Susannah Markandya and James Love Timeline of Paclitaxel disputes 8/23/2001 Taxol Timeline Early government research on Taxol: Prior to 1977: $234,000 Between 1977 & 1990, ($000): 1977: 36 1978: 73 1979: 114 1980: 140 1981: 477 1982: 250 1983: 446 1984: 851 1985: 760 1986: 1,140 1987: 1,568 1988: 1,483 1989: 1,501 1990: 2,150 Source: Dr. Samuel Broder, September 10, 1991 letter to Congressman Ron Wyden. 1960s. NCI tested a crude extract of the Pacific Yew bark in a large-scale screening program. 1971. MC Wanni, HL Taylor and ME Wall, et. Al, publish "Plant antitumor agents. Vi. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia." J Am Chem Society 93:2325-2327, 1971. 1978. Taxol efficacy against tumors first reported. 1983. NCI files a Notice of Claimed Investigational Exemption for a New Drug (IND) for clinical trials of Taxol. The IND is approved and Phase I clinical trials begin. December 30, 1987. Hauser Chemical becomes contractor to NIH, collecting yew tree bark and manufacturing Taxol. June 29, 1988. According to NCI Director Broder, "The first activity of Taxol in treating refractory ovarian cancer was initially documented in an on-site audit conducted by NCI staff on June 29, 1988 involving Protocol T85-0277, entitled 'A Phase II Trial of Taxol (NCS 125973) in Patients with Advanced Ovarian Malignancies.'" (September 10, 1991 letter to Representative Wyden). November, 1988. Dr. Robert E. Wittes, who heads the Cancer Therapy Evaluation Program at NCI, leaves to become Senior Vice President for Cancer Research at Bristol-Myers Company. August 1, 1989. The National Institutes of Health publish a notice in the U.S. Federal Register, indicating the government was seeking a partner for a Cooperative Research and Development Agreement (CRADA) for the continued development of Taxol. Companies are given until September 15, 1989 to respond. September 15, 1989. This is the cut off date for Taxol/CRADA applications. NCI reports receiving applications from BMS, LyphoMed, Rhone-Poulenc and Unimed. BMS's proposal includes participation by Hauser Chemical, the firm then under contract with NCI to produce Taxol. Some firms that did not respond to the CRADA notice later tell Congressional investigators they "didn't propose because of the 'revolving door' situation." December 11, 1989. Dale Shoemaker from the National Cancer Institute tells firms that Bristol-Myers Squibb has been selected as the CRADA partner for Taxol. June, 1990. Dr. Robert E. Wittes leaves Bristol-Myers Squibb to become Chief of Medicine Branch, NCI. August 1, 1990. Eric K. Rowinsky, Lorraine A. Cazenave and Ross C. Donehower publish "Taxol: A Novel Investigational Antimicrotuble Agent," in the Journal of the National Cancer Institute. The article cites 138 scientific papers related to Taxol, beginning in 1968. January 19, 1991. NIH signs the first Taxol CRADA, which gives BMS the exclusive rights to all US NIH funded research on Taxol. BMS agrees to provide NIH with 17 kilos of Taxol and use its "best efforts" to commercialize Taxol. January 23, 1991. Zola Horovitz signs the Taxol Crada for BMS. June 19, 1991. Edward Madigan, Secretary of Agriculture, signs CRADA between USDA Forest Service and BMS, giving BMS exclusive rights to harvest Pacific Yew tree from Forest Service lands. The Department of the Interior gives a similar CRADA to BMS for Pacific Yew Trees on Bureau Land Management (BLM) lands. July 29, 1991. Hearing: U.S. Congress, Committee on Small Business, Subcommittee on Regulation, Business Opportunities, and Energy, Exclusive Agreements Between Federal Agencies and Bristol-Myers Squibb Co. for Drug Development: Is the Public Interest Protected? Hearings, July 29, 1991, Serial No. 102-35. August 15, 1991. Hauser signs multiyear contract with BMS to produce Taxol. In subsequent amendments to contract Hauser agrees to supply bulk Taxol to BMS for about $.25 milligram. June 2, 1992. The NIH holds a meeting to discuss the Fair Pricing for Taxol, under the terms of the CRADA. Attended by Reid Adler, Dr. Bruce Chabner, Dr. Michael Friedman, Dr. Daniel Ihde, Dr. Dwight Kaufman, Dr. Thomas Mays, Dr. Saul Schepartz and Dr. Dale Shoemaker. Dr. Chabner suggestes a meeting with BMS. A briefing paper on Fair pricing is developed, which suggests BMS price the drug at the median of the monthly wholesale cost of 14 cancer drugs plus Recombinant Human Growth Hormone (HGH). The addition of HGH to the list of comparable drugs increases the media price by 72 percent. The briefing paper says NIH will contact PMA, the FDA and HCFA for feedback. July 2, 1992. The NIH holds a meeting to discuss the fair price of Taxol. NIH participants include Reid Adler, Diane Austin, Dr. Thomas Mays, Dr. Saul Schepartz and Dr. Dale Shoemaker. BMS is represented by Mr. Dan Kiser, from Fox, Bennett & Turner. The group asks BMS to provide a written proposal that would be confidential under Section 1905, trade secret exemption from FOIA. Reid Adler suggests BMS can justify a higher cost based upon higher efficacy of drug. BMS doesn't want to discuss a price, but rather an approach. July 17, 1992. The FDA authorized a "treatment IND"/group C- protocol for the experimental cancer drug taxol for certain patients with advanced metastatic ovarian cancer whose disease has either failed to respond or has progressed after initial response to standard chemotherapy. September 22, 1992. Wilson and Robert Wittes file application for US patent No. 07/950,380, the "parent" application for patent refiled on January 6, 1994 (see below). December 29, 1992. The Food and Drug Administration announce the approval of Taxol for ovarian cancer that has failed to respond to other chemotherapy, or has progressed afterward. This was the "fastest review and approval ever performed on an oncology drug." All data is based upon NIH sponsored research and clinical trials. BMS announces wholesale price of $4.87 per milligram, about 10 times the price NIH was paying its contractors for Taxol, and about 20 times the amount BMS pays Hauser for bulk Taxol. After mark- ups by distributors, doctors and others some patients pay more than $8 per milligram for the drug. At this point, when Taxol becomes a commercial product, BMS's only contribution to the development of Taxol was to (1) provide BMS with 17 kilos of Taxol, which it receives in bulk from Hauser, the former government contractor, for about $5 million, (2) to write up the application for marketing approval, and (3) to seek long term sources for the commercial supply of a blockbuster drug. BMS later will claim that its long term contacts with Hauser and Wyerhauser for *future* supplies of Taxol constitute development expenses. BMS still cannot manufacture Taxol on its own. January 25, 1993. Representative Wyden holds hearings on "Pricing of Drugs Co-Developed by Federal Laboratories and Private Companies," in the Subcommittee on Regulation, Business Opportunities and Technology, Subcommittee on Small Business. Dr. Wyndham H. Wilson and Dr. Robert Wittes Chabner and Reid Adler testify for NIH, Dr. Zola Horovitz testifies for BMS and James Love testifies for the Taxpayer Assets Project. There are 8 other witnesses. Dr. Chabner of NIH mounts a vigorous defense of the BMS price. February 24, 1993. U.S. Senate Aging Committee holds hearings on government funded drugs. Some of the discussion concerns Taxol. Senators ask if compulsory licensing would be solution to pricing abuses. Mr. Nader point out that NAFTA and the new GATT will place a number of restrictions on the use of compulsory licenses. Error! Bookmark not defined. September 30, 1993. BMS's Taxol receives marketing approval in the Netherlands. November 17, 1993. South Africa gives BMS marketing approval for Taxol. January 6, 1994. Wyndham H. Wilson and Dr. Robert Wittes file an application for Patent 5,496,846, a method of treating a patient suffering from breast cancer, which comprises: (a) intravenously infusing Taxol into said patient at a continuous dosage rate of between 17.5 to 35 milligrams of Taxol per square meter of patient surface area per 24 hours to infuse between 70 and 140 milligrams of Taxol per square meter of patient surface area into said patient over a period of 96 hours; and (b) repeating said step (a) in 21 day cycles until remission of said patient's breast cancer is obtained. April 13, 1994. FDA approves a supplemental application for Taxol for treatment of metastatic breast cancer in patients who have not responded to first line chemotherapy or who have relapsed after chemotherapy. May, 1994. Hauser enters into a multi-year Supply Agreement with American Home Products ("AHP") to supply bulk paclitaxel to that company through 2004. January, 1995. F. H. Faulding & Co., Australia's largest pharmaceutical company, launches NaPro paclitaxel