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Patent linkage in the United States

July 11, 2023

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This article has been written by Mahesh P Sudhakaran. This article gives a brief overview of key aspects pertaining to patent linkage in the US, covering legal as well as historical aspects of the same.

It has been published by Rachit Garg.

Table of Contents

Introduction

The concept of patent linkage in the United States can be perceived as a system that interlinks the approval of generic drugs(similar drugs/similar in contents and purpose) to the patent status of the original drug that is branded. In easier terms, it means that before a generic drug can be approved for sale by the authorities, it needs to address and cross-check with any existing patents held by the original drug.

However, this system potentially creates a conflict between two important forms of rights which are human rights and intellectual property rights. Intellectual property rights aim to provide incentives to pharmaceutical companies to encourage them to invest in the research and development of new drugs. On the contrary, human rights, such as the right to health prioritize ensuring affordable access to essential medicines for all. A strict application or enforcement of the patent linkage system may cause considerable delays in the availability of cheaper generic drugs. Finding the right balance between protecting intellectual property rights and promoting public health is a complex task. It requires careful consideration from governments, policymakers, and stakeholders to ensure that the patent linkage system does not unduly restrict access to affordable healthcare, especially for vulnerable populations. In the following sections, we will discuss the patent linkage system in the United States which includes discussing its main features, potential benefits, challenges, and the ongoing debates surrounding its impact on human rights and intellectual property rights.

The United States today has the most prominent patent linkage system creating a premise for this debate while also extending its dimensions. With the rampant growth of the global pharmaceutical industry, the need for protection of intellectual property has also grown exponentially. In the past couple of years, the Trade Related Aspects of Intellectual Property Rights (TRIPS) have played a pivotal role when it comes to this debate with regard to Patent Linkage. The TRIPS agreement mandates member countries to establish minimum standards for protecting patents. This perspective of the extensive protection of IP has led to a significant delay in the approval of generic drugs which is in a way the need of the hour. We shall critically examine the patent linkage system in the U.S taking into account the entire process and the laws regarding the same.

Meaning of Patent Linkage

Patent linkage is the system of linking the marketing approval or regulatory approval of generic drugs with the patent status of the original drug. This means that a generic drug cannot be marketed until the patent on the original drug has expired, or until the generic drug manufacturer has obtained a license from the patent holder. This system is adopted to incentivize pharmaceutical innovation and to avoid early patent disputes and infringement claims prior to the marketing of the actual drug. It involves communication carried out between the patent office and regulatory authorities who are entrusted by law with the marketing approval of drugs. Countries that have adopted this system regulatory authorities are mandated to ascertain whether a generic drug infringes an existing patent held by a manufacturer before granting marketing approval to such a drug. This system is said to play a pivotal role in upholding the very essence of intellectual property protection.

History of Patent Linkage in the US

Evolution of patent linkage

The Hatch-Waxman Act was enacted in 1984. This was a response to policymakers’ dissatisfaction with the regulation of prescription drugs. The form of regulation that existed earlier hindered the ability of generic manufacturers to market low-cost copies of brand-name drugs. The Act was a combination of two separate pieces of legislation aimed at bolstering both the brand-name and generic drug industries while maintaining incentives for innovation. Before this Act was enacted, the primary and only federal legislation that governed the pharmaceutical market was the 1962 Kefauver-Harris Amendments to the Food, Drug, and Cosmetic Act (FDCA). These amendments empowered the FDA to mandate the pharmaceutical manufacturers to establish or demonstrate the safety and effectiveness of their respective drugs through pre-approval clinical trials before they could be sold. Clinical trials that were conducted had three phases which were Phase 1, Phase 2, and Phase 3. These phases were concerned with providing data on dosage range, efficacy, and safety.

The Kefauver-Harris Amendments mandated the submission of a New Drug Application (NDA) as the final step for FDA approval. It also included reports of clinical trials and other relevant data. However, the costs pertaining to the development of new drugs and completing the required clinical trials were substantial for both brand-name and generic manufacturers. Generic manufacturers faced additional challenges as they had to conduct their own clinical trials even for drugs whose underlying active ingredient patents had expired. Furthermore, the case of Roche v. Bolar Pharmaceutical Co. case in the late 1970s complicated matters. The Court of Appeals for the Federal Circuit ruled that generic companies conducting testing on patented products solely for seeking FDA approval infringed on the patent holders’ rights. This decision effectively extended product exclusivity periods and threatened the market for generic products.

The lack of available generic drugs and the high cost of brand-name drugs posed problems for patients and public health outcomes. Patients would benefit from affordable generic alternatives once brand-name drug patents expired. The high cost of brand-name drugs could lead to reduced patient adherence and adverse outcomes due to excessive healthcare spending. In this environment, the Hatch-Waxman Act was enacted to address these issues. It created an abbreviated FDA approval pathway, known as the Abbreviated New Drug Application (ANDA) process, specifically for generic drugs that were proven to be pharmaceutically equivalent and bioequivalent to their brand-name counterparts. This streamlined the approval process for generic drugs, allowing them to enter the market more efficiently.

The Act also established a system to adjudicate challenges by generic manufacturers against brand-name drug manufacturers’ market exclusivity. It aimed to strike a balance between the interests of both industries while ensuring competition and access to affordable medications. Moreover, the Hatch-Waxman Act included provisions to provide competition-free periods for innovative drug approvals and extensions of brand-name market exclusivity to incentivize research and development efforts.

Overall, this Act aimed to make low-cost generic drugs more widely accessible, maintain incentives for innovation, and promote competition in the pharmaceutical market. Before the Hatch-Waxman amendments, the application process regarding the approval of generic drugs was based on other factors. These were called “paper” new drug applications(NDA). Initially, these parameters were set forth by the US Food and Drug Administration which scrutinized applications taking into note the merit of each application on a product-by-product basis. This subjective inspection of each application was based on information that is publicly available. This initial process before the amendment did not contain any provisions relating to exclusivity or pre-existing patents and was not able to protect the rights of patent holders.

Drawbacks of the older system

The need for a new system arose when the efficiency of the older system was in question considering the distortions it suffered from in terms of the patent term. There were two major drawbacks or distortions in this regard:

Distortion at the beginning of the patent term

When a patent was granted for a particular drug, the lengthy FDA approval process would cause significant delays in bringing the product to market. Unlike other patented inventions in the market, new drug products required permission from the FDA before they could be sold. This involved carrying out clinical trials, submitting data, and waiting for regulatory review. As a result, the patented drug couldn’t be sold for a certain period of time, causing delays in sale. Ultimately this waiting period cut into the actual patent term and limited the economic advantage the patent holder could gain from their temporary monopoly.

Distortion at the end of the patent term

Normally, when a patent of any invention expires, competitors can enter the market and offer alternative products which leads to price reduction. However, this isn’t the case in the drug industry and generic drug companies faced an additional hurdle. Before they could introduce competing products, they had to undergo rigorous scrutiny and procedure by the FDA. Since manufacturing and conducting studies on competing products during the patent term would cause patent infringement, they had to wait until the patent term expired to initiate the FDA regulatory review procedure. This meant that even after the drug patents had expired, there was an additional period of time when competing products would get trapped in the FDA review process and were unable to enter the market. This artificially extended the period of exclusivity for brand-name drugs beyond the patent expiration date.

