[caption id="attachment_4170" align="alignleft" width="150"] Photo By: NIAID - CC BY 2.0[/caption]
Written By: Hyeongsu Park
Edited By: Kendra Albert
The recent boom in antibody products in the pharmaceutical and biotechnology industries created the needs for a clear standard for antibody patents. The market for therapeutic antibodies is projected to reach hundreds of billion dollars within the next several years, and, as such, a huge amount of money will be at stake in future patent infringement cases regarding therapeutic antibodies. However, currently there is an apparent tension between the USPTO guideline with which antibody patents are granted and the case law with which the validity of existing antibody patents is determined. The antibody “exception” of the USPTO written description guideline says that a claim for an isolated antibody binding to an antigen satisfies the written description requirement even when the specification only describes the antigen and does not have working or detailed prophetic examples of antibodies that bind to the antigen. United States Patent and Trademark Office, Revised Interim Written Description Guidelines Training Materials (1999) at 59–60 [hereinafter Training Materials]; United States Patent and Trademark Office, Written Description Training Materials, Revision 1 (March 25, 2008) at 45–46 [hereinafter Revised Training Materials]. InCentocor v. Abbott, the Court of Appeals for the Federal Circuit (“Federal Circuit”) held that a patentee cannot claim an antibody unless the specification describes it, even if he/she fully characterizes the antigen, and the court vacated a $1.67 billion jury verdict, the largest patent infringement award in U.S. history.
The relationship between Centocor and the USPTO guideline is not clear. Although many commentators generally agree that Centocor at least restricts the scope of the antibody exception, they disagree over interpretation of the post-Centocor antibody exception. For example, while some commentators saw Centocor as preventing inventors from claiming genus antibody claims that are too broad, See, e.g., Douglas Metcalf, Legal Update: Therapeutic Antibody Patent Infringement Litigation: Untested and Uncertain Litigation Strategies Underpin Patents Protecting Multibillion-Dollar Pharmaceuticals, 19 B.U. J. Sci. & Tech. L. 194, 203–04 (2013), others opined that the court in Centocor refused to apply the antibody exception when antigens are not novel, See, e.g., Andrew Serafini et al., Monoclonal Antibody Patents: Evolving Law & Strategies, 25 No. 1 Intell. Prop. & Tech. L.J. 3, 7 (2013).
The paper first studies a number of cases from the late 1980s to the early 2000s regarding the written description requirement for therapeutic antibody patents and then tries to understand Centocor in light of the USPTO written description guideline and the current technological advances in the antibody industry. The paper concludes that the Federal Circuit in Centocor appropriately restricted the scope of the antibody exception in the written description guideline such that the scope of antibody claims does not exceed that of antibodies disclosed in the specification by the patentee.
1. Monoclonal Antibodies
Antibodies are Y-shaped proteins that are produced by the immune system and specifically bind to and neutralize foreign substances. Philip W. Grubb & Peter R. Thomsen, Patents for Chemicals, Pharmaceuticals, and Biotechnology 291 (2010). When a foreign substance enters the body, a specialized kind of white blood cell called B-lymphocyte or B cell is activated and develops into plasma cells that secrete antibody molecules that are specific to the foreign substance (antigen). Id. Different types of B cells respond to different kinds of antigens, and antibodies produced by plasma cells originated from the same type of B cell have the same specificity to the antigen as did the original B cell. See id. Each antibody molecule is very specific to a certain antigen, and such specific binding affinity made antibodies very useful for diagnosing and treating diseases or conducting scientific research. Id. However, until the 1970s, the widespread uses of antibodies were restricted by enormous difficulties associated with the growth and maintenance of B cells as well as the purification of antibodies. Frank H. Stephenson, DNA: How the Biotech Revolution is Changing the Way We Fight Disease 61 (2007). In 1975, George Kohler and Cesar Milstein successfully developed a new cell type called hybridoma by fusing together a mouse myeloma cell, or a malignant plasma cell, and a normal B cell from the mouse spleen. Zhiqiang An, Therapeutic Monoclonal Antibodies: From Bench to Clinic ix (2009); See Stephenson, supra at 61. This hybridoma cell line retained the properties of both parental cells; it produced the antibody associated with the normal B cell and, like the myeloma cell, was able to grow in culture indefinitely. Grubb & Thomsen, supra at 292. Hybridoma cell lines that were derived from the same B cell indefinitely produced monoclonal antibodies (mAb), which specifically bind to the same antigen. Id. By using B cells that were immunized with different antigens, one could produce a variety of hybridoma cell lines, each of which secretes unique monoclonal antibodies. Id. As a result, hybridoma cells enabled scientists to produce a variety of purified monoclonal antibodies in large quantities and use them for various research and therapeutic purposes. See Stephenson, supra at 63. Currently, monoclonal antibodies are used to treat diseases such as leukemia, rheumatoid arthritis, lymphoma, and breast cancer. See Jing Li & Zhenping Zhu, Research and Development of Next Generation of Antibody-based Therapeutics, 31 Acta Pharmacologia Sinica 1198, 1198–1200 (2010).
Since 1986 when the FDA approved the first therapeutic monoclonal antibody product OKT3, an immunosuppressant drug used in organ transplants, Zhiqiang An, supra at ix, therapeutic monoclonal antibodies have become the fastest growing field of protein therapeutics. Ulrich Storz, IP Issues of Therapeutic Antibodies, in Ulrich Storz et al., Intellectual Property Issues: Therapeutics, Vaccines and Molecular Diagnostics (2012) at 1. The global market for therapeutic monoclonal antibodies was estimated to be $44.6 billion in 2011 and is expected to rise to nearly $58 billion in 2016. Esther Boskopper, Market Research Report. Antibody Drugs: Technologies and Global Markets, BIO016G BCC Research Report 1 (2012). Zhiqian An, the Chief Scientist Officer of Epitomics, Inc., a biotech company specialized in monoclonal antibodies, predicted that by 2014, five of the top 10 best selling drugs will be monoclonal antibodies. Zhiqiang An, supra at ix.
