Euroimmun Medizinische Labordiagnostika AG

Patent Trials and Appeals Board

Dec 7, 2020

2020002362 (P.T.A.B. Dec. 7, 2020)

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.
14/346,262 03/20/2014 Wolfgang Meyer 000149US 2672
151167 7590 12/07/2020
Gruneberg and Myers PLLC
1775 Tysons Blvd
5th Floor
Tysons, VA 22102
EXAMINER
FOSTER, CHRISTINE E
ART UNIT PAPER NUMBER
1699
NOTIFICATION DATE DELIVERY MODE
12/07/2020 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):
em@gandmpatent.com
kg@gandmpatent.com
patent@gandmpatent.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte WOLFGANG MEYER and THOMAS SCHEPER1
Appeal 2020-002362
Application 14/346,262
Technology Center 1600

Before ERIC B. GRIMES, DEBORAH KATZ, and JOHN G. NEW,
Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
method of detecting an antibody, which have been rejected as obvious. We
have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
STATEMENT OF THE CASE
The Specification states that, “[t]ypically, antibodies are detected by
. . . firstly sensitive screening and then specific confirmation. . . . [I]n routine
serology, ELISAs (enzyme-linked immunosorbent assay) are often used for

1 Appellant identifies the real party in interest as Euroimmun Medizinische
Labordiagnostika AG. Appeal Br. 1. We use the word “Appellant” to refer to
“applicant” as defined in 37 C.F.R. § 1.42.
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Application 14/346,262

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the screening, whereas immunoblot strips . . . are primarily used as a
confirmation assay.” Spec. 1:22–30. The Specification states that the prior
art discloses immunoblot strips that include a “conjugate control zone, which
indicates that the test strip has been incubated with a labeled anti-patient
immunoglobulin antibody from another animal species.” Id. at 3:7–10. “[I]t
is further known to provide a separate predeveloped calibration strip.” Id. at
3:19–20.
The Specification states, however, that “a test strip which has already
been preincubated does not allow any conclusions to be drawn about the
intensity in which the individual bands would appear under different
laboratory conditions.” Id. at 3:35–4:2. The Specification discloses
immunoblot strips intended to allow “firstly, checking of experimental
parameters, more particularly the addition of patient serum and/or of the
correct conjugate, and, secondly, calibration of the test results while taking
into account the actually prevailing experimental conditions.” Id. at 4:31–35.
Claims 16 and 19–21 are on appeal. Claims 16 and 19, reproduced
below, are illustrative:
Claim 16. A method for detecting at least one antibody
in a patient sample, the method comprising:
inserting at least one patient strip into at least one
incubation channel, wherein a pathogen protein is immobilized
on the at least one patient strip;
incubating the at least one patient strip with a patient
sample, a conjugate and a substrate, so as to allow a reaction
between the at least one antibody in the patient sample and the
pathogen protein immobilized on the at least one patient strip;
capturing incubation quality by a visual inspection of a
control, wherein the control is a separate calibration strip
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comprising at least a conjugate control zone and a calibration
zone, wherein the separate calibration strip is inserted into
another incubation channel and is incubated with a reference
sample, a conjugate and a substrate under experimental
conditions used for the incubation of the at least one patient
strip, wherein the calibration strip and the at least one patient
strip are incubated simultaneously in their respective incubation
channels with the reference sample and the patient sample,
respectively, wherein control bands become visible in the
calibration zone after the calibration strip has been incubated,
and wherein color intensities of the control bands are different;
generating a calibration curve taking the different color
intensities into account, checking whether the calibration curve
is situated within a permissible limit and concluding that said
incubation quality is acceptable when said calibration curve is
situated within a permissible limit, wherein the curve is
compared with a color intensity of at least one band of the at
least one incubated patient strip; and
based on the comparison, ascertaining a quality value for
the reaction of the at least one antibody and the pathogen
protein on the at least one patient strip and determining an
antibody concentration in the patient sample.

Claim 19. The method of claim 16, wherein the
calibration strip further comprises at least one negative control
zone, wherein the negative control zone presents an antigen
which is directed to an antibody.

