Dana-Farber Cancer Institute v. Ono Pharmaceutical Co., Ltd.

Case: 19-2050   Document: 49     Page: 1   Filed: 07/14/2020




   United States Court of Appeals
       for the Federal Circuit
                 ______________________

     DANA-FARBER CANCER INSTITUTE, INC.,
               Plaintiff-Appellee

                            v.

    ONO PHARMACEUTICAL CO., LTD., TASUKU
   HONJO, E.R. SQUIBB & SONS, L.L.C., BRISTOL-
           MYERS SQUIBB COMPANY,
                Defendants-Appellants
               ______________________

                       2019-2050
                 ______________________

     Appeal from the United States District Court for the
 District of Massachusetts in No. 1:15-cv-13443-PBS,
 United States District Judge Patti B. Saris.
                 ______________________

                 Decided: July 14, 2020
                 ______________________

    DONALD ROSS WARE, Foley Hoag LLP, Boston, MA, ar-
 gued for plaintiff-appellee. Also represented by SARAH S.
 BURG, BARBARA A. FIACCO.

     SETH P. WAXMAN, Wilmer Cutler Pickering Hale and
 Dorr LLP, Washington, DC, argued for defendants-appel-
 lants. Also represented by STEVEN JARED HORN, THOMAS
 SAUNDERS; MATTHEW TYMANN, Los Angeles, CA; DIANNE B.
 ELDERKIN, STEVEN D. MASLOWSKI, MATTHEW A. PEARSON,
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 2    DANA-FARBER CANCER INSTITUTE    v. ONO PHARMACEUTICAL
                                                    CO., LTD.


 Akin, Gump, Strauss, Hauer & Feld, LLP, Philadelphia,
 PA.
                ______________________

     Before NEWMAN, LOURIE, and STOLL, Circuit Judges.
 LOURIE, Circuit Judge.
     Ono Pharmaceutical Co. Ltd., Tasuku Honjo, E.R.
 Squibb & Sons, L.L.C., and Bristol-Myers Squibb Co. (col-
 lectively, “Ono”) appeal from the judgment of the United
 States District Court for the District of Massachusetts af-
 ter a bench trial ordering that Dr. Gordon Freeman and Dr.
 Clive Wood be added to U.S. Patents 7,595,048 (“the ’048
 patent”), 8,168,179 (“the ’179 patent”), 8,728,474 (“the ’474
 patent”), 9,067,999 (“the ’999 patent”), 9,073,994 (“the ’994
 patent”), and 9,402,899 (“the ’899 patent”) as co-inventors.
 Dana-Farber Cancer Inst., Inc. v. Ono Pharm. Co., 