In summary, the distortion at the beginning of the patent term caused a delay to the commercialization of patented drugs, and the distortion at the end of the patent term delayed the entry of generic competitors into the market even after the patent has expired. These distortions created a prolonged period of exclusivity for brand-name drugs and limited competition thereby potentially affecting consumer access and affordability.

Hatch Waxman Act

Overview of the Act

The Hatch Waxman Act was enacted with the aim to rectify and deal with the issues stated above. The following titles of the acts concerned with the patent linkage system:

Title I: Abbreviated New Drug Applications:

It amended the Food, Drug, and Cosmetic Act (FDCA), specifically Section 355.
This aimed to tackle the distortion of patent term which was the result of the delayed entry of generic drugs into the market due to the tedious FDA review.
It introduced certain provisions for abbreviated new drug applications (ANDAs), which streamlined and simplified the entire approval process for generic drugs.
It also enabled generic manufacturers to rely on the safety and efficacy data of the branded drugs which avoided the need to repeat extensive clinical trials.

Title II, Part I: Patent Extension:

Amended the U.S. Patent Code and specifically amended Section 271(e) within the same code.
Addressed the distortion of patent term caused by the extension of market exclusivity resulting from the delayed entry of generics due to FDA review.
Provided a mechanism that enabled brand name drug companies to extend their patents by compensating for the time they lost during the FDA review process.

Title II, Part II: Patent Extension:

Further amended the U.S. Patent Code(specifically Section 156)
Aimed to address the distortion of patent terms caused by the loss of assertable market exclusivity time due to the FDA review procedure.
Introduced provisions allowing patent term extensions for brand name drugs to compensate for the time spent on obtaining FDA approval.

In summary, the Hatch-Waxman Act consisted of two titles that deal with the patent linkage system. Title I focused on streamlining the approval process for generic drugs, while Title II addressed the extension of patent terms to account for the time lost during FDA review. These measures aimed to balance the interests of brand-name drug companies and generic manufacturers, promoting competition, affordability, and timely access to generic drugs for consumers.

Contrast with NDA

Post the enactment of the Hatch Waxman Amendment the process of application was referred to as Abbreviated New Drug Application (“ANDA”). The Hatch Waxman Act laid down the legal framework for today’s generic pharmaceutical industry. To draw a contrast between the NDA and ANDA processes let’s examine the requirements of both. The NDA consisted of two adequate and controlled clinical trials, statistical planning and analysis, pharmacodynamic studies, absorption and excretion studies, non-clinical safety pharmacology, and a full description of manufacturing and controls. ANDA significantly departs from the NDA as it also includes a pharmacokinetic comparison of the Bernie drug with the innovator or branded drug or any other drugs that depict bioequivalence.

Certifications

As per the Hatch-Waxman Act, a generic drug applicant is mandatorily required to provide one of the following four certifications for each patent listed in the Orange Book for the innovator drug:

Paragraph I: The applicant certifies that there are no patents listed in the Orange Book for the drug. This means that there are no relevant patents that could potentially block the generic drug from entering the market.
Paragraph II: The applicant certifies that the relevant patents listed in the Orange Book have expired. This indicates that the patent protection for the innovator drug has already ended and allows the generic manufacturer to produce and market their version of the drug without infringing on any existing patent rights.
Paragraph III: The applicant certifies that they will not seek approval of the abbreviated new drug application (ANDA) until after the expiration of the pre-existing patent. This certification acknowledges the existence of a valid existing patent for a particular innovator drug but also ensures that the generic manufacturer will wait until the patent’s expiration before pursuing approval.
Paragraph IV: The applicant certifies that a relevant patent listed in the Orange Book is either invalid or will not be infringed upon by the manufacture, use, or sale of the new generic drug for which the ANDA is submitted. This certification signifies that the generic manufacturer believes the patent is either not valid or not enforceable and that their generic version will not infringe upon any existing patent rights.

These four certifications provide a legal framework for the generic drug applicant to navigate patent-related issues while seeking approval for their generic version of an innovator drug. It permits them to address patent barriers like expired patents or potential patent infringement claims or patents which might impact the market entry of their generic product.

Approval Process

In simpler terms, the application does not necessarily have to carry out preclinical and clinical safety tests as long as it can be established that the generic drug functions similarly to the innovator or branded drug. Another important aspect is that the branded drug is listed in the Orange Book.

The FDA lists all patented pharmaceutical products and medicinal products in the Orange Book. When a company that manufactures generic drugs submits an ANDA, such a company must establish one of the following

The drug isn’t protected by a pre-existing patent.
The original patent has already expired.
The new generic drug won’t won’t be released in the market till the expiry of the originator’s patent.
The existing patent is invalid or the drug is dissimilar and no patent is violated.

Let’s look at this process in a detailed fashion:

Pre-ANDA Meeting: The generic drug manufacturer carries out a meeting with the FDA to deliberate upon the development and submission of an abbreviated new drug application (ANDA).
ANDA Development and Submission: The generic drug manufacturer develops and submits an ANDA to the FDA and the ANDA must establish that the generic drug is bioequivalent to the brand-name drug in question. It has to be proved that such a drug contains the same active ingredients and is similar in terms of strength, dosage form, and route of administration.
Review by FDA: The FDA carries out a review of the ANDA to conclude if the generic drug is safe and effective in nature. The review also needs to derive that it meets the requirements for approval.
Patent Certification: The generic drug manufacturer has to certify and establish with the FDA that the generic drug does not infringe on any existing patents held by the brand-name manufacturer or that the patents will be invalid or they will expire before the generic drug is marketed. When a Paragraph IV certification is filed by the generic drug manufacturer, stating that the brand-name drug patents are invalid or not infringed, this may potentially trigger the patent infringement lawsuit which is commonly also called the “patent dance.”
Approval: The FDA grants final approval for marketing provided it determines that the generic drug is safe and it meets all other criteria for approval.
Market Entry: Post the approval the generic drug can enter the market at a price lower than the brand name drug.

An additional step is added by the patent linkage mechanism in the US that requires the FDA to inform the brand-name manufacturer of any ANDA submissions, giving the brand-name manufacturer an opportunity to challenge the approval of generic drugs in the court of law.

What is the Orange book?

The “Orange Book” is a commonly used terminology for the FDA’s publication which is called “Approved Drug Products with Therapeutic Equivalence Evaluations.” It is a list that is comprehensive in nature consisting of all FDA-approved drugs for usage in the United States. It includes both brand-name drugs and their generic equivalents.

The Orange Book is relevant in terms of patent linkage and generic drug approval because it consists of information pertaining to patents that are associated with brand-name drugs. It also is inclusive of information regarding the therapeutic equivalence of generic drugs. The Orange Book provides insight to generic drug manufacturers and the FDA in ascertaining whether a generic drug can be approved for sale or not.
In terms of patent linkage, the Orange Book consists of a list of patents related to each brand-name drug. This enables generic drug manufacturers to ascertain which patents may be potentially infringed by their generic drug and helps them in certifying to the FDA that their generic drug doesn’t infringe on any of the listed patents. It is also a resource for the FDA that is used to determine whether a Paragraph IV certification is appropriate for a generic drug.
In terms of generic drug approval, the Orange Book provides information about the therapeutic equivalence of generic drugs to their brand-name counterparts. The FDA uses this information to determine whether a generic drug can be approved for sale. If the FDA determines that a generic drug is therapeutically equivalent to its brand-name counterpart, such a drug can be approved for sale without the need for additional clinical testing.
The Orange Book is a paramount resource for both generic drug manufacturers and the FDA due to its relevance in the approval process for generic drugs.