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The claims stand rejected as follows:
Claims 16, 20, and 21 under 35 U.S.C. § 103(a) as obvious based on
Euroimmun AG,2 Gosink,3 Euroimmun 2,4 Orgentec,5 Hanke,6 Abel7 and
optionally also Schneider8 (Ans. 3–4) and
Claim 19 under 35 U.S.C. § 103(a) as obvious based on Euroimmun
AG, Gosink, Euroimmun 2, Orgentec, Hanke, Abel, optionally Schneider,
and Urnovitz9 (Ans. 16).
OPINION
Obviousness: Claims 16, 20, and 21
Claims 16, 20, and 21 stand rejected as obvious based on Euroimmun
AG, Gosink, Euroimmun 2, Orgentec, Hanke, Abel, and (optionally)
Schneider. The Examiner finds that Euroimmun AG teaches methods for
detecting antibodies in human plasma, in which patient strips containing
immobilized pathogen protein are incubated in an incubation tray. Ans. 4. The
Examiner finds that the strips can be scanned or visually inspected. Id. at 5.

2 Euroline EBV Profile 2 (IgG/IgM), 1–2 (Feb. 2010).
3 A system for fully automated, multiparameter autoantibody diagnostics
(June 2010) (http://www.cli-online.com/
index.php?id=767&fromEmag=1&qry=25089) (last visited Aug. 20, 2016).
4 Automated evaluation of membrane-based test systems with
EUROLineScan, 1–4 (2011).
5 Immunoblots by ORGENTEC Diagnostika, 1–2 (Jan. 2011)
(www.orgentec.com/products/pdfs/ Immunoblot_de_IFU_ORG_710.pdf)
(last visited Mar. 19, 2014).
6 DE 100 00 322 A1, published Oct. 16, 2003 (as translated).
7 US 2004/0058385 A1; published Mar. 25, 2004.
8 US 2008/0173806 A1; published July 24, 2008.
9 US 5,447,837, issued Sept. 5, 1995.
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The Examiner finds that Gosink teaches that the system described by
Euroimmun AG allows multiple membrane strips to be incubated in separate
channels of the incubation tray so that “different tests can be combined in
one run” by simultaneously incubating multiple strips. Id. at 5–6. The
Examiner finds that Gosink also teaches that, in this system, “[t]he
membrane strips are incubated with sample containing the human antibody
to be detected, as well as with labeled anti-human antibody conjugate . . .
and with substrate.” Id. at 6.
The Examiner finds that Euroimmun 2 provides further details about
the same assay system; specifically, that it “involves production of a visible
color signal as colored bands on the strips, and that the different band
intensities can be measured and compared.” Id.
The Examiner finds that Hanke also pertains to immunoblot strips,
and teaches including
conjugate control zones [that] produce a band only after
incubation with a conjugate; e.g. where anti-goat IgG antiserum
is applied in the conjugate control zone, it would produce a
band upon incubation with enzyme-conjugated, anti-human IgG
antiserum from goat (i.e., IgG conjugate); and that the same
applies to other immunoglobulins.
Id. at 8. “[T]his allows one to ascertain that the test procedure has been
carried out correctly . . . verification of the functionality of the conjugate
used . . . as well as verification that the correct conjugate has been used.” Id.
at 8–9. The Examiner finds that “Hanke also teaches incubating strips, in
separate incubation channels/wells, with both patient serum and control
serum (i.e., reference sample . . . ).” Id. at 9.
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The Examiner finds that “Orgentec teaches evaluation of test results
through comparison of color intensity with calibration strips included with
the test kit” and “teaches that (separate) included calibration strips allow
easy interpretation of test results.” Id. at 6–7.
The Examiner finds that Abel provides further details regarding
“calibration by immobilizing recognition elements used for analyte
determination in known, but different local concentration in the
measurement areas intended for calibration purposes.” Id. at 7. The
Examiner finds that Abel teaches that “[i]t is possible to generate a standard
curve reflecting the binding activity . . . by applying a single calibration
solution containing a known amount of analyte (i.e., incubating with a
reference sample) to an array with recognition elements at a different
immobilization density.” Id. “[T]his simplified form of calibration allows
one to quantitatively determine the analyte (i.e., ascertaining information
about concentration) using a single calibration solution.” Id.
The Examiner finds that Abel “further indicate[s] that the calibration
solutions would be assayed under largely identical conditions (i.e., under the
same experimental conditions for incubation . . .).” Id. Finally, the Examiner
finds that Abel teaches that, “[b]y selecting the density of the recognition
elements the calibration curves can be of a similar order of magnitude as for
the detection of different analytes, allowing measurements to be performed
at the same time and recorded without a change in instrument settings.” Id.
at 7–8.
The Examiner concludes that it would have been obvious “to have
included a separate calibration strip when performing the methods of
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Euroimmun by applying the known technique of Orgentec, in order to allow
for easy interpretation of test results.” Id. at 9. The Examiner concludes that
