Lars Winther et al.

Patent Trials and Appeals Board

May 27, 2021

2020005320 (P.T.A.B. May. 27, 2021)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
10/097,106 03/13/2002 Lars Winther IMDX-001US0 8528
159930 7590 05/27/2021
Plant & Planet Law Firm
11440 W. Bernardo Court, Suite 300
San Diego, CA 92127
EXAMINER
DIBRINO, MARIANNE
ART UNIT PAPER NUMBER
1644
NOTIFICATION DATE DELIVERY MODE
05/27/2021 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
USPTO@dockettrak.com
ipdocket@pnplf.com
mgodfrey@pnplf.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte LARS WINTHER,
LARS OESTERGAARD PETERSEN, SOEREN BUUS,
JOERGEN SCHOELLER, ERIC RUUD, and OEYSTEIN AAMELLEM
Appeal 2020-005320
Application 10/097,106
Technology Center 1600
Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and
TAWEN CHANG, Administrative Patent Judges.
CHANG, Administrative Patent Judge.
DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims 1–4, 7, 9, 11, 26, 27, 29–33, and 36.
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the real parties in interest as Dako
Denmark A/S and Immudex ApS. Appeal Br. 3.
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STATEMENT OF THE CASE
“The genes located in the human [Major Histocompatibility Complex
(MHC)] locus (HLA locus) encode a set of highly polymorphic membrane
proteins that sample peptides in intracellular compartments and present such
peptide epitopes to antigen specific receptors (TCR) on T-cells.” Spec.
3:33–4:3. “[B]iochemical interactions between peptide epitope specific
membrane molecules encoded by the . . . MHC . . . and T-cell receptors
(TCR) are required to elicit specific immune responses.” Id. at 2:29–33.
The Specification states that “the present invention relates to novel
MHC molecule constructs comprising one or more MHC molecules.” Id. at
1:26–28. According to the Specification, “[t]he constructs of the present
invention can potentially express very high numbers of MHC molecules
(poly-ligands) being well-defined TCR specific ligands,” which “bind with
much higher avidity to antigen specific T-cells than the known prior art
tetramer[ MHC complexes] under comparable conditions.” Id. at 8:16–23.

CLAIMED SUBJECT MATTER
The claims are directed to soluble MHC molecule constructs. Claim 1
is illustrative:
1. A soluble MHC molecule construct in a
solubilizing medium or immobilized onto a solid or semi-solid
support, said MHC molecule construct comprising a soluble
dextran carrier molecule to which is attached a plurality of
binding entities selected from streptavidin and avidin, wherein
at least two or more of said plurality of binding entities are
attached to an average of from 2 to 4 MHC molecules, and
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wherein said MHC molecule construct consists of a total
number of 5 to 25 MHC molecules.
Appeal Br. 21 (Claims App.).2

REJECTION(S)
A. Claims 1–4, 7, 9, 11, 26, 27, 29–33, and 36 are rejected under pre-
AIA 35 U.S.C. 103(a) as being unpatentable over Lihme3 and
Wucherpfennig.4 Ans. 3.
B. Claims 1–4, 7, 9, 11, 26, 27, 29–33, and 36 are rejected under pre-
AIA 35 U.S.C. 103(a) as being unpatentable over Lihme,
Wucherpfennig, and Romero.5 Ans. 3.

2 During prosecution, Appellant made the following species elections:
human MHC class I complex (e.g., HLA-A201/ELAIGILTV/ß2m) as the
MHC complex; CD28 as the biologically active molecule; polysaccharide
(e.g., dextran) as the carrier; fluorescent tag (e.g., APC) as the labeling
compound; soluble support; 1–3 MHC molecules per binding entity; 1 to 35
MHC molecules in total per construct; and streptavidin as the binding entity
for both the MHC/carrier association and the biologically active
molecule/carrier association. Response to Restriction and Election of
Species Requirements (May 31, 2005); Ans. 2. The Examiner also states in
the Answer that, “[s]ince Applicant did not elect a binding entity for the
labeling molecule, the Examiner is examining the claims as they read upon
the labeling compound attached to the carrier molecule or the MHC
molecule.” Final Act. 2.
3 Lihme et al., WO 93/01498, published Jan. 21, 1993 (“Lihme”). We note
that the Examiner refers to Lihme as “WO 93/01498 A1” in the Final Action
and Answer, while Appellant refers to Lihme as “Immunodex” in the Appeal
and Reply Briefs.
4 Wucherpfennig et al., WO 99/42597, published Aug. 26, 1999
(“Wucherpfennig). We note that the Examiner refers to Wucherpfennig as
“WO 99/42597 A1” in the Final Action and Answer.
5 Romero et al., WO 99/50637, published Oct. 7, 1999 (“Romero”).
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OPINION
A. Obviousness rejection over Lihme and Wucherpfennig (claims 1–4,
7, 9, 11, 26, 27, 29–33, and 36)
1. Issue
The Examiner finds that
[Lihme] teaches soluble polysaccharide carrier molecules
having numerous superior advantages, wherein the carrier
molecules are coupled directly or indirectly to
immunoreactive molecules as well as to markers such as
fluorescent labels, that are prepared under mild conditions
using straightforward procedures that allow for highly
controllable addition of the immunoreactive molecules,
wherein these constructs exhibit remarkable stability and
are particularly well suited for use in, for example,
biologically relevant detection, quantification and
targeting procedures. [Lihme] teaches that the carriers of
the invention represents a significant advance with respect
to the enhancement of sensitivity and reliability of
immunodetection and assay procedures.
Final Act. 2–3.
The Examiner finds that “[Lihme] does not teach wherein the carrier
comprises an immunoreactive component that is a peptide antigen in the
MHC binding groove.” Final Act. 4. However, the Examiner finds that
[Wucherpfennig] teaches that it is desirable to make
soluble carrier constructs with at least 5-20
immunoreactive MHC molecules that comprise a peptide
antigen, that the MHC molecules can be attached through
one binding moiety or moieties including streptavidin,
avidin or biotin, and that the carrier molecule may further
comprise fluorescent or radioactive labels and biologically
active molecules such as costimulatory molecules and/or
adhesion protein molecules. Importantly,
[Wucherpfennig] teaches that it is desirable to make these
carrier molecules because they are superior in terms of
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avidity of binding to their cognate TCR ligand, over
monovalent, divalent or tetravalent MHC molecules, and
that these constructs can be used to isolate (and detect) T
cells.
Id. at 4.
The Examiner concludes that a skilled artisan would have had reason
to combine the teachings of Lihme and Wucherpfennig to arrive at the
claimed invention,
in order to make a superior, well-characterized, high
avidity MHC-dextran construct that is particularly well
suited for use in biologically relevant detection,
quantification and targeting procedures, and for purposes
of commercialization, said construct having an
extraordinary high degree of stability in terms of shelf-life
during prolonged storage in solution, said construct made
by a method that exerts a high degree of control of the
preparation process in a straightforward manner and under
mild conditions.
Final Act. 6.
Appellant contends that a skilled artisan would not have had reason to
combine Lihme and Wucherpfennig to arrive at the claimed invention, with
a reasonable expectation of success. Appeal Br. 9–10. Appellant further
contends that secondary considerations, including unexpected results
exhibited by, and commercial success of, the claimed subject matter, support
a finding of non-obviousness. Id. at 14–18.
Appellant does not separately argue the claims. We therefore focus
our analysis on claim 1 as representative. The issues with respect to this
rejection are (1) whether a skilled artisan would have had reason to combine
Lihme and Wucherpfenning to arrive at the invention of claim 1, with a
reasonable expectation of success, and, if so, (2) whether Appellant has
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provided evidence of unexpected results and commercial success of the
claimed subject matter that, when considered together with the evidence of
obviousness, shows claim 1 to be non-obvious.
2. Analysis
Unless otherwise noted, we adopt the Examiner’s findings of fact and
reasoning regarding the rejection of claim 1 as obvious over Lihme and
Wucherpfennig (Final Act. 2–6; Ans. 3–17). We are not persuaded by
Appellant’s arguments, as explained below. Only those arguments timely
made by Appellant in the briefs have been considered; arguments not so
presented in the briefs are waived. See 37 C.F.R. § 41.37(c)(1)(iv)
(2015); see also Ex parte Borden, 2010 WL 191083 at *2 (BPAI Jan. 7,
2010) (informative) (“Any bases for asserting error, whether factual or legal,
that are not raised in the principal brief are waived.”).

