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Improving Orange Book Listing Eligibility for Drug Delivery Device Patents

Several products approved for marketing as drugs in the US are administered using a device (a drug-device combination product). Companies that own such products often file at least one U.S. patent to protect the device. In addition to obtaining patent protection for the device, a company may also wish to list the device patent in the U.S. Food and Drug Administration’s (FDA) “Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations” (Orange Book). Listing a patent in the Orange Book patent provides certain benefits to the owner of a drug product.1 Although the eligibility of drug delivery device patents for listing in the Orange Book for drug products is unclear, this blog provides some suggestions to strengthen eligibility for listing.

In the scenario described above, the company may already have or may be seeking patents to cover the drug aspect of the combination product, in which case the device patent adds to the patent barrier protecting the drug product. However, suppose the drug is old and no longer protected by patent, or the drug is covered by an issued patent with little patent term left. In these scenarios, a patent for the device may provide an additional period of protection for the product.

Several products approved as drugs by the FDA are delivered via a device. These products include prefilled drug delivery systems (e.g., Lantus® Solostar® insulin injector pen, and EpiPen® epinephrine autoinjector), subcutaneous implants (e.g., Nexplanon® etonogestrel implant, and Supprelin LA® histrelin acetate implant), metered dose inhalers (e.g., Proair®, Proventil®, and Ventolin® albuterol sulfate metered aerosols, and QVAR® beclomethasone dipropionate metered aerosol), dry powder inhalers (e.g., SPIRIVA® tiotropium bromide powder) metered spray inhalers (e.g., SPIRIVA® RESPIMAT® tiotropium bromide spray inhaler), metered nasal sprays (e.g., Imitrex® sumatriptan nasal spray), and transdermal patches (e.g., Duragesic® Fentanyl Transdermal System, Vivelle-Dot® Estradiol Transdermal System, and Androderm® Testosterone Transdermal System).

Several of these combination products currently have, or have had in the past, one or more device patents (with or without a claim including the drug composition as an element) listed in the Orange Book. The fact that device patents have been listed for a drug product, however, does not mean listing was legally correct.

The owner of a New Drug Application is required to list in the Orange Book patents that claim “the drug” or a method of using it “with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner engaged in the manufacture, use, or sale of the drug.” 21 U.S.C. § 355(b)(1). The FDA defines “drug product” as “a finished dosage form, e.g., tablet, capsule, or solution, that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients.” 21 C.F.R. § 314.3. A “dosage form” refers to

the physical manifestation containing the active and inactive ingredients that delivers a dose of the drug product. This includes such factors as: “(1) The physical appearance of the drug product; (2) The physical form of the drug product prior to dispensing to the patient; (3) The way the product is administered; and (4) The design features that affect frequency of dosing.

Id. (emphasis added). Thus, patents that claim the drug should be listed, and the meaning of “drug” includes the “finished dosage form” which is “the physical manifestation” of the product including “the way the product is administered.” The statute and rules relating to patent listing do not explicitly address devices used to administer the drug, but the language above suggests that such devices could be eligible for listing.

The FDA has identified the following types of delivery devices as part of the drug product, indicating that patents for such devices should be listed in the Orange Book: “metered aerosols, capsules, metered sprays, gels and pre-filled drug delivery systems.” See 68 Federal Register 36,675, 36680 (June 18, 2003). 2 In each of these examples, performance of the drug-delivery device is critical to proper administration of the approved drug product and clinical efficacy. In contrast, the FDA has prohibited the listing of “process patents, patents claiming packaging, patents claiming metabolites, and patents claiming intermediates.” 21 C.F.R. § 314.53(b)(1).

However, guidance regarding the Orange Book listing requirement is unclear and incomplete regarding patents that claim a drug delivery device, particularly for those that do not recite the drug substance in any of the claims.

While FDA guidance regarding Orange Book listing of drug delivery device patents is unclear, the FDA has not rejected listing of drug-delivery device patents. The FDA does not review patent content for each patent listing, instead it treats listing as a ministerial function. 3 Some companies have notified the FDA they intend list these patents and/or have sought an advisory opinion from the FDA regarding the listing of such patents.4 The FDA has not substantively responded to any of these requests for guidance.5

While the FDA appears to have acquiesced to listing drug delivery device patents in the Orange Book, irrespective of whether those patents contain a claim that recites the drug substance, third parties, such as ANDA or 505(b)(2) NDA filers, may dispute listing by request delisting of a patent. See 21 C.F.R. § 314.53(f)(1). In addition, if sued for patent infringement, the ANDA or 505(b)(2) filer may seek delisting of a patent by filing a delisting counterclaim under 21 USC §355(c)(3)(D)(ii)(I). Courts have not yet ruled on the Orange Book listing of drug delivery patents, although this issue was raised at least once in Hatch-Waxman patent infringement litigation. See King Pharms., Inc. v. Intelliject, Inc., No. 1:11-cv-00065-UNA (D. Del. Jan. 19, 2011). In this suit, the 505(b)(2) NDA filer filed a counterclaim pursuant to FDC Act §505(c)(3)(D)(ii)(I) to seek the delisting of patent information from the Orange Book for a device-related patent on the ground that the patent did not claim the drug product, EpiPen®. The suit was settled and dismissed before this issue was resolved by the court.