379 F. Supp. 3d 53

 (D. Mass. 2019) (“Decision”). Because we con-
 clude that the district court did not err in its inventorship
 determination, we affirm.
                        BACKGROUND
     This appeal presents an inventorship dispute over
 groundbreaking work in the field of cancer treatment.
 Each patent at issue claims a method of treating cancer by
 administering antibodies targeting specific receptor-ligand
 interactions on T cells.
      The human immune system comprises many different
 cell types, but two types of those cells are relevant here:
 dendritic cells and T cells. Dendritic cells detect pathogens
 and present antigens—proteins from a pathogen or tu-
 mor—to T cells. T cells have a variety of functions but, as
 relevant here, are responsible for processing information to
 develop an immune response in the body using receptors
 on their surfaces. The primary receptor on a T cell, the T
 cell receptor, can bind to antigens to activate an immune
 response. But a signal sent to a T cell receptor will not
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 activate the T cell unless a ligand binds to one of its co-
 stimulatory receptors, such as CD28. CD28 has two lig-
 ands, B7-1 and B7-2, which are expressed in dendritic cells
 that have detected infection or cancer. For a T cell to acti-
 vate an immune response, two things must happen: (1) an
 antigen on a dendritic cell must bind to the T cell receptor,
 and (2) a B7 ligand on the dendritic cell must bind to the
 CD28 receptor on the T cell. In the absence of an infection
 or cancer, dendritic cells do not express B7 ligands on their
 surface thus blocking an immune response. B7 ligands also
 bind to an inhibitory receptor called CTLA-4, which is only
 expressed in highly activated T cells. B7 ligands bind more
 tightly to CTLA-4 than to CD28, so if both receptors are
 being expressed, CTLA-4 prevents the B7 ligands from ac-
 tivating the T cell through the CD28 receptor.
     The discovery behind the present patents was the ex-
 istence of an inhibitory receptor on T cells, PD-1, and that,
 when PD-1 binds to one of its ligands, either PD-L1 or PD-
 L2, the T cell is inhibited and does not attack the cell ex-
 pressing the ligand. Expression of the PD-1 ligands in
 healthy cells generally shields them from attack, but some
 tumor cells can also express the ligands, allowing them to
 circumvent an immune response. The patents in this case
 capitalize on the discovery of the PD-1 receptor-ligand in-
 teraction. Each claim recites uses of antibodies that target
 either the PD-1 receptor or its PD-L1 ligand, blocking the
 receptor-ligand interaction. By blocking the interaction,
 the use of the inventions in effect stimulates the immune
 response against tumor cells that would otherwise have
 been hidden by their expression of the PD-L1/L2 ligands.
      The appeal raises the question whether Drs. Freeman
 and Wood should be deemed inventors of the subject matter
 of the ’048, ’179, ’474, ’999, ’994, and ’899 patents alongside
 Dr. Tasuku Honjo. Essential to this determination is a re-
 counting of each researcher’s work and the nature of their
 collaboration.
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                                                    CO., LTD.


     Dr. Honjo, a professor at Kyoto University’s medical
 school, discovered the PD-1 receptor in the early 1990s. He
 isolated its DNA sequence and began working with the pro-
 tein in mouse models with Dr. Nagahiro Minato, a col-
 league studying tumor immunology. Using knockout mice
 (wherein the PD-1 gene is not expressed), they discovered
 that mice without PD-1 showed symptoms typical of auto-
 immune disease, suggesting that the receptor was involved
 in immune-system inhibition. Based on its structure,
 Dr. Honjo believed at that time that PD-1 was in the same
 family of proteins as the inhibitory receptor CTLA-4.
 Drs. Honjo and Minato submitted their research for publi-
 cation, and their work was published in Immunity in Au-
 gust 1999.
     In mid-1998, Dr. Honjo enlisted a graduate student,
 Dr. Yoshiko Iwai, to conduct studies on PD-1 with knockout
 mice and human tumor cell lines. Dr. Iwai found binding
 of the PD-1 protein in a variety of cells, including in tumor
 cells, but she did not identify the molecule that was binding
 to the receptor. She also recognized that her experiments
 may have yielded false positives because she used a specific
 fusion protein. Her work did not continue at that time be-
 cause she took a leave of absence because of illness.
     In September 1998, Dr. Honjo met with representa-
 tives from Ono, now an assignee of Dr. Honjo’s rights in the
 instant patents, and the Genetics Institute, who connected
 him to Dr. Wood, a researcher at Genetics Institute. They
 discussed Dr. Honjo’s work with PD-1, and Dr. Wood
 agreed to collaborate with Dr. Honjo to find the PD-1 lig-
 and. Dr. Wood believed that the PD-1 receptor could be a
 candidate for antibody therapy development, and accord-
 ingly Dr. Honjo shared with him PD-1 reagents and a con-
 fidential draft of the Immunity article.
     In July 1998, Dr. Freeman, a researcher at Dana-Far-
 ber, was studying novel B7 ligands. He ran a search in the
 BLAST database for a sequence of 208 amino acids that
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 forms part of the binding portion of the B7-1 molecule. The
 search yielded 12 results—two of which were from human
 ovarian tumors—and Dr. Freeman began to investigate the
 sequence further, titling it “292” after its label in the data-
 base.
     At this point, the timelines converge. Drs. Wood, Free-
 man, and Honjo began sharing information directly.
 Drs. Wood and Freeman began working together to deter-
 mine whether PD-1 binds to 292, and Dr. Wood informed
 Dr. Honjo that it does. The three dubbed 292 “PD-L1” and
 ran further experiments. Dr. Wood sent Dr. Honjo plans
 for a journal article, and Dr. Honjo sent Dr. Wood anti-
 PD-1 antibodies for further experimentation. Dr. Freeman
 emailed Dr. Honjo for the first time at this point, discussing
 the possibility of a research collaboration on the
 PD-1/PD-L1 pathway.
     The collaboration culminated in a meeting in Cam-
 bridge, Massachusetts in October 1999. At the meeting,
 Dr. Wood disclosed that PD-1 and CTLA-4 had similar
 structures and that PD-L1 antibodies inhibited the
 PD-1/PD-L1 interaction. Dr. Freeman disclosed that 292
 was from a human ovarian tumor and that PD-L1 shares
 20% of its amino acid sequence with B7-1 and B7-2 but does
 not bind to either CD28 or CTLA-4. Dr. Honjo disclosed his
 unpublished knockout mouse data indicating that PD-1 in-
 hibits the immune response.
      After the meeting, the three began exchanging rea-
 gents. Dr. Honjo ran in vitro experiments on the pathway
 indicating that it inhibited the immune response, using
 knockout mouse cells as a control. Drs. Freeman and Wood
 filed a provisional patent application disclosing modulation
 of the immune response via activating or blocking the PD-
 1/PD-L1 pathway, but did not list Dr. Honjo as an inventor.
     In the fall of 1999, Dr. Freeman conducted a second
 BLAST search and identified another B7-like molecule
 that shares 38% of its protein structure with PD-L1. Over
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                                                    CO., LTD.


