Prescription drug prices have long been a source of frustration for the American public and the subject of intense political debates about the best way to lower them without stifling innovation. One of the most significant breakthroughs on this front was the Hatch-Waxman Act of 1984, which established a regulatory framework whereby generic versions of brand-name drugs could enter the market immediately upon the expiration of brand-name drugs’ patents. The linchpin of this regulatory scheme, and for all patent disputes between branded and generic drug makers, is the Food and Drug Administration (FDA) Orange Book.
Basics of the Drug Approval Process
Before diving into the Orange Book, it is helpful to understand the basics of the FDA drug approval process. This process differs for applicants seeking approval of new drugs (also known as “innovator” or “brand-name” drugs) and for those seeking approval of generic versions of existing drugs.
Applicants seeking approval of new drugs are required to submit a New Drug Application (NDA) to the FDA containing the results of the sponsor’s clinical trials. The FDA reviews this data to determine whether the sponsor’s drug meets the FDA’s safety and efficacy standards. While receiving FDA approval for a new drug can deliver enormous value for a pharmaceutical company, the cost is steep; the research and development process, as well as clinical trials, can take years and cost potentially billions of dollars.
Applicants seeking approval of generic versions of existing drugs do not face such extensive hurdles. Rather than submitting an NDA containing the results of costly and time-consuming clinical trials, generic drug sponsors may submit an Abbreviated New Drug Application (ANDA) that demonstrates that the generic version of the drug is “bioequivalent” to the brand-name version (also known as the “reference product”). Generally, bioequivalence means that the drug will work the same way and be as effective as the reference product. ANDA applicants may rely on safety and efficacy data previously submitted by NDA applicants when performing their bioequivalence studies.
What Is the Orange Book?
The Orange Book is the FDA’s official register of drugs that the agency has deemed to be safe and effective, as well as any patents covering those drugs and regulatory exclusivities to which they may be entitled. It contains listings of:
Brand-name drugs for which NDAs have been approved
Generic drugs for which ANDAs have been approved
Patents covering the listed drugs, as well as their expiration dates
Regulatory exclusivity information
The Orange Book allows a user to quickly determine which generic drugs can be substituted for particular brand-name drugs. For example, a search for the brand-name drug “Prozac” would show an NDA by Eli Lilly and Company (the drug’s original sponsor), the active ingredient (fluoxetine hydrochloride), dosage form (capsule), dosage route (oral), and dosage strength (10mg, 20mg, and 40mg). A search for the active ingredient “fluoxetine hydrochloride” would then show the Prozac NDA as the reference product, as well as all approved ANDAs and their sponsors. This lets prescribers know that any approved ANDA for fluoxetine hydrochloride is bioequivalent to Prozac and can be prescribed in its place.
Below, we take a closer look at the contents of the Orange Book.
Drug listings are the heart of the Orange Book. They include prescription drugs (both brand-name and generic), over-the-counter (OTC) drugs, and drugs that have been discontinued. They do not include biologic and biosimilar drugs licensed by the FDA under the Public Health Service Act, drugs that do not have full approval, marketed drugs that are not the subject of an approved NDA or ANDA, or drugs that are compounded by pharmacies or outsourcing facilities.
See below for an example of the Orange Book’s drug listings.
Marketing Status: Refers to whether the drug is available as a prescription, OTC, or has been discontinued
Active Ingredient: The active ingredient as indicated on the FDA-approved drug product label
Proprietary Name: The name accepted by the FDA upon approval of the drug (may contain the active ingredient name in cases of drugs that do not have accepted proprietary names)
Application Number: The NDA or ANDA application number. Application numbers that begin with “N” are NDAs, while those that begin with “A” are ANDAs.
Dosage Form, Route, and Strength: The drug’s dosage, form, and strength as indicated on the FDA-approved drug product label
TE (Therapeutic Equivalence) Code: A code that indicates that a drug is therapeutically equivalent to other approved drugs
RLD (Reference Listed Drug): Indicates that the listed drug is a reference product for ANDA drugs
RS (Reference Standard): Indicates that the listed drug serves as the standard an ANDA applicant must use to prove bioequivalence
Applicant Holder: The party applying for FDA approval of an NDA or ANDA.
An important aspect of the Orange Book for ANDA applicants is the listing of patents covering brand-name drugs and their expiration dates. In addition to safety and efficacy data, the FDA requires NDA applicants to submit any patents covering their drugs’:
Formulations and compositions
Methods of use
The Orange Book does not contain patents covering:
Polymorphs (unless test data is submitted demonstrating that a drug product containing the polymorph will perform the same as the drug product described in the NDA)
The patent data contained in the Orange Book allows ANDA applicants to quickly identify patents that may prevent them from launching generic versions of patented name-brand drugs.
