IP Considerations Associated with
Companion Diagnostic Discovery and Development
Prepared for AIPLA’s MidWinter Institute for CLE Credits for a
Panel Session Titled “IP Value for Personalized Medicine”
2:00 – 3:30 P.M., Thursday, January 31, 2013
Judith A. Roesler, Moderator
Authors:
Mark J. Stewart, Ph.D.Senior Director – Assistant General Patent Counsel
Eli Lilly and Company
Indianapolis, IN 46285
(317) 276-0280
/ Robert L. Sharp
Patent Counsel
Eli Lilly and Company
Indianapolis, IN 46285
(317) 651-1541
Contents
I. Introduction 1
II. The Type of Discovery 2
III. Business Objectives 5
IV. Patentability and Infringement Considerations (US) 6
A. Divided Infringement 6
B. Patent Eligibility 7
C. Inherency 9
V. Patentability concerns outside the U.S. 10
A. Article 53 Prohibitions 10
B. Overlapping Patient Populations 12
C. Selection Inventions in the EPO 12
VI. Partnering and Contracting Challenges 13
I. Introduction
The completion of the Human Genome Project in 2003 along with rapid advances in technology associated with identifying and correlating markers with treatment outcomes necessitates that any company developing a new drug consider a biomarker strategy for such drug. At a conference on personalized medicine in 2007 John Lechleiter, Eli Lilly and Company’s CEO, stated that “the rise of personalized medicine is one of the most important developments in health care today. Personalized medicine will change health care almost across the board . . . But nowhere, I would argue, are the cross-currents of change more powerful or the stakes higher than in the development, manufacture, and sale of prescription medicines. In my industry, we would be powerless to resist personalized medicine, not to say foolish.”
FDA post-market surveillance along with public concerns related to the safety profile of a number of drugs is driving pharmaceutical companies to focus on tailored therapeutic initiatives. Tailored therapy is focused on tailoring the drug, dose, and dosing schedule to the appropriate patient population with the goal of improving individual patient outcomes with greater predictability. A tailored therapeutic focus involves an assessment of the spectrum of patient responses to a drug therapy and attempts to identity biomarkers that help stratify patient populations into groups with more predictable benefit/risk outcomes. This personalized medicine movement appears exciting and is clearly gaining ground; however, the initiative is rife with hurdles.
One particular hurdle in supporting a tailored therapy approach to drug products relates to the fact that many – if not most - large pharmaceutical companies do not have the internal expertise to discover and then commercially develop companion diagnostics that will help identify the right patient, the right dose, and the right schedule. These companies must ultimately find partners with expertise in the appropriate diagnostic or technological area in order to sustain a successful personalized medicine approach. Relying on a diagnostic partner to develop a companion diagnostic that is potentially required in order to obtain approval of a drug significantly complicates an already complex drug development and approval process. Of course, a sound intellectual property strategy is part of that complicated process and central to the successful development and commercialization of a tailored therapeutic. IP strategy drivers for diagnostic related inventions include deep consideration of the following: 1) the type of discovery; 2) the business objectives and associated indirect as well as direct value propositions; 3) patentability and infringement considerations, especially in the US; and 4) the need to collaborate with third parties.
II. The Type of Discovery
Generally, the strength of patent protection is correlated with the type of discovery. Patent claims directed to the composition of matter are the strongest type of protection and would be available for the discovery of a novel biomarker. Such protection could be used, if desired, to exclude others from using the biomarker in any type of diagnostic for any type of drug. Myriad’s patents on the BRCA genes are examples of this type of protection.[1] It remains to be seen, however, whether naturally existing genes and proteins are eligible for patent protection via a composition of matter claim.[2] More likely is a discovery that a known marker or group of markers predicts response or dictates the course of therapy for a particular drug or class of drugs. This type of discovery may result in method of treatment claims which can also be quite valuable especially if such methods read on a drug and/or diagnostic label claim.
