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.
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