Biologics are an increasing share of the pharmaceutical market, and many of them are monoclonal antibody drugs. For broad claims to such antibodies, satisfying the written description and enablement requirements is becoming more difficult, as can be seen in an ongoing patent dispute between Amgen and Sanofi for their monoclonal PCSK9 inhibitor antibody drugs for lowering cholesterol.
Amgen and its PCSK9 rivals Sanofi and Regeneron have been battling over their US patents for years. Here we discuss the most recent developments in that dispute.
What is PCSK9?
In October 2014, Amgen asserted its REPATHA patents against Sanofi’s PRALUENT.
The protein PCSK9 (proprotein convertase subtilisin kexin type 9) binds and promotes degradation of low-density lipoprotein (LDL) receptors (LDLR), which clear circulating LDL, or "bad" cholesterol. PCSK9 lowers LDLR levels resulting in higher LDL cholesterol (LDL-C). Thus, one approach to lower LDL-C is to inhibit PCSK9 binding to LDLR. The FDA has approved two monoclonal PCSK9 inhibitor antibodies for reducing LDL-C, Amgen’s REPATHA (evolocumab) and Sanofi’s PRALUENT (alirocumab), both bind PCSK9 and inhibit LDLR binding.
When did it all begin?
In October 2014, Amgen asserted its REPATHA patents against Sanofi’s PRALUENT. In March 2016, a jury found the patents valid. The court issued and then stayed a permanent injunction against marketing PRALUENT. Sanofi appealed and the case was remanded for a new trial on written description and enablement. Amgen Inc. v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). Amgen sought en banc rehearing and Supreme Court review; both were declined.
The February 2019 jury verdict found claims 19 and 29 of US8,829,165 (‘165) and claim 7 of US8,859,741 (‘741) satisfied the written description and enablement requirements, and as a result, are valid. Sanofi moved for Judgment as a Matter of Law that those claims are Invalid.
Claims 1, 19 and 29 of the ‘165 patent read as follows:
- An isolated monoclonal antibody, wherein, when bound to PCSK9, the monoclonal antibody binds to at least one of the following residues: SI53, 1154, P155, R194, D238, A239,1369, S372, D374, C375, T377, C378, F379, V380, or S381 of SEQ ID NO:3, and wherein the monoclonal antibody blocks binding of PCSK9 to LDLR.
- The isolated monoclonal antibody of claim 1 wherein the isolated monoclonal antibody binds to at least two of the following residues [same as the list in claim 1] of PCSK9 listed in SEQ ID NO:3.
- 29. A pharmaceutical composition comprising an isolated monoclonal antibody, wherein the isolated monoclonal antibody binds to at least two of the following residues [same as the list in claim 1] of PCSK9 listed in SEQ ID NO:3 and blocks the binding of PCSK9 to LDLR by at least 80%.
To claim a genus, while disclosing only species of that genus, the written description requirement includes two tests: the representative species and structural features tests.
Claims 1-2 and 7 of the ‘741 patent read as follows:
- An isolated monoclonal antibody that binds to PCSK9, wherein the isolated monoclonal antibody binds an epitope on PCSK9 comprising at least one of residues 237 or 238 of SEQ ID NO: 3, and wherein the monoclonal antibody blocks binding of PCSK9 to LDLR.
- The isolated monoclonal antibody of claim 1, wherein the isolated monoclonal antibody is a neutralizing antibody.
- The isolated monoclonal antibody of claim 2, wherein the epitope is a functional epitope.
On August 28, 2019, the Court issued a Memorandum (Amgen, Inc., et al. v. Sanofi, et al., Case 1:14-cv-01317-RGA (D. Del.)) holding that the claims are NOT INVALID for lack of written description, as per the jury verdict, but reversing the jury verdict and determined that the claims are INVALID for lack of enablement as a matter of law.
Written description
To claim a genus, while disclosing only species of that genus, the written description requirement includes two tests: the representative species and structural features tests. A patentee must disclose “a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can visualize or recognize the members of the genus.”
Because satisfying the representative species test was sufficient to find validity under written description, the Court did not address the Common Structural Features Test.
The Court found the jury verdict was supported by evidence that the disclosed antibodies were representative of the genus. Experts testified that three-dimensional structure is the appropriate metric for comparison and the three-dimensional structures of the disclosed and the competitor antibodies are similar. Even if the amino acid sequence is the appropriate metric, testimony of 80% sequence similarity between Amgen’s and the competitors’ antibodies support finding structural similarity. There was also testimony of functional similarity; the disclosed antibodies blocked PCSK9 binding to LDLR through various binding interactions, while binding to different residues across the “sweet spot”, where PCSK9 binds LDLR.
