Earlier this month the U.S 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. This case arose when Amgen sued Sanofi and Regeneron, alleging that their monoclonal antibody product, Praluent® (alirocumab), infringed Amgen’s patents (U.S. Patent Nos. 8,829,165 and 8,859,741). Amgen owns and commercially markets a competitor product named Repatha® (evolocumab). The Supreme Court’s refusal to review the case means that the Federal Circuit decision (872 F.3d 1367, Fed. Cir. 2017, “Sanofi”) will stand and the standard for obtaining broad protections for therapeutic monoclonal antibodies will continue to be challenging.
In Sanofi, the Federal Circuit ruled on October 5, 2017 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 doing so, the Federal Circuit essentially overturned the "newly characterized antigen" test and raised the bar for protecting antibody inventions by requiring more data when disclosing and claiming antibodies.
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 to support the claims 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.
While obtaining protection for antibodies is still possible after the Federal Circuit’s decision in Sanofi, certain types of claims are now more susceptible to attack and possible invalidation. We previously reviewed several different types of patent claims that are available to protect antibody inventions and their relative strengths in the wake of Sanofi. Each of the most common types of antibody claims is discussed again below.
Historically, one of the broadest types of claims a company could obtain in an issued patent directed to an antibody was claims describing the antibody by its function. Functional claims to a genus of antibodies typically recite the functional property of an antibody without reciting any structural or sequence information, for example “an antibody that specifically 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 US courts will now require a “representative number” of examples of the genus of claimed antibodies, i.e. a representative number of antibody sequences and associated binding data.
Method of Use/Treatment
Claims directed to the method of use or method of treatment 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 Patent Trial and Appeal Board (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 more likely than not to be found unpatentable. One potential reason for why these types of claims are relatively easy to invalidate is because if you knew the antigen and what it does, it would be obvious to develop an antibody against that antigen to treat people. As such, method of use and method of treatment claims are probably the weakest types of claims for protecting antibodies.
On the opposite side are composition claims directed to the chemical structure of the antibody. These types of claims define an antibody 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 which U.S. Patent and Trademark Office examiner has been assigned to prosecute the application. These types of claims will likely survive invalidation attempts due to their precise definition of the chemical structure of the antibody, leaving little question regarding which antibodies might be encompassed by the claims and which may not be encompassed. However, while antibody sequence claims are a strong type of claim to have, in terms of claim scope they are also the narrowest option, which makes them easier for a competitor to design around.
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 also 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 denied 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.
A final type of claim for protecting an antibody a claim directed to an antibody conjugate. These types of antibody 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 relatively narrower tan other antibody claims because they describe both the antibody sequence and a conjugated drug. Such claims 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 and variants thereof. Nevertheless, these types of claims may be valuable to an antibody patent portfolio.
The recent case law in the antibody space has made it more challenging for companies to obtain broad protections for antibodies, especially in the wake of the Federal Circuit’s Sanofi decision and the Supreme Court’s refusal to review that decision. When patenting antibodies, therefore, it is 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. A patent portfolio can be more valuable when including many different types of claims directed to the antibody and its uses. However, by including at least some claims narrowly tailored to the data available for the antibody, a company can increase the likelihood that the at least some of these claims will be patentable and reduce the chances that at least these claims will be invalidated.
I recently wrote about my experiences teaching a course, Intellectual Property and Healthcare Technologies, at Cornell Law School. I received a lot of questions and comments about that post so I decided to write a follow up with a few more lessons that I learned while teaching at Cornell Law. I hope these lessons can teach both instructors and students (after all, aren’t we all students?) about what worked for me and how some of these lessons can be incorporated into presentations, written materials, and even daily practices.
First, the benefit of collaborations cannot be understated. As I previously mentioned, since my course at Cornell was longer than my course at Harvard, I had the opportunity to expand the subject matter that I taught. To help teach some of the new topics, I engaged experts from the field to help lead the class discussions. In particular, I invited Michael Carrier, a leading expert in pharmaceutical antitrust law and Distinguished Professor at Rutgers Law School, and Joe Fuhrer Jr., Professor Emeritus of Economics Widener University, to teach classes on antitrust and drug pricing, respectively. Not only did I get to know these two professionals better by inviting and hearing them lecturer, but so did the students. Networking is an important part of almost any job, especially in business and law, and the students and I both benefited from having these experts present.
Second, working with students throughout the semester resulted in better final papers. I know many people like to procrastinate when writing their papers, whether it be a final paper for a class, a brief, an agreement, or even a patent application. I know I certainly did. The lesson I learned, however, is that the students who started outlining and writing their papers and submitted their papers to me for comments early on in the semester were the ones who ended up producing the better papers. Rarely is anything you write perfect the first time around. To produce your best possible product, you have to start early, receive feedback (whether from a teacher, a colleague, or a client), and implement the necessary changes to take your paper to the next level.
