Court Opinion

ID: 4165659
Source: CourtListenerOpinion
Date Created: 2017-05-03 15:04:35.903143+00
Date Added: 2024-06-11T14:38:11.545641
License: Public Domain

NOTE: This disposition is nonprecedential.

  United States Court of Appeals
      for the Federal Circuit
                ______________________

NANTKWEST, INC., FORMERLY CONKWEST, INC.,
             Plaintiff-Appellant

                           v.

MICHELLE K. LEE, DIRECTOR, U.S. PATENT AND
    TRADEMARK OFFICE, DEPUTY UNDER
      SECRETARY OF COMMERCE FOR
   INTELLECTUAL PROPERTY AND DEPUTY
 DIRECTOR OF THE UNITED STATES PATENT
         AND TRADEMARK OFFICE,
              Defendant-Appellee
            ______________________

                      2015-2095
                ______________________

   Appeal from the United States District Court for the
Eastern District of Virginia in No. 1:13-cv-01566-GBL-
TCB, Judge Gerald Bruce Lee.
                ______________________

                 Decided: May 3, 2017
                ______________________

   ALAN J. HEINRICH, Irell & Manella LLP, Los Angeles,
CA, argued for plaintiff-appellant. Also represented by
MORGAN CHU, GARY N. FRISCHLING, LAUREN NICOLE
DRAKE; SANDRA HABERNY, Newport Beach, CA.
2                                   NANTKWEST, INC.   v. LEE

    MARY L. KELLY, Office of the Solicitor, United States
Patent and Trademark Office, Alexandria, VA, argued for
defendant-appellee. Also represented by THOMAS W.
KRAUSE, SARAH E. CRAVEN, SCOTT WEIDENFELLER.
                ______________________

     Before PROST, Chief Judge, DYK, and STOLL, Circuit
                        Judges.
     Opinion for the court filed by Circuit Judge DYK, in
            which PROST, Chief Judge, joins.
      Dissenting Opinion filed by Circuit Judge STOLL.
DYK, Circuit Judge.
    The United States Patent and Trademark Office
(“USPTO”) rejected claims 20, 26, and 27 of U.S. Patent
Application No. 10/008,955 (“’955 patent application”) on
the ground that the claims would have been obvious.
NantKwest sought review in district court, pursuant to 35
U.S.C. § 145, asserting that claims 20, 26, and 27 of the
application were nonobvious. The district court granted
the USPTO’s motion for summary judgment of obvious-
ness. NantKwest appeals. We affirm.
                      BACKGROUND
    NantKwest is the assignee of the patent application at
issue, filed by Hans Klingemann (“patent applicant”),
directed to the use of a specific type of immune cells for
treating cancer.
     The immune system can be divided into its innate and
adaptive responses. The innate immune response—which
is the first line of defense—comprises immune cells like
natural killer (“NK”) cells that rapidly attack anything
that they sense as foreign. NK cells generally have lim-
ited target-recognition specificity and attack rather
indiscriminately. The adaptive immune response—which
is the second line of defense—comprises immune cells like
NANTKWEST, INC.   v. LEE                                     3

T cells that attack specific foreign antigens that they have
been trained to recognize. The adaptive immune response
is thus slower but more target-specific. NK cells and T
cells have different cell surface proteins and respond to
certain target cell receptors differently. The patent appli-
cation here concerns the use of a particular cell line 1 of
NK cells—NK-92.
    Despite these differences between NK cells and T
cells, throughout the 1980s and 1990s, various prior art
references taught that both T cells and NK cells were
capable of lysing (destroying) cancer cells. These refer-
ences described in vitro, ex vivo and in vivo experiments
demonstrating this ability. By 1997, NK cells and T cells
were the only two types of immune cells known “to recog-
nize and lyse tumor cells in vivo in mammals.” J.A. 779–
80.
     Two specific prior art references are involved here.
First, U.S. Patent No. 5,272,082, by Santoli et al. (“San-
toli”), taught that a specific cell line of T cells, TALL-104,
can be used in vivo to treat cancer. Second, Gong, Maki,
and Klingemann (the ’955 patent applicant) published a
study (“Gong”) that taught that a specific NK cell line,
NK-92, can lyse cancer cells in vitro with high efficacy.
The question here is whether these references rendered
the ’955 application’s claims obvious.

    1    Immune cells harvested in the laboratory are de-
rived from “cell lines,” which refer to cancerous cells that
continue reproducing more of their own cell type. For
example, tumor cells that produce T cells or NK cells
nonstop (and hence cause cancer) can be removed from a
patient and nourished in the laboratory to reproduce more
T cells or NK cells for subsequent experimental use.
4                                     NANTKWEST, INC.   v. LEE

    On December 7, 2001, the patent application was filed
with a priority date of April 30, 1997. Claim 20, an inde-
pendent claim on appeal here, provides
    A method of treating a cancer in vivo in a mam-
    mal comprising the step of administering to the
    mammal a medium comprising an NK-92 cell line
    ATCC Deposit No. CRL-2407, wherein said cancer
    is recognized and lysed by said NK-92 cell line.
    J.A. 5. Also on appeal are two dependent claims.
Claim 26 teaches that “[t]he method of treating a cancer
described in claim 20 wherein the route of administration
of the cells to the mammal is intravenous and the mam-
mal is human.” Id. Claim 27 teaches that “[t]he method of
treating a cancer described in claim 20 further comprising
the step of administering to said mammal a cytokine that
promotes the growth of said NK-92 cell line.” Id.
    The USPTO Examiner rejected the claims at issue
and found that “it would have been prima facie obvious to
a person of ordinary skill in the art . . . in April 1997 to
combine the teachings of Santoli and Gong to arrive at the
claimed method because Gong . . . teaches use of NK-92
cells to lyse tumor cells, while Santoli . . . teaches in vivo
use of cytotoxic cell lines.” J.A. 8 (internal quotation
marks omitted).
    The applicant then appealed to the Board of Patent
Appeals and Interferences (“Board”). The Board affirmed
the Examiner’s rejection on the ground that a person of
ordinary skill in the art “would have been motivated to
replace the TALL-104 cells in Santoli’s method with NK-
92 cells based on Gong’s disclosure that NK-92 cells
spontaneously kill [leukemia and lymphoma cancer] cells
with high efficiency.” J.A. 10 (internal quotation marks
omitted).
   Pursuant to 35 U.S.C. § 145, NantKwest then filed a
complaint in district court, seeking judgment that claims
NANTKWEST, INC.   v. LEE                                   5

