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The rise of antibody-based treatments in the pharmaceuticals market has been accompanied by developments in U.S. patent law that may adversely affect the scope of intellectual property protections available for such treatments. Some of those developments concern the basic patent eligibility requirement.1 Others concern the written description and enablement requirements.2 This article summarizes both sets of developments and provides some practical advice on how antibody patentees can address them.
ANTIBODIES ARE GLYCOPROTEINS THAT ARE GENERATED by the immune systems of humans and other animals to tag and target pathogenic agents (antigens) for destruction. Although antibodies in their natural state are diverse in form and function, technological advances over the past few decades have enabled the industrial-scale production of monoclonal antibodies: antibodies that possess the same protein sequence and structure, bind to the same antigens, and thus demonstrate relatively predictable therapeutic effects when administered to patients. These breakthroughs in manufacturing consistency and scale in turn have led to a steady procession of regulatory approvals for antibody-based treatments. In 2018, six of the 10 best-selling drugs in the United States included antibodies or molecules incorporating antibody fragments as their active ingredients.3
In their natural state, antibodies are Y-shaped tetrameric molecules composed of two heavy amino acid chains and two light amino acid chains. Each heavy chain has a variable domain (VH), and three or four constant domains (CH1, CH2, CH3, CH4). Each light chain has a variable (VL) and constant (CL) domain. Each of the VH and VL domains include hypervariable regions, also called complementarity determining regions or CDRs, that determine the antigen to which the antibody will bind.
Each arm of the Y is composed of a light chain paired with the VH and CH1 domains of the heavy chain. The vertical segment of the Y is composed of the remaining CH domains of the two heavy chains. Each arm of the Y is referred to as a Fab region; the vertical segment of the Y is referred to as the Fc region. The Fab regions bind a specific portion (epitope) of the antigen of interest; the CDRs within the Fab regions determine to what specific epitope the antibody will bind. The Fc region does not bind to an epitope; instead, it binds to Fc receptors on cells of the immune system to effectuate an immune response. The specific nature of the immune response depends upon the class, or isotype, to which the antibody belongs. Many therapeutic monoclonal antibodies are of the IgG isotype.
Monoclonal antibodies traditionally have been manufactured by exposing an animal subject, such as a mouse, to the antigen of interest; harvesting antibody-producing plasma cells from the subjects; selecting particular antibodies generated by particular plasma cells for their desirable characteristics; then fusing the selected plasma cells with tumor cells to produce cell lines called hybridomas. Due to their tumor-like characteristics, these hybridomas multiply indefinitely and can be used to produce large quantities of the desired monoclonal antibodies.
The past three decades have seen the introduction of numerous artificial modifications to the structure and manufacture of antibodies. These modifications include:
Antibody Patent Claims
The diversity and complexity of current antibody-related technologies is matched by the diversity and complexity of the patents that claim them; moreover, new antibody-related technologies continue to appear frequently. Accordingly, any summary of antibody-related patent claims risks being overly reductive and out of date. For purposes of this article, however, antibody patent claims can be classified as:
COM claims include claims directed to:
COM claims may identify the claimed antibodies using structural limitations. The following table lists different structural limitations that can be used and examples of claim language employing those limitations:
It is not uncommon for COM claims to recite various combinations of these types of limitations.
MOT claims recite a method of treating an illness comprising administering to a patient suffering from that illness a therapeutically effective amount of an antibody. As with COM claims, MOT claims may identify the claimed antibody using multiple types of limitations. MOT claims also may include limitations that require a particular therapeutic outcome (e.g., “a method of treating proliferative disorder A in a subject comprising administering a therapeutically effective amount of antibody B to a subject in need thereof, wherein said administration inhibits the growth of C cells in said subject”).
Diagnostic claims are directed to the use of antibodies to bind and detect the presence of disease-associated antigens in patients (e.g., “a method for diagnosing antigen X-related disease in a human comprising obtaining a tissue sample from said human, contacting said sample with an anti-antigen X antibody, and detecting binding between antigen X in the sample and the antibody”).
All three classes of antibody claims may face issues under 35 U.S.C.S. § 101 and 35 U.S.C.S. § 112.
