The ITC as a forum for biologic and biosimilar patent disputes

Most of the US patent litigation involving biologic and biosimilar drugs has taken place in the district courts. Although a few patent cases involving biologics have been filed in the US International Trade Commission (ITC) over the past 10 years, the number of such cases in district courts has been much larger, and there have been no ITC cases to date involving biosimilars.

This is expected to change soon, as the ITC has several unique features making it an attractive forum for asserting patents against infringing biologics or biosimilars. As the number of biologics and biosimilars on the market rises, patent owners may increasingly turn to the ITC to block infringing versions of those products from entry into the United States.

The growth of biologics and biosimilars

According to EvaluatePharma World Preview 2017, the pharmaceutical industry is set to grow at a pace of 6.5% per year to reach $1.06 trillion by 2022, up from $811 billion in 2018. The share of the market that is attributable to biologics is expected to increase from 25% in 2016 to 30% by 2022. Looking at the top 100 products, biologics are expected to overtake small molecule drugs and account for 52% of sales by 2022. Figure 1, which is taken from EvaluatePharma World Preview 2018, indicates that the market share of biologics is projected to continue increasing through 2024.

Moreover, new breakthrough biologics are likely to be approved as established small-molecule products lose patent protection. Novel biologics are now covering indications typically treated by small molecules such as Alzheimer’s, asthma, HIV, Parkinson’s, allergies, heart failure, osteoporosis, pain, osteoarthritis, stroke, malaria and chronic obstructive pulmonary disease.

Patent expiration and competition from biosimilars are expected to make a big impact over the next five years, increasing the potential for litigation as innovators seek to safeguard their investment in the R&D of biologics. Patent expiry is expected to be 37% greater during 2018 to 2022 than the previous five years for both small molecules and biologics. The peak year of impact is projected by IQVIA to be 2020.

Many of the 359 licensed biologics listed by the US Food and Drug Administration (FDA) in the Purple Book are imported. Moreover, 11 of the 17 biosimilars approved by the FDA as of the date of publication are manufactured in Austria, Ireland, South Korea and Switzerland, respectively, and have been or will be imported into the United States. Many of the biosimilars that are subject to a pending abbreviated Biologics Licence Application (aBLA) filed with the FDA are also manufactured outside the United States and will be imported into the country if approved by the FDA.

Litigating biologic or biosimilar patent cases at ITC

Historically, biologics and small-molecule drugs have made up a relatively small portion of the case load in ITC Section 337 investigations. Over the years, the commission has instituted fewer than 20 investigations involving small-molecule drugs, issuing an exclusionary remedy in at least five of those cases. The low number of such investigations is due to the fact that – as explained in more detail below – to get the benefit from the 30-month stay under the Hatch-Waxman Act, the brand must sue a generic in a US district court. With respect to biologics, the commission has instituted at least 10 investigations involving a claim for patent infringement, of which:

• three resulted in no violation;
• one terminated based on consent order;
• four terminated based on settlement;
• one had the complaint withdrawn; and
• one resulted in the issuance of a limited exclusion order against the defaulting respondent.

However, in recent years, the number of Section 337 investigations filed at the ITC has been on the rise. Over the past few years, the ITC has seen the most new investigations, totalling about 70 to 80 new filings per year. The pharmaceuticals and medical device space has also seen a rise in new investigations, totalling about 15 per year. Following this trend, recent high-profile biologics investigations have involved Recombinant Factor VIII and Factor IX and pegylated erythropoietin.

Recombinant Human Erythropoietin (Inv No 337-TA-568), which was once described by The New York Times as the “mother of all biotech patent cases”, involved a dispute between complainant Amgen and respondents Hoffmann-La Roche involving Roche’s pegylated EPO product Mircera. The investigation was initially dismissed on summary determination of non-infringement, but subsequently remanded by the Federal Circuit. The investigation was ultimately terminated based on a global settlement of both the ITC investigation and a parallel US district court action. No hearing was ever held in the ITC and no exclusion order was ever issued. The settlement allowed Roche to begin selling the accused product under licence in mid-2014.

