For Stem Cells, It Seems That Conception Is Enough
By Kevin E. Noonan --
On Thursday, the Federal Circuit affirmed a District Court determination that the University of Pittsburgh had established, by clear and convincing evidence, that four inventors had been improperly named in U.S. Patent No. 6,777,231 and granting judgment correcting inventorship under 35 U.S.C. § 256. In doing so, the Court's decision raised a paradox with regard to conception of biological inventions (albeit while not making any new law in the process).
The facts of the case, as set forth in the Patent Docs report on the District Court decision, illustrate the influence patenting can have on academic collaboration. As granted, the '231 patent named Adam J. Katz, Ramon Llull, William J. Futrell, Marc H. Hedrick, Prosper Benhaim, Hermann Peter Lorenz, and Min Zhu as inventors, with Katz, Llull, and Futrell having assigned their rights to the University of Pittsburgh and the remaining named inventors assigning their rights to the Regents of the University of California.
The District Court found that Dr. Katz had isolated adipose-derived stem cells, and that Drs. Katz and Llull conceived that these cells could be induced to differentiate into cells from multiple mesodermal lineages, "including bone, cartilage, fat and muscle." The Court credited evidence from laboratory notebooks that Drs. Katz and Llull showed their adipose-derived stem cells could differentiate into several different cell types, including adipose cells, nerve cells, and muscle cells. According to the District Court's Findings of Fact, Dr. Katz also "appreciated" the capacity of these adipose-derived stem cells for self-renewal. The Court found that the earliest date of conception for the invention claimed in the '231 patent was 1996, a date several years before work began at UCLA.
The Federal Circuit recited the following facts which are relevant to the panel decision:
• In 1997, these researchers "explored the idea" that these cells could "transdifferentiate" into other cell types, including bone, cartilage, and muscle, and that Dr. Katz's laboratory notebooks showed experiments on different media formulations that could induce adipose-derived cells to differentiate into bone, muscle, fat, cartilage, and nerve cells; however, these notebooks also established that this differentiation was "not scientifically certain," but the cells were observed to change into muscle and fat cells and maybe into nerve cells.
• At that time, they recognized from the work of others that mesenchymal stem cells can do this too, but these isolated by others from bone marrow.
• "By April 1997, they [the Pittsburgh inventors] had the firm and definite idea that the cells were human, could be genetically modified, secreted hormones, and contained cell-surface bound intracellular signaling moieties, all properties known at the time to scientists in the field."
• A UCLA scientist (Hedrick) was on a one-year fellowship to Dr. Katz's laboratory in 1997, but was not named on a grant proposal on adipose-derived stem cells submitted at that time or in laboratory notebooks on these stem cells.
• Dr. Hedrick did write his own proposal on using these cells.
• An invention disclosure was submitted to the University of Pittsburgh naming the Pittsburgh inventors and Hedrick, stating the invention was isolated cells that could be induced to transform into fat, bone, cartilage, and muscle cells.
• When Dr. Hedrick returned to UCLA after his fellowship in Dr. Katz's lab, he formed the Regenerative Bioengineering and Research ("REBAR") laboratory with the other UCLA inventors.
• Dr. Hedrick and the REBAR group worked on the same cells as the Pittsburgh group, and "determined that the adipose-derived cells were distinct from the prior art bone marrow-derived mesenchymal stem cells because they responded differently to induction media. They also identified various media to induce differentiation in the cells, and identified the presence of an enzyme that is indicative of stem cells in a heterogeneous stromal vascular fraction population. In late 1999 and early 2000, the REBAR lab successfully cloned single adipose-derived cells."
• In March 1999, a provisional patent application was filed by the University of Pittsburgh that named Hedrick as well as the Pittsburgh inventors; a second provisional application was filed in October 1999 naming the same inventors.
• In February 2000, Dr. Hedrick submitted an invention disclosure to UCLA for adipose tissue-derived stem cells, and included the nerve cell embodiments even though he "had not conducted any nerve differentiation experiments."
• In March 2000, an International Patent Application was filed by Pittsburgh naming all the Pittsburgh and UCLA inventors; this is the application that issued as USP 6,777,231.
The '231 patent was granted with the following claims:
1. An isolated adipose-derived stem cell that can differentiate into two or more of the group consisting of a bone cell, a cartilage cell, a nerve cell, or a muscle cell.
2. An isolated, adipose-derived multipotent cell that differentiates into cells of two or more mesodermal phenotypes.
3. An isolated adipose-derived stem cell that differentiates into two or more of the group consisting of a fat cell, a bone cell, a cartilage cell, a nerve cell, or a muscle cell.