 the next year, Dr. Freeman conducted a number of experi-
 ments on this ligand, which he labeled PD-L2.
      In January 2000, Dr. Freeman asked Dr. David Dorf-
 man, a pathologist at the Brigham and Women's Hospital,
 and Dr. Julia Brown, a new postdoctoral researcher, to test
 both normal and tumor tissues and determine whether PD-
 L1 was expressed by them. Dr. Dorfman studied numerous
 cell lines and found high PD-L1 expression in tumors, in-
 cluding squamous cell carcinoma of the tongue, breast lob-
 ular carcinoma, lung and colon adenocarcinoma, and
 anaplastic large cell lymphoma. These immunohistochem-
 istry results were not published until 2003.
     In March 2000, Dr. Freeman emailed Dr. Honjo to tell
 him about PD-L2 and to send its sequence. Drs. Honjo,
 Freeman, and Wood then worked on a journal article docu-
 menting their discoveries concerning PD-L1, and, in a final
 round of edits in April 2000, Dr. Freeman added a sentence
 to the paper stating that PD-L1 was also expressed in can-
 cers and that some tumors may use PD-L1 to inhibit an
 antitumor immune response. This article was published in
 the Journal of Experimental Medicine on October 2, 2000.
     Drs. Wood, Freeman, and Minato all separately devel-
 oped antibody candidates. In March 2000, Drs. Wood and
 Honjo presented results of their PD-1/PD-L1 collaborative
 research at a conference. Dr. Iwai also resumed her knock-
 out mice studies. By May 2000, Drs. Wood, Freeman, and
 Honjo were discussing their development of anti-PD-L1 an-
 tibodies and the possible use of those antibodies in treating
 cancer.
     In June 2000, Dr. Honjo learned of the 1999 provisional
 application filed by Drs. Wood and Freeman, and chal-
 lenged his exclusion as an inventor. By September, the
 three had met again in Cambridge and Drs. Wood and
 Freeman presented the results of their research on PD-L2.
 Dr. Honjo presented some new data from Dr. Iwai’s knock-
 out mice.
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      In October, Dr. Iwai had generated data suggesting
 that mouse melanoma tumors expressing PD-L1 grow
 faster than tumors without PD-L1 expression. Ono identi-
 fies October 2000 as the date Drs. Honjo, Iwai, and Minato
 conceived the claimed inventions. As more data were gen-
 erated by the Iwai experiments, Dr. Honjo stopped sharing
 results with Drs. Freeman and Wood. The three met one
 final time in April 2001.
     Meanwhile, Dr. Honjo’s attorneys were pursuing his in-
 ventorship claim, but Genetics Institute, the assignee of
 Drs. Freeman and Wood’s patents, and its attorneys de-
 clined to voluntarily add him to their patents. Genetics In-
 stitute stated that Dr. Honjo could pursue his inventorship
 claim at the PTO. Inventorship of those patents is not at
 issue here.
     In 2002, Dr. Honjo then filed his own patent applica-
 tion in Japan, disclosing results from Drs. Honjo, Iwai, and
 Minato’s experiments. Each patent at issue in this case
 claims priority from Dr. Honjo’s Japanese patent applica-
 tion; none include Drs. Freeman and Wood as inventors.
 Because Dr. Freeman is an employee of Dana-Farber,
 Dana-Farber is presumably the assignee of any rights he
 has as an alleged inventor of any of the patents in suit.
 Pfizer, which purchased Genetics Institute, is presumably
 the assignee of any rights Dr. Wood has in the patents, but
 Pfizer has transferred its potential interest in the patents
 to Ono. None of these relationships is at issue here.
     Dr. Freeman allegedly learned about the ’048 patent in
 2010 but did not pursue litigation until 2015. Dr. Wood
 may have known of the patents but did not get involved
 until Dana-Farber filed this suit on behalf of Dr. Freeman.
 In 2018, Dr. Honjo won the Nobel Prize in Physiology or
 Medicine, and it is not without interest that in his ac-
 ceptance speech he credited Dr. Freeman as a major collab-
 orator in his work.
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 8    DANA-FARBER CANCER INSTITUTE   v. ONO PHARMACEUTICAL
                                                   CO., LTD.