Legal Framework and key provisions

The legal framework pertaining to patent linkage in the United States is established through the Hatch-Waxman Act which provides a comprehensive system that aims to balance the rights of patent holders and generic drug market entry. By breaking down the key provisions of the Act which include the ANDA process, patent litigation framework, PTR, and exclusivity periods, we gain an understanding into the nuances of the patent linkage system prevalent in the United States. The act contains several provisions related to patent linkage.

ANDA Procedure:

The Act established the ANDA procedure. This procedure allows generic drug manufacturers to seek approval for their versions of existing drugs that have already been approved by the FDA. This procedure has been described in detail above.

Section 101

As per Section 101 of the Act, an ANDA can be filed for a new drug provided such an applicant can establish that it has the same active ingredients, route of administration, dosage form, and strength as a previously approved drug.
The ANDA is subject to automatic approval within 180 days of submission if it meets all the necessary criteria outlined in Section 101.

Bioequivalence

To qualify for an ANDA, the applicant doesn’t need to conduct extensive clinical trials. Instead, they need to demonstrate that their drug is bioequivalent to the original drug by showing similar levels of absorption and efficacy.

Rehearing Option

If the ANDA is not initially approved, the applicant has a thirty-day window to request an expedited rehearing. This rehearing occurs within ninety days and the Secretary of Health and Human Services makes a decision on the same within ninety days after the conclusion of the rehearing.

Paragraph IV certification:

As mentioned above under the Hatch-Waxman Act, the fourth certification route for generic drug manufacturers is called “Paragraph IV” certification. This route is adopted when the generic manufacturer contends that the patent covering the brand-name drug is invalid or that their generic product does not infringe the patent. By filing an Abbreviated New Drug Application (ANDA) with a Paragraph IV certification, the generic manufacturer is considered to be engaging in an act of patent infringement under Section 35 U.S.C. §271, which satisfies the requirement for filing an infringement suit.
Whenever an ANDA contains a Paragraph IV certification, the applicant is required to notify the FDA and the patent holders of the same. This notification should consist of a detailed statement of the factual and legal basis for their assertion with regard to the patent invalidity or non-infringement. If the patent holder initiates a patent infringement lawsuit within 45 days of receiving this particular notice then the FDA automatically suspends the approval of the ANDA for thirty months.
During this 30-month stay, the FDA cannot issue an approval of the generic drug in question unless one of the following occurs:

The court rules that the patent for the brand-name drug is invalid or not infringed.
The court ascertains that the patent for the brand-name drug will be infringed and the patent expires.
Subject to modification the court ascertains that 30 months have passed since the patent owner received notice of the Paragraph IV certification.

The objective the Congress sought to fulfil through the 30-month stay is to provide sufficient time for the parties to resolve their patent-related dispute before the generic product is introduced to the market. It serves as an automatic preliminary injunction against the generic drug company, granted by statute, without requiring the brand-name company to make the usual showings required for a preliminary injunction.
It is important to note that the filing of an ANDA with a Paragraph IV certification is considered a “somewhat artificial” act of patent infringement under 35 U.S.C. §271(e)(2). At this stage, the generic manufacturer has only requested FDA approval to market the drug, and the charge of infringement is technical in nature. If the patentee successfully proves infringement, it may prevent the marketing of the generic drug until the expiration of the patent.
The term “somewhat artificial” in this context here refers to the fact that the act of filing an ANDA with a Paragraph IV certification is considered a technical or procedural infringement rather than an actual, real-world infringement of the patent through unauthorized usage or any other medium.

Patent extension

Title II of the Hatch-Waxman Act introduced provisions concerned with extending the term of patents for pharmaceutical products that undergo regulatory review before commercial marketing. In the normal scenario, patents last for 20 years from the date of the patent application. However, the Hatch-Waxman Act departs from this and allows for the extension of a pharmaceutical patent to compensate for the time lost during clinical testing.
To be eligible for a term extension, the patent holder must choose a single patent if multiple patents cover the same drug. The patent holder has the right to have one-half of the time between the submission of the Investigational New Drug (IND) application and the submission of a New Drug Application (NDA), plus the entire period spent by the FDA in approving the NDA, restored to the patent term. There are certain limitations in terms of the length of the term restoration as the total restored patent term cannot exceed five years. It is also important to note that the remaining term following FDA approval cannot exceed 14 years.
The patentee has to act diligently in order to obtain patent term restoration from the United States Patent and Trademark Office (USPTO). The lack of diligence can offset the augmented patent term. For example, in case four years have passed between the IND and NDA filings, and an additional two years have also passed between the NDA filing and its approval, then in such a scenario the extension period would be four years [(4 ÷ 2) + 2].
It is important to note that patent term extension under the Hatch-Waxman Act is not automatic. The patent owner here must file an application with the USPTO within 60 days of obtaining FDA marketing approval to request a term extension.
The extension procedure kicks off with the submission of an application to the Director of the USPTO within 60 days of receiving such regulatory approval. The application should include information about the product, the patent, and other necessary details. The Secretary of Health and Human Services then decides the appropriate scope and term of the patent extension based on the application information. Once this determination is made as prescribed, a certificate of extension is issued by the Director of the USPTO. This is appended to the original patent.
The Hatch-Waxman Act’s patent extension provisions have influenced the brand name drug industry by providing a predictable period of exclusivity after the initial patent term expires. This allows them to ensure specific patent rights and block potential generic competitors directly. While they may lose some potential longer market exclusivity, they ultimately gain greater certainty and clarity with regard to their rights.
In summary, the Hatch-Waxman Act’s patent term extension provisions for pharmaceuticals offer a mode or a system to compensate for the time lost during clinical testing. Patent holders can request an extension, subject to certain limitations, and must diligently pursue the extension through the USPTO. This provides them with a predictable period of exclusivity after the initial patent term, during which they can protect their rights against generic competitors.

Exclusivities under the Act

Under the Hatch-Waxman Act, several forms of regulatory exclusivity are provided to encourage the development of pharmaceuticals and incentivize generic drug manufacturers to challenge patents. Here is a summary of the different exclusivities allowed:

New Chemical Entity (NCE) Exclusivity:

A five-year exclusivity period is granted to drugs that qualify as a new chemical entity.
NCE exclusivity applies when the FDA approves a drug with an active ingredient that has not been previously approved.
During this particular period, the FDA cannot accept an Abbreviated New Drug Application (ANDA) or a 505(b)(2) application for a drug product containing the same protected active ingredient.

New Clinical Study Exclusivity:

A three-year exclusivity period is awarded for new clinical study data submitted in support of a New Drug Application (NDA) or a supplemental NDA.
This exclusivity only applies to the specific use of the product that was supported by the new clinical study.

Orphan Drug Exclusivity:

The Orphan Drug Act, enacted before the Hatch-Waxman Act, established a seven-year market exclusivity period for drugs developed to treat rare diseases or conditions.
Orphan drug exclusivity prevents the FDA from approving another marketing application for the same drug and indication within that seven-year period.