Overview of Section 101
35 U.S.C.S. § 101 defines what subject matter is eligible in the United States for patent protection. Section 101 in relevant part states that “[w]hoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor.”
Historically, courts have interpreted Section 101 to prevent the patenting of “abstract ideas,” “laws of nature,” and “natural phenomena” (including “products of nature”)—though these judicial exceptions to patent eligibility do not expressly appear in the statute. Courts have justified these judicial exceptions in part on the ground that they existed prior to and independent of human discovery, and that to permit their monopolization through the patent system would unfairly preempt their use by the public.4
Section 101 Applied to Antibodies
Antibodies—absent the modifications discussed above—are the naturally occurring products of biological immune systems, and thus at first glance, would appear to be patent-ineligible under the product-of-nature judicial exception. Courts, however, have long recognized two exceptions to that exception. First, if a natural product is isolated and purified such that it displays “markedly different characteristics” compared to its naturally occurring counterpart, it may be patent-eligible. This exception has been applied by courts to allow patents for purified naturally occurring substances ranging from adrenaline in 1911 to cannabinoids in 2019.5 The exception should apply to monoclonal antibodies as well—though no court has expressly applied the isolated/ purified exception to an antibody COM claim.
Second, human modifications to biological material, such as genetic alterations that result in a bacterium that can consume oil spills, can be patented.6 Thus, antibodies that incorporate artificial modifications should also be held patent-eligible under that precedent.
The Supreme Court’s Decisions in Mayo and Myriad and Their Application
The continued vitality of these exceptions, however, has been called into question by two U.S. Supreme Court decisions from 2012-2013. Neither of these decisions directly concerns antibodies; nevertheless, both have ramifications for life science patents.
In Mayo Collaborative Servs. v. Prometheus Labs., Inc,7 the Supreme Court held patent-ineligible claims to a “method of optimizing [the] therapeutic efficacy” of a drug treatment regimen, wherein the amount of the drug in a patient’s blood “indicates a need” to increase or decrease the dose subsequently administered to the patient. Although the drug in question was not a naturally occurring molecule, the Supreme Court concluded that the claims “set forth laws of nature— namely, relationships between concentrations of certain metabolites in the blood and the likelihood that a dosage of a thiopurine drug will prove ineffective or cause harm.”8 The Supreme Court then looked to determine whether the claims recite “significantly more” than the judicial exception, or merely recite “well-understood, routine, or conventional” matter.9 Because the claims in Mayo were “directed to” laws of nature, and the claim limitations recited nothing more than routine steps, the Supreme Court concluded that the claims were not patent-eligible.10
In Ass’n for Molecular Pathology v. Myriad Genetics,11 the Supreme Court held patent-ineligible claims to “[a]n isolated DNA coding for a BRCA1 polypeptide, said polypeptide having the amino acid sequence set forth in SEQ ID NO:2.” Because the sequence recited in the claim was identical to the naturally occurring BRCA1 sequence, the Supreme Court concluded that “Myriad did not create anything. To be sure, it found an important and useful gene, but separating that gene from its surrounding genetic material is not an act of invention. Groundbreaking, innovative, or even brilliant discovery does not by itself satisfy the Section 101 inquiry.”12
In the wake of Mayo and Myriad, the U.S. Court of Appeals for the Federal Circuit has applied those decisions to delineate two categories of life science claims according to their patenteligibility—including claims involving antibodies.
First, the Federal Circuit has repeatedly found claims to be patent-eligible when “directed to a specific method of treatment for specific patients using a specific compound at specific doses to achieve a specific outcome.”13
The Federal Circuit has distinguished these method-of-treatment claims from the patent-ineligible (and more ambiguously worded) “method of optimizing” claims at issue in Mayo. According to the Federal Circuit, the Mayo claims were patent-ineligible because they did not require the treatment of a specific disease and did not require a physician to administer a specific dose, but instead simply “indicate[d] a need” to adjust dosage. According to the Federal Circuit, the lack of a clear directive in the claim to administer a specific dose gave rise to undue preemption concerns: “[i]n Mayo, ‘a doctor . . . could violate the patent even if he did not actually alter his treatment decision in the light of the test.”14
Second, the Federal Circuit repeatedly has found claims to be patent-ineligible when directed to the observation, detection, or diagnosis of medical phenomena using routine or conventional techniques. Such claims include claims to:
Although these diagnostic claims rest on novel human discoveries and require human activity, the Federal Circuit, synthesizing Mayo and Myriad, reasoned that such claims ultimately are “directed to” the observation of natural phenomena, and that the claim limitations require only routine or conventional laboratory activities (e.g., detecting antibody-epitope binding using a labeled epitope; amplifying naturally occurring DNA sequences using polymerase chain reaction (PCR)).
