United States: The Drug Approval Process: What’s The "Hatch" With The One Hundred Eighty-Day ANDA Exclusivity Period?

Last Updated: June 8 2001
Article by Tony V. Pezzano

A. Introduction

As an incentive for generic pharmaceutical companies to rapidly bring generic drugs to market, Congress rewarded the first generic company to challenge the innovator company’s patent for a given drug with a 180-day exclusivity period in which no subsequent abbreviated new drug application ("ANDA") could be approved for that drug. Since that time, there have been numerous litigations to determine how the statute (21 U.S.C. §355(j)) and corresponding regulations relating to this exclusivity period should be interpreted. On August 6, 1999, the United States Food and Drug Administration ("FDA") published a proposed rule to update its regulations in view of recent court decisions. However, even before this proposed rule could be made final, several courts have rendered decisions that appear to be inconsistent with the FDA’s proposal. The state of the law is discussed below.

B. Discussion

1. What Happened?

After years of legislative efforts to balance the economic interests of research-based drug companies and generic drug companies, Congress passed the Drug Price Competition and Patent Term Restoration Act of 1984 -- Public Law 98-417 ("Hatch-Waxman Amendments"). The Hatch-Waxman Amendments amended §505(j) that is now embodied in 21 U.S.C. §355(j). This section of the statute deals with new drugs and established the ANDA process.

The Hatch-Waxman Amendments increased the availability of generic drugs by establishing a drug approval procedure called an ANDA. The main difference between an ANDA and a new drug application ("NDA") is that in an ANDA, the generic company does not conduct the time-consuming human clinical trials that are required of the innovator company (i.e., a company having a drug approved as a result of an NDA) to obtain FDA approval of an NDA.

While the Hatch-Waxman Amendments permitted the preparation and filing of ANDAs before patent expiration, it generally contemplated that the effective approval date of the generic drug would be on the expiration date of the patent covering the innovator’s original drug. The Act, however, also established another procedure so a generic drug company could challenge a patent and try to enter the market before patent expiration. As part of this procedure, the Hatch-Waxman Amendments added a patent notification system to U.S. law. As a result, generic companies can readily find the patent(s) that cover the innovator’s drug. The Hatch-Waxman Amendments also require that the innovator be notified of the generic’s intent to challenge the patent so that the innovator may take timely legal action.

An innovator drug company that has filed an NDA must file the patent number and the expiration date of 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 is engaged in the manufacture, use, or sale of that drug.1 This information is made publicly available in the FDA’s publication "Approved Drug Products with Therapeutic Equivalence Evaluations" ("Orange Book").

Both the generic companies and the innovator companies are provided with certain benefits by virtue of the ANDA notification system. For the generic companies, the Hatch-Waxman Amendments provide as an incentive a 180-day exclusivity period in which no other ANDA for that drug can be approved.2 This 180-day period is to encourage generic companies to challenge the validity of Orange Book listed patents or to design around these patents to bring more quickly a generic drug to market and also to recoup the possible costs should an innovator enforce its patent against the generic.

For the innovator company, the filing of an ANDA for a product that is intended to be marketed before expiration of the Orange Book patent is an act of patent infringement.3 The Hatch-Waxman Amendments require an ANDA applicant to inform the innovator drug company (specifically, the NDA holder and patent owner) if the ANDA applicant seeks approval of a generic version of the innovator company’s drug before the expiration of the patent information contained in the Orange Book.4 If the innovator drug company brings suit within 45 days, the approval of the generic company’s ANDA is delayed for up to 30 months or until a court rules otherwise.5

An ANDA applicant that files under 21 U.S.C. §355(j) is required to make a patent certification. The ANDA applicant must certify the following with respect to each patent which claims the listed drug for which applicant is seeking approval:

(I) that such patent information has not been filed;

(II) that such patent has expired;

(III) of the date on which such patent will expire; or

(IV) that such patent is invalid or will not be infringed by the manufacture, use, or sale of the new drug for which the application is submitted.6

The first three paragraphs, paragraphs I, II, III, result in no generic drug being sold during the term of the innovator’s patent protection. A paragraph IV certification on the other hand, could result in a generic drug being sold during the term of the innovator’s patent protection. Accordingly, the Hatch-Waxman Amendments provided the innovator company with a favorable forty-five (45) day window in which to bring an action for patent infringement.7

If an action is brought during this 45-day time period by the innovator company, then the generic company’s ANDA cannot be approved for thirty (30) months unless before the expiration of such period: (i) the court decides that such patent is invalid or not infringed; (ii) the court decides that such patent has been infringed and sets a date for approval of the ANDA as provided for in 35 U.S.C. §271(e)(4)(A)8; or (iii) the court grants a preliminary injunction prohibiting the ANDA applicant from engaging in the commercial manufacture or sale of the drug until the court decides the issues of patent validity and infringement.9 In the first of the above three scenarios, ANDA approval is made effective on the date of the court decision. In the second of the above three scenarios, ANDA approval is made effective on the date established by the court. In the third of the above three scenarios, ANDA approval is made effective on the date the court decides that such patent is invalid or not infringed.