20, 26, and 27 of the patent application were nonobvious.
The USPTO moved for summary judgment. In response,
NantKwest argued that this case involves disputes of
factual issues that cannot be resolved on summary judg-
ment, relying on expert reports from Dr. Miller (“Miller”)
and new references submitted for the § 145 proceeding.
The district court granted summary judgment “because
there is no genuine material factual dispute as to whether
the invention claimed in the [patent application] was
obvious over the prior art, as found by both the Examiner
and the Board.” J.A. 15.
   NantKwest appeals. We have jurisdiction under 28
U.S.C. § 1295(a)(1).
                           DISCUSSION
                               I
     This court reviews the district court’s grant or denial
of summary judgment de novo. MicroStrategy Inc. v. Bus.
Objects, S.A., 429 F.3d 1344, 1349 (Fed. Cir. 2005) (cita-
tions omitted). Summary judgment may be granted only
“if the movant shows that there is no genuine dispute as
to any material fact.” Fed. R. Civ. P. 56(a). Claim con-
struction is an issue of law that we review de novo where,
as here, there is no relevant extrinsic evidence. Teva
Pharm. USA, Inc. v. Sandoz, Inc., 135 S. Ct. 831, 841
(2015).
    A patent is obvious if “a skilled artisan would have
been motivated to combine the teachings of the prior art
references to achieve the claimed invention, and that the
skilled artisan would have had a reasonable expectation
of success in doing so.” Proctor & Gamble Co. v. Teva
Pharm. USA, Inc., 566 F.3d 989, 994 (Fed. Cir. 2009)
(internal quotation marks omitted).
6                                    NANTKWEST, INC.   v. LEE

                             II
    NantKwest contends that we should reverse the grant
of summary judgment because the district court used an
incorrect claim construction. Initially, the district court
construed “cancer” to mean a “plurality or multiple cancer
cells.” J.A. 16. However, in addressing the reasonable
expectation of success, the court appeared to consider
“cancer” as meaning “one or more cancer cells.” J.A. 22.
We agree with NantKwest that this is an incorrect con-
struction of “cancer.” The correct construction of the claim
term “treating a cancer” “require[s] lysis of many cells, in
order to accomplish the goal of treating cancer,” and not
merely lysing one or a few cancer cells. J.A. 722.
    However, the district court’s erroneous claim con-
struction creates no basis for reversal. First, we review
the district court’s decision de novo. In addressing the
issue of obviousness, we will use the correct construction,
which renders the district court’s erroneous construction
harmless error. Second, there is no assertion here that the
relevant prior art references taught methods that only
lysed one cancer cell or otherwise lysed insufficient num-
bers of cells for treating cancer.
                             III
                             a
    Under 35 U.S.C. § 145,
    [a]n applicant dissatisfied with the decision of the
    [Board] . . . may . . . have remedy by civil action
    against the Director in [district court] . . . . The
    court may adjudge that such applicant is entitled
    to receive a patent for his invention, as specified
    in any of his claims involved in the decision of the
    [Board], as the facts in the case may appear . . . .
NANTKWEST, INC.   v. LEE                                     7

    In § 145 proceedings, “the district court may consider
new evidence” presented by the applicant that was not
before the Board. Kappos v. Hyatt, 132 S. Ct. 1690, 1696
(2012). If there are genuine issues of material fact, “the
district court must make de novo factual findings that
take account of both the new evidence and the adminis-
trative record before the PTO.” Id. at 1701.
    We agree with the district court that there is no mate-
rial dispute that the combination of Santoli and Gong
used here produced the invention and that persons of
ordinary skill in the art would have been motivated to
combine Santoli and Gong.
    Santoli was an important advance because it showed
that T cells from a cell line, not belonging to a patient, can
be administered into a patient to produce in vivo thera-
peutic effects. Such an approach is called “allogeneic” or
“adoptive immunotherapy.” Santoli specifically taught
that the TALL-104 cell line can be used in adoptive im-
munotherapy in vivo for lysing cancer cells. 2

    2   We reject NantKwest’s argument that Santoli
does not “disclose a successful in vivo therapy for TALL-
104.” Appellant Br. 32. A study of TALL-104 in vivo
therapy in dogs showed clinical responses in eight out of
nineteen dogs tested. Another study showed that mice
treated with TALL-104 cells remained cancer-free for at
least 2 months, while untreated mice all died within 10 to
20 days. In fact, the patent application itself acknowl-
edged that prior TALL-104 studies demonstrated “anti-
tumor activity in vivo . . . to induce remissions of
spontaneous lymphomas in dogs.” J.A. 53; Cesano, J.A.
947, tbl. 3. The alleged post-filing failure of TALL-104
therapy in human clinical trials—not known at the time
of the application—is irrelevant. See In re Vaeck, 947 F.2d
8                                       NANTKWEST, INC.   v. LEE