180-Day Generic Drug Exclusivity:

Generic drug manufacturers are rewarded for challenging the patents associated with approved pharmaceuticals.
The first generic applicant to file a paragraph IV certification, asserting that a listed patent is invalid or not infringed, is granted a 180-day exclusivity period.
During this period, other generic applicants cannot receive FDA approval for the same generic version of the drug.

These various forms of exclusivity aim to balance the interests of innovator pharmaceutical companies and generic drug manufacturers. They provide periods of protection and incentives to encourage innovation, research, and competition in the pharmaceutical industry.

Bolar Amendment

The Statutory Experimental Use Exception, also known as the Bolar Amendment, was introduced as part of the Drug Price Competition and Patent Term Restoration Act of 1984. It is commonly referred to as the Hatch-Waxman Act. The Bolar amendment is codified within 35 U.S.C. §271(e)(1) and provides an exemption from certain claims of patent infringement.

The Bolar Amendment overturned the decision in the case of Roche v. Bolar Pharmaceutical Co., where it was laid down that the experimental use doctrine did not protect the limited use of a patented drug for testing and investigation related to FDA drug approval requirements. The decision in Roche v. Bolar Pharmaceutical Co. allowed originator manufacturers to retain market exclusivity for their products beyond the duration of the patent terms because generic manufacturers could not start developing and seeking approval for competing generic products until after the originator patent expired.
To address this issue, the Bolar Amendment was enacted, allowing generic manufacturers to make, use, offer to sell, or sell within the United States a patented invention solely for uses reasonably related to the development and submission of information under a federal law that regulates the manufacture, use, or sale of drugs or veterinary biological products. This provision allows granting permission to generic manufacturers to commence work on a generic version of an approved drug at any time during the life of the patent provided the work is for the purpose of complying with FDA regulations.
The Bolar Amendment has been instrumental in facilitating the development and timely market entry of generic drugs by providing an exception to patent infringement for activities necessary for obtaining regulatory approval. However, there have been concerns about the potential misuse and abuse of this exception by generic and brand-name drug companies in collusive arrangements that may undermine the intended purposes of the Hatch-Waxman Act.

Subsequent legislation

The Generic Animal Drug and Patent Term Restoration Act, 1988

The Generic Animal Drug and Patent Term Restoration Act (GADPTRA) is a law that came into effect on November 16, 1988. This act amended the Federal Food, Drug, and Cosmetic Act (FD&C Act) in order to allow the approval of generic copies of new animal drug products. Here are some key points about the act:

Abbreviated New Animal Drug Application (ANADA): In order to legally market a generic new animal drug product, the generic sponsor must have an approved ANADA. This application includes information like the reference-listed new animal drug product (RLNAD) being copied, patent information, labeling, ingredients, bioequivalence, human food safety, manufacturing methods, facilities, controls, environmental impact, and an FOI Summary.
Eligibility for Generic Copying: All new animal drugs that were approved for safety and effectiveness on or after November 16, 1988, and are not protected by patent or exclusivity can be copied as generics unless they have been withdrawn from the market for safety or effectiveness reasons.
Marketing Exclusivity: The FD&C Act provides for a period of marketing exclusivity during which generic copies of the RLNAD cannot be approved. This period is typically five years for a new animal drug product that has not been previously approved, with some exceptions and qualifications for pioneer sponsors who may qualify for three years of exclusivity for a newly approved use of an RLNAD.
Waiver from In Vivo Bioequivalence Studies: Certain new animal drug products may be eligible for a waiver from in vivo bioequivalence studies. Typically, true solutions intended for oral or parenteral use may be granted a waiver, while more complex dosage forms or medicated feeds, or feed premixes may not be granted a waiver.
Performing Bioequivalence Studies: The generic sponsor should seek FDA’s concurrence on a protocol for a bioequivalence study before conducting the study. The study must comply with FDA’s Good Laboratory Practices (GLP) regulations.
Suitability Petition: A Suitability Petition is a request to affirm that a proposed generic new animal drug product is sufficiently similar to the RLNAD to permit the submission of an ANADA. The petition can be submitted if the proposed product differs from the RLNAD in terms of dosage form, strength, route of administration, or in certain combinations of active ingredients in animal feed products.
Approval Timeline: The statutory limit for approval of an ANADA is 180 days. However, the actual approval time depends on the quality and completeness of the application and any subsequent amendments.

Note: The Generic Animal Drug and Patent Term Restoration Act (GADPTRA) aimed to extend the benefits of term restoration provisions to veterinary drugs and biological products. However, animal drug products primarily derived from recombinant DNA technology are specifically excluded from receiving the benefit of patent term restoration.

The FDA Modernization Act, 1997

The Better Pharmaceuticals for Children Act falls under the ambit of Section 111 of the Food and Drug Administration Modernization Act of 1997. This Act aims to increase the availability of pharmaceuticals for children. It introduced a provision called “pediatric exclusivity” to incentivize drug manufacturers to conduct research on the effectiveness of their drugs in pediatric populations. Here are some key points about this act:

Purpose: The act aimed to encourage drug manufacturers to conduct studies on the safety and effectiveness of their drugs specifically in children. It recognized the importance of developing appropriate pediatric dosing, formulations and labeling to ensure the well-being of children.
Pediatric Exclusivity: The act introduced a six-month exclusivity period, known as pediatric exclusivity, which could be added to the term of any existing patent or regulatory exclusivity for a drug. This exclusivity applied to children’s drug products that had the same “active moiety” as a previously approved drug.
Extended Exclusivity Term: Pediatric exclusivity effectively added six months to the duration of patent or regulatory exclusivity for a drug. For example, if a drug had New Chemical Entity (NCE) exclusivity, its term would be extended to five years and six months with the addition of pediatric exclusivity.
Timing of Pediatric Exclusivity: As per this Act drug manufacturers had to conduct studies on a pediatric population to be eligible for pediatric exclusivity as requested by the Secretary of Health and Human Services.
Impact of Exclusivity: Pediatric exclusivity incentivizes drug manufacturers to invest in pediatric research and contribute effectively to the availability of safe and effective drugs for children. It aims to address the historical lack of data and appropriate labeling for pediatric use.
Permanence: Initially subject to a sunset provision, Congress made pediatric exclusivity a permanent provision in 2012 with the FDA Safety and Innovation Act. This ensured that the incentives for conducting pediatric research would continue to exist in the long term.

Note: The Better Pharmaceuticals for Children Act and its provision for pediatric exclusivity aimed to promote pediatric research and the availability of safe and effective drugs for children. It provided an additional six-month exclusivity period to drug manufacturers, encouraging them to conduct studies on their drugs in pediatric populations.