In a corresponding regulation promulgated by the FDA for the purpose of implementing a paragraph IV certification under §505(j)(5)(B)(iv), the FDA inserted a requirement that "the applicant submitting the first application has successfully defended against a suit for patent infringement brought within 45 days of the patent owners receipt of notice submitted under §314.95."10 This "successful defense" requirement is not found in the statute (21 U.S.C. §355(j)) and has been the subject of several litigations discussed below.

Inwood

One of the earliest cases to address the issue of 180-day exclusivity was Inwood Laboratories Inc. v. Young.11 Inwood filed a paragraph IV certification alleging that its proposed generic product did not infringe the Orange Book listed patent. Inwood was the first ANDA applicant to file such a certification and the patent holder elected not to sue.12 The FDA approved Inwood’s product and Inwood claimed that it was entitled to 180 days of exclusivity under 21 U.S.C. §355(j)(5)(iv)(II).13 The FDA’s position was that the 180-day exclusivity period commences only when the First Applicant has been sued for patent infringement. The District Court ruled that the statute is clear on its face -- no successful defense was needed -- and therefore it was unnecessary to consider the FDA’s interpretation of the statute. On appeal, and after the 180-day exclusivity period had expired, the Appeals Court vacated the judgment below and remanded the case to the District Court with instructions to dismiss the complaint.

In two cases that were decided almost concurrently (April 14 and 3, 1998, respectively), Mova Pharmaceutical Corp. v. Shalala,14 and Granutec Inc. v. Shalala,15 the Courts of Appeal for the D.C. Circuit and the 4th Circuit, respectively, ruled that the FDA exceeded its statutory authority in imposing the successful defense requirement as a prerequisite to the invocation of the 180-day exclusivity rule by the first applicant under section 355(j)(5)(B)(iv). The successful defense requirement was found to be inconsistent with the statutory text and structure and not justified by a need to protect the essential function of the statute or a clear congressional intent.

Mova

Prior to the District Court action, Mova Pharmaceutical Corp. ("Mova") had first filed an ANDA to market a generic version of micronized glyburide. Pharmacia & Upjohn Company ("Upjohn") filed a patent infringement suit against Mova alleging that Mova’s product infringed an Upjohn patent. In the meantime, the FDA approved an ANDA for the same generic drug submitted by Mylan Pharmaceuticals, Inc. ("Mylan"). Mova brought suit in the United States District Court for the District of Columbia relying on 21 U.S.C. §355(j)(5)(B)(iv).16 The Court held that the language of the statute is plain and obvious -- it was Mova’s first filing of an ANDA and not Upjohn’s infringement suit that required the FDA to withhold approval from subsequent paragraph IV filers.17 Accordingly, the Court granted a preliminary injunction requiring the FDA to suspend its approval of Mylan’s ANDA. The D.C. Court of Appeals upheld this decision as noted above.

Granutec

The District Court in Granutec enjoined the FDA from granting a 180-day marketing exclusivity period to Granutec’s competitor, Genpharm, for the sale of its ranitidine product, a generic form of Zantac.18 Genpharm was the First Applicant but did not meet the "successful defense" requirement.19 The Court did not focus on the statute. Rather, the Court adopted Granutec’s position that the FDA failed to follow its own regulation. The Fourth Circuit Court of Appeals reversed the decision for the reasons found persuasive in Mova, i.e., the language of the statute is plain and obvious, the successful defense requirement is an invalid addition to the statutory requirements for exclusivity.

In response to the above cases, on June 22, 1998, the FDA published its "Guidance for Industry, 180-Day Generic Drug Exclusivity Under the Hatch-Waxman Amendments to the Federal Food, Drug, and Cosmetic Act" ("Guidance"). The purpose of this Guidance was "to provide industry with information on how. . . FDA . . . is applying the 180-day generic drug exclusivity provisions of the Federal Food, Drug, and Cosmetic Act (Act) in view of recent court decisions." The Guidance specifically addressed the "elimination of the ‘successful defense’ requirement." In a nutshell, in view of Inwood, Granutec, and Mova, the FDA would rely on the statute and not its prior regulation that required a "successful defense" in order to award a 180-day exclusivity period. In an interim rule published November 5, 1998 in the Federal Register20, the FDA revoked the "successful defense" requirement explicitly and made the language of the regulation consistent with the statute. The timing of this rule is interesting because it came on the eve of the oral hearing in Purepac Pharmaceutical Co. v. Friedman.21

Purepac - Round 1

Purepac posed the question "must an ANDA applicant be subject to a patent infringement action in order to obtain a 180-day period of exclusivity?" In short, the answer is no.