4. An isolated adipose-derived stem cell that differentiates into a combination of any of a fat cell, a bone cell, a cartilage cell, a nerve cell, or a muscle cell.
5. A substantially homogeneous population of adipose-derived stem cells, comprising a plurality of the stem cell of claim 1, 3 or 4.
6. The adipose-derived stem cell of claim 1, 3 or 4 which can be cultured for at least 15 passages without differentiating.
7. The adipose-derived stem cell of claim 1, 3 or 4 which is human.
8. The cell of any of claim 1, 3 or 4 which is genetically modified.
9. The cell of any of claim 1, 3 or 4, which has a cell-surface bound intercellular signaling moiety.
10. The cell of any of claim 1, 3 or 4, which secretes a hormone.
The Federal Circuit's opinion, by Judge Mayer joined by Judges Rader and Bryson, considered two questions: claim construction and inventorship. Regarding claim construction, the Court affirmed the District Court's determination that the claim term "adipose-derived" had its plain meaning as "derived from fat tissue," and rejected the construction proposed by the REBAR inventors that the term should mean "species of stem cell distinct from the mesenchymal stem cell that is obtainable from bone marrow tissue." The REBAR inventors had determined that adipose-derived stem cells were distinct from mesenchymal stem cells from bone marrow, and thus their construction excluded such bone-marrow derived stem cells that may have migrated to adipose tissue. The District Court had agreed that the specification distinguished bone marrow from adipose tissue derived stem cells, but only with regard to culture conditions and not that the cells represent "separate species." The District Court was not persuaded that the different culture and isolation conditions necessitated that the adipose derived stem cells are different from bone marrow-derived mesenchymal stem cells. The Federal Circuit agreed, and opined that neither the specification (where the term was not expressly defined) nor the prosecution file history supported REBAR inventors' construction. Specifically with regard to the file history argument, the REBAR inventors contended that an amendment proposed by the Pittsburgh inventors (to recite "adipose-derived" in the claims) was a disclaimer of mesenchymal stem cells isolated from fat that would read on prior art stem cells. The panel noted, however, that this amendment was never submitted, since the inventors submitted instead a paper from the REBAR group showing that the cells were different. The panel refused to find a disavowal of subject matter under these circumstances:
A wide chasm exists between the weak inference from the summary that adipose-derived stem cells in this invention must be a different species from mesenchymal stem cells and a clear and unmistakable disavowal as required to limit a claim term.
Turning to inventorship, the panel recited the following fundamental principles:
An inventor need not know that his invention will work for conception to be complete. Price v. Symsek, 988 F.2d 1188, 1196 (Fed. Cir. 1993). . . . He need only show that he had the complete mental picture and could describe it with particularity; the discovery that the invention actually works is part of its reduction to practice. Id. In a joint invention, each inventor must contribute to the joint arrival at a definite and permanent idea of the invention as it will be used in practice. Burroughs Wellcome Co. v. Barr Labs, Inc., 40 F.3d 1223, 1229 (Fed. Cir. 1994).
In this panel's view, the district court had applied these principles properly:
The district court correctly applied this law, finding clear and convincing evidence that Katz and Llull conceived of each claim of the invention through contemporaneous corroboration before the arrival of Hedrick at Pittsburgh in July 1997. It found that they had recorded that their cells could transdifferentiate into multiple mesodermal lineages including bone, cartilage, fat and muscle in laboratory notebooks, letters, a January 1997 invention disclosure for their Auto-Cell Separator, the February 1997 document "What's So Great About Fat?," and the inference that Katz would have only conducted his muscle induction experiment on the cells to confirm his belief that they could differentiate into muscle instead of adipocytes. They had recorded that their isolated cells transdifferentiated into cells resembling a nerve cell in April 1997, as was recorded in a letter to a colleague requesting his help with electrophysiological techniques. While not scientifically certain that they were observing a nerve cell, they did have the firm and definite idea that nerve cells were present, and ordered further confirming tests. Claims 1, 2, 3, and 4 require an isolated adipose-derived stem cell that can differentiate into two or more mesodermal phenotypes, including specifically a fat cell, a bone cell, a cartilage cell, a nerve cell, a muscle cell, or a combination of these. Thus, the entire invention as described by claims 1, 2, 3, and 4 had been conceived and corroborated through these disclosures.
The panel also opined that other limitations recited in the claims, such as the requirement for a substantially homogeneous population of cells (claim 5), the capacity of the cells for self-renewal (claim 6), that the cells must be human (claim 7), could be genetically-modified (claim 8), secreted hormones (claim 9), and contained cell-surface bound intracellular signaling moieties (claim 10) were all "grasped" by Drs. Katz and Llull by April 1997 (at a time prior to Dr. Hedrick beginning his fellowship), at least in part because the scientists in the field recognized that stem cells had these features and capacities.
