Since 1999, the United States Patent and Trademark Office (“Patent Office”) has permitted the claiming of antibodies by disclosing the targeted antigen. In 2002, the Federal Circuit adopted Patent Office guidelines and training materials as persuasive authority for the proposition that a claim directed to any “antibody capable of binding to antigen X” would have sufficient support in a written description that disclosed fully characterized antigens. Enzo Biochem, Inc. v. Gen–Probe, Inc., 323 F.3d 956, 964 (Fed.Cir. 2002). This newly-characterized antigen test was included in the eighth edition of the Manual of Patent Examining Procedure (“MPEP”) and applied in Centocor Ortho Biotech, Inc. v. Abbott Laboratories in 2011. 636 F.3d 1341, 1352 (Fed. Cir. 2011). Under the “newly-characterized antigen” exception to the written description requirement, the written description for an antibody to a novel protein was sufficient “without describing the antibody” when “(1) the applicant fully discloses the novel protein and (2) generating the claimed antibody is so routine that possessing the protein places the applicant in possession of an antibody.” Id. at 1351-52. The exception was included in the Ninth Edition of the Manual of Patent Examining Procedure (“MPEP”) and remained in subsequent revisions made through November 2015.
In Amgen Inc. v. Sanofi, the Federal Circuit rejected the newly-characterized antigen test. 872 F.3d 1367 (Fed. Cir. 2017). Amgen’s petition for rehearing en banc seeking review of that issue was denied on February 23, 2018. The Federal Circuit stated that it is “hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies.” Id. at 1378. The Federal Circuit therefore reasoned that the newly-characterized antigen test “flout[ed] basic legal principles of the written description requirement” because the test “allow[ed] patentees to claim antibodies by describing something that is not in the invention, i.e., the antigen.” Id.
On February 22, 2018, the Patent Office issued a clarification of the written description guidance for claims drawn to antibodies. See U.S. Pat. & Trademark Office, Memorandum from Deputy Commissioner for Patent Examination Policy Robert W. Bahr to the Patent Examining Corps (Feb. 22, 2018). The memorandum noted that, “in view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.” Examiners should continue to follow the guidance in the MPEP regarding the written description requirement (i.e., MPEP 2161.01 and 2163), “except insofar as MPEP 2163 indicates that disclosure of a fully characterized antigen may provide written descriptive support of an antibody to that antigen.” Examiners were instructed to continue to follow 2015 and 2016 training materials related to 35 U.S.C. § 112(a) found at https://www.uspto.gov/patent/laws-and-regulations/examination-policy/examination-guidance-and-training-materials, including the guidance “Antibody Decisions and Their Compliance with the Written Description Requirement”[1] (“Antibody Training Materials”).
The Current Written Description Requirement Related to Antibodies
MPEP 2163 provides that, to satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. The applicant may show possession of an invention by: (1) disclosure of sufficiently-detailed drawings or structural chemical formulas; or (2) disclosure of sufficiently detailed, relevant identifying characteristics such as complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination thereof. Examples of identifying characteristics for some biomolecules include a sequence, structure, binding affinity, binding specificity, molecular weight, and length.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of those characteristics. A “representative number of species” requires the adequately-described species provided to be representative of the entire genus.
With respect to the invention of antibodies, which is generally recognized as an unpredictable art, disclosing one or even a few species will not provide adequate written description of a genus which embraces widely variant species. “The disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’” Such correlations may be established in the specification or may be “known in the art at the time of the filing date.”
Training materials, particularly the Antibody Training Materials, emphasize that, in general, a biomolecule sequence “described only by a functional characteristic, without any known or disclosed correlations between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence” (emphasis in original). The Patent Office is in process of updating the Antibody Training Materials based on the Federal Circuit’s decision in Amgen Inc. v. Sanofi.
Claiming Antibodies Consistent with Recent Caselaw
The Federal Circuit described antibodies in AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285, 1290 (Fed. Cir. 2014):
An antibody is a protein that binds to a foreign substance, called an antigen, to facilitate its removal from the body. The portion of the antigen that binds to the antibody is called the epitope. Each antibody consists of four chains of amino acids, two identical heavy chains and two identical light chains, which are folded into a three-dimensional structure. Each of the heavy and light chains consists of a constant region and a variable region. The variable region is the portion of the antibody in its three-dimensional structure that binds to the antigen and each variable region has three complementarity determining regions (“CDRs”) that interact closely with the epitope of the antigen. Among human antibodies, the variable region of the heavy chains can be divided into seven families: VH1 to VH7; and the variable region of the light chains can be divided into two classes: Kappa and Lambda.
In addition, it should be noted that the CDRs, which are hypervariable regions, form the paratope, which is the portion of the antibody that interacts with the target antigen.[2] The paratope cannot be defined entirely independent of the antigen, because it is generally defined for a given antibody/antigen pair.[3] The paratope of the antibody, in interacting with the antigen, binds to the epitope of the antigen, so that the pair that can be disclosed in the written description as a paratope/epitope pair. Further, many of the residues of the CDR do not interact directly with the antigen, but instead provide structural support, whereas some of the residues in the constant region contact the antibody.[4] Research demonstrates that each CDR has a unique set of contact preferences and thus favors certain amino-acids over others. [5]
As noted above, in Amgen v. Sanofi, the Federal Circuit held that it was “hotly disputed” whether knowledge of the chemical structure of the antigen provides structure-identifying information about the antibody. 872 F.3d at 1378. The Federal Circuit apparently credited testimony that the claims, which disclosed an isolated monoclonal antibody that, when bound to PCSK9, bound to a least one residue of the 15 residue binding region, did not reveal the structure of the antibody because the disclosed antibodies only interacted with certain residues (3 or 4) on the outside of the binding region, but that other antibodies could exist that bound centrally to different residues in the binding region. Amgen Inc. v. Sanofi, 227 F.Supp.3d 333, 342-44 (D. Del. 2017)(lower court opinion).