Purepac filed an ANDA containing a paragraph IV certification for the drug ticlopidine hydrochloride, which was sold under the brand name Ticlid by Roche Laboratories Inc.22 The First Applicant, however, was TorPharm, Inc., and Roche had not sued TorPharm within the 45-day period provided for under 21 U.S.C. §355(j)(5)(B)(iii). Under 21 U.S.C. §355(j)(5)(B)(iv)(I), Purepac’s application could not have been made effective until at least 180 days after the date the Secretary of the FDA received notice from TorPharm of its first commercial marketing of ticlopidine hydrochloride.

Purepac argued that Mova in essence removed "successful" from the "successful defense" requirement found in the regulation while leaving the "defense" requirement in the regulation. The Court did not find this persuasive in view of the Guidance and more particularly in view of the interim rule that the FDA published just before the oral argument in this case. The Appellate Court viewed the regulation as a mere duplication of the statute.23 Therefore, the Court relied on, the statute/interim rule to make its decision. Purepac was denied a preliminary injunction and its ANDA did not receive final approval until a later date. For reasons unrelated to Purepac’s efforts, this later date for Purepac’s approval came well before the end of the 180-day period following TorPharm’s first commercial marketing of ticlopidine hydrochloride.

Another generic company that filed an ANDA for ticlopidine hydrochloride was Teva. However, Teva took a different approach expediting approval of its ANDA for ticlopidine.

Teva - Round 2

Like Purepac, Teva filed a paragraph IV certification for ticlopidine hydrochloride. And like Purepac, Teva was not sued by Roche. Also like Purepac, Teva received tentative approval pending the expiration of TorPharm’s 180-day exclusivity period.

Section 355(j)(5)(B)(iv)(II) of 21 U.S.C. allows the FDA to approve an ANDA before the end of the 180-day exclusivity period upon "the date of a decision of a court in an action described in clause (iii) holding the patent which is the subject of the certification to be invalid or not infringed." Teva sought a declaratory judgment that Roche’s Orange Book listed patent was not infringed and brought suit against Roche in the Northern District of California.24 The suit was dismissed for lack of Article III subject matter jurisdiction because there was no case or controversy. Roche never threatened Teva with litigation. The District Court found it convincing that Roche had sent a letter to Teva stating that:

we are of the opinion that the formulation used in your ticlopidine hydrochloride tablets does not infringe U.S. Patent No. 4,591,592. We will make no claim of patent infringement based on the sale of ticlopidine hydrochloride tablets having the formula that you disclosed to us.

This letter figured into the next litigation.

Teva brought the dismissal for lack of jurisdiction to the attention of the FDA and maintained that the dismissal was a court decision "holding the patent which is the subject of the certification to be invalid or not infringed" within the meaning of 21 U.S.C. §355(j)(5)(B)(iv)(II). The FDA did not agree with Teva’s interpretation, and Teva sued the FDA.25

Teva V. FDA - Round 3

Teva asked the D.C. District Court to grant a temporary restraining order enjoining the FDA from issuing an approval of TorPharm’s ANDA for ticlopidine hydrochloride if such approval would result in exclusivity beyond February 10, 1999 (180 days after the dismissal of Teva’s action in California). Teva also sought a preliminary injunction against the FDA, precluding the FDA from delaying Teva’s ANDA approval for ticlopidine hydrochloride beyond February 10, 1999. The Court stated that "the real question is whether Teva will be able to demonstrate that the. . . Order dismissing Teva’s declaratory judgment suit for lack of subject matter jurisdiction is ‘a decision of a court. . . holding the patent which is the subject of the certification to be invalid or not infringed’."26 The District Court held that Teva would not be able to show that the FDA’s interpretation is improper. Thus, Teva’s requests for a temporary restraining order and a preliminary injunction were denied.27

Teva appealed the District Court decision.28 At the time Teva filed the appeal, TorPharm still did not have FDA approval for its generic ticlopidine hydrochloride product. The Court of Appeals took a different approach. Specifically, the Court’s position was that since the FDA was regulating directly from the statute on a case-by-case basis, it had no particular interpretation of the statute and could not rely on deference under Chevron U.S.A., Inc. v. Natural Resources Defense Counsel, Inc.29, 30 Thus, it was incumbent on the FDA to distinguish its decisions in cases such as Granutec from that in Teva.31 The D.C. Court of Appeals remanded the case to the District Court for the FDA to provide an explanation of what the Court of Appeals viewed as disparate treatment of the two cases. The District Court found the FDA’s explanation not convincing and that its actions were arbitrary and capricious. In view of this decision, the FDA gave final approval of all tentatively approved ANDAs for ticlopidine hydrochloride.

