The Written Description Requirement Why It’s a Good Thing (Seriously) AIPLA Spring Meeting Thursday, May 12, 2011 Amy E. Hamilton Vice President/Deputy General Patent Counsel Eli Lilly and Company

Ariad v. Lilly (Fed. Cir. 2010) ALMOST EIGHT YEARS OF LITIGATION! June 25, 2002 U.S. Patent 6,410,516 granted (‘516 patent) June 25, 2002 Ariad filed suit against Lilly April 2006 Jury Trial August 2006 Bench Trial April 3, 2009 CAFC panel held the asserted claims invalid for lack of written description Dec 7, 2009 en banc CAFC oral arguments March 22, 2010 en banc CAFC held the asserted claims invalid for lack of written description 12 May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 2

35 U.S.C. §112, para 1 The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. 12 May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 3

Policy Rationale “It is part of the quid pro quo of a patent; one describes an invention, and, if the law’s other requirements are met, one obtains a patent…A description of the claimed invention allows the … PTO to examine applications effectively; courts to understand the invention, determine compliance with the statute, and to construe the claims; and the public to understand and improve upon the invention and to avoid the claimed boundaries of the patentee’s exclusive rights.” (emphasis added) Ariad Pharm., Inc. v. Eli Lilly and Co. 598 F.3d 1336, 1345 (Fed. Cir. 2010) 12 May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 4

The Prelude Ruschig (“blaze marks”) Late 80’s-early 90’s PTO rejections (Heightened standard of patentability for biotech!) Amgen (“when an inventor is unable to envision the detailed constitution of a gene so as to distinguish it from other materials, as well as a method for obtaining it, conception has not been achieved until reduction to practice has occurred, i.e., until after the gene has been isolated. “) 12 May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 5

The Prelude Fiers (“An adequate written description of a DNA requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it; what is required is a description of the DNA itself.”) UC v. Lilly (aka the Most Important Case of All Time) (rat proinsulin DNA species insufficient to describe human or broader genus; representative # of species) Enzo (deposits can suffice; abs discussed in dictum; real WD question avoided) University of Rochester (on all fours; “mechanism of action” claims not OK) 12 May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 6

WD is not limited to priority issue “Claims define and circumscribe, the written description discloses and teaches … the statute does not say "The specification shall contain a written description of the invention for purposes of determining priority." And although the issue arises primarily in cases involving priority, Congress has not so limited the statute, and neither will we...” Ariad Pharm., Inc. v. Eli Lilly and Co. 598 F.3d 1336, 1346 and 1349 (Fed. Cir. 2010) 12 May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 7

Genus Claims using a Functional Limitation to Define Boundaries “[T]he specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally- defined genus …merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituted the genus” Ariad Pharm., Inc. v. Eli Lilly and Co. 598 F.3d 1336, (Fed. Cir. 2010) 12 May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 8

Not a heightened standard for biotech “We also reject the characterization, cited by Ariad, of the court's written description doctrine as a "super enablement" standard for chemical and biotechnology inventions. The doctrine never created a heightened requirement to provide a nucleotide-by-nucleotide recitation of the entire genus of claimed genetic material; it has always expressly permitted the disclosure of structural features common to the members of the genus.” (emphasis added) Ariad Pharm., Inc. v. Eli Lilly and Co. 598 F.3d 1336, 1352 (Fed. Cir. 2010) 12May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 9

Representative Number of Species -What Does It Mean? “We held that a sufficient description of a genus instead requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can “visualize or recognize” the members of the genus.” (emphasis added) Ariad Pharm., Inc. v. Eli Lilly and Co. 598 F.3d 1336, 1350 (Fed. Cir. 2010) referring to Regents of the Univ of Cal v. Eli Lilly 119 F.3d 1559 (Fed. Cir. 1997) 12May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 10

Former Test “[T]he test for suffiency is whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date.” In re Gosteli, 872 F.2d 1008, 1012 (Fed. Cir. 1989) (quoting Ralson Purina Co. v. Far- Mar-Co., Inc. 772 F.2d 1570, 1575 (Fed. Cir. 1985). 12May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 11

The New Test “Possession as show in the disclosure is a more complete formulation… [T]he test requires an objective inquiry into the four corners of the specification from the perspective of a person of ordinary skill in the art. Based on that inquiry, the specification must describe an invention understandable to that skilled artisan and show that the inventor actually invented the invention claimed.” Ariad Pharm., Inc. v. Eli Lilly and Co. 598 F.3d 1336, 1351 (Fed. Cir. 2010) 12 May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 12

The specification of the ‘516 patent hypothesizes three classes of molecules potentially capable of reducing NF-kB activity: Specific inhibitors Dominantly interfering molecules, and Decoy Molecules Specific Inhibitors – “The only example of a specific inhibitor given in the specification is I-kB…In the context of this invention, a vague functional description and an invitation for further research does not constitute written disclosure of a specific inhibitor.” Dominantly Interfering molecules – “The specification provides no example molecules of this class.” Decoy molecules – “a mere mention of a desired outcome” 12 May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 13

Battles of the Present and Future What if Ariad had simply stated in the specification that a “specific inhibitor” could be a monoclonal antibody to NF-kB – having made no antibody? Of predicted Top Ten drugs in 2014, six are antibodies (two more are insulin variants). -Reuters 12 May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 14

