Patenting Biotechnology in Japan and recent hot issues

1. Patenting Biotechnology in Japan and recent hot issues AIPLA Mid-Winter Meeting January 25, 2012 Ayako Kobayashi TMI Associates

2. Summary • Patenting stem cells • Patenting antibodies • New Examination Guidelines for applications for Patent Term Extension • Regulations for Biosimilars

3. Patenting stem cells • Novelty - Inherent features of the prior art cell • How to specify new cells • expression profile of surface markers • origin • morphology • preparation method • functions (e.g., “differentiating into XXX.”) • Do the Inherent expression or functions ofthe prior art cells destroy the novelty of the claimed cells?

4. Patenting stem cells • Novelty - Inherent features of the prior art cell • In many cases, the JPO Examiners do not consider the inherent features of the prior art cell. • Rejected Example (JP2007-200588) Claim 1: An isolated adipose-derived stem cell having a marker profile comprising a combination of STRO-01+, CD49d+, and low or undetectable levels of CD106. The Examiner and Appeal Board denied the novelty, citing a reference that failed to mention the expression profile of surface markers when the inventors and the authors of the prior art overlapped.

5. Patenting stem cells • Novelty – Product-by-process claims • The technical scope of a product-by-process claim is NOT limited to the product produced by the process recited in the claim. • Example Claim: An induced pluripotent stem cell obtained by introducing genes Oct3/4, Klf4, …into a somatic cell. The Examiner denied the novelty of iPS cells, citing a reference of ES cells, because: - the ES cells expressed the same surface markers as iPS cells.- the claimed cells possiblycontained cells in which transgene has been spontaneously deleted.

6. Patenting stem cells • Inventive step • The requirement for inventive step does not appear to be high. • Sometimes an advantageous effect compared to the prior art cells is required.

7. Patenting stem cells • Enablement requirement • Very strict. • Functional claims are likely to be rejected. • The Examiners often require to limit the scope of the invention to the level of the working examples.

8. Patenting stem cells • Enablement requirement • Would an enablement rejection be overcome by submitting additional data? • It is more likely that the Examiners will take later-submitted data into consideration in situations where they have already formed an impression that the enablement requirements are satisfied for part of the claimed invention, and the later-submitted data is used to furnish the examples necessary to show that the enablement requirements have also been satisfied for the remainder of the claimed invention. • When the original specification fails to include any experimental data, it is almost impossible to overcome an enablement rejection by submitting additional data.

9. Patenting stem cells • Public order, etc. • Article 32 An invention liable to contravene public order, morality or public health shall not be patented... • When an invention includes a step of destroying an embryo, it will be rejected under Article 32. • An invention of culturing or differentiating method of an already-established ES cell line would be acceptable.

10. Patenting stem cells • Stem cell-related patent rights • To date, there have been no precedents regarding the patentability or infringement of a stem cell-related invention. Thus, the following issues, for example, remain unresolved: • Does the inherent feature of the prior art cells really not destroy the novelty of the claimed cells? • Would practicing an ES cell-related invention using iPS cells constitute infringement under the Doctrine of Equivalents?

11. Patenting Antibodies • When the antigen is known, it is necessary to specify the new antibody using its special features and show that the antibody produces an advantageous effect compared to the prior art. • When the antibody is not sufficiently specified, the Examiner will reject the application due to: • lack of inventive step and/or • failure to comply with the enablement and support requirements.

12. Patenting Antibodies • How to specify a new antibody • CDR sequences – Successful, but the sequences of all six CDRs should be specified • >90% homology of CDR sequences – Not successful • Substitutions in CDR sequences – Not successful • CDR sequences of either Heavy Chain or Light Chain – Not successful • Dissociation Constant (Kd) – Not successful • Sister clone obtained from the same hybridoma – Not successful • Epitope sequences – Successful in many cases

13. Patenting Antibodies • Recent Examples (1) • JP4818107 An isolated antibody or its antigen-binding fragment which specifically binds to the epitope consisting of amino acids 86 to 111 set forth in SEQ ID NO:46. • JP4799863 A pharmaceutical composition that inhibits cancerous growth of cells comprising an antigen or its antigen binding site, wherein the antigen or its antigen binding site binds to an epitope located within position 200 to 400 of EphB4 (SEQ ID NO:1), and wherein the epitope comprises GSCVV.

