In January 2019, the Supreme Court denied certiorari in Amgen Inc., Amgen Manufacturing Ltd., and Amgen USA, Inc. v. Sanofi, Aventisub LLC, Regeneron Pharmaceuticals, Inc., and Sanofi-Avantis U.S., LLC, a case that asked the Court to review the law related to the written description requirement of 35 USC Section 112. We previously discussed the case here. This case arose when Amgen sued Sanofi and Regeneron, alleging that their monoclonal antibody product, Praluent® (alirocumab), infringed Amgen’s patents. In ruling on the case, the Federal Circuit (872 F.3d 1367, Fed. Cir. 2017, “Sanofi”) essentially overturned the “well characterized antigen” test, which allowed an antibody product to be described by the antigen that it binds, and held 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 essence, the Federal Circuit’s decision in Sanofi raised the bar for protecting antibody inventions by requiring more data when disclosing and claiming antibodies. The Supreme Court’s refusal to review the Federal Circuit decision means that the standard for obtaining broad protections for therapeutic monoclonal antibodies will continue to be challenging.
In view of the Federal Circuit’s holding in Sanofi, the question becomes: how can a company build a patent portfolio that can withstand invalidation under Sanofi and withstand other challenges? The answer is: by building a multi-layered portfolio offering many different layers of protection.
A great example of a patent portfolio with many layers, creating a so-called “patent thicket,” is the patent portfolio protecting Humira®, also an antibody. Despite the challenges and invalidations of one of Humira’s core patents (the ‘135 patent) over the summer of 2017, no competitor can market a biosimilar of Humira in the US until at least 2023. This is because Humira® is protected by more than 110 patents, some of which extend its patent term all the way to 2034. Humira’s portfolio is so robust that several biosimilar manufactures have entered into settlement agreements with Abbvie that would delay the U.S. launch of a Humira®-based biosimilar product until 2023 rather than litigate the patents. While 2023 cuts Humira’s patent market exclusivity by more than a decade, Abbvie can still market Humira without competition more than five years beyond the expiration of the ‘135 patent, the patent that was invalidated by the PTAB.
The strength of Humira’s patent portfolio comes from several aspects. First, it is big. There are more than 110 patents protecting various aspects of the drug. Such a large portfolio is designed to continue standing even if a few patents may be invalidated.
Second, Humira’s portfolio is also very diverse. In a presentation in October 2015 entitled “Broad U.S. Humira Patent Estate”, Abbvie outlined its strategy: to cover every aspect of the drug. Abbvie listed 22 patents for various diseases or methods of treatment, 14 on the drug’s formulation, 24 on its manufacturing practices, and 15 “other” patents.
Third, Humira’s portfolio is staggered. By not filing all the patent applications at one time, Abbvie was able to extend Humira’s patent term to 2034, 16 years past the initial expiration of the primary patents in 2018.
Of course, it should be mentioned that a portfolio like Humira’s comes with a very steep price tag and not all companies are in the position to invest that much into patent protection. Nevertheless, creating layers within the portfolio as well as within each patent can greatly enhance the chances that at least some patents and claims will remain valid despite challenges and even changes to the laws.
For antibody patents, this can be done in several ways. First, each patent should claim the subject matter using several different formats yielding differences in scope so that even if some claims are invalidated in a post-grant challenge, other claims within the same patent still remain valid. Let us examine functional claims, for instance. Although functional claims directed solely to antigen binding are likely invalid under Sanofi, claiming by function should not entirely be ignored. Instead such claims can be strengthened by adding backup claims, including a set of narrower claims that include parts of the antibody sequence or other features of the antibody that have a greater chance of withstanding a challenge. Including one or two backup claim sets could thus increase the chances that the entire patent is not invalidated in a challenge. Further, functional elements could be combined with structural elements in the same claim, creating hybrid claims as well.
In addition to including multiple layers of claims within each patent application, the portfolio should also be chronologically staggered to include a range of different patent claims that act to extend the patent term. In the antibody space, there are several different types of claims available to developers of therapeutic antibodies. These include sequence claims, pharmaceutical composition claims, function claims, methods of treatment, and antibody-conjugate claims. To build a strong patent portfolio, each of these patent claims can be utilized at different points in the development process. For instance, the core patent could be a composition patent directed to the complimentarity determining region (CDR) sequences of the actual antibody. Later, claims directed to methods of treatment, compositions, and antibody-conjugates (if applicable) can be included. These later filed patents would serve to extend the patent life of the antibody beyond the expiration of the core composition patent.