“it would have been further obvious to employ a separate calibration strip
containing recognition elements immobilized in multiple zones at different
concentrations by applying the known calibration techniques of Abel”
because Abel “teach[es] that this way of generating a calibration curve
means that one only has to use a single calibration solution.” Id. at 10. The
Examiner reasons that this consideration is particularly pertinent to an
immunoassay because it would “minimize the amount of calibration
antibody needed since antibodies were well-known in the prior art to be
expensive reagents.” Id.
The Examiner also concludes that it would have been obvious to
simultaneously test patient and calibration strips in order to minimize
experimental variability, in view of the teachings of Gosink and Euroimmun
2 of incubating multiple strips in separate incubation channels. Id.
“Additionally, as Abel et al. teaches calibration using a calibration solution
of known analyte concentration, one skilled in the art would readily
appreciate that this calibration solution (i.e., reference sample) would need
to be used separately from the patient sample.” Id. at 11.
The Examiner reasons that “[o]ne would be further motivated to
incubate a separate calibration strip and a test strip in separate incubation
channels as claimed so that both test and calibration reactions were
performed by the same technician at the same time . . . , thereby minimizing
experimental variability.” Id.
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The Examiner also reasons that both Euroimmun references and
Gosink “indicate that the intensities of individual bands on the membrane
strip scan [sic, strips can] be measured by scanner or by camera (i.e.,
visually), and Abel et al. as above teaches generating a calibration curve due
to the concentration dependence of signals.” Id. Thus, “generation of a
calibration curve taking into account such differences would have been
obvious as this merely describes the process of . . . plotting signal intensity
measured vs. concentration.” Id.
The Examiner also concludes that
it would have been obvious to compare the results obtained
using the calibration strip with the results obtained for the
patient strip . . . to determine antibody concentration in the
patient sample examined based on such a comparison by
applying the known technique of Abel et al., who indicate that a
calibration curve can be used for quantitative determination of
analyte.
Id. at 12.
The Examiner concludes that checking whether the calibration curve
is within permissible limits would have been obvious in view of Abel’s
teaching that “calibration curve signals should be of the same order of
magnitude as the analyte detection signals,” as well as Schneider’s teaching
that a calibration curve should be used “only after verifying that all controls
are in an acceptable range and that an acceptable correlation coefficient is
obtained.” Id. at 12–13.
With respect to the recited “quality value,” the Examiner concludes
that it would have been obvious to compare the results of the patient strip
with those of the calibration strip to assess whether results “are observed
similar to those seen on the calibration strip using a known reference
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sample.” Id. at 13. Finally, the Examiner concludes that it would have been
obvious to include a conjugate control zone on the calibration strip, because
Hanke teaches that it would “allow one to ascertain that the test procedure
has been carried out correctly, and specifically in order to allow verification
that the intended conjugate was applied to the strip.” Id. at 14.
We adopt the Examiner’s findings of fact, reasoning, and conclusion
set out in the Final Action and Answer regarding this rejection. We find the
Examiner has established that the subject matter of the rejected claims would
have been obvious to one of ordinary skill in the art at the time the invention
was made over the cited references. We address Appellant’s arguments
below. Only those arguments made by Appellant in the Briefs have been
considered in this Decision. Arguments not presented in the Briefs are
waived. See 37 C.F.R. § 41.37(c)(1)(iv) (2018).
Appellant argues that “Euroimmun AG discloses an antibody test strip
comprising immobilized pathogen protein and an integrated control band in
a qualitative in vivo [sic, in vitro] assay.” Appeal Br. 4. That is,
“Euroimmun AG is a qualitative analysis used to make the binary
determination of the presence or absence of antibodies against the Epstein-
Barr virus. There is no suggestion of a calibration curve as a calibration
curve is not relevant to qualitative analysis.” Id. at 5.
This argument is unpersuasive, because it fails to consider the
teachings of the cited references as a whole. “Non-obviousness cannot be
established by attacking references individually where the rejection is based
upon the teachings of a combination of references.” In re Merck & Co., 800
F.2d 1091, 1097 (Fed. Cir. 1986). Here, the Examiner relies on Orgentec and
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Abel, not Euroimmun AG, for the disclosure of a calibration strip and