14. Patenting Antibodies • Recent Examples (2) • JP4818107 A monoclonal antibody or its Fab fragment, capable of binding to mouse VEGF and human VEGF with Kd values within 10 fold of the other, and is capable of inhibiting the binding of VEGF to a VEGF receptor, and recognizes an epitope comprising residues F17, I83 and Q89 of human VEGF.

15. Patenting Antibodies • Recent Examples (3) • JP4637480 An isolated antibody consisting of a heavy chain variable region and a light chain variable region, wherein: the heavy chain variable region consists of the amino acids set forth in SEQ ID NO:11 that may comprise 3 or less amino acid substitutions; the light chain variable region consists of the amino acids set forth in SEQ ID NO:12 that may comprise 2 or less amino acid substitutions; and the antibody specifically binds to Ang-1 and Ang-2.

16. Patent Term Extension (“PTE”) • More than one PTEs may be granted based on more than one marketing approvals for the same active ingredient in Japan. • The JPO had previously rejected applications for a PTE based on the latter of the two marketing approvals in situations where the former approved drug and the latter approved drug contained the same active ingredient, and were directed to the same disease, even though there were differences in dose or formulation between the two drugs. • Under the new guidelines, the Examiner will compare the former approval and the latter approval in terms of the features recited in the claims, in addition to the active ingredient and the subject disease. When all such features are in common between the former and the latter approval, an application for a PTE based on the latter approval would be rejected.

17. Patent Term Extension • Examples Claim 1: A painkiller containing compound A. Former Approval: A painkillerin a tablet form containing 5mg of compound A. Latter Approval (i): A painkillerin an injectable form containing 5mg of compound A. Latter Approval (ii): A painkiller in a tablet form containing 10mg of compound A. Under Old and New Guidelines An application for a PTE based on latter approval (i) or (ii) would be rejected.

18. Patent Term Extension • Examples Claim 1: A painkiller in an injectable form containing compound A. Former Approval: A painkillerin a tablet form containing 5mg of compound A. Latter Approval (i) : A painkillerin an injectable form containing 5mg of compound A. Latter Approval (ii) : A painkiller in a tablet form containing 10mg of compound A. Under Old Guidelines Applications for a PTE based on the latter approvals would have been rejected. Under New Guidelines An application for a PTE based on latter approval (i) would not be rejected, while latter approval (ii) would be rejected.

19. Patent Term Extension • Examples Claim 1: A painkiller comprising compound A. Claim 2: A painkiller according to claim 1 which is in a tablet form. Former Approval: A painkillerin an injectable form containing compound A. Latter Approval : A painkillerin a tablet form containing compound A. Only claim 1 would be considered. Under New Guidelines An application for a PTE based on the latter approval would be rejected.

20. Patent Term Extension • Examples Patent 1: A painkiller comprising compound A. Patent 2: A painkiller in a tablet form comprising compound A. Former Approval: A painkillerin an injectable form containing compound A. Latter Approval : A painkillerin a tablet form containing compound A. Under Old Guidelines An application for a PTE based on the latter approval would have been rejected for both patents 1 and 2. Under New Guidelines An application for a PTE based on the latter approval would be rejected for patent 1 but would not be rejected for patent 2.

21. Biosimilars • “Guidelines for the Quality, Safety and Efficacy Assurance of Biosimilars” and “Handling of nonproprietary and brand names of Biosimilars” were issued by the MHLW in March 2009. The English translation made by Pharmaceutical Research and Manufactures of America can be obtained at:http://www.phrma-jp.org/archives/pdf/others/PFSB-ELD%20Notification%20of%20Handling%20of%20names%20of%20follow-on%20biologics_No.%200304007.pdfhttp://www.phrma-jp.org/archives/pdf/others/PFSB-ELD%20Notification%20of%20Handling%20of%20names%20of%20follow-on%20biologics_No.%200304011.pdf • The first Application for the Marketing Approval for Biosimilar (G-CSF) was filed on December 26, 2011.

22. Thank you! Ayako Kobayashi TMI Associates ayako_kobayashi@tmi.gr.jp