Motivation to combine/Reasonable expectation of success
Appellant contends that a skilled artisan would not have had reason to
combine Lihme and Wucherpfennig to arrive at the claimed invention, with
a reasonable expectation of success. Appeal Br. 9–10. Appellant contends
that “[Lihme] has nothing to do with T cell detection or MHC molecules,”
while “Wucherpfennig makes no mention of the use of unbranched dextran
carrier molecules and in fact, makes arguments for the importance of using
dendrimer carriers or non-dendrimer branched polymers.” Id. at 10; see also
id. at 11. Appellant contends that, furthermore, “Wucherpfennig teaches
that MHCs are positioned at the termini of branched dendrimer structures, as
opposed to also containing MHC at non-termini positions.” Id. at 11.
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Finally, Appellant contends that Wucherpfennig “prefers constructs of
spherical, and therefore, inflexible carriers.” Id. at 11.
Appellant contends that, [a]ccordingly, Wucherpfennig does not teach
or suggest the important improvement of the instant invention of MHC
carrier molecules with a flexible dextran structure, and does not teach the
advantage of using a MHC multimer that can fold up into a compact
conformation around a T cell.” Appeal Br. 11. Appellant further contends
that “[t]he difference in overall structure and differences in spacing of MHC
molecules likely lead to different engagement with the T cell and the number
of T cell receptors on the T cell surface. This could lead to very different
performance of the construct and also affect the optimal number of MHC
molecules.” Id.
As an initial matter, “[n]on-obviousness cannot be established by
attacking references individually where the rejection is based upon the
teachings of a combination of references. . . . [The reference] must be read,
not in isolation, but for what it fairly teaches in combination with the prior
art as a whole.” In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986).
Thus, to the extent Appellant argues that claim 1 is not obvious because
neither Lihme nor Wucherpfennig discloses or suggests all of the limitations,
we are not persuaded.6

6 Appellant contends in the Reply Brief that it does not improperly argue the
references separately. Reply Br. 9. We are not persuaded because Appellant
in its briefing does appear to argue the references separately, at least on
occasion. For example, Appellant contends in the Appeal Brief that, “if one
skilled in the art were to look primarily to the teachings of Wucherpfennig as
the Examiner does, the instant invention, as claimed, would not be
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Neither do we agree that a skilled artisan would not have had reason
to combine Lihme and Wucherpfennig based on the teachings of the two
references, or that the teachings of the references would have discouraged a
skilled artisan from combining them to arrive at the claimed invention.
Lihme teaches conjugates comprising molecular species covalently
attached to polymeric carrier molecules such as dextrans. Lihme Abstract.
Lihme teaches that molecular species in the context of its invention is used
to denote, among other things, “molecules which are capable of binding
selectively or specifically to one or more target molecules, moieties,
receptors or epitopes,” and that the conjugates of its invention are
“particularly well suited for use . . . in biologically relevant detection,
quantification and targeting procedures, e.g., in the fields of
immunohistochemistry, detection of immunoreactive species, antibody
immobilization, separation or purification, DNA hybridization tests and flow
cytometry.” Id. at Abstract.
Wucherpfennig teaches that its invention
provides a method for detecting T cells having a defined
MHC/peptide complex specificity comprising providing a
monovalent, multivalent or multimeric MHC binding
domain fusion protein or conjugate, as described above
and comprising the defined MHC/peptide complex,
contacting a population of T cells with the fusion protein
or conjugate, and detecting the presence or absence of
binding of the fusion protein or conjugate and T cells in
the population.
Wucherpfennig 9:20–25.

