According to a recent law, the Federal Trade Commission and Department of Justice will review possible pay-for-delay settlements. Will this help biosimilars?

So I believe the act that the president passed in relation to getting information about settlements in the biologics space is in, I believe, the Collins act, and I think it will allow the Federal Trade Commission, the FTC, to at least start getting those documents and those agreements and making sense of if there is anti-competitive behavior that is happening.

We believe that is an important step—long overdue considering the Biologics Price Competition and Innovation Act has been around since 2009. This has existed in the small-molecule space under Hatch-Waxman that the FTC is entitled to get all of these documents.

So I think it’s a positive step, so the question remains whether the FTC has the ability and the powers too really enforce some of the anti-trust options that it might have. Unfortunately, companies have become very good at redefining what is a pay-for-delay settlement, they offer different incentives to the biosimilars companies, and those are not really fitting in the normal standard pay-for-delay descriptions that the Supreme Court has warned against in 2013 I believe.  

Videos

Tahir Amin, DipLP, co-founder and director of intellectual property of Initiative for Medicines, Access, and Knowledge, considers whether a recent law could help biosimilars. 

Tahir Amin: Pay-for-Delay Settlements

How might including patents in the Purple Book affect developers?

For generics point of view, putting patent information in the Purple Book would be a huge improvement to the status quo. Right now, there’s a lot of uncertainty about what patens could be asserted, when they would be asserted, and even how they would be asserted. We’ve heard a lot about the patent dance in literature and publications, but having that listing, much like there’s already that Orange Book for small molecules, would really give guidance to the generics to see what are the patents, what are the expiration dates, and what is a pathway to get to a generic biologic?

I would add from a brand point of view, it would also be very helpful because they would have certainty as well about which patents apply to which products and therefore can put up their own hurdles in terms of what patent information they would like to have listed.

Finally, there is one challenge having information on the Purple Book like the Orange Book, and that is so many biologics patents are process patents, how to make the biologic, or tools to get to the biologic. That’s very different because the Orange Book currently does not allow for listing of process patents, and therefore those aren’t in the Orange Book at all. That would be a big difference to keep an eye out for.

Imron Aly, JD, partner at Schiff Hardin LLP, discusses the impact of listing patents in the FDA's Purple Book.

Imron Aly, JD: Putting Patents in the Purple Book

Would disclosing drugs' list prices in ads help drive down prices for patients?

To be honest, I don’t think disclosing list prices is really going to have the difference that we need to see in the current marketplace, in the current crisis that we’re facing regarding drug pricing.

I think it’s useful to have the list pricing there, but will that really change essentially where the abuse is really happening? We believe it has to lie in changing the patent system, in changing how we hand out 20-year monopoly periods to companies. Until you do that, you really aren’t going to see marked changes, and companies will find other ways to strategically cover up the list pricing in other ways.

I don’t think that’s a measure that really helps. I think that’s really a deflection, if anything, [rather than] going to the source of the problem.

Tahir Amin, DipLP, co-founder and director of intellectual property of Initiative for Medicines, Access, and Knowledge, discusses whether including drugs' list prices in consumer advertising will help drive down prices for patients.

Tahir Amin: Drug Prices in Advertising

What are the key features of the Biosimilar Action Plan?

I would say there are 3 features of the plan that have caught my eye. One is education, 2 is interchangeability, and 3 is international data sharing. 

For the first point for education that is key in the biosimilars world because the US has waited for regulatory agencies abroad to really take the lead and test and determine what would be acceptable to the market and to physicians. So in the US, part of the plan is to improve the education and outreach so everybody will have more knowledge about what’s happening around the world and what can happen here too. 

The second part for interchangeability--what’s very important for any generic drugs to be motivated--is to be interchangeable for the brand and that way, so that there’s a prescription for the brand of course it can be interchangeable with and substituted by a generic. That is proven to be a high hurdle to biosimilars and part of the plan is meant to address that feature as well. 

The third part is international outreach, and this is important, because the plan is trying to get information from other agencies, particularly the [European Medicines Agency, EMA] in Europe, to make sure that what they are doing is working and learn from it and actually try to implement it here in the United States. 