The next issue clarified by the courts was whether a court decision must be a final judgment from which no appeal can be taken, as maintained by the FDA, or any decision of a court, whether appealable or not.

One reason for the Court of Appeals’ decision to remand rather than hold that the Northern District of California’s dismissal for lack of jurisdiction was a court decision within the meaning of 21 U.S.C. §355(j)(5)(B)(iv)(II), was based on the Court of Appeal’s "conclusion that the California decision has estoppel effect. . . supported by the decisions of the United States Court of Appeals for the Federal Circuit."32 Thus, the "dismissal sufficed to estop Syntex from suing Teva for patent infringement."33 However, the law of the Federal Circuit does not support this conclusion. Estoppel stems from a covenant not to sue, not from a dismissal for lack of jurisdiction.34 Perhaps this division will be a basis for a new area for litigation.

Mylan

On January 4, 2000, the D.C. District Court in Mylan Pharmaceuticals, Inc. v. Shalala,35 held that any "decision of a court" can trigger the start of the 180 day exclusivity afforded the first ANDA applicant to file a paragraph IV certification. This conflicts with the FDA’s earlier interpretation that a "court decision" means "final judgment from which no appeal can be taken."

In Mylan, the innovator company was Abbott and the drug was terazosin hydrochloride, sold as Hytrin in both capsule and tablet form. Geneva Pharmaceuticals, Inc. filed the first ANDA containing a paragraph IV certification to both the capsules and tablets. The Orange Book was amended to list a new Abbott patent and Geneva filed a new paragraph IV certification. Abbott sued Geneva based on the new paragraph IV certification with respect to the tablets "but inexplicably failed to assault Geneva’s capsules certification."36 Accordingly, no patent would have precluded Geneva from marketing the capsules upon FDA approval.

The Northern District of Illinois District Court granted Geneva’s motion for summary judgment, declaring Abbott’s patent invalid (8/28/98).37 Abbott appealed and the Federal Circuit affirmed (7/1/99).38

Meanwhile, Mylan filed its ANDA with a paragraph IV certification. Abbott sued and the Northern District of Illinois District Court entered summary judgment in favor of Mylan based on its earlier decision in favor of Geneva (3/4/99).39 Abbott appealed and the District Court’s decision was summarily affirmed (10/4/99).40

The FDA tentatively awarded Mylan with final approval to be granted on 2/9/00 -- 180 days after Geneva began marketing its product (8/13/99). Mylan sued the FDA in an attempt to force the FDA to approve Mylan’s product 180 days after the 8/28/98 summary judgment in favor of Geneva -- 2/24/99. Specifically, Mylan sought declaratory relief -- "judgment that FDA’s refusal to grant Mylan’s ANDA final approval is based on an erroneous interpretation of the Section 355(j)(5)(B)(iv) of the Hatch-Waxman Amendments" -- and injunctive relief -- an injunction against the FDA further delaying approval of Mylan’s ANDA.41

The Court granted Mylan a declaratory judgment that the FDA erroneously interpreted that law but the Court denied injunctive relief. The denial of injunctive relief was made because:

finding of a statutory violation does not automatically require a court to issue an injunction. . . . Mylan has demonstrated neither that it would suffer irreparable harm if an injunction is not issued nor that the balance of harms favors the issuance of an injunction. . . public interest as defined by Congress in the FDCA does not clearly favor Mylan. . . . [p]reserving Geneva’s hard-earned exclusivity in this case would effectuate the Congressional intent of rewarding first applicants for their efforts. . . . it would be inequitable to punish Geneva for justifiedly relying on the FDA’s erroneous interpretation of the statute.42

Bottom line -- it appears based on the Teva and Mylan cases, that any court decision, appealable or not, can trigger the start of the 180 day exclusivity period afforded the first ANDA filed with a paragraph IV certification.

2. What’s Proposed?

On August 6, 1999, the FDA published a proposed rule that would change its regulations as set forth in 21 C.F.R. §314. The following is based on the Description of the Proposed Rule that was published by the FDA. The ninety (90) day period for submitting written comments to the proposed rule has now expired. A final rule is awaited.

The FDA’s proposed rule would revise 21 C.F.R. §314.07 to clarify and modify eligibility requirements for ANDA applicants seeking 180-day marketing exclusivity for a generic drug product. The FDA’s proposed rule is purported to respond to court decisions that have made obvious the need for new regulations.

While the courts have found portions of the statute clear on its face, the FDA maintains that the statutory language describing which applications are eligible for 180-day generic drug exclusivity is ambiguous and has made the following proposals.

