Should Drug-Delivery Device Patents be Listed in the Orange Book?

• Finnegan, Henderson, Farabow, Garrett & Dunner, LLP

Introduction

In December 2016, Congress enacted the 21st Century Cures Act.¹ Section 3038 of this Act addresses “combination products,” that is, products combining two or more regulated components of a drug, medical device, and/or biological product.² Typical examples of combination products include pre-filled syringes, drug-eluting stents, surgical kits, and light-activated drugs and activating light sources.³ These products have become increasingly popular as medical technology has improved. But they present many unique challenges, not only for regulatory purposes (e.g., device clearance and approval), but also for Orange Book listings.⁴

Section 3038 of the Cures Act changed many of the regulations on combination products. For example, for products with an already approved constituent part, applicants need only submit data necessary to meet the standard for device clearance or approval, including data showing any incremental risk or benefit posed by the combination product.⁵ In contrast, before the Cures Act, applicants had to prove the safety and effectiveness of both the approved constituent part and the new constituent part.

Section 3038 also incorporated several provisions of the Hatch- Waxman Act⁶ into the clearance and approval process for one particular class of combination products: drug-delivery devices that have a device primary mode of action and contain an approved drug. A combination product falls into this class when it improves upon the delivery of, or offers a new route of administration for, an approved drug. We will refer to this class of combination products as “section 505(g)(5) drug-delivery devices.”⁷ The use of certain Hatch-Waxman provisions in the Cures Act has, in effect, aligned the clearance and approval process for section 505(g)(5) drug-delivery devices with that for section 505(b)(2) applicants, including the requirement that an applicant submit a certification identifying any patents listed for the approved drug in the Orange Book.⁸

This article assesses whether the incorporation of Hatch-Waxman provisions into the approval process for section 505(g)(5) drug-delivery devices resolves the question whether drug-delivery device patents that do not claim the drug, despite being integral to the administration of the drug, should be listed in the Orange Book.

New Drug Applications and the Orange Book

Under the Federal Food, Drug & Cosmetic Act, an applicant for a new drug must submit to FDA a New Drug Application (NDA), and establish that the drug is safe and effective, among other things.⁹ In addition, an NDA holder must inform FDA of any patents that cover the new drug and the expiration dates of those patents, so that this information can be listed in the Orange Book.¹⁰ In particular, the NDA holder must identify and provide:

any patent which claims the drug for which the applicant submitted the application or which claims a method of using such drug and 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.¹¹

FDA has offered guidance on the scope of this disclosure requirement, stating that if a patent claims the “drug product,” it must be listed in the Orange Book.¹² The term “drug product” has been defined by FDA 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.”¹³ Thus, a key question in determining whether a patent should be listed in the Orange Book is “whether the patent being submitted claims the finished dosage form of the approved drug product,” or whether it claims other packaging such as bottles and containers.¹⁴

For instance, FDA has identified types of patents for “drug products” directed to the drug formulation and delivery device that it believes should be listed in the Orange Book: “metered aerosols, capsules, metered sprays, gels and pre-filled drug delivery systems.”¹⁵ In each of these examples, the drug-delivery device is an integral part of the approved drug product, i.e., critical to the administration of the drug. In contrast, FDA has prohibited the listing of “process patents, patents claiming packaging, patents claiming metabolites, and patents claiming intermediates.”¹⁶

The FDA guidance described above, however, which predates the Cures Act, does not address whether drug-delivery device patents that do not claim the drug, despite being integral to the administration of the drug, should be listed in the Orange Book.¹⁷

Abbreviated New Drug Applications and Section 505(b)(2) Applicants

As described above, NDA holders are required to submit patent information for publication in the Orange Book. This requirement serves an important notice function in the Hatch-Waxman context—it gives generic manufacturers notice of patents that would be infringed by the manufacture, sale, or use of a generic product. This allows for early resolution of challenges before the generic manufacturer markets its product.

In 1984, Congress adopted the Hatch-Waxman Act to achieve a balance between patent protection and generic entry by offering an abbreviated pathway for generic manufacturers to acquire FDA approval and enter the market. Under this Act, a generic manufacturer may seek approval by showing bioequivalence to an approved innovator drug (Reference Listed Drug), and by filing an Abbreviated New Drug Application (ANDA). If it can establish bioequivalence, the generic manufacturer may rely on the safety and efficacy data of the Reference Listed Drug and avoid costly clinical trials.