     Gong taught that the NK-92 cell line showed in vitro
efficacy in lysing cancer cells. In fact, NK-92 was found to
have “high efficiency” in lysing the same leukemia tumor
cell type as TALL-104 did. See J.A. 128, 142. Both TALL-
104 and NK-92 lysed cancer cells via the same mecha-
nism, i.e., in a “non-MHC-restricted” manner, in which
they do not require presentation of antigens on the MHC
cell surface proteins of the tumor cells. J.A. 131, 145.
    Prior art publications by the patent applicant himself
indicated that there was a motivation to seek clinical
applications for the NK-92 cell line. For example, Gong
noted that “[b]ecause of their ability to lyse malignant
cells, NK . . . cells have been utilized in several clinical
trials in cancer patients.” J.A. 140. In a separate publica-
tion, Klingemann et al. cited to the fact that because “NK-
92 cells . . . can lyse [tumor cells] in vitro,” the authors
wanted “[t]o test the suitability NK-92 cells for ex vivo
purging.” 3 J.A. 344. While the appellant is correct that
these experiments are different from allogeneic in vivo
therapy, in that they used the patient’s own NK cells,
they indisputably indicate that skilled artisans were
motivated to pursue clinical applications for NK cells and
the NK-92 cell line.
     Indeed, the ’955 patent application itself referred to
Gong to describe the superior qualities of the NK-92 cell
line. See, e.g., ’955 patent application, ¶ 50 (“The NK-92
cell line has been described by Gong et al. (1994)”); id. at
¶ 74 (“NK-92 cells (Gong et al. (1994)) were derived from

488, 493 (Fed. Cir. 1991) (“[E]xpectation of success must
be founded in the prior art.” (emphasis added)).
    3 Ex vivo purging entails removing “a patient’s [own]

blood . . . cells . . . from the body, activat[ing them] . . . ,
and then return[ing them] back to the patient” for thera-
py, with the effects stemming from the activated cells.
J.A. 7.
NANTKWEST, INC.   v. LEE                                       9

cells obtained from a patient suffering from non-
Hodgkin’s lymphoma.”). The patent application highlight-
ed NK-92’s “superior” in vitro efficacy (as well as the
later-determined in vivo efficacy), compared against other
immune cells, as “activities [that] are . . . unexpected by a
worker in the field of tumor cytotherapy.” Id. at ¶ 121.
The patent application also teaches that NK-92’s in vitro
efficacy was “superior to those activities manifested by
the known preparations of cytolytic cells normally present
in humans,” which suggests NK-92’s therapeutic utility
based on in vitro data. Id. In fact, the ’955 patent applica-
tion concluded from in vitro data that “the NK-92 cells of
the invention are surprisingly and significantly more
effective in lysing patient-derived tumor cells . . . than . . .
the cells from [the TALL-104] cell line[] known in the
field.” Id. at ¶ 104.
     Santoli taught that “[t]here remains a need in the art
for therapeutic methods . . . for cancers which can utilize
cytotoxic T cell lines and avoid the present need . . . for
patient’s own killer cells.” J.A. 130, col. 2, ll. 33–37. San-
toli thus provided an explicit suggestion to use cell lines
(allogeneic therapy) in cancer treatments because of their
greater availability. In fact, the ’955 patent application
itself recognized that prior investigators turned to alloge-
neic therapy in preference to using a patient’s own cells.
See ’955 patent application, ¶ 9 (To overcome the “major
obstacle” of “expand[ing] NK cells . . . in vivo” for clinical
use, “many investigators have turned to the use of estab-
lished NK-like cell lines.”). Thus, prior art references on
successful in vivo therapy using non-allogeneic NK cells
taught toward using cell lines.
    Finally, there were specific studies undertaken to de-
termine whether the NK-92 cell line would be useful for in
vivo therapy. Yan et al. (“Yan”) is a prior art reference
relied on by the Board, in which investigators compared
the in vitro efficacies between TALL-104 and NK-92 cell
lines against various tumors, in order to study the poten-
10                                     NANTKWEST, INC.   v. LEE

tial of using these cell lines for in vivo therapy. J.A. 226
(“To study the potential of using biological reagents in
adoptive immunotherapy, we tested the tumoricidal
capacity of T104 [and] NK92.”). Yan concluded that the in
vitro efficacy of NK-92 was even greater than the in vitro
efficacy of TALL-104, which had already been used for in
vivo therapy. Through this head-to-head comparison, Yan
taught persons skilled in the art to combine the teachings
of Santoli—using a cell line in adoptive immunotherapy—
with the teachings of Gong—the use of the NK-92 cell
line.
                               b
    We also find that it would have been at least obvious
for skilled artisans to try to combine the teachings of
Santoli and Gong.
     When there is a . . . problem and there are a finite
     number of identified, predictable solutions, a per-
     son of ordinary skill has good reason to pursue the
     known options . . . . If this leads to the anticipated
     success, it is likely the product not of innovation
     but of ordinary skill and common sense. In that
     instance the fact that a combination was obvious
     to try might show that it was obvious under § 103.
    KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007).
Generally, the only situations where this does not apply is
where “the inventor would have had to try all possibilities
in a field unreduced by direction of the prior art . . . [or]
where vague prior art does not guide an inventor toward a
particular solution.” Bayer Schering Pharma AG v. Barr
Lab., Inc., 575 F.3d 1341, 1347 (Fed. Cir. 2009).
     Even NantKwest’s expert conceded that in 1997,
skilled artisans knew that NK cells and T cells were the
only two types of immune cells known to have antitumor
efficacy. Moreover, both Santoli and Gong recognized that
TALL-104 and NK-92 cells attack cancer cells via the
NANTKWEST, INC.   v. LEE                                 11

