Impact Of Amgen Inc. v. Sanofi On Patenting Antibody Based Therapeutics

CAR T cells are one of the most promising and innovative therapies for cancer, especially for blood cancers that are resistant to conventional treat­ments. In 2021, market research for global CAR T-cell therapy estimated an existing market size of US$1.7 billion.” Projections suggest that the market size could increase to anywhere between US$6.1 billion and US$13.5 billion in the next few years. Currently, the FDA has approved six CAR T cells, four of which target CD19 for treatment of various lymphomas and B-cell malignan­cies, and two of which target BCMA for treatment of multiple myeloma. In the United States, there are over 600 pending patent applications for CAR T cells and over 100 granted patents. As B-cell malignancies are currently the largest market, this Note will focus on an analysis of this type of antibody-based therapeutic. Of the four patented CAR T cells directed to CD19 to target B-cell malignancies, three have acquired the right to use the technology through li­censes (Breyanzi, Tecartus, and Yescarta), and one owns a patent for the technology (Kymriah). This Note will focus on the Kymriah patent owned by Novartis, which was the first approved patent for CAR T-cell therapy.

II. The Patent Framework and Antibody Patenting

Patents are legal rights that grant inventors a negative right to exclude the making, using, selling, or importing of their inventions for twenty years after filing. The Patent Office grants patents after examining patent applications for novelty, inventive step, and industrial applicability. Patents are intended to en­courage innovation and dissemination of knowledge by rewarding inventors for their efforts and for disclosing their inventions to the public.

Patent infringement occurs when someone makes, uses, sells, or imports a product or process that falls within the scope of a patent’s the claims without authorization from the patent owner. Patent infringement can be direct or in­direct, literal or under the doctrine of equivalents. Patent infringement can re­sult in civil remedies, such as injunctions, damages, or royalties. Patent protection is given by claims only, meaning that only what is claimed by the patent owner is protected by law. Anything that is disclosed, but is not claimed is not protected and can be freely used by others.

A. Enablement and Claimable Material

One of the requirements for obtaining a patent is enablement, which means that the patent application must “describe the invention in such terms that one skilled in the art can make and use the claimed invention.” Enablement is as­sessed based on the claims, which are the legal definitions of the invention’s scope, and the information contained in the specification. The claims must be clear, concise, and supported by information in the specification, which is a written description of the disclosed invention. The claims must also be com­mensurate with the invention’s contribution to the art, meaning that they must not be broader than what is disclosed and enabled by the specification.

The patent enablement requirement is a crucial aspect of patent law that ensures inventors disclose sufficient information and evidence to support their claims and enable others to make and use their inventions. This Section exam­ines how the enablement requirement has evolved and how it has been applied in the field of biotechnology, especially for antibody-based therapeutics. This Section also explores how courts have addressed the challenges and controver­sies of enabling antibody inventions, defining the scope of patentable subject matter, required disclosures of representative species or common structural fea­tures, adequate guidance or direction, and how applicants can describe patent claims to avoid undue experimentation. This Section concludes with a review of the recent Amgen v. Sanofi decision, which has raised the bar for enablement disclosures.

1. The Scope of Patentable Subject Matter under 35 U.S.C. § 101

Diamond v. Chakrabarty, Mayo Collaborative Services v. Prometheus Labs, and Alice Corp. v. CLS Bank International have defined what types of biotechnological inventions are eligible for patent protection. Diamond v. Chakrabarty involved a patent application for a new bacterium that could clean up oil spills. The bacterium was invented by Ananda Chakrabarty, a genetic engineer working for General Electric. The Patent Office rejected his claim, arguing that the bacterium was a product of nature and not eligible for patent protection. Chakrabarty appealed the decision to the Court of Customs and Patent Appeals, which reversed the rejection and held that the bacterium was a human invention despite the fact that it was a living organism. The Supreme Court granted review and affirmed the decision of the lower court, ruling that a living, man-made microorganism is patentable subject matter under 35 U.S.C. § 101. The Court stated that “anything under the sun” created by man can be patented, and that the fact that the organism was alive was not relevant. Dia­mond v. Chakrabarty demonstrates the broad scope of patentable subject matter under 35 U.S.C. § 101, which includes living, man-made microorganisms that have a useful and novel function. The case shows that the patentee must show that the invention is a product of human ingenuity and intervention, and not a product of nature or a law of nature.

