The Antibody Patent Paradox.

• Author: Lemley, Mark A.

ARTICLE CONTENTS INTRODUCTION 997 1. THE SCIENCE OF ANTIBODIES 1001 A. Antibodies and the Immune System 1001 B. Applications of Antibodies 1004 C. The History and Development of Antibody Research 1007 D. Patents and the Antibody Market Today 1010 II. THE DEATH OF ANTIBODY PATENT CLAIMS 1013 A. The Science of Patenting Antibodies 1013 B. Functional Claiming of Antibodies: 1986-2002 1016 C. The Rejection of Functional Claiming for Antibodies: 2004-Today 1020 1. Enablement 1020 2. Written Description 1023 3. Today: The Death of the Antibody Claim 1029 D. Antibody Claims in the Courts Today 1034 III. WHAT'S GOING ON HERE? 1037 A. The Primacy of Structure 1038 B. A Rejection of Functional Claiming 1040 C. The Law Is Following Changes in the Science 1044 D. The Drug-Pricing Backlash 1046 IV. RESOLVING THE PARADOX 1049 A. Do We Still Need Genus Antibody Claims? 1049 B. Practical Alternatives to Functional Antibody Claims 1053 1. Sequence Homology and "Structure-Plus" Claims 1054 2. Means-Plus-Function Claiming and the Doctrine of Equivalents 1055 3. Policy Implications 106l CONCLUSION 1063 INTRODUCTION

Antibodies are the backbone of modern biotechnology. They are the work-horses of molecular-biology research, the principal component in numerous diagnostic tests, and the heart of both the immunity provided by COVID-19 vaccines and of the single most effective COVID therapy. (1) Long before "antibodies" became a household word during the COVID-19 pandemic, engineered antibodies were central to many of the most important and most valuable medical tests and therapies of the past thirty years. (2) Annual revenue from just the top ten best-selling antibody drugs in 2019 reached $79.1 billion--almost double that of the global market for movies and music, combined. (3)

Patent law has long given antibodies broad protection, allowing an inventor who identifies an antibody that targets a particular antigen of interest to claim ownership over not just the particular antibody they developed, but over a genus of antibodies attracted to the same antigen. (4) An inventor who created an antibody that bound to, say, tumor necrosis factor alpha (TNF-a)--the basis of three of the six top-selling antibody therapies - could claim that antibody and almost all other antibodies that bound to it. (5) In part, this claim practice was one of necessity. Unlike typical "small-molecule" drugs, scientists had long identified antibodies not by their precise molecular structure but by what they did. (6) Indeed, characterizing antibodies atom by atom was both impractical and pointless--akin to describing a fighter jet by listing every nut and bolt. (7) "Functional claiming," the ownership of "any device that performs [a] function," was not only permitted but a norm for antibody patents. (8) The form of patent claims thus followed their function.

Things have changed. In the laboratory, it is now easier to identify the physical sequence of a newly discovered antibody. (9) But at the U.S. Court of Appeals for the Federal Circuit, no antibody patent in over a decade has survived a challenge based on overbreadth and inadequate disclosure, (10) with the court regularly throwing out billion-dollar jury verdicts in favor of those patents. (11) Mainly, the patents have fallen victim to patent law's "written description" requirement, the doctrine that requires patentees to disclose "enough" examples of what they invented to show a "person having ordinary skill in the art" (a PHOSITA, or a reasonable expert) that the inventor was in possession of the invention. (12) That doctrine is intended to prevent a patentee from "gun jumping"--filing for a patent application before they have actually nailed down the invention. (13) Emboldened, perhaps, by this expansion of the written description doctrine, the Federal Circuit has also invalidated antibody patents on the related doctrinal ground of enablement, even though the technology is now easier to find and apply. (14)