Because invention requires a huge amount of investment and a long period of research, granting patent rights is necessary to encourage innovation. Patent rights are particularly important for therapeutic antibody products because of their low production costs and high research and development costs. Although manufacturing costs of monoclonal antibodies for generic companies are not as low as those of simple chemical drugs, See Alain Beck et al., Strategies and Challenges for the Next Generation of Therapeutic Antibodies, 10 Nat. Rev. Immunology 345, 349 (2010), huge market prospects for therapeutic antibody products will attract a great number of biosimilar or generic companies into the market once new products are developed. In fact, according to the market research by a business information company Visiongain, the global market for biosimilar monoclonal antibodies is expected to reach $3.2 billion by 2018. See Visiongain, Biosimilar Monoclonal Antibodies: World Market Prospects 2013-2023 (2013). Without proper patent protection of such products, increased competition will drive their market prices to drop, rendering initial innovators who spent tremendous amounts of money to develop the new products unprofitable. See Thomas Poche, The Clinical Trial Exemption from Patent Infringement: Judicial Interpretation of Section 271(e)(1), 74 B.U. L. Rev. 903, 906 (1994). Thus, patent rights are critical to make therapeutic antibodies available to the public. However, at the same time, if the scope of patent rights granted is greater than what inventors actually contributed to the field, granting patents might discourage subsequent innovations to the expense of the public. Therefore, the extent of patent exclusivity should be carefully delineated so that it strikes a balance between encouraging initial discovery and promoting subsequent innovations so that the public can enjoy the benefits of therapeutic antibodies.
This careful distribution of patent rights between initial and subsequent discoveries is particularly challenging in the antibody field because of the technological limitation to fully characterize antibodies. By definition, monoclonal antibodies, or antibodies that bind to a single type of antigen, do not necessarily have the same chemical structure. Antibodies are defined by their functions, and structurally characterizing monoclonal antibodies can be very difficult, especially if those monoclonal antibodies are in fact a mixture of antibodies with distinct structures. Since the structures of antibodies cannot be clearly defined, it is hard for patentees to clearly delineate the boundaries between initial and following innovations in the antibody field. As a result, clarifying the patentability standard for therapeutic antibodies has become an important issue in patent law.
2. Written Description Requirement and the USPTO Written Description Guidelines
The U.S. patent law requires that patent applicants adequately disclose their inventions in their applications in order to obtain valid patent rights. 35 U.S.C. §112 (2012). The purpose of this requirement is to ensure that the public enjoys the full benefit of the innovation in exchange for the limited monopoly granted to the inventors. See Bonito Boats v. Thunder Craft Boats, 489 U.S. 141, 147–51 (1989). 35 U.S.C. §112 outlines three specific disclosure requirements — written description, enablement, and best mode. The written description requirement stipulates that the specification in the patent application must describe the invention sufficiently to show that the inventor is “in possession of the invention.” Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563–64 (Fed. Cir. 1991). More specifically, the Federal Circuit held in Regents of the Univ. of Cal. v. Eli Lilly & Co. that an adequate written description for a chemical compound “requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d 1559, 1566 (Fed. Cir. 1997). When the inventors strive to make the patent claims and thus the monopoly rights as broad as possible, the written description requirement makes sure that there is a quid pro quo bargain between the inventors and the government; the government and thus the public is given meaningful disclosure of the new technology in exchange for being excluded from practicing the invention for a limited period of time. Id. at 922.
Under the USPTO guidelines and case law, claims describing the invention solely by reciting its functional characteristics satisfy the written description requirement only when the inventor disclosed a correlation between that function and a structure that is sufficiently known or disclosed. SeeEnzo Biochem v. Gen-Probe, Inc., 323 F.3d 956, 970 (Fed. Cir. 2002); United States Patent and Trademark Office, Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 “Written Description” Requirement, 66 Fed. Reg. 1099, 1105 (Jan. 5, 2001) (“Guidelines”). However, for therapeutic antibodies, the USPTO seems to apply the written description requirement more leniently than other types of inventions. According to the training materials of the USPTO written description guidelines, first published in 1999 and later revised in 2008, when the inventor sufficiently described a protein (antigen) to warrant the patent rights for the protein, the USPTO advised patent examiners to grant patent rights for monoclonal antibodies that specifically bind to such protein, even when the inventor failed to show that he or she was in possession of the antibodies. Training Materials, supra at 59–60; Revised Training Materials, supra at 45–46.
The USPTO reasoned that the level of skill and knowledge in the art of antibodies at the time of filing was such that “production of antibodies against a well-characterized antigen was conventional.” Training Materials, supra at 59–60. Also, the level of skill in the art of antibodies is such that the structural characteristics of the classes, subclasses, and isotypes of antibody are well known. Revised Training Materials, supra at 46. Therefore, persons of skill in the art would recognize that “the spectrum of antibodies which bind to antigen X were implicitly disclosed as a result of the isolation of antigen X.” Id. at 60. This rationale is implicitly based upon the lock-and-key model of how antibodies bind to an antigen; just as one can derive a shape of a key from a lock that the key can open, a patentee can claim an antibody that binds to an antigen if he/she can fully characterize the antigen. In other words, the required correlation between the function (e.g., binding affinity and specificity) and the structure of antibodies is provided by the lock-and-key model. Through the antibody exception, the USPTO effectively granted to those who discovered a new antigen patent rights for both the antigen and antibodies that bind to the antigen. In other words, the USPTO chose to encourage initial discovery of antigens at the expense of subsequent innovations of antibodies that specifically bind to the antigens. After the guideline, many antibody patents were granted without adequate examples or descriptions of the antibodies, and statistics revealed that by 2008, about half of human gene patents including antibody claims did not have working or prophetic examples of the claimed antibodies. Kazunori Hashimoto & Tomomi Aida, Antibody Patenting without Antibodies: Global Trend, 26 Nat. Biotech. 1341, 1342–43 (2008).
However, it was not until Noelle v. Lederman in 2004 when the Federal Circuit approved the antibody exception to the written description requirement. At the same time, the courtbegan to focus on whether the scope of claimed antibodies is commensurate with that of antibodies disclosed in the specifications.
3. Approval of the Exception: Noelle v. Lederman and Chiron Corp. v. Genetech, Inc.
In Noelle v. Lederman, the Federal Circuit held that a claim for an antibody that is defined by its specific binding affinity to an antigen can satisfy the written description requirement with the specification that discloses a “fully characterized antigen,” thereby approving the antibody exception in the USPTO Guidelines. 355 F.3d 1343, 1349 (Fed. Cir. 2004).