In Mayo Collaborative Services v. Prometheus Labs, Prometheus Labora­tories patented a method of testing the blood of patients who were treated with thiopurine drugs for autoimmune diseases and adjusting the dosage of the drugs based on the levels of certain metabolites in the blood. The patent claimed the use of natural laws that described the relationship between the metabolite levels and the efficacy and toxicity of the drugs. Mayo Collaborative Services, a diagnostic testing lab affiliated with the Mayo Clinic, developed and used its own similar test, which prompted Prometheus to sue for patent infringement. The district court granted summary judgment for Mayo, invalidating the patent as covering natural phenomena. The Federal Circuit reversed, holding that the patent was valid as it involved an application of natural laws, not just an obser­vation. The Supreme Court granted certiorari and reversed the Federal Cir­cuit, ruling that the patent was invalid because it claimed processes that were not patent-eligible subject matter under 35 U.S.C. § 101. The Court stated that the patent did not add enough to the natural laws to transform them into inventive applications, and that the steps in the patent were well known, routine, and conventional. The Court also noted that upholding the patent would un­duly restrict the use of the natural laws for further research and innovation. Mayo Collaborative Services v. Prometheus Labs shows that a patentee must add something more to natural laws or phenomena to transform them into in­ventive applications. To ensure non-preemption, a patentee must claim more than well-known, routine, and conventional steps. Alice Corp. v. CLS Bank International further defines the scope of patent-eligible subject matter under 35 U.S.C. § 101 that was outlined in Mayo. The Court applied a two-step test, known as the Alice/Mayo test, to determine whether a claim is directed to a patent-ineligible concept and if it contains an inventive concept that transforms it into a patent-eligible application. Alice Corp. v. CLS Bank International provides a framework for analyzing patent-eligible subject matter under 35 U.S.C. § 101, based on the two-step test derived from Mayo Collaborative Ser­vices v. Prometheus Labs. The first step is to determine whether the claim is directed to a patent-ineligible concept, such as an abstract idea. The second step is to determine whether the claim contains an inventive concept that is suf­ficient to ensure that the patent amounts to significantly more than the patent-ineligible concept.

2. The Written Description Requirement under 35 U.S.C. § 112

Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co. emphasized the importance of disclosing sufficient information and evidence to support the full scope of the claims, especially for functional claims that cover a broad genus of molecules or methods. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co. reaffirmed the im­portance of the enablement requirement for biotechnological inventions. The case involved a patent claim for a method of reducing harmful effects of cellular stress by regulating gene expression using a transcription factor called NF-κB. The U.S. Court of Appeals for the Federal Circuit invalidated the claim for lack of written description, holding that the specification did not teach how to achieve the claimed result with any molecule that can reduce NF-κB activ­ity. The court emphasized that functional claiming is not inherently improper, but it must be supported by adequate disclosure and enablement, especially in unpredictable fields such as biotechnology. Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co. illustrates the importance of providing a written description of an invention that supports the full scope of the claims, especially for functional claims that cover a broad genus of molecules or methods. The case shows that the patentee must disclose representative species or common structural features of the claimed genus and provide sufficient guidance or evidence for a person skilled in the art to make and use the invention without undue burden or exper­imentation.

3. The Undue Experimentation Test under 35 U.S.C. § 112

In re Wands, In re Wright, and Wyeth v Abbott Laboratories determine whether a person skilled in the art can make and use the claimed invention with­out undue burden or experimentation, considering factors such as the quantity of experimentation necessary, the level of skill in the art, the predictability or unpredictability of the art, and the breadth of the claims.

In re Wands applied a set of factors set forth in Ex parte Forman, to deter­mine whether a patent claim is enabled.The case involved a patent claim for a method of producing monoclonal antibodies using hybridoma technology. The U.S. Court of Appeals for the Federal Circuit reversed the rejection of the claim by the Board of Patent Appeals and Interferences, holding that the claim was enabled by the specification, which disclosed working examples and gen­eral guidance for applying the method. The court identified eight factors to consider in the enablement analysis, including the quantity of experimentation necessary, the level of skill in the art, “the predictability or unpredictability of the art, and . . . the breadth of the claims.”

In In re Wright, the applicant, Dr. Stephen E. Wright filed a patent applica­tion claiming “processes for producing live, nonpathogenic vaccines against pathogenic RNA viruses . . . , vaccines produced by these processes . . . , and methods of using these vaccines to protect living organisms against RNA vi­ruses . . . .” The application contained a general description of the invention, but only one working example of producing a vaccine against a specific virus in chickens. The patent examiner rejected the claims that were broader than the disclosed example, arguing that they were not enabled by the specification and that one of ordinary skill in the art would require undue experimentation to make and use the claimed invention. The Board of Patent Appeals and Interferences affirmed the examiner’s rejection, finding that the physiological activity of RNA viruses was unpredictable, and that the applicant had not provided sufficient guidance or evidence to support the broad scope of the claims. The Federal Circuit also affirmed the rejection, holding that the applicant had not met the burden of showing that his specification enabled his invention across its full scope. The court applied the multifactor test from Wands to determine whether undue experimentation was required and concluded that the applicant had failed to provide an enabling disclosure for his claims. In re Wright demonstrates the difficulty of enabling a broad range of processes, products, and uses based on a single example, especially in unpredictable fields such as bio­technology.