same mechanism, which induced skilled artisans like Yan
to compare the efficacies of these two cell lines. Thus,
TALL-104 and NK-92 were known to be similar and were
among a very limited number of immune cells for use in
anticancer therapy. Given the limited number of possibili-
ties in the prior art and the many explicit suggestions
“toward a particular solution,” Bayer, 575 F.3d at 1347,
we conclude that combining the teachings of Santoli and
Gong would have been at least obvious to try.
                            IV
        NantKwest claims that expert reports by Dr. Mil-
ler submitted for the first time in the district court pro-
ceeding and new prior art references also submitted for
the § 145 proceeding raise genuine disputes of material
fact about the reasonable likelihood of success for combin-
ing Gong with Santoli. We disagree.
    Our cases recognize that there is no general rule that
a skilled artisan cannot reasonably extrapolate in vivo
success from in vitro results. “Obviousness does not
require absolute predictability of success. Indeed, for
many inventions that seem quite obvious, there is no
absolute predictability of success until the invention is
reduced to practice.” In re O’Farrell, 853 F.2d 894, 903
(Fed. Cir. 1988). “[P]roviding proof sufficient to justify
conducting in vivo procedures on humans, while useful, is
not a test of patentability.” PharmaStem Therapeutics,
Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007).
    Rather, our cases hold that whether the skilled arti-
san can extrapolate in vivo success from in vitro results is
highly fact-specific. See In re Gangadharam, 889 F.2d
1101, 1989 WL 127023 (Fed. Cir. 1989) (“The issue . . . is
not whether in vitro results can be used to predict in vivo
success; rather it’s simply whether the [USPTO], in this
case, carried its burden of proving a prima facie case of
obviousness of the claimed invention.” (emphasis in
original)); In re Carroll, 601 F.2d 1184, 1186 (C.C.P.A.
12                                    NANTKWEST, INC.   v. LEE

1979) (holding that there was teaching away because a
witness had stated that in vitro testing was unreliable for
in vivo effectiveness in a specific context).
    The fact that in vitro success does not always trans-
late into in vivo success cannot defeat summary judg-
ment. “[O]bviousness cannot be avoided simply by a
showing of some degree of unpredictability in the art so
long as there was a reasonable probability of success.”
Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir.
2007). Indeed, NantKwest itself simply argues that
“[p]ositive results in vitro do not necessarily establish a
reasonable probability of success for therapeutic use of
that drug in vivo.” Appellant Br. 43 (emphasis added).
But here, as we have discussed above, there is over-
whelming specific evidence that a skilled artisan could
reasonably extrapolate from the in vitro data with respect
to TALL-104 and NK-92 that would reasonably teach
their successful substitution in vivo. 4

     4  NantKwest argues that the Vujanovic et al. refer-
ence (“Vujanovic”) teaches that “although the A-NK and
NA-NK cells used for therapy showed similar levels of
cytotoxicity against HR [gastric cancer] cells tested [in
vitro] (Table I), A-NK cells demonstrated dramatically
and significantly greater antitumor activity than NA-NK
cells in vivo (Table V, Fig. 4).” J.A. 960. From this,
NantKwest concludes that there is “difficulty [in] predict-
ing efficacious in vivo cancer treatments from in vitro
assays,” in particular for NK cells. Appellant Rep. Br. 5.
We reject this out-of-context reading. Vujanovic indeed
teaches that A-NK and NA-NK have similar in vitro
efficacy against gastric cancer cells. J.A. 957, tbl. I. Vuja-
novic also teaches that against gastric cancer cells in vivo,
mice undergoing NA-NK treatment develop only 20% of
the cancer metastases that would develop in untreated
mice, while mice undergoing A-NK treatment develop
NANTKWEST, INC.   v. LEE                                 13

    However, the appellant asserts five specific material
disputes as to whether in vitro success here would trans-
late into in vivo success.
    First, NantKwest argues that Miller shows that there
is a teaching away from using unmodified NK-92 cells in
vivo because Santoli used TALL-104 cells modified to
contain a “suicide gene.” Appellant Br. 38. Santoli thus
“strongly discourages the skilled artisan from attempting
to introduce unmodified [immune] cells into a new host”
without this genetic modification, because such cells may
cause cancer. J.A. 392.
    NantKwest conceded during oral argument that the
claim language here does not require administering
“unmodified” NK-92 cells; that is, administering modified
NK-92 cells is encompassed by the claimed invention.
Oral Arg. 33:40–56. Therefore, whether Santoli teaches
away from using unmodified NK-92 cells is irrelevant.
Furthermore, the prior art had disclosed that TALL-104
cells could be “lethally irradiated,” so that they became
“non-proliferating,” without sacrificing TALL-104’s ability
to lyse cancer cells. J.A. 183. There is no dispute that
there would be motivation to irradiate cell lines to ad-

only 6% of the cancer metastases that would develop in
untreated mice. J.A. 960, tbl. V. To be sure, this is a
statistically significant difference between the NA-NK
and A-NK treatments. However, what NantKwest fails to
highlight is that despite this difference, both NA-NK and
A-NK treatments produced very statistically significant
reductions in cancer metastases as compared to untreated
mice. Vujanovic thus does not support the argument that
NK cells’ in vitro efficacy in antitumor activity cannot be
extrapolated to in vivo success; at most, it only suggests
that the exact magnitude of that success may not be
predictable.
14                                    NANTKWEST, INC.   v. LEE

dress this problem if it arose. 5 Thus, safely using a genet-
ically unmodified immune cell line was already taught in
the prior art.
    Second, NantKwest argues that Miller shows that
there is a teaching away from using allogeneic NK-92
therapy because “[i]t was not well understood at the time
of the invention whether allogeneic NK cells would be
subject to [attack by the] foreign host or whether [the
administered NK cells would] indiscriminate[ly] kill[] . . .
host cells.” J.A. 411.
     This was a broad and general concern known to
skilled artisans. In fact, USPTO expert Dr. Lanier agreed
that the “use of foreign immune cells in allogeneic thera-
pies may be associated with” reactions from the host and
the foreign cells against each other. J.A. 573. It would be
necessary “to test immune cells for reactivity and cytotox-
icity against allogeneic normal host cells in vitro prior to
developing treatments . . . in vivo.” Id. There was no
testimony here that such an adverse reaction was likely
in this context, and there was no testimony that this well-
known, general phenomenon (that administering foreign
cells into a host could cause untoward reactions) would
prevent a skilled artisan from trying NK-92 cells in vivo
while undertaking the necessary and known precautions.
If the need for such pre-administration trials could pre-
vent securing a patent, then no patent on in vivo therapy
would ever issue before clinical trials were complete.
While that appears to have been Dr. Miller’s own view, 6

