Utility Guidelines Homology Claims and AntiSense Molecule Claims

Utility Guidelines, Homology Claims and Anti-Sense Molecule Claims Drew Hissong, Ph. D. dhissong*sughrue. com Sughrue Mion, PLLC 2004. 2. 12 1

The Basic Requirements for Patentability Under U. S. Patent Laws n n 35 U. S. C. § 101 - Utility and Subject Matter 35 U. S. C. § 102 - Novelty 35 U. S. C. § 103 - Non-obviousness 35 U. S. C. § 112 - Disclosure and Claims – First Paragraph • Written Description • Enablement • Best Mode – Second Paragraph • Definiteness 2

Utility Requirements Under 35 U. S. C. § 101 n 35 U. S. C. § 101 – Inventions Patentable Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title. 3

How Do Examiners Determine Utility? n n n On January 5, 2001, the United States Patent and Trademark Office (U. S. PTO) published the final version of the “Utility Examination Guidelines” in the Federal Register. U. S. PTO patent examiners follow these Guidelines when examining patent applications for compliance with the patent statutes. The utility Guidelines are applicable to all areas of technology. However, they are particularly relevant in areas of emerging technologies, such as gene-related technologies, where uses for new materials that have not been fully characterized are not readily apparent. The Guidelines, as published in the Federal Register: http: //www. uspto. gov/web/offices/com/sol/notices/utilexmguide. pdf A more convenient form is available on the U. S. PTO website at: http: //www. uspto. gov/web/menu/utility. pdf 4

What do the Guidelines Require? n n A well-established utility, or An asserted specific, substantial and credible utility. 5

Well-Established Utility n n A specific, substantial, and credible utility which is well-known, immediately apparent, or implied by the specification’s disclosure of the properties of a material, alone or taken with the knowledge of one skilled in the art. For new technologies, a more detailed assertion or explanation will be required. Example: first disclosure of DNA sequence of cow myosin – well known utilities for myosin from many other animal species. Example: monoclonal antibodies that specifically bind a protein only expressed on the surface of virally-infected cells – implied well-established utility in tagging cells with a marker or targeting cells with cytotoxic conjugates. 6

Specific Utility n A utility that is specific to the subject matter claimed. This contrasts with a general utility that would be applicable to the broad class of the invention. n Example: method of screening for a protein of unknown function as a means of diagnosing an unspecified disease – general utility, not specific for the protein. n Example: use of a polynucleotide with no identified open reading frame as a chromosomal marker – general utility, not specific for the polynucleotide. 7

Substantial Utility n n n An utility that defines a “real world” use. An utility that would require additional research to identify or reasonably confirm a “real world” use for the invention is not substantial utility. Use of a protein of unknown function in an assay to identify binding partners of the protein is not a substantial utility. Requires further research to determine protein function. Use of a polynucleotide sequence lacking a defined coding sequence in a screen for the complementary c. DNA is not a substantial utility. Requires further research to determine function of protein encoded by c. DNA. Use of a polynucleotide sequence lacking a defined coding sequence to produce a protein of unknown function, in turn used in antibody production for use in screening for protein expression is not a substantial utility. Requires further research to determine protein function. 8

Substantial Utility “Wheel” Nucleic Acid Protein Probe for disease state e. g. cancer gene mutation Antibody Assay for specific, substantial, credible use 9 Jasemine C. Chambers, U. S. PTO Director, Technology Center 1600

“Throw Away” Utility n A “throw away” utility is an asserted utility that does not meet the tests for a specific or substantial utility. – A throw away utility is a one that is asserted when no other utility is known. – Use of a transgenic mouse as snake food is a utility that is neither specific (all mice could function as snake food) nor substantial (using a mouse costing thousands of dollars to produce as snake food is not a “real world” use). – Use of a protein of unknown function as an animal food supplement or a shampoo ingredient are “throw away” utilities. n However, if a transgenic mouse was specifically generated to serve as a snake food with an enhanced nutrient profile, and disclosed for use as an animal food in the specification, then the test for specific and substantial asserted utility would be considered to have been met. 10

Credible Utility n n An utility asserted by an applicant is considered credible unless: – (A) the logic underlying the assertion is seriously flawed, or – (B) the facts upon which the assertion is based are inconsistent with the logic underlying the assertion. Credibility refers to the reliability of the statement based on the logic and facts that are offered by the applicant to support the asserted utility. 11