In Wyeth v. Abbott Laboratories, the patented invention involved the use of rapamycin for treatment and prevention of restenosis, the renarrowing of an ar­tery after a balloon angioplasty procedure. Rapamycin is a compound that inhibits cell proliferation and has anti-inflammatory properties. Wyeth claimed a method of administering an amount of rapamycin to prevent resteno­sis. Abbott Laboratories challenged the patent, arguing that it was invalid for non-enablement, meaning that the specification did not teach one of ordinary skill in the art how to make and use the claimed invention without undue exper­imentation. The Federal Circuit affirmed the district court’s decision, finding that Wyeth’s patents were invalid for non-enablement. The court applied a multifactor test to determine whether undue experimentation was required and concluded that Wyeth had failed to provide an enabling disclosure for its claims. The court noted that rapamycin may refer to a class of compounds, but Wyeth’s specification disclosed only one rapamycin species, sirolimus. The court also found that the physiological activity of rapamycin was unpredict­able, and that Wyeth had not provided sufficient guidance or evidence to support the broad scope of its claims. Wyeth v. Abbott Laboratories shows that the patentee must provide enough information and direction to enable a person skilled in the art to make and use any compound or composition within the scope of the claim, and not just those that are similar or equivalent to the disclosed species or example.

4. Guidance on Enabling Claims for Antibody-Based Therapeutics Patents

Precedential cases have also provided guidance on how to draft and inter­pret claims for antibody-based therapeutics. For example, in Centocor Ortho Biotech, Inc. v. Abbott Laboratories, which involved a patent claiming a human antibody that binds to a specific epitope on human tumor necrosis factor alpha and has certain functional characteristics, the U.S. Court of Appeals held that Centocor’s patent was invalid for lack of written description because it did not disclose any human antibody that met the claim limitations. The court held that claiming an antibody by its epitope binding and functional characteristics may not be sufficient to meet the written description requirement, unless the specification demonstrates “constructive possession,” enabling “one of skill in the art [to] ‘visualize or recognize’ the claimed antibodies based on the specifi­cation’s disclosure.” The court also indicated that claiming an antibody by its amino acid sequence may be more likely to satisfy the written description re­quirement because it provides a clear and precise identification of the anti­body.

B. Amgen Inc. v. Sanofi

This Note focuses on the recent Supreme Court case Amgen Inc. v. Sanofi. This influential decision by the U.S. Supreme Court has significant implications for the patentability and enforceability of anti-body therapeutics in the United States and beyond. The case involved two competing products, Repatha (evo­locumab) by Amgen and Praluent (alirocumab) by Sanofi, both of which are monoclonal antibodies that target PCSK9 and lower LDL cholesterol levels. Amgen sued Sanofi for infringing its patents that claimed to cover all antibodies that bind and block a certain receptor on PCSK9. Sanofi argued that Amgen’s patents were invalid for lack of enablement, meaning Amgen did not teach how to make the claimed antibodies without undue burden or experimentation. The Supreme Court unanimously agreed with Sanofi and affirmed the invalidity of Amgen’s patents, holding that Amgen did not enable the full scope of its claims, which encompassed potentially millions of antibodies that were not dis­closed or exemplified by Amgen. The Court rejected Amgen’s argument that it was entitled to claim all antibodies based on their function, rather than their structure, so long as it disclosed one way to make them. The Court agreed that a single enablement standard exists but emphasized that broader claims re­quire more enablement. It also noted that balancing incentives for innovation with public benefit is Congress’s domain, and the Court’s role is to apply the enablement requirement as intended by legislation.

This case potentially threatens the patentability and enforceability of anti­body-based therapeutics, especially those that claim broad genera or classes of antibodies based on function or target rather than structure or sequence. The case also raises questions about how to balance the competing interests of re­warding innovation and promoting competition in the biopharmaceutical indus­try.