obtained.” Appeal Br. 11. In any event, even if Appellant were merely
“tak[ing] into account . . . both feasibility [and] motivation to combine,”
Reply Br. 9, we are not persuaded for the reasons discussed below.
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Wucherpfennig does not limit carriers for its constructs to spherical,
inflexible carriers, dendrimers, branched carriers and/or carriers that only
binds MHCs at terminal positions. Instead, Wucherpfennig teaches that, as
used therein, “carrier” simply means “a molecule, particle, composition, or
other microscopic object to which may be conjugated, directly or indirectly,
a multiplicity of MHC binding domains, so as to form a multimeric binding
domain conjugate. Wucherpfennig 19:23–27; see also id. at 39:25–27
(stating that “[t]he carrier must be capable of being conjugated, either
directly or indirectly, to a multiplicity of MHC binding domains”). Indeed,
Wucherpfenning teaches that “[t]he MHC binding domain conjugates of [its]
invention may be produced with any of a large variety of carrier.” Id. at
39:23–25.
Finally, Lihme describes advantages of its constructs comprising a
water-soluble carrier that is preferably a polysaccharide and particularly
dextran. See, e.g., Lihme Abstract, 1:29–2:8; 8:3–9:5, 13:18–17:16. More
specifically, Lihme teaches the importance of the importance of enhancing
the sensitivity of immunochemical assay procedures and further teaches that,
[g]enerally speaking, . . . the use of soluble carriers is to
be preferred, since the presence of the carrier (with the
coupled immunochemically reactive species and
enzymes/marker molecules or the like) in homogeneous
solution rather than as a heterogeneous phase, together
with the relatively great conformational flexibility of such
species in the solution phase, vastly enhances the rate and,
in general, the extent of immunochemical reactivity with
the immunochemical counterpart species which is to be
detected or determined; in immunohistochemical
applications the use of soluble carriers is virtually
essential, since good tissue contact or penetration is
necessary in order to ensure optimal access to the
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immunochemically reactive moieties or epitopes located
on or within the tissue.
Lihme 8:3–23. Lihme also teach specifically that “conjugates according to
the invention based on certain preferred types of polymeric carrier
molecules, viz. polymeric carrier molecules which are substantially linear,
possesses tissue structure penetration properties in spite of a relatively high
total molecular weight.” Id. at 17:12–16.
Because Wucherpfennig teaches, e.g., that multimeric MHC
conjugates comprising a carrier (id. at 7:21–23) may be used to detect T
cells (i.e., that MHCs are “molecules which are capable of binding
selectively or specifically to one or more target molecules, moieties,
receptors or epitopes” to perform a “biologically relevant detection”), and
because Lihme teaches the advantages of using polysaccharide carriers such
as dextrans in immunochemical applications, we agree with the Examiner
that it would have been obvious to use the multimeric MHC binding
domains of Wucherpfennig as the molecular species in Lihme’s construct
comprising the dextran carrier to arrive at the claimed invention.
Appellant contends that, “[e]ven if the examples of Wucherpfennig
are non-limiting, there must be some suggestion or motivation to modify the
structures and such structures are notably different from the preferred
embodiments of [Lihme], not to mention of the claimed invention.” Appeal
Br. 11. Appellant contends that, “if one skilled in the art were to look
primarily to the teachings of Wucherpfennig as the Examiner does, the
instant invention, as claimed, would not be obtained.” Id.
We are not persuaded for the reasons already discussed: Obviousness
analysis requires the consideration of the teachings of both Lihme and
Wucherpfennig, and, as explained above, a skilled artisan would have reason
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to combine the teachings of these references to arrive at the claimed
invention.
Appellant argues that the advantages disclosed in Lihme as to the
dextran carriers are not relevant to the claimed invention and/or “the specific
unexpected properties associated with the present invention (detection of
low-affinity T cells).” Reply Br. 6–7. Appellant argues that, even if Lihme
did disclose certain advantages of its dextran carrier constructs, such
disclosure “has no bearing on a potential combination with MHCs of the
Wucherp[f]ennig [reference,]” because “[t]here would be no way of known
. . . that a hypothetical resulting product from combining with another
reference would have any superior properties particular in the detection of T
cells, a very different field and very different interaction.” Reply Br. 7.
We are not persuaded. As discussed above, Lihme specifically
teaches as one of the advantages of its invention the “enhance[ment] of the
rate and . . . extent of immunochemical reactivity with the immunochemical
counterpart species which is to be detected or determined,” Lihme 8:3–23,
which we find to be relevant to the claimed invention as well as the alleged
unexpected results of detection of low-affinity T-cells (i.e., counterpart
species). Moreover, “[i]n determining whether the subject matter of a patent
claim is obvious, neither the particular motivation nor the avowed purpose
of the patentee controls. . . . [A]ny need or problem known in the field of
endeavor at the time of invention and addressed by the patent can provide a
reason for combining the elements in the manner claimed.” KSR Int’l Co. v.
Teleflex Inc., 550 U.S. 398, 419-20 (2007). Likewise, “[o]bviousness does
not require absolute predictability of success. . . . [A]ll that is required is a
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reasonable expectation of success.” In re O’Farrell, 853 F.2d 894, 903-04
(Fed. Cir. 1988).
Appellant contends that a skilled artisan would be further discouraged
from combining the references to arrive at the claimed invention because
“Wucherpfennig teaches the desirability of having a large number of MHCs
while the invention claims a limited number of MHCs, with a minimum of 5
and a maximum of 25.” Appeal Br. 10; see also Reply Br. 7. Appellant
similarly contends in the Reply Brief that,
[e]ven if [Lihme] taught a preferred number of
immunoreactive molecules, it would have no bearing on a