Credible Utility n An asserted utility is credible if a person of ordinary skill in the art would readily accept that the recited or disclosed invention could be used for the asserted use. – For example, a gene therapy method that can be used to prevent death before the age of 150 years would not be credible. However, a method of treating diabetes using the gene therapy method may be a credible utility. 12

Example #1: Polynucleotide without identified open reading frame Claim 1. A polynucleotide molecule as set forth in SEQ ID NO: 1. n The specification only discloses the polynucleotide molecule set forth in SEQ ID NO: 1, comprising 348 nucleotides (an ORF was not identified), and teaches how to use the polynucleotide molecule as a probe of a c. DNA library. – 1) Well-established utility for the polynucleotide? • No, because there is no disclosure of activity of the protein encoded by the c. DNA. – 2) Specific asserted utility? • No, because the asserted utility (probe) is not specific to the polynucleotide, it would be applicable to polynucleotides in general. 13

Example #1: Polynucleotide without identified open reading frame – 3) Substantial asserted utility? • No, because the protein to be identified by the claimed polynucleotide has an unknown function, the use of the polynucleotide as a probe is not a real-world use. More research would be required to determine the utility of the protein. – 4) Credible asserted utility? • Maybe, but irrelevant because no specific or substantial asserted utility. 14

Example #2: c. DNA with an identified open reading frame, no function known for the polypeptide Claim 1. A c. DNA molecule as set forth in SEQ ID NO: 1. n The specification discloses a c. DNA molecule set forth in SEQ ID NO: 1, comprising 348 nucleotides encoding a polypeptide of 116 amino acids, and teaches how to use the polypeptide in a method of screening for binding partners. No function is given for the polypeptide. – 1) Well-established utility for the polypeptide? • No, because there is no disclosure of activity. – 2) Specific asserted utility? • No, because the asserted utility (screen for binding partners) is not specific to the polypeptide, it would be applicable to polypeptides in general. 15

Example #2: c. DNA with an identified open reading frame, no function known for the polypeptide – 3) Substantial asserted utility? • No, because the polypeptide has an unknown function, as would the binding partners identified using the screen. More research would be required to determine the utility of the polypeptide and the binding partner. – 4) Credible asserted utility? • Maybe, but irrelevant because no specific or substantial asserted utility. 16

Example #3: c. DNA with an identified open reading frame, novel function for the polypeptide Claim 1. A c. DNA molecule as set forth in SEQ ID NO: 1. n The specification discloses a c. DNA molecule set forth in SEQ ID NO: 1, comprising 348 nucleotides encoding a polypeptide of 116 amino acids. Specification asserts novel function for polypeptide in detecting magnetic fields. Specification further teaches the polypeptide can be used in a “biological compass. ” – 1) Well-established utility for the polypeptide? • No, because the asserted activity has not been documented for any previous protein. – 2) Specific asserted utility? • Yes, because the asserted utility (magnetic field detection) is specific to this polypeptide. 17

Example #3: c. DNA with an identified open reading frame, novel function for the polypeptide – 3) Substantial asserted utility? • Yes, the biological compass would have real world utility. – 4) Credible asserted utility? • Maybe. Depends on the data presented in the specification. Because this is a novel activity, need supporting documentation to demonstrate the results are credible. 18

Example #4: c. DNA with an identified open reading frame and homology to ligase Claim 1. A c. DNA molecule as set forth in SEQ ID NO: 1. n The specification discloses a c. DNA molecule set forth in SEQ ID NO: 1, comprising 348 nucleotides encoding a polypeptide of 116 amino acids. An alignment of the polypeptide with the consensus sequence of several mammalian DNA ligases reveals 95% similarity. The specification asserts that SEQ ID NO: 1 encodes a ligase. – 1) Well-established utility for the polypeptide? • Yes, because there is a well-known disclosed activity. 19

Responses to “lack of utility” rejection n n Argue that specification includes an asserted utility that the Examiner overlooked. Argue that specification includes an implied utility based on examples. Evidence of an utility cannot be introduced during prosecution of the application to prove an utility not asserted in the application as filed. However, evidence supporting an asserted utility can be introduced during prosecution when the Examiner finds the asserted utility to be non-credible. Supporting evidence can be from experiments conducted after application was filed. – Submit affidavit under 37 C. F. R. § 1. 132 with supporting experimental data. – Submit affidavit under 37 C. F. R. § 1. 132 asserting/explaining credibility of utility asserted in application as filed. 20

