Ex Parte Johnston et al

Patent Trials and Appeals Board

May 3, 2019

13624332 - (D) (P.T.A.B. May. 3, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/624,332 09/21/2012
21971 7590 05/07/2019
WILSON, SONSINI, GOODRICH & ROSATI
650 PAGE MILL ROAD
PALO ALTO, CA 94304-1050
FIRST NAMED INVENTOR
Stephen Albert Johnston
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.
43638-701.401 4051
EXAMINER
BUNKER, AMY M
ART UNIT PAPER NUMBER
1639
NOTIFICATION DATE DELIVERY MODE
05/07/2019 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):
patentdocket@wsgr.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte STEPHEN ALBERT JOHNSTON and PHILLIP STAFFORD
Appeal2019-001721
Application 13/624,332
Technology Center 1600
Before FRANCISCO C. PRATS, ULRIKE W. JENKS, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
JENKS, Administrative Patent Judge.
DECISION ON APPEAL
Appellants 1 submit this appeal under 35 U.S.C. § 134(a) involving
claims directed to an array containing immobilized peptides. Examiner
rejected the claims as lacking written descriptive support, as not being
enabled, for anticipation, and for obviousness. We have jurisdiction under
35 U.S.C. § 6(b). We REVERSE.
1 The Appeal Brief lists the Arizona Board of Regents on behalf of Arizona
State University, the assignee of record, as the real party in interest. Appeal.
Br. 3. We have considered, and herein refer to, the Specification of Dec. 11,
2012 ("Spec."); Final Office Action of Feb. 28, 2018 ("Final Act."); Appeal
Brief of Aug. 27, 2018 ("Appeal Br."); Examiner's Answer of Oct. 17, 2018
("Answer"); Reply Brief of Dec. 17, 2018 ("Reply Br."); and Transcript
from the oral hearing held Apr. 4, 2019 ("Tr.").
Appeal2019-001721
Application 13/624,332
STATEMENT OF THE CASE
Claims 55, 87, 89-91, 94, 95, 98-103, and 112-115 are on appeal,
and can be found in the Claims Appendix of the Appeal Brief. Claim 55,
representative of the claims on appeal, reads as follows:
55. An array to classify one or more states of health,
comprising at least 100,000 different linear, unbranched peptides
of between 10-30 natural amino acids in length, each of said at
least 100,000 different linear, unbranched peptides having a
unique amino acid sequence, each unique amino acid sequence
chosen without regard to the identity of a particular target or
natural ligand to the target, and each of said at least 100,000
different linear, unbranched peptides having a unique amino acid
sequence occupying a distinct feature of the array, wherein each
of said at least 100,000 different linear, unbranched peptides are
immobilized onto a glass or a silicone surface of the array, and
each of said at least 100,000 different linear, unbranched
peptides peptides [sic] contain no cysteine residues with the
optional exception of a terminal amino acid,
wherein each distinct feature of the array comprises at
least two peptides of a same amino acid sequence,
wherein at least 50 of said at least 100,000 different linear,
unbranched peptides have dissociation constants of between 1
mM and 1 µM to at least one antibody in a sample and show a
common pattern of binding for a health state of a patient to
classify the one or more states of health of the patient, the one or
more states of health of the patient including inflammation,
cancer and infection, and
wherein the array does not include synbodies immobilized
on the surface of the array.
Appeal Br. 25 (Claims Appendix)
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Application 13/624,332
The claims stand rejected2 as follows:
I. Claims 55, 87, 89-91, 94, 95, 98-103, and 112-115 under 35 U.S.C.
§ 112, first paragraph, as failing to comply with the written
description requirement.
II. Claims 55, 87, 89-91, 94, 95, 98-103, and 112-115 under 35 U.S.C.
§ 112, first paragraph, because the Specification (1) does not
reasonably provide enablement for all arrays comprising at least
100,000 of all different linear, unbranched peptides, (2) for at least 50
peptide having the recited dissociation constants.
III. Claims 55, 87, 89-91, 95, 98, 101-103, and 112-115 under 35 U.S.C.
§ 102(b) as being anticipated by Kodadek3 as evidenced by Lee. 4
IV. Claims 55, 87, 89-91, 94, 95, 98-103, and 112-115 under 35 U.S.C.
§ I03(a) as unpatentable over Lee in view of Johnston. 5
V. Claims 55, 87, 89-91, 94, 95, 98-103, and 112-115 under 35 U.S.C.
§ I03(a) as unpatentable over Andresen6 and Chu. 7
2 The filing date of the present application is September 21, 2012, which
precedes the America Invents Act (AIA) effective date of March 16, 2013,
therefore, we apply pre-AIA 35 U.S.C. §§ 112, 102, and 103 in this opinion.
See MPEP § 2159 (Rev. 08.2017).
3 Thomas Kodadek, US 2007/0003954 Al, published Jan. 4, 2007
("Kodadek").
4 Frank D. Lee et al., US 2005/0255491 Al, published Nov. 17, 2005
("Lee").
5 Stephen A. Johnston et al., WO 2008/048970 A2, published Apr. 24, 2008
("Johnston").