     5  It was ultimately determined that NK-92 cells did
not present this risk because they “do not need to be
modified or irradiated to prevent uncontrolled prolifera-
tion.” Appellant Rep. Br. 17 n.2.
    6   Dr. Miller stated the following during deposition:
NANTKWEST, INC.   v. LEE                                    15

that view does not correspond to the existing standard for
patentability. See PharmaStem, 491 F.3d at 1364; Pfizer,
480 F.3d at 1364 (“[A] rule of law equating unpredictabil-
ity to patentability . . . would mean that any new [drug]
. . . would be separately patentable . . . [after its] proper-
ties . . . [are] verified through testing.”).
     Third, NantKwest argues that Yan taught away from
substituting NK-92 for TALL-104 because it showed that
TALL-104 and NK-92 “differed in cytolytic activity
against” the tumors tested. Appellant Br. 34 n.6. Howev-
er, the appellant failed to mention that this difference was
actually the fact that “[t]he NK92 [cell line] was highly
cytotoxic towards all” of the tumors tested, while TALL-
104 only lysed four out of the thirteen tumors tested. J.A.
226. Therefore, NK-92 was much more efficacious than
TALL-104, which would teach a skilled artisan toward the
substitution.
    Fourth, NantKwest argues that Yan does not provide
a motivation to combine because it cautioned that extrap-
olating immunotherapy results from one context to anoth-
er may be unpredictable. Specifically, Yan stated that
“our studies suggest that [immune cells’] cytotoxic activity
towards [cancer cells derived from laboratory] cell lines
cannot be extrapolated to [cancer] cells derived directly

    Q. Is there anything less than an in vivo study in
    mammals using NK-92 cells that could provide a
    reasonable expectation of success for the claimed
    method?
    A. . . . I’m not sure that there’s any predictability
    that I would be comfortable with, short of doing
    those types of experiments with the NK-92 cell
    line.
J.A. 776–77.
16                                    NANTKWEST, INC.   v. LEE

from patients. . . . [S]uch . . . immunotherapy . . . must be
accompanied by careful study of the unique patterns of
activity” of the antitumor immune cells used. J.A. 226.
Contrary to Miller’s assertion that this caveat “admonish-
es against relying on in vitro tests to predict in vivo
activity,” J.A. 439, Yan is not in fact comparing in vitro
and in vivo efficacies. In fact, Yan contains no in vivo
experiments. Rather, Yan is cautioning against extrapo-
lating lysis results against tumors derived from cell lines
to tumors derived directly from patients.
    And as the data shows, this caveat applies only to
TALL-104, but not NK-92. 7 As discussed above, TALL-104
lysed three out of four types of cancer cells derived from
laboratory cell lines, but only one out of nine types of
cancer cells derived directly from patients. In the same
comparison, NK-92 lysed all of the four types of cancers
derived from cell lines and all of the nine types of cancers
derived directly from patients. In other words, NK-92
showed no difference in lysis efficacy against laboratory
cell line cancers and patient-derived cancers. Therefore,
unlike TALL-104, which lyses cancer cells differently
depending on their source, NK-92’s efficacy appears to not
be context-dependent. See Yan, J.A. 226.
    Fifth, NantKwest makes much of the differences be-
tween T cells’ and NK cells’ cell-surface receptors, to
argue that these differences would have made it difficult
to extrapolate NK-92 behavior from TALL-104’s. Howev-
er, while Miller indeed highlights these differences, he
conceded that “NK-92 killing and T-ALL killing [of cancer
cells] has not, to my knowledge, in [1997], been associated
with the[ir] specific receptor pattern.” Miller Deposition,

     7  NantKwest also points out that a similar caveat is
found in two other publications. See Appellant Br. 46–47;
J.A. 953; J.A. 961. Those caveats, like Yan’s, also apply
only to TALL-104.
NANTKWEST, INC.   v. LEE                                  17

ECF 59-1, at 34. Therefore, these cell-surface receptor
differences are not material for the two cell lines’ similar
ability to lyse cancer cells.
                             V
    NantKwest argues that even against a prima facie
case of obviousness, it had presented secondary considera-
tions of nonobviousness that “may raise a genuine issue of
material fact that precludes summary judgment.” Appel-
lant Br. 61. “[E]vidence . . . of . . . secondary considera-
tions must always when present be considered en route to
a determination of obviousness.” In re Cyclobenzaprine
Hydrochloride Extended-Release Capsule Patent Litiga-
tion, 676 F.3d 1063, 1075 (Fed. Cir. 2012) (quotation
marks and citation omitted). However, “[f]or . . . second-
ary considerations to be accorded substantial weight, its
proponent must establish a nexus between the evidence
and the merits of the claimed invention. . . . Moreover,
secondary considerations . . . cannot overcome a strong
prima facie case of obviousness.” Wyers v. Master Lock
Co., 616 F.3d 1231, 1246 (Fed. Cir. 2010) (quotation
marks and citation omitted).
    For secondary considerations of nonobviousness,
NantKwest presents a news article announcing a $48
million investment in NantKwest as evidence of commer-
cial success, and some results from NK-92’s Phase I
clinical trials as evidence of unexpected results.
     With respect to the investment, we agree with the dis-
trict court that there is no direct nexus between the $48
million stock purchase and the merits of the claimed
invention to demonstrate commercial success. The report
indicates that the stock purchase was made for corporate
control purposes.
    NantKwest also contends that it “presented evidence
of the clinical success of NK-92 in vivo therapy . . . [that]
has demonstrated unexpected, superior results in two
18                                      NANTKWEST, INC.   v. LEE