in Australia under the name Anzatax. December 10, 1996. The U.S. Patent and Trademark Office issues a patent (no. 5,583,153) for the use of paclitaxel in the treatment of rheumatoid arthritis to the Regents of the University of California, to which Angiotech Pharmaceuticals, a Canadian pharmaceutical company, has an exclusive license agreement. March 25, 1997. FDA designates (paclitaxel) Taxol as Orphan Drug for treatment of AIDS-related Kaposi's sarcoma. (Despite earlier promises by Bristol Myers Squibb that they would not seek Orphan Drug protection for Taxol.) This application beats by six days the IVAX/NPRO filing for FDA marketing approval for its own version of paclitaxel to treat Kaposi's sarcoma. March 31, 1997. Ivax submits a New Drug Application to the U.S. Food and Drug Administration seeking clearance to market Paxene in the U.S. for the treatment of Kaposi's sarcoma. Ivax is the largest manufacturer and distributor of generic pharmaceutical in the UK. NaPro is the Paclitaxel supplier for Ivax. From a press release dated April 1, 1997: Commenting on Ivax's and NaPro's Paxene development strategy, Dr. Samuel Broder, Ivax's Chief Scientific Officer and former Director of the National Cancer Institute of the National Institutes of Health, said: "Although the paclitaxel compound is not patented, under applicable law FDA is prohibited from accepting applications for generic versions of the drug until, at the earliest, December 28, 1997. There are special issues related to paclitaxel that may seriously complicate the approval process for generic versions of paclitaxel. Accordingly, we are not attempting to obtain approval of Paxene as a generic version of paclitaxel, but rather have undertaken extensive clinical studies and have submitted a full New Drug Application for Paxene. Our studies independently demonstrate the activity of Paxene for Kaposi's sarcoma, and support the benefits of dosing schedules which differ from those approved for Taxol. Apparently Dr. Broder is no longer with Ivax. April 2, 1997. The Netherlands give marking approval to Yewtaxen, a generic Paclitaxel product. April 15, 1997. FDA designates Paclitaxel for treatment of AIDS-related Kaposi's sarcoma to Baker Norton Pharmaceuticals, Inc, a subsidiary of IVAX. May, 1997. NaPro, which manufactures paclitaxel, applies to revoke Bristol-Myers Squibb's UK patent. June 2, 1997. BMS, Johnson & Johnson, Eli Lilly and American Home Products meet with US Ambassador to South Africa Sonn regarding the South African Medicines and Related Substance Control Amendment bill. US officials tell BMS that South Africa's decision to permit registration of non-BMS Paclitaxel is violation of TRIPS, and express disappointment at an April 8, 1997 letter from MCC on this topic. June 24, 1997. BMS is issued U.S. Patent and Trademark Office Patent Number 5,641,803, a use patent on the infusion of Taxol. Claims are: 1. A method for reducing hematologic toxicity in a cancer patient undergoing Taxol treatment comprising parenterally administering to said patient an antineoplastically effective amount of about 135-175 mg/m.sup.2 taxol over a period of about three hours. 2. A method for reducing both hematologic toxicity and neurotoxicity in a cancer patient undergoing Taxol treatment comprising parenterally administering to said patient an antineoplastically effective amount of about 135 mg/m.sup.2 taxol over a period of about three hours. 3. The method of claim 2, wherein said patient is suffering from solid tumors or leukemias. 4. A method for reducing hematologic toxicity in patients suffering from ovarian cancer and undergoing Taxol treatment for such cancer comprising parenterally administering an antineoplastically effective amount of about 135-175 mg/m.sup.2 Taxol over a period of about three hours. 5. A method for reducing both hematologic toxicity and neurotoxicity in a patient suffering from ovarian cancer and undergoing Taxol treatment comprising parenterally administering to said patient an antineoplastically effective amount of about 135 mg/.sup.2 taxol over a duration of about three hours. 6. The method of claim 1, wherein said patient is suffering from solid tumors or leukemias. July 10, 1997. A federal grand jury in Philadelphia returns an 11 count indictment, charging Kai-lo Hsu, Chester S. Ho, and Jessica Chou with crimes relating to the attempted theft of trade secrets from Bristol-Myers Squibb. The trade secrets involved the manufacturing processes for Taxol. The indictment charges that Hsu and Chou agreed to make a preliminary payment of $400,000 to a person they believed to be a corrupt Bristol-Myers Squibb employee to obtain the Taxol technology. July 17, 1997. Bristol-Myers Squibb is granted authorization from the Ministry of Health and Welfare in Japan to market Taxol. July 24, 1997. A district court in the Netherlands denies Bristol-Myers Squibb's request for a preliminary injunction to bar Yew Tree Pharmaceuticals from selling Yewtaxan while the patent case is being heard. -According to BMS, "contrary to what has appeared in other media reports, this interim decision of the Dutch Court did not rule on the (European Short infusion) patent's validity; it ruled on whether there would be an injunction before the trial was to be held. July 29, 1997. In a letter to Vice President Al Gore, Ralph Nader, James Love and Rob Weissman claim that "Bristol- Myers Squibb is asking the U.S. government to bring pressure against South Africa, as well as Canada, the Netherlands, Australia, Indonesia, Pakistan, Taiwan, China, Turkey, Argentina, Thailand and other countries, to protect the BMS monopoly on the sale of Taxol." July, 1997. The Dutch Company, Yew Tree Pharmaceuticals (a joint venture of Nycomed and Pharmachemie) receives approval from the Dutch College (the equivalent of the FDA in the U.S.) to market Yewtaxan (paclitaxel) in the Netherlands. July, 1997. Immunex receives the first approval to market a competing paclitaxel product in North America from the Health Protection Branch in Canada. August 1, 1997. In response to inquires regarding recent developments in Netherlands, Bristol-Myers Squibb issues the following statement: "Yew Tree Pharmaceuticals' approved indication violates BMS's European short infusion patent, a method of use patent. Consequently, BMS filed suit against Yew Tree Pharmaceuticals.A full trial will now begin, with a decision to be rendered in approximately 6 to 12 months.To our knowledge, Yew Tree is not currently marketing paclitaxel in the Netherlands..BMS believes Taxol is entitled to the full ten years of data exclusivity (through 2003) provided under Dutch and European law." August 4, 1997. BMS receives approval, with orphan drug designation, for use of their paclitaxel compound in the treatment of Kaposi's sarcoma. Under the Orphan Drug Act, a drug that receives orphan drug designation by the FDA and is the first product to receive FDA marketing approval for its product claim is entitled to a seven-year exclusive marketing period in the United States. August 5, 1997. Bristol-Myers Squibb announces that the U.S. Food and Drug Administration has cleared Taxol Injection for use in second-line treatment of AIDS- related Kaposi's sarcoma August 8, 1997. Immunex files abbreviated new drug application (ANDA) for generic Paclitaxel Injection. The application contains a "Paragraph IV" certification, that U.S. Patents 5,641,803 and 5,670,537 held by Bristol-Myers Squibb and relating to Taxol are invalid and not infringed by the Immunex paclitaxel product. September 15, 1997. Boehringer Ingelheim (Canada) announces that it has acquired the rights to market the cancer drug Paclitaxel in Canada. September 19, 1997. Ivax Corporation presents clinical data regarding Paxene for Kaposi's sarcoma to the FDA's Oncology Drugs Advisory Committee (ODAC). Earlier this year, IVAX and NaPro submitted a New Drug Application to the United States FDA seeking approval to manufacture and market Paxene in the US for the treatment of Aid's related Kaposi's sarcoma. Ivax has applied for exclusivity under the Orphan Drug Act. According to Ira Loss, an analyst with HSBC, "unless they (Ivax) have some way of showing their drug is in some way different, Bristol-Myers has seven years of exclusivity.'' October 2, 1997. Ben Venue receives a new five-year $9.2 million contract from the National Cancer Institute for the development and manufacture of anti-cancer and anti-AIDS compounds. According to the company's press release, "Ben Venue's long history of work with the National Cancer Institute has contributed to the success of many well-known anti-tumor and anti-AIDS products, including: Taxol." October 6, 1997. Comments of the Consumer Project on Technology to the South African Portfolio Committee on Health, on the