Ex Parte Rong et al

Patent Trial and Appeal Board

Apr 29, 2016

12063233 (P.T.A.B. Apr. 29, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/063,233 0312612009
24353 7590 05/03/2016
BOZICEVIC, FIELD & FRANCIS LLP
Bozicevic, Field & Francis
1900 UNIVERSITY A VENUE
SUITE 200
EAST PALO ALTO, CA 94303
FIRST NAMED INVENTOR
Jianhui Rong
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
UALB-005 5786
EXAMINER
BOESEN, CHRISTIAN C
ART UNIT PAPER NUMBER
1639
NOTIFICATION DATE DELIVERY MODE
05/03/2016 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 JIANHUI RONG, and KEVIN PAUL KANE 1
Appeal2014-000421
Application 12/063,233
Technology Center 1600
Before FRANCISCO C. PRATS, JEFFREY N. FRED MAN, and
TIMOTHY G. MAJORS, Administrative Patent Judges.
MAJORS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
method of detecting cytolytic T lymphocyte (CTL)-recognized antigens,
which have been rejected as failing to satisfy the written description
requirement, and as obvious. We have jurisdiction under 35 U.S.C. § 6(b ).
We reverse.
STATEMENT OF THE CASE
"The invention generally relates to use of cell-based microarrays in
the detection of cytotolytic [sic] T lymphocyte ( CTL )-antigen recognition."
(Spec. i-f 1.) "A key step in developing T cell therapies is ... to identify
1 Appellants identify Jianhui Rong and Kevin P. Kane as the Real Parties in
Interest. (Appeal Br. 3.)
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Application 12/063,233
CTL-recognized antigens selectively expressed by a desired target cell, such
as a tumor cell or virus infected cell." (Id. i-f 3.) "The invention provides
methods ... for rapid, sensitive, and highly specific detection of antigen-
specific interactions between cytolytic T lymphocytes (CTLs) and antigen
presenting cells (APCs)." (Id. i-f 9.) More specifically, "with the
recombinant target APCs being provided on the array as distinct features at
defined locations (addressable locations), [the invention] thus allow[ s] for
correlation with antigen-specific CTL reactivity with a target APC of a
feature at a defined location with the target polynucleotide present on the
array and expressed in the target APC at that location." (Id. i-f 60.)
Claims 1, 2, 6, 7, 24, 25, and 29-31 are on appeal. Claim 1, the only
independent claim on appeal, is illustrative:
1. A method for identifying a cytolytic T lymphocyte
(CTL) antigen, the method comprising:
contacting a sample comprising a cytolytic T lymphocyte
(CTL) with an array comprising a plurality of adherent
recombinant antigen-presenting cells (APCs) adhered to a
surface of the array at different, discrete locations on the array,
wherein the adherent recombinant APCs express different
recombinant polynucleotides encoding different polypeptides,
and wherein the different, discrete locations on the array
correlate with the different recombinant polynucleotides
expressed by the adherent recombinant APCs;
washing the array; and
detecting the presence or absence of caspase activity in
the plurality of adherent recombinant APCs by detecting the
presence of a fluorescent signal generated from a fluorogenic
caspase substrate present in said adherent recombinant APCs;
wherein the presence of a fluorescent signal in an adherent
recombinant APC is indicative of an antigen-specific
interaction between the CTL and the adherent recombinant
APC and indicates the recombinant polynucleotide of the
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adherent recombinant APC encodes a polypeptide that
comprises a CTL antigen.
(Appeal Br. 12 (Claims Appendix).)
The claims stand rejected as follows:
Claims 1, 2, 6, 7, 24, 25, and 29-31 under 35 U.S.C. § 112, first
paragraph, for failing to satisfy the written description requirement.
Claims 1, 2, 6, 7, 24, 25 and 29-31 under 35 U.S.C. § 103(a) as
obvious over van der Bruggen2 in view of Ziauddin,3 Soen,4 Liu,5 and
Amstad.6
DISCUSSION
I. Written Description
"[T]he test for sufficiency [of the written description] is whether the
disclosure of the application relied upon reasonably conveys to those skilled
in the art that the inventor had possession of the claimed subject matter as of
2 P. van der Bruggen et al., A Gene Encoding an Antigen Recognized by
Cytolytic T Lymphocytes on a Human Melanoma, 254 SCIENCE 1643--47
( 1991) ("van der Bruggen").