recent . . . Phase I” clinical trials. Appellant Br. 57. There
is no evidence that the efficacy results were unexpected
compared to what was expected based on the in vitro
data. Indeed, as discussed above, the in vitro data sug-
gested that the in vivo trials would be successful. With
respect to the Phase I trials’ safety results, there was no
support for the conclusion that the NK-92 cell line was
surprisingly safer than the TALL-104 cell line therapy.
See Miller, J.A. 393–94 ¶ 48, J.A. 396 ¶ 53.
    We conclude that the district court properly granted
summary judgment that claims 20, 26, and 27 were
invalid as obvious.
                               VI
        The dissent appears to agree that there is sub-
stantial evidence supporting the district court’s finding of
obviousness. However, the dissent concludes that
NantKwest submitted contrary evidence that raises
genuine issues of material fact.
         The two cases cited by the dissent for the proposi-
tion that “lesser evidence [than what is presented here
was] sufficient to reverse rejections by the PTO in the
past” are clearly distinguishable. Dissent Op. 5. As dis-
cussed above, both Carroll’s and Gandadharam’s holdings
are highly fact-specific. In Carroll, the court held that the
prior art on the in vitro use of an antibiotic did not render
its in vivo use obvious because there was a teaching away
from in vivo extrapolation for that specific antibiotic. In re
Carroll, 601 F.2d at 1186. Carroll does not discuss in vivo
extrapolation generally. In Gandadharam, the court
simply found that “in this case,” the USPTO failed to
“carr[y] its burden of proving a prima facie case of obvi-
ousness” because the sole prior art only made “general
reference . . . [to] positive results that were obtained . . . in
an entirely different context, . . . and [made only] precato-
ry, encouraging statements relating to uncertain future
investigations” of in vivo applications. 1989 WL 127023,
NANTKWEST, INC.   v. LEE                                 19

at *1–2. Here, in contrast, there is in fact teaching to-
wards the invention.
        The dissent also reads Vujanovic, Yan, and
Cesano—as well as Miller’s testimony concerning these
studies—as creating genuine issues of material fact. The
cited passages do not show what Miller argues.
         First, the dissent cites Vujanovic for the teaching
that “[w]e suggest that standard in vitro cytotoxicity
assays with target cells in suspensions have little rele-
vance in predicting the in vivo antitumor activity of
effector cells.” J.A. 962 (emphasis added). This is merely
stating that a certain type of experiment setup (“cells in
suspension” assay) is not suitable for predicting in vivo
results. Indeed, the very next sentence addresses sphe-
roids assays and concludes that “[o]ur results further
imply that in vitro assessment of effector cell functions
with multicellular CA spheroids [assays] instead of CA
cell suspensions [assays] or monolayers [assays] might be
of greater relevance in predicting the in vivo therapeutic
antitumor potential of immune effector cells.” Id; see also
J.A. 956. Therefore, this passage does not support Miller’s
testimony that Vujanovic “caution[s] against relying on in
vitro cytotoxicity results.” J.A. 458 (emphasis added).
        Second, the dissent cites Yan for the teaching that
“our studies suggest that cytotoxic activity towards leu-
kemic cell lines cannot be extrapolated to cells derived
directly from patients. The use of such biologic reagents
in vitro or in vivo for immunotherapy or purging must be
accompanied by careful study of the[ir] unique patterns of
activity . . . .” J.A. 226. From this, Miller concludes that
“Yan admonishes against relying on in vitro tests to
predict in vivo activity.” J.A. 439–40. However, as dis-
cussed above, the cited passage from Yan is speaking
about the differences in lysis efficacy against tumors from
cell lines versus against tumors derived directly from
patients. All of the experiments presented in Yan were
20                                    NANTKWEST, INC.   v. LEE

performed in vitro (albeit for the purpose of studying the
potential of using NK-92 and TALL-104 in vivo). This Yan
passage therefore cannot provide support for Miller’s
warning against in vivo extrapolation.
        Third, the dissent cites Cesano for the teaching
that “the sensitivity of the dogs’ tumors to TALL-104 cell
lysis in vitro did not appear to be a good indicator of
clinical responses.” J.A. 953. This sentence does not
address NK-92 and, as discussed above, NK-92 was
shown to be more efficacious than TALL-104. Therefore,
this would actually teach a skilled artisan toward substi-
tuting NK-92 for TALL-104 (as Yan suggested to do).
        “When opposing parties tell two different stories,
one of which is blatantly contradicted by the record, . . . a
court should not adopt that version of the facts for pur-
poses of ruling on a motion for summary judgment.” Scott
v. Harris, 550 U.S. 372, 380 (2007). That is the situation
here. Miller’s reading of the prior art is contradicted by
the art itself. Miller’s testimony thus does not raise genu-
ine issues of material fact.

                       AFFIRMED
       NOTE: This disposition is nonprecedential.

  United States Court of Appeals
      for the Federal Circuit
                 ______________________

NANTKWEST, INC., FORMERLY CONKWEST, INC.,
             Plaintiff-Appellant

                            v.