Rolling Exclusivity

A literal reading of the statute seems to permit a 180-day exclusivity period for each ANDA applicant to have filed a paragraph IV certification against all subsequent ANDA applicants, so-called "rolling exclusivity." 21 U.S.C. §355(j)(5)(B)(iv). The current regulation interprets the statute as allowing exclusivity only for the applicant that submits the first substantially complete ANDA with a paragraph IV certification.43 Under the proposed rule, the FDA intends to maintain the current interpretation of no rolling exclusivity.

Substantially Complete Anda

Under the proposed rule, only the applicant submitting the first "substantially complete ANDA" with a paragraph IV certification with respect to any patent in the Orange Book for the listed drug would be eligible for exclusivity. The FDA is concerned that ANDAs would be filed without proper bioequivalence data merely to secure exclusivity.

To be "substantially complete," it is proposed that the application must contain all of the information required under 35 U.S.C. §355(j)(2)(A) and 21 C.F.R. §§314.50 and 314.94. This includes bioequivalence studies, or, if appropriate, a request for a waiver of such studies, and the studies must be filed with the ANDA at the time it is initially submitted and must, upon review by the agency, meet appropriate standards for approval. If a new bioequivalence study is required to obtain approval of the ANDA, the application would be considered not substantially complete and the applicant would not be eligible for exclusivity. Moreover, if the first applicant with a paragraph IV certification were to become ineligible for exclusivity, then no applicant for that drug would be eligible for exclusivity.

Another way to lose exclusivity under the proposed rule would be if the First Applicant withdraws its application or changes or withdraws its paragraph IV certification, either voluntarily, or as a result of a settlement or defeat in patent litigation. If the First Applicant then submits a new paragraph IV certification, and there is another applicant that has submitted a paragraph IV certification for the same drug product ("Subsequent Applicant"), neither the First Applicant nor any Subsequent Applicant would be eligible for 180-day exclusivity. However, if there is no Subsequent Applicant, such First Applicant would still be eligible for exclusivity after submitting its new paragraph IV certification.

The FDA has provided an exception in its proposed rule with respect to loss of exclusivity due to an ANDA being not substantially complete. If the agency accepted for filing a substantially complete ANDA prior to the NDA holder’s submission of a late (untimely) filed patent, the ANDA applicant is not required to certify to this patent. However, if the ANDA applicant amends its ANDA to include a paragraph IV certification to the untimely filed patent, and the ANDA applicant later withdraws that paragraph IV certification, the next applicant to file a paragraph IV certification to the untimely filed patent would be eligible for exclusivity.

Purepac Regulation

The FDA proposes amending 21 C.F.R. §314.107(c)(1) to state that the First Applicant would be eligible for 180 days of market exclusivity, even if the First Applicant is not sued for patent infringement by the patent owner or NDA holder in accordance with the Guidance and Purepac.

Multiple Orange Book Patents

If there are multiple Orange Book patents listed for a given drug, then only the applicant submitting the first paragraph IV certification to any of the listed patents would be eligible for exclusivity. If the first applicant submits paragraph IV certifications to multiple patents, then the first court decision finding one of those patents invalid, not infringed, or unenforceable will trigger the running of applicant’s exclusivity.

Mova And Granutec Regulations

Under the proposed rule, if the First Applicant avoids a lawsuit and the related 30-month stay of final approval (for example, by designing around a patent in such a way that its drug product is clearly non-infringing) then the First Applicant should not be denied eligibility for exclusivity.

Housekeeping Regulations

If the First Applicant is sued and loses the patent litigation, under proposed 21 C.F.R. §314.107(c)(4), such First Applicant would be required to change its certification from paragraph IV to a paragraph III, thus losing any claim to exclusivity eligibility. Generic drug products could enter the market before expiration of the innovator’s patent if a Subsequent Applicant prevails in its patent litigation, settles its patent litigation, or is not sued as a result of a paragraph IV certification.

The FDA proposed that all ANDA applications containing paragraph IV certifications for a particular drug product that are received by the FDA on the same day will be eligible for exclusivity if no other ANDA with a paragraph IV certification for the drug product had been filed on an earlier day. All such same day applicants would be considered First Applicants. The FDA envisions that ANDA same day submissions are most likely to occur when an innovator’s 5-year exclusivity barring FDA acceptance of ANDAs expires, or when ANDA applicants wish to challenge a patent listed for an innovator product with 5 years of exclusivity and submit ANDAs at the end of 4 years of exclusivity.44 In the case where six (6) months of pediatric exclusivity has been granted to the innovator company, the ANDA same day submissions are most likely to occur when an innovator’s 5½-year exclusivity barring FDA acceptance of ANDAs expires, or when ANDA applicants wish to challenge a patent listed for an innovator product with 5½ years of exclusivity and submit ANDAs at the end of 4½ years of exclusivity.