In light of the Federal Circuit’s statement that claiming antibodies using the structure of the antigen is improper, can applicants still: (1) claim antibodies with respect to the structure of the antigen (even when the entire epitope is mapped); and (2) effectively claim the genus of antibodies that bind to a particular antigen? And, even if the Patent Office will accept functional language (binds to epitope X or binds to antibody at residues a, b or c), will the patent hold up in litigation?
Part of the resolution of this issue may depend on what happens at the district court on remand from the Federal Circuit’s decision in Amgen v. Sanofi, where the patent disclosed “the topography” of the antigen. The Federal Circuit did not find the patent invalid for lack of written description, but instead remanded for a retrial on that issue with amended jury instructions to eliminate the instruction that the written description requirement can be satisfied by the disclosure of a newly characterized antigen. 872 F.3d at 1376, 1379. The parties’ additional submissions and arguments, and perhaps additional examples from the Patent Office issued in the interim, may demonstrate that using the antigen as a reference can, under certain circumstances, sufficiently disclose the structure of the antibody.
Taken to its logical conclusion, the Federal Circuit opinion will cause difficulties in claiming antibodies because monoclonal antibodies are often described in terms of both their epitope and paratope.[6] According to a recent article, 24% of patent applications to antibodies used the term epitope in the claims.[7] But, the function of binding to a particular epitope or use of the epitope as a structural element of the claims is “describing something that is not in the invention, i.e., the antigen,” which the recent Federal Circuit decision seems to prohibit. The clearest way to satisfy the written description requirement is to describe the sequences in the specification and claim the antibodies by sequence. Those claims, however, will be limited to the defined sequences. Other potential strategies are to claim the “binding fragment” of the antibody, which will encompass only those portions of the antibody involved in binding to the antigen. See Amgen, Inc. v. AbbVie Biotechnology Ltd., IPR2015-01515, Paper 9 at 9. One can also claim substitutions in the amino acid sequences, although these are also subject to lack of written description and enablement objections, particularly if not reduced to practice, because substitutions are themselves unpredictable. See Ex Parte Porro, Appeal No. 2008-0184 (BPAI 2008)(subgenus of “functional variants” within a genus of “variants” must be described by disclosing a representative number of functional variants or by disclosing “structural features that are common to functional variants that distinguish them from the rest of the genus (i.e., structural features that correlate with enzymatic activity regardless of other variations from SEQ ID NO: 11)”). One suggestion has been to use computational simulations to measure “hot spots” and draft narrower claims encompassing only those amino acids that are likely to work.[8]
Functional genus claims, such as to antibodies that “cause[] cell death of Raji cells in cell culture when cross linked with goat antisera,” often fail to satisfy the written description requirement. See Ex Parte Hans J. Hansen, ZhengXing Qu and David M. Goldenberg, Appeal No. 2017-011073, 2017 WL 6817078, at *3 (PTAB Dec. 14, 2017). The applicant needs to provide “structural or functional relationships for reliably, routinely, or even rarely generating other antibodies which have the functional property” required by the functional language of the claims. Id. at *4. Disclosing only a single or a limited number of species “without any structure or reliable methodology to produce other antibodies which necessarily share the functional property” of the claim will likely not satisfy the written description requirement. Id. In AbbVie, where the claims were drawn to “a class of fully human antibodies that are defined by their high affinity and neutralizing activity to human IL-12,” written description was lacking where the applicant failed to “describe representative antibodies to reflect the structural diversity of the claimed genus” and the claim limitation specifying the binding affinity was “merely a desired result, rather than the actual means for achieving that result.” 759 F.3d at 1299-1301. If functional language is to be used in drafting the claims, the applicant needs to provide “specific and detailed guidance on means for routinely achieving the result provided by the Specification” as well as “evidence of a structure-function correlation that is predictable and determinable.” Ex Parte Hans J. Hansen, 2017 WL 6817078 at *5 (citing AbbVie, 759 F.3d at 1300).
[1] The memorandum noted that USPTO personnel should not follow bullet 2 on slide 17 of this presentation which references dicta in Centocor.
[2] Robin, Gautier, et al. “Restricted Diversity of Antigen Binding Residues of Antibodies Revealed by Computational Alanine Scanning of 227 Antibody-Antigen Complexes.” Journal of Molecular Biology, vol. 426, no. 22, 2014, pp. 3729–3743., doi:10.1016/j.jmb.2014.08.013.
[3] Id.
[4] Id.
[5] Sela-Culang, Inbal, et al. “The Structural Basis of Antibody-Antigen Recognition.” Frontiers in Immunology, vol. 4, 2013, doi:10.3389/fimmu.2013.00302.
[6] Deng, Xiaoxiang, et al. “Enhancing Antibody Patent Protection Using Epitope Mapping Information.” MAbs, vol. 10, no. 2, 2017, pp. 204–209., doi:10.1080/19420862.2017.1402998.
[7] Id.
[8] Lathrop, Brian K., and Michael S. Kinch. “Enhancing the Quality of Patent Claims Directed to Biologics with Biophysical Evidence.” Biotechnology Law Report, vol. 34, no. 6, 2015, pp. 213–235., doi:10.1089/blr.2015.29020.lat.