However, the court in this case did not permit the patentee to claim a genus of antibodies that specifically bind to an antigen because the specification of the patent described only the mouse antigen and antibodies to that protein. Id. The court reasoned that the mouse antigen might have different structures from non-murine antigens and that the patentee never fully characterized the non-murine antigens in the application. Seeid. at 1349–50. As a result, the Federal Circuit affirmed the decision of the Board rejecting claims for antibodies that bind to the non-murine antigens.
Two months after the Noelle case, in Chiron Corp. v. Genetech, Inc. the Federal Circuit affirmed the judgment of the district court that invalidated similar genus claims, holding that the patentee cannot claim a genus of monoclonal antibodies that bind to an antigen when the specifications disclosed only the mouse antigen and antibodies. See 363 F.3d 1247, 1251–52 (Fed. Cir. 2004). Chiron sued Genetech for patent infringement, arguing that Genetech’s antibody product for the treatment of breast cancer (Herceptin) infringed Chiron’s patent that claimed a genus of antibodies to the target antigen of Herceptin. Id. at 1251. The Federal Circuit affirmed the jury verdict that invalidated Chiron’s patent for lack of written description and enablement. Id. at 1260. The court held that because the early specifications of the disputed patent disclosed only mouse antibodies and not chimeric or human antibodies, the genus claim for monoclonal antibodies could not claim priority to the filing date of the early specifications. See id. at 1253–54. Interestingly, in Chiron, the Federal Circuit neither cited the Noelle case or the USPTO guidelines nor expressed any opinions upon the antibody exception to the written description requirement.
In sum, while Noelle approved the antibody exception first introduced in the USPTO written description guidelines, both Noelle and Chiron made it clear that the scope of claimed antibodies should be comparable to the applicant’s disclosure. In other words, inventors cannot claim antibodies that bind to a genus of a certain antigen when the inventors only disclosed an antigen species of the genus.
After Noelle and Chiron, legal scholars expressed split opinions on the written description requirement standard of antibody claims. Some commentators expressed concerns about the court’s implied approval of the USPTO guideline in Noelle and its departure from the Eli Lilly written description standard requiring sufficient structural disclosure of the claimed chemical compounds. In fact, some scholars even argued that the antibody exception in the USPTO guideline was misplaced in the first place because “even a fully characterized antigen may be bound by a structurally diverse genus of antibodies.” James Kelley & Gregory Cox, The “Anti”-Written Description Requirement? Antibodies, Example 16, the Guidelines, and Noelle v. Lederman, 87 J. Pat. & Trademark Off. Soc’y 705, 739–41 (2005). They opined that there are no known correlations between an antibody’s structure and its antigen binding function and that it is impossible for one skilled in the antibody art to predict the structure of an antibody based on its binding characteristics to an antigen. Id. at 740. Another scholar also pointed out that the structures of antibodies to a particular antigen not only vary from species to species but also vary from one molecule to another in the same species because a target antigen generally has numerous binding sites, called epitopes, that are recognized by different antibodies. Wenrong Huang, Enzo’s Written Description Requirement: Can It Be An Effective Check Against Overly Broad Biotechnology Claims?, 16 Alb. L.J. Sci. & Tech. 1, 13 (2006). In contrast, other scholars considered the Eli Lilly written description standard to be too restrictive for biotechnology inventions and redundant to the enablement requirement, See, e.g., Sven J.R. Bostyn, Written Description After Enzo Biochem: Can the Real Requirement Step Forward Please?, 85 J. Pat. & Trademark Off. Soc’y 131, 149 (2003); Christopher M. Holman, Is Lilly Written Description a Paper Tiger?: A Comprehensive Assessment of the Impact of Eli Lilly and Its Progeny in the Courts and PTO, 17 Alb. L.J. Sci. & Tech. 1, 78 (2007), and supported the court’s departure from the Eli Lilly standard in Noelle. Holman, supra at 60.
The confusion and heated debates regarding the antibody exception and Noelle were caused by the Federal Circuit never having a case in which validity of antibody claims was directly dependent on whether to accept the antibody exception in the USPTO guidelines as a binding precedent. Even in Noelle, the court’s approval of the antibody exception was not essential to the outcome of the case, making the court’s approval dicta and not binding. See, e.g., Paula D. Davis & Steven P. Caltrider, Timing (of Invention) is Everything: The Essential Role of the Written Description Requirement in Determining Conception, 15 Fed. Circuit B.J. 39, 58–59. (“Dicta in the recent case Noelle v. Lederman, if accepted as precedent for later antibody cases, will lead to inconsistency in written description case law.”); Kelly & Cox, supra at 710. (“[T]he Noelle panel’s purported rule is dicta, at best, which is not binding precedent and should not be persuasive authority for the USPTO, district courts or other panels of the Federal Circuit.”). Thus, CentocorOrtho Biotech, Inc. v. Abbott Labs was important because it was the first case that directly tackled the antibody exception to the written description requirement.
4. Centocor Ortho Biotech, Inc. v. Abbott LabsCentocor involves claims for human antibodies that bind to human tumor necrosis factor a (“TNF-a”).Centocor Ortho Biotech, Inc. v. Abbott Labs, 636 F.3d 1341, 1344 (Fed. Cir. 2011). Antibodies to TNF-a are used to treat autoimmune diseases such as arthritis, Crohn’s disease, and psoriasis. Centocor Ortho Biotech, Inc. (“Centocor”) and Abbott Laboratories (“Abbott”) sought to develop antibodies to human TNF-a that have 1) high affinity to the antigen, 2) neutralizing activity, and 3) reduced immunogenicity. Id. at 1344. However, the two companies took different paths to develop the therapeutic TNF-a antibodies. Centocor first identified a mouse antibody to human TNF-a that had both high affinity and neutralizing activity and then modified the mouse antibody to make it look more human. Id. at 1344–45. In contrast, Abbott constructed a fully-human antibody from scratch by searching a phage library for fully-human antibodies that bind to human TNF-a and then using various techniques to improve their binding affinity, which eventually led to HumiraÒ. Id. at 1345–46. Abbott filed a patent application disclosing the high affinity, neutralizing, fully-human antibody to human TNF-a in 1996 and the patent was granted in 2000. Id. at 1346.
