[Ip-health] Timeline for Fabrazyme, Replagal*

Jamie Love james.love at keionline.org
Tue Jul 15 04:55:14 PDT 2014

Timeline for Fabrazyme, Replagal*

*This timeline was prepared by Claire Cassedy and James Love of KEI, last
revised on July 14, 2014

1990, October 24. Robert J. Desnick, David F. Bishop And Yiannis A. Loannou
file patent application 07602824, titled Cloning And Expression Of
Biologically Active Human Alpha-Galactosi- Dase A.

1994 October 18.  Patent No. 5,356,804 is issued for the Desnick et al
invention, and rights are assigned to Mount Sinai School of Medicine in the
City of New York.  The patent discloses that “This invention was made with
government support under grant No. DK-34045 awarded by the National
Institutes of Health. The Government has certain rights in the invention.”

1995 February 3.  Mount Sinai School of Medicine granted Genzyme
Corporation an exclusive license to its Fabry patent.

1998, January 19.  Genzyme receives an Orphan Drug designation from US FDA,
for Treatment of Fabry’s disease.

1998, June 22.  Transkaryotic Therapies (TKT) receives an Orphan Drug
designation from US FDA, for long-term enzyme replacement therapy for the
treatment of Fabry disease.

1999 December.  Transkaryotic Therapies “in collaboration with the National
Institutes of Health ("NIH"), completed a 26 patient pivotal Phase II study
in patients with Fabry disease . . . The goal of the study was to assess
safety and clinical activity of Replagal, TKT's enzyme replacement therapy,
particularly its effect on pain and kidney function.”

2000 June 16.  TKT announces it has submitted a Biologics License
Application (BLA) for Replagal to US FDA. TKT submitted to the FDA
“approximately one week before [Genzyme] submitted [their] application for
Fabrazyme enzyme.”  According to TKT:

“The submission of TKT's BLA for the treatment of Fabry disease is based on
clinical data from two independent trials conducted at the National
Institutes of Health (NIH) and Royal Free Hospital in the United Kingdom.
 TKT's BLA also includes long-term data from twenty-five patients treated
for approximately one-year as part of a maintenance study at the NIH.”

2000 June. Genzyme submits BLA for Fabrazyme to US FDA.

2000 July. Genzyme submits MAA for Fabrazyme to the EMA.

2000 July 25. Genzyme files a lawsuit against TKT seeking injunctive relief
and damages for patent infringement resulting from TKT’s manufacture and
use of Replagal. The suit alleges infringement of US Patent No. 5.356,804
which Genzyme exclusively licensed from Mount Sinai.

2000 August 8.  EMA grants TKT orphan medicine designation for Replagal in

2000 September 19.  TKT files a lawsuit against Genzyme and Mount Sinai
seeking declaratory judgments that the manufacture, use and sale of
Replagal does not infringe the patent licensed from Mount Sinai and that
the Mount Sinai patent is invalid.

2000 October.  “TKT reported pivotal Phase II clinical results of Replagal
from the NIH study, indicating that the enzyme replacement therapy had
broad clinical effects in treating Fabry disease. Patients receiving
Replagal had comprehensive clinical and biochemical improvement including a
reduction in pain and stabilization or improvement in renal function.”

2000.  Carl Icahn joins the board of trustees of Mount Sinai Medical

2001 January 2.  TKT receives Complete Review Letter (CRL) from FDA stating
that Replagal failed to demonstrate clinical benefits necessary for FDA
approval. Recommends that TKT conduct additional clinical studies and
submit the results to the FDA.

2001 August 3.  TKT receives EU marketing authorization for Replagal from
the European Medicines Agency (EMA) and is granted 10 years of exclusivity
protection through orphan drug status.

2001 August 3.   Genzyme Europe B.V. receives EU marketing authorization
for Fabrazyme from the EMA and is granted 10 years of exclusivity
protection through orphan drug status.

2002 February 20. US District Court enters a summary judgement in favor of
TKT in the case versus Genzyme. Genzyme Corp. v. Transkaryotic Therapies,
Inc., 2002 U.S. Dist. LEXIS 1682

2002 March 20. Genzyme files appeal of decision in favor of TKT by US
District Court on patent infringement case of Replagal.

2003 April 24.  Genzyme receives approval from the US FDA for Fabrazyme and
also received seven years of U.S. Orphan Drug market exclusivity.