Recombinant Factor VIII Products (Inv No 337-TA-956) was a dispute between complainant Baxter and respondent Novo Nordisk involving Novo’s Novoeight product for the treatment of haemophilia, which was instituted on 18 May 2015. The commission instructed the administrative law judge (ALJ) to make findings of fact on the public interest factors and issue a recommended determination on remedy, bond and the public interest. Following a hearing, an initial determination was issued by the ALJ finding no violation on the grounds that:

• one patent was found to be invalid based on anticipation and obviousness, and Baxter was found not to have satisfied the economic prong of domestic industry for this patent; and
• the other asserted patent was found to be valid and infringed, but Baxter was again found not to have satisfied the economic prong of domestic industry for this patent.

The ALJ also recommended the issuance of a limited exclusion order and a cease and desist order if the commission disagreed with the ALJ’s finding of no violation. The commission reversed the initial determination on domestic industry for both patents and indicated that it would review the claim construction, infringement and invalidity rulings with respect to the patent that was found to be invalid, as well as the ALJ’s findings on remedy, bond and public interest. The parties settled the dispute before the commission completed its review, which resulted in the termination of the investigation on 28 September 2016.

Recombinant Factor IX Products (Inv No 337-TA-1066) was a dispute between complainant Bioverativ and respondent CSL Behring involving Behring’s Idelvion product for the treatment of haemophilia, which was instituted on 8 August 2017. Following a claim construction ruling, Bioverativ withdrew the complaint and the investigation was terminated on 6 February 2018.

No investigations have yet been filed or instituted involving biosimilar products. However, it is expected that the situation with respect to biosimilars will change for the following reasons:

• Virtually all biosimilars that have been approved in the United States or are the subjects of pending aBLAs have been targets of litigation in US district courts or at the US Patent Trial and Appeal Board.
• A substantial number of approved biosimilars and biosimilars that are the subjects of pending aBLAs are manufactured abroad and imported into the United States.
• As illustrated in Figure 2, several new biosimilars are expected to be approved in the United States in 2019.

These facts suggest that ITC Section 337 proceedings involving biosimilar products cannot be too far behind.

ITC can provide viable alternative or supplement to ‘patent dance’

The Biologics Price Competition and Innovation Act, which was enacted in 2010, established a regulatory pathway for biologics analogous to the older Hatch-Waxman pathway for small molecule drugs. Like the Hatch-Waxman Act, the Biologics Price Competition and Innovation Act sets up a procedure for resolving patent disputes between the aBLA filer and the reference product sponsor (RPS), but it differs significantly from that of the Hatch-Waxman Act. The key elements of the Hatch-Waxman framework – listing patents in the Orange Book, Paragraph IV challenges to those patents and an automatic 30-month stay of approval on the timely filing of an infringement suit – are absent from the Biologics Price Competition and Innovation Act.

Instead of an Orange Book-type publication detailing all patents claiming a given biological product or methods of using it, the Biologics Price Competition and Innovation Act provides for exchanges of information between the applicant and the reference product sponsor through which the patents relevant to a proposed biosimilar can be identified. The process involves so many steps by each side that it is commonly referred to as the ‘patent dance’. It is intended to result in two rounds of litigation: an “immediate patent infringement action” and a second round of litigation after the applicant has given notice that it will commence commercial marketing of the product in no less than 180 days, which is summarised below.

Immediate patent infringement action under Biologics Price Competition and Innovation Act

• Within 20 days of FDA acceptance of the aBLA, the applicant provides application and process(es) for manufacture (42 USC §262(l)(2)).
• Within 60 days of receipt of aBLA and manufacturing information, the RPS provides the patent list (262(l)(3)(A)).
• Within 60 days of receipt of the (3)(A) list, the applicant may provide a second patent list (262(l)(3)(B)(i)) and claim-by-claim contentions of invalidity, unenforceability and/or no infringement for all patents identified on the (3)(A) and (3)(B) lists or a statement of no intention to market until the patent expires (262(l)(3)(B)(ii)).
• Within 60 days of receipt of any (3)(B) list contentions, the RPS provides a response to the contentions (262(l)(3)(C)).
• Within 15 days after the exchange of contentions, the parties negotiate to agree on the patents subject to immediate patent infringement action (262(l)(4)(A)); the RPS must bring infringement action on the agreed-on patents within 30 days (262(l)(6)(A)).
• If no agreement is made within 15 days, the applicant must notify the RPS of the number of patents (this can be limited to one) and within five days following this notice, the parties exchange lists of patents not exceeding this number (262(l)(5)).
• Within 30 days after the exchange, the RPS must bring an immediate patent infringement action on all patents on the simultaneously exchanged lists (262(l)(6)(B)).