Centocor filed a patent application disclosing both the mouse antibody and the chimeric antibody in 1991. Id. at 1345. Then, Centocor filed a series of continuation-in-part applications (“CIP applications”) in 1993 and 1994. Id. at 1345–46. In 2002, after the regulatory approval of Abbott’s fully-human TNF-a product HumiraÒ, Centocor added the claim for the fully-human TNF-a antibody as another CIP application of the chimeric antibody patent family, and the patent was issued in 2006. Id. at 1346–47. Shortly thereafter, Centocor sued Abbott for patent infringement, arguing that Abbott’s product infringed Centocor’s patent claim for human antibodies. Id. at 1347.
The issue in this case was whether the Centocor’s patent provided adequate written description for the fully-human TNF-a antibody. Id. at 1348. Since Abbott’s patent application was filed in 1996, Centocor relied on a priority claim to the 1994 CIP applications. Id. Thus, the court focused on whether the 1994 CIP applications satisfy the written description requirement of the disputed claims.
The critical difference between Centocor and the previous two cases was that the disputed claims in Centocor recited a human antibody when the specification disclosed the sequence of the human antigen that the claimed antibody binds to. As a result, the validity of the disputed claims depended solely upon the antibody exception and not upon genus-species issues. At trial, the jury found that Centocor’s patent satisfied the written description requirement and that Humira infringed upon the claim. However, the Federal Circuit reversed the jury award of $1.67 billion and invalidated the disputed claims for lack of written description. Id. at 1341.
The Federal Circuit held that an applicant can claim an antibody to a novel protein without describing the antibody under the USPTO Written Description Guideline “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 court found that Centocor failed to satisfy both standards in its 1994 patent application. First, human TFN-α was well known at the time of filing the patent application. Also, the court pointed out that when a patent claim recites antibodies with specific properties (e.g., high affinity, neutralizing activity, and binding specificity at a specific place on the target antigen), merely describing an antigen that the antibodies bind to is not enough to satisfy the written description requirement. Generating antibodies to a certain antigen is routine, but screening those antibodies for certain properties is not. Thus, the Federal Circuit concluded that simple possession of the known TFN-α did not place Centocor in possession of the claimed antibodies.
5.Effects and Policy Consideration of Centocor v. Abbott
In effect, Centocor limited the scope of the antibody exception to antibodies that bind to newly discovered antigens. Furthermore, when a patentee discloses a new antigen in the specification, the patentee can claim antibodies that bind to the antigen and can be easily discovered through routine processes based on the binding affinity to the antigen. The patentee cannot claim a subset of such antibodies that have special properties in addition to the binding property to the antigen because screening for antibodies with these additional characteristics would require more than routine processes.
As a result, Centocor discouraged pharmaceutical companies from claiming for a genus of antibodies that bind to a known antigen. Under Centocor, pharmaceutical companies now need to either structurally characterize the common motif among the binding sites of antibodies that bind to the antigen, which is almost impossible to do with the current technology, or separately claim individual antibodies that bind to the antigen based on their structures, which is susceptible to design-around problems. Some commentators worry that Centocor will reduce incentives to develop therapeutic antibodies because Centocor narrowed the scope of acceptable claims for antibodies that bind to known antigens so much that the claims carry little economic value.
I agree that the strict application of the antibody exception solely to truly novel antigens (i.e., molecules that have never been discovered before) will harm the incentive to innovate because such antigens are rare with the widespread use of genomic sequencing. See Serafini, supra at 7. However, as long as “novel antigens” are broadly interpreted to include known antigens whose novel characteristics are discovered by a patentee, Centocor will not thwart the biotechnology industry from developing therapeutic antibodies because of the recent technological developments in the antibody industry.
Before the 2000s, scientists separated antibodies through screening for molecules that bind to an antigen of interest, but understanding the structures or the amino acid sequences of those antibodies was time-consuming and not readily affordable. The USPTO in the Written Description Guidelines reasoned that further requiring patent applicants to structurally specify the claimed antibodies other than its specific binding affinity to a certain antigen would impose undue burden to innovators.
However, these days, the court’s holding in Centocor no longer imposes an excessive burden to patent applicants because the cost of genomic sequencing and screening of monoclonal antibodies has decreased dramatically. For example, the cost of human genome sequencing decreased from $300 million in 2004 to $48,000 in 2009 and then to $5,000 in recent years. See Michael L. Metzker, Sequencing Technologies – the Next Generation, 11 Nature Reviews 31, 43–44 (2010). Also, development of human or chimeric antibodies and deeper understanding of immunology made it necessary for patentees to show their possession of claimed antibodies by demonstrating their structures, amino sequences, or binding affinities. The Federal Circuit in Centocor took the legalistic approach in finding that Centocor did not possess the claimed antibodies and did not mention any policy considerations in its holding. Still, I think that Centocor was a timely decision to restrict the scope of the antibody exception to the extent that is more appropriate under the current immunological technology.
6.Conclusion
In brief, the Federal Circuit in Centocor made a reasonable counteraction to the USPTO’s antibody exception to the written description requirement after Noelle’s apparent approval of the exception by explicitly restricting the cases in which the exception can be applied. Surely, there are concerns that due to the paucity of truly “novel” antigens, Centocor will essentially abolish the antibody exception and impose an unreasonably strict written description requirement to antibody claims. However, as long as the meaning of “novel” antigens is interpreted broadly to include known molecules with new characteristics, I think that Centocor made a few steps closer to a nice balance between disallowing patent rights beyond disclosure and granting patent rights broad enough to incentivize innovation. After all, the quid pro quo contemplated by the Constitution between monopoly rights granted to patents and public benefits from inventions warrants the USPTO’s requirement that claim scope should be commensurate with disclosure. Granting patent rights for all antibodies that bind to an antigen when the patentee merely disclosed the antigen contradicts the basic quid pro quo of patent law. Centocor’s clarification of the written description standard for monoclonal antibody patents will provide predictability in the written description doctrine and make biotechnology companies pay closer attention to their patent claims and specifications.