Imron Aly, JD, partner at Schiff Hardin LLP, discusses the Biosimilar Action Plan's key features.

Imron Aly, JD: The Biosimilar Action Plan

By 2020, some products that are currently regulated as drugs, like insulin, will be regulated as biologics. Does this fact pose any challenges—or opportunities&mdash;from the patent litigation standpoint?

There is an incredible amount of uncertainty that surrounds the change in regulation of these products, not only with respect to the FDA approval process, but also when it comes to litigation. While the FDA has put out a draft guidance titled “Implementation of the ‘Deemed to be a License’ Provision of the Biologics Price Competition and Innovation Act of 2009”—that’s a mouthful&mdash;there still remain a host of questions for innovators and generic and biosimilar manufacturers.

First of all, there isn’t a complete list of all the drugs that will be changed over, as the FDA has only provided an example list in its draft guidance, so it is unclear specifically which drugs will be affected. It’s possible we could see litigation over those determinations alone.

For drugs that are affected, there are numerous considerations that will be relevant to the innovators and the generic and biosimilar manufacturers.

First, for drugs already approved as of March 23, 2020 either through the 505(b)(2) application process or an [Abbreviated New Drug Application, ANDA], it is not clear how they will be re-assigned as biologics. Those approved under the 505(b)(2) process could become reference products, biosimilars, or interchangeable biologics. Those approved under an ANDA could become either biosimilars or interchangeable biologics. It’s very possible we could see litigation over how these determinations are made alone.

Next are the drugs that are awaiting final approval as of March 23, 2020. In its draft guidance, the FDA has noted that the change-over between application types will be for all drugs that have not been approved prior to March 23, 2020. 

That means that even tentatively approved drugs could have their applications cancelled and would need to submit new applications under the biosimilar pathway, including the additional testing required to establish biosimilarity. This leads to a great deal of uncertainty for generic and biosimilar companies, as they won’t necessarily know whether or when their drugs will be approved and what regulations and what litigation options will be available.

For any of these drugs involved in ongoing litigations as of March 23, 2020, it is unclear how the litigation may change based on the application being cancelled. The changes could have dramatic impacts given the differences in litigation schemes between generic and biosimilar drugs.

For instance, a significant difference in litigation schemes is the 30-month litigation stay under the Hatch-Waxman Act for small-molecule drugs. This essentially assures that a specific generic small molecule cannot be approved until 30 months after the Notice Letter. The [Biologics Price Competition and Innovation Act, BPCIA] litigation scheme for biosimilar drugs does not provide for a similar stay. Innovators may need to seek a preliminary injunction to keep a generic-turned-biosimilar off the market after the application rollover.

Since drugs such as insulin were not previously regulated as biologics, they are currently listed in the Orange Book along with their relevant patents. This is different than other biologic drugs and has an impact on litigation because it takes away one of the biosimilar manufacturer’s incentives for using the BPCIA patent dance, that is obtaining a list of patents that potentially require licensing or litigation, since those patents are already listed and publicly available in the Orange Book. It may also lead to more and earlier [inter partes reviews, IPRs] since the list of relevant patents will already be known.

Additionally, the regulatory exclusivities are impacted by the rollover. Existing 5-year exclusivities for small-molecule drugs will disappear even if they have time left on them, but the 12-year exclusivity for biologic products won’t apply. Therefore, there could be new applications coming earlier than they normally would have these regulatory exclusivities are not overlapping properly. This could significantly move up the timing of litigation.

Biosimilar manufacturers will also face differences when it comes to the exclusivities they can obtain for being the first on the market. Under Hatch-Waxman, the first generic drug to enter the market receives 6-month exclusivity. In comparison, the BPCIA only provides exclusivities for products deemed to be interchangeables, not just biosimilars. Even those may not receive any exclusivity depending on the timing of the litigation.

With all the competing interests and uncertainty, it will be very interesting to see what happens in this space. One situation in particular to watch is with Lantus and its follow-on products. It currently has 1 approved follow-on product, 1 tentatively approved product, and at least 1 pending application that has been accepted by the FDA. It also has pending IPRs and pending litigations. Depending on how it this all stands in 2020, this could be a very interesting case study to follow. Information about the current status of these cases can be found on BiologicsHQ.com, and we’ll be continuing to monitor and update as it develops. 