Homology Claims n n Claims to polynucleotide and polypeptide sequences based on homology to a reference molecule. Homology may be based on sequence homology, identity, or similarity. For example: – Claim 1. An isolated polynucleotide molecule having at least 90% homology over the entire length of the polynucleotide molecule set forth in SEQ ID NO: 1. – Claim 2. An substantially pure polypeptide having at least 85% homology over the entire length of the amino acid sequence of SEQ ID NO: 2. 21

Homology Claims n Homology may be also based on hybridization with a reference sequence. For example: – Claim 1. An isolated polynucleotide that hybridizes under stringent hybridization conditions with the complement of the polynucleotide molecule set forth in SEQ ID NO: 1. – Claim 2. An substantially pure polypeptide encoded by polynucleotide that hybridizes under stringent hybridization conditions with the complement of the polynucleotide molecule set forth in SEQ ID NO: 1. – Claim 3. An substantially pure polypeptide encoded by polynucleotide that hybridizes under stringent hybridization conditions with the complement of a polynucleotide molecule encoding the polypeptide set forth in SEQ ID NO: 2. 22

Homology Claims n For claims to homology with a reference sequence based on percent sequence similarity, what percent of similarity is permitted by the U. S. PTO? – Unclear, moving target depending on particular examiners and supervisors. – Some indication that examiners are being taught to require a certain minimum percentage (90%? ? ? ). – Include reference to all prior art homologues. If art teaches molecules having 80% similarity, need to recite a higher degree of homology. 23

Homology Claims n How to obtain allowance of claims with recitations of low percentages of similarity? – Include function of the homologues in the claims. • Claim 1. An isolated polynucleotide molecule having at least 80% homology over the entire length of the polynucleotide molecule set forth in SEQ ID NO: 1, wherein said isolated polynucleotide has the same activity as the polypeptide encoded by SEQ ID NO: 1. • Claim 2. An substantially pure polypeptide having at least 80% homology over the entire length of the amino acid sequence of SEQ ID NO: 2, wherein said polypeptide has DNA ligase activity. 24

Homology Claims n How to obtain allowance of claims with recitations of low percentages of similarity? – Include reference to critical residues in the claims. • Claim 1. An isolated polynucleotide molecule having at least 80% homology over nucleotides 1 -30 and 98 -135 of the polynucleotide molecule set forth in SEQ ID NO: 1. • Claim 2. An substantially pure polypeptide having at least 80% homology over amino acids 1 -10 and 35 -50 of the amino acid sequence of SEQ ID NO: 2. – The specification should disclose that the unchanged region is critical for the activity of the encoded protein. 25

Homology Claims n How to obtain allowance of claims with recitations of low percentages of similarity? – Include reference to specific variations in the claims. • Claim 1. An isolated polynucleotide molecule having one or more deletions of between 1 and 30 nucleotides in the regions encompassing nucleotide 1 -30 and 98 -135 of the polynucleotide molecule set forth in SEQ ID NO: 1. • Claim 2. An substantially pure polypeptide having between 1 and 10 amino acid deletions in the regions encompassing amino acids 1 -10 and 35 -50 of the amino acid sequence of SEQ ID NO: 2. – The specification should disclose that the unchanged region is critical for the activity of the encoded protein. 26

Homology Claims n How to obtain allowance of claims with recitations of low percentages of similarity? – Include reference to conservative changes in the claims. • Claim 1. An substantially pure polypeptide having between 1 and 10 conservative amino acid changes in the regions encompassing amino acids 1 -10 and 35 -50 of the amino acid sequence of SEQ ID NO: 2. – The specification should disclose that the unchanged region is critical for the activity of the encoded protein, and define acceptable conservative amino acid changes. 27

Homology Claims n How to obtain allowance of claims with recitations of low percentages of similarity? – Consider claims to consensus sequences. • Claim 1. An isolated polynucleotide molecule having at least 80% homology over the entire length of the polynucleotide molecule set forth in SEQ ID NO: 1, wherein said isolated polynucleotide has the same activity as the polypeptide encoded by SEQ ID NO: 1, and further wherein said polynucleotide includes SEQ ID NO: 2. • Claim 2. An substantially pure polypeptide having at least 80% homology over the entire length of the amino acid sequence of SEQ ID NO: 2, wherein said polypeptide has DNA ligase activity, and further wherein said polypeptide includes the amino acid sequence encoded by SEQ ID NO: 2. – The specification should include an alignment of all known members of the protein family, showing which nucleotides and residues are conserved. SEQ ID NO: 2 is the conserved domain. 28