Photo By: NIAID - CC BY 2.0[/caption]
Written By: Hyeongsu Park
Edited By: Kendra Albert
The recent boom in antibody products in the pharmaceutical and biotechnology industries created the needs for a clear standard for antibody patents. The market for therapeutic antibodies is projected to reach hundreds of billion dollars within the next several years, and, as such, a huge amount of money will be at stake in future patent infringement cases regarding therapeutic antibodies. However, currently there is an apparent tension between the USPTO guideline with which antibody patents are granted and the case law with which the validity of existing antibody patents is determined. The antibody “exception” of the USPTO written description guideline says that a claim for an isolated antibody binding to an antigen satisfies the written description requirement even when the specification only describes the antigen and does not have working or detailed prophetic examples of antibodies that bind to the antigen. United States Patent and Trademark Office, Revised Interim Written Description Guidelines Training Materials (1999) at 59–60 [hereinafter Training Materials]; United States Patent and Trademark Office, Written Description Training Materials, Revision 1 (March 25, 2008) at 45–46 [hereinafter Revised Training Materials]. In Centocor v. Abbott, the Court of Appeals for the Federal Circuit (“Federal Circuit”) held that a patentee cannot claim an antibody unless the specification describes it, even if he/she fully characterizes the antigen, and the court vacated a $1.67 billion jury verdict, the largest patent infringement award in U.S. history.
The relationship between Centocor and the USPTO guideline is not clear. Although many commentators generally agree that Centocor at least restricts the scope of the antibody exception, they disagree over interpretation of the post-Centocor antibody exception. For example, while some commentators saw Centocor as preventing inventors from claiming genus antibody claims that are too broad, See, e.g., Douglas Metcalf, Legal Update: Therapeutic Antibody Patent Infringement Litigation: Untested and Uncertain Litigation Strategies Underpin Patents Protecting Multibillion-Dollar Pharmaceuticals, 19 B.U. J. Sci. & Tech. L. 194, 203–04 (2013), others opined that the court in Centocor refused to apply the antibody exception when antigens are not novel, See, e.g., Andrew Serafini et al., Monoclonal Antibody Patents: Evolving Law & Strategies, 25 No. 1 Intell. Prop. & Tech. L.J. 3, 7 (2013).
The paper first studies a number of cases from the late 1980s to the early 2000s regarding the written description requirement for therapeutic antibody patents and then tries to understand Centocor in light of the USPTO written description guideline and the current technological advances in the antibody industry. The paper concludes that the Federal Circuit in Centocor appropriately restricted the scope of the antibody exception in the written description guideline such that the scope of antibody claims does not exceed that of antibodies disclosed in the specification by the patentee.
1. Monoclonal Antibodies
Antibodies are Y-shaped proteins that are produced by the immune system and specifically bind to and neutralize foreign substances. Philip W. Grubb & Peter R. Thomsen, Patents for Chemicals, Pharmaceuticals, and Biotechnology 291 (2010). When a foreign substance enters the body, a specialized kind of white blood cell called B-lymphocyte or B cell is activated and develops into plasma cells that secrete antibody molecules that are specific to the foreign substance (antigen). Id. Different types of B cells respond to different kinds of antigens, and antibodies produced by plasma cells originated from the same type of B cell have the same specificity to the antigen as did the original B cell. See id. Each antibody molecule is very specific to a certain antigen, and such specific binding affinity made antibodies very useful for diagnosing and treating diseases or conducting scientific research. Id. However, until the 1970s, the widespread uses of antibodies were restricted by enormous difficulties associated with the growth and maintenance of B cells as well as the purification of antibodies. Frank H. Stephenson, DNA: How the Biotech Revolution is Changing the Way We Fight Disease 61 (2007). In 1975, George Kohler and Cesar Milstein successfully developed a new cell type called hybridoma by fusing together a mouse myeloma cell, or a malignant plasma cell, and a normal B cell from the mouse spleen. Zhiqiang An, Therapeutic Monoclonal Antibodies: From Bench to Clinic ix (2009); See Stephenson, supra at 61. This hybridoma cell line retained the properties of both parental cells; it produced the antibody associated with the normal B cell and, like the myeloma cell, was able to grow in culture indefinitely. Grubb & Thomsen, supra at 292. Hybridoma cell lines that were derived from the same B cell indefinitely produced monoclonal antibodies (mAb), which specifically bind to the same antigen. Id. By using B cells that were immunized with different antigens, one could produce a variety of hybridoma cell lines, each of which secretes unique monoclonal antibodies. Id. As a result, hybridoma cells enabled scientists to produce a variety of purified monoclonal antibodies in large quantities and use them for various research and therapeutic purposes. See Stephenson, supra at 63. Currently, monoclonal antibodies are used to treat diseases such as leukemia, rheumatoid arthritis, lymphoma, and breast cancer. See Jing Li & Zhenping Zhu, Research and Development of Next Generation of Antibody-based Therapeutics, 31 Acta Pharmacologia Sinica 1198, 1198–1200 (2010).
Since 1986 when the FDA approved the first therapeutic monoclonal antibody product OKT3, an immunosuppressant drug used in organ transplants, Zhiqiang An, supra at ix, therapeutic monoclonal antibodies have become the fastest growing field of protein therapeutics. Ulrich Storz, IP Issues of Therapeutic Antibodies, in Ulrich Storz et al., Intellectual Property Issues: Therapeutics, Vaccines and Molecular Diagnostics (2012) at 1. The global market for therapeutic monoclonal antibodies was estimated to be $44.6 billion in 2011 and is expected to rise to nearly $58 billion in 2016. Esther Boskopper, Market Research Report. Antibody Drugs: Technologies and Global Markets, BIO016G BCC Research Report 1 (2012). Zhiqian An, the Chief Scientist Officer of Epitomics, Inc., a biotech company specialized in monoclonal antibodies, predicted that by 2014, five of the top 10 best selling drugs will be monoclonal antibodies. Zhiqiang An, supra at ix.
