United States Court of Appeals for the Federal Circuit
2008-1468
UNIVERSITY OF PITTSBURGH
OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION,
DR. ADAM J. KATZ, and DR. RAMON LLULL,
Plaintiffs-Appellees,
v.
MARC H. HEDRICK, PROSPER BENHAIM,
HERMANN PETER LORENZ, and MIN ZHU,
Defendants-Appellants.
Glenn J. Pfadenhauer, Williams & Connolly LLP, of Washington, DC, argued for
plaintiffs-appellees. With him on the brief were Adam L. Perlman and David I. Berl.
John Allcock, DLA Piper LLP (US), of San Diego, California, argued for
defendants-appellants. With him on the brief was Stanley J. Panikowski.
Appealed from: United States District Court for the Central District of California
Senior Judge Consuelo B. Marshall
UNITED STATES COURT OF APPEALS FOR THE FEDERAL CIRCUIT
2008-1468
UNIVERSITY OF PITTSBURGH
OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION,
DR. ADAM J. KATZ, and DR. RAMON LLULL,
Plaintiffs-Appellees,
v.
MARC H. HEDRICK, PROSPER BENHAIM,
HERMANN PETER LORENZ, and MIN ZHU,
Defendants-Appellants.
Appeal from the United States District Court for the Central District of California in case
no. 04-CV-9014, Senior Judge Consuelo B. Marshall.
__________________________
DECIDED: July 23, 2009
__________________________
Before MAYER, RADER, and BRYSON, Circuit Judges.
MAYER, Circuit Judge.
Marc H. Hedrick, Prosper Benhaim, Hermann Peter Lorenz, and Min Zhu appeal
the judgment of the United States District Court for the Central District of California
finding that they were not co-inventors of U.S. Patent No. 6,777,231, and granting a
misjoinder motion pursuant to 35 U.S.C. § 256. Univ. of Pittsburgh v. Hedrick, No. 2:04-
cv-09014 (C.D. Cal. June 9, 2008). Because we agree that University of Pittsburgh
researchers Adam Katz and Ramon Llull completed conception of the claimed invention
before the appealing researchers contributed their efforts, we affirm.
BACKGROUND
Cells of the human body are generally tasked to perform specific functions. For
instance, bone cells support the body, and nerve cells transmit signals throughout the
body. These cells may divide and multiply to grow or heal, but a cell’s progeny will
usually remain of the same type as its parent cell—bone cells divide into more bone
cells, nerve cells divide into more nerve cells. This feature is called unipotency, and a
cell that divides to produce progeny is a progenitor cell. However, the more primitive
stem cell is pluripotent, meaning that its progeny may be of various types of cells – a
single stem cell may produce progeny that include both bone cells and nerve cells, for
example. The process of a generic stem cell producing progeny cells of a particular
type is referred to as differentiation. Generally, a cell that is the product of
differentiation is permanently locked into being a progenitor of only that type of cell.
Stem cells also exhibit the quality of producing further stem cells, just as a normal cell
would produce a like cell through division. In a process called self-renewal, a stem cell
cured in an appropriate culture dish would reproduce enough to cover the surface of the
dish with like stem cells. A scientist could then remove cells and place them on a new
culture dish where the process would repeat, producing a new lot of stem cells covering
the surface of the dish. Each iteration is termed a passage, and it was known in the art
in 1997 that stem cells can be passaged at least fifteen times without differentiating.
Katz and Llull are researchers at the University of Pittsburgh (“Pittsburgh”)
studying adipose (fat) tissue in humans. In 1996, the two doctors began a project at
Pittsburgh involving the isolation, culturing, and passaging of cells from human
liposuctioned adipose tissue. They observed that under certain conditions, mature fat
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cells called adipocytes would transform into a more primitive cell having a fibroblast-like
appearance, and under other circumstances, these primitive cells could transform back
to mature adipocytes. They referred to these phenomena as de-differentiation and re-
differentiation. By late 1996, they had developed a method to isolate these de-
differentiated cells from liposuctioned tissue’s stromal vascular fraction.