preferred number specifically for MHCs (as [they are] not
disclosed by [Lihme]), let alone the optimal number of
MHCs on a dextran backbone (5-25). The skilled person
again would not know that superior, unexpected
advantages would be associated specifically with MHCs,
in combination with dextran, in a “less is more” fashion.
Reply Br. 8.
We are not persuaded. Wucherpfennig itself teaches preferred
embodiments wherein the conjugates “comprise about 5 to about 500 MHC
binding domains per carrier, preferably about 10 to about 200 MHC binding
domains per carrier, and most preferably about 20 to about 100 MHC
binding domains per carrier.” Wucherpfennig 7:24–27. Thus,
Wucherpfennig teaches a range of MHC binding domains per carrier that
overlaps the claimed range of 5 to 25 MHC molecules per construct. As our
reviewing court has explained, “[i]n cases involving overlapping ranges, . . .
even a slight overlap in range establishes a prima facie case of obviousness,”
which “shifts the burden to the applicant to show that his invention would
not have been obvious.” In re Peterson, 315 F.3d 1325, 1329–1330 (Fed.
Cir. 2003). As we discuss further below with respect to Appellant’s
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arguments regarding unexpected results, Appellant has not provided
persuasive evidence the claim limitation in question is not obvious despite
the overlapping range.
Moreover, we note that the references teach that the number of
molecules attached to a carrier may affect, e.g., the steric conformation for
binding and the strength of binding to a complementary immunological
component and that the preferred number of MHC molecules per construct
may depend on the density of the binding domains on the surface of the
carrier. Lihme 16:10–18; Wucherpfennig 7:28–8:2. In short, the prior art
suggests that the number of MHC molecules per construct is a result-
effective variable, and “discovery of an optimum value of a result effective
variable in a known process is ordinarily within the skill of the art.” In re
Boesch, 617 F.2d 272, 276 (CCPA 1980).
Appellant contends in the Reply Brief that Wucherpfennig “teaches
that soluble MHC complexes, as presently claimed, should be avoided,
effectively teaching away from combining with the soluble carriers of
[Lihme].” Reply Br. 7. Appellant cites to a portion of Wucherpfennig
stating that “[a] principal difficulty with using soluble MHC/peptide
complexes as probes and therapeutics is that the affinity for the TCR is
relatively low” and that the invention of Wucherpfennig, “by providing
multivalent and multimeric MHC fusion proteins and conjugates[,] addresses
this problem.” Reply Br. 7–8 (quoting Wucherpfennig 50:27–51:2).
As an initial matter, Appellant raises this teaching away argument for
the first time in the Reply Brief, thereby denying the Board the benefit of the
Examiner’s response, without providing any showing of good cause as to
why the late argument should be considered by the Board. Appellant has
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thus waived this argument. See 37 C.F.R. § 41.41(b)(2); Cf. Optivus
Technology, Inc. v. Ion Beam Applications S.A., 469 F.3d 978, 989 (Fed. Cir.
2006) (argument raised for the first time in the Reply Brief that could have
been raised in the opening brief is waived).
In any event, we are not persuaded. “A reference may be said to teach
away when a person of ordinary skill, upon reading the reference, would be
discouraged from following the path set out in the reference, or would be led
in a direction divergent from the path that was taken by the applicant.” In re
Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994). Nothing in the paragraph cited
by Wucherpfennig would suggest to a skilled artisan that a soluble construct,
such as that taught in Lihme, would be undesirable. Indeed, Wucherpfennig
teaches that soluble MHC/peptide complexes are highly useful,
Wucherpfennig 1:23–2:12, and that the invention of Wucherpfennig
provides a solution to the difficulty in the prior art of using soluble
MHC/peptide complexes as probes and therapeutics, id. at 50:27–51:2,
21:22–25 (describing one aspect of the invention as disclosing that
“heterodimeric MHC Class II binding domains, including those of certain
MHC Class II molecules which previously could not be produced as empty,
soluble, stable heterodimers, may be produced using fusion proteins
incorporating dimerization domains”).
Appellant contends that, “[e]ven assuming . . . the references may
superficially appear to be combinable,” a skilled artisan would not be
motivated to make the combination or expect success in doing so because
the art is highly complex and because of “the significant differences in the
chemistries of the two references.” Appeal Br. 10. More particularly,
Appellant contends that “the interaction between MHC molecules and TCR
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is more complex than conventional ligand-receptor models and therefore
advances in the art are particularly challenging.” Id. Appellant notes that
“MHC compounds are labile compounds, not easily obtainable, need to be
folded correctly to be functional, and have low intrinsic binding affinity to
TCRs.” Id.
We are not persuaded. Although Appellant contends that “the
interaction between MHC molecules and TCR is more complex than
conventional ligand-receptor models” for a variety of reasons,
Wucherpfennig already teaches use of the MHC molecules with a carrier,
and, as further discussed below in the context of the Hansen Declaration,
Appellant has not provided any persuasive evidence that a skilled artisan
would not have had reasonable expectation of successfully combining such
MHC molecules with the dextran carrier taught by Lihme, in order to
achieve the advantages of dextran carriers discussed in Lihme. In this
context, we note that “[a]ttorneys’ argument is no substitute for evidence.”
Johnston v. IVAC Corp., 885 F.2d 1574, 1581 (Fed. Cir. 1989).
Appellant cites to the Hansen Declaration7 in support of its arguments
regarding lack of motivation to combine and lack of reasonable expectation
of success. Appeal Br. 13. In particular, Appellant points out that “[t]he
Hansen Declaration states that an expert in this field would not be motivated
to combine the references” because
[Lihme] does not indicate any insufficiencies in the ability
of the disclosed constructs to detect the desired molecular
species and provides no motivation to exchange the
divinyl sulfone entities with any other entities let alone