III. Legal Implication of Amgen Inc. V. Sanofi On Car T-Cell Antibody Therapeutic Patenting

A. Legal Implications of Amgen Inc. v. Sanofi Using CD19 CAR T-cell Patents as a Case Study

As an example of how Amgen Inc. v. Sanofi may affect other antibody-based therapeutics, this Note will examine a scenario involving how a court may analyze a patent for the Kymriah CD19 CAR T-cell therapy owned by Novar­tis. The U.S. Patent No. 10,221,245 B2 covers the same invention field (anti­body-based therapeutics) as the patent at issue in Amgen Inc. v. Sanofi, but for a different target protein and disease. The specification of the patent describes the invention as a genus of antibodies for CAR T-cell construction that bind to specific amino acid residues on CD19, a protein that is expressed on the surface of B cells, thereby killing B cells and treating diseases such as leukemia and lymphoma. The specification also discloses the constructs of twelve CAR T cells that perform these functions and two methods for generating CAR T cells with antibodies that bind to CD19: RNA transfection or RNA electroporation, and lentiviral transduction. The patent’s claims cover CAR T cells with “a single chain antibody or single chain antibody fragment which comprises a hu­manized anti-CD19 binding domain.”

The scope of the claims and the evidence in the specification are more con­sistent than in Amgen Inc. v. Sanofi, but there may still be some differences that could affect the enablement analysis. The claims encompass potentially thou­sands of antibodies that bind to CD19, while the specification only teaches how to make twelve CAR T cells with these antibodies and provides two general methods for finding others. CD19 is a complex protein that has many possible binding sites for antibodies. There may be other residues on CD19 that are also suitable for antibody binding, and different antibodies may bind to the same or different residues with varying degrees of affinity and specificity. Therefore, the claims cover a large and diverse group of antibodies that have the same functional property of binding to CD19 but may have different structural and chemical features.

Figure 2. Schematic of Representative CAR Configurations Directed towards CD19

The Kymriah patent discloses two methods of generating CD19 CAR T cells: (1) CAR T-cell generation by transfecting or electroporating an RNA mol­ecule encoding the desired CARs into the cell, and (2) CAR T-cell generation using viral vectors, such as lentivirus. The transfection method involves in­troducing an RNA molecule that encodes the CAR into the patient’s T cells by either using a chemical reagent (transfection) or applying an electric pulse (elec­troporation). This method results in transient CAR expression, meaning that the CARs will degrade over time and the cells will return to their original state. The disclosed viral vector method involves using a lentivirus vector, a type of retrovirus, to deliver the CAR gene to the patient’s T cells. The lenti­virus integrates the CAR into the T-cell genome, allowing stable and long-term expression of the CAR protein on the T-cell surface. A person skilled in the art may have to perform additional optimization, modification, or validation steps to obtain the entire genus of possible CD19 antibodies from these methods. This may involve considerable time, cost, and effort. As the patent only de­scribes twelve complete CAR T cells, this may not be sufficient to demonstrate the full scope of potential variations within the claimed genus.

The application of the enablement requirement to the Kymriah patent may depend on how a court applies the Amgen v. Sanofi decision. If the court follows the strict standard of requiring enablement for the full scope of the claimed em­bodiments, then the patent may be invalid for lack of enablement under 35 U.S.C. § 112. If the court adopts a more flexible approach that considers factors such as predictability, level of skill, amount of guidance, and breadth of claim language, then the patent may be valid for enabling a person skilled in the art to make and use at least some embodiments of the claimed invention.

Courts have recently applied the new standard for enablement and written description established in Amgen Inc. v. Sanofi to patent cases involving differ­ent technologies and claim types. The courts have generally upheld the validity of claims that are narrow and specific. On the other hand, the courts have generally invalidated claims that covered a broad genus without sufficient guid­ance or examples, following the reasoning of Amgen Inc. v. Sanofi. It appears the trend is to apply a strict standard of requiring enablement for the full scope of the claimed embodiments in most cases, especially in the biotechnology field, where the claims cover a broad genus of compounds or antibodies without suf­ficient guidance or examples.

B. Greater Impacts on Antibody-Based Therapeutic Patents

One impact of Amgen Inc. v. Sanofi is that it limits both the scope of claims and the amount of coverage the claims give. Using the U.S. Patent No. 10,221,245 B2 patent as an example, this may allow competitors to design around the patent by making derivative therapeutics based on other antibody fragments or T-cell receptors that bind and activate but are not covered by the claims. This allows for derivatives to be made of an already patented antibody; and if the coverage of the genus is restricted because of enablement, the deriva­tive therapeutics based on that antibody would not be considered infringing.