The panel rejected the REBAR inventors' contentions that the Pittsburgh inventors' research was "inconclusive," "highly speculative," and not fully realized until their owen contribution to the work. Citing Coleman v. Dines, 754 F.2d 353 (Fed. Cir. 1985), the REBAR inventors argued that an inventor must "know" that the invention contained every limitation of each claim at the time of conception. The panel characterized these assertions as a "misapprehension of what it means to 'know' the limitations of the claims." The District Court found that Katz's laboratory notebooks sufficiently described to those skilled in the art how to isolate the cells from adipose-tissue, at which point they would be in possession of the invention, and the Federal Circuit agreed. Specifically, the Court stated that:
Knowledge in the context of a possessed, isolated biological construct does not mean proof to a scientific certainty that the construct is exactly what a scientist believes it is . . . . Proof that the invention works to a scientific certainty is reduction to practice . . . . The determinative inquiry is not whether [the inventor's] disclosure was phrased certainly or tentatively, but whether the idea expressed therein was sufficiently developed to support conception of the subject matter. In re Jolley, 308 F.3d 1317, 1324 (Fed. Cir. 2002). . . . Evidence need not always expressly show possession of the invention to corroborate conception, and a court may properly weigh evidence that a claimed attribute is merely an obvious property of a greater discovery at issue. Burroughs Wellcome Co. v. Barr Labs, Inc., 40 F.3d 1223, 1231 (Fed. Cir. 1994).
This determination is consistent with well-established law regarding conception. For example, in Burroughs Wellcome Co. v. Barr Labs, Inc., the Burroughs Wellcome defendants argued that for an invention in an "uncertain or experimental discipline, where the inventor cannot reasonably believe an idea will be operable until some result supports that conclusion," conception occurs only when there is experimental confirmation that the invention works for its intended purpose. The Federal Circuit was clear, stating: "[b]ut this is not the law. An inventor's belief that his invention will work or his reasons for choosing a particular approach are irrelevant to conception. Id., citing MacMillan v. Moffett, 432 F.2d 1237, 1239, 167 U.S.P.Q. 550, 552 (CCPA 1970)." This is sufficient for conception, unless there is evidence of subsequent experimental failure: "[a] conception is not complete if the subsequent course of experimentation, especially experimental failures, reveals uncertainty that so undermines the specificity of the inventor's idea that it is not yet a definite and permanent reflection of the complete invention as it will be used in practice. Id. at 1229, citing Rey-Bellet v. Engelhardt, 493 F.2d 1380, 1387, 181 U.S.P.Q. 453, 457-58 (CCPA 1974)."
However, this decision, and the well-established reasoning behind it, does lead to at least an anomaly if not an outright paradox when it comes to biological inventions. Here, the inventors "conceived" of a stem cell derived from adipose tissue that could be induced to differentiate into bone, muscle, fat, and nerve tissue on the basis of (1) isolating cells that could de- and transdifferentiate; (2) some but admittedly inconclusive evidence that these cells could be induced to differentiate under certain experimental conditions; and (3) the "a definite and permanent idea" of adipose-derived stem cells. In contrast, other biological inventions, such as nucleic acids, have been held to require simultaneous conception and reduction to practice, in view of their inherent complexity (see Amgen, Inc. v. Chugai Pharmaceutical Co., 927 F.2d 1200 (Fed. Cir. 1991)). It seems anomalous that cells, which are inherently more complex than nucleic acids should be capable of being conceived more easily and to require less knowledge about their properties (except what can be "definitely and permanently" fixed in the mind of the inventor (and corroborated by documentary evidence). Perhaps an answer to the paradox is that this case is limited to determining who should be named as inventors, i.e., who conceived of the invention. Unlike the situation in an interference, neither the District Court nor the Federal Circuit address when the Pittsburgh inventors could describe the cells sufficiently or produce and differentiate them reliably, activities both courts classified as being part of reduction to practice and hence irrelevant to the question before them (see, e.g., Rasmusson v. SmithKline Beecham Corp., 413 F.3d 1318, 1326 (Fed. Cir. 2005)). The Federal Circuit's decision made abundantly clear that the rubrics for deciding inventorship in the relatively complex biological arts are no different than for any other art, and that conceiving the existence of a cell like a stem cell is enough (so long as subsequent attempts to reduce the invention to practice do not contradict this presumption).
University of Pittsburgh v. Hedrick (Fed. Cir. 2009)
Panel: Circuit Judges Mayer, Rader, and Bryson
Opinion by Circuit Judge Mayer