7 Declaration of Bjarke Endel Hansen under 37 C.F.R. 1.132 (Sept. 20,
2017) (Hansen Declaration).
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MHC molecules. MHC molecules, albeit monomeric,
were known at the time and yet [Lihme] did not think to
employ these, likely because they did not aim for detecting
T-cells and their limited availability at the time. . . . The
Hansen Declaration indicates that Wucherp[f]ennig is
concerned with a different purpose than [Lihne], namely
MHC constructs for T-cell detection, which makes a poor
starting point to think to combine them in the expectation
of making any advancements. The teaching of
Wucherp[f]ennig also does not indicate any
insufficiencies in the ability of the disclosed constructs to
detect T-cells. Rather, Wucherp[f]ennig emphasizes that
the spherical constructs comprise binding entities at the
termini, and that preferred constructs have as many termini
as possible and are dendrimer structures, i.e. highly
branched molecules in which the branches emanate from
a central core. This would not motivate one to modify the
branched carrier with multiple termini emanating from a
central core of Wucherp[f]ennig to obtain a linear or
straight dextran, as disclosed by [Lihme] . . . .
Id. at 13–14; see also Reply Br. 6 (arguing that the fact Lihme discloses a
number of advantages of its dextran carrier constructs “could also be taken
as indication that the disclosure is optimal, and needs no modification”).
That individual references do not suggest deficiencies in their own
disclosures does not, on its own, suggest that a claim is non-obvious: As
discussed above, “[n]on-obviousness cannot be established by attacking
references individually where the rejection is based upon the teachings of a
combination of references. . . . [The reference] must be read, not in isolation,
but for what it fairly teaches in combination with the prior art as a whole.”
In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). Likewise, the fact
that Lihme does not explicitly suggest a construct comprising its preferred
dextran carrier and MHC molecules does not evidence non-obviousness of
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the claimed invention, because Wucherpfennig provides the skilled artisan a
reason to make constructs comprising a carrier and MHC binding domains.
We are similarly unpersuaded by the argument that a skilled artisan
would not have considered combining the references because
“Wucherp[f]ennig is concerned with a different purpose than [Lihne],
namely MHC constructs for T-cell detection.” Appeal Br. 13 (citing Hansen
Decl. ¶ 17). Both Lihme and Wucherpfennig relate to the use, in
immunological assays, of a molecular construct comprising a carrier coupled
to, e.g., a targeting species. Lihme Abstract, 17:27–18:2; Wucherpfennig
Abstract, 4:2–5, 7:21–23, 9:20–27.
In this regard, we note that in the context of § 103 the determination
of whether a reference is within the art to which the claimed subject matter
pertains is “frequently couched in terms of whether the art is analogous,” In
re Clay, 966 F.2d 656, 658 (Fed. Cir. 1992), which in turn depends on “(1)
whether the art is from the same field of endeavor, regardless of the problem
addressed, and (2) if the reference is not within the field of the inventor’s
endeavor, whether the reference still is reasonably pertinent to the particular
problem with which the inventor is involved.” Id. at 658–59. In the case of
Lihme and Wucherpfennig, we find that both criteria are met as both
references are involved in immunoassays and the references are pertinent to
immobilized immuno-molecules such as MHC.
As for the statements in the Hansen Declaration that a skilled artisan
would not have had reason to combine Wucherpfennig’s MHC binding
domains with Lihme’s linear dextran carriers because “Wucherphennig
emphasizes that the spherical constructs comprise binding entities at the
termini, and that preferred constructs have as many termini as possible and
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are dendrimer structures,” Hansen Decl. ¶ 17, we are not persuaded for the
reasons already discussed above: Wucherpfennig does not limit its carriers
to spherical constructs or dendrimers, and Lihme further teaches the
advantages of its preferred polysaccharide carriers such as dextrans.
In short, although we have carefully considered the Hansen
Declaration, we decline to give it controlling weight in light of the totality of
the evidence of record before us. In this regard, we note that “[t]he Board
has broad discretion as to the weight to give to declarations offered in the
course of prosecution. See Velander v. Garner, 348 F.3d 1359, 1371 (Fed.
Cir. 2003) (‘[A]ccord[ing] little weight to broad conclusory statements [in
expert testimony before the Board] that it determined were unsupported by
corroborating references [was] within the discretion of the trier of fact to
give each item of evidence such weight as it feels appropriate.’).” In re
American Acad. of Science Tech Ctr., 367 F.3d 1359, 1368 (Fed. Cir. 2004)
(alterations in original); see also In re Beattie, 974 F.2d 1309, 1313 (Fed.
Cir. 1992) (opinion evidence in declarations has little value without factual
support); Perreira v. Secretary of the Dept. of HHS, 33 F.3d 1375, 1377 n.6
(Fed. Cir. 1994) (“An expert opinion is no better than the soundness of the
reasons supporting it.”).8