Medicines and Related Substances Control Amendment Bill, read, "in our view, generic versions of Taxol should be available now to consumers worldwide. Taxol is a drug developed by the U.S. government. BMS's sole role in the development of the drug was to provide the U.S. government with 17 kilos of Taxol, which BMS acquired in bulk from Hauser Chemical . at a cost to BMS of about $5 million. For its very modest support to the NIH's Taxol development effort, BMS has earned billions of dollars.while BMS charges wholesalers nearly $5 per milligram for Taxol, the company was able to acquire the drug in bulk from a contractor for only $.25 per milligram." October 21, 1997. The Subcommittee on Labor, Health and Human Services and Education and Related Agencies, Committee on Appropriations, US Senate, holds hearings on proposal to extend US health registration protection from 5 to 10 years, in exchange for "R&D" royalty of 3 percent paid to NIH and 3 percent R&D reinvestment requirement. The proposal is rejected. Here is the Error! Bookmark not defined.. December 24, 1997. The FDA responds to the Ivax NDA (New Drug Application) which was filed March 31, 1997, determining NBT Paclitaxel was safe and effective in the treatment of Kaposi's sarcoma but could not be marketed for that indication during BMS's period of exclusivity under the Orphan Drug Act. Baker Norton, a subsidiary of Ivax Corp., receives a "tentative" FDA approval to start marketing its paclitaxel for Kaposi's sarcoma after August 4, 2004, following expiration of the BMS orphan drug exclusivity for the indication. December 1997. Bristol-Myers Squibb begin infringement proceedings in a UK court against both NaPro and Baker Norton (an Ivax subsidary) which have undertaken clinical trials in the UK, using paclitaxel at 175 mg/m2 over 3 hours. Napro and Baker Norton argued that the claim was invalid because it amounts to a claim for a method of treatment, (claims to methods of treatment by surgery or therapy are prohibited by the European Patent Convention). In the UK Court, Judge Jacob J decides that the claim did not amount to a claim for a method of treatment, and that the claim should be construed as covering use of Taxol for making a medicamentation for administration under specified doses and times. December, 1997. Boehringer Ingelheim acquires Ben Venue Laboratories. January 8, 1998. NaPro receives Paclitaxel treatment regime patent. The patent has been assigned number 5,696,153 and is entitled "Therapeutic Regimen for Treating Patients." From the press release: BOULDER, COLORADO--NaPro BioTherapeutics, Inc. announced today that it has received a United States Patent relating to a novel method of administering paclitaxel. This patented method involves administrating smaller, more frequent doses of the drug over a shorter infusion time compared to the administration schedule currently approved by the FDA for Bristol-Myers Squibb's paclitaxel product. January 8, 1998. BMS files a complaint in the U.S. District Court in Newark, New Jersey, alleging infringement by Immunex of two U.S. patents held by BMS pertaining to Taxol. February 23, 1998. On behalf of BMS, Paul Rosenthal of Collier, Shannon, Rill & Scott writes Joseph Papovich at the USTR, asking that the US government bring a special 301 Designation against South Africa on the issue of South Africa's 1997 approval of Yewtaxen, a generic Paclitaxel. Rosenthal asserts BMS has spent move than $500 million on the development of Taxol, a number often quoted by reporters but never explained by BMS. The BMS complaint is that South Africa should have "unfair competition" protection on the data BMS used for marketing approval, and no other company should be permitted to "rely upon" those studies. Rosenthal does not indicate that (1) in the USA, "unfair competition" protection expired on December 29, 1997, or (2) that all of the clinical trial data in dispute are from US government (NIH) data. Nor does he mention (3) that BMS's contribution to the NIH trial data was to provide the government with 17 kilos of Paclitaxel, which BMS acquired in bulk from a former government contractor for about $5 million). February, 1998. Due to the delay in receiving marketing approval for NaPro paclitaxel, NaPro decides to reduce its number of employees by 53 percent, close its British Columbia manufacturing facility and suspend construction of its commercial scale manufacturing facility in Boulder, Colorado. March 20, 1998. Ivax terminates its paclitaxel collaboration with NaPro Biotherapeutics. NaPro had been producing paclitaxel for Ivax since 1996. March 26, 1998. BMS files a complaint in the US District Court for the District of New Jersey; Bristol Myers Squibb Company v. Zenith Goldline Pharmaceuticals, alleging patent infringement of tow of its patents relating to Taxol. Zenith Goldline files various counterclaims based on antitrust and unfair competition. April 9, 1998. FDA gives BMS additional approval for Paclitaxel injections, for first-line therapy for the treatment of advanced carcinoma of the ovary in combination with cisplatin. April 22, 1998. In an important "health registration data" case, a Dutch court ruled against a generic form of Taxol. According to a BMS Press release, the District Court in Utrecht, Netherlands, ordered marketing authorization for Yewtaxan, a version of paclitaxel, be revoked on the grounds that the approval relied upon published scientific findings, and did not fulfill all of the requirements of a complete dossier. The court further held that the Dutch authorities did not have any discretion to accept less than the full requirements or to rely upon data filed by Bristol-Myers Squibb with respect to Bristol-Myers Squibb's TAXOL (paclitaxel). BMS's press release said "by upholding the protection of an innovator company's data, the Dutch Court's ruling reportedly mentioned the importance of preserving the law's incentives for conducting medical research." What the BMS press release did not say was that the BMS data was based upon US NIH sponsored clinical trials, and that the government, rather than BMS, was the innovator. May 1, 1998. US Government puts South Africa on Special 301 Watch list for alleged violations of intellectual property rights. A portion of the announcement reads: "Undisclosed data is not adequately protected under South African Law. The need to protect such protection is demonstrated by the approval in South Africa of a generic copy of a medicine which still has undisclosed data protected from competitors' use in many countries." The "generic copy" referred to is Yewtaxen, a generic Paclitaxel product. The USTR's poorly worded prose confuses the issue somewhat. The dispute isn't over "undisclosed data," but rather the "unfair competition" provisions of the TRIPS, Article 39.3. This article reads in part: "Members, when requiring, as a condition of approving the marketing of pharmaceutical or of agricultural chemical products which utilize new chemical entities, the submission of undisclosed test or other data, the origination of which involves a considerable effort, shall protect such data against unfair commercial use. In addition, Members shall protect such data against disclosure, except where necessary to protect the public, or unless steps are taken to ensure that the data are protected against unfair commercial use." The TRIPS says countries have to provide some type of "unfair competition" protection for investments in data needed for pharmaceutical registration, but it doesn't say how this should be done. In the United States, the "unfair competition" protections for Taxol expired on December 29, 1997, or four months before the USTR brings this action against South Africa. June 4, 1998. Bristol-Myers Squibb and Phyton Inc. sign an agreement to commercialize Phyton's proprietary plant cell fermentation technology. Phyton licensed this technology to Bristol-Myers Squibb exclusively in 1995. June 8, 1998. Ivax and Immunex enter a collaborative agreement to bring to market paclitaxel. Under the terms of this agreement, Ivax acquires the Immunex ANDA for paclitaxel injection, giving it the right to buy bulk paclitaxel from Hauser. Ivax also acquires Immunex's inventories of bulk paclitaxel. In addition, Immunex will help IVAX promote the generic paclitaxel product. The FDA subsequently confirms that this ANDA is the first one filed with the agency. This means that Ivax could be entitled to 180 days of exclusivity. According to the August 1998 Ivax letter to shareholders, "marketing of the ANDA product could possibly begin by mid-year 2000." June 9, 1998. Fujisawa Pharmaceutical Co., Ltd. announces that it has invested US $ 10 million into American BioScience, Inc., formally VivRx Pharmaceuticals, Inc., of Santa Monica, CA, USA. June 