Because invention requires a huge amount of investment and a long period of research, granting patent rights is necessary to encourage innovation. Patent rights are particularly important for therapeutic antibody products because of their low production costs and high research and development costs. Although manufacturing costs of monoclonal antibodies for generic companies are not as low as those of simple chemical drugs, See Alain Beck et al., Strategies and Challenges for the Next Generation of Therapeutic Antibodies, 10 Nat. Rev. Immunology 345, 349 (2010), huge market prospects for therapeutic antibody products will attract a great number of biosimilar or generic companies into the market once new products are developed. In fact, according to the market research by a business information company Visiongain, the global market for biosimilar monoclonal antibodies is expected to reach $3.2 billion by 2018. See Visiongain, Biosimilar Monoclonal Antibodies: World Market Prospects 2013-2023 (2013). Without proper patent protection of such products, increased competition will drive their market prices to drop, rendering initial innovators who spent tremendous amounts of money to develop the new products unprofitable. See Thomas Poche, The Clinical Trial Exemption from Patent Infringement: Judicial Interpretation of Section 271(e)(1), 74 B.U. L. Rev. 903, 906 (1994). Thus, patent rights are critical to make therapeutic antibodies available to the public. However, at the same time, if the scope of patent rights granted is greater than what inventors actually contributed to the field, granting patents might discourage subsequent innovations to the expense of the public. Therefore, the extent of patent exclusivity should be carefully delineated so that it strikes a balance between encouraging initial discovery and promoting subsequent innovations so that the public can enjoy the benefits of therapeutic antibodies.
This careful distribution of patent rights between initial and subsequent discoveries is particularly challenging in the antibody field because of the technological limitation to fully characterize antibodies. By definition, monoclonal antibodies, or antibodies that bind to a single type of antigen, do not necessarily have the same chemical structure. Antibodies are defined by their functions, and structurally characterizing monoclonal antibodies can be very difficult, especially if those monoclonal antibodies are in fact a mixture of antibodies with distinct structures. Since the structures of antibodies cannot be clearly defined, it is hard for patentees to clearly delineate the boundaries between initial and following innovations in the antibody field. As a result, clarifying the patentability standard for therapeutic antibodies has become an important issue in patent law.
2. Written Description Requirement and the USPTO Written Description Guidelines
The U.S. patent law requires that patent applicants adequately disclose their inventions in their applications in order to obtain valid patent rights. 35 U.S.C. §112 (2012). The purpose of this requirement is to ensure that the public enjoys the full benefit of the innovation in exchange for the limited monopoly granted to the inventors. See Bonito Boats v. Thunder Craft Boats, 489 U.S. 141, 147–51 (1989). 35 U.S.C. §112 outlines three specific disclosure requirements — written description, enablement, and best mode. The written description requirement stipulates that the specification in the patent application must describe the invention sufficiently to show that the inventor is “in possession of the invention.” Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563–64 (Fed. Cir. 1991). More specifically, the Federal Circuit held in Regents of the Univ. of Cal. v. Eli Lilly & Co. that an adequate written description for a chemical compound “requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d 1559, 1566 (Fed. Cir. 1997). When the inventors strive to make the patent claims and thus the monopoly rights as broad as possible, the written description requirement makes sure that there is a quid pro quo bargain between the inventors and the government; the government and thus the public is given meaningful disclosure of the new technology in exchange for being excluded from practicing the invention for a limited period of time. Id. at 922.
Under the USPTO guidelines and case law, claims describing the invention solely by reciting its functional characteristics satisfy the written description requirement only when the inventor disclosed a correlation between that function and a structure that is sufficiently known or disclosed. See Enzo Biochem v. Gen-Probe, Inc., 323 F.3d 956, 970 (Fed. Cir. 2002); United States Patent and Trademark Office, Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 “Written Description” Requirement, 66 Fed. Reg. 1099, 1105 (Jan. 5, 2001) (“Guidelines”). However, for therapeutic antibodies, the USPTO seems to apply the written description requirement more leniently than other types of inventions. According to the training materials of the USPTO written description guidelines, first published in 1999 and later revised in 2008, when the inventor sufficiently described a protein (antigen) to warrant the patent rights for the protein, the USPTO advised patent examiners to grant patent rights for monoclonal antibodies that specifically bind to such protein, even when the inventor failed to show that he or she was in possession of the antibodies. Training Materials, supra at 59–60; Revised Training Materials, supra at 45–46.
The USPTO reasoned that the level of skill and knowledge in the art of antibodies at the time of filing was such that “production of antibodies against a well-characterized antigen was conventional.” Training Materials, supra at 59–60. Also, the level of skill in the art of antibodies is such that the structural characteristics of the classes, subclasses, and isotypes of antibody are well known. Revised Training Materials, supra at 46. Therefore, persons of skill in the art would recognize that “the spectrum of antibodies which bind to antigen X were implicitly disclosed as a result of the isolation of antigen X.” Id. at 60. This rationale is implicitly based upon the lock-and-key model of how antibodies bind to an antigen; just as one can derive a shape of a key from a lock that the key can open, a patentee can claim an antibody that binds to an antigen if he/she can fully characterize the antigen. In other words, the required correlation between the function (e.g., binding affinity and specificity) and the structure of antibodies is provided by the lock-and-key model. Through the antibody exception, the USPTO effectively granted to those who discovered a new antigen patent rights for both the antigen and antibodies that bind to the antigen. In other words, the USPTO chose to encourage initial discovery of antigens at the expense of subsequent innovations of antibodies that specifically bind to the antigens. After the guideline, many antibody patents were granted without adequate examples or descriptions of the antibodies, and statistics revealed that by 2008, about half of human gene patents including antibody claims did not have working or prophetic examples of the claimed antibodies. Kazunori Hashimoto & Tomomi Aida, Antibody Patenting without Antibodies: Global Trend, 26 Nat. Biotech. 1341, 1342–43 (2008).
However, it was not until Noelle v. Lederman in 2004 when the Federal Circuit approved the antibody exception to the written description requirement. At the same time, the court began to focus on whether the scope of claimed antibodies is commensurate with that of antibodies disclosed in the specifications.
3. Approval of the Exception: Noelle v. Lederman and Chiron Corp. v. Genetech, Inc.
In Noelle v. Lederman, the Federal Circuit held that a claim for an antibody that is defined by its specific binding affinity to an antigen can satisfy the written description requirement with the specification that discloses a “fully characterized antigen,” thereby approving the antibody exception in the USPTO Guidelines. 355 F.3d 1343, 1349 (Fed. Cir. 2004).
