Peter O. Krutzik et al.

Patent Trials and Appeals Board

Jan 3, 2020

13175566 - (D) (P.T.A.B. Jan. 3, 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.
13/175,566 07/01/2011 Peter O. Krutzik STAN-447DIV 2835
77974 7590 01/03/2020
STANFORD UNIVERSITY OFFICE OF TECHNOLOGY LICENSING
BOZICEVIC, FIELD & FRANCIS LLP
201 REDWOOD SHORES PARKWAY
SUITE 200
REDWOOD CITY, CA 94065
EXAMINER
CHEN, STACY BROWN
ART UNIT PAPER NUMBER
1648
NOTIFICATION DATE DELIVERY MODE
01/03/2020 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):
docket@bozpat.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte PETER O. KRUTZIK and GARRY NOLAN
Appeal 2018-009138
Application 13/175,566
Technology Center 1600
Before FRANCISCO C. PRATS, TAWEN CHANG, and
DEVON ZASTROW NEWMAN, Administrative Patent Judges.

NEWMAN, Administrative Patent Judge.
DECISION ON APPEAL
STATEMENT OF THE CASE
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims 22, 25, 29–33, 37–43, and 46–53 as
obvious. 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(a). Appellant identifies the real party in interest as Board of Trustees
of the Leland Stanford Junior University. Appeal Br. 3.
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Application 13/175,566

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CLAIMED SUBJECT MATTER
The Specification teaches:
The present invention is drawn to multiplex cellular
assays that employ Detectable Cell Barcodes (DCB). In certain
embodiments, different cell samples are labeled with different
amounts of a DCB marker, e.g., by treatment with different
concentrations of a DCB label that binds to a cell (e.g., a cell-
reactive form of a fluorophore or a cell-reactive molecular mass
marker). This gives each sample a unique signature upon
analysis (e.g., flow cytometric detection and/or mass
spectrometer analysis).
Spec. ¶ 3.
The Specification discloses kits for performing the assays, which can
include “one or more DCB labels . . . in any convenient form, including as
dry reagents (e.g., lyophilized) or in a liquid buffer (e.g., as a suspension,
dissolved, etc.).” Id. ¶ 99. The DCB labels are provided “in a form that
facilitates DCB labeling of multiple cell samples,” such as “in an amount
that is optimized for DCB labeling reactions.” Id. ¶ 100. For instance, each
of the one or more DCB labels may be provided “in a single container (or
tube) in which a dilution scheme (e.g., the serial dilution factor) that will
allow differential labeling of multiple cell samples based on DCB intensity
is known,” or provided “such that subsequent dilution by the user is not
required (meaning they are pre-measured/diluted for the user).” Id. ¶¶ 101–
102. The claims at issue2 are directed to a kit containing at least two
different concentrations of DCB labels.

