Listing of drug delivery device patents in the USFDA’s Orange Book: What the patent drafters can learn from Lantus^® soloSTAR^® device lawsuit?

1. Patent listing in the Orange Book

The United States Food and Drug Administration (USFDA) maintains a publication, known as the Orange Book (OB), which includes a list patents related to all New Drug Application (NDA) products [1]. These patents, known as OB-listed patents, are submitted by the NDA holders to the USFDA, which consequently lists them in the OB. A major purpose of the OB listing mechanism is to acquaint the Abbreviated NDA (ANDA) filers with the patent rights of the NDA holder in relation to the approved NDA product. Accordingly, the filing of ANDA application referring to the aforementioned NDA product as “reference listed drug” requires appropriate patent certifications in relation to each of the OB listed patents [2]. Among the various patent certifications, the Paragraph-IV certification is of paramount importance as only this can lead to a cascade of events including, initiation of patent litigation; a 30-month automatic stay of marketing approval of the ANDA product; early market entry of the generic product; and 180-day exclusivity for the first ANDA filer(s). This mechanism, called as “drug-patent linkage’, is enforced in the US by the ‘The Drug Price Competition and Patent Term Restoration Act of 1984ʹ, commonly known as the Hatch-Waxman (HW) Act [2].

This HW Act aims to strike a balance of benefits between the NDA holders (the pioneer pharmaceutical companies) and ANDA filers (the generic pharmaceutical companies). The NDA holders are empowered to trigger a 30-month stay on marketing approval of the ANDA product, a time-period that allows them to prove infringement of their OB-listed patent by the ANDA filers in a Federal Court. However, if prevailed in the patent litigation, the ANDA filer could initiate the commercialization of its generic drug earlier than the usual expiry of the OB-listed patent. Furthermore, the first ANDA filer(s) are incentivized with a period of 180 days of market exclusivity for their generic product. Therefore, the system in whole aims to weed-out the patents, which provide unnecessary monopoly to the NDA holders, thereby providing early access of cheaper alternate and generic versions of the highly priced proprietary products to the public while also safeguarding the interests of those NDA holders, who possess genuine patents.

2. Eligibility criteria for patents to be listed in the OB

It is noteworthy that only certain types of patents could be listed in the OB. Section 314.53(b) of Title 21 of Code of Federal Regulations (CFR) specifies that the patents eligible for OB listing should claim ‘drug substance’ (active pharmaceutical ingredient), ‘method of treatment’ or ‘drug product’ [2]. Furthermore, the USFDA recognizes the term ‘drug product’ to include a finished dosage form and encompasses the way in which the product is intended to be administered. Nevertheless, the regulations provide no explicit disclosure on the eligibility of OB-listing for drug delivery devices (hereinafter, referred to as DDDs). DDDs are specialized drug delivery tools, which are essential for effective and/or convenient administration of corresponding drugs. Interestingly, the USFDA has considered several DDDs such as capsules, metered dose devices, prefilled delivery devices under the purview of the term ‘drug product’ [3,4]. The performance of these DDDs results in for proper administration of the drug, and consequently ensuring the desired therapeutic efficacy of the drug product. Alternatively, the regulation also states the ineligibility criteria for OB-listing for certain patent types such as packaging patents, process patents (for e.g., chemical synthesis), metabolite patents, and intermediate patents [2].

3. USFDA’s role in listing of patents in the OB

Historically, the USFDA has maintained its role in listing of patents in the OB to be ‘purely ministerial’ and has also expressed inability to police the correctness of the patent information due to insufficient resources and expertise [5–7]. In past, several pharmaceutical companies have attempted to seek clarity on OB-listing requirements of patents claiming DDDs, but the USFDA has generally refrained from commenting on such queries [7–10]. Consequently, the present regulations, statutes, and guidelines are ambiguous in this context and provide no clear information about the eligibility criteria of patents claiming DDDs.

As a general trend, the USFDA accepts the patents on DDDs from the NDA holders and lists them in the OB without evaluating the claim-scope thereof. This practice clearly grants an advantage to the NDA applicants/holders, as they can list any patents of their choice in the OB and reap the benefits thereof as previously discussed. Nevertheless, the statute enables the ANDA filers to dispute the OB-listing of a ‘wrongly listed’ patent [11]. Moreover, the delisting of such ‘wrongly listed’ OB-patent could also be sought by the ANDA filers during patent litigation in Federal Courts using a ‘patent delisting counterclaim’ [12].