Ha Kung Wong, JD, partner at Venable LLP, discusses how upcoming changes to the regulation of biologics are generating industry uncertainty. 

Ha Kung Wong, JD: Upcoming Changes to Biologics Regulation

Well, I was just reading this morning that the now soon-departing CEO of Pfizer actually said that business will return to normal next year, so despite some of the price stalling that has gone on, I don’t think that’s going to change. I think they’re just waiting to have the public elections happens, see what happens, waiting for the issues to shift somewhere else and then they’ll start all over again. 

If we look at the trends over the last 6 to 8 years, we’ve seen price hikes on average of 68%. There’s no reason to think that the pharmaceutical companies are going to stop hiking the prices, and this is why we believe it is imperative we start to be more strict with how we give pharmaceutical companies the power through the patent system and other exclusivities such that they’re able to do this over and over again, as our reports have shown, the longer they have these exclusivities for, they annually hike these prices up. I don’t see that being a solution. 

Tahir Amin, DipLP, co-founder and director of intellectual property of Initiative for Medicines, Access, and Knowledge, discusses whether companies' promises to stop raising drug prices will benefit patients.

Tahir Amin: Rising Drug Prices

Why will US patients have to wait longer for biosimilar adalimumab than EU patients?

The Humira question is really an interesting one. In Europe the patent litigations had already been underway, whereas in the US, they were trailing a little bit behind. So once the first filer for any biosimilar product settled in Europe—setting the dates and everything that went with that&mdash;it made it harder for others to challenge it in the US and be incentivized to continue litigation when there was a sure bet and a sure launch date coming up that probably couldn’t have been beaten anyways with a long, drawn-out fight. 

Imron Aly, JD, partner at Schiff Hardin LLP, explains how European cases influenced US patent litigation over Humira. 

Imron Aly, JD: Settlements Over Humira

Are there some ongoing cases that biosimilar stakeholders are watching closely at the moment?

, which is in the Eastern District of Pennsylvania, the first antitrust case between a biosimilar manufacturer and a reference biologic sponsor. That case involves the biologic Remicade (which is infliximab) and alleges that Johnson & Johnson engaged in a plan to keep Pfizer’s biosimilar Inflectra off the market. According to Pfizer, Johnson & Johnson had a plan involving exclusive contracts with insurance companies, which included reimbursement schemes, explicit promises not to cover Inflectra, and bundling arrangements which resulted in Pfizer’s biosimilar being kept off medical plans or only being available for patients who have already failed on Remicade. 

Johnson & Johnson had filed a motion to dismiss the complaint, but it was recently denied on August 10. Stakeholders are going to continue to follow this case very carefully, though, to see how the courts will apply antitrust laws to the complex world of biosimilar competition. 

A second set of cases that stakeholders are following are 

in the District of New Jersey which are both pending cases* involving biosimilars of Humira. 

We’ve seen that AbbVie has already settled with Mylan, Samsung Bioepis, and Amgen related to their US biosimilar versions of Humira, which will keep these biosimilars off the market until around 2023. AbbVie has also settled with Samsung Bioepis/Biogen and Amgen concerning their biosimilars of Humira in the [European Union, EU]. It will be interesting to see if these settlements continue, particularly with respect to Boehringer Ingelheim considering its biosimilar.

at the time of filming. AbbVie and Sandoz have since reached a settlement.

Ha Kung Wong, JD, partner at Venable LLP, addresses ongoing biosimilar cases that stakeholders are watching closely.

Ha Kung Wong, JD: Noteworthy Ongoing Biosimilar Litigation

What have some of the recent changes to inter partes reviews (IPRs) and post-grant reviews (PGRs) meant for biologic patent holders and biosimilar challengers?

According to PTAB statistics—and PTAB is the Patent Trial and Appeal Board&mdash;bio and pharma and chemical patent IPRs have continued to file preliminary responses at similar rates as they were prior to the rule change allowing new testimonial evidence to be submitted, with about 85% of patent owners choosing to submit a preliminary response. 