6 Reiko Andresen and Carsten Grotzinger, Deciphering the Antibodyome -
Peptide Arrays for Serum Antibody Biomarker Diagnostics, 6 CURRENT
PROTEOMICS 1-12 (2009) ("Andresen").
7 Keting Chu, US 2009/0176664 Al, published July 9, 2009 ("Chu").
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Claim Construction
We begin with claim interpretation so we can properly compare the
scope of the claims to the prior art. "During examination, 'claims ... are to
be given their broadest reasonable interpretation consistent with the
specification, and ... claim language should be read in light of the
specification as it would be interpreted by one of ordinary skill in the art."'
In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1364 (Fed. Cir.
2004)(quotingin re Bond, 910 F. 2d. 831,833 (Fed. Cir. 1990)). Therefore,
we first tum to the Specification to interpret the limitations set out in
independent claim 5 5.
(i) Preamble: An array to classify one or more states of health
"If the preamble adds no limitations to those in the body of the claim,
the preamble is not itself a claim limitation and is irrelevant to proper
construction of the claim." IMS Technology, Inc. v. Haas Automation, Inc.,
206 F.3d 1422, 1434 (Fed. Cir. 2000). The preamble in context with the
relevant portion of the body of claim 55 reads as follows:
An array to classify one or more states of health,
wherein at least 50 of said at least 100,000 different linear,
unbranched peptides have dissociation constants of between 1
mM and 1 µM to at least one antibody in a sample and show a
common pattern of binding for a health state of a patient to
classify the one or more states of health of the patient, the one or
more states of health of the patient including inflammation,
cancer and infection.
Appeal Br. 25 (Claims Appendix). Here, the preamble informs us that the
array, a structure, is used to classify states of health. The question is does
the preamble recitation of "classify[ing] one or more states of health" by
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itself limit the claim structurally? See Hewlett-Packard Co. v. Bausch &
Lomb Inc., 909 F.2d 1464, 1468 (Fed. Cir. 1990) ("[A]pparatus claims cover
what a device is, not what a device does."). On this point we agree with
Examiner and do not find that this preamble recitation provides structural
information; instead, we agree that this recitation describes the intended use
of the array. See Ans. 15, 18, 22.
"Where ... a patentee defines a structurally complete invention in the
claim body and uses the preamble only to state a purpose or intended use for
the invention, the preamble is not a claim limitation." Rowe v. Dror, 112
F.3d 473, 478 (Fed. Cir. 1997). As discussed in more detail below (see vii),
the one or more states of health is something that is classifiable by the array
after applying samples to it and comparing results between different
samples. However, it is not itself a structural component of the array.
Accordingly, we find that the preamble informs that the claim is directed to
an array, a structure, but does not provide any other structural information.
(ii) Claim body: comprising at least 100,000 different linear, unbranched
peptides of between 10---30 natural amino acids in length, each of said at
least 100,000 different linear, unbranched peptides having a unique amino
acid sequence
Neither Appellants nor Examiner raise any issues with respect to this
limitation. Accordingly, we find that this limitation references linear
unbranched peptides made up of natural amino acids having a peptide length
between 10-30 amino acids.
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(iii) each unique amino acid sequence chosen without regard to the
identity of a particular target or natural ligand to the target, and each of
said at least 100,000 different linear, unbranched peptides having a unique
amino acid sequence occupying a distinct feature of the array
Examiner has interpreted the term "chosen without regard to the
identity of a particular target or natural ligand to the target" to encompass
"any method of choosing peptide sequences, including computer
generation/selection, mental selection, random selection etc." Ans. 4.
Examiner has interpreted the term "having a unique amino acid sequence" as
referring "to any level of diversity of structure and/or sequence, including
any change in length and/ or structure by one or more amino acids of the
array such as the addition/removal of a protecting group, a single variation, a
single addition, single deletion and/or a single difference in an amino acid or
monomer of the peptide sequence." Ans. 4.
Appellants emphasize that "the disclosure provides for arrays that are
not disease or condition specific." Appeal Br. 13. Specifically, Appellants
contend that the amino acids are chosen without regard to a particular target
or natural ligand. See Ans. 21. In other words, the peptides are chosen and
not selected based on any particular disease epitopes. See Tr. 7-8.
The Specification discloses that the production of the peptide micro
arrays utilizes software. Spec. ,II 40. "A library chosen by random
selection, once selected is of known identity and can be reproduced without
repeating the initial random selection process." Spec. ,r 49. Here, each
peptide sequence in the array was originally randomly selected using
software, however, this does not mean that the peptide located in each
feature (i.e. dot) on the array is unknown.
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Therefore, this limitation is interpreted to refer to the selection of the
unique structure of a peptide that is placed onto the array, that selection must
be random and each randomly selected unique peptide is placed on a distinct
dot ("feature") on the array. That is the random process of selecting a linear,
unbranched peptide of between 10-30 natural amino acids in length is
repeated for each of the 100,000 unique peptides that are placed onto
different dots on the array.