4. Antitrust litigation for ‘improper’ OB listing of Lantus^® soloSTAR^® device patent

In a recent antitrust litigation in the US, a patent listed in the OB was held to be ‘improper for OB-listing’ by the United States Court of Appeals for the First Circuit (CAFC) [12]. The patent in question (US8556864, hereinafter ‘864 patent) had been listed in the OB by Sanofi-Aventis US LLC (hereinafter Sanofi) for Lantus^® soloSTAR^®, which is an autoinjector device product for administration of insulin glargine. The ‘864 patent claims the ‘drive mechanism’ of the device and the mechanical components involved therein. However, the patent does not per se claim the complete DDD. It is noteworthy that due to the aforementioned patent, Sanofi was able to induce the statutory 30-month stay on approval of another competing insulin glargine autoinjector product (KwikPen^®) from Eli Lilly through a Hatch-Waxman lawsuit, which was later settled by both parties out of the Court [13]. In the later isolated CAFC proceeding, the challenger against ‘864 patent, César Castillo Inc. contended that the ‘864 patent should not considered eligible to be listed in the OB. Furthermore, it was argued that the ‘wrong listing’ of such patents should be barred by the Court as it would lead to ‘sham’ Hatch Waxman litigations, thereby causing unnecessary stay of approval of the generic versions of the drug product. Earlier, the District Court of Massachusetts had dismissed an antitrust lawsuit against Sanofi for OB listing of ‘864 patent citing the ‘ambiguities in the FDA’s listing requirements’. However, the CAFC reversed the lower Court decision, due to the fact that the patent in question was not claiming the drug of the corresponding NDA product, and was directed to merely a ‘drive mechanism’ of the device. CAFC also noted that there was no explicit disclosure of the drug of NDA (insulin glargine), therefore the ‘vital link’ between the DDD and drug could not be established, which could render the DDD as a ‘drug product.’

5. Expert opinion

For the past few years, USFDA has been attempting to improve the transparency and clarity of miscellaneous regulations related to drug approval pathways and drug-patent linkage system. Consequently, on 5 January 2021, The Orange Book Transparency (OBT) Act of 2020 was signed into law by the (then) US President Donald Trump [11], which intends to revise certain provisions of Section 505 of the Federal Food, Drug and Cosmetic Act. Although the recently signed OBT Act does not provide a resolution to the long pending ambiguity regarding the eligibility for OB-listing of patents on DDDs, it requires the US Comptroller General to prepare a report on OB-listed patents claiming the ‘an active ingredient or formulation of a drug in combination with a device that is used for delivery of such drug,’ along with recommendations about the categories of the patents claiming DDDs, which should be suitable for OB-listing. These developments indicate that, in due course the OBT Act is intended to incorporate well-defined OB-listing eligibility criteria for DDDs to the existing regulations.

Nevertheless, in the current absence of relevant statutory guidance, the NDA applicants/holders should utilize the implicit teachings from the recent CAFC opinion in Lantus^® soloSTAR^® device lawsuit. The ‘864 patent contains 10 claims, all of which were directed toward different aspects of ‘drive mechanism’ only. Moreover, the specification of the ‘864 patent provides no disclosure for the DDD and drug (soloSTAR^® and insulin glargine, respectively) related to the corresponding USFDA-approved product. The CAFC expressed that the statute and regulations clearly require that only the patents that claim the drug (i.e. drug substance and drug product) for which NDA has been submitted are eligible for OB listing. Therefore, even considering Lantus^® soloSTAR^® device as a ‘drug product’ under the statutory definition, the ‘864 patent lacks sufficient disclosure for being eligible for OB listing.

Additionally, the author would like to emphasize that although the present statutes do not define the eligibility criteria for OB-listing of patents claiming DDDs, they sufficiently express that a patent, which does not claim the drug is not eligible for OB-listing for the corresponding NDA product.

Considering these facts, the patent drafting should be performed in a meticulous manner to ensure the OB-listing of the patents claiming DDDs. Particularly, the NDA owners/applicants who intend to list their patent(s) covering a DDD in the OB should consider including information about the specific drug(s) in the patent specification. In addition, a correlation between the delivery device and drug should be disclosed in the patent specification to further improve its acceptability for OB listing. Therefore, it is highly recommended to add some claims and working examples directed to the specific DDD, as well as correlation between drug and delivery device, which represent the product of the corresponding NDA.

Alternatively, the ANDA filers should rely upon the remedies of ‘patent dispute’ and ‘patent delisting’ mechanisms against the OB-listed patents with deficiencies similar to ‘864 patent.

To conclude, the evolution for specific regulations for OB listing of DDDs is underway, and it is expected to benefit both the NDA holders as well as ANDA filers in discrete ways. Nevertheless, till the new regulations are finalized, the implicit guidance for drafting DDD patents should be adopted from Lantus^® soloSTAR^® device lawsuit.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Acknowledgments

The author would like to thank the diligent taxpayers of India and NIPER-Hyderabad for providing resources to prepare the present manuscript (NIPER-H/2021/201).

Funding

This paper was not funded.