3 Junald Ziauddin & David M. Sabatini, Microarrays of cells expressing
defined cDNAs, 411NATURE107-10 (2001) ("Ziauddin").
4 Y oav Soen et al., Detection and Characterization of Cellular Immune
Responses Using Peptide-MHC Microarrays, 1 PLoS BIOLOGY 429-38
(2003) ("Soen").
5 Luzheng Liu et al., Visualization and quantification of T cell-mediated
cytotoxicity using cell-permeablefluorogenic caspase substrates, 8 NATURE
MEDICINE 185-89 (2002) ("Liu").
6 P.A. Amstad et al., Detection of Caspase Activation In Situ by
Fluorochrome-Labeled Caspase Inhibitors, 31 BIO TECHNIQUES 608-16
(2001) ("Amstad").
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the filing date." Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351
(Fed. Cir. 2010) (en bane). "[H]ow the specification accomplishes this is not
material." In re Herschler, 591F.2d693, 700-701(CCPA1979) (internal
citations omitted) ("The claimed subject matter need not be described in
haec verba to satisfy the description requirement. It is not necessary that the
application describe the claim limitations exactly, but only so clearly that
one having ordinary skill in the pertinent art would recognize from the
disclosure that appellants invented processes including those limitations.")
The Examiner rejected all the claims on appeal for failure to satisfy
the written description requirement. These rejections are based on the
addition of the step of "washing the array" to claim 1. (Final Act. 2.)
The Examiner argues the "cited support [for the washing step] is not
commensurate in scope with the current claim." (Id. at 3; Ans. 2.) More
particularly, the Examiner contends that "washing" is described in the
context of two embodiments that are narrower than claim 1. For example,
the Examiner finds that the embodiment described in paragraph [0125] of
the Specification, which expressly describes washing the array, also recites
that target cells (i.e., APCs) are (i) "loaded" with a fluorogenic caspase
substrate, and (ii) "coincubated" with CTLs "for a time sufficient for
specific interaction between target cells and CTLs." (Ans. 2.) Because
"claim 1 contains no limitations regarding 'loading' or coincubation time,"
the Examiner contends claim 1 does not satisfy the written description
requirement. (Id.; Final Act 3--4.)7
7 The Examiner makes a similar argument with respect to the "washing"
embodiment in paragraph [0152]. The Examiner finds that embodiment
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We disagree. As Appellants correctly point out, the Specification
expressly describes the "washing" step in at least two microarray examples
- each a somewhat more detailed embodiment of subject matter appearing
in claim 1. (Appeal Br. 4; Spec. i-fi-f 125 and 152.) It is immaterial here that
these disclosures come from the "Detailed Description" of the invention, as
opposed to the "Summary of the Invention" (Ans. 2) or some other portion
of the Specification. Indeed, written description support can come from any
portion of the disclosure. MPEP § 2163 ("It is now well accepted that a
satisfactory description may be in the claims or any other portion of the
originally filed specification."); Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555,
1565 (Fed. Cir. 1991) ("drawings alone may provide a 'written description'
of an invention as required by Sec. 112"). The key question is what these
"washing" examples convey to the skilled person. And we find that these
multiple examples are sufficient to show the inventors' possession of a more
generally applicable step of "washing the array" as in claim 1.
The amendment of claim 1 to include a "washing" step was, therefore,
permissible. Appellants need not import all the additional detailed language
from one or both of the particular embodiments, as the Examiner suggests
(Final Act. 3--4), to establish written description support. ScriptPro, LLC v.
Innovation Assocs., 762 F.3d 1355, 1359 (Fed. Cir. 2014) ("It is common,
specifies the number of CTL cells used (3 .6 x 106 cells/ml in 2 mls) and
recites the incubation temperatures and duration (37°C for 4 hours). (Ans.
2-3.) According to the Examiner, without such detail added into claim 1,
the claim lacks written description support. (Id.; Final Act. 3--4.)
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and often permissible, for particular claims to pick out a subset of the full
range of described features, omitting others. ")8
We conclude that the Examiner has not shown by a preponderance of
the evidence that claims 1, 2, 6, 7, 24, and 29-31 fail to satisfy the written
description. Accordingly, we reverse.