Third, examples, example, examples! The life science industry is certainly filled with examples on any given topic, particularly when it comes to drugs and the controversies surrounding them. One of the biggest improvements I made to my slides this year was adding more real-life examples. If we talked about building a diverse patent portfolio, we looked at Humira® and the 100+ patents protecting that drug. If we talked about antitrust, we examined the current case surrounding Remicade®and allegations of inappropriate rebates and bundling. If we talked about potential legislative reforms to the brand and generic/biosimilar dynamic, we evaluated recent proposals by Congress, the FDA, and the Trump administration. I also encouraged students to include specific case studies and examples in their papers to better illustrate the points they were trying to make. Providing examples not only puts concepts into perspective, it also makes presentations and papers more engaging.
Fourth, I encouraged students to publish their works. As mentioned in my first point, networking is a very important part of one’s job in business and law. Another part of the job is getting your name out there and being recognized. One great way of doing that is to write and publish your work. When I first started practicing, I was fortunate enough to work with partners who really valued the benefit of publishing legal articles whether it be in newspapers, magazines, or business journals. As a result, I got into a habit of writing and publishing my work. Many of my speaking opportunities down the road and clients that I engaged came because someone read something that I wrote. Since my class was a writing class and students had to write a paper, I also wanted to encourage them to try to get their papers published. By publishing their papers, not only are the students be able to add a publication to their resumes, but they also start getting their names out there.
Finally, take any opportunity you can find for personal and professional growth. Since I had to drive every week to and from Cornell (about an hour and forty-five minutes each way), I spent a lot of time in the car by myself. I took this time to listen to audiobooks through Audible. In fact, the best thing I did for myself last year was to invest in Audible. I listened to everything from negotiation books such as Never Split the Difference, to personal development books such as The Power of Habit, to fun books like Crazy Rich Asians. I admittedly did not achieve many of the professional goals I had set for myself for 2018, but I did achieve my goal of reading (or listening to) at least 60 books in 2018! I have a whole list of books that I can highly recommend if anyone is interested. Time alone in a car is not only a good time for reflection, but also a good time to consume information. Listening to audiobooks was a great way for me to learn a lot of new content while also making my drive more enjoyable.
I hope you enjoyed learning from my experiences. Please feel free to reach out with any questions or comments.
Last week Bristol Myers Squibb (BMS) announced that it planned to acquire Celgene in a deal valued at $74 billion. Following the acquisition, the resulting company will have nine products in its portfolio that each generate more than $1 billion a year. This portfolio will include 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. Revlimid® sales exceeded $8 billion in 2017, but there are questions surrounding its long-term value since it may face generic competition in 2022 by Dr. Reddy’s.
A settlement conference is scheduled for tomorrow, January 10, 2019, in the Hatch-Waxman patent case between Celgene and Dr. Reddy’s. To date, the parties have not been able to reach a settlement. However, this may now change with Bristol Myers at the table.
Celgene has many patents protecting Revlimid®, including a composition of matter patent covering lenalidomide (U.S. Patent No. 5,635,517) which expires in October 2019. The other patents mainly fall into two categories: method-of-use or indication patents and polymorph patents. The method-of-use patents mostly expire by 2023 but the polymorph patents, including U.S. Patent Nos. 7,855,217 and 7,465,800, do not expire until 2024 and 2027, respectively. Revlimid’s® long-term value thus stems from these polymorph patents which look to extend Revlimid’s® monopoly past 2022.
In terms of generic competition, Celgene faced an early threat from Natco back in 2010, which ended in a settlement in 2014 that would allow Natco to enter the market with a limited quantity of product in 2022 and gradually increasing to an unlimited quality in 2026. At least according to this settlement, the generic cliff for Revlimid® would not fully be 2022, but rather 2026. This agreement most likely includes, although we have not been able to verify through public documents, an acceleration or most-favored-nation provision that would allow Natco to enter the market sooner if a subsequent generic was able to obtain a better entry date.
Since Natco, several other companies have filed ANDA’s against Revlimid®, including Dr. Reddy’s, Zydus, Cipla, and Lotus Pharmaceuticals. The case with Dr. Reddy’s is the furthest along. Although a trial date has not yet been scheduled, it would likely take place in the second or third quarter of 2019, as the parties have thus far been engaging in discovery.
The trial will likely focus on the polymorph patents and Dr. Reddy’s argument 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. Celgene, on the other hand, will likely argue that even though Dr. Reddy’s product is amorphous at certain stages, it is also crystalline at others. There is at least some support for this type of argument as the Federal Circuit suggested in a 1994 case (Zenith Laboratories, Inc. v. Bristol-Myers Squibb Co.) that a drug that is not infringing when made or sold, but converted into a patented polymorph when ingested, may be infringing.
