What is patent linkage?
Abbreviated NDAs
Orange Book for small molecule drugs
Purple Book for biologics
Disclosures to branded company and opportunity to sue
ANDA first-to-file 180-day exclusivity period
Challenging patents using USPTO IPR proceedings
Patent term of Orange Book Patents

The concept of patent linkage is a contentious issue in the healthcare industry as it concerns the involvement of drug authorities with patent infringement considerations. This article explores how the patent linkage doctrine works in the United States.

What is patent linkage?

"Patent linkage" is generally understood to be the practice of linking the granting of marketing approval or any other regulatory approval for a generic or biosimilar medicinal product to the status of a patent for the originator reference product. Consequently, if there is a valid patent covering the drug that is the subject of a new drug approval, the drug authority may:

  • refuse the application;
  • refuse to grant a marketing authorisation until the patent expiration;
  • inform the patent owner to enable it to take any relevant action; or
  • refuse to grant the application, depending on the length of the remaining term of the patent.

The argument to support patent linkage is based on upholding the IP rights, by ensuring that drugs are not approved if they infringe a third-party patent. However, advocates against patent linkage often argue that it is not conducive to a competitive market as it extends the period of market exclusivity enjoyed by originator companies, preventing or delaying entry of generic medicines and biosimilars into the market.

The United States is one of the key jurisdictions adopting patent linkage. As well as adopting the concept itself, the United States also seeks to include obligations for other countries to adopt patent linkage as part of trade agreement negotiations.

Abbreviated NDAs

The process of marketing of generic drugs was statutorily enacted in the United States as part of the Drug Price Competition and Patent Term Restoration Act 1984 (as amended) (commonly called the "Hatch-Waxman Amendments"). The system of generic approval provided by this statute is similar to legislation enacted in Canada and Europe and has largely been harmonised internationally. Prior to the Hatch-Waxman Amendments, an original generic application, called a "paper" new drug application (NDA), had approval parameters that were subjectively determined by the US Food and Drug Administration (FDA) on a product­by-product basis and the efficacy and safety were based on the review of publicly available information. Further, there were no provisions for data exclusivity nor, in particular, bars to product approval based on a patent filed with the FDA.(1) As a result of the enactment of the Hatch-Waxman Amendments, an additional "abbreviated" process for approval of competitive generics after expiry of the originator product's patent and data exclusivity was created.

To give an idea of the scope of "abbreviation", a typical full NDA is composed of:

  • two adequate and well­controlled clinical trials;
  • formal statistical planning and analysis;
  • human dose-ranging, pharmacokinetic and pharmacodynamic studies;
  • absorption, distribution, metabolism and excretion studies;
  • non-clinical safety pharmacology, pharmacology, pharmacokinetic, pharmacodynamic, genotoxicity, fertility and toxicology studies; and
  • a full description of the chemistry, manufacturing and controls (CMC).

Additional clinical safety or efficacy studies that develop information on drug-drug interactions, human safety pharmacology (QT prolongation) and special populations may also be required.

In contrast, an abbreviated NDA (ANDA) is composed only of:

  • a pharmacokinetic comparison of the generic to the innovator/branded drug product or other FDA-designated reference drug that demonstrates bioequivalence;
  • a copy of the innovator labelling revised to reflect changes in manufacturer and contact information; and
  • the CMC section.

Said differently, an ANDA application is not required to repeat preclinical and clinical safety and efficacy research so long as it can be demonstrated that the generic product performs in the same manner as the innovator drug (ie, that the generic product is bioequivalent to the innovator drug). The innovator/branded drug is listed in the FDA's Approved Drug Products with Therapeutic Equivalence Evaluations publication (known as the "Orange Book") and is known as the "reference listed drug" (RLD).

Occasionally, especially with older drugs, the innovator may withdraw from the market, thereby effectively eliminating an RLD for new generics to reference in their ANDA submission. In that event, the FDA may designate another drug – typically one of the earlier generic drugs – as the reference standard (RS) so that additional generics may enter the market and use the RS in place of the RLD. New generics may then enter on comparison to that RS.

To support the successful development of generic drug products, the FDA issues product-specific guidance for generic drug development. This guidance helps generic drug applicants understand the data the FDA recommends providing within the ANDA to establish bioequivalence for pharmaceutically equivalent drug products

In the United States, the current average review time from submission to final approval for ANDAs is approximately 39 months (29 months to tentative approval).(2) The recently enacted Generic Drug User Fee Act and its successor, the FDA User Fee Reauthorization Act 2017, provide for fee revenue to increase the Office of Generic Drug's resources. The FDA has committed to assessing and acting on ANDAs within 10 months (or eight months for priority track) of submission.

Orange Book for small molecule drugs

Orange Book patent listing
By law, to take advantage of a bar to FDA approval of an ANDA during the patent term, an NDA holder must list each patent that claims the drug or a method of using the drug that is the subject of the NDA (or amendment or supplement to it) and with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use or sale of the drug product.