Patent Expiration Regulation

If the patent for which the First Applicant filed a paragraph IV certification expires, then the First Applicant is no longer eligible for exclusivity and the FDA may approve all otherwise eligible ANDAs. This is currently covered by C.F.R. §314.94(A)(12(viii), which states that exclusivity cannot extend beyond the term of the patent.

Delay In Marketing A Generic Product - Triggering Period

The FDA has expressed concern that generic-innovator settlements, and delay in obtaining FDA approval, have resulted in the delay of generic products reaching market. To address these delays, the FDA has evolved a new concept, the "triggering period."

Under the present regulations, the commencement of the 180-day exclusivity period for the First Applicant is either the first commercial marketing of the First Applicant’s product, or a decision of a court holding the patent invalid, not infringed, or unenforceable,45 whichever is earlier. The FDA reverts to the Mova and Purepac decisions, where the court suggested that, to prevent unreasonable delay in the final approval of subsequent generic drug applications, the FDA could require that a First Applicant bring its product to market -- and thus begin the running of exclusivity -- within a prescribed time period. To this end, the FDA proposes setting a time for the exercise of exclusivity, specifically a 180-day "triggering period" during which there must either be a court decision regarding the patent favorable to the First Applicant or the First Applicant must begin commercial marketing of its product. If neither of these events occurs during the triggering period, then the First Applicant would lose its eligibility for exclusivity and subsequent ANDAs would be eligible for immediate approval.

The new "triggering period" is separate and distinct from the 180-day "exclusivity period." In fact, under the proposed rule, the triggering period may occur before, during, or after the exclusivity period.

The term "trigger" in the proposed rule refers to the two statutory conditions, one of which must be met, for exclusivity to begin: (1) a court decision finding the patent to be invalid, unenforceable, or not infringed by the ANDA product; and (2) first commercial marketing of the ANDA product. The term "triggering event" in this proposed rule refers to the occurrence of one of the two statutory triggers.

The triggering period would begin upon the earlier of: (1) tentative approval of a subsequent ANDA with a paragraph IV certification for the same drug product; (2) expiration of a 30-month stay of ANDA approval due to patent litigation; (3) expiration of a preliminary injunction prohibiting marketing of an ANDA product; or (4) expiration of the statutorily described exclusivity periods for the listed drug.46

If, within the 180-day triggering period, the beginning of exclusivity was not triggered, then the First Applicant would no longer be eligible for exclusivity and the agency could approve subsequent ANDAs at the end of the triggering period. Thus, there could be no generic drug product marketed during the triggering period if the First Applicant does not begin commercial marketing of its product.47

The FDA has also proposed shortening the length of the triggering period to 60 days if a First Applicant has already received final approval at the time of the tentative approval of a subsequent ANDA, and either has not been sued as a result of its patent certification, or has been sued and the case was settled or dismissed without a decision on the merits of the patent claim.48

The agency is proposing that if the First Applicant is sued as a result of its paragraph IV certification and the patent litigation is ongoing, then the triggering period would not begin at least until the 30-month period has lapsed. At the end of the 30-month period, the triggering period would begin on the date a subsequent applicant receives tentative approval, or if a subsequent applicant had previously received tentative approval, then on the date the 30-month period expired. During the 180-day triggering period, the First Applicant would have to begin marketing its product, or obtain a final court decision, to obtain its exclusivity.

Decision Of A Court

The FDA has proposed keeping the present regulation definition of a "court decision" as being the decision of the court that enters final judgment from which no appeal can be or has been taken.49 This proposal appears to conflict with the recent decision in Mylan, therefore, a new definition may be required for the regulation. Similarly, the FDA has proposed that a dismissal of a declaratory judgment action would not be a court decision, and would be unnecessary in view of the FDA’s proposed triggering period. This proposal appears to conflict with the decision in Teva and may need to be reworked. Although, it may be more acceptable if the triggering period is enacted and upheld by the courts.

Settlement Agreements

Under the current statutes and regulations, settlement agreements are not addressed.50 For example, the 180-day exclusivity period may never run if the First Applicant enters into an agreement with an innovator company not to market its product.51 Therefore, an agreement between the innovator company and the generic company could maintain one product on the market until the expiration of an otherwise unenforceable patent. The triggering period approach would preclude any delay beyond 180 days after the second ANDA applicant for the drug received tentative approval. If the 180-day triggering period were enacted, Section 314.107(c)(3) of 21 C.F.R., which requires an ANDA applicant to actively pursue ANDA approval or risk immediate approval of a subsequent ANDA, would be rendered superfluous and deleted.