Patenting antibodies has become more challenging in the wake of the Federal Circuit’s decision in Sanofi. When patenting antibodies, it is now more important to review each antibody on a case-by-case basis and decide which features to claim, and how best to claim them, based on the amount of data and investment available. By taking advantage of the different types of patents claims that are available for antibodies and by including backup claims in the form of layering, a company can increase the likelihood that at least some of the claims will remain patentable when the patent is subject to invalidation.
On Monday, February 11, 2019, the US Patent Trial and Appeals Board (PTAB) denied Dr. Reddy’s petition requesting institution of inter partes review (IPR) of Celgene’s myelodysplastic syndromes (MDS) patents (IPR2018-01504, IPR2018-01507, IPR2018-01509). This is the latest development in a dispute that has garnered much attention since Bristol Myers Squibb (BMS) announced last month that it planned to acquire Celgene in a deal valued at $74 billion. The question now is how does Dr. Reddy’s loss at the PTAB change Dr. Reddy’s overall strategy and outlook? The short answer is that while Dr. Reddy’s best-case scenario is likely off the table, little else has changed.
We previously wrote about the Celgene/Dr. Reddy’s dispute here. At the heart of the dispute is Celgene’s Revlimid®, a derivative of thalidomide (lenalidomide) used to multiple myeloma (MM), transfusion-dependent anemia due to myelodysplastic syndromes (MDS), and mantel cell lymphoma. Many patents protect Revlimid®, including a composition of matter patent covering lenalidomide (U.S. Patent No. 5,635,517) which expires in October 2019, method-of-use patents which expire by 2023, and two polymorph patents, including U.S. Patent Nos. 7,855,217 and 7,465,800, which do not expire until 2024 and 2027, respectively. Revlimid’s® long-term value thus stems from these two polymorph patents.
Dr. Reddy’s ability to get onto the market before 2023 depends on its ability to get around the patents, mainly the polymorph patents. To do this, Dr. Reddy’s is suing Celgene in district court litigation over the two polymorph patents and five patents directed at treating MM. With regards to the polymorph patents, Dr. Reddy’s will argue that is does not infringe those patents because its generic product is “amorphous” lenalidomide, whereas the patents are limited to “crystalline” lenalidomide. Dr. Reddy’s thus believes it can circumvent the polymorph patents.
The case is currently in the discovery phase with discovery ending this month or next, and then the case will presumably move on to trial later this year. We probably will not see a decision from the court before Q4 2019 or even Q1 2020. If there is an appeal, that will typically take a year, which means that a final decision could be expected in early 2021.
So now the question is how did the IPR factor into all this. Dr. Reddy’s chose to challenge three MDS patents through an IPR. This included U.S. Patent Nos. 9,056,120; 8,404,717; and 7,189,740. Dr. Reddy’s did not challenge the MM patents or the polymorph patents in this way possibly because: (a) IPRs are limited to Section 102 and Section 103 issues, whereas Dr. Reddy’s appears to be arguing that its product does not infringe, and (b) a win on invalidity in an IPR would open the door for other generics to launch their products, whereas a win on non-infringement in a district court litigation would keep other generics off the market. If Dr. Reddy’s had the IPRs instituted in February 2019, a final written decision would have been expected in February 2020, and an appeal of that decision would add another year to about February 2021. If Dr. Reddy’s managed to win the IPR and also win on the two polymorph patents, then it could enter the market with respect to MDS in early 2021. Even though MDS is a smaller indication than MM, Dr. Reddy’s product could still slowly eat into Celgene’s MM profits through off-label use.
Since the IPRs were not instituted, and the hurdle to appealing the denial is high especially in light of recent case law, Dr. Reddy’s has lost a valuable opportunity to enter the MDS market early. However, not all is lost. If Dr. Reddy’s prevails in showing non-infringement of the two polymorph patents by early 2021, then it just needs to wait until the method-of-use patents expire to enter. While Natco’s agreement allows it to enter the market with a limited supply in March 2022, Dr. Reddy’s will be able to enter with a full supply as soon as the patents expire. Revlimid®’s longevity assumes that no generic will fully enter before 2026 but Dr. Reddy’s will be able to do just that if it prevails at trial on the non-infringement issue.