     The parties’ inventorship dispute began in the United
 States District Court for the District of Massachusetts.
 Dana-Farber brought suit alleging that Drs. Freeman and
 Wood should be added as inventors on Dr. Honjo’s patents.
 Dana-Farber presented an eight-point theory justifying
 Drs. Freeman and Wood’s inventorship: (1) Dr. Freeman
 found the 292 sequence; (2) Drs. Freeman and Wood jointly
 disclosed PD-L1; (3) Drs. Freeman and Wood discovered
 that PD-1/PD-L1 binding inhibits T cell activation; (4)
 Dr. Freeman contributed the idea of treating cancer by
 blocking the pathway in his April 2000 edits to the re-
 searchers’ journal article; (5) Dr. Freeman provided rea-
 gents that Dr. Iwai used in her mouse model; (6) Dr.
 Freeman, through Dr. Dorfman, discovered that human
 PD-L1 is expressed across a number of tumors; (7)
 Drs. Freeman and Wood discovered PD-L2; and (8)
 Drs. Freeman and Wood developed relevant antibodies.
     In a 111-page opinion, the district court considered
 each of Dana-Farber’s points. Ultimately, the court cred-
 ited Drs. Freeman and Wood’s discovery of the PD-L1 lig-
 and, 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 ex-
 pression in various tumors as contributions significant to
 the conception of all six patents.
    Ono appealed, and we have jurisdiction under 

28 U.S.C. § 1295

(a)(1).
                        DISCUSSION
     District courts may order the correction of patent in-
 ventorship by the U.S. Patent and Trademark Office “on
 notice and hearing of all parties concerned.” 

35 U.S.C. § 256

(b). “[A] valid patent requires correct inventorship.”
 In re VerHoef, 

888 F.3d 1362, 1365

 (Fed. Cir. 2018), as
 amended (May 7, 2018). Inventorship is a question of law
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 CO., LTD.


 reviewed de novo, but the district court’s underlying find-
 ings of fact are reviewed for clear error. Vapor Point LLC
 v. Moorhead, 

832 F.3d 1343, 1348

 (Fed. Cir. 2016) (citing
 Gen. Elec. Co. v. Wilkins, 

750 F.3d 1324, 1329

 (Fed. Cir.
 2014) and then Trovan, Ltd. v. Sokymat SA, Irori, 

299 F.3d 1292, 1301

 (Fed. Cir. 2002)).
    