(iv) wherein each of said at least 100,000 different linear, unbranched
peptides are immobilized onto a glass or a silicone surface of the array
The Specification suggests numerous materials that can be used for
the array and these materials include glass and silicone surfaces. Spec. ,r 61.
Therefore, this limitation is interpreted to describe the substrate that receives
the peptides, and the substrate encompasses glass or silicone.
(v) each of said at least 100,000 different linear, unbranched peptides
peptides [sic] contain no cysteine residues with the optional exception of a
terminal amino acid
The Specification provides:
A microarray is prepared by robotically spotting distinct
polypeptides [of20 amino acids in length] on a glass slide having
an aminosilane functionalized surface. Each polypeptide has a
C-terminal glycine-serine-cysteine as the three C-terminal
residues and the remaining ( 1 7) residues determined by a
pseudorandom computational process in which each of the 20
naturally occurring amino acids except cysteine had an equal
probability of being chosen at each position. . . . The
concentration of peptide or other compound determines the
average spacing between peptide molecules within a region of
the array.
Spec. ,r 62.
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Examiner has interpreted the limitation "contain[ s] no cysteine
residues" to "refer to the exclusion of all cysteines in the peptide except for
an optional C-terminal cysteine which provides a point of attachment of the
peptide to the support." Ans. 4. Appellants does not dispute this
interpretation. Therefore, this limitation is interpreted to refer to the amino
acid structures making up the peptides in the array and cysteine, if present, is
only located at the C-terminal position of a peptide.
(vi) wherein each distinct feature of the array comprises at least two
peptides of a same amino acid sequence
Examiner has interpreted the combination of "each of the different
peptides having a unique sequence ... and each of the different peptides
occupying a distinct feature of the array," and "wherein each distinct feature
of the array comprises at least two peptides of the same sequence" to refer to
100,000 different peptides on the array having a unique sequence.
Although the term "feature" is not specifically defined in the
Specification, Appellants contend that this is a term of art and describes the
surface area occupied by a peptide on the array. 8 The Specification explains
8 During oral argument, Appellants counsel clarified that a "feature" is a
term of art in the array field that describes a particular spot on the array that
contains a single attached protein. See Tr. 6: 12-14 ("So a feature is
considered to be a distinct physical space within the array. Within that
feature, you have peptides of the same sequence"); see also Appeal Br. 7
("i.e. each feature of the array is occupied only by molecules of the same
peptide"). Although we do not find a definition in the Specification that
defines "feature," the Specification and the claims reasonably describe that a
feature is referencing a particular area on the array substrate. Compare
claim 55 recitation of "each of said at least 100,000 different linear,
unbranched peptides having a unique amino acid sequence occupying a
distinct feature of the array" with claims 55 recitation "wherein each distinct
feature of the array comprises at least two peptides of a same amino acid
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that "polypeptides are chemically synthesized ... , and then diluted 4: 1 with
phosphate buffered saline prior to spotting [ onto the array substrate]. The
concentration of peptide or other compound determines the average spacing
between peptide molecules within a region of the array." Spec. ,r 62. We
find that the "feature" limitation when read in the context of the claim in
light of the Specification as understood by one of ordinary skill in the art to
describe an area on the array to which the peptide is attached. The
Specification discloses that multiple molecules can be attached to a
particular area of the array. See Spec. ,r 62. The Specification describes that
a particular spot size will have a particular spot area that can then receive a
certain number of peptides within that area. See Spec. ,r 63 ("An exemplary
calculation of spacing is as follows: spot size: 150 µm, spot area: 17 671
µm2, nanoprint deposition volume."). Accordingly, we find that "feature" as
recited in the claims describes a region (i.e., area or dot) on the array that
can bind a particular compound. The limitation, therefore, is interpreted to
be referencing an area on the array surface to which multiple peptides
having the same amino acid sequence are attached.
sequence;" see also Spec. ,r 62 ("The polypeptides are chemically
synthesized, dissolved in dimethyl formamide ... , and then diluted 4: 1 with
phosphate buffered saline prior to spotting [the peptide onto the array
surface]. The concentration of peptide or other compound determines the
average spacing between peptide molecules within a region of the array.").
Accordingly, we find that "feature" as recited in the claims reasonably
describes a particular surface area (i.e. dot) on the array.
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(vii) wherein at least 5 0 of said at least 100,000 different linear,
unbranched peptides have dissociation constants of between 1 mM and 1 µM
to at least one antibody in a sample and show a common pattern of binding
for a health state of a patient to classify the one or more states of health of
the patient, the one or more states of health of the patient including
inflammation, cancer and infection.