By 1997, Katz and Llull had explored the idea that these cells could
“transdifferentiate” into lineages other than adipocyte cells, including bone, cartilage,
and muscle. They recorded their observations, including that their cells appeared to
change to the shape and form of non-adipose cells, contemporaneously in laboratory
notebooks, a January 1997 invention disclosure for their cell isolator device, and a
document titled “What’s So Great About Fat?” in February 1997. Reading literature
from Arnold Caplan, another researcher in stem cells, they began to recognize that the
mesenchymal stem cells Caplan was harvesting from bone marrow bore similarities to
those they had isolated from adipose tissue. Caplan’s cells differentiated into bone,
muscle, fat, and cartilage lineages, among others, and showed the ability to be
passaged fifteen times without differentiating.
On January 20 and 24, and February 6, 1997, Katz wrote in his laboratory
notebook that he had experimented with media to induce his cells to differentiate into
muscle. In other entries, Katz described media and protocols that differentiated the
cells into bone, muscle, fat, cartilage, and nerve cells. While not scientifically certain, he
and Llull believed that they had observed cells changing into cells resembling muscle
and fat cells, and commented to another colleague via email their intrigue over seeing
“several forms that do resemble those of a neuron.” They decided to do further studies
2008-1468 3
to substantiate that this was in fact a nerve cell, asking their colleague for the use of his
electrophysiological techniques. By April 1997, they 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.
In July of 1997, Hedrick joined the Pittsburgh laboratory for a yearlong fellowship.
During his time in the lab, Katz submitted a grant proposal summarizing his work with
Llull, stating that their “lab has developed techniques to harvest, isolate, culture,
passage, dedifferentiate, differentiate, and genetically alter” adipose-derived progenitor
cells efficiently. While some researchers other than Katz and Llull were listed in the
proposal, Hedrick was not. Hedrick was also not mentioned in Katz’s laboratory
notebook in connection with any work on adipose-derived stem cells, though other
researchers involved in the work were mentioned. Hedrick, however, wrote his own
research proposal setting forth some experiments on Katz’s cells. In April of 1998,
Katz, Llull, and Hedrick submitted an invention disclosure to Pittsburgh stating that the
isolated cells could be induced to transform into fat, bone, cartilage, and muscle tissues,
and listed the first date of conception as October 1996.
In June of 1998, Hedrick’s fellowship ended, and he returned to UCLA where he
formed the Regenerative Bioengineering and Research (“REBAR”) laboratory with
Benhaim and Lorenz. There, Hedrick and his colleagues worked on the same
populations of adipose-derived cells as Katz and Llull were using at Pittsburgh. Zhu
would join the lab in June 1999. The REBAR researchers determined that the adipose-
derived cells were distinct from the prior art bone marrow-derived mesenchymal stem
2008-1468 4
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. Meanwhile, Katz continued to research the exploitable potential
of his cells at Pittsburgh.
In March 1999, Pittsburgh filed a provisional patent application, claiming a
method of differentiating adipose-derived stem cells into bone, fat, cartilage, and
muscle. The application listed Katz, Llull, William Futrell, and Hedrick as inventors. In
October 1999, they filed a second provisional patent application listing the same
inventors, acknowledging ongoing experimentation to find the cells in human
liposuctioned fat tissue and the similarities to bone marrow-derived mesenchymal stem
cells.
In February 2000, Hedrick submitted an invention disclosure to UCLA for stem
cells derived from adipose tissue, listing 1997 as the date of first conception and his first
successful test. Although he had not conducted any nerve differentiation experiments,
he also asked the UCLA technology transfer office to include nerve cells in the patent
application. About the same time, he provided Pittsburgh’s patent counsel with
information to include in a patent application, including recipes for induction media and
the suggestion to include nerve cells.
In March 2000, Pittsburgh filed an international patent application listing all seven
named inventors, Katz, Llull, Futrell, Hedrick, Benhaim, Lorenz, and Zhu. This patent
2008-1468 5
would issue as U.S. Patent No. 6,777,231 (“’231 patent”), having the following 10
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 pluality 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.