2003 October 9.  US District Court issues decision affirming that TKT’s
Replagal did not infringe on Genzyme’s Fabrazyme. Genzyme Corp. v.
Transkaryotic Therapies, Inc., 346 F.3d 1094 (Fed. Cir. 2003)

2004 January.  TKT “determined that it would cease its efforts to seek the
approval of Replagal from the FDA and withdrew its BLA for Replagal.”

2005 June 28.  Shire Human Genetic Therapies AB acquires Transkaryotic
Therapies Inc. (TKT) for $1.6 billion.

2006 October 20.  Mount Sinai is granted a 1440 day patent term extension
on US Patent no. 5,356,804 (the patent in question). The new patent
expiration date is set for September 27, 2015.

2007 November 15.  The Boston Globe reports Carl Icahn has acquired 1.5
million shares in Genzyme.

2008   Sept 15 to October 2008.   The Food and Drug Administration (FDA)
conducted an inspection of the Genzyme Allston Landing Facility, and
“documented significant deviations from current good manufacturing practice
(CGMP) in the manufacture of licensed therapeutic drug products, bulk drug
substances, and drug components. These products include Fabrazyme,
Cerezyme, and Myozyme.”

2009 February 27.   The US FDA sends Warning Letter NEW-08-09W regarding
the manufacturing problems at the Allston Landing Facility.  The letter
closes by noting that “If corrective actions cannot be completed within 15
working days, state the reason for the delay and the time within which the
corrections will be completed. Failure to promptly correct these deviations
may result in further regulatory action without further notice. Such
actions may include license suspension and/or revocation, seizure or

2009 June 16.   Genzyme announced a virus in a manufacturing facility in at
Allston, Massachusetts where Fabrazyme was manufactured would cause a halt
in the production of Fabrazyme.  Working with a Fabrazyme Stakeholders
Working Group (“FSWG”), Genzyme issued a “Guidance to the Fabry Community
on the Management of Fabrazyme Supply” recommending that physicians reduce
the use of Fabrazyme to approximately 80 percent of normal levels.

2009 July.  Genzyme resumed production of Fabrazyme but at lower than
anticipated volumes.

2009 September 23.  A meeting of the U.S. Fabrazyme Stakeholders Working
Group approves a  “Revised Guidance to the U.S. Fabry Community”
recommending physicians reduce the use of Fabrazyme to 30 percent of normal
levels for the remainder of 2009 (a reduction that was subsequently
extended several times).

2009 October 8-November 13. During an inspection by the US FDA, inspectors
find that Genzyme’s “systems for ensuring manufacturing quality were
inadequate resulting in production delays, critical shortages of medically
necessary products to consumers and drugs contaminated with metal, fiber,
rubber and glass particles. These manufacturing problems violated the FDA’s
regulations for manufacturing practice. Genzyme also temporarily suspended
manufacturing of some products due to a viral contamination in a bioreactor
that makes bulk amounts of its drugs.”  These manufacturing failures cause
extended shortages of Fabrazyme in the US.

2009 December 22.  At the request of the US FDA, Shire submits a new BLA
application Replagal.

2010 February 17.  Genzyme writes to health care professionals, noting it
“must extend the period of 30 percent Fabrazyme supply allocation until the
end of June 2010.”

2010 February 22.   Genzyme Corporation announced it has received notice
from Icahn Partners LP and certain of its affiliates of their intention to
nominate four individuals to Genzyme’s board of directors: Carl C. Icahn,
Dr. Steven Burakoff, Dr. Alexander J. Denner and Dr. Richard Mulligan..
 According to an SEC proxy statement, Icahn owns or controls ownership to
13,100,100 share of Genzyme, equal to 4.91 percent of Genzyme stock.  On
February 22, 2010, the shares traded at $56.04, placing the value of the
Icah holdings at $734 million.

2010 February 24.  Shire issues a press release stating that as a result of
the US FDA requesting additional pharmacokinetic comparability data, Shire
has withdrawn its’ December 2009 BLA, and at the suggestion of the FDA, has
requested and received a Fast Track Designation.  Shire immediately
initiates a rolling BLA submission.