Examiner, in the Answer, parses this limitation into two phrases that
each need interpretation. For the art rejection, Examiner interprets the part
of the limitation requiring the ability of 50 or more unbranched peptides
exhibiting the claimed dissociation constant to at least one antibody to
classify the one or more states of health as being an intended use limitation
(see Ans. 33). For the enablement rejection, Examiner interprets the part of
the limitation regarding the fact that at least 50 of said at least 100,000
different linear, unbranched peptides have dissociation constants of between
1 mM and 1 µM to at least one antibody in a sample to require recitation of
the structures of the peptides that are placed onto the support. We address
these interpretations below:
(a) to determine dissociation constants of antibody in a sample
requires knowledge of the peptide structure
For the enablement rejection, Examiner takes the position that in order
to satisfy this particular claim limitation the Appellants must "provide
adequate description of such core structure and function related to that core
structure such that the Artisan could determine the desired effect." Ans. 6-
7. Examiner specifically points out that the Specification does not provide
any dissociation constants for any peptides. See Ans. 7. Examiner therefore
questions whether an array containing 100,000 different linear peptides
would contain sequences that meet the recited dissociation constant to at
least one antibody. See Ans. 8. Examiner's position is that unless you
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disclose the structures of peptides that are put onto the array it would not be
possible to determine whether "all samples from all patients, in all
combinations" contain antibodies that would meet the recited dissociation
constant.
At the oral hearing, Appellants council explained that when 100,000
different peptides are printed onto an array substrate where the peptide
density at every one of the features does not exceed 6 nm, any serum sample
is expected to contain at least one antibody that would bind to at least 50 of
the immobilized different peptides within the recited low binding constant
range. 9 There is an expectation that at least 50 spots would inherently meet
the recited dissociation constants in an array having 100,000 different
peptide features provided the high local concentration of peptide in each
9 During oral argument, Appellants' counsel explained that when you have
an array of 100,000 peptides within the size range claimed there is an
expectation that at least 50 of those peptides will bind to an antibody from a
patient sample at the recited low affinity. See Tr. 14 ("when you have
enough peptides, and here, the enough peptides is the 100,000 different
linear unbranched peptides, and it's also the amino acid length of the
peptides themselves ... The applicants know that they're going to have
peptides that are not going to bind as strong to the antibody, but it [still]
gives valuable information. It's something that the inventors needed to have
in order to be able to discriminate the diseases."). This interpretation is
reasonably supported in the Specification. See Spec. ,r 74; see also ,r
45("The number of compounds is a balance between two factors. The more
compounds, the more likely an array to include members having detectable
affinity for any target of interest. . . . Therefore, a relatively small number of
peptides can provide a good representation of total sequence space, and
include members capable of specific albeit low affinity interactions with a
wide variety of targets. For example, 500-25,000 random peptides can
cover evenly the entire shape space of an immune system (107 to 108
antibodies in humans).").
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feature is a defined as explained in the Specification. See Tr. 14. For
purposes of this appeal, we determine that the recited binding dissociation
limitation imparts a structural requirement to the array. That requirement is
a spacing limitation at each distinct feature of the at least two peptides,
namely the at least two peptides must be spaced apart from each other at a
mean average spacing of no greater than 6 nm. See Spec. ,r 55.
(b) classifying the one or more states of health of the patient is an
intended use limitation
The Specification explains that a state of health is determined by
comparing "binding profiles of normal volunteers, Breast Cancer patients,
and patients at risk of breast cancer who clinically have had a second,
different primary tumor following an initial remission of Breast Cancer."
Spec. ,r 27 ( citing Figure 7). "For example, the binding profile can be
compared with binding profiles known to be associated with different
diseases or stages of diseases or lack of diseases .... Remarkably, the same
array can generate different and informative profiles with many different
samples representing different disease states, disease stages, lack of disease
and the like." Spec. ,r 43. "Another application lies in analyzing samples
from vaccinated patients to determine whether an adequate protective
immune response is developing. The pattern of response in one patient can
be compared, for example, with a patient who has been naturally infected
with the pathogen and survived, a similarity of response pattern indicating
the patient is likely to survive and a dissimilarity that the patient will get
worse or die at least in the absence of alternate treatment." Spec. ,r 77.
In other words, in order to determine a patient's state of health, the
Specification explains that this requires making a comparison between at
least two samples. The samples could encompass different patient
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populations, e.g., normal healthy patients versus those suspected of having a
disease; it could also encompass a comparison between samples taken from
the same patient at different points in time (i.e. before or after vaccination to
determine if there is an immune response). Thus, for an array to "classify
one or more states of health" requires a process step that compares the
results between different samples using at least two arrays side-by-side.
Because the limitation of "classify[ing] one or more states of health" as
recited in the claim refers to the way the array is used, we agree with the
Examiner that this limitation is directed to the use of the array and does not
affect the structure of how the peptides are attached to each distinct feature
of the array. See above fn. 8.
(viii) wherein the array does not include synbodies immobilized on the
surface of the array
The Specification provides that "arrays can include other compounds
known to bind particular targets, such as proteins, in a sample. These
compounds can be antibodies, synbodies or peptides among others." Spec.
,r 64. This limitation is interpreted to specifically exclude one particular
type of compound, namely synbodies, from the array.
