sive patent licensee, rather than any “.documented agreement,” and clarifies that a copy of any order entered by the court terminating the 30-month or 7-1/2.-y ear period includes an order described in § 314.107(b)(3)(vii) and (vii) (see section V.M.5).Provides that all information required by § 314 107(e)(1) must be sent to the applicant's NDA or ANDA rather than to OGD or the appropriate division in OND (see section V 3.1.5).21 C.F.R. § 314.108 New drug product exclusivity(§ 314.108)No substantive changes from the proposed rule.21 C.F.R. § 314.125 Refusal to approve an NDA (§ 314.125)Clarifies that FDA may refuse to approve a 505(6)(2) application if it does not contain a patent certification or statement pith respect to each listed patent for a drug product approved in an NDA that is pharmaceutically equivalent to the drug product for which the original 505(b)(2) application is submitted and that was approved before the original 505(b)(2) application was submitted (see section V.H).21 C.F.R. § 314.127 Refusal to approve an ANDA (§ 314.127)No substantive changes from the proposed rule (see section V.L.).21 C.F.R. § 320.1 Definitions (§ 320.1)No substantive changes from the proposed rule (see section V.A).21 C.F.R. § 320.23Basis for measuring in vivo bioavailability or demonstrating bioequivalence (§ 320.23)No substantive changes from the proposed rule (see section V.N).

Excipients not identified in these regulations are referred to as “non-exception excipients.” FDA’s exception excipient regulations at 21 C.F.R. § 314.94(a)(9) find their parallel in 21 C.F.R. § 314.127(a)(8)(ii), which addresses the grounds for an FDA refusal to approve an ANDA for a parenteral, ophthalmic, or otic drug product. For example, 21 C.F.R. § 314.127(a)(8)(ii)(B) states: “FDA will consider an inactive ingredient in, or the composition of, a drug product intended for parenteral use to be unsafe and will refuse to approve the [ANDA] unless it contains the same inactive ingredients, other than preservatives, buffers, and antioxidants, in the same concentration as the listed drug. . .” (emphasis added).

The FDA’s regulations are similar, mandating rejection of an abbreviated new drug application (what an application for generic approval is called) if the ANDA “is insufficient to show that the active ingredient is the same as that of the reference listed drug. 21 C.F.R. §314.127(a)(3)(i); see 21 C.F.R. §314.127(a)(3)(ii) (identical language for products with multiple active ingredients) There’s that word again – “same.”

According to ISTA, the company’s petition “stressed that a sponsor of an ANDA must include in the application a copy of the reference listed drug’s ‘currently approved labeling,’” pursuant to 21 C.F.R. § 314.94(a)(8)(i), and that “[b]ecause of the labeling change, ‘the currently approved labeling’ for ISTA’s bromfenac ophthalmic solution product is for once-per-day dosing.” Furthermore, ISTA’s petition “argued that FDA cannot permit an ANDA to omit the once-per-day dosing instructions, because it would have the effect of rendering the drug less safe,” pursuant to 21 C.F.R. § 314.127(a)(11) and § 314.161(a). FDA promptly denied ISTA’s petition, saying that “(1) we consider Xibrom and Bromday two separate drug products rather than one product with old and new labeling, (2) we do not think the Bromday dosing regimen is less safe than the Xibrom dosing regimen, and (3) we did not require Xibrom to be withdrawn as a condition of the Bromday approval,” and the lawsuit ensued.

Excipients not identified in these regulations are referred to as “non-exception excipients.” These regulations find their parallel in 21 C.F.R. § 314.127(a)(8)(ii), which addresses the grounds for an FDA refusal to approve an ANDA for a parenteral, ophthalmic, or otic drug product. For example, 21 C.F.R. § 314.127(a)(8)(ii)(B) states: “FDA will consider an inactive ingredient in, or the composition of, a drug product intended for parenteral use to be unsafe and will refuse to approve the [ANDA] unless it contains the same inactive ingredients, other than preservatives, buffers, and antioxidants, in the same concentration as the listed drug. . . .”Notwithstanding FDA’s exception excipient regulations, the Agency has, on occasion, but only in very limited circumstances, waived its exception excipient regulations to permit the receipt and approval of an ANDA for a drug product containing a non-exception excipient change from the RLD.

. . omission of an indication or other aspect of labeling protected by patent or accorded exclusivity under [FDC Act § 505(j)(5)(D)].However, FDA’s regulations at 21 C.F.R. § 314.127(a)(7) further provide that to approve an ANDA that omits an aspect of labeling protected by patent or exclusivity, FDA must find that the “differences do not render the proposed drug product less safe or effective than the listed drug for all remaining, non-protected conditions of use.”In Bristol-Myers Squibb Co., v. Shalala, 91 F.3d 1493 (D.C. Cir. 1996), the U.S. Court of Appeals for the District of Columbia Circuit held that FDA may approve an ANDA for a generic drug even though the labeling of the generic product does not include one or more indications that appear in the labeling of the RLD upon which the ANDA is based.