The Medicare Prescription Drug, Improvement, and Modernization Act of 2003

The Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA) introduced various key changes to the original Hatch-Waxman Act regarding the approval process for generic drugs in the United States. Here are some key points regarding the MMA and its effect on the Hatch-Waxman Act:

Limitation on 30-Month Stays: Under the MMA, only one 30-month stay is permitted on the approval of a generic drug when patents are listed in the Orange Book (the FDA’s publication of approved drug products with patent information). This provision aims to prevent strategic delays in the availability of generic drugs.
Declaratory Judgment: If a patent holder fails to file an infringement action within 45 days of notification of a paragraph IV Abbreviated New Drug Application (ANDA), the generic applicant can request a district court to issue a declaratory judgment on the patent’s validity. This provision encourages the timely resolution of patent disputes.
Counterclaim for Orange Book Modification: In cases where a brand-name drug company initiates a patent infringement suit against an ANDA applicant, the generic firm can file a counterclaim requesting the modification or deletion of patent information listed in the Orange Book. Monetary damages are not awarded in such suits under the MMA.
Commencement of 180-Day Generic Exclusivity: The MMA specifies that the 180-day generic exclusivity period begins with the first commercial marketing of the generic drug. This exclusivity can be forfeited under certain circumstances, such as failure to meet specific time constraints or obtaining FDA marketing approval.
Filing of Agreements: The MMA requires that agreements between brand-name and generic companies regarding the production, sale, or marketing of a pharmaceutical or a 180-day market exclusivity must be filed with the Federal Trade Commission (FTC) and the Department of Justice. This measure helps monitor potential antitrust violations and “pay-for-delay” settlements.

Note: The MMA aimed to expedite the availability of generic drugs by addressing potential barriers and encouraging timely resolution of patent disputes. These provisions introduced changes to patent linkage and the Hatch-Waxman Act, enhancing competition and affordability in the pharmaceutical market.

The Food and Drug Administration Amendments Act of 2007

The Food and Drug Administration Amendments Act (FDAAA) of 2007 introduced significant changes to prescription drug policy in the United States. One of the key provisions of the FDAAA was related to the grant of New Chemical Entity (NCE) exclusivity to enantiomers of previously approved racemates. This provision had implications for patent linkage and the Hatch-Waxman Act. Here are the key points regarding how this law affected patent linkage and the Hatch-Waxman Act:

NCE Exclusivity for Enantiomers: The FDAAA allowed the FDA to grant exclusivity to a non-racemic drug if it was approved for a different use than the previously approved racemic version. This meant that a single enantiomer of a previously approved racemate could be considered a new chemical entity, qualifying for exclusivity.
Impact on Patent Linkage: Patent linkage refers to the practice of linking the approval of generic drugs to the status of patents held by brand-name drug manufacturers. The provision in the FDAAA regarding NCE exclusivity for enantiomers added complexity to patent linkage. If a brand-name drug consisted of a racemic mixture and a generic manufacturer developed and sought approval for the single enantiomer, the FDAAA allowed for the possibility of granting exclusivity to the enantiomer under certain conditions. This affected the timing of generic entry and the resolution of patent disputes between brand-name and generic manufacturers.
Influence on the Hatch-Waxman Act: The Hatch-Waxman Act, enacted in 1984, established the framework for the approval of generic drugs and provided provisions for resolving patent disputes between brand-name and generic drug manufacturers. The FDAAA’s provision on NCE exclusivity for enantiomers added complexity to the Hatch-Waxman Act. It introduced new considerations and criteria for determining exclusivity and the resolution of patent disputes in cases involving racemic mixtures and single enantiomers.

In conclusion, the FDAAA of 2007, with its provision on NCE exclusivity for enantiomers, had significant implications for patent linkage and the Hatch-Waxman Act. It introduced complexities in the approval process for generic drugs and the resolution of patent disputes, particularly in cases involving racemic mixtures and single enantiomers.

The Biologics Price Competition and Innovation Act of 2009

The Biologics Price Competition and Innovation Act of 2009 (BPCIA) brought certain changes in terms of the regulation of biological products within the United States. This act strictly compelled the marketing applications for “biological products” to be submitted as biologics license applications (BLAs) under the Public Health Service Act (PHS Act), with certain exceptions during a 10-year transition period. Key points regarding the BPCIA and its effects on patent linkage and the Hatch-Waxman Act are as follows:

The Transition from FD&C Act to PHS Act: The BPCIA mandated that approved marketing applications for biological products under section 505 of the FD&C Act would be deemed to be licenses for those products under section 351 of the PHS Act as of March 23, 2020. This transition allowed sponsors of affected biological products time to prepare for the regulatory shift, while also ensuring a seamless transition between the regulatory pathways.
Impact on Patent Linkage: Patent linkage refers to the connection between generic drug approval and the status of patents held by brand-name manufacturers. The BPCIA’s introduction of a new regulatory pathway for biosimilars and interchangeable biologics affected the patent linkage framework. It established procedures for identifying and resolving patent disputes specifically related to follow-on biologics. This provided a framework for resolving intellectual property issues and balancing incentives for innovation and competition.
Effect on Hatch-Waxman Act: The BPCIA addressed the unique characteristics of biologics by establishing a separate regulatory pathway for biosimilars and interchangeable biologics. This was necessary because biologics are structurally complex and differ from small-molecule drugs covered by the Hatch-Waxman Act. The BPCIA created an expedited regulatory pathway for biosimilars and interchangeable and defined exclusivities available to both brand-name and follow-on firms. These provisions aimed to promote competition while ensuring patient safety and efficacy standards were met.

In conclusion, the BPCIA of 2009 introduced a new regulatory framework for biological products, including biosimilars and interchangeable biologics. This act had implications for patent linkage by establishing procedures for resolving patent disputes related to follow-on biologics. It also recognized the unique characteristics of biologics compared to small-molecule drugs covered by the Hatch-Waxman Act and provided a separate pathway for regulatory approval, encouraging competition while maintaining appropriate safety and efficacy standards.

The GAIN Act of 2012

The Generating Antibiotic Incentives Now (GAIN) Act, enacted as part of the FDA Safety and Innovation Act, addresses the critical issue of antibiotic resistance and aims to incentivize the development of new antibiotics. The act provides several provisions to support the development, review, and market exclusivity of qualified infectious disease products (QIDPs) targeting serious or life-threatening infections.

Key points regarding the GAIN Act and its effects on patent linkage and the Hatch-Waxman Act are as follows:

Incentivizing Development: The GAIN Act acknowledges the declining pipeline of new antibiotics and the lack of commercial value associated with their development. To encourage innovation, the act extends the term of market exclusivity granted by the FDA for QIDPs. This additional five years of exclusivity is in addition to existing exclusivity periods provided by the Hatch-Waxman Act, such as new chemical entity exclusivity, orphan drug exclusivity, or pediatric exclusivity. The extended exclusivity aims to enhance the commercial value of antibiotics and incentivize manufacturers to invest in their development.
Expedited Review and Development: Drugs designated as QIDPs under the GAIN Act receive expedited regulatory processes. These drugs are granted fast-track and priority review status, accelerating their development and review by the FDA. The act also requires the FDA to issue new guidance on the development of pathogen-focused antibiotics, providing clear development pathways for drug makers targeting specific bacteria. The act emphasizes the importance of updated clinical trial guidance to ensure that antibiotic development aligns with scientific and regulatory standards.
Pathogen Listing and Threat Assessment: The GAIN Act mandates the FDA to compile a list of “qualifying pathogens” that pose a serious threat to public health. This list is periodically updated and created in consultation with relevant stakeholders, including the CDC, medical care professionals, and clinical researchers. By identifying and prioritizing pathogens, the act helps guide the development of antibiotics to address the most pressing public health needs.
Impact on Patent Linkage and Hatch-Waxman: The GAIN Act does not directly impact patent linkage or the specific provisions of the Hatch-Waxman Act. However, by extending the exclusivity period for QIDPs, it provides an additional period of market protection for innovative antibiotics. This extended exclusivity may indirectly affect patent linkage by allowing manufacturers to maintain market exclusivity for a longer duration, potentially deterring generic competition during the exclusivity period.