Noelle v. Lederman 355 F.3d 1343 (Fed. Cir. 2004) Claim to antibody binding CD40L invalid because human antigen not described Would have granted the claim if the antigen had been described The antigen is not the claimed invention! Dictum 12 May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 15

Cartoon Understanding 12May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 16 No describable relationship between structure of antigen and the antibody which binds that antigen

Closer to Scientific Reality 12 May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 17

Hypothetical Functional Claim: A monoclonal antibody that binds human NF- kB. Under Ariad v. Lilly it should not grant: 1.Merely drawing a fence around the outer limits of purported genus is not an adequate substitute for describing a variety of materials constituted the genus 2.No disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can “visualize or recognize” the members of the genus.” 3.Does not show that the inventor actually invented the invention claimed. 12May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 18

Dicta of earlier cases should not be raised to the level of a holding “The PTO would find compliance with 112, paragraph 1, for a claim to an isolated antibody capable of binding to antigen X, notwithstanding the functional definition of the antibody, in light of the well defined structural characteristics for the five classes of antibody, the functional characteristics of antibody binding, and the fact that the antibody technology is well developed and mature. Enzo Biochem v. Gen-Probe, Inc., 323 F.3d 956, 964 (Fed. Cir. 2002) “Therefore, based on our past precedent, as long as an applicant has disclosed a "fully characterized antigen," either by its structure, formula, chemical name, or physical properties, or by depositing the protein in a public depository, the applicant can then claim an antibody by its binding affinity to that described antigen.” Noelle v. Lederman, 355 F.3d 1342, 1349 (Fed. Cir. 2004) [referring to Enzo] There is no universal antibody structure allowing correlation of antibody structure with antigen binding function as would be needed for adequate written description of “Antibody that binds protein X” claim. 12 May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 19

12 May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 20 An epidemic of antibody patents granting without antibodies K. Hashimoto and T. Aida. Antibody patenting without antibodies: a global trend. Nature Biotechnology 26:1341, 2008 a.27% of human gene patents include antibody claims b.94% of the main antibody claims cover all antibodies or all mAbs c.45% patents with ab claim not supported by experimental antibody production

12 May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 21 The hazard of allowing functional claims unsupported by adequate written description

12 May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 22

12 May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 23 Functional Limitations Only 1.An isolated recombinant anti-TNF-α antibody or antigen-binding fragment thereof, said antibody comprising a human constant region, wherein said antibody or antigen binding fragment (i) competitively inhibits binding of A2 (ATCC Accession No. PTA-7045) to human TNF-α, and (ii) binds to a neutralizing epitope of human TNF-α. in vivo with an affinity of at least 1 x10 8 liter/mole, measured as an association constant (Ka), as determined by Scatchard analysis. 2. The antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen- binding fragment comprises a human constant region and a human variable region. 3. The antibody or antigen-binding fragment of claim 1, which comprises at least one human light chain and at least one human heavy chain.

12 May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 24 Centocor v. Abbott 97 USPQ2d 1870 (Fed. Cir. 2011) Right result Failed WD because no description of fully human high affinity, A2-specific antibody to TNF-α Antigen known in the art Centocor argued that a functional language of the claim provided the WD “[S]pecification does not provide a single antibody that satisfies the claim limitations.”

12 May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 25 Centocor v. Abbott 97 USPQ2d 1870 (Fed. Cir. 2011) “There is nothing in the specification that conveys to one of skill in the art that Centocor possessed fully- human antibodies or human variable regions that fall within the boundaries of the asserted claims.” Claims are a wish list Then all hell breaks loose A la Enzo and Noelle, cites PTO WD guidelines with reverence

12 May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 26 Centocor v. Abbott 97 USPQ2d 1870 (Fed. Cir. 2011) “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. Here, both the human TNF-a protein and antibodies to that protein were known in the literature…Claiming antibodies with specific properties, e.g., an antibody that binds to human TNF-a with A2 specificity, can result in a claim that does not meet written description even if the human TNF-a protein is disclosed because antibodies with those properties have not been adequately described.”

12May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 27 Centocor v. Abbott 97 USPQ2d 1870 (Fed. Cir.2011) How did we get here? Antibodies are Y-shaped Therefore, there is a structure-function relationship NOOOOOOOOOO! The part of the antibody responsible for binding is completely unpredictable=no structure-function relationship! Whether or not the ab is easily generated (PHYSICALLY, not mentally) is irrelevant

12 May 2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 28 Benefits of Strong Enforcement of Written Description Requirement More Predictable Freedom to Operate Unencumbered by claims covering all solutions to a problem yet to be solved Absence of functional claims to molecules without a disclosed structure-function correlation Returns incentive to develop actual invention Fairness reigns Longer PTE if shorter prosecution Let the predictability of the science drive the process a

12May2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 29 Thus, although written description and enablement often rise and fall together, requiring a written description of the invention plays a vital role in curtailing claims that do not require undue experimentation to make and use, and thus satisfy enablement, but that have not been invented, and thus cannot be described.” Ariad Pharm., Inc. v. Eli Lilly and Co. 598 F.3d 1336, 1352 (Fed. Cir. 2010)

12May2011PRIVILEGED AND CONFIDENTIAL Copyright © 2011 Eli Lilly and Company 30 Amy E. Hamilton (317) Eli Lilly and Company Lilly Corporate Center Indianapolis, IN 46285