Patent Portfolio Sale: Fosphenytoin and Propofol

CYDEX PHARMACEUTICALS INC.
PATENT PORTFOLIO SALE OPPORTUNITY:
CAPTISOL-ENABLED™ FOSPHENYTOIN AND PROPOFOL PRODUCT
OPPORTUNITIES

Table of Contents

I. Executive Summary Snapshot ....................................................................I-1
II. Overview ..................................................................................................II-1
III. Intellectual Property ................................................................................III-1
IV. Market Data ........................................................................................... IV-1
V. Deal Summary ......................................................................................... V-1

DISCLAIMER
THE INFORMATION THAT HAS BEEN PROVIDED IS BELIEVED TO BE COMPLETE TO THE EXTENT
PROVIDED AND DESCRIBED, BUT NEITHER ICAP OCEAN TOMO NOR CYDEX PHARMACEUTICALS
INC. MAKE ANY WARRANTY THAT IT IS COMPLETE FOR ALL PURPOSES OR ANY SPECIFIC
PURPOSE, INDUSTRY, OR BUSINESS. EACH PARTY CONSIDERING THE PORTFOLIO IS CAUTIONED
TO MAKE ITS OWN ANALYSIS REGARDING THE UTILITY AND COVERAGE OF THE PORTFOLIO,
AND TO SEEK INDEPENDENT ASSISTANCE IN DOING SO.

I. Executive Summary Snapshot

The advanced drug formulation technology of CyDex’s, Captisol®, is based on a modified cyclodextrin
molecule that enables creation of new products by significantly improving the solubility, stability,
bioavailablity, safety and dosing of active pharmaceutical ingredients (APIs). Captisol® is one of a series
of anionically charged sulfobutyl ether β-cyclodextrins (SBE-CDs) that were originally synthesized and
patented by scientists from the University of Kansas Higuchi Biosciences Center for Drug Delivery
Research.

Five Captisol-enabled products currently are approved for market by CyDex licensees, and numerous
formulations using Captisol technology in various therapeutic areas and dosage forms are currently
advancing in the pipelines of other CyDex partners.

On behalf of Cydex, ICAP Ocean Tomo is offering for sale a portfolio of patents and patent applications
covering two important close-to-market, 505(b)(2), Captisol-enabled product opportunities:

• Captisol-enabled™ Fosphenytoin (CE-FOS). Fosphenyltoin is an approved injectable drug for
epilepsy (US tradename Cerebyx). However, this drug is formulated at high pH, and must be
stored refrigerated. CE-FOS, which includes a small amount of Captisol, offers the advantages of
converting from refrigerated storage at high pH to room temperature storage at a more bio-
compatible pH. Product stability of CE-FOS at room temperature is 24 months. CE-FOS has
already demonstrated to be bioequivalent to the marketed Cerebyx product. The product is
nearly market-ready with an open IND, and requiring filing of the Final Report to gain marketing
approval.

• Captisol-enabled™ Propofol. Propofol (US tradename Diprivan) is an injectable general
anesthetic which is only slightly soluble in water, and is formulated in a white, oil-water
emulsion. CE-Propofol represents an improved formulation with enhanced stability, reliability,
and effectiveness versus propofol, while reducing the potential for pain and allergic response.
In terms of development, a stable formulation of CE-Propofol has been identified, and a clinical
study has been completed. Marketing approval would require clinical BABE (bioabsorption
bioequivalence) studies, manufacturing batch approval and FDA filing.

This portfolio should be of interest to any pharmaceutical manufacturer, distributor, branded generic
company or specialty pharma company looking to enhance their product offering, including those
companies focused on injectable product opportunities.

I-1

Deal Summary

Interested parties should contact ICAP Ocean Tomo for additional information on this portfolio.