Figure 2. Top 10 biotech medicines global spending and expected first biosimilar availability in the United States

Second round of litigation under Biologics Price Competition and Innovation Act

• When the applicant provides the required 180 days’ notice of commercial marketing, the RPS is then free to assert and seek preliminary injunctions on other patents on the parties’ (3)(A) or (3)(B) lists that were not selected for immediate patent infringement action (262(l)(8)).

ITC alternative or supplement

There are several situations in which the ITC could be an attractive alternative or supplement to the Biologics Price Competition and Innovation Act patent dance. As discussed below, a necessary predicate to each of these situations is that the ITC has jurisdiction over the accused product. For example, this arises when an approved biosimilar has been imported; a biosimilar that is the subject of a pending aBLA has been imported for uses not protected by the safe harbour of 35 USC §271(e)(1); and/or import and infringement are imminent.

RPS does not want to wait

Despite the name ‘immediate patent infringement action’, there is nothing immediate about the first round of litigation under the Biologics Price Competition and Innovation Act. It can take over eight months to file an infringement suit if the parties go through the patent dance steps outlined above. If the RPS forgoes the dance and proceeds in the ITC, it can expect to go to trial in about nine months.

Ability to assert all relevant patents

Not only could an RPS following the patent dance have to wait over eight months to file suit, it could also be limited to asserting only one patent. The Biologics Price Competition and Innovation Act allows the biosimilar applicant to limit the immediate patent infringement action to only one patent; any other patents cannot be asserted until the applicant gives its 180 days’ notice of commercial marketing. In the ITC, the RPS could assert all relevant patents in one or more complaints. To the extent that one complaint is filed and there are a significant number of unrelated patents, the complaint may be severed into multiple investigations under new Commission Rule 210.10(a)(6), which became effective on 7 June 2018.

Attacking biosimilar applicant on two fronts

Even if the RPS chooses to follow the Biologics Price Competition and Innovation Act patent dance through the filing of an immediate patent infringement action, it could assert any additional patents that were not selected for the first round of litigation in the ITC without having to wait for the applicant’s 180-day notice.

RPS has lost right to enforce a patent or obtain injunctive relief

If the RPS fails to list a patent on its (3)(A) list, it loses the right to assert that patent in district court (35 USC §271(e)(6)(C)). If it lists a patent but fails to file an infringement suit within 30 days of the (4)(A) or (5)(B) lists, or if it files suit within 30 days but the suit is dismissed without prejudice or was not prosecuted in good faith, the only relief for infringement of that patent in a district court is a reasonable royalty (35 USC§271(e)(6)(B)). There are no such restrictions on the RPS’s ability to assert such patents in the ITC.

Newly issued patents

If the RPS obtains a new patent that is relevant to the biosimilar after the service of the (3)(A) list, it must supplement its (3)(A) list within 30 days of the patent’s issuance. The applicant must provide its contentions regarding that patent within 30 days thereafter. The RPS cannot assert this later-issued patent until the second round of litigation, after the applicant provides its 180-day notice of commercial marketing (§262(l)(7)). There is no such restriction against asserting a newly issued patent in the ITC.

Applicant fails to provide application or manufacturing information

Some biosimilar applicants have failed to cooperate in providing their aBLAs and/or the manufacturing information required (§262(l)(2)(A)). The RPS can obtain this information under the Biologics Price Competition and Innovation Act, but it can be a time-consuming process in a district court. The relevant information could be obtained much faster at the ITC, where discovery proceeds immediately on institution of an investigation and at a much faster pace than in a district court.

Long time before an applicant can launch the biosimilar

Section 262(k)(7) of the Biologics Price Competition and Innovation Act provides 12 years of market exclusivity from the first approval of the reference product, but allows aBLAs to be filed four years after approval. Thus, the RPS can have up to eight years of exclusivity remaining when the patent dance commences. Similarly, the dance may have commenced and the applicant provided a statement under §262(l)(3)(B)(ii)(II) with respect to a patent that has many years to run. This is analogous to a Paragraph III certification under the Hatch-Waxman Act and means that the applicant will not begin commercial marketing until that patent expires.