As part of its ANDA submission, the generic manufacturer must make a certification with respect to the Orange Book patents covering the Reference Listed Drug.¹⁸ The manufacturer can certify that: (I) there are no patents covering the Reference Listed Drug; (II) the patents have already expired; (III) the generic manufacturer will not launch its product until after the patents have expired; or (IV) the patents are invalid or will not be infringed. The last of these categories is referred to as a Paragraph IV Certification. If an ANDA applicant makes a Paragraph IV Certification, it must notify the patent owner(s).¹⁹ This filing and certification is an artificial act of infringement,²⁰ and the patent owner(s) may initiate infringement proceedings against the generic manufacturer before market entry. This benefits both the NDA holder, as FDA will stay approval of the ANDA for thirty months pending litigation,²¹ and the generic manufacturer, who no longer has to finance development only to launch “at risk” of infringement.

Some may also seek approval for a drug that may vary from a Reference Listed Drug in, for example, dosage form or strength, but that is nevertheless similar enough to a Reference Listed Drug to benefit from the Reference Listed Drug’s safety and efficacy data.²² These applications are called section 505(b)(2) applications. Section 505(b) (2) applicants must provide additional clinical testing data addressing the differences between the applied-for product and the Reference Listed Drug. Section 505(b)(2) applicants must also provide patent information relating to the proposed drug (like NDA holders) and certify as to any patents covering the Reference Listed Drug identified in the Orange Book (like ANDA holders).²³ Thus, 505(b)(2) applicants operate as a hybrid between NDA holders and ANDA applicants.

Impact of the 21st Century Cures Act on Drug-Delivery Device Patents

The Cures Act imported much of the above-described Hatch- Waxman infrastructure into the clearance and approval process for section 505(g)(5) drug-delivery devices, requiring the same patent certification and notice requirements that would apply to section a 505(b)(2) applicant. Thus, it appears that drug-delivery device patents should be listed in the Orange Book just like 505(b)(2) patents. Such a determination would align with the notice function of the Orange Book, as an applicant would not have to assess whether it must design around a patent, whether a patent will expire before launch, or whether invalidity/non-infringement positions must be developed before launch.²⁴ Likewise, patent owners would be relieved of the burden of monitoring the market for potentially infringing devices because applicants would have to notify patent owners about their new product under the statute.²⁵

Moreover, requiring listing of these drug-delivery device patents is consistent with FDA guidance. Drug-delivery device patents integral to the administration of the drug fall under the FDA’s definition of “drug product,” as shown by the examples FDA has provided for properly listed “drug product” patents. It should not matter that the device patent does not also claim the drug, for it is arguably still a patent for “which a claim of patent infringement could reasonably be asserted” under the conditions provided in 21 U.S.C. § 355(b)(1).

Although FDA has offered no formal guidance on this issue, it has not actively rejected listing of these drug-delivery device patents todate. Indeed, several companies have explicitly notified FDA that they will list these patents and have not received a response suggesting listing would be improper.²⁶ And, ultimately, FDA has listed device patents from these companies without objection. Although FDA does not specifically approve each listing, it manages the platform and oversight of the system without determining if each listing is appropriate. FDA likewise allows companies to delist upon request, at least until a Paragraph IV Certification has been filed.²⁷

Nevertheless, there remain concerns with listing drug-delivery device patents that do not claim the drug. As an initial matter, the Hatch- Waxman Act and the Orange Book were designed to maximize patent protection for new drugs while allowing for cost-effective and timely generic entry. Allowing listing of drug-delivery device patents untethered to the actual drug (in that they do not claim the drug) introduces a slippery slope, arguably opening the door to a broader swath of device-patent listing.