35 U.S.C. § 116

(a) provides the standard for joint in-
 ventorship:
     When an invention is made by two or more persons
     jointly, they shall apply for patent jointly and each
     make the required oath, except as otherwise pro-
     vided in this title. Inventors may apply for a patent
     jointly even though (1) they did not physically work
     together or at the same time, (2) each did not make
     the same type or amount of contribution, or (3) each
     did not make a contribution to the subject matter
     of every claim of the patent.
      Ono challenges the district court’s decision on two ba-
 ses: (1) the district court’s legal analysis of conception, and
 (2) the district court’s factual findings regarding inventor-
 ship. We address each argument in turn.
                               A
     Ono argues that as a matter of law the district court
 erred by relying on contributions of Drs. Freeman and
 Wood that were too far removed from the claimed subject
 matter of the patents; it also argues that these contribu-
 tions were made public and were hence in the prior art be-
 fore the alleged conception. In Ono’s view, the patents
 claim specific methods of treating cancer using PD-1 or PD-
 L1 blocking antibodies, and Drs. Honjo and Minato dis-
 cussed the possible use of PD-1 for treating cancer in Octo-
 ber 2000 in conjunction with data received from Dr. Iwai’s
 knockout mice experiments. Thus, Ono submits, these ex-
 periments, performed independently of Drs. Freeman or
 Wood, were what led directly to the conception of the
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                                                     CO., LTD.


 claimed inventions, and the previous work was at most
 speculative because it was not in vivo. Ono also notes that
 the patents were issued over Drs. Freeman and Wood’s
 1999 provisional application as evidence that the patents
 claim treatments that were novel and nonobvious over Drs.
 Freeman’s and Wood’s alleged contributions.
     Ono also argues that Drs. Freeman’s and Wood’s al-
 leged inventive contributions should be deemed irrelevant
 to inventorship because their work with Dr. Honjo was
 published in October 2000 in the Journal of Experimental
 Medicine before conception of the patented inventions.
 Ono urges us to adopt a legal rule that once a contribution
 is made public, it “no longer qualifies as a significant con-
 tribution to conception.” Appellants’ Br. 39.
     Dana-Farber responds that Ono offers an erroneous
 view of the law. According to Dana-Farber, Ono’s rule
 would require each joint inventor to individually have con-
 ceived the complete invention and have participated in a
 particular moment of conception, which is inconsistent
 with law.
     We agree with Dana-Farber. Ono asks us to adopt an
 unnecessarily heightened inventorship standard. “[A] joint
 invention is simply the product of a collaboration between
 two or more persons working together to solve the problem
 addressed.” Fina Oil & Chem. Co. v. Ewen, 

123 F.3d 1466, 1473

 (Fed. Cir. 1997) (citing Burroughs Wellcome Co. v.
 Barr Labs., Inc., 

40 F.3d 1223, 1227

 (Fed. Cir. 1994)). 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 con-
      tribution 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.
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 Pannu v. Iolab Corp., 

155 F.3d 1344, 1351

 (Fed. Cir. 1998);
 quoted in VerHoef, 

888 F.3d at 1366

. There is no “explicit
 lower limit on the quantum or quality of inventive contri-
 bution required for a person to qualify as a joint inventor.”
 Eli Lilly & Co. v. Aradigm Corp., 

376 F.3d 1352, 1358

 (Fed.
 Cir. 2004) (quoting Fina Oil, 

123 F.3d at 1473

). “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.” Burroughs Wellcome, 

40 F.3d at 1227

 (cit-
 ing 

35 U.S.C. § 116

).
      Ono attacks the inventorship case for Drs. Freeman
 and Wood on the ground that they failed to participate in
 certain experiments that led to the conception of the
 claimed invention, but the statute and our case law make
 clear that joint inventors need not contribute to all aspects
 of a conception. See, e.g., Eli Lilly, 376 F.3d at 1359–59; 

35 U.S.C. § 116

(a). 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.
     Ono’s argument that work from Drs. Honjo, Freeman,
 and Wood’s collaboration was too speculative until the Oc-
 tober 2000 knockout mice studies is likewise misguided.
 Conception is the touchstone of the joint inventorship in-
 quiry, Sewall v. Walters, 

21 F.3d 411, 415

 (Fed. Cir. 1994),
 and conception is complete when an idea is definite and
 permanent enough that one of skill in the art could under-
 stand the invention, Burroughs Wellcome, 

40 F.3d at 1228

.
 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. 