On October 29, 2004, Pittsburgh filed the instant action seeking the removal of
named inventors Futrell, Hedrick, Benhaim, Lorenz, and Zhu. Futrell voluntarily
dismissed himself from the suit leaving the REBAR researchers as the only defendants.
The district court held a hearing to construe the patent claims. Among the constructions
disputed was the term “adipose-derived,” as is present in each claim. The REBAR
researchers argued that the construction should be limited to a “species of stem cell
distinct from the mesenchymal stem cell that is obtainable from bone marrow tissue”
while Katz and Llull argued for a plain meaning: cells “derived from fat tissue.” The
court determined that the specification supports the plain meaning, and there was no
disavowal of any other meaning in prosecution. So it adopted the definition proffered by
Katz and Llull.
2008-1468 6
The district court then found that Katz and Llull had conceived the claimed
invention as construed prior to Hedrick’s arrival at Pittsburgh. In addition to the
background set out above, the court supported its holding by finding that Katz and Llull
must have conceived that the cells they possessed were pluripotent by February 1997,
because there was no reason for Katz to have conducted his experiment attempting to
induce his adipose-derived cells into non-adipose muscle cells except to confirm that
the cells were in fact pluripotent stem cells. The court also found that Katz’s laboratory
notebooks would have enabled a scientist skilled in the field to isolate his adipose-
derived cells and differentiate them into each of the lineages claimed in the ’231 patent.
The REBAR researchers appeal the construction of “adipose-derived”, and the
conclusion that they were not joint inventors of the claimed invention. We have
jurisdiction pursuant to 28 U.S.C. § 1295(a)(1).
DISCUSSION
Claim construction is a question of law that we review de novo. Cybor Corp. v.
FAS Techs., Inc., 138 F.3d 1448, 1454-55 (Fed. Cir. 1998) (en banc). When not clearly
defined in the specification, claim terms are given the meaning they would have to one
of ordinary skill in the art at the time of the invention. Phillips v. AWH Corp., 415 F.3d
1303, 1312-13 (Fed. Cir. 2005). “[T]he specification is the single best guide to the
meaning of a disputed term,” and we read the claim terms in view of the specification.
Id. at 1321 (internal quotations removed). The specification may impart a definition that
differs from a term’s ordinary meaning only when it demonstrates “an intent to deviate
from” that meaning. Voda v. Cordis Corp., 536 F.3d 1311, 1320 (Fed. Cir. 2008)
(citations omitted). Prosecution history may not be used to limit the scope of a claim
2008-1468 7
unless the applicant took a position before the Patent Office that would lead a
competitor to believe that the applicant had disavowed coverage of the relevant subject
matter. Schwing GmbH v. Putzmeister AG, 305 F.3d 1318, 1324-25 (Fed. Cir. 2002).
Such a disavowing statement must be so clear as to show reasonable clarity and
deliberateness. Omega Eng’g, Inc. v. Raytek Corp., 334 F.3d 1314, 1325 (Fed. Cir.
2003).
The district court found that one of ordinary skill would interpret the term
“adipose-derived” to mean simply “derived from fat tissue.” The REBAR researchers do
not disagree that this is the term’s plain meaning, but argue that the construction must
also include that the stem cell is “a species of stem cell distinct from the mesenchymal
stem cell (‘MSC’) that is obtainable from bone marrow tissue.” This construction is
necessary for their claim of inventorship because they alleged that their research
proved that the inventive stem cells were in fact distinct from the prior art mesenchymal
stem cells. They posit that the district court’s construction would allow inclusion of prior
art mesenchymal stem cells that traveled from the bone marrow and became lodged in
fat tissue, where they are then extracted. They also argue that the specification makes
clear that the inventive aspect of the adipose-derived stem cells is not that they are
simply recovered from adipose tissue.
