In Dana-Farber Cancer Institute, Inc. v. Ono Pharm. Co., Ltd., the Federal Circuit agreed with the district court that two inventors should be added to a family of PD-1 cancer treatment patents, even though their contributions may be prior art to the claimed invention and not expressly recited in the claims.
The Patents At Issue
The patents at issue relate to methods of treating cancer using antibodies targeting PD-1/PD-L1 receptor-ligand interactions on T cells. Specifically, inventorship of six patents was before the court: U.S. Patent No. 7,595,048; U.S. Patent No. 8,168,179; U.S. Patent No. 8,728,474; U.S. Patent No. 9,067,999; U.S. Patent No. 9,073,994; and U.S. Patent No. 9,402,899.
The Federal Circuit cited claim 1 of the '474 patent as representative:
1. A method for treatment of a tumor in a patient, comprising administering to the patient a pharmaceutically effective amount of an anti-PD-1 monoclonal antibody.
As summarized in the Federal Circuit decision, "[t]he discovery behind the present patents was the existence of an inhibitory receptor on T cells, PD-1, and that, when PD-1 binds to one of its ligands, either PD-L1 or PDL2, the T cell is inhibited and does not attack the cell expressing the ligand." As further explained in the decision, "[e]ach claim recites uses of antibodies that target either the PD-1 receptor or its PD-L1 ligand, blocking the receptor-ligand interaction" which "stimulates the immune response against tumor cells that would otherwise have been hidden by their expression of the PD-L1/L2 ligands."
The Invention Timeline
The patents originally named four Japanese inventors as co-inventors, and originally were assigned to Ono Pharmaceutical Co., Ltd. The inventorship issue before the court was whether Dr. Freeman of Dana-Farber Cancer Institute and Dr. Wood of Genetics Institute also should be named as inventors.
The Federal Circuit decision provides more details on events leading up to the invention, but the basic timeline includes the following:
- Before any collaboration with Dr. Freeman or Dr. Wood, Dr. Honjo discovered the PD-1 receptor and, along with other originally named co-inventors, determined it was "involved in immune-system inhibition," and binds to "a variety of cells, including in tumor cells," but did not identify the binding partner(s).
- After collaborating with Dr. Honjo, Dr. Freeman and Dr. Wood collectively (1) discovered two PD-1 binding ligands, named "PD-L1" and "PD-L2"; (2) determined binding of PD-1 to PD-L1 or PD-L2 inhibits an immune response; (3) determined antibodies to PD-L1 and PD-1 can block the inhibition of the immune response; and (4) discovered PD-L1 is expressed in a variety of tumors.
- Before the patents-in-suit were filed, "Drs. Freeman and Wood filed a provisional patent application disclosing modulation of the immune response via activating or blocking the PD1/PD-L1 pathway, but did not list Dr. Honjo as an inventor."
- Before the patents-in-suit were filed, "Drs. Honjo, Freeman, and Wood ... worked on a journal article documenting their discoveries." "Dr. Freeman added a sentence ... stating that PD-L1 was also expressed in cancers and that some tumors may use PD-L1 to inhibit an antitumor immune response." The article was published in the Journal of Experimental Medicine in October 2000.
- The patents-in-suit have a 2002 priority date and are supported by additional work by the originally named co-inventors, including animal study data "suggesting that mouse melanoma tumors expressing PD-L1 grow faster than tumors without PD-L1 expression," and specific antibody candidates.
The Arguments For Inventorship
As summarized in the Federal Circuit decision, the district court determined that Dr. Freeman and Dr. Wood should be added as inventors based on:
- Drs. Freeman and Wood's discovery of the PD-L1 ligand,
- Dr. Wood's discovery that PD-1/PD-L1 binding inhibits the immune response,
- Drs. Freeman and Wood's discovery that anti-PD-1 and anti-PD-L1 antibodies can block the pathway's inhibitory signal, and
- Dr. Freeman's immunohistochemistry experiments confirming PD-L1 expression in various tumors.