generation of a calibration curve, as well as a reason to modify the system of
Euroimmun AG to include these aspects of the claimed method.
Appellant also argues that Orgentec’s calibration strips, “while
separate, are not incubated with a reference sample, a conjugate and a
substrate. The evidence of record is that of the calibration strip of Orgentec
Diagnostica is pre-developed.” Appeal Br. 5. Appellant argues that the
“Examiner has erred by concluding that a disclosure of a separate pre-
incubated calibration strip, is suggestive of incubating a separate calibration
strip.” Id. at 6.
Appellant argues that Abel discloses a kit comprising an “array of
immobilized recognition elements. Arrays are described as being based on
simple glass or microscope plates (paragraph [0005]) and thus, there is no
suggestion of generating a calibration curve by incubating a separate
calibration strip. An array is not a calibration strip.” Id. Appellant also
argues that Abel “does not disclose simultaneous incubation of patent [sic]
strip with a calibration strip. . . . There is no disclosure or suggestion of the
concept of simultaneous incubation of a calibration strip with a patient
strip.” Id. at 7.
Appellant concludes that “the Examiner’s motive appears to be based
on opportunity, insofar as Gosink and Euroimmun 2 disclose the ability to
incubate multiple patient strips at one time. However, the mere possibility of
simultaneous incubation of a calibration strip and a patient strip fails to
provide any motive to do so.” Id.
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These arguments are not persuasive. As found by the Examiner,
Orgentec teaches an immunoblot system for antibody detection. Orgentec 1.
Orgentec states that its system allows “semi-quantitative evaluation of test
results through comparison of colour intensity with the calibration strips
included with the test kits.” Id. Orgentec does not describe incubation of its
calibration strips, and the Specification states that the Orgentec calibration
strip is predeveloped. Spec. 7:20–25.
However, Abel discloses a “kit for the simultaneous qualitative and/or
quantitative determination of a multitude of analytes.” Abel ¶ 22. Abel’s kit
comprises “at least one array of biological or biochemical or synthetic
recognition elements immobilized in discrete measurement areas . . . for
specific recognition and/or binding of said analytes.” Id. ¶ 24. Abel makes
clear that its teachings are applicable to immunoassays. See id. ¶ 223
(“Immunoassay for the Determination of 8 Cytokines”).
Abel states that an “essential feature of the kit according to the
invention comprises arrangements to calibrate recorded luminescence
signals in the presence of one or more analytes.” Id. ¶ 107. Abel teaches that
one calibration method is “the addition of calibration solutions with known
concentrations of the analytes to be determined to a predetermined number
of arrays.” Id.
Abel also teaches that its “invention permits a further possibility for
calibration.” Id. ¶ 108. Specifically, “it is essentially not necessary to add a
large number of calibration solutions with different, known concentrations to
one or more arrays, but to immobilize the . . . recognition elements used for
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analyte determination in known, but different local concentration in the
measurement areas intended for calibration purposes.” Id. Abel states that,
[j]ust as a calibration curve can be generated by applying
various calibration solutions of different analyte concentrations
on an array with recognition elements at a single uniform
immobilization density so too is it possible in principle to
generate such a standard curve reflecting the binding activity
and frequency of the binding events between an analyte and its
tracer elements by applying a single calibration solution to an
array with recognition elements at a different immobilization
density.
Id.
Abel states that “[a] further subject of [its] invention is therefore a kit
which comprises several measurement areas with biological or biochemical
or synthetic recognition elements immobilized therein at a different,
controlled density being provided.” Id. ¶ 109. Abel teaches that a calibration
curve can be established by application of a single calibration solution to an
array having recognition elements immobilized in different areas with a
sufficiently large variation of densities. Id.
Abel also states that its system “offers the possibility of conducting
many kinds of duplication or multiple performance of similar measurements
using relatively small quantities of sample solutions, reagents or optionally
calibration solutions on one and the same platform under largely identical
conditions.” Id. ¶ 70 (emphasis added).
Thus, Abel discloses that a calibration curve can be generated using
an array having recognition elements (e.g., antibody or antigen, depending
on what is intended to be detected) immobilized at different, known
concentration or density. While it is true, as Appellant points out, that an
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array is not an immunoblot strip, a skilled artisan would recognize that the