Id.

 (citing Applegate v.
 Scherer, 

332 F.2d 571, 573

 (CCPA 1964) and Oka v.
 Youssefyeh, 

849 F.2d 581

, 584 n.1 (Fed. Cir. 1988)). While
 Dr. Iwai’s work provided important in vivo data, in vivo
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 verification is not required for a conception to be definite
 and permanent. See In re Isaacs, 

347 F.2d 887, 889

 (CCPA
 1965) (holding that in vivo testing was not required to es-
 tablish utility for claims to interferon). Moreover, the rec-
 ord is clear that Dr. Iwai’s work was conducted after Dr.
 Freeman had shown expression of PD-L1 in human tumors
 and Dr. Honjo had shown that PD-L1 expression causes tu-
 mor growth, so as a factual matter, PD-L1’s potential util-
 ity in treating human cancers was developed jointly with
 Dr. Freeman before Dr. Iwai’s work.
     Ono also argues that the Honjo patents were issued
 over Drs. Freeman and Wood’s 1999 provisional patent ap-
 plication, so the latter contributions were thus not signifi-
 cant to the dispute over inventorship of Dr. Honjo’s
 patents. As a factual matter, it is unclear that Drs. Free-
 man and Wood’s contributions to the inventions are co-ex-
 tensive with the disclosure of their provisional application.
 Regardless, joint inventorship does not depend on whether
 a claimed invention is novel or nonobvious over a particu-
 lar researcher’s contribution. Collaboration and concerted
 effort are what result in joint inventorship. Eli Lilly, 

376 F.3d at 1359

. The novelty and nonobviousness of the
 claimed inventions over the provisional application are not
 probative of whether the collaborative research efforts of
 Drs. Honjo, Freeman, and Wood led to the inventions
 claimed here or whether each researcher’s contributions
 were significant to their conception.
     Ono also urges us to hold categorically that research
 made public before the date of conception of a total inven-
 tion cannot qualify as a significant contribution to concep-
 tion of the total invention. Such a rule would ignore the
 realities of collaboration, especially that collaboration gen-
 erally spans a period of time and may involve multiple con-
 tributions. It is certainly true that simply informing
 another about the state of the prior art does not make one
 a joint inventor. Hess v. Advanced Cardiovascular Sys.,
 Inc., 

