Jonathan Davies, PhD, Finnegan, Henderson, Farabow, Garrett & Dunner LLP

	The passage of the Drug Price Competition and Patent Term Restoration Act of 1984, commonly referred to as the Hatch-Waxman Act, gave rise to the modern generic drug industry. The Act also created a specialized form of patent litigation, known as Abbreviated New Drug Application (ANDA) litigation. While the Hatch-Waxman Act established an abbreviated approval process for generic versions of small-molecule drugs, the Act did not create a framework for the approval of follow-on biologics, which are also referred to as “biosimilars” and “generic biologics.”

Legislation recently introduced in the US Congress seeks to address this issue and to create an approval process for follow-on biologics. These bills, HR 1427: “Promoting Innovation and Access to Life-Saving Medicine Act,” sponsored by Representative Henry Waxman, its Senate counterpart, S 726; and HR 1548: “Pathway for Biosimilars Act,” sponsored by Representative Anna Eshoo, contain several provisions that, if enacted, are likely to create a specialized patent litigation framework that differs from the ANDA litigation developed under the Hatch-Waxman Act over the past 25 years. 

	Biologic drugs are isolated from living matter or produced in living cells using modern technologies, including recombinant DNA biotechnologies and hybridoma technologies.[1] Biologics, including antibodies, enzymes, immunomodulators, and growth factors, differ from small-molecule drugs in several important respects. In comparison to small-molecule drugs, biologics are large and complex molecules or mixtures of molecules. Moreover, biologics are produced in living cells, which creates the potential for greater variability based on factors such as the precise host cells or organisms used to produce the biologic, the growth conditions used to culture the host cells or organisms, and the methods of purification used to isolate the desired biologic from host cell contaminants. Biologics also present unique safety issues, including the potential to produce undesired immune responses. Product variability and the unique biologic-specific safety concerns are significant issues in the development of an approval process for follow-on biologics, and will need to be addressed in any proposed legislation.

	“Biosimilarity” and “Interchangeability” Standards May Impact Infringement

	The complexity and variability of biologics, combined with the inability to characterize them to the same extent as small-molecule drugs, create challenges for the development of an approval process for follow-on biologics. These challenges also preclude adopting a therapeutic equivalence standard similar to that applied to the approval of generic small-molecule drugs under the Hatch-Waxman Act. Instead, Representatives Waxman and Eshoo propose the adoption of “biosimilarity” and “interchangeability” standards in HR 1427 and HR 1548.

	HR 1427 defines biosimilar as “no clinically meaningful difference between the biological product and the reference product would be expected in terms of the safety, purity, and potency if treatment were to be initiated with the biological product instead of the reference product.”[2] HR 1548 requires that a follow-on biologic applicant demonstrate biosimilarity “based upon data derived from (I) analytical studies that demonstrate that the biological product is highly similar to the reference product . . . (II) animal studies . . . ; and (III) a clinical study or studies . . . that are sufficient to demonstrate safety, purity, and potency.”[3]

	With respect to “interchangeability,” HR 1427 requires that “the biological product is biosimilar to the reference product; and . . . the patient can be switched one or more times between the reference product and the biological product without an expected increase in the risk of adverse effects.”[4] HR 1548 adopts a similar definition for interchangeability, requiring that the biological be “biosimilar to the reference product and any biological product licensed [as interchangeable to the reference product]; and . . . can be expected to produce the same clinical result as the reference product . . . ; and . . . the risk of alternating or switching between the use of the biological product and the reference product . . . is not greater than the risk of using the reference product without alternation or switching.”[5] Neither bill outlines specific standards that must be met to establish biosimilarity or interchangeability and instead directs the Food and Drug Administration (FDA) to develop them. Additionally, both bills grant the Secretary of Health and Human Services broad discretion in determining what, if any, testing and studies need to be performed to establish biosimilarity and interchangeability.[6]

	The similarity standards proposed in both bills create new issues for any related patent litigation. For example, because neither bill requires a follow-on biologic to be identical to its reference product, follow-on biologic applicants may be incentivized to argue that their follow-on biologic does not infringe any patent(s) covering the reference biologic product or the method of its manufacture. Indeed, depending on the standards adopted by the FDA, a generic manufacturer might be able to obtain approval for its follow-on biologic on the basis that it is “biosimilar” or “interchangeable”—i.e., produces the same clinical result&mdash;but argue that the biologic is different enough from the claimed invention to avoid infringing any patent(s) covering the reference biologic product.[7] Further, because a follow-on biologic need not be identical to the reference product, a generic manufacturer will likely attempt to make the follow-on product in a manner different from any patented process. Such a design-around process creates obvious concerns that the follow-on biologic may not be truly “biosimilar” or “interchangeable” with the reference product. But, the flexibility inherent in these standards makes it much more difficult for the reference drug manufacturer to protect its investment. As a result, these scenarios will increase litigation costs because testing and characterization of follow-on biologics, inspections of manufacturing sites, and depositions of those involved in developing follow-on biologics and their method of manufacture will become more common to establish infringement as compared to current Hatch-Waxman litigation.