Another possible venue for challenging the polymorph patents would be through an inter partes review (IPR) proceeding. Dr. Reddy’s, however, chose not to challenge the polymorph patents that way, focusing instead on challenging three MDS patents which expire in 2022. There are two potential reasons why Dr. Reddy’s chose not to challenge the polymorph patents through an IPR. First, IPR challenges are limited to Section 102 and Section 103 issues, meaning that you are challenging the validity of those patents. Dr. Reddy’s appears to be arguing that its product does not infringe, which is not an appropriate argument for an IPR. Second, if Dr. Reddy’s were to challenge the polymorph patents in an IPR and win, then it would open the door for other generics to launch their products. By arguing non-infringement in a district court litigation rather than invalidity in an IPR, Dr. Reddy’s can keep other generics off the market.
To date, Celegene and Dr. Reddy’s have not been able to resolve their differences and it appears as though they are headed for trial. One main obstacle to settlement has been Celgene’s prior settlement agreement with Natco, which limits what Celgene can offer Dr. Reddy’s.
Nevertheless, Dr. Reddy’s probably wants to beat Natco to the market. If Dr. Reddy’s can successfully show non-infringement of the polymorph patents, and wait for the expiration of the other patents, then it could enter the market with an unlimited quantity by 2022. This would be a better outcome than the one that Natco received.
BMS’s presence at the table may change the dynamics of any potential settlement. While Celgene may not have had the ability or the economics to broker a settlement, the new BMS/Celgene entity with its new product pipeline and business model just may.
We will keep you informed of any new developments following the January 10 settlement conference.
With the JP Morgan Healthcare Conference taking place this week in San Francisco, we thought it would be worth looking at the issues that biotech companies need to remember about intellectual property (IP) when pitching to investors. At BioPharma Law Group, we help our clients prepare and finetune their presentations to investors, and we also act as judges in startups competitions. Based on these experiences, we provide below a list of IP issues that start-ups should keep at the top of their mind when making an investor pitch.
First, know your own IP. Make sure you are familiar with your patent portfolio and know exactly which patent applications you have filed, where they stand in prosecution, and who owns them. If you are licensing IP from somewhere else, whether it be a university or other company, be prepared to discuss whether your license is exclusive or not. If the technology involves core IP, and your license is not exclusive, you may have to explain why you think you do not need an exclusive license. Moreover, know the scope of your patents. Be prepared to talk about at least your main claims and how they cover the product that you are trying to develop and eventually market. If your claims do not cover the product, be prepared to discuss why and what you can do to improve them. This may include strategies for filing continuation applications or follow on applications to yield the desired claim scope.
Second, know proper IP terminology. Do not say that you have a “patent” when in fact you only have a patent application on file. Patent terminology can be difficult for the lay person. Practitioners such as us do not always appreciate this fact since we deal with patents and patent applications on a daily basis, but we cannot emphasize enough the importance of accurately and properly discussing your IP. Investors know IP terminology and using improper terminology will not only confuse the investors, but it could also reduce the value of your technology in their eyes or give the impression that the start-up is not really ready for investment. Saying that you have an “international patent in many countries” can mean a variety of things, or it can mean nothing at all. Work with your company’s IP counsel to make sure you understand what you actually have in your IP portfolio and what you need to focus on in your presentation.
Third, know your competitor IP. Unless you discovered some groundbreaking technology, chances are you have competitors. Every company looking for investors has IP competition. Be prepared to discuss your competitors, their IP (i.e. the patent landscape for your market), and what your company’s strategy is for steering around any IP landmines. This may include plans for licensing certain competitor IP or designing around it.
Fourth, know your company IP strategy. Have an IP strategic plan. Investors do not expect you to have dozens of patent applications already filed but they do expect you to be able to tell them how you plan on building on what you already have and avoiding known patent threats in your target market. Further, any strategic plan should include cost estimates and ballparks for patent applications you plan to file in the future and where you plan to file them and why. Other key components include fleshing out whether your company will be filing on a platform technology, improvements on established technology, or new embodiments of technology. Your company may also need to license or acquire certain IP already existing in your field to bring your product to market. Be prepared to discuss how and when you plan on accomplishing that goal.
Finally, know the current patent and regulatory environment and how it may impact your strategic IP plan. Depending on your specific technology, the current patent climate may have significant implications on your ability to get the claims you want. Top of the list of issues today include 35 U.S.C. Section 101 subject matter issues and 35 U.S.C. Section 112 written description issues. If you are developing biologics, the current climate favoring biosimilars and generic drugs may be problematic for you. If your technology falls within the types that may be affected by today’s uncertain patent and regulatory climates, be prepared to discuss how you plan on mitigating that risk and what backup positions you might pursue.
Good luck to everyone participating in JP Morgan this week!
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.