Conclusion
Based on the interpretation of each limitation as discussed above, the
array as recited in claim 55 has the following structural limitations:
(1) contains at least 100,000 distinct features (i.e. dots or areas) to which
peptides are attached on the substrate; (2) each feature contains a peptide of
only a single sequence structure and it is a different amino acid sequence
from every other feature; (3) the peptides are immobilized onto a glass or
silicone substrate; ( 4) the peptide does not contain cysteine residues with the
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exception of terminal cysteine used to attach the peptide to the substrate; ( 5)
the peptides are linear unbranched peptides; ( 6) each feature contains at least
two peptides having the same amino acid sequence; (7) because the array
must have at least 50 of the peptides meet the recited dissociation constant if
contacted with a patient sample, the mean average space between the
peptides in a single feature is 6 nm or less; and (8) the array does not contain
synbodies.
I. Written Description
Examiner finds that the claims contain subject matter that is not
described in the Specification in such a way that it would reasonably convey
that one skilled in the art would understand that inventor had possession of
the claimed invention. Ans. 5-6. Specifically, Examiner finds that adequate
description requires providing "core structure [information] and function
related to that core structure" so that one of ordinary skill could determine
that the array has the desired effect. Ans. 6-7. Examiner notes that
Appellants working example only disclose an array with peptide
concentrations of 1 mg/ml and having only 10,000 peptides, with no
dissociation constants disclosed, and undisclosed peptides. See Ans. 7.
Examiner cites Balboni, 10 Gao, 11 Andresen, and Hilpert 12 as evidence "that
not all microarrays comprising all random peptides having any structures
10 Balboni et al., Multiplexed Protein Array Platforms for Analysis of
Autoimmune Diseases, 24 ANNU. REV. IMMUNOL. 391--418
(2006)("Balbone").
11 Gao et al., High density peptide microarrays. In situ synthesis and
applications, 8 MOLECULAR DIVERSITY 177-187 (2004)("Gao").
12 Hilpert et al., Cellulose-bound Peptide Arrays: Preparation and
Applications, 24 BIOTECH. GENETIC ENG. REV. 31-106 (2007)("Hilpert").
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and/or all concentrations will function to bind at least one of all antibodies in
all samples from all patients, such that all states of health in all patients can
be classified." Ans. 8. Because of the limited information in the
Specification, Examiner finds that the written descriptive support is not
sufficient to convey that inventor was in possession of arrays having
100,000 peptides attached. See Ans. 9.
Appellants direct our attention to the various experimental protocols
disclosed in the Specification. Specifically, citing example 3 which shows
the use of the arrays with "samples from about 200 cancer patients having
various kinds of cancer including glioma, sarcoma, and pancreatic clustered
together." Appeal Br. 12. Appellants direct our attention to the various
examples that show different binding patterns with patients having different
states of health. Appeal Br. 12-13 (citing examples 3, 5, and 6, as well as
figures 5 and 6). Appellants contend that "the disclosure provides for arrays
that are not disease or condition specific." Appeal Br. 13.
We find Appellants have the better position. As discussed in the
claim construction section above, the array as recited in claim 55 is directed
to a structure that (1) contains at least 100,000 distinct features (i.e. dots or
areas) to which peptides are attached on the substrate; (2) each feature
contains a peptide of only a single sequence structure and it is a different
amino acid sequence from every other feature; (3) the peptides are
immobilized onto a glass or silicone substrate; ( 4) the peptides do not
contain cysteine residues with the exception of terminal cysteine used to
attach the peptide to the substrate; ( 5) the peptides are linear unbranched
peptides; ( 6) each feature contains at least two peptides having the same
amino acid sequence; (7) because the array must have at least 50 peptides
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that meet the recited dissociation constant if contacted with a patient sample,
the mean average space between the peptides in a single feature is 6 nm or
less; and (8) the array does not contain synbodies. In other words, the
claims are directed to a product - an array - with specific structural features
including with regard to (a) the total number of dots on the array, (b) the
types of peptides that are printed on those dots, and thus, the number of
different peptides printed on the array, ( c) how many such peptides are
printed within a dot, and ( d) the spacing of the peptides within the dot.
Examiner's written description rejection, however, is directed to the
functioning and use of the array rather than to the structure of the array as
claimed. The rejection questions whether the array can achieve the binding
constants as recited when the array is in use. See Ans. 7 ("no dissociation
constants were provided"). Examiner relies on Hilpert as evidencing the
difficulty of finding the right concentration for attaching peptides to a slide.
Hilpert teaches that when peptides are attached to the array at a high density
this can cause difficulties in assessing interaction with the molecule of
interest. Hilpert 34. Even if packing peptides onto a substrate at a high
density can have a negative effect on the functional interaction with a
specific antibody, this does not raise doubt that the peptide can be
successfully attached to the array substrate. Examiner also questions
whether an array with random peptides can function to bind at least one
antibody in all samples. Ans. 8.
Examiner acknowledges that the Specification provides attaching
10,000 peptides that are 20 residues in length onto a glass slide. See Ans. 7.
It is not clear, however, why Examiner would doubt that one of ordinary
skill in the art could not attach more peptides, for example 90,000 more
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peptides onto the array, or that one of ordinary skill could attach peptides
that are 30 amino acids in length instead of the 20 amino acid length as
disclosed in the Specification.