106 F.3d 976

, 981 (Fed. Cir. 1997) (holding that
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 explaining the state of the art and providing well-known
 information found in textbooks was insufficient for joint in-
 ventorship). But a collaborative enterprise is not negated
 by a joint inventor disclosing ideas less than the total in-
 vention to others, especially when, as here, the collabora-
 tors had worked together for around one year prior to the
 disclosure, and the disclosure occurred just a few weeks
 prior to conception. 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 obvi-
 ously 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.
                              B
     Next, Ono raises a series of challenges to the district
 court’s factual analysis for each patent. We begin where
 Ono focuses the majority of its argument, the ’474 patent.
                        i. ’474 patent
     Claim 1 of the ’474 patent recites a “method for treat-
 ment of a tumor in a patient, comprising administering to
 the patient a pharmaceutically effective amount of an anti-
 PD-1 monoclonal antibody.” ’474 patent col. 25 ll. 13–15.
 According to Ono, Dr. Freeman’s alleged contribution to
 discovering PD-L1 was locating the 292 sequence in the
 BLAST database, but he played no meaningful role in the
 discovery that the PD-1/PD-L1 pathway is inhibitory. Ono
 also contends that Dr. Freeman’s work is not a significant
 contribution to the invention of the ’474 patent because the
 ’474 patent claims rely on anti-PD-1 antibodies, not PD-L1
 antibodies.
     Ono argues that Dr. Wood likewise should not be cred-
 ited as a joint inventor on the ’474 patent because his work
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 on the PD-L1 pathway was not a significant contribution
 to the claims. Ono submits that the district court over-
 stated Dr. Wood’s contributions and that Dr. Wood’s work
 merely confirmed information that Dr. Honjo had already
 discovered.
     Dana-Farber responds that Ono failed to argue that
 the inventors’ contributions differ from patent to patent be-
 fore the district court. According to Dana-Farber, “the
 claimed methods are all based on conception of the same
 core invention: blocking the PD-1/PD-L1 interaction so that
 the tumor cannot use the pathway to evade immune sys-
 tem attack.” Appellees’ Br. 41 (emphasis omitted). Dana-
 Farber cites the district court’s fact finding that knowing
 the structure and function of PD-L1 was essential to all the
 claimed inventions.
     We agree with Dana-Farber, and with the district
 court, that Drs. Freeman and Wood are joint inventors of
 the ’474 patent. The ’474 patent claims use of anti-PD-1
 antibodies in treating cancer and does not explicitly men-
 tion 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 tu-
 mors. The ’474 patent claims need not explicitly recite PD-
 L1 for research on PD-L1 to have been a significant contri-
 bution to conception of the invention.
     The record certainly confirms this reality. The district
 court credited testimony from Dana-Farber’s expert, Dr.
 Kenneth Murphy, that not all antibodies that bind to a re-
 ceptor or ligand block the signal. Ono’s expert, Dr. Mark
 Greene, did not contest that Dr. Honjo needed to under-
 stand the receptor-ligand interaction to develop effective
 therapeutic antibodies. But even apart from expert testi-
 mony, Dr. Honjo’s own efforts underscore the importance
 of understanding the receptor-ligand relationship to con-
 ception. In 1992, Dr. Honjo discovered PD-1 and theorized
Case: 19-2050    Document: 49     Page: 15    Filed: 07/14/2020




 DANA-FARBER CANCER INSTITUTE   v. ONO PHARMACEUTICAL     15
 CO., LTD.


 that it played a role in inhibiting the immune response.
 But despite having this knowledge, Dr. Honjo still enlisted
 collaboration with the Genetics Institute to search for lig-
 ands for PD-1. Even under Ono’s view of the facts,
 knowledge of PD-1 was itself insufficient for Dr. Honjo to
 conceive of the method claimed in the ’474 patent.
     It is clear based on the record that Drs. Freeman and
 Wood both contributed to conception of the ’474 patent. Dr.
 Freeman connected the 292 sequence to PD-1 and directed
 important immunohistochemistry experiments revealing
 that several types of tumors express PD-L1. Dr. Wood pro-
 vided Dr. Honjo with the first confirmation that the PD-
 1/PD-L1 interaction was inhibitory, supported by experi-
 mental data. Drs. Freeman and Wood’s work on PD-L1,
 Dr. Wood’s discovery that the PD-1/PD-L1 interaction in-
 hibits the immune response, and Dr. Freeman’s discovery
 of PD-L1 expression by human tumors were significant
 building blocks upon which the ’474 patent is built.
                  ii. The remaining patents
     Each of the remaining patents recites treatment of tu-
 mors, lung cancer, or melanoma by administering anti-PD-
 1 or anti-PD-L1 antibodies. Ono makes arguments about
 the remaining patents, but each argument depends signif-
 icantly on our acceptance of its arguments regarding the
 ’474 patent. As we concluded above, discovery of PD-1 in a
 vacuum was insufficient for conception. Drs. Freeman and
 Wood’s work linking PD-1 to its ligand and expression in
 tumors was a significant contribution to each of these pa-
 tents’ conception.
     Ultimately, the decision in this appeal rests on the ex-
 tensive factual determinations made by the district court
 relating to the work performed together by Drs. Wood and
 Freeman, and Dr. Honjo that were not clearly erroneous,
 and the court made no errors of law.
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 16   DANA-FARBER CANCER INSTITUTE    v. ONO PHARMACEUTICAL
                                                    CO., LTD.


                         CONCLUSION
     We have considered the parties’ remaining arguments
 but find them unpersuasive. Because we conclude that the
 district court did not err in holding Drs. Freeman and Wood
 should be included as joint inventors of the ’048, ’179, ’474,
 ’999, ’994, and ’899 patents, we affirm the district court’s
 conclusions.
                         AFFIRMED