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Revisiting the Debate on an Orange Book for the Biologics Price Competition and Innovation Act
By Andrew S. Wasson 1

resident Obama signed the Biologics Price Competition and Innovation Act (BPCIA) into law more than a year ago, yet industry stakeholders, lawyers and academic commentators continue to actively debate key provisions of the statute. The BPCIA authorizes FDA to approve an application under new subsection 351(k) of the Public Health Service Act (a subsection (k) application) to market a biological product on the basis of an earlier finding of safety, purity, potency and effectiveness, as long as the applicant can demonstrate at least biosimilarity to the earlier application.2 It is difficult to debate the merits of the BPCIA, however, without using the Hatch-Waxman Amendments to the Federal Food, Drug and Cosmetic Act (Hatch-Waxman) as a point of reference. Notably, Hatch-Waxman directs FDA to publish patent information associated with drug products that it receives from new drug application (NDA) holders on a regular basis (this publication is known as the Orange Book).3 The BPCIA contains no analogous provision. The lack of an Orange Book-like publication for BLA products will likely have significant ramifications. This article concludes that further regulatory or legislative action is necessary to require the publication of BLA patent information because: (1) a scheme that lacks such a publication may discourage competition, (2) original concerns about gaming the system may be unwarranted given the current structure of the BPCIA and (3) a reasonable, but ostensibly unconfirmed, hypothesis underpins the rationale for leaving out such a publication from the BPCIA. Patent information plays a central role in the regulatory and litigation scheme established by Hatch-Waxman. Hatch-Waxman states that an applicant who files an NDA must include the patent number and expiration of any patent claiming the product and 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.4 The statute further states, [u]pon approval of the application, the Secretary shall publish information submitted under the two preceding sentences.5 Elsewhere in the statute, Hatch-Waxman specifies

The Orange Book under Hatch-Waxman

additional parameters for this publication. Hatch-Waxman also provides that the Secretary shall revise the list every 30 days to include all drugs approved within the last 30-day period.6 FDA elaborated on its vision of this publication in an early set of proposed rules.7 FDA stated that, [a]though not required by the act, the list, as published, also identifies all drug products that qualify under the act for periods of exclusive marketing, regardless of patent status, and states therapeutic equivalence evaluations for approved multisource prescription drug products.8 FDA also stated, [a]s a general rule, FDA intends to use the list and its supplemental updates as the primary means of announcing information regarding patent status, exclusivity, type of bioequivalence study needed, and eligibility for consideration in an ANDA.9 Thus, even though Hatch-Waxman provided FDA with minimal guidance, it still broadly authorized the publication of patent information. The Orange Book is critical to Hatch-Waxman patent litigation. For example, an applicant who submits an application under either Section 355(j) or 355(b)(2) of Hatch-Waxman must address each patent submitted by the NDA-holder (each ultimately published in the Orange Book).10 Under the infamous Paragraph IV Certification, a generic applicant can certify that a patent is invalid or will not be infringed by the manufacture, use, or sale of the new drug for which the application is submitted.11 Effectively speaking, the generic applicant reviews the Orange Book and files the appropriate certification with regard to each patent listed for the reference listed drug. Litigation often ensues after the generic filer sends the NDA holder and patentee notice of its Paragraph IV Certification and its legal and factual basis for challenging each patent.12 If an NDA-holder files suit after the statutory 45-day period, FDA cannot approve the ANDA for a period of 30 months from the date of receipt of the Paragraph IV Certification(s) by both the NDA holder and patentee (known as the 30-month stay.)13 While the Orange Book looms large in Hatch-Waxman litigation, it is important to separate the role it plays as a source of information versus the role played by patent information generally in the statute.


Posted with July/August 2011 permission of the Food and Drug Law Institute (FDLI) 2011. Originally published in FDLIs Update.w w w . f d l i . o r g

The BPCIA Lacks a Publication for Patent Information

The BPCIA does not compel the central compilation or publication of patent information. Rather, the BPCIA sets out a series of deadlines where the parties negotiate which patents will be the subject of litigation. Heres how the process works in more detail: FDA notifies the subsection (k) applicant that its application is accepted for review; The applicant must provide a copy of its application to the sponsor within 20 days of this notification; The sponsor has 60 days to provide the applicant with a list of patents for which the reference product sponsor believes a claim of patent infringement could reasonably be asserted or such other patents exclusively licensed by the sponsor; Within 60 days of receiving the sponsors list, the applicant may provide the sponsor with its own list of patents which it believes could reasonably be asserted; Within the same time period, the applicant must provide a detailed statement of its factual and legal basis why each patent on the sponsors list is invalid, unenforceable, or will not be infringed by the applicants proposed product, or alternatively, that the applicant will not market its product until the patent expires; Within 60 days of receiving the applicants statement, the sponsor must respond with a statement demonstrating why the proposed product will infringe each patent on the list and a response to the allegations of invalidity and unenforceability.

