62 Gross et al. governmental approval (9). On the other hand, Hatch-Waxman provides that an applicant for an ANDA or a 505(b)(2) applicant must make an appropriate certifi- cation respecting marketing of the generic drug vis-a-vis any patents for the same drug that are listed by the brand-name NDA holder in FDA’s list of “Approved Drug Products With Therapeutic Equivalence Evaluations” (commonly referred to as the “Orange Book”) (10) Where the generic applicant certifies that there are no patents listed in the Orange Book (a "Paragraph I Certification”) or that any listed patents have pre- viously expired (a “Paragraph II Certification”), the drug may enter the market- place immediately upon FDA approval. Where the applicant certifies that any listed patent has not yet expired but will expire on a particular date and that it will not enter the market until after that date (a “Paragraph III Certification”), FDA may approve the ANDA and make it effective as of the patent expiration date Where the applicant for generic approval intends to market the drug prior to expiration of any patent(s) listed in the Orange Book, the applicant makes a certifica- tion that, in its opinion, the patent(s) are not infringed or are invalid (a “Paragraph IV Certification”), and it notifies the NDA holder and patent owner accordingly (11). In such instance, the statute provides that the NDA holder/ patent owner may then initiate a patent infringement action against the applicant for generic approval and FDA must suspend approval of the ANDA or 505(b)(2) application for up to 30 months (the “30-month stay”), subject to the earlier of a court determination or the expiration of the listed patent(s) (12) In an effort to encourage generic drug entry into the pharmaceutical mar- ket, the Hatch-Waxman Act provides a commercial incentive to those generic com- panies who are the first to file ANDAs incorporating Paragraph IV Certifications challenging infringement or validity of Orange Book-listed brand-name pharmaceu- tical patents. Thus, in the event the listed brand-name patent(s) are adjudged to be invalid or not infringed prior to their normal expiration date(s); the first generic filer(s) entitled to approval of their ANDAs receive a 180-day exclusivity period during which no other ANDA can be approved for the same product (13). In such circumstances, the first entity or entities to file an ANDA can be the only generic marketer(s) for 180 days. In addition, Hatch-Waxman incorporates several provisions limiting the fil- ing or approval of ANDAs and 305(b)(2) applications in view of marketing “exclu- sivities” previously obtained by a brand-name NDA holder. Chief among such limitations is a 5-year bar on submitting an application for generic drug approval following approval of an NDA on a “new chemical entity” (NCE) (14), and a 3-year bar on obtaining approval of a generic drug application following approval of an NDA based on new clinical investigations respecting a previously approved drug, (15). There is also a 7-year bar on obtaining approval of any drug application fol- lowing approval of an orphan drug for the same indication (16). Finally, pediatric exclusivity, which is granted upon completion of pediatric studies requested by FDA, prevents generic drug approval for an additional 6 months after expiration of any pertinent patent listed in the Orange Book. Pediatric exclusivity also extends the 3-year, 5-year, and 7-year exclusivities by 6 months (17) FDA's approval scheme for ANDAs containing Paragraph I, Il, II, or IV Cer- tifications is illustrated in Figures 1 and 2 (18). Since enactment of Hatch-Waxman, several amendments have been made to enhance and prevent abuse of the Hatch-Waxman scheme. For instance, changesGeneric Drug-Approval Process: Hatch-Waxman Update 63 ANDA patent certification option ao Vo | | | | eons meta erate marta FIGURE 1 ANDA Patent Certifications, made to Hatch-Waxman in the Medicare Prescription Drug Improvement, and Modernization Act of 2003 (hereinafter “the 2003 Statutory Changes”) were designed to limit brand-name companies to the opportunity to obtain a single 30-month stay of approval of ANDA or 505(b)(2) applications for the resolution of patent infringement litigation respecting listed drug patents. More recently, the Food and Drug Administration Amendments Act of 2007 (FDAAA) provided that optically pure enantiomers of previously approved drugs may be considered new chemical entities and thus receive 5 years of market exclusivity if certain conditions are met. FDAAA also prevents delay of generic approval based on a third-party submission of citizen petitions suggesting that generic applications should not be approved, unless delay is necessary to protect public health. LISTING PATENTS IN THE ORANGE BOOK Requirements In 1984, for the first time, Hatch-Waxman required each NDA applicant to identify any patent which claims the drug for which the NDA was submitted or a method of using such drug which the applicant believed could reasonably be asserted against potential generic infringers (19). The patent information must be submitted dur- ing the pendency of the NDA. On the other hand, if a patent eligible for listing in the Orange Book is granted after approval of the NDA (or even after the filing of an ANDA secking approval of a generic equivalent of the listed product), then the patent information must be