	Filing of a Patent Infringement Lawsuit Will Not Stay Approval

	Under the Hatch-Waxman Act, a generic applicant must provide the holder of the approved New Drug Application (NDA) with notice of the filing of its ANDA. The timely filing of a patent infringement lawsuit by the NDA-holder generally initiates a “thirty month stay,”[8] during which time the FDA cannot approve the ANDA in the absence of a final court judgment in favor of the generic applicant.

	Although both HR 1427 and HR 1548 require that the follow-on biologic applicant alert the Biologic License Application (BLA) holder that an application was filed, neither bill includes a statutory stay of approval of the follow-on biologic application if the BLA holder timely files a patent infringement lawsuit.[9] The lack of a statutory stay of approval will impact resulting litigation under either bill, but that impact may be greater if HR 1427 is passed.

	The marketing exclusivity [10] awarded to a BLA holder under HR 1427 parallels the approach taken under the Hatch-Waxman Act. In particular, HR 1427 provides for three years of exclusivity if a “major substance” of the biologic was previously approved and five years of exclusivity if no “major substance” was previously approved.[11] HR 1427 also provides the potential for up to an additional six months pediatric exclusivity and another six months of exclusivity for a “significant therapeutic advance,” which includes a new treatment indication.[12] Thus, under HR 1427, the BLA holder can potentially obtain up to six years of exclusivity, independent of any patent protection, during which no follow-on biologic could be approved.

	It is highly likely, however, that patent litigation arising from a follow-on biologic application will continue even after the period of exclusivity provided for in HR 1427 has expired. This likelihood creates the potential for an “at-risk” launch of the follow-on biologic, a situation in which the applicant markets its product before any final judgment in the patent litigation. The increased potential for at-risk launches is likely to result in an increased number of preliminary injunction filings and possibly appeals to the U.S. Court of Appeals for the Federal Circuit. Therefore, when deciding where to file suit, BLA holders will need to consider a court’s track record with respect to preliminary injunctions and whether the court provides for a shorter time to trial in order to minimize the possibility of an at-risk launch.

	Proponents of HR 1427 will likely argue that at-risk launches should not be a concern because the bill incentivizes early submission of a follow-on application by permitting submission of an application at any time during the period of exclusivity and awarding market exclusivity to the first follow-on biologic to achieve interchangeable status.[13] Given, however, the amount of lead-time that is necessary to develop, manufacture and test a follow-on biologic, it is much more likely that a follow-on application will be filed during the later stages of the BLA holder’s period of exclusivity leaving insufficient time to complete any related patent litigation prior to expiration of the exclusivity period.

	The impact on at-risk launches, preliminary injunction filings, and time to trial might be less significant if HR 1548 is passed because Representative Eshoo’s bill provides for twelve years of exclusivity, independent of any patent protection.[14] A BLA holder can also obtain an additional six months of pediatric exclusivity and up to two additional years of exclusivity for a “medically significant new indication.”[15] Although HR 1548 permits a follow-on biologic applicant to submit an application at the later of either four years after approval of the reference product or the date of commencement of guidance from the FDA related to the criteria for determining biosimilarity, interchangeability, and immunogenicity, the period of exclusivity may be sufficiently long enough to permit completion of the litigation before a follow-on biologic application could be approved. If, however, it would take a generic manufacturer eight to ten years to develop a follow-on biologic, the chances for an at-risk launch could increase dramatically even under HR 1548.[16]

	President Obama has indicated his support for the development of a framework for approval of follow-on biologics. In fact, the fiscal year 2010 federal budget includes a proposal to develop this approval process.[17] Also, Representative Waxman has indicated that his follow-on biologics legislation is “one of [his] highest priorities this year.”[18] Regardless of what form a final follow-on biologics bill takes, the following considerations will be important to prepare for any future follow-on biologics approval process and the resulting patent litigation.

	1. Understand your patent portfolio: Notably absent from both HR 1427 and HR 1548 is the creation of an Orange Book [19] equivalent for follow-on biologics. Instead, both bills require the BLA holder to identify relevant patents when requested by the follow-on biologic applicant.[20] Assess your patent portfolio now to have a firm understanding of which aspects of your products and/or processes are protected, the scope of the patent protection, how much patent term remains, and whether you own or license-in the technology. Also, enlist the help of your outside legal counsel to conduct a complete due diligence investigation so that when the time comes, you will be prepared to identify those patents that cover your biological product.

