Nucleonics' IP holdings include a strategic set of patents and patent applications, both internally-generated and in-licensed, that provide the company with freedom-to-operate in commercializing expressed RNAi (eiRNA) for therapeutic gene silencing applications as well as protection of the company's proprietary discoveries in RNAi. Nucleonics' IP activities include the ongoing evaluation, licensing, and internal and collaborative development of key technologies required for design, manufacturing, formulation, and delivery of DNA vector-based therapeutics as well as core RNAi technologies for RNAi-mediated gene silencing.

Nucleonics welcomes inquiries about sublicensing Nucleonics' IP, and also welcomes the opportunity to review relevant and complementary technologies available for licensing. Please explore the headings below for more information on Nucleonics' intellectual property portfolio. Additional patent applications will be added to the list below when published.

US Patent 6,506,559 Genetic Inhibition by Double-Stranded RNA, Fire et al., inventors. Issued Jan 14, 2003. US Patent Applications 2003/0051263, 2003/0055020, 2003/0056235, Genetic Inhibition by Double-Stranded RNA, Fire et al., inventors.

Nucleonics maintains a non-exclusive license to the landmark Fire et al. patent family owned by the Carnegie Institute of Washington. In addition to the US patent issued in 2003 with claims covering in vitro RNAi in animal and plant cells, a number of divisional applications and foreign applications drawing priority from the original Fire et al. filing in 1997 are currently in prosecution, and include claims to in vivo methods of RNA interference in research and animal therapeutics.

US Patent Application 2002/0114784. Composition and Method for In Vivo and In Vitro Attenuation of Gene Expression Using Double Stranded RNA. Li et al. inventors. (Priority Date: Jan. 28, 1999).

Nucleonics maintains an exclusive license (with sublicensing rights) from the Medical College of Georgia Research Foundation with respect to this patent family. The patent application represents the first disclosure of working examples of RNAi in vertebrates. Its Australian counterpart has issued in both standard and innovation patent forms (AU 2004100997, AU 776150) and it is being prosecuted in other foreign jurisdictions as well. The zebrafish studies disclosed in this application have been published in Developmental Biology 217:392 (2000).

US Patent 5,624,803. In Vivo Oligonucleotide Generator, and Methods of Testing The Binding Affinity of Triplex Forming Oligonucleotides Derived Therefrom. Noonberg and Hunt, inventors. Issued April 29, 1997.

Nucleonics has an exclusive license (with sublicensing rights) in the area of therapeutics from the University of California to this foundational intellectual property covering the use of RNA Polymerase III, Type III promoters for expression of short RNAs. These Pol III promoters, such as the U6, H1 and 7SK promoters, are the workhorses for expression of RNAs up to several hundred nucleotides in length, including short hairpin RNAi (shRNA). They are at the core of Nucleonics' plasmid vector technology for RNAi, as well as of the vast majority of RNAi expression vectors described in the scientific literature. Use of these promoters is considered essential for the timely development of expressed RNAi therapeutics. Prosecution of foreign counterparts is in process

US Patent Application 2004/0147476. Methods and Compositions for Inhibiting the Function of Polynucleotide Sequences. Satishchandran and Pachuk, inventors. (Priority Date: April 21, 1999).

Nucleonics has a co-exclusive license with Wyeth Pharmaceuticals to this patent family currently being prosecuted in the United States and foreign jurisdictions. Among the earliest filings to disclose methods of RNAi mediated gene silencing in mammals, these discoveries emerged from in vitro and in vivo studies on the behavior of RNA expression plasmids originally developed to provide plasmid-based cytokine adjuvants and viral antigens for DNA vaccine development.

PCT WO 01/04313 Methods and Compositions for Preventing the Formation of Aberrant RNA During Transcription of a Plasmid Sequence. Satishchandran and Pachuk, inventors. (Priority Date: July 9, 1999).

Co-exclusive license with Wyeth Pharmaceuticals. This patent discloses functional improvements and novel designs for nucleic acid vectors in order to increase specific, desired expression patterns and reduce or eliminate background or undesired transcriptional activity which commonly takes place in suboptimally-designed vectors used in heterologous gene expression applications in vivo, ex vivo, and in vitro.

US Patent Application 2004/0152117. Use of Post-Transcriptional Gene Silencing for Identifying Nucleic Acid Sequences That Modulate the Function of a Cell. Giordano et al, inventors. (Priority Date: Jan. 31, 2001).