MICHELLE K. LEE, DIRECTOR, U.S. PATENT AND
    TRADEMARK OFFICE, DEPUTY UNDER
      SECRETARY OF COMMERCE FOR
   INTELLECTUAL PROPERTY AND DEPUTY
 DIRECTOR OF THE UNITED STATES PATENT
         AND TRADEMARK OFFICE,
              Defendant-Appellee
            ______________________

                       2015-2095
                 ______________________

   Appeal from the United States District Court for the
Eastern District of Virginia in No. 1:13-cv-01566-GBL-
TCB, Judge Gerald Bruce Lee.
                ______________________

STOLL, Circuit Judge, dissenting.
    Absent the procedural safeguards provided to the non-
moving party at the summary judgment stage, I might
very well agree with the majority that the PTO demon-
strated the obviousness of these claims. When evaluating
a case on appeal from summary judgment, however, “[t]he
evidence of the non-movant is to be believed, and all
2                                     NANTKWEST, INC.   v. LEE

justifiable inferences are to be drawn in his favor.” An-
derson v. Liberty Lobby, Inc., 477 U.S. 242, 255 (1986).
NantKwest submitted evidence and accompanying expert
testimony showing that an ordinarily skilled artisan at
the time of the invention would not have had a reasonable
expectation of success in combining Santoli’s in vivo
results for TALL-104 cells with Gong’s in vitro experi-
ments for NK-92 cells. Drawing all reasonable inferences
in favor of NantKwest, as we must, this evidence creates
a genuine dispute of material fact that bars the grant of
summary judgment. Because the majority explains away
NantKwest’s evidence instead of giving it the weight
required by law, I respectfully dissent.
                             I.
    As an initial matter, the difference between in vitro
and in vivo testing is critical to understanding the diffi-
culty in using results from the former to predict efficacy
in the latter. In vitro experiments typically occur in the
controlled environment of a petri dish or test tube; in vivo
experiments are performed in a living organism. J.A. 886.
Experiments in vitro cannot account for the variable
environment of a living organism and cannot replicate a
cell line’s interaction with the host’s immune system,
among other things. J.A. 384, ¶ 24; J.A. 886. This dispar-
ity in testing environments can lead to unpredicted in
vivo results. For example, cell lines with encouraging
cytotoxic activity in vitro can unexpectedly lose all activi-
ty in vivo. J.A. 414, ¶ 93. The host’s immune system can
even destroy the cell line, rendering it ineffective in vivo.
Id. It is also possible for the cell line to trigger severe
immune reactions in the host that produce serious com-
plications.   J.A. 393, ¶ 47.     Therefore, demonstrated
cytotoxic activity in vitro does not always translate to
success in vivo.
NANTKWEST, INC.   v. LEE                                   3

                             II.
    The presence of each claimed element in the prior art
is insufficient to render a claim obvious. Rather, there
also must be a motivation to combine the prior art and an
ordinarily skilled artisan must have had a reasonable
expectation of success in doing so. Kinetic Concepts, Inc.
v. Smith & Nephew, Inc., 688 F.3d 1342, 1360
(Fed. Cir. 2012) (internal quotation marks and citations
omitted). Whether a skilled artisan would have had a
reasonable expectation of success is a question of fact,
Cumberland Pharm. Inc. v. Mylan Institutional LLC,
846 F.3d 1213, 1222 (Fed. Cir. 2017), and contemporane-
ous evidence of what skilled artisans thought at the time
of the invention can help inform our inquiry into whether
the expectation of success was reasonable. In re Carroll,
601 F.2d 1184, 1186–87 (C.C.P.A. 1979). When determin-
ing whether a person of ordinary skill possessed a reason-
able expectation of success in predicting in vivo efficacy
based on in vitro results, we have recognized that “simply
because a drug gives positive results in vitro, it does not
necessarily follow that there is a reasonable probability of
success for therapeutic use of that drug in vivo.” In re
Gangadharam, 889 F.2d 1101, 1989 WL 127023, at *3
(Fed. Cir. 1989)    (non-precedential)    (citing   Carroll,
601 F.2d at 1186).
    The majority concludes that a person of ordinary skill
in the art would have been motivated to combine Santoli
with Gong because Santoli demonstrated in vivo efficacy
for TALL-104 cells, Gong detailed NK-92’s in vitro ability
to lyse cancer cells, and the prior art indicated a desire to
seek clinical applications for the NK-92 cell line.
Maj. Op. 7–9. NantKwest’s arguments that a person of
ordinary skill in the art would not have had a reasonable
expectation of success in combining Santoli with Gong
were not persuasive to the majority in light of the “over-
whelming specific evidence that a skilled artisan could
reasonably extrapolate from the in vitro data with respect
4                                     NANTKWEST, INC.   v. LEE

to TALL-104 and NK-92 that would reasonably teach
their successful substitution in vivo.” Maj. Op. 12. In
reaching its conclusion, the majority failed to give
NantKwest’s evidence the weight it deserved and declined
to draw all reasonable inferences in NantKwest’s favor.
     Numerous contemporaneous references identified by
NantKwest warned that in vitro results were not predic-
tive of in vivo efficacy in this field. For example, the
Vujanovic reference questioned the correlation between in
vitro studies and in vivo behavior for the NK-92 cell line:
“We suggest that standard in vitro cytotoxicity assays
with target cells in suspensions have little relevance in
predicting the in vivo antitumor activity of effector cells.”
J.A. 962 (emphasis added). As confirmed by Dr. Miller,
this passage from Vujanovic “caution[s] against relying on
in vitro cytotoxicity results, such as those in Gong, to
predict in vivo behavior.” J.A. 458, ¶ 94. Yan contains
similar warnings. Yan concluded his comparison of NK-
92 and TALL-104 cells by noting: “[O]ur studies suggest
that cytotoxic activity towards leukemic cell lines cannot
be extrapolated to cells derived directly from patients.
The use of such biologic reagents in vitro or in vivo for
immunotherapy or purging must be accompanied by
careful study of the unique patterns of activity . . . .”
J.A. 226 (emphasis added). Dr. Miller reiterated that
“Yan admonishes against relying on in vitro tests to
predict in vivo activity,” which was consistent with “the
common understanding in the art.” J.A. 439–40, ¶ 48.
Finally, in Cesano’s article describing a Phase I Clinical
Trial for TALL-104 in dogs, the authors acknowledged
that, “[s]urprisingly, the sensitivity of the dogs’ tumors to
TALL-104 cell lysis in vitro did not appear to be a good
indicator of clinical responses.” J.A. 953 (emphasis add-
ed).
    NantKwest’s evidence and supporting expert testimo-
ny laid bare the uncertainty in this complex field. As Dr.
Miller explained, the authors in the above references did
NANTKWEST, INC.   v. LEE                                     5

