On Monday, October 22, 208, the US Court of Appeals for the Federal Circuit issued another blow to Allergan’s deal with the Saint Regis Mohawk Tribe (“Tribe”) by refusing to reconsider an earlier decision that rejected use of tribal sovereign immunity in inter partes reviews (IPRs). This is the latest setback for Allergan and the Tribe in their efforts to avoid IPRs before the Patent Trial and Appeals Board (“PTAB”).
 
As a general background, in September 2017, Allergan announced that they entered into an agreement with the Saint Regis Mohawk Tribe (the Tribe) in which Allergan transferred ownership of all Orange Book-listed patents for RESTASIS® (Cyclosporine Ophthalmic Emulsion) 0.05% to the Tribe, while being granted exclusive licenses in the patents related to the product. The patents transferred to the Tribe included U.S. Patent Nos. 8,629,111; 8,633,162; 8,642,556; 8,648,048; 8,685,930 and 9,248,191. RESTASIS® is an important product for Allergan since it generated around $1.5 billion in 2017. By transferring ownership of the RESTASIS® patent portfolio to the Tribe, Allergan and the Tribe hoped to dismiss the ongoing IPRs of the RESTASIS® patents based on the Tribe’s status of being a recognized sovereign tribal government to which sovereign immunity applies.
 
Thus far, however, Allergan’s strategy to avoid IPR challenges has faced significant hurdles. In February 2018, the PTAB rejected the attempt to dismiss based on tribal sovereign immunity, finding that Allergan retained ownership in the patents and the Tribe retained nothing more an “illusory or superficial right” to sue for infringement of the challenged patents. According to the PTAB, “[i]n view of the recognised differences between the state sovereign immunity and tribal immunity doctrines, and the lack of statutory authority or controlling precedent for the specific issue before us, we decline the tribe’s invitation to hold for the first time that the doctrine of tribal immunity should be applied in IPR proceedings.”
 
In July 2018, the Federal Circuit upheld the PTAB’s decision, concluding that tribal sovereign immunity cannot be asserted in IPRs, and therefore cannot be used to dismiss the IPRs filed against Allergan.
 
A month later, in August 2018, Allergan and the Tribe requested a panel rehearing and an en banc rehearing. This request was denied on Monday.
 
Despite the recent denial, Allergan and the Tribe can still appeal to the U.S. Supreme Court.
 
Allergan’s controversial move to circumvent IPRs in an effort to stave off generic drug entry adds fuel to the ongoing debate over IPR proceedings. We will keep you informed of developments related to IPRs as they occur.

On October 10, 2018 President Trump signed into law the “Patient Right to Know Drug Prices Act” (S.2554) which requires antitrust scrutiny of biosimilar settlements by the Federal Trade Commission (FTC).  The law amends the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 to require Reference Product Sponsors and biosimilar applications to submit their settlement agreements to the FTC for review. The bill was introduced in March 2018 by Senators Susan Collins (R-Maine), Clair McCaskill (D-Missouri), and Debbie Stabenow (D-Michigan).
 
The new law will allow the FTC to access the terms of a deal without seeking additional authority from the commission. It will also allow the FTC to track biosimilar deals and develop a data record of relevant terms, similar to what has been down with small molecule generics.
 
The law comes at an important time. Humira®, which is the best-selling drug in the world yielding more than $18 billion in sales in 2017, entered the market in Europe this past Tuesday on October 16, 2018. However, no biosimilars of Humira® are expected to enter the market in the US until at least 2023. This is because in the US, AbbVie not only maintains a robust patent portfolio protecting Humira®, it has also reached deals with multiple biosimilar manufacturers, including Amgen, Samsung Bioepis, Mylan, Sandoz, and as of yesterday, Fresenius Kabi, to hold off competition until 2023.
 
Apart from this new law, other legislations addressing settlement agreements are also moving forward in Congress. It will be interesting to see if these legislations will increase the entry of biosimilars on the US market.
 
We will keep you informed of any new developments in this field.
 

It has been one year since the Federal Circuit issued its opinion in Amgen v. Sanofi that raised the hurdle for protecting antibody inventions by requiring more data when disclosing and claiming antibodies. Since the court decision on October 5, 2017, it has become more challenging for pharmaceutical companies to obtain broad protections for therapeutic monoclonal antibodies. While obtaining protection for antibodies is still very much possible in this current climate, certain types of claims are now more susceptible to attack and possible invalidation. Below we analyze the different types of claims protecting antibody inventions and discuss their relative strengths in the wake of Sanofi.