Because the written description doctrine prevents inventors from filing patent applications too early, the doctrine has long operated with the conceit that the more knowledge a PHOSITA possesses about the field, the less a patent must show to demonstrate possession of that invention. (15) With antibodies, however, a paradox has emerged. In the early days of the industry, when scientists often knew little about the precise molecular and genetic structures of antibodies and lacked tools to easily find them, the law permitted broad patents covering any antibody that bound to a particular target with a certain specificity; identifying those characteristics was the only practical way to describe newly discovered antibodies. (16) Now that scientists understand the chemical structure of antibodies better--including an appreciation for just how genetically diverse antibodies are, even those that bind to a single target--functional patent claims to antibodies' antigens are routinely being held invalid for failing the enablement or written description doctrines. (17) Today, scientists know that the discovery of one or even dozens of antibodies that bind to a particular target with a particular specificity doesn't exclude the possibility that many other antibodies with different structures do the same. (18) Instead of requiring scientists to disclose more information when their colleagues start out knowing less, patent law now requires them to disclose more information about each invention when their colleagues know more. This development cuts against patent law's precept that "there is an inverse correlation between the level of skill and knowledge in the art and the specificity of disclosure necessary to satisfy the written description requirement." (19) We call this the antibody patent paradox.

The antibody patent paradox may be part of a broader shift in patent doctrine, what one of us has called "the death of genus claims." (20) Or it may be an extension of the concerns about the abuse of functional claiming in other areas like software. (21) Or it could be the result of trying to fit one of the most complex biological molecules we know in the single, convoluted sentence that is a patent claim. (22) Or perhaps it is simply the result of a circumstance in which the more we learn, the more we learn what we don't know. (23) We explore all of these possibilities. (24)

Regardless of the explanation, the antibody patent paradox lies at the heart of several critical questions in patent policy: how broad patent claims should be to encourage invention; whether patent law is and should be technology-specific; and how we accommodate follow-on innovation after an initial, pioneering disclosure. (25) If we get those questions wrong, we could end up with a second paradox--how the patent-fueled success of antibody technology made it impossible to get the very kinds of patents that drove innovation in the first place. As a matter of innovation policy, we think the end of functional antibody claims is a problem, but the likely effects on innovation are complicated. We suggest some possible middle ground that might save narrower antibody genus claims.

In Part I, we explain the science of antibodies, how it has changed, and why antibodies are so complex. In Part II, we discuss the parallel history of the law, beginning with broad protection for functional antibody claims and ending with the current period of hostility to antibody patents. Part III considers several possible explanations for this shift, none of which are completely satisfactory. In Part IV, we explain how the antibody patent paradox is central to many of the current policy debates in patent law, and we offer some guidance as to how to resolve the paradox. We conclude by suggesting broader implications for the written description doctrine and patent claims for other complex technologies.

1. THE SCIENCE OF ANTIBODIES

   1. Antibodies and the Immune System

      The human immune system is dynamically adaptive: it can respond, in real time, to both unknown and unforeseen foreign invaders, like novel pathogenic bacteria and viruses. (26) The key to this adaptive immune system is the body's ability to quickly and precisely flag such threats as potentially harmful even though the immune system hasn't encountered them before. (27) Once a threat is identified, the immune system also needs the tools to neutralize and dispose of it without harming healthy tissue or commandeering too many of the body's resources. (28) An overaggressive immune response risks harming the body by attacking foreign but benign material, (29) while an apathetic immune response risks yielding the body to systemic infections. (30) Functional adaptive immune systems must therefore be precise without sacrificing flexibility. (31)

      This marriage of precision and flexibility is largely mediated by a class of complex proteins known as immune receptors, specifically antibodies and T-cell receptors. (32) These immune receptors are produced by two types of immune-system cells--B cells and T cells for antibodies and T-cell receptors, respectively--that circulate throughout the blood and the lymphatic system. (33) Antibodies and T-cell receptors jut out from the surface of their respective cells until they eventually come in contact with a complementary large molecule known as an antigen. (34) If recognized as a foreign substance, this contact causes the particular immune cell carrying the immune receptor to both proliferate--that is, to divide and make copies of itself--and signal other components of the immune system to bind to the offending material. (35) The upshot of this interaction is that more immune receptors specific to the particular antigen will be produced and that interactions between B cells and T cells will allow the body to "remember" the offending antigen if it attacks the body again. (36) In this way, the immune system can continually adapt to new threats without entirely forgetting...