JOHN L MARSHALL
Broker in Hopedale, MA

2002004, Apr 11, 2002

Sep 9, 1999

09/392462

NELSON S. YEW - WEST UPTON MA, US
MALGORZATA PRZBYLSKA - ARLINGTON MA, US
JOHN MARSHALL - HOPEDALE MA, US
RONALD K. SCHEULE - HOPKINTON MA, US
JENNIFER TOUSIGNANT - CAMBRIDGE MA, US
SENG H. CHENG - WELLESLEY MA, US

A61K048/00, C07H021/04, C12P019/34, C12N015/64, C12N015/88

514/044000, 435/091100, 435/091400, 435/458000, 536/023100

Unmethylated plasmid DNA vectors are a major contributor to the inflammatory response associated with gene delivery. Results of clinical studies where CF subjects were subjected to either aerosolized liposomes alone or cationic lipid:DNA complexes indicated that bacterial derived plasmid DNA may be inflammatory. Additionally, unmethylated CpG dinucleotides have been shown to be immunostimulatory and are present at a much higher frequency in bacterially derived plasmid DNA compared to vertebrate DNA. The invention provides for methods of modulating the immunostimulatory response to gene delivery by modifying the plasmid delivered to the cell. The plasmid is modified to reduce or eliminate the immunostimulatory response in order to preserve the efficacy of gene transfer but reduce the associated toxicity. In a preferred embodiment, the invention provides for a method of reducing inflammatory response to gene delivery by methylating CpG motifs of the plasmid vector and or removing CpG motifs of the plasmid vector.

5981275, Nov 9, 1999

Apr 14, 1997

8/839552

Donna Armentano - Belmont MA
John Marshall - Hopedale MA
Nelson S. Yew - West Upton MA
Seng H. Cheng - Wellesley MA
Richard J. Gregory - Westford MA

Genzyme Corporation - Cambridge MA

C12N 1500

4353201

The invention is directed to a transgene expression system comprising a transcription unit which contains a transgene operably linked to expression control sequences, preferably the CMV promoter, and which is delivered simultaneously with all or part of the adenovirus E4 genomic region to a cell in order to facilitate persistent expression of the transgene. The components of the transgene expression system can be delivered by vectors including plasmids and/or viruses and may be complexed with cationic amphiphiles to facilitate entry into a cell. The invention is also directed to methods for the production of the transgene expression system. The invention is further directed to compositions that contain the transgene expression system and to methods for the use of such compositions to deliver transgenes encoding biologically active proteins to cells.

2001004, Dec 6, 2001

Jun 18, 1999

09/335689

JENNIFER D. TOUSIGNANT - CAMBRIDGE MA, US
SIMON J. EASTMAN - HUDSON MA, US
EDWARD R. LEE - NATICK MA, US
RONALD K. SCHEULE - HOPKINTON MA, US
SENG H. CHENG - WELLESLEY MA, US
J. NIETUPSKI - MILLBURY MA, US
QIUMING CHU - MELROSE MA, US
JOHN MARSHALL - HOPEDALE MA, US

A61K048/00, A61K009/22, A61K009/127

424/450000, 424/468000, 514/044000, 435/458000

The effective introduction of foreign genes and other biologically active molecules into targeted mammalian cells is a challenge still facing those skilled in the art. Gene therapy, for example, requires successful transfection of target cells in a patient. The present invention relates to novel micellar complexes of cationic amphiphilic compounds that facilitate delivery of biologically active molecules to the targeted cells of a mammal. The novel micellar complexes are comprised of a cationic amphiphile, a biologically active molecule, a derivative of polyethylene glycol (PEG), and optionally, a co-lipid. A further aspect of the invention is the use of targeting agents in any of the methods that effectuate the delivery of biologically active molecules into the cells of mammals. A targeting agent is usually any molecule, peptide sequence, or large protein that preferentially targets or binds to specific mammalian cells.

2003022, Nov 27, 2003

Nov 8, 2002

10/291041

Nelson Yew - West Upton MA, US
Malgorzata Przybylska - Arlington MA, US
John Marshall - Hopedale MA, US
Ronald Scheule - Hopkinton MA, US
Jennifer Tousignant - Cambridge MA, US
Seng Cheng - Wellesley MA, US

Genzyme Corporation

A61K048/00

514/044000, 536/023200

Unmethylated plasmid DNA vectors are a major contributor to the inflammatory response associated with gene delivery. Results of clinical studies where CF subjects were subjected to either aerosolized liposomes alone or cationic lipid:DNA complexes indicated that bacterial derived plasmid DNA may be inflammatory. Additionally, unmethylated CpG dinucleotides have been shown to be immunostimulatory and are present at a much higher frequency in bacterially-derived plasmid DNA compared to vertebrate DNA. The invention provides for methods of modulating the immunostimulatory response to gene delivery by modifying the plasmid delivered to the cell. The plasmid is modified to reduce or eliminate the immunostimulatory response in order to preserve the efficacy of gene transfer but reduce the associated toxicity. In a preferred embodiment, the invention provides for a method of reducing inflammatory response to gene delivery by methylating CpG motifs of the plasmid vector and/or removing CpG motifs of the plasmid vector.

