Patenting Antibodies and Antibody Patents

1. Patenting Antibodies and Antibody Patents Joint Committee Educational Session of AIPLA’s Biotechnology and IP Practice in Europe Committees October 26, 2012 Moderator: James J. Kelley Senior Director – Assistant General Patent Counsel Eli Lilly and Company

2. Patenting Antibodies in Europe The EPO‘s Approach to Assessing Inventive Step for Antibody Claims Dr. Andreas Hübel Michalski • Hüttermann & Partner, Düsseldorf Germany Patenting Antibodies in Europe: Claim types and their associated inventive step issues Louise Holliday D Young & Co LLP, Southampton UK Antibodies and the EPO: An Industry Perspective Andrew G. Smith Eli Lilly and Company Limited, Windlesham, Surrey UK

3. Written Description & Antibodies

4. Written Description Law: General Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010) (en banc) (cert. denied). Carnegie Mellon Univ. v. Hoffmann-La Roche Inc., 541 F.3d 1115 (Fed. Cir. 2008). Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916 (Fed. Cir. 2004). Enzo Biochem Inc. v. Gen-Probe Inc., 323 F.3d 956 (Fed. Cir. 2002). Regents of the Univ. of Cal. v. Eli Lilly & Co., 119 F.3d 1559, 1566 (Fed. Cir. 1997) (rehearing denied) (cert. denied). Fiers v. Revel, 984 F.2d 1164 (Fed. Cir. 1993). Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 927 F.2d 1200 (Fed. Cir. 1991). In re Wands, 858 F.2d 731 (Fed. Cir. 1988). 35 U.S.C. § 112(a)

5. Written Description Law: Antibodies Abbott GmbH & Co., KG v. Centocor Ortho Biotech, Inc., Case No. 09-11340-FDS (D. Mass. Sep. 25, 2012) Centocor Ortho Biotech, Inc. v. Abbott Labs., No. 10-1144, (Fed. Cir. Feb. 23, 2011) (cert. denied). In re Alonso, 545 F.3d 1015 (Fed. Cir. 2008). Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005). Chiron Corp. v. Genentech Inc., 363 F.3d 1247 (Fed. Cir. 2004). Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004). The Johns Hopkins University v. Cellpro Inc., 152 F.3d 1342 (Fed. Cir. 1998).

6. Written Description: Other • USPTO Written Description Guidelines • USPTO Training Examples

7. Literature • The “Anti”-Written Description Requirement? Antibodies, Example 16, The Guidelines, and Noelle v. Lederman • 87 J. Pat. & Trademark Off. Soc’y 705 (2005) • James J. Kelley and Gregory A. Cox (Eli Lilly and Company)

8. Written Description for Antibodies Questions for Discussion

9. Impact • Antibodies can be claimed broadly and functionally.  • What are the ramifications to patients, the public, companies, universities, start-ups, and the industry in granting functionally-defined broad antibody claims? • Describe the importance of antibody therapies to patients.  Does one antibody suffice for all patients?  Give examples.  Compare and contrast with small molecule therapeutics.

10. Impact • How likely is patent litigation for antibody products?  • How likely is it that a drug developer could face multiple patent infringement suits from the holders of functionally-defined antibody claims of overlapping scopes?  • Do broad antibody patents inhibit the development of competing and possibly better products?

11. Exception? Comparison with other therapeutic molecules • Antibodies can be claimed functionally and broadly while such is generally not the case for other types of therapeutic molecules.  • Are antibodies treated specially?  • What justifies special treatment for some therapeutic molecules over others?  • Should therapeutic antibodies be shielded from competition by broad functionally-defined claims when competition in other areas of other types of therapeutic molecules is robust and generally beneficial?

12. Law • What is the law of written description for genus claims?  • Is it firmly settled, or is there uncertainty about it? • What does this law mean for antibody claims?

13. Abbott v. Centocor (IL12 Abs) • Centocor’s STELARA® (anti-IL12; psoriasis) • $281 million in H1 2012; ~$500 million in 2013 • Suits in August 2009 after Abbott prevailed in interference. • Abbott’s briakinumab • U.S. and European regulatory applications withdrawn in January, 2011.

14. Abbott v. Centocor (IL12 Abs) • 6,914,128, • 29. A neutralizing isolated human antibody, or antigen-binding portion thereof that binds to human IL-12 and disassociates from human IL-12 with a Koff rate constant of 1×10-2 s-1 or less, as determined by surface plasmon resonance. • 7,504,485 • 1. A pharmaceutical composition comprising an isolated human antibody, or antigen-binding portion thereof, which is capable of binding to an epitope of the p40 subunit of IL-12, and further comprising an additional agent. • 11. The composition of any one of claims 1-4, wherein the antibody, or the antigen binding portion thereof, dissociates from the p40 subunit of IL-12 with a Kd of 1×10-10 or less or a Koff of 1×10-3 s-1 or less, as determined by surface plasmon resonance.