In conclusion, the GAIN Act was enacted to address the growing threat of antibiotic resistance and stimulate the development of new antibiotics. By providing extended market exclusivity, expediting regulatory processes, and offering clear guidance for antibiotic development, the act aims to incentivize innovation in this critical area of medicine. While the act does not directly impact patent linkage, the extended exclusivity for QIDPs may indirectly influence the competitive landscape by providing manufacturers with a longer period of market protection.

Patent Protection v generic entry

The patent linkage system in the US is a legal framework that is concerned with the regulation and the approval system of generic drugs by the FDA taking into account potential infringement of existing patents. This system herein mandates the FDA to notify patent holders in case an application for a generic drug is submitted, giving the patent holder the opportunity to challenge such an application and work on extending their patent protection.

Firstly, patent protection encourages pharmaceutical companies with a strong motive to invest in research and development for bringing new innovative drugs into the market. It also enables these companies to attempt to reclaim certain significant costs related to developing and testing new drugs. However, this also creates the possibility of limiting access to affordable medications, as patented drugs are mostly way more expensive than their generic counterparts.

Furthermore, the generic entry is pivotal for increasing access to affordable medicines, particularly in countries with relatively lower incomes. Generic drug manufacturers can reduce the cost of healthcare as a whole by competing toe to toe with branded drugs which would in turn be beneficial for patients, governments, and insurers. This will in turn increase the possibility of persons being ready to take treatment and hamper the growth of chronic diseases to a substantial extent.

The patent linkage system strives to strike a balance between these conflicting interests. While it provides patent holders with a framework to protect their intellectual property rights, it also aims to ensure timely access to affordable generic drugs. As it allows the FDA to consider patent infringement issues during the drug approval process, there is a high chance that it helps to prevent patent abuse and delay of generic entry.

Criticism

The patent linkage system, implemented in the United States, was enacted with an objective to facilitate pharmaceutical innovation and promote competition. This system aimed to achieve this goal by granting 180 days of marketing exclusivity to the first generic drug manufacturer that successfully challenged a patent. However, this system has several drawbacks that have attracted criticism:

Misuse of 180-day marketing exclusivity: The patent linkage system in the United States grants the first successful filer of a paragraph IV certification 180 days of marketing exclusivity. However, this provision can be misused. In some cases, it may be more profitable for generic manufacturers to accept payments from brand name companies to delay entering the market, rather than launching their generic products. This can lead to collusive agreements that restrict competition and keep drug prices high.
Possibility of collusion: The 180-day exclusivity period provides an opportunity for collusion between brand-name and generic drug manufacturers. If the potential loss of profit margin for the brand name drug company exceeds the potential profit margin for the generic drug, they may engage in collusive agreements to delay market entry. Such agreements artificially inflate drug prices violating antitrust laws. This ultimately leads to consumers being at disadvantage as their interests are compromised.
Misuse of stay period: The patent linkage system includes provisions for a stay of approval following the filing of an infringement action. Originally intended to account for the expected duration of litigation, this stay can be misused. Brand-name drug companies may list additional patents in the Orange Book after a generic’s abbreviated new drug application (ANDA) filing, forcing the ANDA applicant to recertify their application and triggering a new stay. This strategic control of patent issuance allows brand-name drug companies to prolong their monopolies indefinitely, even if subsequent patents are found invalid or not infringed.
Delayed entry of generic drugs: The patent linkage system, which requires generic drug marketing approval to be withheld until relevant patents expire, causes significant delays in the entry of generic drugs into the market. Regulatory authorities typically take several years to approve generic drugs, resulting in a four-year delay on average. This delay extends the market monopoly of innovator products beyond the expiration of their patents and hampers access to affordable generic medicines.
Lack of encouragement for innovation: Contrary to the intended purpose of the patent system, the patent linkage system does not necessarily encourage innovation. Pharmaceutical companies often file follow-on patents derived from a single original patent to extend their monopolies. These follow-on patents are listed in patent registers to delay generic entry under the patent linkage system. As a result, access to affordable generic medicines is further delayed, hindering competition and innovation in the pharmaceutical industry.
Abuse of low-quality patents: The negative impact of the patent linkage system on access to generic medicines is particularly evident in countries where patent offices grant low-quality patents. In the United States, pharmaceutical companies may file additional low-quality patents with the Food and Drug Administration (FDA) to be registered in the Orange Book. This practice grants a 30-month stay, extending the originator’s monopoly. Such abuse further limits competition and increases the cost of generics indirectly, potentially burdening consumers with higher drug prices.

Judicial pronouncements

The Roche v. Bolar (1984)

The Roche v. Bolar decision is very commonly accredited for the congressional enactment of the Drug Price Competition and Patent Term Restoration Act of 1984. This judgment holds monumental importance in terms of laying down the foundation to the patent linkage system in the U.S today.

Facts:

Roche Products, Inc. held a patent for flurazepam hydrochloride, the active ingredient in their brand-name prescription sleeping pill “Dalmane.” The patent expired on January 17, 1984. Bolar Pharmaceutical Inc., a generic drug manufacturer, aimed to market a generic version of Dalmane after the patent expired. In order to obtain marketing approval from the FDA, Bolar needed to conduct tests and gather data, which could take more than two years. To expedite the process, Bolar obtained 5 kilograms of the patented active ingredient for testing purposes before the patent’s expiration. Roche filed a complaint against Bolar, alleging patent infringement. The United States District Court for the Eastern District of New York initially ruled in favor of Bolar, stating that their use of the patented ingredient for testing was de minimis and experimental. Roche appealed the decision to the Court of Appeals for the Federal Circuit (CAFC).

Issues:

The main issue was whether Bolar’s limited use of the patented drug for testing purposes, specifically related to FDA drug approval requirements during the final six months of the patent term, constituted patent infringement. Bolar argued for two exceptions: the experimental use exception and the creation of a new exception based on public policy favoring generic drugs.

Ratio laid down:

The CAFC ruled that the experimental use exception in US patent law is narrow. While experiments conducted for scientific curiosity or amusement do not antagonize the interests of the patentee, if the products of the experiment are sold or used for the experimenter’s convenience or business adaptation, they constitute patent infringement. Bolar’s intended use of the patented active ingredient for testing purposes did not fall within the traditional limits of the experimental use exception, and it was solely driven by business reasons. Therefore, Bolar’s use was considered an infringement of the patent. Regarding the public policy justification for a new exception, the CAFC stated that courts should not pick and choose among congressional enactments. Congress had already addressed these issues through legislation, including the Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman Act). The court’s role was to interpret and apply existing legislation, rather than debating policy arguments.

Aftermath:

The CAFC reversed the district court’s decision and remanded the case to determine an appropriate remedy, potentially including an injunction, as requested by Roche. In 1984, Congress enacted the Hatch-Waxman Act, which introduced a new exception to patent rights, commonly known as the “Bolar” exception or the regulatory review exception. This exception allows the limited use of patented inventions for purposes related to the development and submission of information required by federal laws regulating drugs. The Act also provided additional provisions such as patent term extensions and patent linkage requirements.