The ability to make derivatives of disclosed patented antibody-based ther­apeutics may reduce patent owners’ market share and revenue. It may also un­dermine patent owners’ incentive to invest in further research and development. The decision could also discourage innovation and investment in new antibody-based therapies by reducing the scope and strength of patent protection for these inventions. Patents reward biopharmaceutical companies for investing in re­search and development of novel therapies, which frequently entail high risks and costs. By giving companies temporary exclusive control over their prod­ucts, patents help them to recover their investments and support further innova­tion. Patents for antibody-based therapies that are harder to acquire or easier to invalidate may cause companies to lose their interest in finding new therapies. This may eventually reduce patients’ ability to access these therapies and the variety of therapies available.

C. Implications on the Patent System and Inventorship

Amgen Inc. v. Sanofi may have broader implications on the patent system and inventorship as a whole. It may affect how patents are granted and enforced for other types of biotechnological inventions, such as vaccines, gene therapies, and biosimilars. The case may also affect how inventors draft and disclose their inventions in their patent applications, as well as how they conduct their re­search and development activities.

First, the case may raise the bar for enablement and sufficiency for biotech­nological inventions, especially those that claim broad genera or classes of mol­ecules or products based on their function or target, rather than their structure or sequence. The case may require inventors to disclose more details and examples in their patent applications to support their claims, such as multiple embodi­ments, variants, alternatives, methods, or parameters. The case may also require inventors to conduct more experiments and tests to demonstrate that their inven­tions can be made and used across the breadth of their claims without undue burden or experimentation. Additionally, patent drafters may need to provide more comprehensive and specific disclosures in their patent applications for bi­otechnological inventions, as well as more evidence of their feasibility and util­ity.

Second, the case may increase the risk of invalidity and noninfringement challenges for biotechnological inventions, especially those that claim broad genera or classes of molecules or products based on their function or target ra­ther than their structure or sequence. The case may expose inventors to more prior art that may anticipate or render obvious their inventions, such as other molecules or products that have the same or similar function or target but dif­ferent structure or sequence. The case may also expose inventors to more com­petitors that may design around their patents by making derivative therapeutics based on other molecules or products that have the same or similar function or target but different structure or sequence, and that are not covered by the patents’ claims.

While overall Amgen Inc. v. Sanofi seemingly has a negative impact on pa­tenting antibody-based therapeutics, there may be positive outcomes associated with the case. The decision may balance the interests of rewarding innovation and promoting competition in the biopharmaceutical industry. The case may en­courage inventors to disclose more information and examples in their patent ap­plications, which may benefit the public by increasing the availability and dissemination of scientific knowledge and technology. The case may also en­courage inventors to claim more narrow and specific inventions, which may benefit competitors by increasing the opportunities and incentives for develop­ing new and improved therapeutics that are not covered by the patents. Addi­tionally, it could stimulate more innovation and diversity in the development of biotechnological inventions. By exposing inventors to more competitors that may design around their patents, the case could inspire inventors to explore new avenues and possibilities for creating novel and useful therapeutics based on different molecules or products that have the same or similar function or target but different structure or sequence. This could lead to more discoveries and breakthroughs in the field, as well as more opportunities for patenting new in­ventions that are not anticipated by or obvious from the prior art.

Conclusion

In conclusion, the patentability of antibody-based therapeutics, such as the Kymriah CD19 CAR T-cell therapy, may be affected by the Supreme Court de­cision in Amgen v. Sanofi. The decision raised the bar for the enablement re­quirement under 35 U.S.C. § 112 and requires patent applicants and owners to provide more evidence and guidance in their specifications to support the full scope of their claims. The outcome of this case may have significant implica­tions for innovation and competition in the antibody-based therapeutics field, which is one of the most active and promising areas of biotechnology.

CAR T cells are an important therapy that can potentially cure various types of cancer by using the patient’s own immune cells. However, the develop­ment of CAR T-cell technology may be hindered by the Amgen v. Sanofi deci­sion, which may affect the patentability of antibody-based therapeutics. The decision may invalidate or narrow the scope of many existing patents that cover a broad range of antibodies. These impacts may reduce the incentive and reward for investing in CAR T-cell research and development, which may in turn affect the availability and affordability of CAR T-cell therapy for patients who need it. The Supreme Court decision in Amgen Inc. v. Sanofi has changed the patent landscape for antibody-based therapeutics, by making it harder to enable a broad range of antibodies with a specific function, and by opening the door for more competing practices to not be an infringement upon the existing patented tech­nologies. Although the Amgen Inc. v. Sanofi case initially appears detrimental to antibody patenting, it may foster innovation and competition in biopharma by prompting more detailed disclosures and narrower claims, thereby spurring the development of diverse and novel therapeutics.