so to speak, when the generic applicant is initially evaluating a proposed product. Further, in the Hatch-Waxman context, the second set of negotiations is similarly unnecessary: all parties are well-aware that the NDA-holder may sue the generic applicant on any patent listed in the Orange Book and possibly additional patents related to ANDA. Therefore, the BPCIA achieves in a very convoluted way, the same result that Hatch-Waxman achieves more efficiently with the Orange Book.

Policy Analysis
Why then, did the BPCIA depart so dramatically from the precedent set by Hatch-Waxman? The rationale appears to be most cogently documented in remarks made in 2007 by former Commissioner of the Federal Trade Commission, Pamela Jones Harbour.15 Commissioner Harbour stated I would be very skeptical of a follow-on biologic approval pathway that included an Orange Book-like system of patent listings.16 She elaborated that [e]ach Orange Book listing represents a new hurdle for would-be entrants and that it would easier, and more tempting to game an Orange Book for biologics.17 In particular, she noted, biologics manufacturer might make small tweaks to its manufacturing process, generate new patents, and list them in a biologic Orange Book at the last minute or make other questionable Orange Book listings that would thwart follow-on entry plans.18 Commissioner Harbours concern appears to spring from her view that the patent landscape for biologics is at core fundamentally different from the patent landscape for small molecule drugs governed by Hatch-Waxman. She stated, [P]harmaceutical drugs usually are covered by a relatively small number of patents, owned by a small number of firms but, [b]iologics, in contrast, may be covered by a much greater number of patents including research tool patentsowned by multiple entities.19 Therefore, the BPCIA lacks an Orange Book-type publication, it appears at least in part, out of concern that sponsors would have an increased opportunity to game the system due to differences in technology and patenting patterns. While Commissioner Harbours comments set forth a compelling rationale, several reasons exist why we should revisit this position. First, Commissioner Harbours vision of an Orange Book-like publication understandably draws from the Hatch-Waxman context, where litigation springing from filed patent information inevitably leads to a 30-month stay. Critically, however, on a theoretical level, publication of patent information does not necessarily entail a stay of application approval. These concepts can be decoupled. Indeed, in the context of the BPCIA (which lacks a 30-month stay) the risk of gaming the system should be no greater than the current risks present in Update

Next, the BPCIA sets out a framework for patent resolution negotiations whereby the parties enter into a 15-day period of good faith negotiations to determine the patents-at-issue. If the parties fail to agree within this period, then the applicant and sponsor exchange patent lists once again. First, the applicant communicates to the sponsor the number of patents it intends to include in its list. Then, the applicant and sponsor exchange lists that contain the initially-determined number of patents. The sponsor must bring suit with respect to each patent included in these lists within 30 days. Unlike Hatch-Waxman, the BPCIA lacks an equivalent provision to a 30-month stay. The centralized publication of patent information in the Orange Book eliminates the need for the first set of exchanges in the BPCIA. In the Hatch-Waxman regime, the generic applicant knows which patents the innovator believes could be reasonably asserted against generic versions of its product by virtue of the Orange Book.14 Importantly, this notice occurs at time zero,

Posted with permission of the Food and Drug Law Institute (FDLI) 2011. Originally published in FDLIs Update. July/August 2011

the current statute. Second, while it is certainly anecdotally true that biologics may be covered by a greater number of patents than small-molecule drugs (e.g., more methods of manufacturing patents), this is not necessarily the case. Additional empirical research should be undertaken which confirms or denies this hypothesis. Finally, it should be noted that decisions about patent information are not made in a vacuum and may have ramifications in the scientific community as a whole. For example, Orange Book patents are cited on whole nearly two times as often as comparable non-Orange Book patents.20 There may be something to be said for the dissemination scientific technology found in patents which are demonstrably successful. Furthermore, the argument can also be made that the full disclosure of patent information encourages competition by creating additional certainty of the patents an innovator is most likely to assert against biosimilar applicants. Uncertainty about relevant patents may discourage many potential applicants from entering the biosimilars field. Just recently, Craig Wheeler, CEO of Momenta Pharmaceuticals said, [i]nitially, when you are thinking of starting an investment, you wont see the patents you will be hitting up against until you get the list from the brand company.21 On the other hand, if BLA-holders file patent information in a public manner, then subsection (k) applicants (and especially smaller, early-stage companies) may be more likely to make investments in this area, such as considering how to manufacture a biosimilar applicant differently than the innovator. That is not to say that an Orange Book-like publication would prevent such companies from undertaking their own freedom-to-operate patent searches. Combining patent searches with the information of a central repository, however, may give potential subsection (k) applicants the confidence to make large investments in a way that relying on patent searches alone may not provide.

is warranted to test the hypothesis that the biologics patent landscape is any different than the patent landscape for small molecule drugs. Therefore, additional legislative or regulatory action is necessary to include a central publication of patent information into the BPCIA. FDLI Mr. Wasson is an Associate in the law firm of Frommer Lawrence & Haug LLP in New York, NY.