16, 1998. Cytoclonal Pharmaceuticals sign a license and research agreement with BMS on two technologies relating to the production of paclitaxel. June 30, 1998. BMS receives an NDA 20-262/S-024 for a Taxol indication: in combination with cisplatin, for the first- line treatment of non-small cell lung cancer in patients who are not candidates for potentially curative surgery and/or radiation therapy. July 24, 1998. NaPro BioTherapeutics announces that its marketing and distribution partner in Australia, F.H. Faulding & Co. Ltd., has received a favorable ruling from the Federal Court in Australia in a 1994 action instituted against Bristol-Myers Squibb Company to invalidate certain existing BMS Australian petty patents. The patents in question had been awarded to BMS in 1993 and 1994 and claimed certain methods of administering paclitaxel. In a related matter, the court ruled against BMS in a 1995 counter-suit which claimed that Faulding had infringed these BMS patents." August 18, 1998. SuperGen files an ANDA with the FDA for paclitaxel. August 20, 1998. The Court of Appeal, in the case of Bristol-Meyers Squibb v Baker Norton and Napro upholds Jacob J's order revoking the patent. The patent was titled: "use of Taxol . for manufacturing a medicamentation . for the administration of 135-175 mg/m Taxol over a period of about three hours or less . for treating cancer and simultaneously reducing neutropenia." Taxol had been administered in high doses over a long period and gave rise to an adverse side effects. The Court found that a lecture given before the priority date had pre-published the patent. The lecture left no-one in any doubt that Taxol was worth trying in low doses and over shorter periods as an anti-cancer drug. The reduced neutropenia was an inevitable result of that manner of treatment and was therefore a discovery rather than an invention. Moreover, despite the appearance of the claim in Swiss-style, it was in reality a claim to a method of treatment and, as such, was excluded from patentability. All of the details of administering the drug (along with pre- medication) were matters decided by the doctor. August 24, 1998. Hauser terminates its original agreement with American Cyanamid Company, the terms of which restricted Hauser from supplying companies on a global basis, and announces a new non-exclusive agreement whereby it will supply bulk paclitaxel to Immunex Corporation and its collaborative partner Ivax Corporation. August 25, 1998. NaPro BioTherapeutics announces that it has received a favorable ruling from the United Kingdom Patent Court in its patent proceeding against Bristol-Myers Squibb Company. The court ruled in favor of NaPro on NaPro's claim that a patent owned by BMS was invalid in the United Kingdom. The BMS patent in question relates to methods for administration of the anti-cancer agent paclitaxel. August 28, 1998. According to the Ivax letter to shareholders, the company has begun marketing paclitaxel in Argentina through its subsidiary, Elvetium. August, 1998. Mr Dean Stull, Hauser CEO and President, reports that Hauser's potential capacity for producing paclitaxol is estimated at 200 kilograms per year, however paclitaxel is still produced on a much smaller scale because "BMS controls about 95 percent of the market." Mr Stull concludes, "we believe that prices well below the current prices can be met with future supplies and still be competitive and profitable." August, 1998. Both Immunex and Ivax file ANDAs requesting FDA approval of generic paclitaxel products and have certified in their ANDA applications that certain use patents held by BMS relating to Taxol are invalid or not infringed by their products. BMS challenges this certification, and files lawsuits for infringement of such patents. Ivax files a counterclaim against BMS to invalidate the patents, and has also asserts claims against BMS for violations of Federal anti-trust laws and unfair competition. Ivax, through its subsidiary Baker Norton Pharmaceuticals, also files a new drug application with the FDA for Paxene, for use in the treatment of Kaposi's sarcoma. November 4, 1998. Angiotech Pharmaceuticals, enters into an agreement to acquire an exclusive license from NeoRx Corporation for two U.S. patents and related patent applications which will broaden Angiotech's coverage of paclitaxel in non-cancer applications, including potential uses of paclitaxel in cardiovascular applications. According to Angiotech, the Company's initial technologies are based on the reformulation of paclitaxel, into medical device coatings, systemic treatments and topical gels. November 7, 1998. Professor Hilary Thomas, professor of oncology at the University of Surrey, UK, comments on the reluctance to British health authorities to fund the use of Taxol for ovarian cancer: "We in Britain are now the poor relation in Europe. The use of Taxol has been standard in the United States and most of Europe for some time. I have a patient from the Lebanon who was getting Taxol before she came here, and in Greece, which has a population of only eight million, they are spending more on the drug than we are in Britain, with a population of almost 60 million." December 8, 1998. Since 1997, Bristol-Myers Squibb has contributed $ 319,675 to the Republican party and $127,800 to the Democratic party, and spent $2, 820,579 on lobbying expenses, according to Consumer Projects on Technology. January 29, 1999. The European Committee for Proprietary Medicinal Products (CPMP) recommends approval of Ivax's Paxene to treat AIDS-related Kaposi's sarcoma. February, 1999. Liposomal Encapsulated Paclitaxel (LEP) is licensed to Pharmacia Corporation for worldwide development and commercialization. Early 1999. Hauser announces it is withdrawing from the paclitaxel business and selling a portion of its inventory to an undisclosed buyer. 1999. NaPro restarts manufacturing paclitaxel following an agreement with Abbott Laboratories. March 6, 1999. Baker Norton receives its first patent approval for its oral method of administering paclitaxel in Australia. The patent has been issued by the Commonwealth of Australia's Patent Office, and will be effect until October 2016. March 8, 1999. US District Court for the Eastern District of Pennsylvania begins United States v. Kai-ho Hsu Hearing, (No. 9 732 301). Kai-ho Hsu is charged with attempted theft of the plant cell tissue culture technology to make Taxol, from an allegedly corrupt Bristol-Myers Squibb employee. Three days later the Court of Pennslyvania denies Kai-ho Hsu's motion to dismiss two counts of indictment. March 9, 1999. The US Federal Trade Commission expands its probe to determine whether giants in the pharmaceutical industry are unfairly stifling generic competition. The agency's investigation, which now involves Eli Lilly & Co., DuPont Co., Abbott Laboratories and Hoechst AG, is prompted by concerns about spiraling drug-price inflation and possible anti-competitive practices, according to the FTC. The drugs under scrutiny (which have patents that are about to expire) have combined sales of more than $5 billion annually. April 1999. Donna Gibson plant physiologist, in Ithaca, New York, and co-inventors at Washington State University and Cornell Research Foundation, file for a new patent (09/126,229) on a process for enhancing production of paclitaxel using cell cultures from the yew tree. According to Agricultural Research Magazine, "Gibson's invention could significantly expand commercial production of taxanes to levels higher than any previously reported." April 29, 1999. Bristol-Myers Squibb submits a regulatory application to the U.S. FDA to gain marketing approval for Taxol Injection, administered sequentially to standard combination therapy, for the treatment of node-positive breast cancer. May, 1999. Bristol-Myers Squibb Company and Genentech, Inc. enter into an agreement to continue clinical research and enhance the safe use of Herceptin and Taxol in the treatment of metastatic breast cancer. May 1999. At the annual meeting of the American Society of Clinical Oncology in Atlanta, three studies are presented in which Paxoral, an oral paclitaxel system developed by Baker Norton Pharmaceuticals shows encouraging preliminary results. Two of the studies were conducted in conjunction with the Netherlands Cancer Institute in Amsterdam, while the third was in conjunction with the Cancer Therapy and Research Center & Brooke Army Medical Center in San Antonio, Texas. June 22, 1999. Bristol-Myers Squibb Company submits a regulatory application to the U.S. FDA to gain marketing approval for Taxol Injection, in combination with Genentech, Inc.'s Herceptin (Trastuzumab). Bristol-Myers Squibb's NDA seeks approval for the indication of TAXOL in combination with Herceptin as first-line therapy for women with metastatic breast cancer who overexpress the HER2 protein. (Approximately 25-30% of all breast cancer tumors overexpress HER2, which is a poor predictor for patient outcome.) July 21, 1999. European Commission sign the Decision to grant a Marketing Authorization for Ivax's Paxene (paclitaxel), in the 15 member-states of the European Union, for the treatment of AIDS-related Kaposi's sarcoma, but not cancer. According to Ivax, this European approval will be held by Norton Healthcare Limited, the company's subsidiary in the United Kingdom. August 2, 1999. Galena a.s., Ivax's subsidiary in the Czech Republic, begins to market the company's Paxene for the treatment of AIDS-related Kaposi's sarcoma. According to Ivax, the product was approved by the Czech Ministry of Health in mid-March but had been awaiting government pricing. September 17, 1999. The Oncologic Drugs Advisory Committee (ODAC) unanimously recommends that the U.S. Food and Drug Administration approve Taxol (paclitaxel) Injection for sequential administration to doxorubicin-containing therapy for the treatment of node-positive breast cancer. 