The dividing line between a patent-eligible method-oftreatment claim and a patent-ineligible diagnostic or detection claim is not always clear. For example, the Federal Circuit recently found patent-ineligible a method claim reciting steps that required administering a drug (inhaled nitric oxide or iNO) to certain patients, while withholding administration to other patients determined to be at risk of adverse events. In this instance, the Federal Circuit reasoned that
[t]he invention is not focused on changing the physiological state of the patient to treat the disease. The claimed invention is focused on screening for a natural law. Information about an adverse event was observed by the inventors. The patent instructs doctors to screen for that information. Once the information is detected, no iNO treatment is given. And as far as the claim specifies, the patient’s state may remain unchanged and natural bodily processes may proceed.19
Takeaways from Section 101 Case Law
Some important lessons are suggested by these and other recent Federal Circuit decisions with respect to preserving the patent eligibility of antibody claims:
Although patent eligibility under Section 101 previously has been characterized as an issue of law, capable of resolution without detailed examination of the factual record, the the Federal Circuit in Berkheimer v. HP Inc.20 ruled that the subsidiary issue of whether claim limitations recite routine or conventional subject matter is a question of fact. Accordingly, patentees seeking to insulate antibody claims against potential Section 101 threats in litigation may wish to allege, where possible, any nonroutine or unconventional aspects of the claimed subject matter in their pleadings at the start of litigation. This is because a court generally must accept such allegations as true in situations where a defendant moves to dismiss the litigation at the pleadings stage and must view those allegations in a light most favorable to the patentee in situations where a defendant attempts to obtain summary judgment of patent-ineligibility.21
One important question that remains unanswered by the Federal Circuit and by lower courts is whether and to what extent the Supreme Court’s Myriad jurisprudence may affect the patent eligibility of antibody COM claims. As a substantive matter, antibodies clearly are distinguishable from the isolated DNA sequences at issue in Myriad: unlike those DNA sequences, the fundamental utility of isolated monoclonal antibodies does not lie in their being a physical embodiment of the sequence information contained therein. And, as a procedural matter, antibody COM claims that recite narrow structural or functional limitations should be relatively well insulated from Section 101 threats in litigation, as any naturally occurring antibodies that meet the claimed structural or functional limitations likely would have been uncovered and addressed during patent prosecution.
The present state of affairs under Mayo and Myriad may soon change. The Federal Circuit and the U.S. biotechnology industry have expressed growing dissatisfaction with the Supreme Court’s Mayo and Myriad jurisprudence. And in a July 2019 order, the en banc Federal Circuit issued 80-plus pages of colloquy criticizing those Supreme Court decisions for, among other things, harming incentives to develop new diagnostic and therapeutic technologies, establishing a de facto prohibition against diagnostic claims, and sowing uncertainty as to the patent eligibility of other types of life science claims.22 As of the time of publication, Congress is considering draft legislation that would, among other things, abrogate the “abstract ideas,” “laws of nature,” and “natural phenomena” judicial exceptions to Section 101.
Overview of Section 112
35 U.S.C.S. § 112 sets forth a written description requirement and an enablement requirement for patent specifications. The written description requirement demands that a patent specification provide a written description of the invention sufficient to convince a person of ordinary skill in the art (POSA) that the inventors were in possession of the claimed invention as of the patent’s filing date. The enablement requirement demands that a patent specification enable a POSA to practice the claimed invention without having to engage in undue experimentation.