The Arguments Against Inventorship
On appeal, Ono raised arguments against adding Drs. Freeman and Wood as inventors, including:
- Their experiments were too far removed from the claimed methods of treatment and lacked in vivo support.
- The patents at issue were granted over the earlier Freeman and Wood provisional application.
- The asserted contributions of Drs. Freeman and Wood were published prior to the invention of the patents.
- "[E]xperiments performed independently of Dr. Freeman and Dr. Wood were what led directly to the invention of the patents at issue."
The Federal Circuit Decision
The Federal Circuit decision was authored by Judge Lourie, and joined by Judges Newman and Stoll.
The decision cites the statutory basis for joint inventorship (35 USC § 116(a)) and settled law regarding its application:
To be a joint inventor, one must:
(1) contribute in some significant manner to the conception or reduction to practice of the invention, (2) make a contribution to the claimed invention that is not insignificant in quality, when that contribution is measured against the dimension of the full invention, and (3) do more than merely explain to the real inventors well-known concepts and/or the current state of the art.
People may be joint inventors even though they do not physically work on the invention together or at the same time, and even though each does not make the same type or amount of contribution."
Considering the arguments against inventorship, the Federal Circuit explained:
[T]he statute and our case law make clear that joint inventors need not contribute to all aspects of a conception. .... That Drs. Freeman and Wood were not present for or participants in all the experiments that led to the conception of the claimed inventions does not negate their overall contributions throughout their collaboration with Dr. Honjo.
Addressing the experimental data supporting the patents, the Federal Circuit reminded:
Conception is the touchstone of the joint inventorship inquiry .... An inventor need not know, however, that an invention will work for its intended purpose in order for conception to be complete, as verification that an invention actually works is part of its reduction to practice.
Regarding the "prior art" arguments, the Federal Circuit stated:
[J]oint inventorship does not depend on whether a claimed invention is novel or nonobvious over a particular researcher's contribution. Collaboration and concerted effort are what result in joint inventorship. ...
The Federal Circuit refused to adopt a rule that "research made public before the date of conception of a total invention cannot qualify as a significant contribution to conception of the total invention." According to the court, "Such a rule would ignore the realities of collaboration, especially that collaboration generally spans a period of time and may involve multiple contributions." Addressing the issue further, the Federal Circuit distinguished prior publication from inventorship:
[A] collaborative enterprise is not negated by a joint inventor disclosing ideas less than the total invention to others .... Inventorship of a complex invention may depend on partial contributions to conception over time, and there is no principled reason to discount genuine contributions made by collaborators because portions of that work were published prior to conception for the benefit of the public. Earlier publication of an invention is obviously a potential hazard to patentability, but publication of a portion of a complex invention does not necessarily defeat joint inventorship of that invention, and it does not here.
The Federal Circuit also addressed the fact that Drs. Freeman and Wood's contributions are not explicitly recited in the claims, finding that they nevertheless were essential to the claimed methods:
The '474 patent claims use of anti-PD-1 antibodies in treating cancer and does not explicitly mention PD-L1. But PD-1 is just a receptor. Unless one also knows that the PD-1 receptor binds to at least one ligand that inhibits the immune response, such as PD-L1, there would be no reason to use anti-PD-1 antibodies to treat tumors.
Thus, the Federal Circuit concludes:
The '474 patent claims need not explicitly recite PD-L1 for research on PD-L1 to have been a significant contribution to conception of the invention.
Accordingly, the Federal Circuit agreed with the district court that the contributions of Dr. Freeman and Dr. Wood amounted to "a significant contribution to each of these patents' conception."
Complex Inventorship Of Complex Inventions
The court's lengthy review of the invention timeline underscores that determining inventorship of complex inventions is no simple task, particularly when researchers are at different institutions, studying different facets of an invention at different times. Interesting aspects of this decision include the court's lack of concern about the added inventors' prior publications and earlier patent application, and the court's willingness to look beyond express claim language to additional discoveries underlying the claimed methods.
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