2010 April 14-20.  According to a Shire SEC filing,

“Mt. Sinai School of Medicine of New York University (“Mt. Sinai”)
initiated lawsuits against Shire in Sweden on April 14, 2010 , and in
Germany on April 20, 2010, alleging that Shire’s enzyme replacement therapy
(“ERT”) for Fabry disease, REPLAGAL, infringes Mt. Sinai’s European Patent
No. 1 942 189, granted April 14, 2010.   Mt. Sinai sought injunctions
against the use of REPLAGAL in these jurisdictions until expiration of the
patent. Mt. Sinai has been granted Supplementary Protection Certificates
(“SPC”) in respect of the patent in certain EU countries (including Sweden
and Germany) which, where granted, extends the patent until August 2016.
Where no SPC has been granted, the patent expires November 2013.

2010 April 22. Genyzme issues "Direct Healthcare Professional Communication
on the supply of Fabrazyme (agalsidase beta)" which notes "Further
extension of the delay in the normal supply and recommendations on
treatment for patients experiencing clinical deterioration."  The
communication states that "Until at least the end of September 2010,
Genzyme will only have sufficient Fabrazyme to meet 30% of the global

2010 April 24.  US Orphan drug exclusivity expires.

2010 May 24. Genzyme signs consent decree to correct violations at Allston,
MA, manufacturing plant and a fine of $175 million.

2010 June 9.  Carl Icahn receives settles a proxy battle with Genzyme by
placing two persons on the Genzyme Board of Directors:   Steven Burakoff, a
director of the Tisch Cancer Institute at the Mount Sinai Medical Center,
and Eric Ende, a former biotechnology analyst at Merrill Lynch.

2010 July 23.  Shire files an opposition against Mount Sinai’s patent
before the European Patent Office.

2010 August 2.  Fabry patients Joseph M. Carik, Anita Hochendoner, and
Anita Bova request the Secretary of DHH to exercise Bayh-Dole march-in
rights and grant compulsory licenses to use patents related to the
manufacture of Fabrazyme (agalsidase beta). The grounds for the request are
that the patent owner and its exclusive licensee have harmed the public
health by severely rationing the supply of agalsidase beta, the only
approved therapeutic treatment for Fabry disease..

2010 Oct 22. The European Medicines Agency issues a press release titled:
"European Medicines Agency reviews treatment recommendations for Fabrazyme.
 The EMA statement reported a recommendation to restore full doses of
Fabrazyme or Replagal for most patients, and read in part:

The Committee for Medicinal Products for Human Use (CHMP) noted that since
the introduction of a lower dose of Fabrazyme in June 2009, there has been
a steady increase in the number of reported adverse events, matching the
increase in the number of patients on the lower dose. At first, most of the
events were pain-related, soon followed by reports of events affecting the
heart, the central nervous system and the kidneys. This pattern suggests a
progression of Fabry disease. Recently, a decrease in number of reported
adverse events has been observed, which reflects the fact that more
patients have either been switched to Replagal or have started receiving a
full dose of Fabrazyme again.

2010 December 1.  The US NIH rejects Fabry’s patients’ request for a
compulsory license, though the decision references the ongoing patent
litigation in Europe and reports that Mount Sinai has committed to the NIH
to “not pursue an injunction against the marketing and sale of Replagal
during any period of an existing or future shortage of Fabrazyme.”

2010 December 8.  Shire commences patent invalidity proceedings in the UK.
Mount Sinai in turn, counterclaiming alleging infringement in the UK

2010.  December 10.  Shire tells a German court they intend to initiate a
complaint for compulsory license before the Federal Patent Court.

2011 January 3.  Sally Strauss writes to Ann Hammersla in the NIH
Technology office, copying Dennis Charney, the Dean of the Mount Sinai
School of Medicine.   “This letter shall serve as Mount Sinai School of
Medicine's first monthly submission to the NIH pursuant to its request and
Determination not to exercise its March-in-Authority.”  Strauss says:

“With respect to the request for a license to the 804 patent and related
patents owned by Mount Sinai, we note that Shire has advised us that it may
file a motion with a German court seeking a compulsory license for the
territory of Germany. Shire has stated that it also intends to seek a
preliminary decision on such compulsory license in the event that a finding
of infringement is made in the pending infringement proceedings allowing
Mount Sinai to impose an injunction against Repligal. We have confirmed to
Shire and to the German court overseeing the infringement action that we
will not enforce an injunction during any period of drug shortage.”

A fact not clear from Sally Strauss’s January 3, 2011 report is that Mount
Sinai’s offer to forgo an injunction was only through September 30, 2011.

2011 January 13.  Joseph M. Carik and Amber Britton, both suffering for
Fabry's disease, file a citizens petition with the US FDA, asking that the
FDA prevent Genzyme from exporting Fabrazyme, since patients in the United
States are suffering from a shortage, but patients outside the United
States can benefit from the Shire product, Replagal, which is not available
for sale in the United States.