Section 112 Applied to Antibodies
In the past, the enablement requirement has not presented significant obstacles to the patentability of antibody claims above and beyond those faced by other types of patent claims. Indeed, two of the seminal Federal Circuit cases on enablement were antibody cases; in both, the Federal Circuit concluded that methods used to generate and screen antibodies against specific antigens were “well-known” and “routine.”23 That situation, however, may be changing. Two recent Delaware district court rulings have held that claims directed to broad genuses of antibodies were non-enabled where practicing the full scope of the claims would require a POSA to engage in essentially the same amount of work as the patentees—even where the work in question was “routine.”24
The written description requirement has been a source of confusion as applied to antibody claims. This confusion arose in part due to a conflict between the United States Patent and Trademark Office (USPTO) and the Federal Circuit over what is known as the well-characterized antigen test.
In 2000 and 2008, the USPTO published training materials indicating that a broad functional claim reciting “an antibody capable of binding to antigen X” would satisfy the written description requirement if the patent specification adequately described the antigen in question by reference to its sequence and physical properties—even if the specification did not expressly describe the claimed antibodies—because generating antibodies to that antigen constituted “routine” technology.25
The Federal Circuit, however, in a quartet of decisions, narrowed and ultimately abrogated the well-characterized antigen test:
Takeaways from Section 112 Case Law
Although antibody written description and enablement case law tends to be highly fact-specific, these developments suggest some important lessons as to how to draft antibodyrelated patent claims and patent specifications to mitigate potential written description and enablement issues:
The current state of Section 101 and Section 112 jurisprudence presents a number of risks for antibody-related patent claims in the United States.
As to Section 101, the Federal Circuit, following the Supreme Court’s Mayo and Myriad precedent, appears to have drawn a distinction between method-of-treatment claims, which it considers patent-eligible, and diagnostic claims, which it considers patent-ineligible. Whether and under what circumstances Mayo or Myriad may apply to other types of life science patent claims remains uncertain. That uncertainty is a source of continuing frustration for both the Federal Circuit and the biotechnology industry; such uncertainty might be resolved in the near future through Congressional reform of Section 101.
As to Section 112, broad antibody genus claims potentially may present enablement concerns, and the abrogation of the well-characterized antigen test by the Federal Circuit means that patentees no longer can obtain broad claims to a genus of antibodies capable of binding a certain antigen where the antibodies themselves are not adequately described in the patent specification. However, claims that define antibodies by functional limitations potentially may meet the written description requirement if a sufficiently diverse set of exemplary antibody species is disclosed in the specification. In view of the above risks and uncertainties, antibody patentees should continue to pursue a variety of claim types and should include as much detail and data as possible about the structure and function of the claimed antibodies in their patent specifications.
Christopher E. Loh is a partner at Venable LLP. He practices complex patent litigation in the areas of pharmaceuticals, biotechnology, and chemistry. As lead or co-counsel, Chris has litigated patent cases involving oncology therapies, anti-HIV therapies, anti-hepatitis drugs, antidepressants, and statins. He has argued before numerous federal district courts and the U.S. Court of Appeals for the Federal Circuit, and he has won in inter partes review proceedings before the Patent Trial and Appeal Board on behalf of patent owners.
To find this article in Lexis Practice Advisor, follow this research path:
RESEARCH PATH: Intellectual Property & Technology > Patents > Patent Prosecution > Practice Notes
For a roadmap of the major aspects of the litigation process, see
> PATENT LITIGATION FUNDAMENTALS
RESEARCH PATH: Intellectual Property & Technology > Patents > Patent Counseling & Transactions > Practice Notes
For strategies that a patentee may utilize when facing patent eligibility challenges early in litigation, see
> PATENT ELIGIBILITY: OVERCOMING EARLY LITIGATION CHALLENGES
RESEARCH PATH: Intellectual Property & Technology > Patents > Patent Litigation > Practice Notes
For guidance on whether counsel for a patent owner should conduct a pre-litigation infringement and validity investigation and analysis before filing an infringement suit, see
> PRE-LITIGATION OPINION ON PATENT INFRINGEMENT AND VALIDITY
For a discussion on the disclosure-dedication doctrine and how it can be avoided by careful drafting of patent claims and specification, see
> CLAIM DRAFTING: AVOIDING DISCLOSUREDEDICATION
For an analysis of the supplemental examination, an important but relatively underutilized U.S. Patent and Trademark Office procedure that is available to patent owners under the America Invents Act to strengthen their patents, see
> SUPPLEMENTAL EXAMINATION FUNDAMENTALS
For a summary of the U.S. Patent and Trademark Office (USPTO) 2019 Revised Patent Subject Matter Eligibility Guidance, see
> USPTO PATENT SUBJECT MATTER ELIGIBILITY GUIDELINES 2019
1. 35 U.S.C.S. § 101. 2. 35 U.S.C.S. § 112. 3. See The Top 20 Drugs by 2018 U.S. Sales, FiercePharma, June 17, 2019. 4. See Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130 (1948). 5. See Parke-Davis & Co. v. H.K. Mulford Co., 189 F. 95 (C.C.S.D.N.Y. 1911); United Cannabis Corp. v. Pure Hemp Collective Inc., 2019 U.S. Dist. LEXIS 66092 (D. Colo. Apr. 17, 2019). 6. Diamond v. Chakrabarty, 447 U.S. 303, 310 (1980). 7. 566 U.S. 66 (2012). 8. 566 U.S. at 77. 9. 566 U.S. at 79. 10. 566 U.S. at 79–80. 11. 569 U.S. 576 (2013). 12. 569 U.S. at 591. 13. See Vanda Pharms. Inc. v. West-Ward Pharms. Int’l Ltd., 887 F.3d 1117, 1136 (Fed. Cir. 2018); see also Natural Alternatives Int’l, Inc. v. Creative Compounds, LLC, 918 F.3d 1338 (Fed. Cir. 2019); Endo Pharms. Inc. v. Teva Pharms. USA, Inc., 919 F.3d 1347 (Fed. Cir. 2019). 14. Vanda Pharms. Inc., 887 F.3d at 1135. 15. Athena Diagnostics, Inc. v. Mayo Collaborative Servs., LLC, 915 F.3d 743 (Fed. Cir. 2019). 16. Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371 (Fed. Cir. 2015). 17. Roche Molecular Sys. v. Cepheid, 905 F.3d 1363 (Fed. Cir. 2018). 18. Cleveland Clinic Found. v. True Health Diagnostics LLC, 760 Fed. Appx. 1013 (Fed. Cir. 2019). 19. INO Therapeutics LLC v. Praxair Distrib. Inc., 782 Fed. Appx. 1001, 1008 (Fed. Cir. 2019) (nonprecedential). 20. 881 F.3d 1360, 1365 (Fed. Cir. 2018). 21. See Cellspin Soft, Inc. v. Fitbit, Inc., 927 F.3d 1306 (Fed. Cir. 2019); Berhkeimer, 881 F.3d at 1365. 22. See Athena Diagnostics, Inc. v. Mayo Collaborative Servs., 927 F.3d 1333 (Fed. Cir. 2019). 23. Hybritech v. Monoclonal Antibodies, 802 F.2d 1367 (Fed. Cir. 1986); In re Wands, 858 F.2d 731 (Fed. Cir. 1988). 24. MorphoSys v. Janssen Biotech, 358 F. Supp. 3d 354, 372 (D. Del. 2019) (granting summary judgment of non-enablement based upon a finding that “a POSA would require substantial time and effort to discover antibodies within the claims that are not conservative variants of the disclosed antibodies.”); Amgen Inc. v. Sanofi, 2019 U.S. Dist. LEXIS 146305 at *36 (D. Del. Aug. 28, 2019) (granting motion for judgment as a matter of law of non-enablement: “despite the routine techniques employed, it appears that a person of ordinary skill in the art would still be required to do essentially the same amount of work as the inventors of the patents-in-suit, or engage in a trial-and-error process of amino acid substitution as even conservative substitutions may have unexpected results.”) (internal quotations and citations omitted). 25. See USPTO Written Description Training Materials (Rev. 1 Mar 25, 2008), pp. 45–46. 26. 355 F.3d 1343 (Fed. Cir. 2004). 27. 636 F.3d 1341 (Fed. Cir. 2011). 28. 759 F.3d 1285 (Fed. Cir. 2014). 29. 759 F.3d at 1291. 30. 759 F.3d at 1301. 31. 872 F.3d 1367 (Fed. Cir. 2017). 32. 872 F.3d at 1379. 33. Amgen Inc., 2019 U.S. Dist. LEXIS 146305 at *14, 36-37