Circuit’s decision leaves the validity of Teva’s estoppel defense in flux. Until this question is affirmatively answered, RLD sponsors’ assertions to FDA when listing patents in the Orange Book must be made carefully to avoid a potential equitable estoppel defense to an induced infringement action. Patents, especially method of use patents, must be carefully described in use codes when listing patents in the Orange Book via FDA Form 3542, and sponsors must claim each section of the labeling that contains protected information. These forms and assertions must also be kept current, particularly following subsequent approvals and labeling revisions.We will continue to monitor new cases that may arise related to pharmaceutical labeling carve-out regulations, and keep you informed of any legal updates. 21 CFR 314.94(a)(8)(iv). FDCA Sec. 505(j)(2)(A)(viii); 21 CFR 314.94(a)(12)(iii). There is a similar provision for 505(b)(2) applicants. See FDCA Sec. 505(b)(2)(B); 21 CFR 314.50(i)(1)(iii). 21 CFR 314.127(a)(7).[View source.]

s approved for multiple indications, thereby avoiding any relevant method-of-use patent listed in the Orange Book. 21 U.S.C. § 355(j)(2)(A)(viii). Mechanically, the FDA assigns “use codes” for approved indications that correspond to Orange Book-listed patents methods of use, and those use codes also appear in the Orange Book; skinny labels remove that indication and therefore that use code for the generic.Typically, the ANDA applicant must propose a label that is identical to the brand’s except that the skinny label provisions allow a generic applicant to “carve out” indications that correspond to still-patented methods of use. See Caraco Pharm. Labs., Ltd. v. Novo Nordisk, A/S, 566 U.S. 399, 406 (2012); see also 21 C.F.R. 314.94(a)(8)(iv) and (12)(iii)(A). The FDA has the authority to approve a generic using a skinny label if the proposed omissions “do not render the proposed drug product less safe or effective than the listed drug for all remaining, non-protected conditions of use.” 21 C.F.R. 314.127(a)(7).The Long and Fraught History Behind this CaseIn 1995, the FDA approved GSK’s Coreg® for three separate indications: (1) “treatment of mild to severe heart failure of ischemic or cardiomyopathic origin, usually in addition to diuretics, ACE inhibitor, and digitalis, to increase survival”; (2) “reduc[ing] cardiovascular mortality in clinically stable patients who have survived the acute phase of a myocardial infarction and have a left ventricular ejection fraction of ≤40% (with or without symptomatic heart failure)”; and (3) “management of essential hypertension.”Teva submitted its ANDA for generic carvedilol in 2002. At the time the Orange Book listed two relevant GSK patents - one claiming the carvedilol compound and one, the ’069 patent, claiming a method of using carvedilol to treat congestive heart failure. Teva certified it would not market its generic until 2007 when the carvedilol compound patent expired, a paragraph III certification, and provided a paragraph IV certification a

The statute permits ANDA filers to “carve out” patented indications on the label of a proposed product (i.e., a “skinny label”), which the FDA will allow if the carved out indication “do[es] not render the proposed drug product less safe or effective than the listed drug for all remaining, nonprotected conditions of use.” 21 C.F.R. § 314.127(a)(7).After a jury returned a verdict for GSK, finding that, inter alia, Teva induced infringement of GSK’s patent by marketing a generic version of GSK’s Coreg® drug with a skinny label, the district judge granted Teva’s JMOL motion on inducement. The Federal Circuit reversed in a first decision in October 2020, finding the jury’s verdict was supported by the evidence of record.Subsequently, the panel granted panel rehearing, where it reached the same conclusion: Teva induced infringement of the asserted patent.

Use in an intensive care setting is not expressly disclosed in any proposed ANDA labeling. Hospira’s reliance on a single sentence about a different type of “overlap” at issue in Caraco does not control the outcome here.From there it was relatively easy for FDA to conclude that “permitting ANDA sponsors to omit information from the labeling related to use for ICU sedation does not render the product less safe or effective for the remaining use of sedation of non-intubated patients prior to and/or during surgical and other procedures,” which is a finding that must be made in labeling carve-out cases pursuant to 21 C.F.R. § 314.127(a)(7).Whether FDA’s side-stepping of several of the issues the Agency initially raised last January was a deliberate attempt to avoid having to address those thorny issues, or the result of an epiphany that this is, to the Agency at least, a “straight 8 case” is unclear.