Patent owners in the Hatch-Waxman context often elect not to file an infringement suit within 45 days of receiving a Paragraph IV notice, thus giving up the 30-month stay, if a Paragraph III certification or orphan drug exclusivity prevents the generic from launching for several years in any event. No one wants to spend money on litigation before they have to. The RPS in the biosimilars context might similarly want to defer litigation when market exclusivity or a Section II statement with respect to a late-expiring patent delays the launch of the biosimilar for many years.

If the RPS begins the patent dance but fails to file suit on any patents on the (4)(A) or (5)(B) lists within 30 days, it loses the right to obtain injunctive relief for infringement of that patent in a US district court. As mentioned above, if the RPS fails to list a patent on the (3)(A) list, it loses the right to bring any action for infringement of that patent in the US district courts. There are no such restrictions in ITC proceedings. Thus, if the RPS wishes to defer litigation until a time closer to the expiration of its market exclusivity period or the expiration of a patent named in a Section II statement, it can assert its patents in the ITC even though it may have given up some or all of its rights to relief in a district court.

Obtaining jurisdiction over accused imports

As mentioned above, to benefit from a 30-month stay under the Hatch-Waxman Act, a brand must sue a generic filer in a US district court. Therefore, Hatch-Waxman cases involving imported small molecule drug products are not brought in the ITC. However, imported licensed biologics and biosimilars, imported medical devices and imported small molecule drugs covered by non-Orange Book patents (eg, patents covering their methods of manufacture) – none of which are subject to a stay of approval on the filing of an infringement suit – are viable candidates for ITC Section 337 jurisdiction.

There are further restrictions under which ITC jurisdiction can be obtained with respect to an unapproved biosimilar product that is the subject of a pending aBLA. Although 35 USC §271(e)(2)(C) makes it an act of infringement to file an aBLA if the applicant seeks to market the biosimilar before the expiration of the relevant patents, Section 337 of the ITC Statute requires more: the import of an infringing product into the United States, a sale for import or a sale in the United States after import. The filing of an aBLA for a foreign-made biosimilar indicates that the biosimilar will eventually be imported for sale within the United States if the aBLA is approved. This might support declaratory judgment jurisdiction in a US district court, but the ITC has no express authority to issue declaratory judgments.

However, the ITC will assert jurisdiction over infringing products whose import into the United States is “imminent” or, as the commission has put it, when the infringement is in its “incipiency”. Such imminent import might be found where the aBLA applicant provides its 180-day notice of commercial marketing near, on or after the biosimilar’s approval. Obtaining jurisdiction is less likely if notice is given early in the aBLA process as permitted by the Supreme Court in Sandoz v Amgen (137 Supreme Court 1664 (2017)). In this case, Sandoz gave notice “[one] day after the FDA informed Sandoz that its application had been accepted for review”. The Supreme Court held that this was permissible since notice may be provided at any time “before licensure”. Because such early notice is given at a time when approval by the FDA is far from certain, it is unlikely to support ITC jurisdiction under the theory of imminent import.

Whether aBLA holders will follow Sandoz’s approach and provide early notice or provide notice near, on or after approval is unclear. However, aBLA holders will be sure to consider that notice of commercial marketing triggers the right by the reference product sponsor to seek preliminary injunctive relief. This may discourage aBLA holders from giving early notice.

Under Section 337, the ITC also has broad powers to address import practices, including those in their incipiency. As noted by the commission in Application for the Continuous Production of Copper Rod (Inv No 337-TA-89): “the provision relating to unfair methods of competition in the import of goods is broad enough to prevent every type and form of unfair practice” including jurisdiction to “prevent acts in their incipiency”. Such incipient activities that can give rise to jurisdiction over a biosimilar product pre-approval or otherwise are a “contract for sale” as well as assembling a “stock of infringing articles” before their import. Just as the commission has recognised its authority to prevent the incipient import of infringing articles before their import, so too does the commission have jurisdiction to prevent the incipient sale of a stockpile of infringing articles after their import into the United States (eg, when stockpiling occurs in anticipation of FDA approval).

The ITC also has jurisdiction over imported articles for accused activities outside of the safe harbour under 35 USC §271(e)(1). For example, if an aBLA filer has imported a product for the purpose of clinical or preclinical tests for FDA approval and the patent owner believes that the applicant’s uses of the product have exceeded what is permissible under Section 271(e)(1), the commission assumes jurisdiction and dismisses the complaint on the merits if the safe harbour applies.

