at ¶ 22, also suggests that mAbs 96 and 108 inhibit the binding of EGF to EGFR significantly better than the other monoclonal antibodies tested. See id. These results are summarized in another document found in one of Bellot's folders, dated November 21, 1986, though the handwriting is again not Bellot's.*fn32 See DTX933: RPR10948; Tr. 457 lines 21-22.

Although these loose documents, along with several others, do suggest that the named inventors might have known that mAb 108 inhibits the binding of EGF to EGFR, there is a significant amount of other evidence suggesting that they failed to appreciate Element (iii). First, all of the Meloy/Rorer scientists' testing was done in vitro on noncancerous cells, whereas Claim 1 refers to cancer cells that are mitogenically stimulated by EGF. Second, as recently as the summary judgment stage of this case, Schlessinger submitted a sworn affidavit stating: "I cannot remember whether we [the named inventors] had also performed tests to confirm our belief that the antibodies [96 and 108] inhibited the binding of EGF to the EGF receptor before I approached Dr. Hurwitz. . . . [O]ne of our early, crude tests showed that mAb 108 did not inhibit the binding of EGF to the EGF receptor."*fn33 PTX275 at ¶ 18.

Third, an undated document in Kris' handwriting that was found in one of Bellot's folders states, "Does Ab inhib [sic] EGF effect," beneath which it states "96 -- INHIB" and "108 -- No effect." DTX198: RPR7255. This document seems to indicate that Kris performed an experiment in which he concluded that while mAb 96 does inhibit the binding of EGF to EGFR, mAb 108 does not. At trial, Kris was uncertain what he meant when he wrote the words "no effect," testifying that it was the "first time" he had seen the piece of paper. See Tr. 831 line 1 to 832 line 1.

Fourth, several papers co-authored by the named inventors suggest that the named inventors had concluded that mAb 108 does not inhibit the binding of EGF to EGFR. A May 1987 draft manuscript entitled "Point Mutation at the ATP Binding Site of EGF-Receptor Abolishes Protein Tyrosine-Kinase Activity and Impairs Normal Receptor Cellular Routing," authored by A.M. Honneger,*fn34 Schlessinger, Bellot, and others (the "Honneger paper"), states that "IgG-108 . . . does not interfere with the binding of EGF to the receptor (Bellot et al., in preparation)."*fn35 PTX224-008. Thus, at this point it appears that the named inventors did not believe that mAb 108 inhibited the binding of EGF to its receptor, or at the very least were sufficiently unsure of 108's inhibition effect that they failed to notice what was, in fact, a clear misstatement of its properties. Subsequently, Irit Lax,*fn36 Schlessinger, Bellot, Givol, and others prepared a manuscript entitled "Domain deletion in the extracellular portion of the EGF-Receptor reduces ligand binding and impairs cell surface expression" (the "Lax paper"), which was submitted for internal review at Rorer on October 1, 1987, long after the Weizmann scientists began their research with mAb 108. See PTX059. This paper states, "mAb 108 . . . does not interfere with the binding of EGF to the receptor and mAb-96 . . . blocks the binding of EGF to the receptor (Bellot et al., in preparation)." PTX059-008. Here, the named inventors co-authored a manuscript in which they appear to hold the belief that while mAb 96 does inhibit the binding of EGF to EGFR, mAb 108 does not. All witnesses now agree that both mAb 96 and mAb 108 do in fact inhibit binding of EGF to EGFR.*fn37 Notably, there is no document produced by the named inventors during this same time period where they unequivocally state that mAb 108 does inhibit the binding of EGF to EGFR.

Thus, at the time of the meeting described in Section F, infra, Schlessinger and the members of his laboratory at Meloy/Rorer were aware that mAbs 96 and 108 bound to the protein portion of the extracellular domain of EGFR, inhibited the growth of HFF cells, and that 96 was an IgM antibody, while 108 was an IgG antibody. However, the record does not support the conclusion that they had fully characterized mAb 108's ability to inhibit the binding of EGF to EGFR; rather, they appeared to be confused about the existence of this property.

E. The Weizmann/Yeda Research Project

In early 1986, Sela and Pirak submitted a grant proposal to the Yeda-Fund, an organization affiliated with the Weizmann that subsidizes applied scientific research, i.e., research that might lead to commercially useful products.*fn38 See Pirak WS at ¶ 38. The proposal suggested that EGF could be used as a carrier for anti-cancer drugs by conjugating, or chemically attaching, EGF to known drugs. See PTX029. Sela and Pirak also proposed conjugating anti-cancer drugs to monoclonal antibodies that bind to the EGF receptor in order to compare the effectiveness of EGF and monoclonal antibodies as carriers. See id. As explained in the proposal, "[t]he purpose of the study proposed here is to prepare several conjugates of small anti-neoplastic drugs,*fn39 directly or via bridges, to EGF on one hand, and to monoclonal antibodies against epidermal growth factor receptor on the other, and to compare their efficiencies on EGF receptor-rich tumors in vitro and, ultimately, in vivo." PTX029-003 to 004. Thus, the ...

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