See below for an example of an Orange Book patent listing.
Product Number: (FDA internal use)
Patent Number: The patent number as provided by the applicant holder (most frequently, the NDA holder/branded drug company who under the statute must list the patents that could “reasonably be asserted ‘if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug’”)
Patent Expiration: The date the patent is scheduled to expire
Drug Substance/Drug Product/Patent Use Code: Indicates whether the product covers an active ingredient (Drug Substance), a formulation of a drug (Drug Product), or a method of using a drug (Patent Use Code). A full list of Patent Use Codes is available here.
Delist Requested: Indicates whether the patent owner has requested that the patent be delisted from the Orange Book; patent owners must delist patents that have been invalidated by a district court or the Patent Trial and Appeal Board within 14 days of the decision.
Submission Date: The date the patent was submitted
Regulatory Exclusivity Information
Patent protection is not the only market protection available to pharmaceutical companies. NDA and ANDA filers may also apply for certain regulatory exclusivities that, if granted, prevent the FDA from approving either generic versions of NDA drugs or additional ANDAs for existing generics. Exclusivities may be granted for a new chemical entity, new indication, new dosage form, and pediatric exclusivity, among others. Exclusivities are time-limited and operate independently of patent protection.
See below for an example of Orange Book regulatory exclusivity information.
Product Number: (FDA internal use)
Exclusivity Code: The type of exclusivity for which the drug qualifies. A full list of exclusivity codes can be found here.
Exclusivity Expiration Date: The date on which the exclusivity period will expire
The Orange Book and Pharmaceutical Patent Litigation
The Orange Book plays a central role when it comes to patent disputes between brand-name drug makers and generics — a type of litigation known as Hatch-Waxman litigation.
The Hatch-Waxman Act (officially known as the Drug Price Competition and Patent Term Restoration Act) establishes the regulatory procedures by which generic drugs may apply for and receive FDA approval. The Hatch-Waxman Act balances rewarding branded pharmaceuticals for their investment in innovation while bringing generic formulations to market quickly to lower drug prices. To do this, the Hatch-Waxman Act granted NDA holders an extension on their patent life to account for the time the NDA holder spent getting approval from the FDA for its pharmaceutical product. To balance that, the Act also allows generic drug makers to develop alternatives to brand-name drugs while the brand-name drug patents are still in force so that the generic version can enter the market immediately upon the brand-name drug patents’ expiration. Generic drug makers are protected from patent infringement suits for any activities related to the filing of their ANDAs during this time (known as the Hatch-Waxman “safe harbor”). Without the protections of the safe harbor, generic drug makers would be forced to wait to conduct their bioequivalence studies until the name brand-name drug’s patents expire, thereby delaying generic entry to the market and extending the term of the brand-name drug’s patent protection.
The Orange Book comes into play when a generic drug maker files its ANDA. For each patent covering the reference product, the ANDA filer must make one of the following patent certifications:
No patent information has been submitted to the Orange Book (“Paragraph I certification”);
The patent has expired (“Paragraph II certification”);
The product will not be marketed until the patent expires (“Paragraph III certification”); or
The patent is invalid, unenforceable, or will not be infringed by the manufacture, use, or sale of the product for which the ANDA is submitted (“Paragraph IV certification”)
Generic drug makers choose Paragraph IV certifications when they want to enter the market before the NDA holder’s patent expires. However, this comes at a cost; a Paragraph IV certification is considered an artificial act of infringement and allows the NDA holder to sue the generic drug applicant for patent infringement. If the NDA holder files a patent infringement suit within 45 days of receiving a notice of a Paragraph IV certification, the suit triggers an automatic 30-month stay during which the FDA will not grant the ANDA final approval.
If the ANDA applicant is successful in its challenge of the name-brand drug’s patent, i.e. by getting a judgment of non-infringement and/or invalidity, the applicant may enter the market and need not wait for the patent to expire (if the patent remains valid). The Hatch-Waxman Act also rewards the first ANDA filer to successfully challenge an NDA holder’s patent with a 180-day period of exclusivity during which no subsequent ANDAs on the reference product may be approved. By offering exclusivity in exchange for successfully challenging an NDA holder’s patent, the Hatch-Waxman Act encourages the entry of generic drugs to the market as soon as possible.
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.
Kelly Allenspach Del Dotto is a principal in the Delaware office of Fish & Richardson P.C. Her practice focuses on complex patent litigation, with an emphasis on life sciences, biotechnology, and pharmaceutical litigation, including Hatch-Waxman litigation. Kelly has worked on a variety of technologies, including, for example,...