15. Abbott v. Centocor:Abbott’s Application • More than 300 variants of a parental Ab were described by sequence and by binding affinity. • Bind to an epitope located on the p40 subunit of IL-12. • Very many fell within functional claim limits.

16. Abbott v. Centocor:Jury Verdicts • Invalid: • Enablement • Obvious • Written Description

17. Abbott v. Centocor:Written Description Facts • STELARA® is in the VH5 family, but all of Abbott’s Abs are in the VH3 family. • Centocor: The asserted claims, all of which defined a genus of antibodies based on their ability to bind and neutralize IL-12, were invalid because the patent did not disclose enough examples within each VH family to support the genus claims. • STELARA® is in the kappa family, but all of Abbott Abs are in the lambda family.

18. Abbott v. Centocor:Written Description Facts • STELARA® and Abbott’s Abs bind at different places. • The dozens of contacts between STELARA® and IL-12 are all different than the dozens of contacts that [Abbott’s Ab] makes with IL-12; not contact is the same at a chemical and structural level. • The amino acid sequence of STELARA® and [Abbott’s Abs] are about 50% different. • The only antibody sequences described in the Abbott patents are in [a single] lineage and there is only about a 10% difference among the sequences.

19. Genus Claims • Is there any way for a specification to comply with the WDR for a functionally-claimed genus of antibodies?  If so, how? • Representative Number of Species? • Identifying Structural Characteristics? • Structure-Function Correlation? • What number of representative species might suffice when the diversity of structures within the genus is not known? • What number or diversity of structures might have sufficed in Abbott v. Centocor? • What are the identifying structural characteristics of a functionally-defined antibody? • Is there a structure – function relationship between variable region functions and the structure of variable regions? If so, how does one describe that?

20. Scope • What are the perceived and real risks for narrow vs. broad antibody claims? • What scope is sufficient?  • What scope might be justified under the facts of Abbott v. Centocor (IL12 Abs)? 

21. Pick your poison • What are the roles of predictability in obviousness and written description? • Once a target is disclosed, aren’t all functionally-defined antibody claims involving that target obvious under KSR? • “When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp.” KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007). “If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.” Id. • The trade-off.  What is truly better for “biotech?”

22. The Antibody Exception? • Is there an exception to the law of written description for antibodies?  • Does the PTO actually examine antibody applications for compliance with the written description requirement? • If there is no exception, • Why do so many think that there is an exception?  • Explain the apparent lack of conformance among the Guidelines and the Law on the one hand and Example 13 and PTO practice on the other. • Why are so many antibody claims functional rather than structural?

23. The Antibody Exception? • What is the evidence for and against the proposition in Example 13 that • “[i]t does not appear that persons of skill in the art consider knowledge of the amino acid sequence of variable regions critical for purposes of assessing possession of an antibody?”  • Which art?  Which persons?  What level of skill? Which antibody?

24. The Antibody Exception? • “While our precedent suggests that written description for certain antibody claims can be satisfied by disclosing a well-characterized antigen, that reasoning applies to disclosure of newly characterized antigens where creation of the claimed antibodies is routine.”  Centocor v. Abbott, CAFC, February 23, 2011 slip op. at 19. • So, is the exception limited to claims that merely require binding to a newly-discovered, well-characterized antigen, as opposed to say more specific functions like neutralizing, binding with particular strength, or binding to a specific “epitope?”  • Does the exception extend to all functional limitations in antibody claims? 

25. The Antibody Exception? • Are there justifications for the exception?  If so, what are they? • Can the Office change its approach without being made to change by the courts?  • What about the changes made in the examples in 2008?  • When considering changing, what about the settled expectations of the patenting community?  • Considering Ariad and Centocor, and now Abbott, are the expectations of the patenting community settled?

26. Abbott v. Centocor:Enablement • On SJ, Dist. Ct. found infringement of some claims, which would include Abs with a VH5 heavy chain such as STELARA®. • “The patents describe using the Vaughan phage display library to make antibodies of the invention, but the Vaughan publication cited in the patents shows only VH1, VH3, and VH4 antibodies coming out of that library, and specifically does not provide any examples of antibodies that came from a VH5 family.” • Centocor witness testified that the patents do not enable making an antibody with a VH5 heavy chain from a phage library. • The jury presumably accepted these arguments.

27. Abbott v. Centocor:Obviousness • Art motivated IL-12 antibodies to treat AI. Obvious to try. • Neutralizing antibodies to p40 subunit of IL-12 = KNOWN. • Human antibodies to IL-12 from patients = KNOWN. • Use of transgenic mice to make human Abs to human antigens with rate constants in claims = KNOWN. • Making human antibodies to human IL-12 using transgenic mouse technology. = KNOWN. • Making human Abs in claims using transgenic mice = PREDICTABLE. • Phage display for making high affinity, neutralizing human antibodies to human proteins, such as IL-12 = KNOWN. • Making pharmaceutical compositions of antibodies = KNOWN. • Claims = predictable!

28. Abbott v. Centocor:Obviousness • Centocor: “When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp.” KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007). “If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.” Id.