principle disclosed by Abel applies equally to a two-dimensional array and a
one-dimensional strip.
Based on Abel’s disclosure, it would have been obvious to modify the
system taught by the Euroimmun references and Gosink to include a
calibration strip having antigen immobilized on it at different, known
concentrations in order to allow generation of a calibration curve by
application of a single calibration solution (or reference sample, as recited in
claim 16). Orgentec teaches that a calibration strip enables semi-quantitative
evaluation of results, and thus provides a reason to include the calibration
arrangement described by Abel.
In addition, Abel states that an advantage of its system is the ability to
carry out similar measurements using a sample solution and a calibration
solution on the same platform under largely identical conditions, and
Euroimmun 2 shows that its system includes an incubation tray having ten
incubation channels. Euroimmun 2 (“EUROBlotCamera” photo). Thus, it
would have been obvious to simultaneously incubate a patient strip and a
calibration strip in separate channels of the incubation tray used in the
system described by the Euroimmun references and Gosink.
For the reasons discussed above and those provided in the Answer, we
affirm the rejection of claim 16. Claims 20 and 21 fall with claim 16 because
they were not argued separately. 37 C.F.R. § 41.37(c)(1)(iv).
Obviousness: Claim 19
Claim 19 stand rejected as obvious based on Euroimmun AG, Gosink,
Euroimmun 2, Orgentec, Hanke, Abel, (optionally) Schneider, and Urnovitz.
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The Examiner recognizes that the references discussed with respect to the
previous rejection “do not specifically teach that the calibration strip further
comprises a negative control zone,” as recited in claim 19. Ans. 16. The
Examiner finds that Urnovitz discloses an “immunoassay on a solid support
(test strip), in which a negative control can be bound to a discrete area on the
solid support as a negative control zone.” Id.
The Examiner finds that Urnovitz teaches that “[t]he negative control
does not give rise to a detectable event in a normal specimen, and allows one
to verify the correctness of the detection.” Id. at 17. The Examiner concludes
that it would have been obvious to include a negative control zone on the
calibration strip made obvious by Euroimmun AG, Gosink, Euroimmun 2,
Orgentec, Hanke, and Abel “to verify that the reference sample/ calibration
sample reaction has been correctly conducted; one would be motivated to do
this in accordance with common scientific practice to include controls.” Id.
We adopt the Examiner’s findings of fact, reasoning, and conclusion
set out in the Final Action and Answer regarding this rejection. We find the
Examiner has established that the subject matter of claim 19 would have
been obvious to one of ordinary skill in the art at the time the invention was
made over the cited references.
With respect to the rejection of claim 19, Appellant reiterates the
arguments previously presented regarding the rejection of claims 16, 20, and
21. Appeal Br. 8–11. These arguments are unpersuasive for the reasons
previously explained.
Appellant also argues that, “[w]hile the Examiner articulates a cogent
structure, the Examiner commits further error, as the cited art fails to suggest
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an incubated calibration strip.” Id. at 12. As explained above, however, we
agree with the Examiner that the cited art does, in fact, suggest an incubated
calibration strip.
Appellant further argues that: (a) Orgentec’s calibration strip is pre-
incubated, and there would be no reason to put a negative control zone on a
pre-incubated calibration strip (Appeal Br. 12); (b) Abel discloses an array,
and an array would not suggest a negative control zone on a calibration strip
(id.); and (c) “Urnovitz simply discloses a negative control zone in a patient
strip and fails to suggest a negative control zone in an incubated calibration
strip” (id. at 13).
Each of these arguments, however, is directed to a single reference in
isolation, and fails to address what would have been suggested by the cited
prior art when considered as a whole. “Non-obviousness cannot be
established by attacking references individually where the rejection is based
upon the teachings of a combination of references. . . . [Each reference] must
be read, not in isolation, but for what it fairly teaches in combination with
the prior art as a whole.” Merck & Co., 800 F.2d at 1097. The arguments
addressed to Orgentec, Abel, or Urnovitz individually are therefore
unpersuasive.
For the reasons discussed above and those provided in the Answer, we
affirm the rejection of claim 19.
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DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
16, 20, 21 103(a) Euroimmun AG,
Gosink, Euroimmun 2,
Orgentec, Hanke, Abel,
Schneider
16, 20, 21
19 103(a) Euroimmun AG,
Gosink, Euroimmun 2,
Orgentec, Hanke, Abel,
Schneider, Urnovitz
19
Overall
Outcome
16, 19–21

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