To the extent that there might be a concern by the Examiner that one
of ordinary would not be able to replicate a particular array, the
Specification explains that software was utilized to provide random
sequences for the first 1 7 positions ( where the amino acids were chosen
from 19 naturally occurring amino acids and not including cysteine) of a 20-
residue peptide and having the three carboxy terminal amino acids glycine-
serine-cysteine as the carboxy-terminus linker. Spec. ,r 140. The
Specification further explains that "[a] library chosen by random selection,
once selected is of known identity and can be reproduced without repeating
the initial random selection process." Spec. ,r 49. In other words, the
random aspect of the array is only in the initial selection of the unique
peptides that are applied to each dot. Thus, each dot in the array contains a
peptide whose structure is known in order to re-produce the array. See Spec.
,r,r 49, 62.
Examiner contends that "it is not known whether an array of 100,000
different linear, unbranched peptides of 10 amino acids in length will bind to
the same antibodies to produce the same common pattern of binding as a
different array of 100,000 different, linear unbranched peptides of 30 amino
acids in length, such that all states of health are classified in samples from all
subjects." Ans. 26. It appears that the Examiner's rejection interprets that
each array slide is different. Here, the Specification is clear that the random
aspect of the peptide is only with respect to the selection of the initial
peptide. See Spec. ,r,r 49, 62, 140. Once the peptide has been randomly
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generated by the computer, it is then produced so that it can be printed onto
a slide, and the peptide is known and thereby the slide can be reproduced
without needing to repeat the random selection process. See Spec. ,r 49.
Thus, the Specification is not contemplating using different randomly
created slides in order to determine a state of health in a patient but, instead,
is using slides that are identical for comparison between a patient and a
healthy cohort or a patient sample over time to determine a state of health.
The evidence of record does not support Examiner's position that the
written descriptive support provided in the Specification is insufficient to
describe the full scope of the array as presently claimed. Accordingly, we
reverse the written description rejection.
II. Enablement
Examiner finds that the Specification does not reasonably provide
enablement for all arrays comprising at least 100,000 of different linear
unbranched peptides having a unique sequence. Ans. 9-10. Examiner finds
that undue experimentation would be required in order to determine
dissociation constants for at least 50 of the 100,000 different linear
sequences. Ans. 13. Examiner finds that the Specification teaches 10,000
random peptides spotted onto glass slides, and there is no indication that an
array with 100,000 different peptides would produce the same result. See id.
at 27.
Appellants contend that the Specification provides ample guidance in
pre-synthesizing peptides that are then spotted onto an array. See Appeal Br.
14. Appellants contend that the disclosure specifies various methods to
determine the relative binding of the sample to the array. Id.
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It is not clear from Examiner's enablement rejection whether
Examiner questions the ability to bind 100,000 peptides onto an array
support surface or whether Examiner questions the binding constant of
peptides that are part of the array. Either way, we are not persuaded by
Examiner's position. We agree with Appellants that the Specification
provides ample guidance with respect to the manufacture and classifying
multiple conditions using an array. Appeal Br. 14 (citing Spec. ,r,r 51-64,
98-1-1, 0121, and 122); see Reply Br. 12. As Appellants point out "the
specification describes that peptides can be pre-synthesized and spotted onto
an array." Spec. ,r 51. The issue appears to be that Examiner doubts that a
random set of peptides provided on an array with the required structural
features noted above would bind at least one antibody in a sample at the
recited binding affinity.
The Specification explains that "the same array can generate different
and informative profiles with many different samples representing different
disease states, disease stages, lack of disease and the like." Spec. ,r 43. The
Specification explains that the binding profile of a sample is compared "with
binding profiles known to be associated with different diseases or stages of
diseases or lack of diseases." Spec. ,r 43. In this case, the same array is used
to compare a binding profile from a patient with known samples. It is the
comparison to the known sample that allows for determination of a disease
state.
Dissociation constants of between 1 mM and 1 µM to at least one
antibody as presently claimed are considered low affinity binding events.
See Spec. ,r 43. Appellants direct our attention to Dr. Woodbury's
declaration that describes that "[i]t was surprising to us that the array format
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of the claims captured informative lower affinity binding events." See
Woodbury Dec. 13 ,r 7. During oral argument Appellants' counsel explained
that by placing 100,000 different peptides of the claimed amino acid length
onto an array surface each on a different one of a 100,000 spots, and also
having more than one identically structured peptide in that same spot at a
certain maximal mean average distance and exposing that surface to a serum
sample, it would be expected that at least 50 of the dots would bind at least
one antibody from the sample at the low dissociation constant of between 1
mM and 1 µM. See above fn 8. In other words, an array that contains
100,000 randomly select peptides would be expected to have at least 50
peptides that react with at least one antibody from any patient sample at a
dissociation between 1 mM and 1 µM. See Spec. ,r 93 (Example 1 ( citing
Figure 1, and Figure 12), noting that this phenomena occurs when even just
10,000 different peptides of the claimed amino acid length were used).
Different binding patterns of monoclonal and polyclonal antibodies to
different peptides is also observed with these arrays, and many antibodies
bind more than one peptide on the array. See Spec. ,r,r 32, 93, 94 (citing
Figures 11 and 12).