2011 January 19.  Jones Day, representing Mount Sinai, writes to Dr. v.

2011 February 16. France-based Sanofi-Aventis acquires Genzyme for $20.1
billion.  The Wall Street Journal reports “Sanofi is paying $74 a share, or
$20.1 billion, plus a contingent value right, or CVR—a pledge of additional
payment of up to $14 a share if Genzyme meets certain sales and
manufacturing targets.”   Shares trade at $76.25 before they are actually
purchased in April.

2011 March 1.  Mount Sinai informs the NIH that it has been served with
Shire’s motion for a compulsory license for the territory of Germany.

2011 May 12.  Alan Black, the attorney representing Fabry’s patents Joseph
M. Carik and Amber Britton submits additional documentation to the FDA on
the practice of Genzyme to provide European patients with full doses of
Fabrazyme, while rationing or providing no access to U.S. patients.

2011 March, 25.   Genzyme announces that because of  a new manufacturing
failure for  Fabrazyme supplies, the company will reallocate stocks away
from U.S. to foreign patients, in order to “share the impact of this loss”

2011 April 13.  Mount Sinai’s Sally Strauss sends “supplemental materials”
to the NIH:

This letter provides further details on: (1) our ongoing commitment to the
NIH, the Fabry patient/physician community, and Shire that Mount Sinai will
not seek to enforce an injunction against Replagal during any period of an
existing or future shortage of Fabrazyme; (2) the status of the compulsory
license proceeding in Germany; and, (3) Genzyme's confirmation that it has
not changed its allocation of Fabrazyme to the United States market.  . . .

Mount Sinai has repeatedly issued written commitments to the NIH and to
Shire that it will not seek to enforce an injunction against Shire's
product Replagal during any period where there is a current or future
shortage of Fabrazyme.  For example, after Mount Sinai received the German
Court's infringement decision authorizing an injunction, it reached out to
Shire in a letter dated January 19, 2011 to reiterate that it would not
seek to enforce an injunction against the marketing and sale of Replagal
during any period of an existing or future shortage of Fabrazyme. Further,
Mount Sinai explicitly committed not to pursue the enforcement of an
injunction in Germany before September 30, 2011 and to provide Shire with
specific notice on July 1, 2011 as to whether it will extend this
categorical commitment. (We have attached this letter and an English
translation at Tab B). Consistent with this commitment, Mount Sinai
submitted a reduced bond with the Mannheim Court only related to that
portion of the Court's judgment requiring Shire to provide financial
information and an accounting. If Mount Sinai had sought to•enforce an
injunction it would have had to place a much higher bond with the Court.
(We have attached the bond submission and a corresponding translation at
Tab C 2). Mount Sinai confirmed this commitment to Shire yet again in
connection with the lawsuit in the United Kingdom where Shire sued Mount
Sinai attacking the validity of our patent, and Mount Sinai counterclaimed
with an infringement action. In two sequential letters to Shire (attached
hereto in Tab D) Mount Sinai reiterated that it will not seek to enforce an
injunction during any period of shortage. Finally, Mount Sinai voiced this
commitment most recently to the German Court overseeing Shire's motion for
a compulsory license (Tab E). 3

. . . Mount Sinai believes that based on the above information, there are
no new facts that

would warrant the NIH to reverse its earlier decision and issue a march-in
petition at this time  . . .

2011 July 1.   Sally Strauss files Mount Sinai’s seventh monthly report
regarding Fabrazyme issues with Ann Hammersla at NIH, with additional
details on the issue of the Mount Sinai position on the injunction:

Mount Sinai continues to stand by its commitment not to enforce the
Mannheim Court's judgment regarding the imposition of an injunction of the
sale of Repligal in Germany. We had previously advised Shire that we would
commit to not pursuing an injunction through September 30, 2011. We have
recently advised Shire that we would extend this categorical commitment at
least through December 31, 2011.