1999. The FDA approves Taxol to treat early stage breast cancer in patients who have already received chemotherapy with the drug, doxorubicin. November 19, 1999. Ivax enters into a product collaboration and development services agreement with Bristol-Myers Squibb. According to Ivax, "in the field of oncology, BMS has been granted an option to license Ivax's patented system for the oral administration of paclitaxel on terms to be agreed upon. Additionally, each party has agreed to respect the other's lawful data protection rights in its marketing of paclitaxel in the European Union...The initial term of the agreement is three years." December 2, 1999. SuperGen enters into a licensing and research agreement with the Clayton Foundation for Research and its technology transfer organization, Research Development Foundation. Under the terms of the agreement, SuperGen acquires worldwide rights to inhaled versions of formulations of a number of taxanes, including paclitaxel. December 22, 1999. Cytoclonal Pharmaceutics announces recent publication of a scientific work. Dr Arthur P Bollon, Chairman and CEO of Cytoclonal explains, "these new findings add further insight into the mechanism of Taxol action and offer potential for improving cancer treatment with this drug or related compounds." The genetic basis conferring resistance to Taxol is being developed by Cytoclonal as a potential test for determining Taxol sensitivity in human cancer and in designing improved Taxol alternatives. Patents are pending for this new technology. January and October 2000. SuperGen is issued two United States patents for a Cremophor-free formulation of paclitaxel. According to SuperGen, "these patents are expected to have important clinical and strategic implications, as such a formulation obviates the need of pre- medication, which is currently required with the use of paclitaxel." January 4, 2000. The District Court for the District of New Jersey grants Bristo-Myers Squibb's motion to dismiss some of the antitrust and unfair competition counterclaims. BMS's motion for summary judgment on the remaining antitrust and unfair competition counterclaims is denied on March 17, 2000. February 3, 2000. SuperGen Inc is issued U.S. Patent No. 6,017,948, covering the company's water-miscible formulation of the generic compound paclitaxel. SuperGen was founded in 1990 by Joe Rubinfeld, who was previously vice president at BMS. February 29, 2000. The District Court for the District of New Jersey issues a ruling invalidating all claims of patents being asserted by Bristol-Myers Squibb against five generic drug companies, with the exception of a few specific claims directed solely to the use of Taxol to treat ovarian cancer. According to BMS, "in order to pursue an immediate appellate review of the District Court's invalidity findings, the Company voluntarily relinquished all rights in the remaining ovarian tumor specific claims of its patents." March 3, 2000. US District Court for the District of New Jersey grants Zenith Goldline's motion summary judgment of invalidity. March 17, 2000. The federal judge presiding over the Taxol- related patent litigation between Ivax and Bristol-Myers Squibb rejects BMS's attempt to avoid a trial on the issue of whether BMS committed fraud and/or inequitable conduct in obtaining the Taxol-related patents. In denying BMS's motions for summary judgment, the Court rules that Ivax has produced evidence which could support an ultimate finding that Bristol committed fraud and/or inequitable conduct before the United States Patent Office by failing to disclose material information relevant to Bristol's patent applications and by making various misrepresentations to the patent examiner who reviewed Bristol's patent applications, all with an intent to deceive the Patent Office. March 17, 2000. Bristol-Myers Squibb press release states: "Ivax Corporation issued strong language this morning that was in direct proportion to their current inability to launch a generic version of Taxol." March 20, 2000. Ivax's Polish subsidiary obtains approval to market paclitaxel in Poland to treat breast and ovarian cancer. April 10, 2000. US District Court Judge William Wall issues a ruling invalidating key provisions of patents covering Taxol. Bristol-Myers Squibb filed patent infringement suits relating to Taxol against nine generic pharmaceutical companies in 1997, including Ivax of Florida, Mylan Laboratories of Pittsburgh, and Schein Pharmaceutical of New Jersey. This ruling invalidates all Taxol patent claims, with a few exceptions relating to the use of the product to treat ovarian cancer. April 13, 2000. Bigmar announces that it has entered into an exclusive, five-year distribution and supply agreement with Indena to develop, manufacture and distribute a generic version of Taxol. Indena, which is based in Milan, will supply the raw material, paclitaxel, and Bigmar will manufacture the generic drug. April 16, 2000. Ivax's shares plunge 31% following Bristol- Myers Squibb's press release regarding American BioScience's impending Taxol patent. Bristol's shares rose 6%. April 26, 2000. Ivax receives approval to market Paxene in Canada for the treatment of AIDS-related Kaposi's sarcoma. Phillip Frost, M.D, Chairman and CEO of Ivax said, "this approval of Paxene in Canada.builds upon approvals for this product in the European Union, Poland and the Czech Republic." May 13, 2000. Paclitaxel is to be made available to all women in England and Wales with ovarian cancer following the long awaited ruling by the National Institute for Clinical Excellence, which advises the NHS in England and Wales on the clinical and cost effectiveness of medicines. According to the British Medical Journal, the recommendation is expected to cost the NHS an additional œ7m ($11.2m) a year to treat the 1000 patients each year who have been denied paclitaxel because their health authorities have refused to pay the œ7000 for a course of treatment. May 25, 2000. U.K Court of Appeals unanimously upholds a 1998 lower court's ruling in favor of Ivax in which a Bristol-Myers Squibb's patent relating to the use of Taxol was invalidated. In its decision, the Court of Appeals additionally awards Ivax an increase in the amount of costs, including legal fees, that it may recover from Bristol. May, 2000. According to Bristol Myers Squibb's press release: "American BioScience Inc informs BMS that it owns a long-standing application with the US Patent and Trademark Office to obtain a patent covering a range of single unit dosage forms of paclitaxel. ABI says it expects the patent to issue shortly, and therefore ABI says it will sue BMS for patent infringement unless BMS agrees to negotiate a license under the patent, and demands that BMS list the patent in the FDA's Orange Book (Approved Drug Products with Therapeutic Equivalence Evaluations) as soon as it is issued." June 8, 2000. NaPro announces that it has expanded its development and marketing relationship for paclitaxel with F. H. Faulding & Co (an Australian pharmaceutical company) to include all of central America, South America and Mexico, as well as South Africa and certain additional territories in South East Asia and Middle East. Faulding has secured exclusive development and distribution rights to NaPro paclitaxel in some 75 countries worldwide. June 10, 2000. Aphios Corporation is granted a Chinese Patent for isolation of Taxol from yew needles, entitled "Method and Apparatus for Extracting Taxol from Source Material." The patent is available for licensing to Chinese pharmaceutical companies and/or multinational pharmaceutical companies interested in doing