Nucleonics-owned IP which covers novel methods for plasmid-expressed RNAi suitable for large scale genomics applications, such as determining the functional consequences of reducing the expression of unknown or poorly-characterized gene(s) and discovery of novel gene targets for cellular pathway modulation and disease intervention. The patent family details methods of intracellular RNAi expression suitable for functional genomics as well as therapeutic applications specifically demonstrated to avoid the cellular stress reponse initially believed to prohibit the practical use of RNAi in mammalian somatic cells. In particular, it represents a breakthrough in the field of expressed interfering RNAi by establishing that intracellular expression of dsRNAs, including long dsRNAs, does not trigger a stress response in stress-response competent mammalian cells.

US Patent Application 2005/0039224 Transfection Kinetics and Structural Promoters. Pachuk and Satishchandran, inventors. (Priority Date: Oct. 22, 2001)

Nucleonics-owned IP features designs for improving the strength of existing RNA polymerase promoter sequences and creating novel promoter elements in DNA expression vectors.

US Patent Application 2004/0180438 Methods and Compositions for Silencing Genes Without Inducing Toxicity. C. Pachuk, inventor. (Priority Date: April 26, 2002)

Nucleonics-owned IP describes methods for delivering RNAi to a cell while avoiding non-specific, dsRNA stress responses, using active and passive techniques.

US Patent Application 2005/0239728 Double Stranded RNA Structures and Constructs, and Methods for Generating and Using the Same. Pachuk et al., inventors. (Priority Date: July 31, 2002).

Nucleonics-owned IP covering novel short and long RNA silencing molecules including forced hairpin and partial hairpin double stranded RNA structures, methods for their synthesis and delivery via expression vectors and use in gene silencing.

PCT WO 2004/035765 Double Stranded RNA Structures and Constructs, and Methods for Generating and Using the Same. Pachuk et al., inventors. (Priority Date: July 21, 2002)

Nucleonics-owned IP disclosing novel short and long RNA silencing molecules, and modes of their expression and use. Features multiple-target dsRNAs and methods for achieving preferential folding and processing.

PCT WO 2004/076629 Methods and Constructs for Evaluation of RNAi Targets and Effector Molecules. C. Pachuk, inventor. (Priority Date: February 27, 2003).

Nucleonics-owned IP disclosing novel reporter-target sequence fusion constructs suitable for screening or selecting highly active RNAi or eiRNA sequences in high-throughput assay format.

PCT WO 2005/040388 Multiple-Compartment Eukaryotic Expression Systems. Pachuk and Satishchandran, inventors. (Priority Date: August 22, 2003).

Nucleonics-owned IP disclosing novel expression constructs and methods for directing and optimizing RNA synthesis in multiple cellular compartments, sub-compartments, and functional domains of a eukaryotic cell, including various nuclear, cytoplasmic, and mitochondrial compartments.

U.S. Patent 5,874,565 Nucleic Acids Comprising a Highly Conserved Novel 3' Terminal Sequence Element of the Hepatitis C Virus. Rice and Kolykhalov, inventors. Issued February 23, 1999

Nucleonics maintains a non-exclusive license from Apath, LLC to intellectual property rights for the use of conserved sequences within the 3' non-coding region of the hepatitis C virus genome discovered by Dr Charles M. Rice and colleagues.

U.S. Patent 6,127,116 Functional DNA Clone for Hepatitis C Virus (HCV) and Uses Thereof. Rice and Kolykhalov, inventors. Issued October 3, 2000.

Nucleonics maintains a non-exclusive license from Apath, LLC to this continuation-in-part of the 5,874,565 filing (see above) covering functional HCV replicons comprising the 3' conserved sequence element of HCV.

U.S. Patent 6,392,028 Functional DNA Clone for Hepatitis C Virus (HCV) and Uses Thereof. Rice and Kolykhalov, inventors. Issued May 21, 2002.

Nucleonics maintains a non-exclusive license from Apath, LLC to this continuation of the 6,127,116 filing (see above), covering functional HCV replicons comprising the 3' conserved sequence element of HCV.

PCT WO 2005/014806 Conserved HBV and HCV Sequences Useful for Gene Silencing. Pachuk et al., inventors. (Priority Date June 12, 2003).

This Nucleonics-owned filing is based on the selection of specific HBV and HCV sequence elements and combinations thereof suitable for use as therapeutic RNAi and eiRNA targets. This application discloses sequences conserved among several hundred independent isolates of HBV and HCV and further discloses examples of specific shRNA and eiRNA vectors able to inhibit viral replication and protein expression in hepatocytes.

U.S. Patent 5,981,505 Compositions and Methods for Delivery of Genetic Material. Weiner et al., inventors. Issued November 9, 1999.