Contact Information

Please direct all inquiries regarding this portfolio to:

Cameron Gray, Ph.D, J.D. Thomas Reilly, Ph.D, MBA
Senior Vice President Senior Vice President
ICAP Ocean Tomo ICAP Ocean Tomo
Telephone: (312) 327-8175 Telephone: (302) 528-9009
Email: Cameron.Gray@us.icap.com Email: Thomas.Reilly@us.icap.com

I-2

II. Overview

CE-Fosphenytoin

Fosphenytoin (Cerebyx) is approved in the United States for parenteral administration in the short term
(five days or fewer) treatment of epilepsy. Fosphenytoin is a prodrug of phenytoin, and was created
address dosing issues with phenytoin including, required storage at high pH, induction of pain on
injection, poor solubility, and inability for intramuscular delivery. However to limit the conversion of
Fosphenytoin to phenytoin during storage, the prodrug must be kept under refrigeration at 2°C to 8°C,
and should not be stored at room temperature for more than 48 hours.

CE- FOS is an advanced formulation of Fosphenytoin which offers the significant advantages of lower pH
stability (7.0 to 8.5 for CE-FOS vs. 8.6 to 9.0 for Fosphenytoin 1) and storage at room temperature. The
CE-FOS product is bioequivalent to the marketed Cerebyx product. In this formulation, Captisol is
added not to solubilize the Fosphenytoin, but to solubilize any insoluble phenytoin that may form during
the product shelf-life. 2 CE-FOS has been proven to have two year stability at 25°C/60%RH, and may be
stored in either bags or syringes.

CE-Propofol

Propofol (2, 6-diisopropylphenol or 2, 6-bis (1-methylethyl)-phenol)) is an injectable, potent, short-
acting, non-barbiturate sedative-hypnotic agent for use in the induction and maintenance of anesthesia
or sedation. Intravenous injection of a therapeutic dose of propofol rapidly induces anesthesia usually
within 40 seconds from the start of injection. The formulation of this portfolio consists of: propofol; a
sulfoalkyl ether cyclodextrin (SAE-CD); and an aqueous liquid carrier. This formulation has the following
advantages over existing propofol formulations:

• Unlike existing formulations, this formulation is pharmaceutically stable and does not degrade
on exposure to light, oxidation or the presence of divalent or trivalent cations.

• The formulation also reduces pain on injection as compared to the known emulsion type
propofol formulations.

• It minimizes the allergic response and microbial contamination typically associated with
propofol parenteral formulations.

1
http://www.medscape.com/druginfo/monograph?cid=med&drugid=13896&drugname=Fosphenytoin+Inj&monot
ype=monograph
2
Narisawa S. and Stella V. J., Increased Shelf-Life of Fosphenytoin Solubilizaton of a Degradant, Phenytoin, through
Complexation with (SBE)7m-β-CD. J. Pharm. Sci. 87, (8),926-930

II-1

• It reduces lipid loading due to the lack of oil in the current parenteral formulation.

• The formulation can be sterile filtered unlike emulsion-type formulations of sedative hypnotics.

• It can be lyophilized 3 or otherwise dried to yield a solid formulation.

Technology Platform

Following is a pictorial representation of the technology platform used by both CE-FOS and CE-Propofol.

3
Lyophilization is a way of drying something that minimizes damage to its internal structure
II-2

III. Intellectual Property

The patent portfolio contains two (2) issued US patents and fifteen (15) related foreign counterparts.

Serial Priority Patent Expiration
Title Country Filing Date Issue Date
Number Date Number Date

Cyclodextrin Enabled Drugs
Fosphenytoin
Polar Drugs or Prodrug
Compositions with Extended *United
09/096,747 6/12/1998 6/13/1997 6133248 10/17/2000 6/12/2018
Shelf-life Storage and a Method States
of Making Thereof
Australia
Compositions with Extended
Phillips 80591/98 6/12/1998 6/13/1997 750207 10/24/2002 6/12/2018
Shelf-life Storage and a Method
Ormonde &
of Making Thereof
Fitzpatrick
Polar Drugs or Prodrug Austria
98928901 6/12/1998 6/13/1997 E253941 11/12/2003 6/12/2018
Shelf-life Storage and a Method Sonn &
of Making Thereof Partner
Belgium
Gevers & 98928901 6/12/1998 6/13/1997 986403 11/12/2003 6/12/2018
Vander
of Making Thereof
Haeghen
European
Union
Plougmann, 98928901 6/12/1998 6/13/1997 986403 11/12/2003 6/12/2018
Vingtoft &
of Making Thereof
Partners
France
Cabinet 98928901 6/12/1998 6/13/1997 986403 11/12/2003 6/12/2018
Regimbeau
of Making Thereof
Germany
Von
Compositions with Extended 69819721.6-
Kreisler 6/12/1998 6/13/1997 986403 11/12/2003 6/12/2018
Shelf-life Storage and a Method 08
Selting
of Making Thereof
Werner
Italy
Jacobacci & 98928901 6/12/1998 6/13/1997 986403 11/12/2003 6/12/2018
Partners
of Making Thereof