not feel confident in predicting in vivo activity based on in
vitro experiments at the time of the invention. J.A. 439–
40, ¶ 48; J.A. 458, ¶ 94. This creates a dispute of material
fact regarding the reasonable expectation of success. In
my view, the majority’s willingness to discredit Dr. Mil-
ler’s understanding of the disclosures in Vujanovic and
Yan does not dispose of the genuine dispute of material
fact. Although the majority believes its view of the prior
art references is superior to Dr. Miller’s, its analysis is not
supported by citations to the USPTO’s expert report or
the district court opinion. See Maj. Op. 19–20. Dr. Mil-
ler’s opinion, on the other hand, is illuminated by the
background knowledge of a skilled artisan in this field,
and I am not convinced that his opinion lacks support in
the record. The result is a genuine dispute of material
fact that I believe is not suited for resolution at the sum-
mary judgment stage.
    Indeed, we have found lesser evidence sufficient to re-
verse rejections by the PTO in the past. In Carroll, for
example, the PTO’s Board of Appeals rejected as obvious
claims of a patent for treating M. paratuberculosis with
lauric acid based on the patentee’s master’s thesis. The
thesis disclosed two types of studies: 1) in vitro studies,
from which the patentee reported that lauric acid com-
pletely inhibited the growth of three strains of M. paratu-
berculosis, and 2) in vivo studies, from which the patentee
reported the suitability of a certain strain of C57 black
mice as laboratory animals for studying the diseases
caused by M. paratuberculosis. Carroll, 601 F.2d at 1185.
An expert in the field, Dr. Merkal, discounted the patent-
ee’s thesis at the time of its publication because, among
other reasons, “in vitro testing was an unreliable indica-
tor for the in vivo effectiveness.” Id. at 1186. When the
patentee sought a patent for his later discovery that
mammals can be treated with lauric acid orally to treat
M. paratuberculosis, the PTO argued that the claims were
obvious because his earlier thesis disclosed lauric acid’s
6                                     NANTKWEST, INC.   v. LEE

activity in vitro and that mice were suitable animals for
studying the disease. Id. at 1185–86. Our predecessor
court disagreed with the PTO, relying principally on
Dr. Merkal’s “contemporaneous evaluation of appellant’s
thesis[] that one skilled in this art would have given no
weight to the findings reported therein.” Id. at 1186–87
(emphasis added).
     Similarly, in Gangadharam, we held that the Board of
Patent Appeals and Interferences erred in finding a
reasonable expectation of success for using CQQ to treat
tuberculosis in mammals (in vivo) based on in vitro re-
sults. Gangadharam, 1989 WL 127023, at *3 (non-
precedential). The Board relied on a single reference
authored in part by the applicant to reject the claims. It
found that the Gangadharam reference’s disclosure of
“very positive in vitro bactericidal activity of CQQ against
the [pertinent] bacteria reported by Gangadharam cer-
tainly favors the in vivo use of said compound in the
treatment of tuberculosis in mammals.” Id. at *1. But
simply “[r]emarking that the positive in vitro results
‘favored’ use in vivo does not meet the statutory stand-
ard,” we explained, and therefore the PTO “fell woefully
short of its burden” to establish a reasonable expectation
of success. Id. at *2. Importantly, the Gangadharam
reference contained a proviso that further studies were
needed “before CQQ can be suggested as a possible anti-
mycobacterial drug for treating humans with [tuberculo-
sis],” and a contemporaneous article warned that in vitro
tests were neither equivalent to, nor a substitute for, in
vivo experiments. Id. at *2–3. Because “there [wa]s
evidence in this record . . . regarding the noncorrelation of
in vivo from in vitro efficacy generally and with respect to
tuberculosis,” we found that the PTO failed to demon-
strate a reasonable expectation of success. Id. at *3; see
also Abbott Labs. v. Sandoz, Inc., 544 F.3d 1341, 1350–52
(Fed. Cir. 2008) (affirming non-obviousness in context of
district court’s grant of preliminary injunction because,
NANTKWEST, INC.   v. LEE                                   7

inter alia, the patentee’s evidence demonstrated that “it
was not predictable” how an antibiotic would perform in
vivo based on in vitro experiments using a closely related
antibiotic).
    As was the case with both Carroll and Gangadharam,
the record here contains ample evidence that persons of
ordinary skill in the art were skeptical about the ability of
in vitro tests to predict in vivo efficacy for the two rele-
vant cell lines. Vujanovic, Yan, and Cesano—in the very
same articles where they discussed the promising in vitro
results for the NK-92 and TALL-104 cell lines—proceeded
to expressly caution against inferring efficacy in vivo
based on these outcomes. A reasonable reading of these
references supports the conclusion that one skilled in the
art would not have had a reasonable expectation of suc-
cess in combining Santoli’s in vivo testing for TALL-104
with Gong’s NK-92 cell line. Because NantKwest is the
non-movant at the summary judgment stage, it is a
reasonable inference that we must draw in its favor. See
Anderson, 477 U.S. at 255.
                            III.
    Our standard of review for the grant of summary
judgment requires us to believe the evidence of the non-
movant and to draw all reasonable inferences in its favor.
The majority did neither in finding the claims in
NantKwest’s patent application obvious. Accordingly, I
respectfully dissent.