2 Applicant has separately pursued claims directed toward the method of the
assay in other applications (see, e.g., US 8,003,312). The claims before us
relate solely to a kit containing the specified components.
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Claim 22, reproduced below, is illustrative of the claimed subject
matter:
22. A kit comprising:
(a) a first container comprising a first concentration of a
detectable cell barcode (DCB) label, wherein:
(i) the DCB label comprises: i. a fluorophore and
ii. a reactive moiety that forms a covalent bond with
molecules in or on a cell, wherein the reactive group is
selected from the group consisting of: an amine-reactive
group, a thiol-reactive group, a hydroxyl reactive group,
and an aldehyde-reactive group, and
(ii) the first container does not comprise an
antibody; and
(b) a second container comprising a second concentration
of the DCB label, wherein:
(i) the DCB label in the first container is identical
to the DCB label in the second container,
(ii) the concentration of the DCB label in the first
container is different than the concentration of the DCB
label in the second container, and
(iii) the second container does not comprise an
antibody.
Appeal Br. 9 (Claims Appendix).
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REFERENCES
The prior art relied upon by the Examiner is provided below:
Name Reference Date
Archer et al. US 2005/0069962 A1 March 31, 2005
Gordon et al. US 5,486,452 January 23, 1996
DELFIA Eu-Labelling Kit 1244-302 May 2000, available from
www.perkinelmer.com/labsolutions/resources/docs/man_1244-302.pdf
(hereinafter, “the DELFIA Kit”)
Generic DELFIA Reagents (September 2003, available from
www.perkinelmer.com/labsolutions/
resources/docs/MAN_AD0005P-12.pdf) (hereinafter “Generic DELFIA
Reagents”)
REJECTIONS
The following grounds of rejection by the Examiner are before us on
review:
Claims 22, 25, 30–33, 37–43, and 46–53 are rejected under pre-AIA
35 U.S.C. § 103(a) as being unpatentable over Archer, the DELFIA Kit, and
Generic DELFIA Reagents. Ans. 3.
Claim 29 is rejected under pre-AIA 35 U.S.C. § 103(a) as being
unpatentable over Archer, the DELFIA Kit, Generic DELFIA Reagents, and
Gordon. Ans. 7.
OPINION
Unless otherwise indicated herein, we adopt the Examiner’s findings
of fact, reasoning on scope and content of the claims and prior art, and
conclusions set out in the Final Action and Answer. Only those arguments
made by Appellant in the Appeal Brief and properly presented in the Reply
Brief have been considered in this Decision. Arguments not so presented in
the Briefs are waived. See 37 C.F.R. § 41.37(c)(1)(iv) (2015); see also Ex
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parte Borden, 93 USPQ2d 1473 (BPAI 2010) (informative) (“Any bases for
asserting error, whether factual or legal, that are not raised in the principal
brief are waived.”).
Claims 22, 25, 30–33, 37–43, and 46–53
The Examiner finds that Archer teaches “labeling reagents used in
methods of cell sorting, such as FACS [fluorescence-activated cell sorting].”
Ans. 4. The Examiner finds that the labeling reagent comprises a label that
is a detectable moiety. Id. The Examiner finds that the label, in either a
functionalized or non-functionalized state, “qualifies as a DCB label” as
taught by the Specification. Id. The Examiner finds that Archer teaches
labels that can be a fluorescent dye covalently attached to monovalent
antigen fragments or a “non-antibody monomeric protein via a reactive
group, such as succinimidyl esters” and that the label binds to a target-
binding antibody to form a complex that will bind to an antigen cell of
interest. Id. at 4–5. In this regard, the Examiner finds Archer teaches that
the label is a DCB that is “subsequently functionalized to bind to a cell.” Id.
at 5.
The Examiner finds that it would have been obvious “to have
provided the labels without the secondary antibodies, motivated by the
desire to have flexibility in customizing (i.e., one would be able to use any
secondary antibody of choice).” Id. The Examiner finds that the DELFIA
kit “provides such an embodiment where the tags (labels) are not conjugated
to proteins/antibodies, allowing the user to choose any protein/antibody to
bind to the tag.” Id. The Examiner finds that the “multiple unconjugated
labels” (not comprising antibodies) that are provided by the DELFIA kit