II. Obviousness
The Examiner rejected all the claims on appeal as obvious over van
der Bruggen in view of Ziauddin, Soen, Liu, and Amstad.
The Examiner finds that van der Bruggen "teaches a method [51Cr
assay] for identifying a gene encoding an antigen recognized by cytolytic T
lymphoctyes (CTLs) on a human melanoma." (Final Act. 5.) The Examiner
finds that van der Bruggen does not, however, teach: (i) "contacting a
sample comprising a CTL with an array"; (ii) "an array comprising a
plurality of adherent recombinant antigen-presenting cells (APCs) adhered
to a surface of the array at different, discrete locations on the array, wherein
the adherent recombinant APCs express different recombinant
polynucleotides encoding different polypeptides, and wherein the different,
discrete locations on the array correlate with the different recombinant
polynucleotides expressed by the adherent recombinant APCs" (Final Act.
6-7); or (iii) "detecting ... caspase activity in APCs by detecting the
presence of a fluorescent signal generated from a fluorogenic caspase
8 We do not agree that Appellants are arguing "they can pick and choose any
words from the specification to construct an amended claim" as contended
by the Examiner. (Ans. 2.) Rather, Appellants have persuasively shown
how the two examples of washing arise in essentially the "same context as
recited in Claim 1." (Appeal Br. 4-5.)
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substrate present in the APCs ... [where the] signal in an APC is indicative
of an antigen-specific interaction between the CTL and the APC and
indicates the APC contains a target polynucleotide encoding a[] [CTL]
antigen." (Final Act. 9-10.)
The Examiner turns to Soen and Ziauddin as teaching, respectively,
"detection and characterization of cellular immune response using peptide-
MHC microarrays" and "microarrays of cells producing defined cDNAs."
(Final Act. 7-8.) The Examiner finds that Ziauddin teaches "an array
comprising a plurality of adherent recombinant antigen-presenting cells
( APCs) adhered to a surface of the array at different, discrete locations ....
[and] the advantage of using reverse transfection cell microarrays with
defined addresses to rapidly uncover the function of genes and to identify
the gene products with desired properties." (Id.) The Examiner then
combines van der Bruggen with Soen and Ziauddin, concluding, inter alia,
that the skilled artisan "would have recognized the advantages of
substituting an array taught by Ziauddin for solutions containing mixtures of
different cells taught by van den [sic] Bruggen to rapidly identify the gene
products that trigger CTL binding and initiation of cell death pathway in
APCs." (Final Act. 8-9.)
The Examiner turns to Liu as teaching the detection of fluorogenic
caspase substrate activity in cells as a signal of the desired antigen-specific
interaction. (Final Act. 9. )9 The Examiner finds that Liu teaches "presence
of a fluorescent signal in a APC is indicative of an antigen-specific
9 The Examiner relies on Amstad as showing "washing" of the cells and
using a "fluorogenic multi-caspase substrate." (Final Act. 10-11.)
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interaction between the CTL and the APC and indicates the APC contains a
target polynucleotide encoding an antigen specifically recognized by the
CTL." (Final Act. 10.) The Examiner concludes one of skill in the art
"would have recognized the advantages of substituting the method using
cell-permeable fluorogenic caspase substrates for the visualization and
quantification of T cell-mediated cytotoxicity taught by Liu for the standard
51 Cr-release assay taught by van den [sic] Bruggen in an array taught by
Ziauddin." (Final Act. 10.)
Appellants make two arguments in response. First, Appellants argue
the cited combination of prior art fails to teach each element of claim 1, but
Appellants' explanation is limited to deficiencies of van der Bruggen. In
particular, Appellants contend "none of the cited passages disclose that the
signal in van der Bruggen was detected or present in an adherent
recombinant APC." (Appeal Br. 6.) Second, Appellants argue that "[i]t was
not predictable that an adherent APC could maintain its adherence to a
substrate following antigen-specific CTL interaction." (Appeal Br. 7.)
Rather, according to Appellants, "the ordinarily skilled artisan would not
expect that an adherent cell undergoing an interaction that leads to CTL-
mediated killing as detected by caspase activity induction would maintain an
address on a substrate as required by the present claims." (Appeal Br. 8.)