Because satisfying the representative species test was sufficient to find validity under written description, the Court did not address the Common Structural Features Test.
Enablement
Enablement, separate and distinct from written description, assesses whether “one skilled in the art … could practise the claimed invention without undue experimentation.” Factors considered include: (1) quantity of experimentation necessary, (2) amount of direction or guidance, (3) presence or absence of working examples, (4) nature of the invention, (5) state of the prior art, (6) relative skill of those in the art, (7) the art’s predictability or unpredictability, and (8) claim breadth. The full claim scope “is not enabled when there is an embodiment within the claim's scope that a person of ordinary skill … would be unable to practice without undue experimentation.”
For patents claiming a broad genus while disclosing only species of that genus, the specification should disclose a sufficient number of antibodies to represent the structural diversity of the genus and sub-genus.
In view of the above factors, the Court concluded that undue experimentation would be required to enable the claims given that:
- The number of antibodies potentially falling, and that would need to be tested to determine whether they actually fall, within the claim scope is at least in the millions. That is, there are at least millions of candidate antibodies that might block PCSK9 binding LDLR.
- Substitutions in an antibody’s sequence may unpredictably affect its function. Thus, knowledge of the structure-function relationship would not eliminate the need to test newly-created antibodies to determine whether they have the claimed functions.
- Even though routine techniques are employed to identify undisclosed antibodies within the genus, an artisan would either need “to do essentially the same amount of work as the inventors” and discover them de novo, or proceed with a trial-and-error process of amino acid substitution and screening them for the desired properties, as even conservative substitutions may have unexpected results.
- Despite 26 working examples, the patents do not teach how to predict whether an antibody will bind or whether its sequence will bind to specific PCKS9 residues. The “roadmap” disclosed by the patents is almost exactly the same as the patentee's initial research to discover the disclosed antibodies.
- The amount of time and effort required to enable the full claim scope would be substantial. Sanofi’s expert testified that an artisan might never know whether the entire claim scope had been discovered, and even after “immunizing mice for a hundred years. There might be [] an antibody that [no one] come[s] up with[,] in that time period … but it might be still out there waiting to be found.”
However, the ground has shifted and practitioners should be cognizant and appreciative of the scientific predictability of the subject that is being claimed.
Practice Points:
Notwithstanding the outcome of any appeal, we can say the following about the defence and prosecution of antibody claims.
For patents claiming a broad genus while disclosing only species of that genus, the specification should disclose a sufficient number of antibodies to represent the structural diversity of the genus and sub-genus. In addition to amino acid sequences for antibodies disclosed, when available, three-dimensional structural data for them and their binding to the epitope should be provided. In addition to broad genus claims, claims should also be drafted that are as narrow and directed as possible. The number of antibodies within the scope of the claims should not be so large in number (“millions”) and, to the extent possible, should be able to be made through intelligent substitution, rather than by trial and error. Furthermore, the number of antibodies needing to be tested to determine whether they are functional and fall within the claim scope should be kept as small as possible. The patent should also provide significant guidance or direction to a person of ordinary skill in the art. For instance, the working examples should teach how to predict from an antibody's sequence whether it will exhibit the claimed properties (e.g., binding characteristics). The experimentation necessary to enable the full scope of the claims should take as little time and effort as possible.
What is next?
Finally, even the Court notes, Amgen will likely appeal the ruling invalidating the disputed claims for lack of enablement. Accordingly, in order to understand the full effect of this ruling, it will be necessary to wait until the likely appeal is decided by the Federal Circuit. However, the ground has shifted and practitioners should be cognizant and appreciative of the scientific predictability of the subject that is being claimed.
Mark Cohen
Senior Partner
Chair of the Life Science Practice Group
Mark Cohen is a Founder of Pearl Cohen Zedek Latzer Baratz LLP, Senior Partner, and Chair of the Life Science Practice Group,. Mark’s practice focuses on patent prosecution, opinion and commercial transactional matters in the pharmaceutical, chemical, biological, and medical device areas,. He is well-versed in all aspects of patent prosecution, intellectual property management, guidance and strategic advice, technology assessment, and licensing matters. His work includes management of large patent portfolios, negotiating terms, drafting agreements, and counseling start-ups. He has been involved in large due diligence matters; infringement, validity and patentability opinions; licensing matters; and opposition proceedings in Europe.
Pearl Cohen Zedek Latzer Baratz, LLP (“Pearl Cohen”) is an international law firm with offices in New York, Boston, Los Angeles, London and Tel-Aviv . The Firm represents innovation-driven enterprises including Fortune 500 and small-cap emerging companies, start-ups and entrepreneurs, investors in the enterprises they form, academic institutions and government-related entities.
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