FDA regulations further provide that, when filing an NDA, the applicant should include:

patent[s] that claim the drug or a method of using the drug . . . [which] consist of drug substance (active ingredient) patents, drug product (formulation and composition) patents, and method-of-use patents.

The applicant should exclude "[p]rocess patents [and] patents claiming packaging" under 21 Code of Federal Regulations section 314.53(b)(l).

The statute also separately provides for periods of data exclusivity – for example, new chemical entity exclusivity – which may expire before or after the Orange Book patents. The period of data exclusivity is largely impervious to third-party legal challenges.(3)

Challenging patents listed in Orange Book
For an ANDA to be accepted for review, the ANDA applicant must certify against each of the patents then-listed in the Orange Book. If the ANDA applicant intends to launch its generic product before an Orange Book patent has expired, it must certify to the FDA and notify the patentee and NDA holder, that the patent is invalid, unenforceable and/or that the ANDA product does not infringe any valid and enforceable claim. Under the statute, the patent holder is then authorised to seek a judgment of infringement. Generally, if the patent holder files a complaint within 45 days of receiving the notice, a 30-month stay of regulatory approval is automatically applied, although FDA review may progress and tentative approval may be obtained.

Another avenue to challenge a patent involves requesting that the FDA ask an NDA holder to confirm the patent information in the Orange Book. When patent information is submitted to the FDA for publication in the Orange Book, the NDA applicant attests to the accuracy of the information. The FDA does not evaluate the accuracy of any information related to the patent listing. A challenger may write to ask that that the FDA request the NDA holder to confirm the information listed in the Orange Book. However, the FDA is unable to force delisting of the patent.(4)

An improper listing was recently successfully challenged in the First Circuit as outside the scope of authorisation for listing and improper conduct that could serve as the basis of an antitrust violation of section 2 of the Sherman Act. Here, the patent claimed a part of the device used to administer the drug. The First Circuit found that this was too tenuous a connection and that Sanofi had improperly listed patent claims that "do not mention the drug for which the sNDA was submitted" and therefore it could not have claimed "the drug".(5)

Another potential avenue for challenging Orange Book listings involves a counterclaim in response to a patent infringement suit filed by the patent holder as part of a declaratory judgment following the certification of non-infringement notice. In one such case, a generic applicant filed a counterclaim seeking to delist a patent on the basis that the patent did not claim or disclose either the drug substance, drug product or method of use. The case was dismissed pursuant to a settlement agreement before the court ruled substantively. In 2012, the US Supreme Court permitted a generic drug manufacturer to assert a counterclaim alleging an improper use code listed in the Orange Book, in response to allegations that the generic manufacturer's product infringed method-of-use claim.(6)

Since these rulings, the Orange Book Transparency Act 2020 was passed, which requires the FDA to list and publish drug patent and exclusivity information. The FDA has created an internal working group to improve the transparency of the Orange Book.

Purple Book for biologics

The Purple Book for biologics lists licensed biologics and their approved corresponding licensed biosimilars. In particular, the Purple Book enables users to see whether biologics licensed under section 35l(k) of the Public Health Service Act (the PHS Act) have been determined to be biosimilar to or interchangeable with a brand-name product (also known as a "reference biological product"). Additionally, the Purple Book provides information on existing reference biological product exclusivity. Although the Purple Book includes exclusivity information, it does not include an expiration date for all biologics, and the lack of an expiration date does not mean a product is not eligible for statutory exclusivity. Moreover, the Purple Book does not list patents for biologics or include manufacture or process patents. In contrast to the Orange Book and the statutory requirements under the Hatch-Waxman Amendments, the PHS Act does not prohibit the FDA from receipt, review or approval of a biologic application that relies on a reference biologic product with unexpired patent listings in the Purple Book.

Disclosures to branded company and opportunity to sue

An ANDA applicant seeking FDA approval of a generic RLD must make certain disclosures related to patents for the RLD. If an ANDA applicant seeks approval before a patent has expired on the basis that the patent is invalid, unenforceable or not infringed, the applicant must submit a paragraph IV certification to the FDA. When doing so, the applicant must also provide the NDA holder and the patent holder(s) notice of the paragraph IV certification. The notice must describe the factual and legal basis for the ANDA applicant's claim that the patent is invalid, unenforceable or not infringed.