However, the court in this case did not permit the patentee to claim a genus of antibodies that specifically bind to an antigen because the specification of the patent described only the mouse antigen and antibodies to that protein. Id. The court reasoned that the mouse antigen might have different structures from non-murine antigens and that the patentee never fully characterized the non-murine antigens in the application. See id. at 1349–50. As a result, the Federal Circuit affirmed the decision of the Board rejecting claims for antibodies that bind to the non-murine antigens.
Two months after the Noelle case, in Chiron Corp. v. Genetech, Inc. the Federal Circuit affirmed the judgment of the district court that invalidated similar genus claims, holding that the patentee cannot claim a genus of monoclonal antibodies that bind to an antigen when the specifications disclosed only the mouse antigen and antibodies. See 363 F.3d 1247, 1251–52 (Fed. Cir. 2004). Chiron sued Genetech for patent infringement, arguing that Genetech’s antibody product for the treatment of breast cancer (Herceptin) infringed Chiron’s patent that claimed a genus of antibodies to the target antigen of Herceptin. Id. at 1251. The Federal Circuit affirmed the jury verdict that invalidated Chiron’s patent for lack of written description and enablement. Id. at 1260. The court held that because the early specifications of the disputed patent disclosed only mouse antibodies and not chimeric or human antibodies, the genus claim for monoclonal antibodies could not claim priority to the filing date of the early specifications. See id. at 1253–54. Interestingly, in Chiron, the Federal Circuit neither cited the Noelle case or the USPTO guidelines nor expressed any opinions upon the antibody exception to the written description requirement.
In sum, while Noelle approved the antibody exception first introduced in the USPTO written description guidelines, both Noelle and Chiron made it clear that the scope of claimed antibodies should be comparable to the applicant’s disclosure. In other words, inventors cannot claim antibodies that bind to a genus of a certain antigen when the inventors only disclosed an antigen species of the genus.
After Noelle and Chiron, legal scholars expressed split opinions on the written description requirement standard of antibody claims. Some commentators expressed concerns about the court’s implied approval of the USPTO guideline in Noelle and its departure from the Eli Lilly written description standard requiring sufficient structural disclosure of the claimed chemical compounds. In fact, some scholars even argued that the antibody exception in the USPTO guideline was misplaced in the first place because “even a fully characterized antigen may be bound by a structurally diverse genus of antibodies.” James Kelley & Gregory Cox, The “Anti”-Written Description Requirement? Antibodies, Example 16, the Guidelines, and Noelle v. Lederman, 87 J. Pat. & Trademark Off. Soc’y 705, 739–41 (2005). They opined that there are no known correlations between an antibody’s structure and its antigen binding function and that it is impossible for one skilled in the antibody art to predict the structure of an antibody based on its binding characteristics to an antigen. Id. at 740. Another scholar also pointed out that the structures of antibodies to a particular antigen not only vary from species to species but also vary from one molecule to another in the same species because a target antigen generally has numerous binding sites, called epitopes, that are recognized by different antibodies. Wenrong Huang, Enzo’s Written Description Requirement: Can It Be An Effective Check Against Overly Broad Biotechnology Claims?, 16 Alb. L.J. Sci. & Tech. 1, 13 (2006). In contrast, other scholars considered the Eli Lilly written description standard to be too restrictive for biotechnology inventions and redundant to the enablement requirement, See, e.g., Sven J.R. Bostyn, Written Description After Enzo Biochem: Can the Real Requirement Step Forward Please?, 85 J. Pat. & Trademark Off. Soc’y 131, 149 (2003); Christopher M. Holman, Is Lilly Written Description a Paper Tiger?: A Comprehensive Assessment of the Impact of Eli Lilly and Its Progeny in the Courts and PTO, 17 Alb. L.J. Sci. & Tech. 1, 78 (2007), and supported the court’s departure from the Eli Lilly standard in Noelle. Holman, supra at 60.
The confusion and heated debates regarding the antibody exception and Noelle were caused by the Federal Circuit never having a case in which validity of antibody claims was directly dependent on whether to accept the antibody exception in the USPTO guidelines as a binding precedent. Even in Noelle, the court’s approval of the antibody exception was not essential to the outcome of the case, making the court’s approval dicta and not binding. See, e.g., Paula D. Davis & Steven P. Caltrider, Timing (of Invention) is Everything: The Essential Role of the Written Description Requirement in Determining Conception, 15 Fed. Circuit B.J. 39, 58–59. (“Dicta in the recent case Noelle v. Lederman, if accepted as precedent for later antibody cases, will lead to inconsistency in written description case law.”); Kelly & Cox, supra at 710. (“[T]he Noelle panel’s purported rule is dicta, at best, which is not binding precedent and should not be persuasive authority for the USPTO, district courts or other panels of the Federal Circuit.”). Thus, Centocor Ortho Biotech, Inc. v. Abbott Labs was important because it was the first case that directly tackled the antibody exception to the written description requirement.
4. Centocor Ortho Biotech, Inc. v. Abbott Labs
Centocor involves claims for human antibodies that bind to human tumor necrosis factor a (“TNF-a”). Centocor Ortho Biotech, Inc. v. Abbott Labs, 636 F.3d 1341, 1344 (Fed. Cir. 2011). Antibodies to TNF-a are used to treat autoimmune diseases such as arthritis, Crohn’s disease, and psoriasis. Centocor Ortho Biotech, Inc. (“Centocor”) and Abbott Laboratories (“Abbott”) sought to develop antibodies to human TNF-a that have 1) high affinity to the antigen, 2) neutralizing activity, and 3) reduced immunogenicity. Id. at 1344. However, the two companies took different paths to develop the therapeutic TNF-a antibodies. Centocor first identified a mouse antibody to human TNF-a that had both high affinity and neutralizing activity and then modified the mouse antibody to make it look more human. Id. at 1344–45. In contrast, Abbott constructed a fully-human antibody from scratch by searching a phage library for fully-human antibodies that bind to human TNF-a and then using various techniques to improve their binding affinity, which eventually led to HumiraÒ. Id. at 1345–46. Abbott filed a patent application disclosing the high affinity, neutralizing, fully-human antibody to human TNF-a in 1996 and the patent was granted in 2000. Id. at 1346.