submitted within 30 days after grant of the patent (20) The information submitted during pendency of an NDA must be set forth in FDA Form 3542a, while information for listing submitted after approval of an NDA must64 Paragraph IV certification — Gross et al. Daye Patertholder doesnot ue he FDA, may approve ANDA assur 0 rogulterycenations are ulled Patentholer suse gener ‘oplcant win 48 eave tigger ot {tomate 30-me say | (Genaricappeant may enter a= * Nos s0-ro say not oxied Toss say eres Us FDA may be abet» BRA “S ‘compary’s aver tne FOA ‘anne! approve ANDA unt Daten enprae spoleant, DA can aprove ANDA and 180-57 cus period begin 3 Soorove ANDAG rcs beyond ps patent empation ay xclusty 13 bop rst ri applica upon makeing ‘one or mare generic Sppliants may ener gevore al Fas pod oleart may cans 180-sy sxcusiy Sn oretoa FIGURE 2. Paragraph IV Certifications. Spproves afer ne fi gonee be incorporated in FDA Form 3542 (21). Under Hatch-Waxman, the generic appli- cant must make a patent certification as to each such listed patent (22), and if the patent is not listed until after filing of the ANDA, amend its application accordingly (23). On the other hand, if the brand-name company fails to submit the patent infor- mation for listing in the Orange Book within the 30-day period after the grant of the patent, the generic applicant need not submit an amended certification and the patent owner may not initiate an infringement suit under 35 USC §271(e)(2) (24).Generic Drug-Approval Process: Hatch-Waxman Update 65 Further, a brand-name company cannot obtain a 30-month stay of generic approval based on the listing of a patent after the filing of the ANDA (25). In one recent case, Eisai, the NDA holder, owned a patent which claimed the active pharmaceutical ingredient doneprezil hydrochloride in its commercial drug products Aricept® and Aricept ODT® (26). While Eisai properly submitted the forms to list its patent for Aricept in 1996, Eisai failed “by ... repeated oversights” to submit the proper forms and information to FDA for Orange Book listing of the patent for Aricept ODT, which was approved in 2005 (27). Accordingly, FDA did not list the patent until more than 5 months after the generic party filed its ANDA (28). By reason of such error, which the district court characterized as “more than merely ‘clerical,’” (29) the ANDA applicant did not have to submit a Paragraph IV certifica- tion, and Eisai was not entitled to the 30-month stay of approval of the ANDA that the prompt commencement of suit would have achieved. Additionally, the district court dismissed the lawsuit for lack of subject matter jurisdiction due, in part, to the ANDA applicant's failure to submit a Paragraph IV certification. The patents for which information must be submitted in connection with an NDA include those directed to the drug substance (active ingredient), the drug product (formulation or composition), and methods of use (indications) approved for the listed drug product (30). The patents thus submitted to FDA are listed in the Orange Book (31), and are the “listed patents” or “Orange Book patents”. Since enactment of Hatch-Waxman, brand-name companies have submitted patents for listing in the Orange Book directed to a wide range of subject matter, which include different forms of an active drug substance, for example, anhydrous or hydrated forms, salts, enantiomers or crystal forms of the active substance, dif- ferent formulations of the drug, metabolites formed in patients after administration of the drug, and methods of use of the drug whether or not previously approved by FDA (32). The listing of multiple patents in the Orange Book has compelled ANDA and 505(b)(2) applicants to make multiple patent certifications and, in some instances, resulted in the imposition of multiple 30-month stays of generic product approvals, with consequent delays of generic entry into the market. FDA does not review the propriety of patents submitted by NDA holders for listing in the Orange Book because FDA “does not have the expertise to review patent information” (33). Rather, if the accuracy or relevance of patent information submit- ted for listing in the Orange Book is disputed by an ANDA or 505(b)(2) applicant it must notify FDA. The agency will then ask the NDA holder to confirm the correct- ness of the patent information, and unless the NDA holder withdraws or amends its patent information, FDA “will not change the patent information in the” Orange Book (34). The agency’s failure to review patent listings in the Orange Book for possi- ble delisting provoked criticism, and prompted proposals for reform. In response to such criticisms, FDA implemented several rule changes in 2003 (hereafter “the 2003 Rule Changes”). Under those regulations, drug substances that are the same active ingredients as the subject of NDAs, but in different physical forms, that is, polymorphs (35), must be submitted for listing in the Orange Book. An NDA holder or patent owner must, however, establish that a polymorph claimed ina patent will “perform the same as the drug product described in the NDA with respect to such characteristics as dissolution, solubility, and bioavailability” for list- ing (36). To establish such “sameness” for a polymorph, the NDA holder or patent owner must submit detailed test data in five different categories, using forms spec- ified in the 2003 Rule Changes (37)