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As evidence, Appellants submitted the Russell, 10 Abrams, 11 Zagury, 12 and
Martz13 references, which Appellants argue shows "the knowledge in the art
indicated that loss of adherence [of the target cell to substrate] was an early
event in antigen-specific CTL interactions that lead to APC killings."
(Appeal Br. 7-8.)
Appellants' first argument is not persuasive. As the Examiner noted,
"Appellant argues the references individually." (Ans. 3.) The Examiner's
rejection is, however, "based on the combination of references," (id.) and it
is clear that the Examiner relies upon references such as Ziauddin and Liu as
teaching, respectively, the adherence of cells to a microarray and detection
of fluorogenic caspase activity in cells that have interacted with CTLs.
(Final Act. 8-10.) We are not, therefore, persuaded that the combined
teachings of the cited art fail to disclose all the elements of the claims.
Whether a person of ordinary skill in the art would have predictably
combined the references with a reasonable expectation of success is,
however, another matter. Based on the teachings of Russell, Abrams,
Zagury, and Martz, which Appellants submit in rebuttal to the Examiner's
10 John H. Russell et al., A Novel and Distinct Effect of the Cytotoxic T
Lymphocyte-Target Interaction, 140 J. IMMUNOLOGY 427--432 (1988)
("Russell").
11 Scott I. Abrams et al., Cytotoxic T Lymphocyte-Induced Loss Of Target
Cell Adhesion And L ysis Involve Common And Separate Signaling
Pathways, 142 J. IMMUNOLOGY 1789-1796 (1989) ("Abrams").
12 D. Zagury et al., Isolation and characterization of individual functionally
reactive cytotoxic T lymphocytes: conjugation, killing and recycling at the
single cell level, 5 EUR. J. IMMUNOLOGY 818-822 (197 5) ("Zagury").
13 Eric Martz, Early Steps In Specific Tumor Cell Lysis By Sensitized Mouse
T Lymphocytes, 115 J. IMMUNOLOGY 261-267 (1975) ("Martz").
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findings, we are not convinced that the skilled person would have combined
the prior art to arrive at the method of testing CTL-APC interactions by
detecting caspase activity on a microarray as claimed. In re Hedges, 783
F.2d 1038, 1039 (Fed. Cir. 1986) ("if the applicant comes forward with
reasonable rebuttal, whether buttressed by experiment, prior art references,
or argument, the entire merits of the matter are to be reweighed").
Russell and Abrams constitute objective evidence, showing that the
knowledge in the art at the time of invention was that cells undergoing an
interaction with CTLs lose adherence to a substrate as a distinct event that
precedes cell death and lysis - and we have been presented with no
persuasive evidence to the contrary. (Russell, Abstract, pp. 427-428, Figs.
2-3; Abrams, Abstract, 1789-1791; Appeal Br. 8-11.)14 With this
knowledge, it is doubtful the skilled person would have used a microarray
for testing the CTL-APC interactions in the manner claimed. Rather than
expecting success, where the interactions could be visualized by a
fluorescent signal at discrete locations on the microarray that correspond to
specific APCs expressing particular polypeptides/CTL-antigens at those
discrete locations, the skilled person more likely would have expected the
APCs to lose adherence to the microarray and the claimed method not to
work as intended. (Appeal Br. 8.) Appellants' second argument is,
therefore, persuasive.
14 Zagury and Martz teach that cells undergoing CTL interaction become
programmed to undergo apoptosis and lysis, and that lysis may occur
promptly following the interaction. (See, e.g., Zagury, pp. 819-820, Fig. 3;
Martz, pp. 261-263.)
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The Examiner discounts the teachings of Russell, Abrams, Zagury,
and Martz, arguing those references are not commensurate in scope with the
claimed invention. (Ans. 4.) The Examiner points to teaching in Russell
and Abrams that the substrate is washed. (Id.) Claim 1, however, also
includes a step where the array is washed. (Appeal Br. 9.) The Examiner
specifically contends that, in Russell and Abrams, there are "six vigorous
rounds of negative and positive pressure [washing] by a Pasture pipette to
dislodge adherent L929 cells." (Ans. 4.) Russell actually states that the
washing is performed "to dislodge loosely adherent cells." (Russell, p. 428
(emphasis added); Abrams, p. 1790 ("each well was subjected to six
vigorous cycles of negative and positive pressure by a Pasteur pipette on the
fluid to detach loosely bound TC [target cells]") Insofar as the Examiner is
suggesting that this "washing" caused the general loss of adhesion of cells
interacting with CTLs observed in Russell and Abrams, that fails to explain
why loss of adhesion was not observed in cells that interacted with antibody
plus complement (but not CTL). (See Russell, pp. 428--429 ("Only in the
CTL cultures is there a significant difference in total and soluble release
kinetics"), Fig. 3.)