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Patents play a major role in both the Hatch-Waxman and the BPCIA, although each statute handles patent information very differently. The lack of an Orange Book-type publication in the BPCIA places additional uncertainty and risk on a subsection (k) applicant, who will not definitely know the patents in play until after its application has been filed. This uncertainty may lead to a decrease in competition because such applicants may be less likely to invest in biosimilars. Furthermore, given the current structure of the BPCIA, an Orange Book-type publication may not create the issues originally feared. First, decoupling any publication of patent information from a bar to regulatory approval should alleviate concerns about gaming the system through misuse. Second, additional empirical study


16. 17. 18. 19. 20.


Mr. Wasson would like to thank Brian J. Malkin for his comments and insight on this article. I referred to an applicant filing a subsection (k) application, as a subsection (k) applicant. The Orange Book is known officially as Approved Drug Products with Therapeutic Equivalence Evaluations, but informally known as the Orange Book because of its orange cover in print but is also available electronically at http://www.accessdata. 21 U.S.C. 355(b)(1)(G); see also 21 U.S.C. 355(c)(2) (obligating NDA holder to update patent information as new patents are issued not later than thirty days after the date the patent involved is issued; see also 21 U.S.C. 355(j)(7)(A)(i) (the list shall also contain whether in vitro or in vivo bioequivalence studies, or both such studies, are required for applications filed under this subsection which will refer to the drug published). 21 U.S.C. 355(b)(1)(G). 21 U.S.C. 355(j)(7)(A)(ii). 21 CFR Parts 10, 310, 314, and 320: Abbreviated New Drug Application Regulations; Proposed Rule. 54 Fed. Reg. 28,872, 28,876 (June 10, 1989); see also Abbreviated New Drug Application Regulations; Patent and Exclusivity Provisions, 59 Fed. Reg. 50,338 (Oct. 3, 1994) (final rule). Id. Id. 21 U.S.C. 355(j)(2)(A)(vii) (for Abbreviated New Drug Application (ANDA) submissions; 21 U.S.C. 355(b)(2)(A) (for 505(b)(2) applications). For simplicitys sake, we focus on the requirements for an applicant who submits an ANDA under 21 U.S.C. 355(j), although we recognize that many of the provisions referred to herein have analogous provisions for Section 505(b)(2) applications. 21 U.S.C. 355(j)(2)(A)(vii)(IV). By regulation, FDA has extended this to include certifications that a patent is unenforceable. See 21 C.F.R. 314.94(a)(12)(i)(A)(4). 21 U.S.C. 355(j)(3)(D)(ii). 21 U.S.C. 355(j)(5)(B)(iii). The thirty-month stay can terminate earlier; for example, if the district court decides that the patent is invalid or not infringed (including any substantive determination that there is no cause of action for patent infringement or invalidity) or if the court enters a settlement order or consent decree stating that the patent that is the subject of the certification is invalid or not infringed. 21 U.S.C. 355(j)(5)(B)(iii)(I). It should be noted that FDA regulations direct NDA holders to submit patent information only with respect to certain types of patents: drug substance (e.g. active ingredient), drug product (e.g. formulation), and method-of-use patents. 21 C.F.R. 314.53(b). Pamela Jones Harbour, The Competitive Implications of Generic Biologics, ABA Sections of Antitrust and Intellectual Property Law, Intellectual Property Antitrust: Strategic Choices, Evolving Standards, and Practical Solutions (San Francisco, California, June 14, 2007). Id. at 16. Id. Id. Id. Andrew S. Wasson, Biosimilars: Contemplating an Orange Book (Jan. 25, 2011) available at (last accessed May 20, 2011). Reported in Brenda Sandburg, Biosimilars Pathway: Lack of Orange Book For Patents Worries Momenta, The Pink Sheet (May 10, 2010).


Posted with July/August 2011 permission of the Food and Drug Law Institute (FDLI) 2011. Originally published in FDLIs Update.w w w . f d l i . o r g