2003014, Jul 31, 2003

Nov 22, 2002

10/301867

Jennifer Tousignant - Cambridge MA, US
Simon Eastman - Hudson MA, US
Edward Lee - Natick MA, US
Ronald Scheule - Hopkinton MA, US
Seng Cheng - Wellesley MA, US
J. Nietupski - Millbury MA, US
Quiming Chu - Melrose MA, US
John Marshall - Hopedale MA, US

GENZYME CORPORATION

A61K009/127, C12N015/88

424/450000, 435/458000

The effective introduction of foreign genes and other biologically active molecules into targeted mammalian cells is a challenge still facing those skilled in the art. Gene therapy, for example, requires successful transfection of target cells in a patient. The present invention relates to novel micellar complexes of cationic amphiphilic compounds that facilitate delivery of biologically active molecules to the targeted cells of a mammal. The novel micellar complexes are comprised of a cationic amphiphile, a biologically active molecule, a derivative of polyethylene glycol (PEG), and optionally, a co-lipid. A further aspect of the invention is the use of targeting agents in any of the methods that effectuate the delivery of biologically active molecules into the cells of mammals. A targeting agent is usually any molecule, peptide sequence, or large protein that preferentially targets or binds to specific mammalian celis.

6331524, Dec 18, 2001

Apr 7, 1997

8/835213

Ronald K. Scheule - Hopkinton MA
Rebecca G. Bagley - Natick MA
Simon J. Eastman - Hudson MA
Seng H. Cheng - Wellesley MA
John Marshall - Hopedale MA
David J. Harris - Lexington MA
Edward R. Lee - Natick MA
Craig S. Siegel - Woburn MA
S. Catherine Hubbard - Belmont MA
Duane E. Johnson - Encinitas CA
Daniel C. Maneval - San Diego CA
H. Michael Shepard - Rancho Santa Fe CA
Richard J. Gregory - Westford MA

Genzyme Corporation - Framingham MA

A61K 4800, C12N 1588, C12N 1563

514 44

Novel cationic amphiphiles are provided that facilitate transport of biologically active (therapeutic) molecules into cells. The amphiphiles contain lipophilic groups derived from steroids, from mono or dialkylamines, or from alkyl or acyl groups; and cationic groups, protonatable at physiological pH, derived from amines, alkylamines or polyalkylamines. There are provided also therapeutic compositions prepared typically by contacting a dispersion of one or more cationic amphiphiles with the therapeutic molecules. Therapeutic molecules that can be delivered into cells according to the practice of the invention include DNA, RNA, and polypeptides. Representative uses of the therapeutic compositions of the invention include providing gene therapy, and delivery of antisense polynucleotides or biologically active polypeptides to cells. With respect to therapeutic compositions for gene therapy, the DNA is provided typically in the form of a plasmid for complexing with the cationic amphiphile. Novel and highly effective plasmid constructs are also disclosed, including those that are particularly effective at providing gene therapy for clinical conditions complicated by inflammation.

2013013, May 30, 2013

Nov 24, 2010

13/511768

Hanlan Liu - Lexington MA, US
Chris Willis - Southborough MA, US
Renu Bhardwaj - Ashland MA, US
Diane P. Copeland - Billerica MA, US
Abizer Harianawala - Acton MA, US
Jeffrey Skell - Westborough MA, US
John Marshall - Hopedale MA, US
Jianmei Kochling - Wellesley MA, US
Gerard Palace - Framingham MA, US
Judith Peterschmitt - Watertown MA, US
Craig Siegel - Woburn MA, US
Seng Cheng - Natick MA, US

GENZYME CORPORATION - Cambridge MA

C07D 319/16, A61K 45/06, A61K 31/4025

514422, 548526

The hemitartrate salt of a compound represented by the following structural formula: (Formula I Hemitartrate), which may be used in pharmaceutical applications, are disclosed. Particular single crystalline forms of the Formula (I) Hemitartrate are characterized by a variety of properties and physical measurements. As well, methods of producing crystalline Formula (I) Hemitartrate, and using it to inhibit glucosylceramide synthase or lowering glycosphingolipid concentrations in subjects to treat a number of diseases, are also discussed. Pharmaceutical compositions are also described.

2001003, Oct 18, 2001

Feb 6, 2001

09/777743

Robin Ziegler - Sterling MA, US
Seng Cheng - Wellesley MA, US
John Marshall - Hopedale MA, US
Mark Goldberg - Needham MA, US

A61K048/00, A61K038/47, A61K031/663

514/044000, 424/094610, 514/102000

Methods are disclosed for treatment of patients suffering from accumulation of a metabolite within macrophages, such as in lysosomal storage diseases. The methods comprise treating the patient with a macrophage depleting amount of a bisphosphonate compound, such that apoptosis of macrophages is induced and the metabolite is released into circulation so that the metabolites may be eliminated from the patient. The methods may further include administration of a gene therapy vector for the treatment of lysosomal storage diseases.