III-1


Japan
Inoue & 502895/10 6/12/1998 6/13/1997
Associates
of Making Thereof
Netherlands
Nederlands
ch 98928901 6/12/1998 6/13/1997 986403 11/12/2003 6/12/2018
Octrooibure
of Making Thereof
au
Portugal
A.G.
DaCunha 98928901 6/12/1998 6/13/1997 986403 11/12/2003 6/12/2018
Ferreira,
of Making Thereof
Lda.
Spain
Duran- 98928901 6/12/1998 6/13/1997 986403 11/12/2003 6/12/2018
Corretjer
of Making Thereof
Polar Drugs or Prodrug Sweden
Compositions with Extended Strom &
98928901 6/12/1998 6/13/1997 986403 11/12/2003 6/12/2018
Shelf-life Storage and a Method Gullikson
of Making Thereof AB
Switzerland
Micheli & 98928901 6/12/1998 6/13/1997 986403 11/12/2003 6/12/2018
Cie Sa
of Making Thereof
Polar Drugs or Prodrug United
Compositions with Extended Kingdom
98928901 6/12/1998 6/13/1997 986403 11/12/2003 6/12/2018
Shelf-life Storage and a Method Carpmaels
of Making Thereof & Ransford


Propofol
Formulations Containing
*United
Propofol And A Sulfoalkyl Ether 10/102,066 3/19/2002 3/20/2001 7,034,013 4/25/2006 3/19/2022
States
Cyclodextrin
Canada
Formulations Containing
Goudreau
Propofol And Sulfoalkyl Ether 2,441,744 3/19/2002 3/20/2001 3/19/2022
Gage
Cyclodextrin
Dubuc

III-2

IV. Market Data

• There are approximately 152,000 cases of status epilepticus each year in the U.S., resulting in
annual patient cost of $3.8 to $7.0 billion.

• In 2006, total US sales of Cerebyx were $71 million, and the market had growth of 16 percent
per year since 1998. Since then, generics have entered the market – Cerebyx annual sales are
now under $10 million.

• The total Propofol market size is projected to increase to $2.46 B by the year 2012. 4

• More generally the total anasthesia market size is projected to increase to $6.16 B by year
2012. 5

4
http://imshealth.com/imshealth/Global/Content/Static%20File/AMJ2006.pdf
5
http%3A%2F%2Frahuloliver.com%2Fresources%2FMGMT573_Project_Presentation_LEP.ppt&rct=j&q=propofol+
market+size&ei=_gzrS9PQMor58AaQve3BBA&usg=AFQjCNHJEL6WCDY6GQ78vy34DXyUFNloaw
IV-1

• The U.S. drug delivery system industry is $80.2 billion and demand is expected to grow 10
percent annually through 2012. 6 One of the most challenging problems for the pharmaceutical
industry in development of new drugs is poor solubility of lead compounds. In many cases, poor
water-solubility can delay and even prevent the commercialization of promising new drugs. The
use of Captisol to create a more soluble compound will be valuable to pharmaceutical
companies as they look to commercialize new technologies.

6
“Drug Delivery Systems to 2012 - Market Research, Market Share, Market Size, Sales, Demand Forecast, Market
Leaders, Company Profiles, Industry Trends,” Fredonia Group Study, March 2008.
IV-2

V. Deal Summary
Interested parties should contact either Cameron Gray or Thomas Reilly:

Cameron Gray, Ph.D, J.D. Thomas Reilly, Ph.D, MBA
Senior Vice President Senior Vice President
ICAP Ocean Tomo ICAP Ocean Tomo
Telephone: (312) 327-8175 Telephone: (302) 528-9009
Email: Cameron.Gray@us.icap.com Email: Thomas.Reilly@us.icap.com

Appendix

V-1

Patent Portfolio Sale: Fosphenytoin and Propofol

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