The next major question is whether this IPR result, or lack thereof, will impact any settlement discussion between the parties. Settlements are almost always business decisions. To date, Celgene and Dr. Reddy’s have not been able to resolve their differences, likely due, in part, to Celgene’s prior settlement agreement with Natco, which limits what Celgene can offer Dr. Reddy’s. From Celgene’s perspective, they are likely to argue that because they “won” in the IPR setting where the bar is lower, they have a stronger hand. This, however, ignores the fact that different issues will be disputed in the litigation. Dr. Reddy’s will still argue that their generic does not infringe and that has not changed with the IPR result.
We will continue following this case and will keep you informed of any new developments.
On February 6, 2019, the US Patent Trial and Appeal Board (PTAB) announced that it has instituted Mylan Pharmaceuticals, Inc.’s inter partes review (IPR) proceeding against Biogen MA Inc’s multiple sclerosis drug, Tecfidera® (IPR2018-01403). Tecfidera® sales exceed $4 billion a year and account for nearly 48% of Biogen’s sales, but there are now questions about its long-term value since it may face generic competition sooner than expected.
The focus of the IPR is on U.S. Patent No. 8,399,514 (the ‘514 patent) which is directed to a method of treating multiple sclerosis in a subject by administering a specific daily dosage, namely 480 mg, of fumarates, specifically dimethyl fumarate (DMF) and/or monomethyl fumarate (MMF). Claim 1 below is reproduced below:
1. A method of treating a subject in need of treatment for multiple sclerosis comprising orally administering to the subject in need thereof a pharmaceutical composition consisting essentially of
(a) a therapeutically effective amount of dimethyl fumarate, monomethyl fumarate, or a combination thereof, and
(b) one or more pharmaceutically acceptable excipients, wherein the therapeutically effective amount of dimethyl fumarate, monomethyl fumarate, or a combination thereof is about 480 mg per day.
The IPR will focus specifically on the 480 mg per day dosage amount. To win, Mylan will have to prove that it would have been obvious to one skilled in the art to administer a dosage of 480 mg per day. Biogen has already shown that a 720 mg dose was efficacious but a 320 mg dose was not statistically significant. Biogen has previously argued that the magnitude of the clinical efficacy of the 480 mg dose was unexpected and therefore, not obvious. Therefore, a key issue is whether it would have been obvious to a person of ordinary skill in the art to optimize the effective dose and arrive at a dosage of 480 mg per day.
The ‘514 patent is at the heart of the Tecfidera® patent portfolio because it has an expiration date of 2028. Other patents protecting Tecfidera® have expiration dates in April 2019, October 2019, and June 2020, according to the Orange Book. The ‘514 patent is, therefore, critical to protecting Tecfidera’s long-term value beyond 2020.
The new IPR, however, threatens that long-term value. A final decision in an IPR is typically announced 12 months after the IPR has been instituted. In this case, it means that we will probably have a final decision around February of 2020, not accounting for any appeals. If Mylan wins the IPR, it would have to wait until at least the June 2020 patent expires before launching a generic competitor drug. Again, this does not account for any appeals in the IPR. Nevertheless, the earliest possible launch for Mylan could occur in June 2020 which significantly cuts into Tecfidera’s market exclusivity.
The important question now is whether the ‘514 patent can withstand an IPR challenge by Mylan Pharmaceuticals, Inc. While Biogen’s stock dropped more than 7% when it was announced that the IPR was instituted, just because an IPR is instituted by the PTAB does not necessarily mean that a patent will be revoked. Around 60% of petitions are instituted in the pharma space. Once instituted, the likelihood that a patent claim will be cancelled is around 46%, which is a lower percentage compared with other technological areas.
Moreover, the ‘514 patent has already faced an IPR and won. In 2017 it successfully overcame a challenge from Kyle Bass and the Coalition for Affordable Drugs (IPR2015-01993). That IPR was also based on a Section 103 obviousness argument. In that IPR, the PTAB held that the petitioner failed to present any evidence that refuted Biogen’s claims that the magnitude of the clinical efficacy of the 480 mg dose was unexpected and thus, not obvious.