Centocor filed a patent application disclosing both the mouse antibody and the chimeric antibody in 1991. Id. at 1345. Then, Centocor filed a series of continuation-in-part applications (“CIP applications”) in 1993 and 1994. Id. at 1345–46. In 2002, after the regulatory approval of Abbott’s fully-human TNF-a product HumiraÒ, Centocor added the claim for the fully-human TNF-a antibody as another CIP application of the chimeric antibody patent family, and the patent was issued in 2006. Id. at 1346–47. Shortly thereafter, Centocor sued Abbott for patent infringement, arguing that Abbott’s product infringed Centocor’s patent claim for human antibodies. Id. at 1347.
The issue in this case was whether the Centocor’s patent provided adequate written description for the fully-human TNF-a antibody. Id. at 1348. Since Abbott’s patent application was filed in 1996, Centocor relied on a priority claim to the 1994 CIP applications. Id. Thus, the court focused on whether the 1994 CIP applications satisfy the written description requirement of the disputed claims.
The critical difference between Centocor and the previous two cases was that the disputed claims in Centocor recited a human antibody when the specification disclosed the sequence of the human antigen that the claimed antibody binds to. As a result, the validity of the disputed claims depended solely upon the antibody exception and not upon genus-species issues. At trial, the jury found that Centocor’s patent satisfied the written description requirement and that Humira infringed upon the claim. However, the Federal Circuit reversed the jury award of $1.67 billion and invalidated the disputed claims for lack of written description. Id. at 1341.
The Federal Circuit held that an applicant can claim an antibody to a novel protein without describing the antibody under the USPTO Written Description Guideline “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 court found that Centocor failed to satisfy both standards in its 1994 patent application. First, human TFN-α was well known at the time of filing the patent application. Also, the court pointed out that when a patent claim recites antibodies with specific properties (e.g., high affinity, neutralizing activity, and binding specificity at a specific place on the target antigen), merely describing an antigen that the antibodies bind to is not enough to satisfy the written description requirement. Generating antibodies to a certain antigen is routine, but screening those antibodies for certain properties is not. Thus, the Federal Circuit concluded that simple possession of the known TFN-α did not place Centocor in possession of the claimed antibodies.
5. Effects and Policy Consideration of Centocor v. Abbott
In effect, Centocor limited the scope of the antibody exception to antibodies that bind to newly discovered antigens. Furthermore, when a patentee discloses a new antigen in the specification, the patentee can claim antibodies that bind to the antigen and can be easily discovered through routine processes based on the binding affinity to the antigen. The patentee cannot claim a subset of such antibodies that have special properties in addition to the binding property to the antigen because screening for antibodies with these additional characteristics would require more than routine processes.
As a result, Centocor discouraged pharmaceutical companies from claiming for a genus of antibodies that bind to a known antigen. Under Centocor, pharmaceutical companies now need to either structurally characterize the common motif among the binding sites of antibodies that bind to the antigen, which is almost impossible to do with the current technology, or separately claim individual antibodies that bind to the antigen based on their structures, which is susceptible to design-around problems. Some commentators worry that Centocor will reduce incentives to develop therapeutic antibodies because Centocor narrowed the scope of acceptable claims for antibodies that bind to known antigens so much that the claims carry little economic value.
I agree that the strict application of the antibody exception solely to truly novel antigens (i.e., molecules that have never been discovered before) will harm the incentive to innovate because such antigens are rare with the widespread use of genomic sequencing. See Serafini, supra at 7. However, as long as “novel antigens” are broadly interpreted to include known antigens whose novel characteristics are discovered by a patentee, Centocor will not thwart the biotechnology industry from developing therapeutic antibodies because of the recent technological developments in the antibody industry.
Before the 2000s, scientists separated antibodies through screening for molecules that bind to an antigen of interest, but understanding the structures or the amino acid sequences of those antibodies was time-consuming and not readily affordable. The USPTO in the Written Description Guidelines reasoned that further requiring patent applicants to structurally specify the claimed antibodies other than its specific binding affinity to a certain antigen would impose undue burden to innovators.
However, these days, the court’s holding in Centocor no longer imposes an excessive burden to patent applicants because the cost of genomic sequencing and screening of monoclonal antibodies has decreased dramatically. For example, the cost of human genome sequencing decreased from $300 million in 2004 to $48,000 in 2009 and then to $5,000 in recent years. See Michael L. Metzker, Sequencing Technologies – the Next Generation, 11 Nature Reviews 31, 43–44 (2010). Also, development of human or chimeric antibodies and deeper understanding of immunology made it necessary for patentees to show their possession of claimed antibodies by demonstrating their structures, amino sequences, or binding affinities. The Federal Circuit in Centocor took the legalistic approach in finding that Centocor did not possess the claimed antibodies and did not mention any policy considerations in its holding. Still, I think that Centocor was a timely decision to restrict the scope of the antibody exception to the extent that is more appropriate under the current immunological technology.
6. Conclusion
In brief, the Federal Circuit in Centocor made a reasonable counteraction to the USPTO’s antibody exception to the written description requirement after Noelle’s apparent approval of the exception by explicitly restricting the cases in which the exception can be applied. Surely, there are concerns that due to the paucity of truly “novel” antigens, Centocor will essentially abolish the antibody exception and impose an unreasonably strict written description requirement to antibody claims. However, as long as the meaning of “novel” antigens is interpreted broadly to include known molecules with new characteristics, I think that Centocor made a few steps closer to a nice balance between disallowing patent rights beyond disclosure and granting patent rights broad enough to incentivize innovation. After all, the quid pro quo contemplated by the Constitution between monopoly rights granted to patents and public benefits from inventions warrants the USPTO’s requirement that claim scope should be commensurate with disclosure. Granting patent rights for all antibodies that bind to an antigen when the patentee merely disclosed the antigen contradicts the basic quid pro quo of patent law. Centocor’s clarification of the written description standard for monoclonal antibody patents will provide predictability in the written description doctrine and make biotechnology companies pay closer attention to their patent claims and specifications.