Generally, the first step in initiating a biomarker strategy is to find a biomarker or group of biomarkers that correlate with efficacy or some other treatment consequence of a particular drug. For example, the presence, absence, or level of a protein marker (e.g., lower or higher than “normal”) may indicate whether a particular drug will effectively and/or safely treat a particular disease in a distinguishable patient population.
Identifying a biomarker or group of biomarkers that correlate with a particular drug treatment component more often than not does not involve the discovery of a previously unknown biomarker. In a more common scenario, the biomarkers are generally known proteins; however, their association with the particular drug being studied is unknown. The discovery is usually based on a retrospective analysis of pre-clinical or clinical trial samples taken from animals or patients that have been treated with a particular drug. The samples are screened for the presence of various known markers to determine whether any marker or subset of markers correlate with efficacy or some other treatment consequence. Often these types of discovery efforts are undertaken by the drug developer or involve some type of “fee for service” arrangement with a partner that does mostly “rule based” activities on a pay-as-you-go basis. Unless the partner has the ability to take a discovered correlation and develop that into a commercial companion diagnostic product, it is imperative that any arrangement involving intellectual property arising from the initial discovery give the drug developer the ability to partner and develop a companion diagnostic. Generally this means that the drug developer secures ownership or at least control of such IP. Interestingly, it is this initial “correlation” discovery that generates the most valuable (other than claims to the therapeutic composition or the specific use thereof) and potentially far-reaching IP as it can impact exclusivity for both the drug and the associated diagnostic.
Method of treatment claims should be drafted with both the drug label and diagnostic label in mind. Drug labels can be general in nature or refer to specific “types” of assays. The following are three examples of drug labels going from general to more specific in terms of referencing assays:
1) the XALCORITM label states that the drug is indicated for the treatment of patients with locally advanced metastatic non-small cell lung cancer that is ALK-positive as detected by an FDA approved test;[3]
2) the HERCEPTINTM label states the detection of HER2 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy. Due to differences in tumor histopathology use FDA-approved tests to assess HER2 protein overexpression AND HER2 gene amplification. Overexpression was tested using IHC and amplification was tested using FISH.[4]
3) the ZELBORAFTM label states that the drug is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. In addition, the label notes that in clinical studies patients were tested using the cobas® 4800 BRAF V600 Mutation test which is designed to detect mutations in DNA isolated from formalin-fixed, paraffin-embedded human melanoma tissue.[5]
For example, a method claim focusing on the drug label where a marker is identified and the directions are to use a FDA-approved test would consist of some variation of the following: A method of treating disease X in a patient, comprising testing for the presence of biomarker group Y in a biological sample from the patient and administering a therapeutically effective amount of Drug to the patient if the sample tests positive for biomarker group Y. A claim directed at a specific diagnostic assay would include limitations associated with how the presence of the biomarker is determined. Such claims can be extremely valuable as they have the potential to extend the exclusivity of the drug against generic competitors as any generic would be required to also include reference to the diagnostic test to meet FDA requirements.
Companion diagnostic (CDx) labels that are associated with a FDA approved test or device will reference the companion drug. For example, the Vysis ALK Break Apart FISH probe test states that the “kit is a qualitative test to detect rearrangements involving the ALK gene via FISH in FFPE non-small cell lung cancer tissue specimens to aid in identifying those patients eligible for treatment with Xalcori® (crizotinib). This test is for prescription use only.”[6]
A method claim focusing on a diagnostic label that mentions a particular drug would consist of some variation of the following: A method of identifying patients with disease X eligible for treatment with Drug Z comprising testing a biological sample from the patient for the presence of biomarker Y, wherein the patient is eligible for treatment with Drug Z if biomarker Y is present.