Caraco Pharmaceutical Laboratories, Ltd. v. Novo Nordisk (2012)

In this case, the issue was regarding the use code for Novo Nordisk’s drug named, Prandin.
Caraco had filed an ANDA seeking approval for producing a generic version of the same drug.
Novo Nordisk further changed the use code of the same drug thereby undermining any contention raised by Caracin.
The Supreme Court while ruling in favor of Caracin stated that the Counterclaim provision in the Hatch Waxman Act allowed any challenges to unpatented use of a drug.
This decision set forth the rights of a generic drug marketer and provided them with a mechanism to challenge use codes. (Use codes here mean the codes that describe the approved methods of using a particular drug)

Merck KGaA v. Integra Lifesciences I, Ltd (2005)

In the instant case, Integra Lifesciences sued Merck for supplying a particular patented compound to other drug companies for the purpose of preclinical research.
Merck stated that the federal law allowed the same as if the invention was used only for the development and submission of information under a federal drug law, the same does not constitute patent infringement.
The Supreme Court here in its unanimous opinion observed that federal law permitted the use of patented compounds in preclinical studies, as long as there was a reasonable basis to believe the compound could be the subject of an FDA submission.
This decision clearly clarified that research activities that are “reasonably related” to the development of information for FDA approval are exempt from patent Infringement.

Sanofi-Aventis U.S. LLC v. Watson Laboratories, Inc. (2013)

In this case, the Federal Circuit stated that a generic drug manufacturer could be liable for induced infringement of a method-of-use patent if it carries out marketing of its generic drug for infringing use. The Court also observed that the patent owner must establish that the generic manufacturer had prior knowledge of the patent and intentionally induced infringement.

FTC v. Bristol Myers Squibb (2003)

This case is one of the prime examples of the misuse of the patent linkage system. In this case, the Federal Trade Commission (FTC) debt forth that the Bristol-Myers Squibb company has been engaged in a series of anticompetitive practices to forcefully prevent or to delay the entry of low-price generic products: two anti-cancer drugs, namely, Taxol and Platinol, and Buspar the anti-anxiety product. Bristol-Myers filed several patents for the three drugs that did not meet the criteria for listing in the orange book.

Sunovion Pharm., Inc. v. Teva Pharm. USA, Inc. et al., Dr. Reddy’s(2013)

In the case of Sunovion Pharm., Inc. v. Teva Pharm. USA, Inc. et al., Dr. Reddy’s Laboratories sought FDA approval for a generic version of the sleep medication Lunesta®.

The patent listed in the Orange Book claimed a specific form of the active ingredient in Lunesta®.
The patent stated that the active ingredient should be “essentially free” of a particular compound isomer, meaning less than 0.25% of the isomer.
Dr. Reddy’s ANDA specified a limit of “no more than 0.6%” for the isomer content.
The ANDA specification overlapped with the range covered by the patent claim.
To avoid infringement, Dr. Reddy’s submitted a certification to the court.
The certification stated that they would manufacture their generic drug with the isomer quantity falling between 0.3% and 0.6% of the active ingredient.

The district court allowed Dr. Reddy’s motion for summary judgment with regard to non-infringement based on the certification.

On appeal, the Federal Circuit disagreed and ruled that Dr. Reddy’s had infringed the patent.
The Federal Circuit stated that if a product falls within the scope of an issued patent and is being sought for FDA approval, infringement is inevitable.
The court disregarded Dr. Reddy’s certification as an unconventional and unenforceable “guarantee.”
Allowing Dr. Reddy to avoid infringement based on the certification would contradict the fundamental principles of patent law.

Therefore, in the Sunovion Pharm. case:

The Federal Circuit determined that the drug substance specification provided in the ANDA controlled the analysis of infringement.
Dr. Reddy’s separate promise to manufacture the drug in a non-infringing manner was deemed irrelevant.
The specifications included in the ANDA or paper NDA serve as the focal point for the direct infringement analysis.

However, the applicant’s specifications may not be conclusive in the infringement analysis if there is evidence suggesting potential changes in the drug’s chemical or physical properties over time or under certain conditions.

Eli Lilly v. Medtronic(1990)

The Supreme Court case of Eli Lilly v. Medtronic involved a dispute over patent infringement related to the development and marketing of an implantable cardiac defibrillator. Eli Lilly claimed that Medtronic’s activities infringed its patents, while Medtronic argued that its actions were protected under the regulatory review exemption.

Eli Lilly filed a lawsuit against Medtronic, alleging infringement of their patents for an implantable cardiac defibrillator.
Medtronic argued that their activities were “reasonably related to the development and submission of information” required under the Federal Food, Drug, and Cosmetic Act (FDCA).
The District Court ruled in favor of Eli Lilly, stating that the exemption did not apply to medical devices, and thus Medtronic’s actions constituted infringement.
The Court of Appeals reversed the decision, stating that Medtronic’s activities could be exempted if they were undertaken to develop the information necessary for regulatory approval under the FDCA.
The Supreme Court agreed to hear the case to determine whether the regulatory review exemption covered medical devices or was limited to drugs.

The Supreme Court’s analysis focused on the interpretation of the statutory phrase “a Federal law which regulates the manufacture, use, or sale of drugs” in the regulatory review exemption. They concluded that the phrase referred to a comprehensive regulatory scheme rather than a specific provision of law.

The Court highlighted that the Drug Price Competition and Patent Term Restoration Act of 1984 aimed to address distortions caused by premarket regulatory approval requirements.
The Act provided a patent-term extension for certain products and introduced the regulatory review exemption to allow competitors to engage in activities necessary for obtaining regulatory approval.
Eli Lilly’s argument that the exemption only applied to drugs was deemed implausible, as Congress was aware of the distortions caused by regulatory approval requirements for both drugs and devices.
The Court also noted that the Act excluded new animal drugs and veterinary biological products from the patent term extension and regulatory review exemption.

The Court addressed the argument that the existence of abbreviated new drug applications (ANDAs) suggested that the exemption applied only to drugs. However, they clarified that the ANDA provisions were specific to drug products and did not limit the broader scope of the regulatory review exemption.

ANDAs required certifications regarding patents named in the pioneer drug application, but these provisions only applied to drug-related applications.
The purpose of creating an act of infringement in the ANDA proceedings was to enable judicial adjudication upon which the ANDA schemes depended.
Therefore, the Court affirmed that the regulatory review exemption applied to a broader range of products, including medical devices, based on a comprehensive regulatory framework.

This decision, combined with the earlier ruling in Merck KGaA v. Integra Lifesciences I, expanded the application of the regulatory review exemption to include pre-clinical trials reasonably related to the development and submission of data required under federal laws.

Warner-Lambert v. Apotex(2003)

In this case, the issue revolved around the use of the drug gabapentin and its off-label application. Warner-Lambert had initially obtained FDA approval for gabapentin as a treatment for epilepsy. However, they later discovered that the drug had therapeutic uses for certain neurodegenerative diseases and secured a method-of-use patent specifically covering those uses.
Despite the lack of FDA approval for gabapentin’s use in neurodegenerative diseases, physicians started prescribing the drug off-label for that purpose. In fact, a significant portion of gabapentin sales, estimated at 89%, was attributed to the treatment of neurodegenerative diseases.