Dismissal Of Litigation

Newly proposed regulation 21 C.F.R. §314.07(g) would cause the 30-month stay of ANDA approval period to end if the underlying litigation is dismissed, with or without prejudice. In the case of a settlement or licensing agreement between an innovator and a generic company, this amendment would allow subsequent ANDAs to be approved as of the time the litigation was terminated.

Waiver Of Exclusivity

The current regulations do not address whether a First Applicant can waive its 180-day exclusivity period to permit approval of a subsequent applicant.52 Under proposed regulation 21 C.F.R. §314.107(e), the First Applicant that has obtained 180 days of exclusivity by commercial marketing or a court decision of non-infringement, invalidity or unenforceability53 can waive exclusivity in favor of one or more subsequent applicants. Before the exclusivity period begins to run, only the First Applicant is eligible for exclusivity. At that time, the First Applicant may only waive its eligibility for exclusivity in favor of all subsequent applicants but not a specific applicant(s).

Multiple Strengths

The FDA has been allowing each strength of a drug product to be independently eligible for a separate exclusivity period. The FDA will continue with this interpretation.

3. What’s In Store?

It appears that the FDA’s proposed regulations may still require some modification to address the issues raised by the recent rulings in Teva and Mylan. In view of the litigious background underlying the proposed regulations, once issued, the new regulations will likely face challenges, particularly based on the newly conceived triggering periods.

Endnotes:

1 21 U.S.C. §355(b)(1).

2 21 U.S.C. §355(j)(5)(B)(iv).

3 35 U.S.C. §271(e)(2).

4 21 U.S.C. §355(j)(2)(B)(i).

5 21 U.S.C. §355(j)(2)(B)(iii).

6 21 U.S.C. §355(j)(2)(A)(vii).

7 21 U.S.C. §355(j)(5)(B)(iii).

8 Under this section if a court finds that there is patent infringement, then the court shall order the effective date of approval of the drug or veterinary biological product involved in the infringement to be a date not earlier than the date of expiration of the patent which has been infringed.

9 21 U.S.C. §355(j)(5)(B)(iii).

10 21 U.S.C. §314.107(c)(1).

11 12 USPQ2d 1065 (D.D.C. 1989), vacated as moot, 43 F.3d 712 (D.C. Cir. 1989).

12 The first ANDA applicant to file a paragraph IV certification will be referred as the "First Applicant."

13 Throughout this paper, the current section numbers have been used. Before the Food & Drug Administration Modernization Act of 1997 was enacted, the 180-day exclusivity period was described in §505(j)(4)(B)(iv) of the Hatch-Waxman Amendment. As a result of the Modernization Act, new provisions resulted in the sections being renumbered.

14 46 USPQ2d 1385 (D.C. Cir. 1998).

15 46 USPQ2d 1398 (4th Cir. 1998).

16 See Mova Pharmaceutical Corp. v. Shalala, 41 USPQ2d 2012 (D.D.C. 1997).

17 41 USPQ2d at 2014. The decision cites the earlier decision in Inwood Laboratories, Inc. v. Young, 12 USPQ2d (D.D.C. 1989), vacated as moot, 43 F.3d 712 (D.C. Cir. 1989).

18 Novopharm Ltd., Granutec’s parent company, had entered into a licensing agreement with Glaxo Wellcome, Inc. whereby Glaxo would make a substantial monetary payment to Granutec and Granutec would delay entry into the market 15 days before the expiration of Glaxo’s patent. While this raised interesting antitrust issues, such issues will not be discussed in this paper.

19 Ranitidine exists in two forms that the FDA considers equivalent, Form 1 and Form 2, which are covered by different patents, specifically U.S. Patent Nos. 4,128,658 and 4,521,431, respectively. Genpharm filed a paragraph IV certification with respect to Form 2 ranitidine. Glaxo, Inc., the innovator company, brought an action for patent infringement within the 45-day period provided for by statute and prevailed. Glaxo, Inc. v. Genpharm Pharmaceuticals, Inc., C.A. Nos. K-92-1831 and K-93-422 (d. Md. Oct. 23, 1995). Genpharm filed a subsequent paragraph IV certification with respect to Form 1 ranitidine and Glaxo brought a second action for patent infringement within the 45-day period provided for by statute. At the time of Granutec, this second action was pending.

20 63 FR 59710.

21 49 USPQ2d 1365 (D.C. Cir. 1998).

22 The Ticlid NDA was owned by the parent company of Roche Laboratories, Hoffmann-La Roche Inc. and the Orange Book listed patents were owned by a related company, Syntex (U.S.A.) Inc. For convenience, all of these companies will be referred to as Roche.

23 49 USPQ2d at 1369.