Analysing ITC public interest factors

Where a patent is found valid and infringed, and the domestic industry requirements are satisfied, the ITC must issue an exclusion order unless such an order would contravene the public interest. In 2010 the commission began delegating authority to the ALJs to take evidence and hear arguments on the statutory public interest factors, and this has occurred in approximately 100 investigations to date. However, historically, the denial of an exclusion order on public interest grounds by the commission or by the Office of the US Trade Representative on behalf of the president has been extremely unusual.

The commission has not yet decided whether exclusion of a biosimilar or biologic product would be against the public interest. Public interest concerns are less likely to be an obstacle to obtaining exclusion orders against infringing biosimilars, provided that demand can be met by the RPS’s product or another alternative product. Under the Biologics Price Competition and Innovation Act, a biosimilar must be “highly similar” to the reference product it is intended to mimic, with “no clinically meaningful differences in terms of safety, purity, and potency”. One likely key difference between a biosimilar and its reference product is price. However, in the context of small-molecule drugs, the commission has ruled that the lower cost of an infringing generic did not weigh against an exclusion order. The result should likely be the same for biosimilars.

Outside the biosimilars context, biologics cases may raise substantial public interest issues. For example, in Recombinant Factor VIII (Inv No 337-TA-956), after considering evidence on the public interest factors, the ALJ recommended a limited exclusion order and a cease and desist order, if a violation was found. However, the ALJ further recommended that these orders should not apply to imports for clinical trials within the scope of the safe harbour of 35 USC §271(e)(1), and that patients now taking Novoeight be given until 60 days after the conclusion of the presidential review period to transition to alternative products. In its review of the ALJ’s recommended remedy, the ITC asked the parties and the public to address several issues relating to the possible exclusion of the accused Novoeight haemophilia treatment, including:

• the alternatives to the accused product, and what criteria should be used to identify them;
• the likelihood that a patient currently using Novoeight and who has insurance coverage for Novoeight will also have insurance coverage for a comparable medication;
• the costs that patients will incur in the process of switching from Novoeight to a comparable alternative;
• the therapeutic and safety advantages, if any, of Novoeight over other competing medications;
• whether patients have better therapeutic outcomes with Novoeight than other alternatives, and if so, the risks of requiring a patient to switch from Novoeight to a medicine that is less effective;
• whether the ITC should take into account haemophilia A patients’ well-documented fear of developing an inhibitor upon switching haemophilia A medications;
• whether any remedial order should be delayed to allow all individuals who are currently using Novoeight to transition to a different medicine;
• whether any remedial order should be tailored to allow current users to continue to obtain Novoeight; and
• whether any remedial order should be tailored to allow individuals who are seeking treatment for haemophilia A for the first time to have access to Novoeight if alternative medications are not suitable.

After extensive submissions by the parties and third parties, including patients, caregivers, medical doctors and directors of haemophilia treatment centres, the 956 investigation terminated based on settlement before any of the foregoing issues were addressed by the ITC.

The commission’s concerns about the foregoing issues suggest that a key consideration in biopharma investigations is whether the patients currently being treated with the accused product can make a seamless transition to an alternative product. In future investigations, the commission may likely consider tailoring an exclusion order to facilitate such a transition if warranted (eg, by delaying enforcement or allowing continued access for certain patients). This would be consistent with the upward trend of tailored exclusion orders that have issued in other investigations involving different technologies since the commission began delegating authority to the ALJs to take evidence on the statutory public interest factors. For example, in one investigation involving mobile communications devices (Inv No 337-TA-710), the commission allowed a four-month transition period and, in another investigation involving television sets (Inv No 337-TA-910), an ALJ recommended a delay of enforcement for as many as 12 months.

Comment

Besides the usual advantages of filing a Section 337 complaint (eg, no personal service, jurisdiction or venue issues, speed of the proceeding and streamlined process for obtaining injunctive relief), the ITC may be especially attractive for disputes involving biosimilars to the extent that it frees the patent owner from the cumbersome and time-consuming restrictions of the patent dance under the Biologics Price Competition and Innovation Act. Although there have been no Section 337 investigations involving biosimilars to date, Section 337 investigations involving biologics appear to be on the rise, and it is likely that patent owners will soon start to take advantage of Section 337 investigations as a powerful tool for enforcing patents against imported biosimilar products as well.