Moreover, any perceived efficiency gains might be minimal, at best. Patent searching is not overly difficult these days, and generic manufacturers must still search for other excluded categories of patents, such as process patents. Further, litigation brought pursuant to the Hatch-Waxman Act and its contemplated artificial act of infringement might also include drug-device patents integral to administration of the drug. District courts have allowed unlisted patents to be introduced into ANDA litigation as “sufficiently related” patents.²⁸ And the United States Court of Appeals for the Federal Circuit has upheld jurisdiction when not all patents have had Paragraph IV Certifications, provided there is one Paragraph IV Certification to establish jurisdiction.²⁹ Additionally, if the patent owner does not include the device patents in the litigation, the generic manufacturer may likely bring a declaratory judgment action as the “case or controversy” requirement is likely satisfied by filing the application for clearance or approval with FDA.

Last, the Orange Book is not the only system that provides notice of what patents may protect a product. Even outside of the field of medicine, products covered by patents are often marked with the relevant patent number. Compliance with the provisions of the marking statute (although voluntary)³⁰ thus provides an equivalent notice function that may make any listing in the Orange Book redundant.

Conclusion

There are several reasons for and against listing in the Orange Book drug-delivery device patents integral to the administration of the drug, that do not otherwise claim the drug. But in light of Congress’s recent alignment of the regulatory pathways for combination products, companies should consider a strategy for listing patent information for drug-delivery devices. Ultimately, there are many efficiency and notice-related benefits attached to listing in the Orange Book, and the opportunity to delist remains should the regulatory landscape change in the future.