While the new Mylan IPR will also rely on prior art to prove whether the 480 mg dose was obvious or not, Mylan relies on at least one new prior art reference, Schimrigk 2004. The new reference, according to Mylan, shows that “doses of 720 mg/day, 360 mg/day, and those in between, such as 480 mg/day, were likely to be efficacious to treat MS.” In instituting the IPR, the PTAB acknowledged that there was a factual dispute regarding whether Schimrigk 2004 does in fact establish efficacy at 360 mg/day but decided to leave that question for trial. Also to be determined in the IPR will be the question of whether knowledge of efficacy of dimethyl fumerate (DMF) for the treatment of MS at the 720 mg/day dose and/or 360 mg/day dose would have provided sufficient motivation to a person of ordinary skill in the art to optimize the dose of DMF in the treatment of MS and arrive at a 480 mg dose.
Whether Mylan can succeed where the Coalition of Affordable Drugs has failed remains to be seen. We will keep you informed of any new developments in this case.
On January 22, 2019 the Supreme Court affirmed the Federal Circuit’s ruling in Helsinn Healthcare S.A. v. Teva Pharmaceuticals USA, Inc. (“Helsinn”) that a secret sale qualifies as prior art under the under the America Invents Act (AIA). The question in this case was whether an inventor’s sale of an invention to a third party qualifies as prior art for purposes of determining patentability under the AIA even though that third party was obligated to keep the invention confidential pursuant to a non-disclosure or confidentiality agreement. By affirming the Federal Circuit’s holding that secret sales do qualify as prior art under the AIA, Helsinn emphasizes the importance of filing patent applications before engaging in any type of activities that may constitute a sale.
As way of background, Helsinn Healthcare S.A. and MGI Pharma, Inc. entered into two agreements in 2001 regarding Helsinn’s palonosetron pharmaceutical product, a drug used in the prevention and treatment of chemotherapy-induced nausea and vomiting. In the first agreement, a license agreement, MGI agreed to distribute, promote, market, and sell Helsinn’s palonosetron product. In the second agreement, a supply and purchase agreement, MGI agreed to purchase exclusively from Helsinn any palonosetron product approved by the US Food and Drug Administration (FDA). While both agreements were disclosed publicly in press releases and Form 8-K filings, none of those disclosures mentioned specifics about the product, including its dosage formulations. Two years later, Helsinn filed provisional patent applications covering the product that ultimately resulted in patent protection for the formulation, including U.S. 8,598,219.
In 2011, Teva Pharmaceutical sought FDA approval to sell a generic version of Helsinn’s palonosetron product. In the Hatch-Waxman litigation that ensued, Teva argued that Helsinn’s patent was invalid because the invention was “on sale” more than a year before the first provisional patent application was filed through the Helsinn-MGI agreements.
The district court rejected Teva’s invalidity argument, holding that the post-AIA on-sale bar “requires that the sale or offer for sale make the claimed invention available to the public.” In the district court’s view, the invention was not on sale in the Helsinn-MGI agreements because it was not available to the public.
The Federal Circuit, however, reversed. In doing so, it rejected the requirement that specific details of the invention be disclosed publicly for it to constitute a sale.
The Supreme Court sided with the Federal Circuit, holding that a sale of an invention to a third party can qualify as prior art under § 102(a) even if that third party is required to keep the invention confidential. In doing do, the Supreme Court rejected the argument that Congress excluded secret sales from the on-sale bar in enacting the AIA, and found instead that “[t]he addition of ‘or otherwise available to the public’ is simply not enough of a change for us to conclude that Congress intended to alter the meaning of the reenacted term ‘on sale.’”
The biggest take-away from Helsinn is that it emphasizes the importance filing patent applications early and not only relying on a confidentiality agreement when entering into discussions with a potential party. These patent applications should be filed before any sort of public disclosure or other patent-invalidating activities that constitute an offer for sale, such as a license agreement or supply agreement, or which may later be found to constitute an offer for sale, take place. Even early stage companies that have not fully committed to a final product should file a provisional patent application prior to entering into discussions with a potential partner. That provisional patent application can provide the company with an earlier filing date, but also importantly, it can protect the product from possible patent invalidation down the road.
BioPharma Law Blog posts updates and analyses on IP topics, FDA regulatory issues, emerging legal developments, and other news in the constantly evolving world of biotech, pharma, and medical devices.