could have been used in Archer’s method, wherein “the labels would
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inherently be capable of binding cells non-specifically, regardless of
Archer’s intention that the label be conjugated to an antibody prior to its use
as a labeling reagent.” Ans. 5.
The Examiner concludes that the remaining claim limitation,
providing a first, second, and sometimes a third concentration of DCB label
having at least a two-fold difference, “would have been an obvious variation
in the preparation of kit reagents.” Id. The Examiner finds that the Generic
DELFIA Reagents market reagents in different amounts in which “vials of
different amounts of the same reagent are provided for sale.” Id. at 5–6.
The Examiner finds that
[d]ifferent amounts are desirable depending on the amount that
the user needs for their particular method, just as different
concentrations would have simply been a matter of user
preference depending on how much is needed (i.e., if a large
amount is needed, a higher concentration of the dye in a vial
would allow for the user to have more product in a smaller
container).
Id. at 6. The Examiner concludes that the skilled artisan would have found it
“obvious to have packaged a label in three different amounts (such as 0.2 ml
(as is included in the DELFIA® kit), and 1.0 ml, and 5.0 ml) or three
different concentrations.” Id. The Examiner finds the skilled artisan would
have found motivation to offer varying amounts or concentrations of the
reagent “for use in smaller to larger applications (e.g., smaller amounts for
experimental/validation purposes, larger amounts for large-scale assays
following experimentation/validation with the smaller amounts).” Id.
The Examiner concludes that the combination of teachings suggests
“a kit comprising one or more aliquots of varying amounts of a label (or a
defined mix of labels) comprising a detectable moiety, that is capable of
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binding cells non-specifically, and does not comprise an antibody (i.e., the
container does not comprise an antibody).” Ans. 6. The Examiner further
finds that other non-claimed reagents necessary to complete the assay are
disclosed in the cited references and, with regard to claims 32 and 33, that
the claim element “specifically binding” is “recognized [in] the act of an
antibody binding to an analyte” because “every protein is reasonably
considered to be a specific isoform.” Id. at 6–7.
Appellant argues that Generic DELFIA Reagents “simply describes a
list of reagents that can be purchased . . . [that] are not packaged in a kit in
any combination, much less a kit that contains two containers containing the
same reagent or different concentrations of the same reagent, as claimed.”
Appeal Br. 6. Appellant argues that the reagents “do not comprise a reactive
moiety that forms a covalent bond with molecules in or on a cell” and would
not have led the skilled artisan “to make compounds that comprise a reactive
moiety that forms a covalent bond with molecules in or on a cell, much less
molecules that contain ‘an amine-reactive group, a thiol-reactive group, a
hydroxyl reactive group, and an aldehyde-reactive group’” as claimed. Id.
Appellant further argues that each of the reagents is provided “at a
concentration of 50mmol/L” and not in different concentrations as claimed.
Id. at 6–7. Appellant argues that “varying the concentration of a reagent is
not an obvious variation of varying the volume of the reagent (as described
by DELFIA Reagents publication).” Id. at 7.
According to Appellant, “changing the concentration of reagents can
have profound effects on a reaction” and that “scaling up a reaction (which
appears to be the reason for supplying different concentrations of reagents
advanced by the Examiner) does not typically involve changing the
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concentrations of the reactants. Rather, if one wants to make more product,
one typically makes the same reaction but at a larger volume.” Id. Thus,
Appellant argues, the skilled artisan would not have envisioned “[s]elling the
same reactant at two different concentrations in order to make more or less
product” when flexibility of smaller amounts is possible by ordering the
larger volume of product and using “more or less of the label.” Id.