8 Appellant criticizes the Examiner’s explanation, in response to the
statement in the Hansen Declaration that Lihme “provides no motivation to
exchange the divinyl sulfone entities with any other entities let alone MHC
molecules,” that “divinyl sulfones are not the immunoreactive molecules” in
Lihme that would be replaced by the MHC molecules to arrive at the
claimed invention. Ans. 8–9; Appeal Br. 4–5. We disagree with
Appellant’s characterization of the Examiner’s clarification as “misleading
and/or off-point.” Appeal Br. 4. We understand Appellant’s argument is not
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Finally, Appellant suggests that the rejection is based on improper
hindsight. Reply Br. 10. We are not persuaded because, as discussed above,
while “[a]ny judgment on obviousness is in a sense necessarily a
reconstruction based upon hindsight reasoning,” the Examiner’s rejection is
based on the disclosures of Lihme and Wucherpfennig and thus properly
“takes into account only knowledge which was within the level of ordinary
skill at the time the claimed invention was made and does not include
knowledge gleaned only from applicant’s disclosure.” In re McLaughlin,
443 F.2d 1392, 1395 (CCPA 1971).

Unexpected results and commercial success
Appellant contends that, even if the Examiner has established a prima
facie case of obviousness, Appellant has rebutted such prima facie case with
the Hansen Declaration, which Appellant alleges evidences that a skilled
artisan would not have expected the claimed construct “to be capable of
detecting . . . low-affinity T-cells, which . . . were completely undetectable
with the available methods at the time the application was filed.” Appeal Br.
14, 15–16. Appellant also contends that “it would not be expected from
[the] teaching[s] of [Lihme and Wucherpfennig] alone that there would be
an optimum in the number of binding entities and MHCs in the [claimed]
construct.” Id. at 14–15, 16.

focused on the divinyl sulfones but is, rather, that a skilled artisan would not
have had reason to use MHC with the dextran carriers of Lihme. However,
we find Appellant has not persuasively addressed the Examiner’s broader
point that a skilled artisan would have had reason to use the MHC molecules
disclosed in Wucherpfennig with the dextran carriers of Lihme to arrive at
the claimed invention.
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We are not persuaded. We agree with Appellant that “[o]ne way for a
patent applicant to rebut a prima facie case of obviousness is to make a
showing of ‘unexpected results,’ i.e., to show that the claimed invention
exhibits some superior property or advantage that a person of ordinary skill
in the relevant art would have found surprising or unexpected.” In re Soni,
54 F.3d 746, 750 (Fed. Cir. 1995). However, “by definition, any superior
property must be unexpected to be considered evidence of non-obviousness.
Thus, in order to properly evaluate whether a superior property was
unexpected, the [fact-finder] should have considered what properties were
expected.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1371 (Fed. Cir.
2007). In addition, “it is well settled that unexpected results must be
established by factual evidence. ‘Mere argument or conclusory statements
in the specification does not suffice.’” In re Geisler, 116 F.3d 1465, 1470
(Fed. Cir. 1997) (quoting In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir.
1984)). Finally, “when unexpected results are used as evidence of
nonobviousness, the results must be shown to be unexpected compared with
the closest prior art,” In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed.
Cir. 1991), and “[t]he evidence presented . . . must be commensurate in
scope with the claims to which it pertains.” In re Dill, 604 F.2d 1356, 1361
(CCPA 1979).
Dr. Hansen states that “[i]t was surprising that the Dextramers[, which
falls within the claims], could detect low affinity antigen-specific T-cells
that are completely undetectable with a tetrameric MHC molecule
construct.” Hansen ¶ 28; see also Reply Br. 7 (contending that the
“unexpected level of superior performance [of the claimed construct] simply
cannot be derived from a simple combination of the prior art”).
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We are not persuaded, however, that this evidence supports the
nonobviousness of the claims. As an initial matter, Dr. Hansen does not
explain why a construct comprising a greater number of MHC molecules per
carrier would not be expected to be able to detect lower affinity antigen-
specific T-cells when compared to a construct comprising four MHC
molecules, given that Wucherpfennig teaches that “multimeric MHC binding
domain conjugates . . . have far greater avidity for their cognate TCRs, and
far greater biological activity, than monovalent MHC binding domains, or
even divalent or tetravalent MHC binding domain constructs” and
hypothesizes that this increase in avidity may be due to “a substantially two-
dimensional array of MHC binding domains . . . mak[ing] contact with an
area of a T cell membrane bearing a multiplicity of T cell receptors.”
Wucherpfennig 35:16–24.
Moreover, we are not persuaded that the evidence cited in the Hansen
Declaration shows unexpected results as compared to the closest prior art, or
commensurate with the scope of the claims. Dr. Hansen, for example, does
not explain why MHC tetramers, rather than the constructs described in
Wucherpfennig, are the closest prior art to which comparisons should be
made. Similarly, although the Hansen Declaration generally states that the
Dextramers used in the comparison with MHC tetramers comprises 5–25
MHC molecules, it is unclear how many MHC molecules were in fact
attached to the dextran carriers in the Dextramers used in the comparison, or
whether the Dextramers used comprises a mixture of constructs having
different numbers of MHC molecules attached. Thus, it is unclear, for
example, whether a construct comprising only 5 MHC molecules would
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have also achieved the alleged unexpected results as compared to MHC
tetramers.
Dr. Hansen further states that it is unexpected that “more HLA
molecules correlate with increased binding only up to a certain optimum,”
“in part because Wucherp[f]ennig teaches structures with larger number of
MHC binding domains (termini), in preferred embodiments [of] 20–100 per
carrier.” Hansen Decl. ¶¶ 20–24. However, we are not persuaded that this
result is in fact unexpected, because both Lihme and Wucherpfennig suggest
that the optimal number of a targeting species per carrier depends in part on
steric effects and thus on the molecular weight of the carrier and targeting
species and the density of the species on the carrier. See, e.g., Lihme 15:17–
24, 23:28–24:22; Wucherpfennig 7:28–8:2. Indeed, Exhibit A referred to in
the Hansen Declaration similarly suggests that the optimal ratio of MHC
molecules to dextran carrier is not necessarily 5–25 MHC molecules as
claimed but, rather, depends on the molecular weight of the dextran carrier.
Appeal Br., Evidence App., Ex. A (showing optimal ratio to be in the range
of 40 to 50 molecules where the dextran carrier has a molecular weight of
500kD).
Furthermore, because claim 1 is not limited with respect to the
molecular weight of the carrier molecules, the alleged unexpected results is
also not commensurate with the scope of the claim. That is, for certain
constructs falling with the claim (e.g., where the molecular weights of the
dextran carrier molecules are higher than 270 kD), the claimed number of
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MHC molecules may not provide superior results, much less unexpectedly
superior results, as compared to the prior art.9
Appellant argues in the Reply Brief that the Examiner’s rejection is
based on “highly technical arguments that are . . . misleading and/or off-
point.” Reply Br. 4–5. Appellant points in particular to the Examiner’s
finding that Appellant’s evidence of unexpected results is not commensurate
with claim scope, because “sensitivity of the Dextramer carriers is in part
due to the higher number of fluorochromes on the Dextramer carriers,”
which is not a feature recited in claim 1, and because evidence Appellant
relies on to show unexpected results refers to specific Dextramers that “have
some discrete undisclosed number of MHC molecules and fluorochromes
thereon and a particular peptide bound to the MHC class I binding groove,”
none of which are specified in claim 1. Ans. 14, 16; Appeal Br. 4, 5.
Appellant contends that these “additional features”
are not at the core of the invention and they are not what
provide the unexpected properties described in the
evidence of record - namely the features currently recited
in the claims: MHC dextran backbone and specific
numerical range of MHCs employed. The Examiner
cannot simply dismiss the evidence rebutting her