Interestingly, bio/pharma and chemical patent owners have submitted new testimonial evidence at higher rates than other technologies, with 48% of bio/pharma IPRs having new testimonial evidence submitted with the preliminary response, and 58% for chemical patent IPRs. 

This is in comparison to about 35%-40% of preliminary responses including new testimonial evidence for other technology types. We at Fitzpatrick are planning on doing an analysis specifically for biologic drug patents to see if these statistics differ from the broader bio/pharma and chemical industry and hope to report on that analysis soon. 

Overall, there may be a slight impact of allowing new testimonial evidence as according to the PTAB itself, institution rates have declined in the last 2 years from 67% in the fiscal year 2016 to 63% in fiscal year 2017, and 60% in fiscal year 2018 so far. 

It’s unclear if these declining institution rates are in any way impacted by the allowance of testimonial evidence at the patent owner preliminary response stage, but it certainly could have contributed. The important thing to keep in mind, though, is that the impact of such testimonial evidence is highly, highly fact-specific, so it really is difficult to make general statements about it.

I think a more interesting question is the potential effect of the proposed Hatch-Waxman Integrity Act of 2018 on IPRs and PGRs in the pharma space. It’s pretty significant. If enacted, this would essentially require an [Abbreviated New Drug Application, ANDA] or biosimilar applicant to choose between using the ANDA/biosimilar approval pathway or challenging a patent in an IPR or PGR proceeding. 

This would likely virtually eliminate the use of IPRs and PGRs in the biologic and small-molecule drug space. The benefits of quicker resolution of the dispute via IPR would likely be outweighed by losing the opportunity to challenge many patents under section 101 or 112—so that’s utility, enablement, indefiniteness&mdash;as these are not available in IPRs. 

With regard to PGRs, these challenges are available, but they’re only available for 9 months after patents are granted, so it’s less likely to coincide with a Hatch-Waxman litigation. So far, we’ve seen very few PGRs in the biologics context, so the availability of section 101 or 112 challenges in PGRs do not yet appear to be much of an incentive to go down this pathway. But we’re seeing PGRs in the biologics space really pick up, though, in the last couple of months, and in fact I’ve been involved with 5 of them in just the last 4 months, so it’ll be interesting to see how this sorts out in the future.

Ha Kung Wong, JD, partner at Fitzpatrick, Cella, Harper and Scinto, addresses recent changes to inter partes review (IPR) and post-grant review (PGR) proceedings with respect to biologic drugs.

Ha Kung Wong: Changes to IPRs and PGRs for Biologics

Have drug makers decided whether is it better for a biosimilar manufacturer to disclose more information upfront, or to abstain from the "patent dance" entirely?

I don’t think we can say that there has been any one consolidated or consistent decision among biosimilar manufacturers as a whole, as far as whether to engage in the patent dance or how far to proceed into it, as there are so many factors that go into the equation making each situation really unique. 

However, we can use the data we have collected for BiologicsHQ to look at what has happened particularly since the 

decision last June though. Out of all the complaints filed related to proposed biosimilars of CDER-listed reference products, all but 2 of them have stated that the parties at least began the patent dance.

 Only 2 of these complaints alleged that the biosimilar manufacturer refused to participate in the patent dance all together, and 1 of those noted that while the biosimilar manufacturer refused to participate in the patent dance, it did later provide access to its [Abbreviated Biologics License Application, aBLA] pursuant to an agreement, although not the patent dance provisions.

Therefore, we are seeing that overall biosimilar manufacturers, generally speaking, have been choosing to disclose at least some information up front. There have been a number of disputes over providing “other” information besides the aBLA and over how quickly and how completely biosimilar manufacturers have given over their aBLAs though. 

In fact while most biosimilar manufacturers are providing their aBLAs, few have been willing to turn over all the “other” information about manufacturing the innovators have requested.

Ha Kung Wong, JD, partner at Fitzpatrick, Cella, Harper and Scinto, discusses how manufacturers now approach the "patent dance" in light of Sandoz v Amgen.

Interviews