business in China. July 10, 2000. Bristol-Myers Squibb Company announces that the US FDA has approved a novel, shorter (three hour) administration regimen for Taxol injection for the treatment of advanced ovarian cancer. August 1, 2000. US Patent and Trademark Office issues American BioScience Inc., Patent no. 6,096,331, which covers a range of single unit dosage forms of paclitaxel. ABI has allegedly developed a new process that permits a patient to receive higher doses of Taxol with fewer side effects. At first Bristol-Myers Squibb refuses to inform the FDA of this new patent. August 11, 2000. American BioScience brings a suit against Bristol-Myers Squibb in US District Court for the Central District of California, alleging that under the federal Food, Drug and Cosmetics Act, BMS was obligated to submit the patent to the FDA for listing in the Orange Book. ABI seeks a Temporary Restraining Order. ABI and Bristol quickly come to an agreement; as part of a proposed settlement between ABI and Bristol, the parties agree that (1) the court would enter a finding that ABI's patent should be listed in the Orange Book, and (2) Bristol would maintain the listing of the patent in the Orange Book. The Court enters a Temporary Restraining Order and orders BMS to list the ABI patent in the FDA's Orange Book. As directed by the Court, Bristol-Myers Squibb lists the ABI `331' patent. According to BMS' press release, "if ABI's patent remains listed in the Orange Book, and if ABI sues others for patent infringement, the ability of generic drug companies to market generic versions of Taxol could be delayed. ABI's motion for a preliminary injunction to continue the listing is being scheduled. If ABI is unsuccessful on that motion, Bristol-Myers Squibb will be required to take all steps to remove the listing of the ABI patent from the Orange Book. Bristol-Myers Squibb has an option to take a non-exclusive license on the patent from ABI and is considering its options both with respect to the litigation and the license." Once a patent has been listed in the Orange Book, a generic applicant is required to file with FDA a certification explaining the applicant's position on whether the patent is valid or whether it will be infringed by the manufacture, use or sale of the applicant's proposed generic drug. The patent holder then has 45 days in which to file a patent infringement suit against the generic applicant, and such a suit could block FDA from granting final approval for the generic application for up to 30 months. August, 2000. Ivax receives tentative approval from the US FDA to begin marketing its generic paclitaxel, but this is contingent on Ivax resolving its patent disputes. August/September, 2000. Bristol-Myers Squibb and Roche Holdings AG announce their research collaboration agreement to investigate the effectiveness of combination therapy involving Taxol and Roche's Herceptin (trasruzumab). The therapy targets metastatic breast cancer. September 1, 2000. In the amicus brief of the Federal Trade Commission for the case American Bioscience, Inc. v. Bristol- Myers Squibb, the Commission asks the judge to consider the anti-competitive ramifications of the proposed settlement. "First, another court might find any judicial finding that the patent met the statutory requirements for listing on the Orange Book persuasive, or even conclusive, thus hindering a generic company's attempt to challenge the listing. Second, the order to maintain the listing would conflict with any later court order requiring Bristol to delist the patent, and resolving the conflicting court orders could further forestall generic entry." The brief also announced the Commission's investigation of ABI and Bristol, and asked the court to consider its pendency when deciding on the proposed settlement. September 7, 2000. A Los Angeles federal district court judge, William Matthew Byrne reverses his recent ruling and orders BMS to de-list the patent. The federal district court dissolves the Temporary Restraining Order, ruling that the court does not have jurisdiction to issue a permanent restraining order requiring BMS to list a patent held by ABI in the Orange Book. He also declines to approve the settlement between ABI and BMS. BMS and ABI appeal. September 7, 2000. American BioScience files a lawsuit for patent infringement against Baker Norton Pharmaceuticals, Zenith Goldline Pharmaceuticals and Ivax in the District Court for the Central District of California. September 7, 2000. President of National Organization for Women, Patricia Ireland issues a statement in which she says; "By exposing Bristol-Myers' blatant manipulation of the regulatory and judicial systems, NOW intends to pressure the company to stop its unconscionable, and so far successful campaign to block FDA approval of a generic version of Taxol.we are calling on Bristol-Myers to stop this irresponsible corporate behavior." September 7, 2000. According to Nurse Week, experts estimate that the price of Taxol would drop about one-third in the first six months if a generic drug were introduced on the market, and by about half after that. September 11, 2000. BMS files a petition with the US District Court for the Southern District of New York requesting the court to settle the dispute between ABI and Ivax, asking the court whether BMS should remove the ABI patent from the Orange Book. September 11, 2000. In a press release, Bristol Myers Squibb asserts that it has invested over $1 billion in research and development of Taxol, nearly $500 million of which has been invested since 1997, but provides no details to justify its claims. September 13, 2000. BMS stands to gain almost $1 million each additional day the patent dispute remains tangled in the courts, according to Wall Street analysts cited by Reuters. Consumer Projects on Technology estimate the value of the delay is upward of $3 million a day. September 13, 2000. The Ninth Circuit Court of Appeals denies a petition to stay a federal judge's order requiring Bristol-Myers to take its patent off the government's list of Taxol patents. According to Ivax, "if the patent were kept on the list, a cheaper version of the drug could have been delayed for up to three years." September 15, 2000. FDA grants final approval for Ivax's ANDA for generic paclitaxel 6 mg/mL injection (packaged in 30 mg/5 mL, 150 mg/25 mL, and 300 mg/50 mL multiple-dose vials). Ivax's first to file position entitles the company to 180 days of shared market exclusivity with BMS. The product will be marketed through Ivax's subsidiary, Zenith Goldline Pharmaceuticals. Neil Flanzraich, vice chairman and president of Ivax states, "we strongly believe the system must be changed to eliminate opportunities for abuse by those seeking to prevent or delay generic competition." September 18, 2000. NaPro, together with its licensee Abbott Laboratories, files a patent infringement suit in the US District Court of the District of Colorado against Bristol-Myers Squibb. NaPro alleges infringement of US patent no. 5,972,992 and no. 5,977,164, relating to paclitaxel. Trial date is set for June 2002. September 19, 2000. James Love, Director of Consumer Project on Technology, reports that Bristol Myers Squibb quotes $6.09 per milligram as the "average wholesale price" of Taxol, and that one generic manufacturer "told us in August that their costs of manufacture for Taxol was $.07 per milligram, or about 1 percent of the BMS price." September 20, 2000. Ivax announces that it has begun its selling program for its generic Taxol product. Neil Flanzraich, vice chairman and president of Ivax said, "we fully anticipated that American BioScience and Bristol-Myers would again seek to use or abuse the legal process by filing lawsuits against Ivax, or even the FDA, to try to block Ivax's launch of this important generic cancer product. Sure enough, we have just learned that American BioScience intends to sue the FDA." According to Ivax, the price of Onoxol is 80% of Bristol's Taxol. September 20, 2000. ABI files a complaint in the District Court for the District of Columbia against the FDA; (American BioScience. v. Donna E. Shalala, et al.,) which seeks by temporary restraining order and a rescission of Baker Norton Pharmaceutical's final marketing approval for its generic paclitaxel product. On October 3, 2000, the Court denies ABI's request for preliminary injunctive relief. Thereafter, ABI seeks an emergency injunction pending appeal from the United States Court of Appeals for the District of Columbia Circuit, which is denied on October 13, 2000. September 26, 2000. Bigmar files an Abbreviated New Drug Application for generic version of Taxol, following a distribution and supply agreement reached with Indena SpaA in April. September, 2000. Mylan Laboratories receives