The Examiner also argues that "the four references ... teach that there
is a time lag between a signal generated by contact with CTLs and cell
lysis." (Ans. 4.) The point of this argument is unclear. Russell and Abrams
show that loss of adhesion occurs quickly and before lysis (see, e.g., Russell,
pp. 428-29, Figs. 2-3.) This loss of adhesion remains the factor that would
have discouraged the combination of prior art proposed by the Examiner -
as "it was not predictable that an adherent APC would maintain its
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adherence to a substrate, and thus maintain its 'address', following antigen-
specific CTL interaction that induces caspase activity." (Appeal Br. 7.)
Finally, the Examiner argues that "the four references ... teach that as
many as 40% of the adherent cells remain attached following contact with
CTLs." (Ans. 4.) The Examiner has not adequately explained this
contention. It appears the Examiner's 40% value may stem from Fig. 3 of
Zagury, but this relates to the percent of cells undergoing lysis not the
percent of "cells [that] remain attached [to a substrate] following contact
with CTLs" as argued. (Compare Ans. 4 with 7 /18/12 Office Action at 12
("Zagury teaches 40% of EL4 cells are not lysed after 3 hours of contact
with CTLs").) It is nevertheless true, as the Examiner has pointed out and as
Appellants concede, that a minority of cells in Russell and Abrams may
remain attached to the substrate. (Appeal Br. 8-9.) Appellants argue that
"[ o ]ne of ordinary skill in the art would expect that an APC that remained
adherent had not undergone an antigen-specific CTL interaction." (Appeal
Br. 9; Reply Br. 4.) The Examiner characterizes this as a "statement without
any supporting facts." (Ans. 5.) Although more definitive evidence on this
question would have been welcomed, Appellants' position can be reasonably
inferred from Russell, Abrams, Zagury, and Martz.
Whether these references show that a minority of cells remain
attached following interaction with CTLs is not, however, decisive. Nothing
in the record persuades us that a person of ordinary skill in the art, upon
consideration of Russell, Abrams, Zagury, and Martz, would have
predictably combined the prior art as proposed by the Examiner with a
reasonable expectation of success. The claimed method, read as a whole,
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requires the plurality of adherent recombinant antigen-presenting cells
(APCs) maintain their adherence at different, discrete locations on the array
even after an antigen-specific interaction with a CTL. 15 As confirmed
throughout the Specification, that is the point - otherwise one could not
detect the fluorescent signals present in the APCs and then correlate those
signals with the relevant polynucleotide, polypeptide, and CTL antigen
based on the different, discrete locations of the APCs on the array as in
claim 1. (See, e.g., Spec. i-fi-f 15, 21, 60, 62, 67, 98, 105, 110, 125, 128, Figs.
1-3.) At least Russell and Abrams discourage use of microarrays to test
CTL-APC interaction as claimed because those references teach that most
(potentially all) cells undergoing such an interaction would lose adherence to
the substrate. To conclude otherwise would permit hindsight to override the
objective evidence before us.
For the reasons above, we conclude that the Examiner has not
established by a preponderance of the evidence that claims 1, 2, 6, 7, 24, 25,
and 29-31 are obvious. We thus reverse.
SUMMARY
We reverse the rejections of Claims 1, 2, 6, 7, 24, 25, and 29-31 under
35 U.S.C. § 112, first paragraph, for failing to comply with the written
description requirement.
15 Appellants are in agreement. (Appeal Br. 7 ("in order to identify the CTL
antigen which mediates the antigen-specific CTL-APC interaction, the
recombinant APC must maintain its address by adherence to the array even
after an antigen-specific CTL-APC interaction that results in induction of
caspase activity.")
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We reverse the rejections of Claims 1, 2, 6, 7, 24, 25 and 29-31 under
35 U.S.C. § 103(a) as obvious over van der Bruggen in view of Ziauddin,
Soen, Liu, and Amstad.
REVERSED
14