Homology Claims n n For claims to homology based on hybridization, must include specific conditions in specification (e. g. , salt concentration, temperature of hybridization, length of washing steps, etc). Consider including a range of conditions to provide written description support for claims as filed (as well as amended or new claims in case of prior art). – Low stringency – Medium stringency – High stringency Incorporate by reference manuals that explain and describe hybridization conditions (e. g. , Sambrook et al. , Molecular Cloning: A Laboratory Manual). Some examiners require amendment of claims to recite hybridization conditions in the claims. 29

Homology Claims n Enablement Issues? – Does the specification teach how to isolate and screen for those molecules falling within the scope of the claims? – Does the specification include a description of how to use the homologues? n Written Description Issues? – Does the genus of homologues encompassed by the scope of the claims include too many variations, indicating lack of written description support? 30

Anti-Sense Oligonucleotide Claims n n n A DNA molecule which is complementary to the sense strand (that which functions as a template for the synthesis of m. RNA) but is not involved in transcription. Typical claims: – An antisense oligonucleotide that inhibits expression of a nucleic acid encoding protein X. – A method of treating disease X comprising administering the antisense oligonucleotide of SEQ ID NO: 1 to a patient in need of treatment. – A method of treating disease X comprising administering an antisense oligonucleotide that inhibits expression of a nucleic acid molecule encoding polypeptide Y. Robert Schwartzman, U. S. PTO Art Unit 1636. 31

Anti-Sense Oligonucleotide Claims: Patentability Issues n Utility - If no known function for target nucleic acid: – antisense oligo would likely lack utility – also raises enablement (how to use) and possibly written description issues – function as a probe for the target protein not sufficient to serve as an utility for antisense oligo. 32

Anti-Sense Oligonucleotide Claims: Patentability Issues n n n Written Description - may lack written description if the claim reads on targeting many different nucleic acids without a representative number of examples of the antisense molecules. Provide sufficient written description support in specification, including description of the additional versions (splice variants, allelic variants, etc. ) of the gene. Provide evidence that antisense targets identified in one version correlate with targets in other versions. 33

Anti-Sense Oligonucleotide Claims: Patentability Issues n n n Enablement Requirement State of the art is such that there are likely functional antisense molecules that could effectively target most genes. However, the identity of a specific sequence is difficult to predict without some experimentation. Claim to a specific antisense molecule may require evidence of showing it is functional. The current state of predictability for antisense may support a broad claim to antisense molecules; however, may read on prior art. 34

Anti-Sense Oligonucleotide Claims: Patentability Issues n n Obviousness Potential for rejection if prior art suggests inhibition of gene by antisense or other means, and the gene sequence was known. The current knowledge and level of skill in the art is high. May need to narrow claims to specific antisense oligos to overcome prior art. 35

Anti-Sense Oligonucleotide Claims: Drafting specification and claims n n n Adequately describe scope of the claimed invention. Provide working examples in the specification. Provide support/discussion regarding areas of unpredictability: – Target accessibility: • folding/structure of target RNA • Target RNA-protein interactions – Lack of correlation between in vitro and in vivo – Lack of correlation between animal model and human – Efficient delivery to cells – Cell targeting for specific disorders – Oligo affinity/stability in vivo 36

Anti-Sense Oligonucleotide Claims: Drafting specification and claims n n Cite journal articles in cases of known unpredictability. Claim specific antisense molecules by sequence where there is evidence of activity, in addition to broad claims. Provide evidence of activity of specific antisense molecules Provide data from “gene walk” experiments. 37

Anti-Sense Oligonucleotide Claims: Responding to Rejections n n n Submit objective evidence that in vitro results correlate to in vivo use. Submit objective evidence that claimed subject matter is not unpredictable. Provide expert opinions based on objective evidence. Provide objective evidence that a particular animal model is generally accepted as representative of disease or methods of treating, particularly for humans. Objective Evidence includes: – – Case law Journal articles Experimental data Comparisons commensurate with the disclosure as filed. 38

Thank You. Any questions? 39