tentative approval from the FDA to manufacture and market their paclitaxel injection. Mylan's tentative approval is limited to the smallest vial size (30 mg/5mL), which has about 15 percent of the market share. The company will have to wait until Ivax's 180 days exclusivity expires. October 2, 2000. Ivax brings suit in a Florida state court, accusing BMS and American BioScience of posing as adversaries while conspiring to block Ivax's generic Taxol from winning regulatory approval. Specifically, Ivax is suing BMS and ABI for abuse of process, violations of Florida's Antitrust Act, violations of Florida's Deceptive and Unfair Trade Practices Act, and fraud arising from a series of alleged illegal acts committed by the companies designed to block Ivax from bringing its generic version of Taxol to market. October 3, 2000. District Court Judge Colleen Kollar- Kotelly rules that the approval of Ivax's generic form of Taxol had been properly granted under the FDA's regulations. October 4, 2000. The U.S. District Court in Washington D.C. rejects the motion of American BioScience, Inc and Bristol- Myers Squibb to grant an injunction requiring the FDA to rescind and revoke its final marketing approval of Ivax's generic Taxol product. Neil Flanzraich, president of Ivax says, "The repeated efforts of American BioScience and Bristol-Myers to delay or prevent Ivax's generic Taxol product from coming to market are not surprising considering that Bristol-Myers makes $3-4 million each additional day its Taxol monopoly is extended." October 11, 2000. FTC announces that it plans to conduct a "focused study of generic drug competition [to] examine whether brand-name and generic drug manufacturers have entered into agreements, or have used other strategies, to delay competition from generic versions of patent-protected drugs." In addition it will look into "whether drug companies have manipulated certain provisions of the Hatch- Waxman Act to delay the marketing of generic drug products." FTC is also currently "investigating BMS and American BioScience alleged collusion to use judicial system to get FDA to list a broad BMS patent protecting Taxol, in order to delay Ivax." October 16, 2000. Court of Appeals for the DC Circuit denies the motion of American BioScience to enjoin the FDA's approval of Ivax's generic version of Taxol pending ABI's appeal of a similar denial rendered by the U.S. District Court in Washington, D.C. on October 4th. Like the District Court, the Court of Appeals concludes that ABI failed to demonstrate that it was likely to succeed on the merits of its claim that the FDA improperly approved Ivax's anti- cancer drug. October 16, 2000. ABI files a lawsuit against U.S. FDA (Amercian BioScience, Inc. v. Donna E. Shalala, et al.) for the second time over its approval of Ivax's generic version of Taxol. Baker Norton Pharmaceuticals moves to intervene and opposes ABI's request for preliminary injunction. October 16, 2000. According to a Chemical Market report, one industry source said, "the introduction of generic drugs is not expected to augment paclitaxel demand. Rather, future growth for the API is dependent on the development and approval of new indications, creating a larger patient base." October 18, 2000. BMS abandons its lawsuit against Ivax, which it had filed in the Federal District Court for the Southern District of New York to attempt to obtain a declaratory judgment regarding a patent issued to American BioScience, Inc. for a formulation of paclitaxel. The action had sought a judicial ruling as to whether the ABI patent should be listed in the FDA's Orange Book. According to Neil Flanzraich, "Bristol-Myers' voluntary withdrawal of one of these lawsuits is further evidence of its lack of merit." October 24, 2000. Phytogen Life Science is issued a U.S. Patent (no. 6,136,989) on certain aspects of it's paclitaxel production processes and product composition, entitled "Method for high yield and large scale extraction of paclitaxel from paclitaxel-containing material". According to Phytogen, the Company has also filed a PCT for European patent protection. October 31, 2000. NaPro is issued US patent no. 6,140,359, titled, `Injectable Composition.' Subsequently, NaPro amends its lawsuit against Bristol-Myers Squibb, initiated September 18, to include this patent. Leonard Shaykin, Chairman and CEO of NaPro states, "we intend to defend our intellectual property rights not only against BMS, but also against any others who may infringe our patents." November 8, 2000. US District Court in Washington D.C. enters a preliminary injunction against American BioScience, Inc. and orders ABI to refrain from pursuing the litigation it filed against the FDA on October 16, 2000, in the Central District Court of California. The D.C. Court holds that the California action was duplicative of the litigation that ABI had previously filed in the D.C. Court, which sought to rescind Ivax's approval for its generic version of Taxol. In October, the D.C. Court specifically determined that ABI was unlikely to succeed in its lawsuit and denied ABI's motion for a preliminary injunction ordering the FDA to revoke its approval of Ivax's generic version of Taxol. The D.C. Court also prospectively enjoined ABI from filing any additional duplicative lawsuits. "We are obviously pleased with the decision. In effect, the Court told ABI, `Enough is enough!'" said Neil Flanzraich, president and vice chairman of Ivax. November 13, 2000. According to their Quarterly Report, "To advance the development and commercialization of NaPro paclitaxel, NaPro has entered into 20-year exclusive agreements with Abbott Laboratories and F.H. Faulding & Co., Ltd. for the clinical development, sales, marketing and distribution of NaPro paclitaxel..The Abbott territory includes the U.S. and Canada. The Faulding territory includes Latin America, Asia, South Africa and much of the Middle East. NaPro continues to seek partners for Europe and Japan." November 28, 2000. NeoPharm, Inc. announces the issuance of a new patent covering claims for use of Liposomal Encapsulated Paclitaxel (LEP). This new patent covers the novel administration of LEP and a more desirable side effect profile. LEP is currently in Phase II/III clinical trials in a number of countries worldwide under the direction of Pharmacia. James Hussey, President and CEO of NeoPharm, says: "We intend to further strengthen the intellectual property around our electrostatic liposomes in general, and LEP in particular in the future." December 2000. BMS receives a new patent, which covers the use of Taxol with another drug, cisplatin. BMS seeks to list the patent in the FDA's Orange Book. December 2000. Mattew Estevex, writing in Latin Trade, reports on Ivax's plans to market generic Taxol in Latin America. "We are very committed to bringing low-cost generics to Latin America," explains Ivax President Neil Flanzraich December 2000. According to the British National Formulary, the price of Norton's paclitaxel in the UK is 112.31pounds for 30mg per 5ml single use vial, (aprox. $5. 35 per 1mg) and the price of Bristol's taxol in the UK is 124.79 pounds for 30mg per 5ml single use vial (aprox. $5. 95 per 1mg). (Generic brand is 89.9% of the brand name.) End of 2000. Ivax's announces fourth-quarter profit rise of 82 percent to $31 million. Generic competition slowed Bristol-Myers's Taxol sales growth to 7 percent in 2000, from 23 percent a year earlier. End of 2000. BMS reports in their SEC 10-K form for 2000 that the company earns between $4 and $5 million per day on Taxol, based on the annual sales figure of $1.592 billion. 2000. According to Datamonitor, sales of paclitaxel in the US alone, reached $1 billion during 2000. January 8, 2001. NaPro receives approval in Israel to sell its version of paclitaxel under the trade name Biotax. NaPro has established an exclusive supply and distribution agreement with Tzamal Pharma for development and distribution of Napro paclitaxel in Israel. This is the only approved paclitaxel in Israel other than BMS's Taxol. January 16, 2001. Ivax announces that it has sold more than $30 million of Onxol (Ivax's generic version of Taxol) in the United States during the 10-week period ending Dec. 31, in line with estimates. February 8, 2001. Xechem International announces that the US Patent & Trademark Office has issued Patent No. 6,177,456, containing broad claims to novel second generation paclitaxel analogs. According to Xechem's president & CEO, Dr Ramesh Pandey: "With the exclusivity afforded by the various issued patents for second generation paclitaxel, we hope to develop unique new products of choice in this important and burgeoning area. Xechem is also working on an Abbreviated New Drug Application (ANDA) for generic paclitaxel for submission to the U.S. FDA in the next few months." February 28, 2001. Xechem International announces that the Commissioner of Patents at the Commonwealth of Australia Patent Office has awarded patent 724,929 to Xechem for its (second generation) paclitaxel analogs. February, 2001. Latin Trade reports on the price of Taxol citing Bristol-Myers Squibb as the source. United States $4. 