9 Appellant characterize as “misleading and/or off-point” the Examiner’s
finding that Appellant’s unexpected results argument is not persuasive
because the claim does not recite any particular molecular weight of the
dextran carrier, whereas evidence shows that “the ‘optimal’ number of MHC
increases . . . as the size (molecular weight) of the dextran carrier increases.”
Ans. 10; Reply Br. 5. We are not persuaded for the reasons discussed above:
The Examiner’s point is relevant both to whether the alleged unexpected
results are in fact unexpected, as well as to whether Appellant has provided
evidence of unexpected results commensurate with the scope of the claims.
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obviousness rejections by identifying pieces and parts of
that evidence that are not present in Claim 1. If the
technical basis for the superior performance and success
of the invention correlates with the features recited in
Claim 1, then the evidence is appropriate to establish such
superior performance.
Appeal Br. 6.10
We do not agree with Appellant’s characterization of the Examiner’s
statements as misleading or off-point. As discussed above, “[t]he evidence
presented to rebut a prima facie case of obviousness must be commensurate
in scope with the claims to which it pertains.” In re Dill, 604 F.2d at 1361.
Because Appellant appears to rely only on particular embodiment(s) of the
invention (i.e., the Dextramers used in the comparisons in Exhibits A and B)
to support its unexpected results argument, Appellant bears the burden of
showing that the results obtained using the embodiment(s) provide a
reasonable basis for concluding that the untested embodiments encompassed
by the claims would behave in the same manner as the tested
embodiment(s). See, e.g., In re Lindner, 457 F.2d 506, 508 (CCPA 1972).

10 Appellant takes issue with the Examiner’s finding that Appellant
“predicate[s its] allegation of unexpected results with regard to an optimal
number of MHC molecules on dextran carriers on results [it] explain[s] in
the specification as being an artefact of not removing excess non-carrier
bound MHC from the reaction medium when performing the immunoassay
of T cell binding to the MHC dextran carriers.” Ans. 12; Reply Br. 8.
Appellant contends that “[t]here is no valid reason to disregard data on the
basis of a loose reference to background staining.” Reply Br. 8. We need
not rely on this finding of the Examiner to affirm the rejection; thus, we do
not adopt this finding and do not address Appellant’s arguments with respect
thereto.
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As we have already noted, “[a]ttorneys’ argument is no substitute for
evidence.” Johnston, 885 F.2d at 1581.
Finally, Appellant contends that evidence of commercial success and
the “superiority [of the constructs of the invention] compared to other state
of the art MHC molecule constructs . . . found throughout literature” also
supports the non-obviousness of the claims. Appeal Br. 17–18. Appellant
cites to Exhibits C and D as evidence of commercial success. Id. at 17.
Appellant alleges that “Exhibit C is a collection of positive statements from
customers using the claimed technology” and “Exhibit D is a google.scholar
search on “Dextramer™” and “Pentamer Proimmune™,” a competing
technology,” showing number of hits per year. Appellant contends that
“[c]learly the development is different for Dextramer™ (increasing) than
pentamers (decreasing).”
We are not persuaded. Objective indicia of non-obviousness include,
in addition to unexpected results, “commercial success . . . , industry praise
. . . , copying by others, and . . . long-felt but unsatisfied need.” Apple Inc. v.
Samsung Electronics Co., Ltd., 839 F.3d 1034, 1052 (Fed. Cir. 2016).
However, for these objective evidence of secondary considerations to be
accorded substantial weight, Appellant must establish a “nexus” between the
evidence and the merits of the claimed invention. Wyers v. Master Lock Co.,
616 F.3d 1231, 1246 (Fed. Cir. 2010). Moreover, while “it is presumed that
the commercial success is due to the patented invention” where a patentee
can demonstrate (1) “commercial success, usually by significant sales in a
relevant market,” and (2) “the successful product is the invention disclosed
and claimed in the patent,” “the success is not pertinent” “if the feature that
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creates the commercial success was known in the prior art.” Galderma
Labs, L.P. v. Tolmar, Inc., 737 F.3d 731, 740 (Fed. Cir. 2013).
In this case, we agree with the Examiner that Appellant has not
provided evidence sufficient to establish the commercial success of the
claimed invention, or established a pertinent nexus between any alleged
success and the claimed invention. Ans. 15–17. As the Examiner points
out, Exhibit C merely provides six quotes from unidentified individuals. To
the extent these quotes are positive and demonstrates some commercial
success of Dextramers, there is no evidence that they are representative of
the success of Dextramers in a relevant market. More importantly,
Appellant provides no persuasive evidence that any alleged commercial
success is due to features of the claimed invention not known in the prior
art.11 Appellant’s discussion of Exhibit D is similarly if not more lacking in
(1) tying a change in the number of hits in google.scholar to the commercial
success of an embodying product and (2) showing that any such alleged
commercial success is due to features of the claimed invention not known in
the prior art.
Appellant contends in the Reply Brief that “the arguments on
commercial success has been greatly underestimated and not taken properly
into account,” contending in particular that
[t]his invention has been successfully patented in all
other jurisdictions where a corresponding patent

