This week's Expert View comes from Jonathan Roses, a patent attorney at Boston, USA-based law firm Wolf Greenfield. In the context of an ever-evolving regulatory landscape, Mr Roses provides insights into how to successfully navigate the complexities of the US Food and Drug Administration's all-important "Orange Book."

In 1984, Congress passed and the President signed into law the Drug Price Competition and Patent Term Restoration Act, better known as the Hatch-Waxman Act.

As part of its creation of the modern generic drug, patent term restoration, and regulatory exclusivity schemes, Hatch-Waxman created the Orange Book to enable potential sponsors of new generic drugs to assess which patents might be asserted against them if they were to receive approval for and market a proposed generic product.

The Orange Book thus satisfied a notice purpose that was lacking in the pre-Hatch-Waxman world, where parties considering development and launch of a generic product lacked certainty as to the patent infringement risk associated with that endeavor.

To accomplish this notice goal, Hatch-Waxman required NDA holders to submit "patent information" for publication in the Orange Book – that is, a listing of any patent that claims the drug that is the subject of the NDA (the "reference listed drug" or "RLD") or a method of using the drug, and for which a claim of patent infringement could reasonably be asserted if a person not licensed by the patent owner engaged in the manufacture, use, or sale of the drug.

The other key function of the Orange Book is tied to the so-called "30-month stay." In particular, generic drug applicants are required to submit a patent certification or statement for each patent listed in the Orange Book for the RLD.

If the applicant submits a "paragraph IV certification," which certifies their belief that a listed patent is invalid, unenforceable, or will not be infringed by the manufacture, use, or sale of the proposed generic drug, it must give notice of that certification to both the NDA and patent holder.

If the NDA holder or patent owner then sues the generic firm for patent infringement within 45 days after receiving the notice, the Food and Drug Administration (FDA) is prohibited by statute from effectively approving the generic application for 30 months following receipt of the notice (subject to potential early termination or extension).

FDA practice and subsequent legislation

Though FDA's interpretation of Hatch-Waxman and its implementing regulations have developed since 1984, the general requirements for the Orange Book have remained largely unchanged. In particular, for several decades FDA policy has mandated Orange Book listing for patents that claim:

  1. the drug (ie, the active pharmaceutical ingredient, drug substance, or "DS") for which the NDA was submitted;
  2. the drug product (ie, finished dosage form, formulation or composition in which the DS is present, or "DP"); and
  3. a method of using the drug, provided the patent claims an indication or other condition of use described in the NDA and approved by FDA.

Notably excluded from this mandatory requirement are patents that claim only a process (eg, synthetic methods for preparing the DS or DP), packaging, DS metabolites, or synthetic intermediates.

These long-standing FDA policies and practices were recently codified in the Orange Book Transparency Act of 2020, including, for the first time, an express statutory prohibition on submitting patent information outside of the prescribed categories.

Despite these strictures, the FDA has repeatedly stated its position that its role in Orange Book listing is "purely ministerial." In other words, while FDA will review Orange Book listing forms submitted by NDA holders for formal compliance, it will not conduct any substantive review as to the appropriateness of the requested listing. This means that any patent information submitted to FDA that is formalistically compliant will be listed in the Orange Book. And therein lies the rub.

Potential for abuse of the Orange Book listing scheme

The natural consequence of a lack of review of Orange Book listing submission is the potential for an essentially automatic 30 month stay of a generic's application, regardless of the propriety of the Orange Book listing, or the validity or scope of the patent.

This possibility has drawn significant scrutiny, from the public, policymakers, the FDA, and other government agencies – most recently a September Statement from the Federal Trade Commission (FTC) indicating that it intends to scrutinize improper Orange Book listings as potentially being illegal unfair methods of competition.

The underlying policy concerns resulting from unfairly preventing generic competition include increased cost of prescription drugs and delivery devices and reduced patient choice and access.

But competing policy considerations and the complex, sometimes ambiguous, and often shifting the FDA position on what Orange Book listings are proper or improper (particularly in fringe cases) can place NDA holders in the position of having to make difficult decisions on what patents to list and what to omit from the Orange Book.

Worse yet, while the FTC's position on potential over-listing in the Orange Book is relatively clear, it has been suggested that failure to list a patent in the Orange Book that should have been listed could itself have anticompetitive effects, because doing so would fail to provide notice of patent infringement liability to potential generic filers.

Best practices in Orange Book listing

In view of this shifting, uncertain, and litigation-prone environment, NDA holders must take special care in assessing Orange Book listings (both when listings are required and on a periodic basis to ensure continued compliance and minimization of risk).

This assessment should first and foremost involve consultation with patent counsel. Because the standard for Orange Book listing requires determining whether "a claim of patent infringement could reasonably be asserted," the analysis must consider legal concepts particular to patent law (eg, claim construction, literal infringement, infringement under the doctrine of equivalents, and issues of divided infringement).

Second, patent counsel should have access not only to technical experts, but also regulatory personnel at the company. This is because assessment of claim scope often requires a nuanced understanding of both the science behind the approved drug and its manufacture, and also the scope and content of the NDA itself, which governs the infringement analysis.

Third, while an expansive view of the NDA holder's patent portfolio is merited to ensure the listing of all patents that must be listed, increased scrutiny and a skeptical view should be taken to assess more "fringe" cases that do not clearly slot into one of the statutorily enumerated categories.

This view should be informed not only by FDA guidance, but also history of litigation by private parties and government agencies. While bright lines may be elusive, past practice may be informative and useful in guiding decision making.

Fourth, particularly for borderline cases, it is important to weigh the risks of both listing and not listing a given patent in the Orange Book. This includes risk of allegations of anticompetitive action (for improperly listing a patent or not listing a patent, thereby failing to serve the notice purpose of the Orange Book), but also market risks for the drug (what other patents are listed in the Orange Book for the RLD, and how might a particular additional listing effect generic competition?).

Finally (and this is only so far down in the list because it should be taken as a given), NDA holders must make bona fide best efforts to comply with the statutory and regulatory frameworks for Orange Book listing.

Because of the current risk and intense scrutiny on these practices, a careful and conservative approach is paramount – as suggested by the fact that the person submitting an Orange Book listing form attests to its compliance under penalty of perjury.

Originally Published by The Pharma Letter

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