2011 August.  The 10 year EU Orphan exclusivity for Replagal and Fabrazyme

2012 January. New Genzyme facility in Framingham, MA is approved by US FDA
and EMA for the production of Fabrazyme.

2012 March 14.  Shire withdraws Replagal US FDA BLA, and issues a statement
with says in part:

Lexington, Massachusetts, US – March 14, 2012 – Shire plc (LSE: SHP,
NASDAQ: SHPGY), the global specialty biopharmaceutical company, announced
today that it has withdrawn its Biologics License Application (BLA) for
REPLAGAL (agalsidase alfa) with the US Food and Drug Administration (FDA).
 Shire has been in ongoing dialogue with the FDA since the supply shortage
of the only US approved treatment for Fabry disease. In 2009, and again in
2011, the FDA encouraged Shire to submit an application for the approval of
REPLAGAL. The information in the application included relevant updates such
as manufacturing and open long-term clinical trial data. These discussions
led the Company to file a BLA last November in anticipation of a quick
review process and eventual approval - allowing Shire to supply more US
patients with a therapy they desperately needed at the time. Recent
interactions with the FDA have led the Company to believe that the agency
will require additional controlled trials for approval. No concerns over
the product’s safety profile were raised by the FDA. Shire has concluded
that the likely additional studies would cause a significant delay, and an
approval of REPLAGAL for US patients would only be possible in the distant
future. Shire has therefore decided to withdraw its BLA.  Shire has been
providing REPLAGAL free of charge to around 140 US patients – about 20% of
the treated US patients - through treatment access programs.

2012 May 9.  Mount Sinai grants Shire a non-exclusive license to the patent
in connection with the on-going sales of Replagal in the European Union.
Shire and Mt. Sinai agree to settle all proceedings in connection with the
validity and infringement by REPLAGAL of Mt. Sinai’s European Patent No. 1
942 189.  The parties agree to discontinue all court and related
proceedings in this dispute.  Shire also reported that:

“Mt. Sinai has granted Shire a non-exclusive license to the patent in
connection with the on-going sales of REPLAGAL in the EU and in certain
other non-EU territories. Shire has made an up-front cash payment to
Mt.Sinai and will make additional cash payments based on REPLAGAL sales
over the license term.”

2012.  June  25.  BioCentury publishes a report suggesting the Shire BLA
decision was related to FDA concerns about Shire manufacturing practices.

2012.  November 15.  The Mount Sinai Medical School issues a press release
announcing it will be renamed the Icahn School of Medicine at Mount Sinai.

Mount Sinai President and CEO Kenneth L. Davis, MD and Chairman of the
Boards of Trustees Peter W. May announced today that the Mount Sinai School
of Medicine has been renamed the Icahn School of Medicine at Mount Sinai in
honor of Trustee Carl C. Icahn. Mr. Icahn, whose latest gift is the largest
in Mount Sinai's history and among the biggest ever given to a medical
school, signed the formal agreement Tuesday, November 13, 2012 at his
offices in midtown Manhattan.  The new name was approved by the Boards of
Trustees on September 24 in recognition of Mr. Icahn's many years of
dedicated service to the institution, his leadership in advancing medical
science, and his nearly $200 million in lifetime giving to Mount Sinai. In
addition, the Institute for Genomics and Multiscale Biology
<http://icahn.mssm.edu/research/institutes/genomics-institute>will be
renamed the Icahn Institute for Genomics and Multiscale Biology.

2013.  February 13.  The NIH writes to Alan Black, stating:

The December 2012 report from Genzyme stated that: (1) U.S. Fabry patients
remain on full dose regimens, (2) Genzyme continues to  accommodate new
patients with full dosing and without placing them on a waiting list; and
(3) Genzyme is able to provide full doses of Fabrazyme to patients
transitioning to Fabrazyme as a result of the Shire PLC’s decision to
withdraw its FDA Biologics License Application for Replagal Based on Mount
Sinai’s and the Genzyme’s representations in their respective December 2012
reports and the ability of U.S. Fabry patients to obtain full doses of
Fabrazyme, NIH has closed the above march-in case.

2013.  November 27.  Judge Howell of the US District Court for the District
of Columbia grants a motion by the US Department of Health and Human
Services (DHHS) to dismiss Civil Action 12-00272, a civil action by Joseph
m. Carik and other Fabry patients, seeking to compel the FDA to take steps
"ensure an adequate supply of the medications they need."

2015.  September 27.  The Mount Sinai patent number 5,356,804 expires in
the United States.

2016.  August. Mount Sinai’s European patent (based upon US Patent
5,356,804) expires in Europe.

James Love.  Knowledge Ecology International
http://www.keionline.org, KEI DC tel: +1.202.332.2670, US Mobile:
+1.202.361.3040, Geneva Mobile: +41.76.413.6584,   twitter.com/jamie_love

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