In Amgen v. Sanofi, the Federal Circuit ruled that in order to obtain broad patent coverage for a class of antibodies that bind to a particular antigen and perform a particular function, companies must disclose a sufficient number of representative antibodies across the claimed genus or establish a clear relationship between the function of the antibody and the genus of the antibody in their specification. In Sanofi, the claims were directed to a monoclonal antibody that bound to one or more of 15 different amino acid residues on the sequence of the target antigen and performed a certain function (e.g., blocked the antigen from binding to its target). Claim 1 of U.S. Patent No. 8,829,165 ("'165 patent") is representative. It recites:

“An isolated monoclonal antibody, wherein, when bound to PCSK9, the monoclonal antibody binds to at least one of the following residues: S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, or S381 of SEQ ID NO:3, and wherein the monoclonal antibody blocks binding of PCSK9 to LDL[-]R.”

To support its claim that antibodies that bound one of the 15 residues or any combination of them were covered by the patent, Amgen disclosed two specific antibodies with binding data and affinity data. These data probably would have been sufficient prior to Sanofi. In Sanofi, however, the Federal Circuit ruled that such disclosure was insufficient. The court noted that patent specifications must disclose a representative number of species of the genus of claimed antibodies in order satisfy the written description requirement. The Federal Circuit did not, however, provide any guidance as to what a “representative number” of species would be. Therefore, it still remains an open question as to what counts as a representative number of species remains today.

Below we review several types of antibody-related claims in search of trends on which types of claims have fared better than others in the last year.

By Function
Historically, one of the broadest types of claims a company could get to an antibody was by its function. Functional claims to a genus of antibodies typically recite the functional property of an antibody without reciting any sequence information, for example “an antibody that binds to target Y”. Similarly, functional claims can be in the form of competition claims where “an antibody that competes with antibody X for binding to antigen Y” is covered.  While such broad claims can cover nearly any antibody in a group of antibody products that are directed to the same target, such functional claims are becoming increasingly vulnerable in light of Sanofi, as courts will require a “representative number” of examples of the genus, i.e. a representative number of antibody sequences and associated binding data.

Method of Use/Treatment
Method of use or method of treatment claims have also proven to be vulnerable as these types of claims have not fared well when challenged in an Inter Partes Review (IPR) at the PTAB. These types of claims are by far the most popular target of IPR petitioners. In a study of antibody-related IPR petitions, the IPR petition grant rate on method of treatment claims is 65% (24 petitions granted, 13 denied), but, in all 6 of the Final Written Decisions to date, all instituted claims were held unpatentable.  Therefore, it appears that if the PTAB institutes an IPR on a method of treatment antibody claim, those claims are likely to be found unpatentable. One potential reason for why these types of claims are easy to invalidate is because if you knew the antigen and what it does, it would be obvious to develop an antibody to treat people against that antigen. As such, method of use and method of treatment claims are probably the weakest types of claims in protecting antibodies.

Sequence
On the opposite side are sequence claims. These types of claims define an antibody by its structure, which is most commonly claimed by its six complementary determining regions (CDRs), by its two variable regions, or even by its heavy and light chain sequences (both cDNA and peptide sequences). Patent prosecutors keen on obtaining the most protection for clients will attempt to claim sequences by the shortest and fewest number of sequences possible. Often times the amount of sequence data needed to pass examination hurdles will depend on the examiner. These types of claims will likely survive invalidation attempts because they are specific to one particular antibody. However, while antibody sequence claims are a strong type of claim to have, they are also the narrowest option, which makes them easier for a competitor to design around.

Pharmaceutical Composition
Besides claiming the antibody itself, a company can claim a pharmaceutical composition or formulation. While these types of claims are theoretically easier to design around because they include the antibody structure, they appear to be successful in surviving IPR challenges at the PTAB. In fact, the PTAB rarely institutes challenges to composition claims, and when it has, the claims almost always survive. Antibody formulation claims are the second most frequently challenged type of antibody claim behind method of treatment claims, discussed above. However, of the 13 IPRs that have been filed against claims to antibody formulations, three were instituted and 10 were denied. In the three instituted IPRs, all of the claims survived the challenge. Of the IPR petitions that were denied, most were because the petitioner failed to establish “a reasonable likelihood that the petitioner would prevail.” It is likely that these types of claims survive challenges because there is high unpredictability in the art since even small changes in antibody formulations can have unexpected effects on protein aggregation, viscosity, and other factors, making it harder to prove that such formulations are predictable and obvious. As such, pharmaceutical formulation patent are important to include when deciding how to protect antibodies.

