Biologics are a fast-growing class of therapeutic compounds. In the United States, patent litigation between biologic manufacturers and biosimilar applicants occurs under the Biologics Price Competition and Innovation Act (BPCIA) at both the federal district court and appellate levels. Since many of the top-selling pharmaceuticals in the United States are biologics, there can be high stakes in BPCIA litigation.
In this series, we will discuss the fundamentals of biosimilar regulation and patent litigation under the BPCIA, starting with an introduction to biologics and biosimilars.
What is a biologic and how is it different from a small molecule drug?
Biologics are a diverse category of pharmaceutical products that are often produced or isolated from living sources, such as cells. They are used to prevent or treat a variety of medical conditions. Examples of biologics include blood, blood components, vaccines, monoclonal antibodies, therapeutic proteins, and gene therapy products. (See, e.g., FDA resources: Biosimilar and Interchangeable Products and What Are ‘Biologics’ Questions and Answers.)
Biologics differ from small molecule drugs in many respects. Unlike small molecule drugs, which are typically chemically-synthesized and have well-defined structures, most biologics are large, complex molecules, and they may consist of heterogeneous mixtures that cannot be easily characterized. In addition, because biologics are often made using living organisms, they require complex manufacturing processes that can lead to differences between manufactured lots.
Typical Small Molecule vs. Biological Drugs
Typical Small Molecule Drugs
Typical Biological Drugs
Derived from living sources; complex manufacturing processes
Well-defined chemical structures
Heterogeneous mixtures; difficult to characterize
Manufacture lots may differ
Approved under the FD&C Act as a New Drug Application (NDA)
Approved under the PHS Act as a Biologics License Application (BLA)
What is a biosimilar drug and how is it different from a generic drug?
According to the BPCIA, a biosimilar is defined as a biologic that is “highly similar” to an existing FDA-approved reference biological product (“notwithstanding minor differences in clinically inactive components”) and has “no clinically meaningful differences … [from] the reference product in terms of [its] safety, purity, and potency.” 42 U.S.C. § 262(i)(2). Like generic drugs, biosimilars are approved through an abbreviated regulatory pathway and typically cost less than their biosimilar counterparts.
But there are important differences between biosimilars and generics. For example, whereas generic drugs have the same active ingredients as brand-name drugs, biosimilars are not necessarily identical to their reference products. Instead, biosimilars must be “highly similar” to their reference products in terms of their characteristics, mechanisms of action, and functions. (See, e.g., FDA resource: Biosimilar and Interchangeable Products.) In addition, whereas generic drug applicants must show that their products are bioequivalent to brand-name drugs in terms of the rate and extent that the active ingredient is released at the treatment site, biosimilar applicants must show there are no “clinically meaningful” differences in the safety and effectiveness of their products as compared to reference products. Biosimilars and generic drugs are also approved through separate regulatory pathways, and the laws that govern them, including laws on market entry and patent dispute resolution, are different.
Typical Generics vs. Biosimilars
For Typical Generics
For Typical Biosimilars
Branded drug listed in the Orange Book with associated patents
Reference product listed in the Purple Book without associated patents
New chemical entities can enjoy 5 years of data exclusivity; supplemental approvals based on new clinical trials enjoy 3 years of market exclusivity
New biologics enjoy 4 years of data exclusivity and 8 additional years of market exclusivity; no exclusivities for supplemental approvals
Hatch-Waxman Act provides abbreviated pathway for generic drug
BPCIA provides abbreviated pathway for biosimilar or interchangeable product
Generic drugs are required to have identical active ingredients as brand-name drugs
Biosimilars are required to be highly similar to their reference products
Generic drugs are required to be bioequivalent to brand-name drugs
Biosimilars are required to have no clinically meaningful differences in safety and effectiveness as compared to reference products
Generic drugs may be automatically substituted for a brand-name drug at the pharmacy (under current state laws)
Biosimilars cannot be automatically substituted for a reference product at the pharmacy (under current state laws); however “interchangeable” biosimilars may be automatically substituted for the referenced product
Relatively less expensive to develop (compared to biosimilar)
Relatively more expensive to develop
(compared to generic)
Relatively shorter development time
(compared to biosimilar)
Relatively longer development time
(compared to generic)
How does a biosimilar applicant obtain FDA approval?
The BPCIA provides an abbreviated pathway to expedite the biosimilar approval process, which entails “a rigorous evaluation to ensure  patients [of the] efficacy, safety, and quality” of biosimilar products. (See FDA resource: Biosimilar Development, Review, and Approval.) FDA may rely on “existing scientific knowledge about the safety and effectiveness of [an approved] reference product to support approval” of a corresponding biosimilar. (Id.) To leverage the nonclinical and clinical data of the reference product, the biosimilar applicant must prove “its proposed biosimilar product is highly similar to and has no clinically meaningful differences from the FDA-approved reference product” based on comparative data. (Id.) This may lead to faster product approval and thus earlier access for patients.
There are currently 26 FDA-approved biosimilars. FDA has approved biosimilars for nine different reference products, including Remicade®, Humira®, Neulasta®, Rituxan®, Avastin®, Herceptin®, Enbrel®, Neupogen®, and Epogen®.
What is the difference between a biosimilar and an interchangeable?
An interchangeable is a biosimilar that meets additional requirements under the BPCIA. 42 U.S.C. § 262(k)(4). An interchangeable is “expected to produce the same clinical result as [its] reference product in any given patient.” Id. at § 262(k)(4)(A)(ii). And, for an interchangeable that will be “administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the [interchangeable] and the reference product is not greater than the risk of using the reference product without such alteration or switch.” Id. at § 262(k)(4)(B).
An approved interchangeable may be substituted for the reference product without first consulting the prescriber, depending on the pharmacy laws and practices in the state. See id. at § 262(i)(3). In contrast, if a patient wants to receive a biosimilar that has not been approved by FDA as interchangeable, the patient may need a prescription from their healthcare provider written specifically for that biosimilar.
To obtain approval as an interchangeable an applicant may need to perform additional clinical testing. For example, the applicant might conduct “switching studies” that show the proposed interchangeable will not increase safety risks or decrease product effectiveness if it is switched with the FDA-approved reference product.
There are currently no FDA-approved interchangeable biosimilars.
Authors: Michael Anderson, Kayleigh McGlynn, Tracea Rice, Jenny Shmuel, Cheryl Wang
The opinions expressed are those of the authors on the date noted above and do not necessarily reflect the views of Fish & Richardson P.C., any other of its lawyers, its clients, or any of its or their respective affiliates. This post is for general information purposes only and is not intended to be and should not be taken as legal advice. No attorney-client relationship is formed.
Cheryl Wang’s intellectual property litigation practice spans a wide range of technology, including life sciences, pharmaceuticals, biotechnology, software, hardware, and medical devices. Ms. Wang has worked on a variety of technologies, including pharmaceutical formulations, antibodies, biologics, immunotherapy, CRISPR, sleep apnea devices,...
Jenny Shmuel, Ph.D., represents clients on a range of intellectual property matters, with an emphasis on medical device and pharmaceutical technologies. She has extensive experience in pre-suit diligence, case management, expert and fact discovery, and brief writing, and has examined and cross-examined witnesses at trial.
Over the last...
Kayleigh McGlynn is a litigation associate in the Boston office of Fish & Richardson P.C. Kayleigh was previously a summer associate at Fish.
During law school, Kayleigh served as the electronic supplement editor for the Boston College Law Review and editor-in-chief of the Boston College Intellectual Property &...