The evidence of record does not support Examiner's position that the
Specification fails to provide an enabling disclosure for the scope of the
claims as presented. Accordingly, we reverse the enablement rejection.
III. Anticipation by Kodadek
Examiner finds that Kodadek teaches an array containing synthetic
molecules. Ans. 14--16. "Kodadek teaches that a robotic spotter is used to
13 Declaration by Dr. Neal Woodbury signed June 7, 2016 ("Woodbury
Dec.").
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print the molecules onto the chemically modified glass slide ( corresponding
to glass surface; and spotting onto an array, claim 96) (paragraph [0043],
lines 6-8)." Ans. 15. "Kodadek [also] teaches that the peptides can be
synthesized on a solid support in accordance with conventional techniques
(corresponding to being synthesized onto the surface) (paragraph [0075],
lines 3-5)." Id.
Appellants argue that not every element of the claimed invention is
disclosed by the reference (Appeal Br. 15), that "the peptides [in Kodadek]
are chosen with regard to the identity of a particular target pathway, disease
or organism" (id. at 15), and that Kodadek disavowed the use of a peptide
array (id. at 16).
In an anticipation rejection, "it is not enough that the prior art
reference ... includes multiple, distinct teachings that [ an ordinary] artisan
might somehow combine to achieve the claimed invention." Net MoneyIN,
Inc. v. VeriSign, Inc., 545 F.3d 1359, 1371 (Fed. Cir. 2008). To anticipate,
Kodadek would need to "clearly and unequivocally" disclose a composition
meeting all the limitations of the claims. In re Arkley, 455 F.2d 586, 587
(CCP A 1972). That requirement does not mean that the claimed invention
must be described in Kodadek in ipsissimis verbis, In re Schaumann, 572
F .2d 312, 317 (CCP A 1978), but the description in Kodedek must be
"sufficient to put the public in possession of the invention." In re LeGrice,
301 F.2d 929, 933 (CCPA 1962). That is not the case here.
Kodadek teaches a method of constructing an array to "provide a
platform for the determination of 'immune signatures.' This refers to the
pattern of binding of antibodies or T cells to an array of synthetic
compounds." Kodadek ,r 22. Kodadek teaches that the pattern of binding
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can be predictive of a disease state or it can differentiate between disease
states. Id. ,r 14. The method includes:
(a) constructing an array of synthetic molecules having a
plurality of structures; (b) contacting said array with a complex
biological mixture obtained from animals or cells that exhibit a
physiological state of interest, resulting in the capture of certain
biological molecules or cells by certain molecules immobilized
on the array; ( c) assessing binding of certain captured molecules
or cells to this array through the use of a labeled reagent that
binds specifically to a given class of captured molecules or
proteins; and ( d) comparison of this binding pattern with the
binding pattern of an appropriate control sample that does not
represent the physiological state of interest.
Kodadek ,r 11.
Kodadek teaches that the binding elements may be synthetic peptides
or peptoids. Id. ,r 73. Peptides range in length from about 6 up to about 35
to 50 amino acids polypeptide(s), proteins. Id. ,r 75. Kodadek teaches that
one or more binding elements can be immobilized on the support surface,
and can range in number from 2-100,000 different sensing elements. Id. ,r
66. Kodadek teaches that the binding elements are immobilized on supports
including for example: glass (e.g., a chemically-modified glass slide), latex,
plastic, membranes, microtiter, wells, mass spectrometer plates, beads ( e.g.,
cross-linked polymer beads) or the like. Id. ,r 87. Kodadek teaches using a
"C-terminal cysteine residue ... to facilitate coupling to the array surface."
Id. i-fl33.
We do not agree with Appellants that Kodadek does not encompass
peptides that are chosen without regard to the target. Appeal Br. 15. Here,
Kodadek teaches that "a ligand may be wholly random, partially random,
biased or non-biased." Kodadek. ,r 65. A ligand that is randomly generated
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would reasonably meet the limitation of "chosen without regard to the
identity of a particular target" as claimed.
We also do not agree with Appellants that the prosecution history of
Kodadek disavowed the use of a peptide array. Appeal Br. 16. The excerpt
cited by Appellants are directed to the prosecution of different claims and at
best establish that peptides and peptoids are structurally different molecules.
Identifying structural differences between peptides and peptoids that may
affect their binding to antibodies is not a disavowal of the use of peptides on
an array.