24 Teva Pharmaceuticals USA, Inc. v. Syntex (U.S.A.), Inc., Civil Action No. 98-02314 CAL.

25 Teva Pharmaceuticals USA, Inc. v. FDA, 1999 U.S. Dist. LEXIS 14531 (D.D.C. 1999).

26 Id. at *16.

27 The District Court in Teva did note "the possibility that the patent holder might attempt to avoid the court-decision trigger by disclaiming any intention of bringing suit, thereby rendering a district court without jurisdiction to hear a declaratory judgment action for patent infringement." While this equitable concern mattered to the Court, it did not dissuade the Court from applying legal principles.

28 Teva Pharmaceuticals, USA, Inc. v. FDA, 51 USPQ2d 1432 (D.C. Cir. 1999).

29 467 U.S. 837, 842-44 (1984).

30 Chevron sets up two questions - (1) has Congress directly spoken to the precise question at issue? and (2) if Congress has not precisely addressed the question at issue, was the agency’s answer based on a permissible construction of the statute? If the answer to question 1 is yes, then the agency and the courts must give effect to the unambiguous express intent of Congress. However, if the statute is silent or ambiguous with respect to a specific issue, then there is an express delegation of authority to the agency to elucidate a specific provision of the statute by regulation. Such legislative regulations are given controlling weight unless they are arbitrary, capricious, or manifestly contrary to the statute.

31 Granutec involved a partial summary judgment based in part on an admission, whereas Teva involved a dismissal for lack of jurisdiction based in part on a letter acknowledging non-infringement. The Appellate Court’s position was that both cases involved an admission, the only difference being the mode with which the court disposed of the case.

32 51 USPQ2d at 1436.

33 51 USPQ2d at 1437.

34 See Amana Refrigeration Inc. v. Quadlux Inc., 50 USPQ2d 1304, 1306 (Fed. Cir. 1999).

35 53 USPQ2d 149 (D.D.C. 2000).

36 53 USPQ2d at 1452.

37 Abbott Labs. v. Geneva Pharmaceuticals, Inc., 51 USPQ2d 1301 (N.D. Ill.).

38 Abbott Labs. v. Geneva Pharmaceuticals, Inc., 182 F.3d 1315, 51 USPQ2d 1307 (Fed. Cir. 1999).

39 Abbott Labs. v. Mylan Pharmaceuticals, Inc., 37 F. Supp. 2d 1076 (N.D. Ill. 1999).

40 Abbott Labs. v. Mylan Pharmaceuticals, Inc., 1999 U.S. App. LEXIS 28057 (Fed. Cir. 1999).

41 Mylan Pharmaceuticals, Inc. v. Shalala, 53 USPQ2d 1449 (D.D.C. 2000).

42 53 USPQ2d at 1463.

43 21 C.F.R. §314.07(c).

44 See 21 U.S.C. §355(j)(5)(D)(ii).

45 The statute, 21 U.S.C. §355(j)(5)(B)(iii)(I), refers to a court decision that the patent is invalid or not infringed. In contrast, the present regulation, 21 C.F.R. §314.107(b)(3)(B)(ii), refers to a final order that the patent is invalid, unenforceable, or not infringed.

46 See 21 U.S.C. §355(j)(5)(D)(ii) and 21 U.S.C. §505A(a).

47 The FDA states that the 180-day length of the triggering period is derived from the statutory provision governing 180 days of exclusivity and that this provision quite clearly allows (and Congress, therefore, presumably contemplated) the possibility of a 180-day period during which there is no generic drug product on the market.

48 The FDA states that the possible 60-day triggering period in this case is based upon limited data from a July 1998 Congressional Budge Office study entitled "How Increased Competition from Generic Drugs Has Affected Prices and Returns in the Pharmaceutical Industry," and a March 1999 internal FDA study (available in Docket 85N-0214). However, these studies are well after the 1984 Hatch-Waxman Amendments date and this 60-day period appears to stretch Congress’ intent.

49 21 C.F.R. §314.07(e).

50 Settlement and licensing agreements have been under investigation by the Federal Trade Commission with regard to antitrust issues. Such antitrust issues are not addressed in this paper.

51 In connection with Cardizem CD, Hoechst, the innovator company, paid to Andryx, the generic company, $40 million dollars per year not to sell its FDA-approved generic version of Cardizem CD until the parties ended their litigation. Other generic companies had received tentative approval but could not enter the market until the expiration of the exclusivity period or expiration of the patents.

52 The FDA notes that in Boehringer Ingelheim Corp. v. Shalala, 993 F. Supp. 1 (D.D.C. 1997) the court did not sustain a challenge to a waiver. In that case, Genpharm waived its exclusivity in favor of Granutec with respect to ranitidine hydrochloride. The court ruled that there is nothing to indicate that Congress even thought about waivers. Accordingly, the FDA was entitled to administrative deference in view of Chevron.

53 21 U.S.C. §355(j)(5)(B)(iv)(I) or (II).

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