The REBAR researchers contend that the specification describes the prior art
mesenchymal stem cells in one way, and describes the inventive adipose-derived cells
differently, as an improvement upon the mesenchymal stem cells. The district court
found that the specification distinguishes between mesenchymal stem cells and
adipose-derived stem cells. While the specification says that the mesenchymal stem
2008-1468 8
cells require costly prescreening of culture materials, the inventive cells can be
passaged in culture in an undifferentiated state not requiring prescreened lots of serum.
Compare ’231 Patent col.1 ll.35-39 with id. col.2 ll.16-18 and col.16 ll.1-4. However, the
specification does not say that the cells are a separate species from mesenchymal stem
cells collected from bone marrow as the REBAR researchers argue, just that those
derived from bone marrow have different isolation requirements than those derived from
adipose tissue. The court cannot impute a reason for the difference in isolation
requirements of cells harvested from bone marrow versus those harvested from adipose
tissue by requiring them to be of a separate species. Nor can we conclude that the
hypothetical bone marrow originating stem cell that traversed and became lodged in
adipose tissue would not lose the qualities that make it more difficult to isolate than its
adipose-derived neighbors. That other similar prior art cells are described differently
than the inventive cells does not rise to an intent to deviate from the meaning of the
terms describing the inventive cells. Voda, 536 F.3d at 1320.
We similarly do not find the REBAR researchers’ prosecution history argument
persuasive. A patentee may limit the meaning of a claim term by making a clear and
unmistakable disavowal of scope during prosecution. Purdue Pharma L.P. v. Endo
Pharms., Inc., 438 F.3d 1123, 1136 (Fed. Cir. 2006). The researchers argue that Katz
and Llull clearly and unambiguously disclaimed any construction of adipose-derived that
could read on prior-art mesenchymal stem cells when they overcame a rejection of
claims by introducing the term adipose-derived. They argue that at an interview
recorded in a summary, Katz and Llull “agreed that a submission to distinguish between
adipose derived stem cell and bone marrow derived stem cell will be submitted.” The
2008-1468 9
subsequent submission was a paper by a UCLA group that included REBAR
researchers showing that the mesenchymal stem cells and the inventive stem cells
differed in their intrinsic properties. The examiner then agreed with the inventors that
the “adipose-derived stem cells are distinct from the mesenchymal stem cells” of the
prior art, but also noted that the claims were “now in condition for allowance” without
requiring an amendment. This is not a disavowal. The examiner’s summary is certainly
terse, and its terseness does not allow a definition of any claim terms. It does not state
why the adipose-derived stem cells in the invention are distinct from mesenchymal stem
cells, and thus does not explicitly characterize the invention at all, let alone in a specific
manner to overcome prior art. See Purdue Pharma, 438 F.3d at 1136. 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.
Inventorship is a question of law that we review de novo, based on underlying
facts which we review for clear error. Hybritech Inc. v. Monoclonal Antibodies, Inc., 802
F.2d 1367, 1376 (Fed. Cir. 1986). A joint invention is the product of collaboration
between two or more persons working together to solve the problem addressed. 35
U.S.C. § 116 (2006). The inventors need not work physically together or
contemporaneously to be joint inventors; nor must each inventor contribute equally or to
each claim of the patent. Id. The inventors named in an issued patent are presumed
correct, and a party alleging misjoinder of inventors must prove its case by clear and
convincing evidence. Eli Lilly & Co. v. Aradigm Corp., 376 F.3d 1352, 1358 (Fed. Cir.
2008-1468 10
2004). The movants must also show that the persons to be removed did not contribute
to the invention of any of the allowed claims.
Conception is the touchstone of inventorship under 35 U.S.C. § 116. It is “the
formation in the mind of the inventor, of a definite and permanent idea of the complete
and operative invention, as it is hereafter to be applied in practice.” Burroughs
Wellcome Co. v. Barr Labs., Inc., 40 F.3d 1223, 1228 (Fed. Cir. 1994) (quoting
Hybritech, 802 F.2d at 1376). The test for conception is whether the inventor had an
idea that was definite and permanent enough that one skilled in the art could
understand the invention; the inventor must prove his conception by corroborating
evidence, preferably by showing contemporaneous disclosures. Burroughs, 40 F.3d at
1228. Such corroborating evidence is taken as a whole; conception of an entire
invention need not be reflected in a single source. Price v. Symsek, 988 F.2d 1188,
1196 (Fed. Cir. 1993). An inventor need not know that his invention will work for
conception to be complete. Id. 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. Id. at 1229.