Nucleonics maintains a license from the Wistar Institute to this patent covering technology developed by David Weiner and collaborators for facilitated prophylactic and therapeutic administration of DNA vectors using bupivacaine:DNA complexes.

U.S. Patent 5,837,533 Complexes Comprising a Nucleic Acid Bound to a Cationic Polyamine Having an Endosome Disruption Agent. R. Boutin, inventor. Issued November 17, 1998.

Nucleonics maintains a co-exclusive license with Wyeth Pharmaceuticals to this patent. This is the first of 4 related patents to issue (see below) from work originally done at Apollon Inc.(acquired by Wyeth Vaccines) and includes broad composition claims to diverse nucleic acid delivery complexes. Compositions comprise a nucleic acid such as a DNA vector complexed to a transfer moiety, which includes polyamines, endosomal membrane disruption agents, and cellular receptor-targeting agents.

U.S. Patent 6,127,170 Multifunctional Complexes for Gene Transfer into Cells Comprising a Nucleic Acid Bound to a Polyamine and Having a Endosome Disruption Agent. R. Boutin, inventor. Issued October 3, 2000.

Nucleonics maintains a co-exclusive license with Wyeth Pharmaceuticals to this patent which is a continuation-in-part of the U.S. Patent 5,837,533 filing (above) with additional claims to compositions of multifunctional nucleic acid delivery complexes.

U.S. Patent 6,379,965 Multifunctional Complexes for Gene Transfer into Cells Comprising a Nucleic Acid Bound to a Polyamine and Having an Endosome Disruption Agent. R. Boutin, inventor. Issued April 30, 2002.

Nucleonics maintains a co-exclusive license with Wyeth Pharmaceuticals to this patent which was a divisional application of patent 6,127,170 above with further claims to compositions of multifunctional nucleic acid delivery complexes.

U.S. Patent Application 2002/0155607 Multifunctional Molecular Complexes for Gene Transfer to Cells. R. Boutin, inventor. (Priority Date: September 29, 1995).

Nucleonics maintains a co-exclusive license with Wyeth Pharmaceuticals to this divisional filing of patent 6,379,965 (above), which claims methods of using the polyamine-based multifunctional complexes to deliver nucleic acids to cells.

U.S. Patent 6,217,900 Vesicular Complexes and Methods of Making and Using Same. Ciccarelli et al., inventors. Issued April 17, 2001.

Nucleonics maintains a co-exclusive license with Wyeth Pharmaceuticals to this patent claiming novel compositions and processes for making defined nucleic acid or protein delivery vesicles or particles comprising local anaesthetics (e.g. bupivacaine).

U.S. Patent 6,383,512 Vesicular Complexes and Methods of Making and Using Same. Ciccarelli et al., inventors. Issued May 7, 2002.

Nucleonics maintains a co-exclusive license with Wyeth Pharmaceuticals to this divisional filing of patent 6,383,512 (above) claiming methods for delivery to cells of nucleic acids and proteins using vesicles containing local anaesthetics and further compositions of these vesicles.

PCT WO 03/093449 Methods for Delivery of Nucleic Acids. C. Satishchandran, inventor. (Priority Date: May 6, 2002).

Nucleonics-owned IP which discloses novel formulations for nucleic acid delivery to cells. The formulations feature spermine-based compounds for DNA complexation, cell targeting and endosomal escape, and various oil-in-water emulsions comprising nucleic acids and cationic amphiphiles.

US Patent 6,989,265 Bacteria With Reduced Genome. Blattner, et al. inventors. Issued January 24, 2006.

Non-exclusive license from Scarab Genomics, LLC. The Scarab technology provides Nucleonics with superior host strains for manufacturing of plasmid DNA.

US Patent 5,851,804 Chimeric Kanamycin Resistance Gene. Snyder & Satishchandran, inventors. Issued December 22, 1998.

Co-exclusive license with Wyeth Pharmaceuticals covering the modified kanamycin resistance gene used in Nucleonics eiRNA vectors. This gene allows for antibiotic selection in bacteria during plasmid manufacturing but will not confer broad resistance to therapeutically relevant aminoglycoside antibiotics in a bacterial cell theoretically acquiring the vector during infection of an individual to whom the plasmid was administered.

US Patent 6,168,918 Method of Detecting Foreign DNA Integrated in Eukaryotic Chromosomes. Satishchandran et al. inventors. Issued January 2, 2001.

Co-exclusive license with Wyeth Pharmaceuticals covering methods developed for safety assurance of therapeutically administered plasmid DNA.