References

1. 21st Century Cures Act of 2016, Pub. L. No. 114-255, § 3038, 130 Stat. 1033, 1105-10 (2016) (amending 21 U.S.C. §§ 353(g), 360(j)(h)(4)).
2. FDA, About Combination Products (Sept. 8, 2016). Available at: https://www.fda.gov/ CombinationProducts/AboutCombinationProducts/default.htm.
3. FDA, Guidance for Industry and FDA Staff: Current Good Manufacturing Practice Requirements for Combination Products (Jan. 2017). Available at: https://www.fda.gov/ downloads/RegulatoryInformation/Guidances/UCM429304.pdf (citing Code of Federal Regulations, Title 21, Section 3.2(e)).
4. The Orange Book is formally known as the Approved Drug Products with Therapeutic Equivalence Evaluations publication. See FDA, Approved Drug Products with Therapeutic Equivalence Evaluations, Orange Book Preface. Available at: https://www.fda.gov/Drugs/ DevelopmentApprovalProcess/ucm079068.htm.
5. 21 U.S.C. § 353(g)(3)-(6).
6. The Hatch-Waxman Act is formally known as the Drug Price Competition and Patent Term Restoration Act of 1984. See Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. 1585 (amending 21 U.S.C. § 355).
7. Federal Food, Drug, & Cosmetic Act § 505(g)(5) codified the relevant provision of the Cures Act for this category of products.
8. Compare 21 U.S.C. § 353(g)(3)-(5), with 21 U.S.C. § 355(b)(2).
9. 21 U.S.C. § 355(b)(1).
10. 21 U.S.C. § 355(j)(7)(A)(i).
11. 21 U.S.C. § 355(b)(1) (emphases added).
12. 21 C.F.R. § 314.53(b)(1).
13. 21 C.F.R. § 314.3; see also Pfizer, Inc. v. FDA, 753 F. Supp. 171, 176 (D. Md. 1990).
14. Patent Submission Rules for Applications for FDA Approval to Market a New Drug, 68 Fed. Reg. 36,676, 36,680 (June 18, 2003).
15. Patent Submission Rules for Applications for FDA Approval to Market a New Drug, 68 Fed. Reg. 36,676, 36,680 (June 18, 2003); see also FDA, Draft Guidance for Industry: Bio- Availability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action 7 (2003) (suggesting that, for a nasal aerosol, the “container, valve, actuator, dust cap, associated accessories, and protective packaging” are part of the drug product). Available at: https://www.fda.gov/downloads/Drugs/.../Guidances/ucm070111.pdf.
16. 21 C.F.R. § 314.53(b)(1).
17. The Pharmaceutical Research and Manufacturers of America (PhRMA) Comments on Docket No. FDA-2011-N-0830: Abbreviated New Drug Applications and 505(b )(2) Applications; Proposed Rule, 80 Fed. Reg. 6802 (Feb. 6, 2015), June 8, 2015, FDA Docket No. FDA-2011-N-0830-0016 at 8.
18. 21 U.S.C. § 355(j)(2)(A)(vii).
19. 21 C.F.R. § 314.95.
20. 35 U.S.C. § 271(e).
21. This benefit arises only if the patent owner(s) brings suit within 45 days of receiving the Paragraph IV Certification. 21 C.F.R. § 314.107(b)(3)(i)(A).
22. 21 U.S.C. § 355(b)(2); see also Guidance for Industry, Applications Covered by Section 505(b)(2). Available at: https://www.fda.gov/downloads/Drugs/Guidances/ ucm079345.pdf.
23. 21 U.S.C. § 355(b)(2)(A)(i)-(iv).
24. Dennis Crouch. Editorial: The Orange Book Should Include Process Patents or Be Eliminated, May 4, 2006. Available at: https://patentlyo.com/patent/2006/05/editorial_the_o.html.
25. 21 U.S.C. § 353(g)(5)(A); accord 21 U.S.C. § 355(b)(2)-(3).
26. GlaxoSmithKline Request for Advisory Opinion Concerning “Orange Book” Listing of Patents, January 10, 2005, FDA Docket No. 2005A-0015; Ropes & Gray on behalf of AstraZeneca, Request for Advisory Opinion Concerning “Orange Book” Listing of Patents, August 10, 2006, FDA Docket No. 2006A-0318; Ropes & Gray on behalf of AstraZeneca, Request for an Advisory Opinion – “Orange Book” Listings of Patents, June 21, 2007, FDA Docket No. 2007A.026; Finnegan on behalf of Forest Laboratories, Inc., Request for Advisory Opinion Regarding Patents Listable in the Orange Book in connection with NDA No. 202-450, May 12, 2011, FDA Docket No. FDA-2011-A-0363; Novo Nordisk Inc., Request for Advisory Opinion, Nov. 26, 20 12, FDA Docket No. FDA-20 12-A-1169.
27. See, e.g., Teva Pharms. USA, Inc. v. Sebelius, 595 F.3d 1303, 1318 (D.C. Cir. 2010); Ranbaxy Labs. Ltd. v. Leavitt, 469 F.3d 120 (D.C. Cir. 2006).
28. See, e.g., Shire LLC v. Corepharma, LLC, No. 14-5694 (RMB/JS), -6095 (RMB/JS), 15-1454 (RMB/JS), 2015 WL 4508108 (D.N.J. July 24, 2015). Arguably, this could extend to drugdelivery device patents integral to the administration of the drug that do not otherwise claim the drug.
29. AstraZeneca Pharms. v. Apotex Corp., 669 F.3d 1370, 1377 (Fed. Cir. 2012) (“[T]he requirements for jurisdiction in the district courts are met once a patent owner alleges that another’s filing of an ANDA infringes its patent under § 271(e)(2), and this threshold jurisdictional determination does not depend on the ultimate merits of the claims.”); Merck Sharp & Dohme Corp. v. Sandoz, Inc., No. 12-3289 (PGS), 2013 WL 591976 (D.N.J. Feb. 14, 2013); Research Found. of State Univ. of N.Y. v. Mylan Pharm., No. 09-184-LPS, 2012 WL 1901267 (D. Del. May 25, 2012). Notably, however, these cases involved unlisted drug patents, not device patents.
30. 35 U.S.C. §287.

Author Biographies

David K. Mroz is a U.S. patent attorney at Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, where he practices all aspects of patent law across a wide spectrum of technologies, including medical device, computer science, biotechnology, pharmaceutical, robotics, e-commerce, and consumer electronics. He represents innovative companies in complex, high-risk litigations, at both the trial and appellate levels. Mr. Mroz also works with clients to strategically develop and license patent portfolios worldwide, often with the goal of avoiding litigation.

Sydney R. Kestle is a U.S. patent attorney at Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, where she focuses her practice on several areas of patent law, including litigation in U.S. district courts and proceedings before the Patent Trial and Appeal Board (PTAB) of the U.S. Patent and Trademark Office (USPTO). Her work covers various industries, including biotechnology, industrial manufacturing, and medical device.

Paula E. Miller is a U.S. patent attorney at Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, where she focuses her practice on several areas of patent law, including patent litigation, patent prosecution, and proceedings before the U.S. Patent and Trademark Office (USPTO). She has a technical background in biomedical engineering.