Antibody-Drug Conjugates
A final type of patent for protecting an antibody is to develop antibody conjugates. These types of claims describe an antibody with a particular sequence fused to, or conjugated to, a drug. In an IPR challenge to Kadcyla®, an antibody-drug conjugate consisting of the monoclonal antibody trastuzumab, Herceptin®, linked to the cytotoxic agent emtansine, the PTAB ultimately upheld the claims because a person skilled in the art at the time of the invention would have expected Herceptin®-maytansinoid immunoconjugates to be unacceptably toxic. While claims to antibody conjugates may survive obviousness challenges, it is important to remember that they are also narrower because they describe both the antibody sequence and a drug. They will also likely face challenges as to how much data and support is required to be in the specification to broadly claim the antibody conjugate. Nevertheless, these types of claims may be valuable to an antibody patent portfolio.

The case law in the antibody space has made it more challenging for companies to obtain broad protections for therapeutic monoclonal antibodies, especially in the wake of the Sanofi decision. To maximize the value of your antibody portfolio, it is therefore important to review the antibodies on a case-by-case basis and decide which features to claim based on the amount of data and investment available.

Brand companies employ a variety of mechanisms to maintain their market exclusivity and delay generic entry. We have recently written about Johnson & Johnson’s rebate and bundling schemes in trying to hinder uptake of a Remicade® biosimilar. We have also written about Allergan’s attempts to sell its patents covering Restasis® to an Indian tribe in an effort to avoid inter partes review challenges. Well, Allergan again finds itself again in the middle of a dispute that touches on intellectual property, this time Allergan is alleged to have engaged in anticompetitive practices to delay generic competition because of its misuse of citizen petitions.

While citizen petitions are supposed to allow citizens an opportunity to raise legitimate safety concerns with the U.S. Food and Drug Administration (FDA), they have often been misused by innovator drug companies as a way of delaying generic market approval. One study analyzed all citizen petitions filed with the FDA between 2011 and 2015 that targeted pending generic drugs and found that innovator manufacturers file 92% of all the citizen petitions, with the FDA denying nearly all these petitions.

This situation arose recently in a class action case filed against Allergan Inc. alleging antitrust violations aimed at protecting its dry-eye drug Restasis®. Amongst other violations, the suit alleged that Allergan filed four baseless citizen petitions in an effort to hinder generic competition. Allergan filed a motion to dismiss this claim asserting that the suit was “meritless”.

Last week, however, U.S. District Judge Nina Gershon shot down Allergan’s efforts to sidestep the suit and sided with plaintiff union benefit plans and various pharmaceutical purchasers, claiming that it is probable that Allergan acted dishonestly in hindering generic competition.

In its ruling, the Federal judge declined to apply the Noerr-Pennington doctrine, which shields good-faith petitioning of the government even if it results in a competitive edge. She provided two reasons for not applying the doctrine.

First, Judge Gershon noted that the doctrine does not protect “objectively baseless” petitioning. Since the FDA denied each of Allergan’s petitions, the Judge found that it could be probably that the petitions were scientifically unfounded.

Second, Judge Gershon noted that that the doctrine does not protect actions that are solely intended to hinder competition. Since Allergan petitioned the FDA repeatedly asking for testing of generic Restasis® in human, something not required for generic drugs, and then did not appeal the FDA’s rejections of its petitions but instead filed subsequent petitions using duplicative motives, the Judge found that Allergan’s actions could show that Allergan filed the petitions with improper motives. According to Judge Gershon, “[i]t is highly plausible that a company willing to engage in such conduct was intending to delay the entry of generics into the market, rather than seeking to protect the public health.”

Citizen petitions are a legally protected act so attacking them under antitrust law has traditionally been difficult. To prove that a citizen petition violates the law, plaintiffs have to show they are so baseless that they constitute a total sham. This case shows that its is possible to clear the first hurdle in demonstrating that citizen petitions are a sham and thus shows a possible path forward for generic drug plaintiffs hit with such petitions in future disputes.