The patent owner then has an opportunity to sue the ANDA applicant for patent infringement. As noted previously, if the patent holder initiates a patent infringement lawsuit against the ANDA applicant within 45 days of receiving notice, ANDA final approval will be stayed for 30 months from the later of when the NDA holder or patent owner(s) receives the paragraph IV certification, unless the NDA has new chemical entity exclusivity. In this case, ANDA final approval will be extended to seven-and-a-half years from the date of NDA approval.(7)

ANDA first-to-file 180-day exclusivity period

The first ANDA applicant to file a paragraph IV certification is awarded exclusivity vis-a-vis other ANDA applicants for a 180-day exclusivity period. This exclusivity period is given to the first ANDA applicant in exchange for the ANDA applicant risking exposure to patent litigation by filing a paragraph IV certification and giving the requisite notice to the NDA holder and patent owner(s). An ANDA applicant does not need to win a patent infringement suit to retain eligibility for the 180-day exclusivity period.(8)

Challenging patents using USPTO IPR proceedings

An inter partes review (IPR) is a type of post-grant proceeding before the Patent Trial and Appeal Board (PTAB) that allows parties to challenge claims in a patent based on prior art and printed publications. Introduced in 2012 under the America Invents Act, IPRs are now the most utilised mechanism for challenging patents in post­grant proceedings at the PTAB. Adjudicated by a three-administrative judge panel of the PTAB, IPRs have a resolution deadline of just 18 months, requiring careful preparation by the challenger and swift responses from the patent owner.

According to statistics provided by the US Patent and Trademark Office (USPTO), the institution rate of IPRs has been decreasing from year to year. The rate was historically higher than 60%, most recently in 2019, and has now fallen to about 57% in 2021. However, drug patents continue to have a high institution rate. As of June 2021, in IPRs involving Orange Book patents, 62% were instituted, only 15% resulted in final written decisions finding all instituted claims invalid.

This means that a well-drafted petition will more likely than not result in an institution of at least one ground asserted in the petition. Importantly, of the instituted petitions that resulted in final written decisions, 50% of the final written decisions found at least one instituted claim to be invalid, while 44% found all of the instituted claims to be invalid. This means that if a petition is instituted, at least one asserted claim will more likely than not be invalidated, if not all of the asserted claims. Therefore, an institution will put a heavy burden on the patent owner as to whether a district court case should proceed to trial.

Patent term of Orange Book Patents

For patents granted by the USPTO after 8 June 1995, in general, there is a 20-year patent life term from the date of the first effective patent application filing. Having said this, the practical term of protection of the marketed product is often less than 20 years because patents are often granted well before a product's actual commercial marketing.

Many factors affect the effective patent term length, including the pre-market approval requirements applied to certain products regulated under the Federal Food, Drug and Cosmetic Act (FD&C Act). Frequently, these products must undergo extensive testing in humans (and possibly animals) to demonstrate their safety and efficacy to the FDA before the agency will approve the product for commercial marketing.

As a result, to promote product development and innovation, in 1984, Congress chose to enact legislation affording the opportunity to extend patent terms under certain circumstances to compensate patent holders for patent time lost while developing a product and awaiting FDA premarket approval. The legislation allows these patent holders to gain back some of the lost patent time.(9)

While there is much focus given to patent term restoration issues for pharmaceuticals, often little attention is given to medical devices in this regard. However, a subset of medical devices, class Ill devices subject to pre-market approval under section 515 of the FD&C Act can qualify for patent term restoration based on the development and pre-approval process requirements established by the FDA for them.

In the relevant part, under the patent term extension statute at 35 US Code section 156, the owner of record of a patent (or its agent) must submit to the PTO an extension request within the 60-day period beginning on the date the class Ill medical device received approval for commercial marketing. For the purposes of an extension request for a class Ill device subject to pre-market approval, the "regulatory review period" that can be recouped is defined as the sum of the following:

  • the period beginning on the date a clinical investigation on humans involving the device was begun and ending on the date a premarket approval application was initially submitted with respect to the device to the FDA; or
  • the period beginning on the date the application was initially submitted with respect to the device to the FDA and ending on the date such application was approved by the FDA.

For further information on this topic please contact Khelin N Aiken, Ellen Y Cheong or Genevieve Razick at Baker McKenzie by telephone (+1 202 452 7000​) or email ([email protected], [email protected] or [email protected]). The Baker McKenzie website can be accessed at www.bakermckenzie.com.


(1) Notably, the "paper" NDA still exists under section 505(b)(2)

(2) See "Activities Report of the Generic Drugs Program | GDUFA II Quarterly Performance".

(3) However, it is possible to file a citizen's petitions with the FDA, requesting the FDA to take action.

(4) 21 Code of Federal Regulations section 314.53(f).

(5) In re Lantus Direct Purchaser Antitrust Litig, 950 F3d 1, 8 (1st Cir 2020).

(6) Caraco Pharmaceutical Laboratories, Ltd v Novo Nordisk A/S, 566 US 399 (2012).

(7) 21 USCA section 355(j)(5)(F)(ii).

(8) See Mova Pharms Corp v Shalala, 140 F3d 1060 (DC Cir 1998).

(9) See Title II of the Drug Price Competition and Patent Term Restoration Act (Public Law 98-417).