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
2008-1468 11
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 district court found that conception of a substantially homogeneous
population of the cells as required by claim 5 was satisfied by a September 1997 grant
proposal describing efficiently harvesting and isolating these cells. While this writing
was dated after Hedrick arrived at Pittsburgh, it does not mention Hedrick among the
many other collaborators.
The district court also found that Katz and Llull grasped that their cells could self-
renew as he recorded on March 20, 1997, satisfying the requirements added in claim 6.
The court found that those skilled in the field at that time knew of no examples of stem
cells that could not self-renew for at least 15 passages as the claim requires. Finally,
the court found that Katz and Llull had the firm and definite idea that the cells were
2008-1468 12
human, could be genetically modified, secreted hormones, and contained cell-surface
bound intracellular signaling moieties by April 1997 as these properties were known at
the time to scientists in the field. Thus, they had conceived of the cells with the qualities
required by claims 7, 8, 9, and 10, completing conception of the entire claimed
invention.
The REBAR researchers do not attack these factual findings, but rather argue
that Katz and Llull’s research was inconclusive until Hedrick and the other researchers
added their efforts. They argue that other evidence showed that Katz and Llull’s work
remained “highly speculative” through the end of Hedrick’s fellowship. They argue that
Katz and Llull were required to “know” that the invention contained every limitation of
each claim at the time of conception, see Coleman v. Dines, 754 F.2d 353, 359 (Fed.
Cir. 1985), but that the evidence did not establish that they had this knowledge until the
REBAR researchers helped them confirm the claimed properties. Their argument is
premised upon a misapprehension of what it means to “know” the limitations of the
claims.
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. Conception requires a definite and permanent idea of the operative invention,
Burroughs, 40 F.3d at 1230, and “necessarily turns on the inventor’s ability to describe
his invention.” Id. at 1228. Proof that the invention works to a scientific certainty is
reduction to practice. Therefore, because the district court found evidence that Katz
and Llull had formed a definite and permanent idea of the cells’ inventive qualities, and
had in fact observed them, it is immaterial that their knowledge was not scientifically
2008-1468 13
certain and that the REBAR researchers helped them gain such scientific certainty.
“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). 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. Thus, they had
disclosed a “completed thought expressed in such clear terms as to enable those skilled
in the art to make the invention.” Coleman, 754 F.2d at 359.
The REBAR researchers also argue that the district court erred by filling in holes
in Katz and Llull’s conception with knowledge that a skilled artisan would have had at
the time when no corroborating evidence of their own knowledge was produced. We do
not find clear error in using such evidence as corroboration. “Under the ‘rule of reason’
standard for corroborating evidence, . . . the trial court must consider corroborating
evidence in context, make necessary credibility determinations, and assign appropriate
probative weight to the evidence to determine whether clear and convincing evidence
supports a claim of co-inventorship.” Ethicon, Inc. v. U.S. Surgical Corp., 135 F.3d
1456, 1464 (Fed. Cir. 1998) (internal citations omitted). 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, 40 F.3d at 1231. Here, the greater discovery is
that stem cells can be derived from adipose tissue. It was not improper for the district
court to recognize that skilled artisans at the time of the alleged conception would have
2008-1468 14
known the obvious properties that these stem cells self-renew for at least 15 passages
as in claim 6, that the cells contain cell-surface bound intracellular signaling moieties for
claim 9, and secreted hormones for claim 10, and to credit Katz with having the firm and
definite idea that these properties existed in his cells.
CONCLUSION
Accordingly, the judgment of the United States District Court for the Central
District of California is affirmed.
AFFIRMED
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