	2. Understand your product and manufacturing processes: A thorough understanding of your products and their manufacturing processes is essential. With the help of your scientists and manufacturing engineers, carefully review every aspect of your product and how it is made. Such a review will help you to determine whether a generic manufacturer could design around your patents yet still establish “biosimilarity” or “interchangeability.” This review may also provide insight as to the length of time it might take a generic manufacturer to develop its follow-on biologic and the problems it might encounter, making you better informed as to when you might expect a company to file a follow-on biologic application.

	3. Stay ahead of the curve: HR 1427 and HR 1548 both provide for extensions of exclusivity based on pediatric studies and/or new therapeutic advances. Consult with your product, clinical, and regulatory teams to determine whether pediatric studies are feasible or whether new uses are being investigated. And continue to think about how follow-on biologics legislation will impact your company and its patent litigation strategy. Although it is unclear what form the final follow-on biologics bill will take, it is clear from HR 1427 and HR 1548 that follow-on biologics patent litigation and strategy will likely differ from current Hatch-Waxman ANDA litigation. Keeping abreast of this information now will allow your company to move quickly and decisively if and when follow-on biologics legislation is passed. PC

	1. See Center for Biologics Evaluation and Research website, “What Are ‘Biologics’ Questions and Answers,” available at http://www.fda.gov/AboutFDA/CentersOffices/CBER/ucm133077.htm.

	2. See HR 1427, 111th Cong. § 3(a)(2), at p. 4, l. 21 - p. 5, l. 3 (2009), available at http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=111_cong_bills&docid=f:h1427ih.pdf (emphasis added).

	3. See HR 1548, 111th Cong. § 101(a)(2), at p. 3, ll. 5-22 (2009), available at http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=111_cong_bills&docid=f:h1548ih.pdf (emphasis added).

	4. See HR 1427, § 3(a)(2), at p. 5, ll. 4-20.

	5. See HR 1548, § 101(a)(2), at p. 7, l. 3 - p. 8, l. 9.

	6. See HR 1427, § 3(a)(2), at p. 6, ll. 7-23; HR 1548, § 101(a)(2), at p. 4, l. 20 - p. 5, l. 4.

	7. In response to a recently released report by the Federal Trade Commission regarding the approval of follow-on biologics, Rep. Eshoo responded that “[w]e have absolutely no experience with the similarity standard which will be used for biologics, for the approval of biosimilars. . . . How can you be assured this will not open a path for patent work-arounds?” See IPLaw 360, “Lawmakers Slam FTC Biologic Report,” June 12, 2009.

	8. Under certain circumstances, the length of the stay of ANDA approval may be different than thirty months. See, e.g., 21 U.S.C. § 355(j)(5)(F)(ii).

	9. See HR 1427, § 3(b)(2), at p. 44, l. 18 - p.45, l. 21; HR 1548, § 101(a)(2), at p. 26, ll. 5-22.

	10. During this period the FDA would not be able to approve the follow-on biologic application. See HR 1427, § 3(a)(2), at p. 16, l. 22 - p. 22, l. 20; HR 1548, § 101(a)(2), at p. 11, l. 19 - p.14, l. 20.

	11 See HR 1427, § 3(a)(2), at p. 16, l. 22 - p. 17, l. 18.

	12. The six-month exclusivity period available for a significant therapeutic advance “shall” be reduced to three months if gross annual U.S. sales of the biologic exceed one billion dollars. See HR 1427, § 3(a)(2), at p. 22, ll. 3-17.

	13. See HR 1427, § 3(a)(2), at p. 24, l. 1 - p. 26, l. 2; p. 32, l. 22 - p. 33, l. 25.

	14. See HR 1548, § 101(a)(2), at p. 11, l. 19 - p. 12, l. 3.

	15. See HR 1548, § 101(a)(2), at p. 12, l. 24 - p. 14, l. 20.

	16. See Federal Trade Commission Report, “Emerging Health Care Issues: Follow-on Biologic Drug Competition,” June 2009, at p. iii.

	17. See Letter from Rep. Waxman to President Obama, dated June 8, 2009, regarding fiscal year 2010 federal budget proposal to establish a pathway for FDA approval of generic biologics.

	19. The FDA maintains a publication termed “Approved Drug Products with Therapeutic Equivalence Evaluations, commonly referred to as the “Orange Book,” which contains a list of approved New Drug Applications and related patent information.

	20. See HR 1427, § 3(a)(2), at p. 30, l. 14 - p. 32, l. 21; HR 1548, § 101(a)(2), at p. 21, l. 8 - p. 24, l. 5. 

	Sanya Sukduang is a partner and Jonathan Davies is an associate at Finnegan, Henderson, Farabow, Garrett & Dunner LLP. Any opinions expressed herein are the personal views of the authors and are not intended to represent the views of Finnegan, Henderson, Farabow, Garrett & Dunner, LLP. 

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