Apotex, a pharmaceutical company, sought FDA approval for their generic version of gabapentin but solely for the FDA-approved use in epilepsy treatment. Warner-Lambert filed a lawsuit against Apotex, arguing that the sale of generic gabapentin by Apotex would induce infringement of Warner-Lambert’s method-of-use patent for the treatment of neurodegenerative diseases. Warner-Lambert presented evidence indicating that Apotex was aware or should have been aware that a substantial portion of its generic gabapentin sales would be used for infringing purposes.
However, the court disagreed with Warner-Lambert’s argument. They ruled that unless there was clear evidence demonstrating that Apotex actively instructed, promoted, or engaged in activities to encourage doctors to prescribe gabapentin for neurodegenerative diseases, Apotex’s mere knowledge of the drug’s likely off-label use was irrelevant. The evidence showed that Apotex would sell gabapentin with a product label stating it was approved for epilepsy treatment. As a result, Apotex could not be held liable for inducing direct infringement by doctors and their patients.
In summary, the court’s decision in Warner-Lambert v. Apotex clarified that for a party to be held liable for inducing infringement, there must be explicit proof of activities encouraging infringing uses beyond mere knowledge of likely off-label usage in the market.

Valeant Pharmaceuticals North America LLC v. Mylan Pharmaceuticals Inc.(2020)

In this case, the issue at hand was the proper venue for ANDA litigation in Hatch-Waxman cases under 35 U.S.C. § 271(e)(2). The Federal Circuit had not previously established a clear precedent on this matter due to the impact of the Supreme Court’s decision in TC Heartland LLC v. Kraft Foods Grp. Brands LLC, which disrupted previous interpretations of venue and personal jurisdiction. However, in this case, the Federal Circuit provided guidance on where the proper venue does not lie in ANDA litigation.
Valeant Pharmaceuticals filed a lawsuit against several Mylan entities in the District of New Jersey. The defendants included Mylan Pharmaceuticals, Inc. (MPI), a West Virginia corporation with its principal place of business in Morgantown, West Virginia; Mylan Laboratories Ltd. (MLL), an Indian corporation with its principal place of business in Hyderabad, India; and Mylan Inc., a Pennsylvania corporation with its principal place of business in Canonsburg, Pennsylvania. The litigation centered around Dow Pharmaceutical Sciences’ anti-fungal drug Jublia® (efinaconazole), which was protected by nine Orange Book-listed patents.
Valeant argued that the venue was proper in New Jersey based on several allegations, including Mylan’s business activities in the district and its intention to sell the generic version of efinaconazole there. The Mylan defendants moved to dismiss the case for improper venue, asserting that none of them resided, were incorporated, or had established places of business in New Jersey, and no act of infringement occurred there.

The District Court granted Mylan’s motion to dismiss on the grounds of improper venue, relying on Federal Circuit precedent from In re Cray and In re ZTE. The Federal Circuit, in its opinion authored by Judge O’Malley and joined by Judges Newman and Taranto, affirmed in part, reversed in part, and remanded the decision.
The Federal Circuit addressed the question of proper venue in the Hatch-Waxman litigation as a “case of first impression” after the TC Heartland decision. The court analyzed the status of the proper venue by examining where the infringing act occurred, which is a requirement explicitly stated in the venue statute. The issue at hand was the nature of the infringing act under § 271(e)(2), which defines the act of infringement as the submission of an ANDA for a drug protected by an Orange Book-listed patent.
The court acknowledged that prior to TC Heartland, the venue had been considered proper if personal jurisdiction was established, based on Federal Circuit cases such as Acorda Therapeutics Inc. v. Mylan Pharmaceuticals Inc. and VE Holding Corp. v. Johnson Gas Appliance Co. However, TC Heartland overturned these precedents. The court also noted that cases like Bristol-Myers Squibb Co. v. Mylan Pharmaceuticals Inc. had recognized that the statute was directed towards future acts of infringement, rather than the administrative act of filing the ANDA.
Based on statutory construction principles and the plain language of the venue statute, the court concluded that the venue was not proper in all judicial districts where a generic product specified in an ANDA is likely to be distributed. It was only proper in districts where acts occurred that could categorize the defendants as a “submitter” under § 271(e). The court emphasized that the act of submitting the ANDA itself constituted the infringing act under the statute, rejecting arguments to the contrary.
Regarding the MLL defendant, who was a foreign entity, the Federal Circuit reversed the District Court’s decision. It determined that a foreign defendant can be sued in any judicial district and remanded the case for the District Court to evaluate whether this defendant’s involvement warranted overcoming the motion to dismiss under Rule 12(b)(6).
It should be noted that the court did not address the suggestion by the District Court that an act of infringement may have occurred in the District of Maryland, where the FDA received the ANDA. The precise contours of relevant acts involved in the preparation and submission of an ANDA were left for future cases.
Overall, this decision provided guidance on the proper venue in ANDA litigation under the Hatch-Waxman Act and clarified that the act of submitting an ANDA itself is the infringing act under § 271(e)(2).

Bayer AG v. Housey Pharmaceuticals(2002)

In this case, Bayer AG and Bayer Corporation appealed a Delaware district court decision that dismissed Housey Pharmaceuticals’ claims of patent infringement.
Housey held patents on a method of screening for protein inhibitors and activators, which were used in determining the potential of compounds for pharmaceutical development.
Housey sought to enforce its patents through reach-through licensing arrangements, including reach-through royalties and lump sum payments based on the licensee’s research and development budget.
The court found that reach-through royalties were agreed upon by two licensees, Eli Lilly, and SCIOS, Inc., while a lump sum payment arrangement was agreed upon by Takeda Chemical Industries, Ltd.
The court determined that Housey had not exerted undue influence over its clients in the pharmaceutical industry and that the reach-through royalty provisions were agreed upon for efficient valuation of the patent license.
The court’s decision upheld the reach-through licensing arrangement, providing support for the research tools industry and resolving conflicting legal doctrines.
The case establishes that patents on research and discovery methods, even if they do not directly cover drug products, can have significant use and value in the pharmaceutical development process.
The decision clarifies that importing information obtained through a patented method or importing drugs discovered using information derived from the patented method are not considered acts of infringement under U.S. law.
The ruling has implications for owners of U.S. patents on research and discovery methods, highlighting the limitations of patent protection for information and products derived from overseas research facilities.
Companies relying on proprietary research or discovery methods should assess how the case may affect their drug discovery strategies and business plans.

Note: This case demonstrates the court’s acceptance of reach-through licensing arrangements for research tools and emphasizes the distinction between information and physical products in terms of patent protection.

Conclusion

To conclude, the patent linkage system in the US has been on the receiving end of many debates as it has been contended that it values the interests of pharmaceutical companies over affordable medicines. While this particular system of patent linkage has its edge over incentivizing innovation and preventing any early patent-related issues or disputes, it causes substantial delays with regard to the approval of generic drugs. This would indeed result in making medicines more costly and limiting access to medication as well. It is important for policymakers to ensure that they ultimately strike some form of balance between protecting intellectual property and ensuring that medicines are affordable and accessible.

References

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