Therefore, listing of a device patent in the FDA’s Orange Book for drug-device combination products can present a quandary. While a company may choose to list such patents, an ANDA filer or 505(b)(2) NDA filer may seek delisting.

What can a Company do to improve patent listing eligibility for its device patent?

When drafting the drug delivery device patent application, include disclosure describing the drug product/s to be administered with the device, and the method of administration using the device. Include claims to the device and drug product together, such as a kit, or device filled with the drug product, and a method of using the device to administer the drug product.

If the drug aspect of the combination product is still patentable, the patent(s) for the drug should be filed before or on the same date as the device patent application, since the device patent application containing a description of the drug could become prior art to the drug patent (and vice versa if the device is disclosed in the drug patent application).

If the device patent application has already been filed, review the disclosure carefully for mention of the drug product, even a generic description of it, and add claims to the device plus drug and method of administration if the application disclosure supports such claims.

If it is too late to add claims, e.g., if the patent has issued and there are no pending continuing applications, consider listing the patent and filing a petition for an advisory opinion and to provide notice of intent to list the patent.

1 Having a patent listed in the Orange Book at the time an Abbreviated New Drug Application (ANDA) or 505(b)(2) New Drug Application that references the drug product is filed, allows the drug approval holder to block approval of the ANDA) or 505(b)(2) NDA either until the patent expires, or, if the ANDA filer or 505(b)(2)NDA filer challenges the patent via a “PIV” certification and the drug approval holder sues by the deadline, for at least 30 months while the patent suit is ongoing. See 21 U.S.C. § 355(j)(5)(B). In addition, the ANDA filer/505(b)(2) NDA filer must give notice to the drug approval holder and patent owner regarding the patent challenge, with a description of the legal basis for the assertion that the patent is invalid or will not be infringed. See 21 U.S.C. § 355(j)(2)(B).

2 In the preamble to the final rule 314.53(b), the FDA noted several comments that distinguished between “packaging and devices such as metered dose inhalers and transdermal patches, which are drug delivery systems used and approved in combination with a drug.” See 68 Fed. Reg. 36,676, 36,680 (June 18, 2003). FDA’s response to these comments stated that
Section 314.3 defines a “drug product” as “* * * a finished dosage form, for example, tablet, capsule, or solution, that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients.” The appendix in the Orange Book lists current dosage forms for approved drug products. The list includes metered aerosols, capsules, metered sprays, gels, and pre-filled drug delivery systems. The key factor is whether the patent being submitted claims the finished dosage form of the approved drug product. Patents must not be submitted for bottles or containers and other packaging, as these are not “dosage forms.”

Id.

In addition, the FDA has recognized that for metered dose inhalers and dry powder inhalers, the drug product includes both the drug formulation and the drug delivery system:

The device with all of its parts, including any protective packaging (e.g., overwrap), and the formulation together constitute the drug product. Unlike most other drug products, the dosing and performance and therefore the clinical efficacy of a DPI may be directly dependent on the design of the device.

Draft Guidance for Industry: Metered Dose Inhaler (MOI) and Dry Powder Inhaler (DPI) Drug Products, lines 113-116 (October 1998).


3 See FDA Responses to Frequently Asked Questions on Patents and Exclusivity, Question 19, at https://www.fda.gov/Drugs/DevelopmentApprovalProcess/ucm079031.htm.

4 See, e.g., Request for Advisory Opinion by GlaxoSmithKline, Docket No. FDA-2011-A-0363 (Jan. 10, 2005); Request for Advisory Opinion by AstraZeneca, Docket No. FDA-2006-A-0063 (formerly 2006A-0318) (Aug. 10, 2006); Request for Advisory Opinion by AstraZeneca, Docket No. FDA-2007-A-0099 (formerly 2007A-0261) (June 21, 2007); Request for Advisory Opinion by Forest Laboratories, Inc., Docket No. FDA-2011-A-0363 (May 12, 2011); and Request for Advisory Opinion by Novo Nordisk Inc., Nov. 26, 2012, FDA Docket No. FDA-2012-A-1169. See also, The Pharmaceutical Research and Manufacturers of America (PhRMA) Comments to Proposed Rule “Abbreviated New Drug Applications and 505(b)(2) Applications” (80 Fed. Reg. 6802 (Feb. 6, 2015)(Docket No. FDA-2011-N-0830)), pages 8-9.

5 On May 23, 2013, FDA issued an Interim Response to Novo Nordisk’s Request for Advisory Opinion, FDA Docket No. FDA-2012-A-1169. This Interim Response stated “FDA has been unable to reach a decision on your request due to the need to address other Agency priorities. . . . . We will respond to your request as soon as possible given the numerous demands on the Agency's resources.”