87 per 1mg Argentina $1. 90 per 1mg Brazil $1.29 per 1mg Mexico $1.18 per 1 mg Venezuela $1.09 per 1mg March 5, 2001. NaPro signs an agreement with F.H Faulding & Co Limited. This agreement covers the marketing and distribution of NaPro paclitaxel under Faulding's tradename Anzatax in the European Union and contiguous countries. March 6, 2001. Abbott Laboratories and NaPro file an ANDA with the US FDA for paclitaxel. March 30, 2001. BMS and ABI bring Ivax before the Washington, D.C., Court of Appeals, which rules that an original October 3 motion filed by BMS, which upheld the FDA's approval of Ivax's right to market a generic version of Taxol, be reheard in the district court. The appellate court bases its ruling on the grounds that FDA had not presented to the District Court any written record of the processes it used to reach its decision. It ordered the motion to be reheard by the District Court after the filing of the full administrative record. "According to Ivax, this is based on procedural grounds and is unlikely to affect the final outcome of the motion." April 6, 2001. FDA files its administrative record and American BioScience renews its motion for a temporary restraining order or preliminary injunction. On April 19, 2001, the district court again denied ABI's motion. ABI appeals this ruling. April 9, 2001. Abbott Labs and NaPro BioTherapies jointly file a US FDA application to produce a generic version of Taxol. April 2001. Ivax's period of exclusivity for being the first to file for generic Taxol expires. April 19, 2001. The U.S. appeals court for the Federal Circuit upholds part of a decision last year by Kollar- Kotelly, Newark, N.J., [00-3298] that narrowed the scope of what Bristol-Myers may claim in a patent-infringement case. Specifically, the court lifted a stay, opening the door for Ivax to pursue antitrust and unfair competition counterclaims against Bristol-Myers. The decision also is a setback for American BioScience, which had asked the court to order federal regulators to revoke the generic drug's approval. The Santa Monica, Calif., company argued FDA lacked authority to approve Ivax's drug before a separate legal case in California had been resolved. But the court dismissed that charge, ruling the California action duplicated litigation brought by the firm in 1999, which also sought to overturn FDA's approval of Ivax's ANDA. April 20, 2001. US Court of Appeals for the federal circuit affirms New Jersey District Court's grant of summary judgment invalidating 8 out of 10 of BMS's asserted patent claims relating to Taxol. With respect to the two remaining claims, the court remanded the case to the district court for further proceedings. May 1, 2001. Senators John McCain, R-Ariz., and Charles Schumer, D-N.Y., introduce the Greater Access to Affordable Pharmaceuticals Act (GAAP) (S. 812), bipartisan legislation to improve access to generic drugs and clean up abuses under the 1984 Hatch-Waxman Act. According to Senator Schumer, "the 1984 Hatch-Waxman Act was designed to promote the growth of a generic drug industry, while providing additional patent protection for research-based brand-name drugs. But while the law has established a market for generics, it has been seriously undermined by patent law loopholes that have allowed brand-name drugmakers to use a host of tactics - including colluding with generic drug manufacturers - to delay the approval of lower-cost alternatives by several years." May 4, 2001. The appellate court orders that the American BioScience's appeal against the April, 19 district court ruling be expedited. May 14, 2001. In a news conference, National Organization for Women (NOW) President Patricia Ireland states, "Bristol Myers-Squibb is getting rich by putting women's lives and health at risk, and Congress is letting this and other pharmaceutical giants get away with it." May 14, 2001. The SPAN Coalition announces that it will organize consumer and patient groups across the country to initiate a series of class action lawsuits against pharmaceutical companies that prevent competition and endanger public health. NOW announces that it will lead the latest class action suit against Bristol-Myers Squibb for tactics it used to prevent patient access to lower-priced versions of Taxol, a treatment for breast and ovarian cancer. A federal court ruled in March of last year that the tactics included "an intent to deceive" the government. "Consumers have no regulatory avenue for relief from market abuses by pharmaceutical companies," stated Tim Fuller, SPAN founder and Executive Director of the Gray Panthers. May 15, 2001. A study presented during the Annual Meeting of the American Society of Clinical Oncology finds that paclitaxel plus Estramustine is a safe and effective treatment for hormone refractory prostate cancer patients. May 22, 2001. At a conference in New York, Neil Flanzraich (President and Vice Chairman of Ivax) tells analysts and investors that as "Taxol is derived in part from Pacific yew trees and therefore is considered difficult to make, generic competition may be limited by raw-material supplies." May 29, 2001. Ivax announces that the FDA has approved an additional manufacturer of the paclitaxel active ingredient, as well as an additional manufacturer of finished product for Ivax's' paclitaxel injection product. June, 2001. Ivax announces that its pharmaceutical subsidiary is changing its name to Ivax Pharmaceuticals, (formerly Zenith Goldline Pharmaceuticals) and our pharmaceutical research and development company has changed its name to Ivax Laboratories, (formerly Baker Norton Pharmaceuticals). Their subsidiaries in Czechoslovakia and Hungary are also incorporating "Ivax" as part of their names, and their principal European subsidiary, Norton Healthcare Limited, is in the process adopting the Ivax name. June 8, 2001. Ivax receives patent: U.S. Patent and Trademark Office issues a notice of allowance in connection with another of its patent applications relating to an oral formulation of paclitaxel. This allowance follows the issuance of U.S. Patent Number 5,968,972 entitled "Method for Increasing the Oral Bioactivity of Pharmaceutical Agents." June 12, 2001. NaPro BioTherapeutics and drug maker and licensee Abbott Laboratories file a patent infringement suit in the US District Court for the Western District of Pennsylvania against Mylan Laboratories over alleged infringement of US Patent numbers 5,733,888 and 6,140,359, relating to paclitaxel. June 21, 2001. NaPro and JCR Pharmaceuticals Co. Ltd., enter into a mutually exclusive supply and distribution agreement for NaPro paclitaxel in Japan. (NaPro licenses paclitaxel in Japan to JCR) June 23, 2001. The UK National Institute for Clinical Excellence (NICE), which advises the NHS in England and Wales on the clinical and cost effectiveness of medicines, has issued guidance recommending paclitaxel for chemotherapy in non-small cell lung cancer. June, 2001. The US National Organization of Women says it will lead the latest class action suit against BMS for stifling generic version of Taxol, including moves to add irrelevant patents to extend their product cycles. July 20, 2001. Xechem, a subsidiary of Xechem International, obtains notice of regulatory approval from the Indian Government to import and sell generic Chinese paclitaxel in India. Xechem is also seeking approval to import and/or sell generic paclitaxel in Indonesia and other Pacific Rim Countries, Africa, Europe, South America Countries and the US. Xechem's president and CEO, Dr Ramesh C Pandey, says, "Xechem will adhere to its aggressive plans to sell generic paclitaxel and its new paclitaxel formulation (and other new generation paclitaxel analogs) in as many geographic jurisdictions throughout the world as possible including the US." July 24, 2001. Mylan Laboratories announces that the FDA has approved its ANDA for Paclitaxel Injection, 6 mg/mL, packaged in 30 mg/5 mL, 100 mg/16.7 mL, and 300 mg/50 mL multiple-dose vials. July 30, 2001. Bedford Laboratories, a unit of Germany's Boehringer Ingelheim International AG, receives FDA approval to market paclitaxel. This unexpected competition triggers a 11.2% plunge in the share price of Ivax. In the second quarter of this year paclitaxel sales accounted for in excess of 25% of Ivax's total revenue. August 4, 2004. Orphan Drug protection expires for BMS's taxol indication for Kaposi's sarcoma.