The Examiner responds that, although “none of the cited references
disclose varying concentrations of the same reagent” and the reagents in
Generic DELFIA Reagents are “marketed at one concentration as ready-to-
use,” “differences in concentration (similar to differences in proportion)
would have been an obvious variation in the preparation of kit reagents with
a predictable result (no variation in activity of the reagent would be expected
when adjusted to the desired concentration).” Ans. 9–10.
In support, the Examiner cites Dystar Textilfarben GmbH & Co.
Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1368 (Fed. Cir. 2006),
which holds that “an implicit motivation to combine exists . . . when the
‘improvement’ is technology-independent and the combination of references
results in a product or process that is more desirable, for example because it
is . . . more efficient.” The Examiner further cites to MPEP 2144.04 for the
proposition that prior legal decisions with sufficiently similar facts can
provide supporting rationale for an obviousness rejection, as well as for prior
legal decisions holding that, for instance, “scaling up [a prior art process
capable of being scaled up] and [recitation of] relative dimensions where
there would be no difference in performance” do not confer patentability.
Ans. 9–10. The Examiner finds “[i]t would have been obvious to have
packaged a label in three different amounts (such as 0.2 ml (as is included in
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the DELFIA® kit), and 1.0 ml, and 5.0 ml) or three different
concentrations.” Id. at 10–11. The Examiner finds the skilled artisan would
have been motivated to offer different concentrations “by the ability to offer
the user varying amounts of reagent for use in smaller to larger applications
(e.g., smaller amounts for experimentation/validation purposes, larger
amounts for large-scale assays following experimentation/validation with the
smaller amounts).” Id. at 11. The Examiner also finds that “the rationale for
packaging the reagent as a concentrate for purposes of saving space would
remain a reasonable alternative rationale” that would have motivated
providing more than one concentration. Id.
We select claim 22 as representative of the claims subject to this
ground of rejection. 37 C.F.R. § 41.37(c)(1)(iv). We agree with the
Examiner that the cited references support a prima facie case of obviousness
with respect to claim 22 and that Appellant has not provided sufficient
rebuttal evidence or evidence of secondary considerations that outweighs the
evidence supporting the prima facie case.
Archer discloses a “chemical moiety or protein that retains it’s [sic]
native properties . . . when attached to a labeling reagent,” including binding
activity. Archer ¶ 44. Archer discloses detectable fluorophores as labels
that “can bind selectively to a conjugated molecule such that the conjugated
molecule, when added subsequently along with a substrate, is used to
generate a detectable signal.” Id. Archer teaches that the labeling reagents
“have affinity for a specific region of the target-binding antibody” and can
comprise monovalent antibody fragments or monomeric proteins covalently
attached to a label. Id. ¶ 57. Archer teaches that multiple labels can be used
in a single sample:
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The discrete labeling reagents subsets are added to the target-
binding antibodies wherein the affinity of the antibody and ratio
of labeling reagent to target-binding antibody determines the
subsets of immunolabeled complexes. This results in an infinite
number of immuno-labeled complex subsets that are
distinguished by i) the target-binding antibody, or ii) a ratio of
label to labeling reagent, or iii) a ratio of labeling reagent to the
target binding antibody or iv) by a physical property of the
label.
Id. ¶ 58. In this manner, the method can be used to identify and quantitate
multiple targets in a sample, distinguished by their relative binding affinity.
Id. Archer discloses kits containing the labels, and materials for use of the
method on immobilized materials and with fixed cells. Id. ¶¶ 150–157.
The DELFIA kit discloses an Eu-Labelling reagent with an amine-
reactive isothiocyanate group at one end, and a DTTA group at the other, as
shown in Figure 1, reproduced below:

Figure 1 depicts the chemical structure of the Eu-Labelling reagent.
DELFIA Kit 1. The label is an unconjugated amine-reactive moiety that can
form a covalent bond with molecules in or on a cell, by binding to a protein
or antibody: “[t]he DTTA group forms a stable complex with Eu3+ and the
isothiocyanate-group reacts with the primary aliphatic amino group on the
protein at alkaline pH to form a stable covalent thiourea bond.” Id. The
label itself is not an antibody and can be provided in the unconjugated form
in a kit, to be conjugated to an amine group in the antibody or protein of
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choice. Id. at 2. Both Archer and the DELFIA kit teach use of labels that
act through reactive groups (succinimidyl esters in Archer, amine groups in
the DELFIA kit) to form covalent bonds to target cells. We find the
ordinarily skilled artisan would have found it obvious to substitute one type
of label with another. The Federal Circuit has recognized that those skilled
in the art know to substitute one known equivalent for another. See In re
Omeprazole Patent Litigation, 483 F.3d 1364, 1374 (Fed. Cir. 2007)
(“[T]his court finds no . . . error in [the] conclusion that it would have been
obvious to one skilled in the art to substitute one ARC [alkaline reactive
compound] for another.”). We further agree with the Examiner that this
substitution was desirable because it would have provided “flexibility in
customizing” as “one would be able to use any secondary antibody of
choice.” Ans. 5. As the Examiner explains, “[t]he DELFIA® kit provides
such an embodiment where the tags (labels) are not conjugated to
proteins/antibodies, allowing the user to choose any protein/antibody to bind
to the tag.” Id. Appellant does not argue that this substitution of labels
would not have been reasonably successful or contend that the molecular
components of the claimed kit patentably distinguish it over the prior art;
Appellant argues only that the provision of a kit with the claimed two or
more concentrations of the DCB label would have been nonobvious. See
Appeal Br. 6–8.
Generic DELFIA Reagents is a bulletin that discloses reagents
“suitable for highly sensitive end point measurements in separation based
assays such as those for detection of protein-protein binding and cell
adhesion.” Generic DELFIA Reagents 1. The bulletin states that the
reagents are sold in different size containers, e.g. 5 µg and 1 mg vials, of the
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same antibodies. Id. The reagents are supplied “as ready-for-use solution in
50 mmol/L Tris-HCl buffered saline” and each vial “contains either 10 µg,
50 µg, 200 µg or 1 mg Eu/Tb/Sm-labeled protein.” Id. at 2.
We are not persuaded by Appellant’s argument that the components
disclosed by Generic DELFIA Reagents do not comprise a reactive moiety
forming a covalent bond with molecules in or on a cell as claimed and that
the publication would not have led one to make compounds comprising a
reactive moiety (see Appeal Br. 6). Non-obviousness cannot be established
by attacking the references individually when the rejection is predicated
upon a combination of prior art disclosures. In re Merck & Co. Inc., 800
F.2d 1091, 1097 (Fed. Cir. 1986); see also In re Keller, 642 F.2d 413, 426
(CCPA 1981) (finding “one cannot show nonobviousness by attacking
references individually where, as here, the rejections are based on
combinations of references” (citations omitted)). The Examiner cited
Archer as disclosing a reactive moiety forming a covalent bond with
molecules, not Generic DELFIA Reagents alone (see Ans. 5–6).
The Examiner cites Generic DELFIA Reagents for the teaching that
the skilled artisan would have found it obvious to provide a kit having
multiple amounts of a reagent in separate containers for ease of use by the
skilled artisan. Id. at 5–7. The Examiner finds that the skilled artisan at the
time of the invention “would been motivated to do so to offer convenience to
the end user with a reasonable expectation of success.” Id. at 12. We agree
that the motivation provided by the Examiner is reasonable, and are not
persuaded by Appellant’s argument to the contrary (see Appeal Br. 6–8). As
noted by the Examiner, the Federal Circuit has stated:
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an implicit motivation to combine exists not only when a
suggestion may be gleaned from the prior art as a whole, but
when the “improvement” is technology-independent and the
combination of references results in a product or process that is
more desirable, for example because it is stronger, cheaper,
cleaner, faster, lighter, smaller, more durable, or more efficient.
Because the desire to enhance commercial opportunities by
improving a product or process is universal—and even
common-sensical—we have held that there exists in these
situations a motivation to combine prior art references even
absent any hint of suggestion in the references themselves. In
such situations, the proper question is whether the ordinary
artisan possesses knowledge and skills rendering him capable
of combining the prior art references.
Dystar, 464 F.3d at 1368. See also Belden Inc. v. Berk-Tek LLC, 805
F.3d 1064, 1073 (Fed. Cir. 2015) (“[O]bviousness concerns whether a
skilled artisan not only could have made but would have been motivated to
make the combinations or modifications of prior art to arrive at the claimed
invention.”).
The question applied here, therefore, is whether the cited references
provided an implicit motivation for creating the kit of claim 22, and whether
the skilled artisan possessed knowledge and skills rendering the artisan
capable of combining the teachings of Archer, the DELFIA kit, and Generic
DELFIA Reagents to create the kit of claim 22. We find the artisan would
have been so motivated and so capable; namely, we agree with the Examiner
that manipulation of reagents to obtain the desired amount or concentration
of an active component was within the skill of the ordinary artisan. Given
DELFIA Reagents’ disclosure that it was useful to provide different amounts
of the claimed reagents for the convenience of the user, we also agree with
the Examiner that an ordinary artisan had good reason to provide a kit
containing the components of claim 22 with two or more concentrations of
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DCB components, and that combining the teachings of the cited references
was within the knowledge and skill of the artisan at the time of the
invention. Appellant’s argument to the contrary is unsupported by evidence,
and is therefore unpersuasive. See Estee Lauder, Inc. v. L’Oréal, S.A., 129
F.3d 588, 595 (Fed. Cir. 1997) (An argument made by counsel in a brief
does not substitute for evidence lacking in the record). We affirm the
rejection of claim 22. Appellant does not argue claims 25, 30–33, 37–43,
and 46–53 separately (see Appeal Br. 5–8), and those claims fall with claim
22. 37 C.F.R. § 41.37 (c)(1)(iv).
Claim 29
Appellant does not argue claim 29 separately (see Appeal Br. 8), but
relies on the arguments with respect to claims 22, 25, 30–33, 37–43, and 46–
53. For the reasons stated above, we likewise affirm the rejection of claim
29.
CONCLUSION
The Examiner’s rejections are affirmed.
DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
22, 25, 30–
33, 37–43,
46–53
103 Archer, DELFIA
kit, Generic
DELFIA Reagents
22, 25, 30–
33, 37–43,
46–53

29 103 Archer, DELFIA
kit, Generic
DELFIA Reagents,
Gordon
29
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Overall
Outcome
22, 25, 29–
33, 37–43,
46–53

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