NOTE: This disposition is nonprecedential.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-GBLTCB, 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 obviousness. 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 limited 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 application here concerns the use of a particular cell line1 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 references 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 recognize 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. (“Santoli”), 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 derived 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 independent claim on appeal here, provides 

A method of treating a cancer in vivo in a mammal 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 mammal 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 NK92 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 judgment, 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) (citations 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 construction 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 construction 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 construction 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 numbers 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 administrative record before the PTO.” Id. at 1701. 

We agree with the district court that there is no material 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 therapeutic effects. Such an approach is called “allogeneic” or 

“adoptive immunotherapy.” Santoli specifically taught 

that the TALL-104 cell line can be used in adoptive immunotherapy in vivo for lysing cancer cells.2

2 We reject NantKwest’s argument that Santoli 

does not “disclose a successful in vivo therapy for TALL104.” 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 acknowledged that prior TALL-104 studies demonstrated “antitumor 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 TALL104 and NK-92 lysed cancer cells via the same mechanism, 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 publication, Klingemann et al. cited to the fact that because “NK92 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 therapy, with the effects stemming from the activated cells. 

J.A. 7.

 
NANTKWEST, INC. v. LEE 9

cells obtained from a patient suffering from nonHodgkin’s lymphoma.”). The patent application highlighted 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 application 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. Santoli 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 allogeneic 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 established 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 determine 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 person 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 possibilities 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. Miller submitted for the first time in the district court proceeding and new prior art references also submitted for 

the § 145 proceeding raise genuine disputes of material 

fact about the reasonable likelihood of success for combining 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 artisan 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 translate into in vivo success cannot defeat summary judgment. “[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 overwhelming 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. reference (“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] predicting 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. Vujanovic 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 translate 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 adonly 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 genetically 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 therapies 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 cytotoxicity 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 wellknown, 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 prevent 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 proliferation.” 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 unpredictability to patentability . . . would mean that any new [drug] 

. . . would be separately patentable . . . [after its] properties . . . [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. However, 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 TALL104 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 extrapolating immunotherapy results from one context to another 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 “admonishes 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 extrapolating 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 between 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. However, 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 considerations of nonobviousness that “may raise a genuine issue of 

material fact that precludes summary judgment.” Appellant Br. 61. “[E]vidence . . . of . . . secondary considerations must always when present be considered en route to 

a determination of obviousness.” In re Cyclobenzaprine 

Hydrochloride Extended-Release Capsule Patent Litigation, 676 F.3d 1063, 1075 (Fed. Cir. 2012) (quotation 

marks and citation omitted). However, “[f]or . . . secondary 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 commercial 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 district 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 suggested 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 substantial 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 proposition 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 discussed 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 obviousness” because the sole prior art only made “general 

reference . . . [to] positive results that were obtained . . . in 

an entirely different context, . . . and [made only] precatory, 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 towards 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 relevance 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 spheroids 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 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[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 discussed 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 substituting 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 purposes 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 genuine 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-GBLTCB, Judge Gerald Bruce Lee.

______________________ 

STOLL, Circuit Judge, dissenting. 

Absent the procedural safeguards provided to the nonmoving party at the summary judgment stage, I might 

very well agree with the majority that the PTO demonstrated 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.” Anderson 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 experiments 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 difficulty 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 disparity in testing environments can lead to unpredicted in 

vivo results. For example, cell lines with encouraging 

cytotoxic activity in vitro can unexpectedly lose all activity 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 complications. 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 contemporaneous 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 determining whether a person of ordinary skill possessed a reasonable 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 “overwhelming 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 predictive 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 NK92 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 added).

NantKwest’s evidence and supporting expert testimony 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. Miller’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. Miller’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 summary judgment stage.

Indeed, we have found lesser evidence sufficient to reverse 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 completely inhibited the growth of three strains of M. paratuberculosis, 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 patentee’s thesis at the time of its publication because, among 

other reasons, “in vitro testing was an unreliable indicator 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 results. Gangadharam, 1989 WL 127023, at *3 (nonprecedential). 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 certainly 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 standard,” 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 antimycobacterial drug for treating humans with [tuberculosis],” 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 demonstrate 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 relevant 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 success 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 nonmovant 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.