4Antisense Technologies Antisense Oligonucleotides (Oligos)Catalytic Nucleic Acids: Ribozymes and DnazymesTriplexPnas and Other Nonstandard Nucleic AcidsAptamersDecoysNucleic Acid ModificationsOligo-based Gene Regulation and Gene Therapy
5Issued U. S. Patents Classified in 536/24 Issued U.S. Patents Classified in 536/24.5 – Nucleic Acid Expression Inhibitors (as of July 17, 2001)Data obtained using USPTO WEST subclass search for all issued patents citing 536/ Nucleic Acid Expression Inhibitor
6Case Law Antisense-Specific: Enzo Biochem Inc. v. Calgene Inc., 52 USPQ2d 1129 (Fed. Cir. 1999)Enablement - antisense highly unpredictableDecision is based on patents with effective filing dates of at least 1989 and the technology at that timeDecision does not necessarily determine the outcome for examination of antisense patent applications recently filed because current knowledge and level of skill in the art is high (antisense has progressed as a technology since 1989)
8Antisense Oligonucleotide Claims Consider a Broad Claim To:An antisense oligonucleotide that inhibits expression of a nucleic acid encoding protein X.
9Utility Requirement Utility generally not an issue for antisense. If no function for target nucleic acid (protein or regulatory) is shown or was known:antisense would likely lack utilityalso raises enablement (how to use) and possibly written description issuesprobe function alone for target not sufficient to provide utility for antisense, but may be for purposes other than claiming antisense.
10Written Description Requirement Written description generally not an issue for broad claims to antisense oligos inhibiting expression of a nucleic acid encoding a protein.May lack written description if the claim reads on targeting many different nucleic acids.Analysis turns on what is shown in the specification and what was known about the various versions of the gene at the time of filing.Provide evidence that antisense targets identified in one gene correlate with targets in other versions of the gene.
11Enablement Requirement Probability of finding functional antisense oligonucleotide to a target gene is high.Predictability of any single antisense oligonucleotide being effective is lowClaim to specific antisense oligonucleotide may require evidence of functionThe current state of predictability for antisense may support a broad claim to antisense oligonucleotidesBut this may also raise prior art issues depending on what was known at the time of filing
12Pharmaceutical and Method Claims Consider Broad Claims To:A pharmaceutical composition comprising an antisense oligonucleotide that inhibits expression of a nucleic acid encoding protein X.A method of treating a disease comprising administering an antisense oligonucleotide that inhibits expression of a nucleic acid encoding protein X.
13Enablement Analysis for In Vivo Method Claims Describe scope of the claimed inventionCite known unpredictability in the art via journal articlesIndicate amount of guidance in the specificationIndicate presence or absence of working examplesIdentify additional experimentation that would be required
14Enablement Requirement Commonly Cited References Used by Examiners to Support Unpredictability in Antisense:Crooke, S.T. “Basic principles of antisense therapeutics”, Chapter 1, pages 1-50, Handbook of Experimental Pharmacology, Vol. 131, “Antisense Research and Application”, Ed.Cooke, S.T., Springer-Verlag, New York, 1998.Crooke, S.T. “Progress in antisense technology: the end of the beginning”, Methods in Enzymology, Vol. 313, pages 3-45, 2000.Agrawal et al. “Antisense therapeutics: is it as simple as complementary base recognition?”, Molecular Medicine Today, Vol. 6, Pages 72-81, February 2000.Jen et al. “Suppression of gene expression by targeted disruption of messenger RNA: available options and current strategies”, Stem Cells, Vol. 18, pages , 2000.Sun et al. “Catalytic nucleic acids”, Pharmacological Reviews, Vol. 52, Pages , 2000.
15Enablement Requirement Commonly Cited Unpredictable Factors for Antisense:Predicting target accessibilityTarget folding/structureAntisense/target protein interactionsLack of correlation between in vitro and in vivoEfficient delivery to cells and cell targeting for specific disordersOligo affinity/stability in vivo* Predicting target accessibility.- Screening for best sites still required in most cases for in vivo.* Efficient delivery to cells and cell targeting for specific diseases/conditions.- Adequate intracellular levels of ODNs in view of poor transit across cell membranes.- Immunologic effects from unmethylated G-C sequences and modified ODNs.- Toxicity effects from high concentrations and/or ODN modifications.* ODN Affinity/Stability in vivo- Intracellular ODN breakdown by nucleases.- Largely overcome by chemical modifications of sugar, base and backbone which retain the RNase-H activation.* In vitro (cell culture) results are generally not considered predictive and/or representative of successful in vivo delivery and/or treating disorders.* Evidence should be provided that an animal model is art recognized, especially for human applicability.
16Enablement Requirement Modulation of targetIn vitro (cell culture) results generally in vivo successAnimal model shown may not be art recognizedHuman data is not ordinarily required by the examiner for in vivo claimsBut may be the only evidence to enable treatment claimsDisorder dependent issue
17ObviousnessExpect an obviousness rejection against broad antisense claims to known genes if the prior art suggested inhibiting the gene by antisense or other means and the gene sequence was known.The current knowledge and level of skill in the art is high such that one of ordinary skill in the art would expect at least one effective antisense against every known gene (e.g. a full-length antisense), absent evidence to the contrary.Narrow claims to specific antisense oligos may be free of the art, since there may be no motivation to modify the prior art to achieve the specific antisense sequence claimed.
18RecommendationsClaim functional antisense oligos by specific sequence if you have evidence of activity.List Results of “Gene Walk”Showing activity of each oligo“Gene walk” data may provide representative number of species for broad breadth/scope for a generic claim, but there is no magic numberIf you can’t claim antisense because of 112 issues, try claiming probes.
19RecommendationsProvide claims commensurate in scope with the disclosure of the specificationConsider the scope of the target nucleic acid.Consider the scope of disease/disorder being treated.Consider the scope of route of administration.Consider the scope of vector delivery system.
20RecommendationsProvide objective evidence that in vitro results are representative of in vivo applicability.Respond to examiner-cited unpredictable factors with objective evidence to the contrary.Expert opinions are more favorably viewed when supported using objective evidence.Provide objective evidence that a particular animal model is generally accepted as representative of disease or methods of treating, particularly for humans.
21Recommendations Objective Evidence Case law Journal articles Experimental dataComparisons commensurate with the disclosure as filed.
22QUESTIONS? John LeGuyader Robert Schwartzman SPE - Art Unit 1635 (703)Robert SchwartzmanActing SPE - Art Unit 1636(703)
23Patenting Antisense Oligonucleotides and Methods Robert A. Schwartzman, Ph.D.Acting Supervisory Patent ExaminerArt Unit 1636