Patenting Antisense Oligonucleotides and Methods

1
Patenting Antisense Oligonucleotides and Methods

• Robert A. Schwartzman, Ph.D.
• Acting Supervisory Patent Examiner
• Art Unit 1636

2
Antisense Art Unit

• Art Unit 1635
• John LeGuyader, SPE
• Created October 1996

• Art Unit 1636
• George Elliott, Ph.D. SPE
• On fellowship at the National Academy of Sciences

3
Mechanism of Antisense
4
Antisense Technologies

• Antisense Oligonucleotides (Oligos)
• Catalytic Nucleic Acids Ribozymes and Dnazymes
• Triplex
• Pnas and Other Nonstandard Nucleic Acids
• Aptamers
• Decoys
• Nucleic Acid Modifications
• Oligo-based Gene Regulation and Gene Therapy

5
Issued U.S. Patents Classified in 536/24.5
Nucleic Acid Expression Inhibitors (as of July
17, 2001)
6
Case Law

• Antisense-Specific
• Enzo Biochem Inc. v. Calgene Inc., 52 USPQ2d 1129
  (Fed. Cir. 1999)
• Enablement - antisense highly unpredictable
• Decision is based on patents with effective
  filing dates of at least 1989 and the technology
  at that time
• Decision 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)

7
Gene Walk
8
Antisense Oligonucleotide Claims

• Consider a Broad Claim To
• An antisense oligonucleotide that inhibits
  expression of a nucleic acid encoding protein X.

9
Utility 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 utility
• also raises enablement (how to use) and possibly
  written description issues
• probe function alone for target not sufficient to
  provide utility for antisense, but may be for
  purposes other than claiming antisense.

10
Written 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.

11
Enablement Requirement

• Probability of finding functional antisense
  oligonucleotide to a target gene is high.
• Predictability of any single antisense
  oligonucleotide being effective is low
• Claim to specific antisense oligonucleotide may
  require evidence of function
• The current state of predictability for antisense
  may support a broad claim to antisense
  oligonucleotides
• But this may also raise prior art issues
  depending on what was known at the time of filing

12
Pharmaceutical 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.

13
Enablement Analysis for In Vivo Method Claims

• Describe scope of the claimed invention
• Cite known unpredictability in the art via
  journal articles
• Indicate amount of guidance in the specification
• Indicate presence or absence of working examples
• Identify additional experimentation that would be
  required

14
Enablement 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 307-319, 2000.
• Sun et al. Catalytic nucleic acids,
  Pharmacological Reviews, Vol. 52, Pages 325-347,
  2000.

15
Enablement Requirement

• Commonly Cited Unpredictable Factors for
  Antisense
• Predicting target accessibility
• Target folding/structure
• Antisense/target protein interactions
• Lack of correlation between in vitro and in vivo
• Efficient delivery to cells and cell targeting
  for specific disorders
• Oligo affinity/stability in vivo

16
Enablement Requirement

• Modulation of target
• In vitro (cell culture) results generally ? in
  vivo success
• Animal model shown may not be art recognized
• Human data is not ordinarily required by the
  examiner for in vivo claims
• But may be the only evidence to enable treatment
  claims
• Disorder dependent issue

17
Obviousness

• Expect 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.

18
Recommendations

• Claim 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 number

19
Recommendations

• Provide claims commensurate in scope with the
  disclosure of the specification
• Consider 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.

20
Recommendations

• Provide 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.

21
Recommendations

• Objective Evidence
• Case law
• Journal articles
• Experimental data
• Comparisons commensurate with the disclosure as
  filed.

22
QUESTIONS?

• John LeGuyader
• SPE - Art Unit 1635
• [phone]
• john.leguyader_at_uspto.gov

• Robert Schwartzman
• Acting SPE - Art Unit 1636
• [phone]
• robert.schwartzman_at_uspto.gov

23
Patenting Antisense Oligonucleotides and Methods

• Robert A. Schwartzman, Ph.D.
• Acting Supervisory Patent Examiner
• Art Unit 1636