Less valuable are discoveries of assays and assay reagents as claims covering this type of subject matter do not generally impact the drug label and are usually easy to design around. The discovery and patenting of new platform technologies, however, can be extremely valuable to a diagnostic company with the capability of using such technology to bring companion diagnostics to market. With respect to considering proper claim scope in view of the assay(s) used to detect the presence, absence, or level of the biomarker(s), it is important to consider how a potential competitor may attempt to avoid patent infringement while at the same time demonstrating the equivalence of its device to a legally marketed device. A 510(k) is a premarket submission made to the FDA to demonstrate that the device to be marketed is substantially equivalent to a legally marketed device, the predicate. Substantial equivalence is established with respect to intended use, design, energy used or delivered, materials, chemical composition, manufacturing process, performance, safety, effectiveness, labeling, biocompatibility, standards, and other characteristics, as applicable. When drafting claims, it is important to consider other feasible methods or techniques for measuring the biomarker and include in the specification and/or claims basis for reasonable alternative steps in order to account for the relative low hurdle for a 510(k) on a different, but “substantially equivalent,” diagnostic.
III. Business Objectives
Pharmaceutical companies must evaluate how to protect potential biomarkers throughout the drug development lifecycle. While there are some companion diagnostics developed late in the drug lifecycle, particularly to differentiate a late-stage or even launched product in the marketplace, most biomarkers are considered early in the development lifecycle. Unfortunately for these early development stage discoveries, at the time the initial discovery is made, it is completely unclear as to whether the discovery has commercial value and could lead to the development of a companion diagnostic.
Furthermore, pharmaceutical companies without the core capability to commercially develop and sell diagnostic kits or assays are often conflicted as to whether to devote limited resources to file patents that may not necessarily extend the exclusivity for the drug product but instead relate primarily to such diagnostic kits and assays. The two overarching considerations that drive the IP strategy associated with a correlation invention discovered by a pharmaceutical company early in the drug product lifecycle are as follows: the drug developer must have freedom-to-operate in the use of the biomarker(s) for the clinical trials necessary for gaining approval of the drug; and if the use of the marker as a diagnostic is required by either a regulatory agency or a reimbursement agency, the drug developer must ensure the diagnostic is available to the health care provider or patient.
Depending on the competitive landscape related to the drug, drug target and potential biomarkers, waiting to file a patent application until more data is generated and there is more certainty regarding the commercial value could be problematic. It is entirely possible that a competitor working with the same drug target could discover a biomarker correlation that, if patented, could create a freedom-to-operate risk. Freedom-to-operate risks can be mitigated either by publishing the relevant data or by filing a patent application. Although potentially more costly, filing a provisional application is the most efficient way to create prior art for a competitor that may make a similar discovery in the future. In addition, the commercial value of the invention can be reassessed within the provisional year and the application can be updated during that time as well. If a PCT application is filed at the year date, the owner has an additional 18 months to assess the value before spending more resources to prosecute the patent globally.
Finally, to ensure that, if required, a diagnostic can be made available to the healthcare provider or patient, a diagnostic assay kit must be commercially developed and approved by the FDA. A partner may be unwilling to devote resources to what will be perceived as an extremely risky business proposition without some assurance of exclusivity should both the drug and companion diagnostic be successful. Without patent protection ensuring a diagnostic partner of exclusivity for a proposed diagnostic, pharmaceutical companies will be forced to pay significantly more to cover the partner’s risk of competing diagnostics in the marketplace.
IV. Patentability and Infringement Considerations (US)
Although the patent law should be applied consistently across all technologies, the unique nature of biomarker-related inventions has raised some interesting legal issues in terms of how traditional legal principles should be applied to such inventions. These issues include: 1) divided infringement; 2) patent eligibility; and 3) inherent anticipation.
A. Divided Infringement
The U.S. Court of Appeals for the Federal Circuit recently addressed the issue of whether a method claim can be infringed if the steps of the claim are not performed by a single entity.[7] Method of treatment claims associated with biomarker correlations are especially susceptible to divided infringement issues as a claim may require that the steps be performed by a doctor or other caregiver (treating the patient by administering the drug) and a laboratory technician (performing an assay to detect a biomarker).