11 Even if we were to treat Exhibit C as evidence of industry praise, which
seems somewhat more apt, Exhibit C is nonetheless unpersuasive as to the
non-obviousness of the claims, in particular because there is no persuasive
evidence that any praise directed to MHC Dextramers are tied to features of
Dextramers not known in the prior art.
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application has been filed, including Europe, Australia
and Japan. The granted patents cover a commercial
product that forms the very basis of Immudex ApS (the
coApplicant): all sales to date stem from the sale of
dextran-products, including MHC Dextramers, as
claimed. Despite a vast development in the field of T cell
detection over the past 10 years, no one has been able to
provide a product superior to the MHC-dextramers
developed by Immudex, and covered by the claims. It
remains the first choice and state-of-the art product for T-
cell detection.
Reply Br. 8–9. We reiterate that “[a]ttorneys’ argument is no substitute for
evidence.” Johnston, 885 F.2d at 1581. Moreover, having presented only
Exhibits C and D as evidence of commercial success in the Appeal Brief,
Appeal Br. 17, Appellant cannot not now rely on additional evidence in the
Reply Brief. See 37 C.F.R. § 41.41(b)(2); Cf. Optivus Technology, Inc. v.
Ion Beam Applications S.A., 469 F.3d 978, 989 (Fed. Cir. 2006) (argument
raised for the first time in the Reply Brief that could have been raised in the
opening brief is waived).
Finally, we are not persuaded that the alleged superiority of MHC
Dextramers to other “state of the art MHC molecule constructs” supports the
non-obviousness of the claims. Appeal Br. 17–18. Appellant contends that
Dolton12 shows that, in contrast to influenza-specific MHC II tetramer
molecule constructs, influenza-specific MHC II Dextramer™ molecule
constructs were able to identify the influenza-specific T-cell population
“spiked into blood from healthy negative donor[s].” Id. at 17. However, the

12 G. Dolton et al., Comparison of Peptide-Major Histocompatibility
Complex Tetramers and Dextramers for the Identification of Antigen-
Specific T cells, 177 CLINICAL & EXPERIMENTAL IMMUNOLOGY 47 (2014).
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comparison to tetramers are inapt for the reasons already discussed above;
namely that prior art such as Wucherpfennig discloses constructs comprising
a greater number of MHC molecules per carrier than the tetramers of the
comparison.
We are also not persuaded by Appellant’s citation of additional
publications allegedly “demonstrating the Dextramer™ superiority
compared to other state of the art MHC molecule constructs.” Id. at 18.
“The party seeking the patent bears the burden to overcome the prima facie
case of obviousness with evidence of secondary considerations, such as
commercial success.” In re Applied Materials, Inc., 692 F.3d 1289, 1299
(Fed. Cir. 2012). A listing of references with a conclusory statement that
they show the superiority of an embodying product, without any
explanation, does not satisfy Appellant’s burden.
Accordingly, for the reasons discussed above, we affirm the
Examiner’s rejection of claim 1 as obvious over Lihme and Wucherpfennig.
Claims 2–4, 7, 9, 11, 26, 27, 29–33, and 36, which are not separately argued,
fall with claim 1.
B. Obviousness rejection over Lihme, Wucherpfennig, and Romero
(claims 1–4, 7, 9, 11, 26, 27, 29–33, and 36)
Unless otherwise noted, we adopt the Examiner’s findings of fact and
reasoning regarding the rejection of claim 1 as obvious over Lihme,
Wucherpfennig, and Romero (Final Act. 2–7; Ans. 3–18). We are not
persuaded by Appellant’s arguments, as explained below. Only those
arguments timely made by Appellant in the briefs have been considered;
arguments not so presented in the briefs are waived. See 37 C.F.R.
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§ 41.37(c)(1)(iv) (2015); see also Ex parte Borden, 2010 WL 191083 at *2
(informative).
The Examiner cites Romero for teaching Appellant’s elected species
of MHC Class I molecules comprising HLA-A2.1/ß2m/ELAIGILTV. Final
Act. 6–7. The Examiner concludes that “[i]t would have been prima facie
obvious to one of ordinary skill in the art at the time the invention was made
to have used the MHC class I molecule taught by [Romero] in the carrier
construct of the combined references,” in order to monitor T cell responses
and/or isolate T cells as taught by Romero and/or Wucherpfennig. Id. at 7.
Appellant concedes that Romero teaches “multicomponent
complexes” that “engage[] a plurality of immune complexes” comprising an
MHC molecule, a ß2 microglobulin molecule, and a peptide, wherein there
are preferably at least four immune complexes per multicomponent
complex. Appeal Br. 19. However, Appellant contends that Romero does
not remedy the deficiencies of the combination of Lihme and
Wucherpfennig. Id. at 18. Appellant contends that, as with Wucherpfennig,
“Romero does not teach the use of polysaccharide carriers or dextran
carriers,” and “there would be no motivation to combine Romero with
[Lihme] since Romero relates to an art not mentioned in [Lihme] (binding of
T-cells).” Id.
As discussed above, we do not find the combination of Lihme and
Wucherpfennig to be deficient. Likewise, we are not persuaded by
Appellant’s argument with respect to Romero and Lihme for the same
reasons discussed with respect to the combination of Wucherpfennig and
Lihme, namely that the combined teachings of the cited references would
have provided a skilled artisan with a reason to use the MHC molecules
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disclosed in Wucherpfennig and Romero as the targeting species attached to
the dextran carriers disclosed in Lihme.
Accordingly, we affirm the Examiner’s rejection of claim 1 over
Lihme, Wucherpfennig, and Romero. Claims 2–4, 7, 9, 11, 26, 27, 29–33,
and 36, which are not separately argued, fall with claim 1.

CONCLUSION
In summary:
Claim(s)
Rejected
35
U.S.C. §
Reference(s)/Basis Affirmed Reversed
1–4, 7, 9, 11, 26,
27, 29–33, 36
103(a) Lihme,
Wucherpfennig
1–4, 7, 9,
11, 26, 27,
29–33, 36

1–4, 7, 9, 11, 26,
27, 29–33, 36
103(a) Lihme,
Wucherpfennig,
Romero
1–4, 7, 9,
11, 26, 27,
29–33, 36

Overall
Outcome
1–4, 7, 9,
11, 26, 27,
29–33, 36

TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R.
§ 1.136(a)(1)(iv).

AFFIRMED