We do, however, agree with Appellants that Kodadek does not
disclose every limitation of the claims. Specifically, Kodadek does not
affirmatively teach excluding cysteine residues in all positions but the
terminal C-terminal residue. Kodadek suggests that "[a] C-terminal cysteine
residue was included in each molecule to facilitate coupling to the array
surface." Kodadek ,r 133. A teaching that the C-terminal residue was
included for the purpose of attaching the peptide to a substrate may render
the exclusion of cysteine residues in other parts of the molecule obvious for
purposes of controlling the attachment of the peptide to the slide but it does
not necessarily and inevitably indicate Kodadek teaches excluding cysteine
from other parts of the peptide. In fact, we note that Kodadek contemplates
synthesizing peptide on a solid support, as such excluding incorporating
cysteine into such peptides at positions other than the link to the solid
support is not a necessity. See Kodadek ,r 75; see Transcript 22 ("Unless
you're adding on and you're doing in situ chemistry" then you could have
cysteine incorporated into the peptide). The evidence of record does not
support the position that Kodadek excludes cysteine residues from all but the
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terminal amino acid and thereby anticipates claim 55. Accordingly, we
reverse the rejection of claim 55 and any of it depends. 14
IV. Obviousness over Lee and Johnston
Examiner finds that Lee teaches an array containing a collection of
polypeptide analytes generated by fragmentation of a protein in order to
generate peptides that are 5-30 amino acids in length. Ans. 17. Lee
"teach[ es] a method of characterizing a plurality of candidate antibodies for
binding affinity." Id. at 18. Examiner finds that Lee's arrays can comprise
up to 100,000 distinct locations. Id. at 17. Examiner acknowledges that Lee
does not teach amino acids omithine and norleucine. Id. at 19. Examiner
relies on the teachings of Johnston for teaching "synthetic amino acids [that]
include ornithine and norleucine to convey special properties." Id.
Appellants contend that "Lee's array includes all possible amino acids
within the peptide sequences, including cysteine." Appeal Br. 18.
Appellants contend that the structure disclosed in Johnson is directed to
synbodies - a structure specifically excluded by the claims. Id. at 17.
On this record we find Appellants have the better position.
"[E]xaminer bears the initial burden, on review of the prior art or on any
other ground, of presenting a prima facie case of unpatentability." In re
Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992). In satisfying this initial
burden, "[i]t is impermissible to use the claimed invention as an instruction
14 We also agree with Appellants position (see Appeal Br. 16) that the
Examiner has not sufficiently established that Kodadek even if viewed in
combination with Lee discloses the average spacing of the peptides as being
1--4 nm apart as recited in claims 99 and 100.
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manual or 'template' to piece together the teachings of the prior art so that
the claimed invention is rendered obvious." In re Fritch, 972 F.2d 1260,
1266 (Fed. Cir. 1992). Stated differently, to establish obviousness, there
must be "an apparent reason to combine the known elements in the fashion"
recited in the claims. KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,418
(2007).
Lee creates arrays from fragmentation of larger proteins; hence, the
arrays would include peptides containing cysteine in other locations. See
Lee ,r,r 129, 166, 168; see Appeal Br. 18. Johnston teaches spotting between
500-1,000,000 test polypeptides that are 20 amino acids long onto a slide.
Johnston 18: 15-16. Johnston teaches that "the polypeptides can be attached
to the surface through the C-terminus. The sequence of the polypeptides
was generated randomly from 19 amino acids, excluding cysteine." Id.
18: 16-18. However, as Appellants point out Johnston's arrays are directed
at synthetic antibodies a structure that is specifically excluded from the
present claims. Reply Br. 17. Thus, "Johnston fails to cure deficiencies of
Lee at least because Johnston also fails to teach arrays constructed with
different linear, unbranched peptides of between 10-3 0 natural amino acids
in length occupying a distinct feature of the array." Id. at 18; see Appeal Br.
18-19.
Here, Examiner's prima facie case is premised on finding that Lee
teaches all the limitations recited in claim 55, and is only relying on Johnson
for teaching the synthetic amino acids omithine and norleucine as recited in
claim 94. See Ans. 17-19. Examiner in the Answer changes the rejection
and now directs our attention to Johnson's teaching as encompassing arrays
that contain randomly generated sequences of 19 amino acids, specifically
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excluding cysteine, and using a pseudorandom computational process to
arrive at the various peptides. See Ans. 31. Examiner however has not
explained how or why one of ordinary skill in the art would go from Lee's
arrays derived from fragmentation of proteins (Lee ,r,r 45, 49, 115, 126, 140,
221, 243, 315, 317) that would contain cysteine to using Johnston's protocol
of creating an array. Johnston 18: 12-26. Specifically, Examiner has not
explained why one of ordinary skill in the art would use only part of
Johnston's protocol to create synthetic peptides, i.e., the part of creating the
linear peptide, and omit the creation of the synbody as taught in Johnston.
In other words, just because the reference could possibly be dissected to
contain individual elements that could be combined to arrive at the present
claims does not mean that the Examiner has provided a sufficiently
articulated rationale to do so. A rejection for obviousness must include
"articulated reasoning with some rational underpinning to support the legal
conclusion." KSR Int'! Co. v. Teleflex Inc., 550 U.S. at 418, quoting In re
Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006).
Because Examiner has not provided adequate evidence in conjunction
with sound technical reasoning to establish that one of ordinary skill would
arrive at the array as claimed based on the combined teaching of Lee and
Johnston, we reverse the rejection under 35 U.S.C. ,r 103.
V. Obviousness over Andresen and Chu
Examiner finds that Andresen teaches analysis of antibodies from
human serum. Ans. 20. Examiner finds that Andresen also teaches
synthetic peptide arrays in varying density formats, having peptides between
8-13 amino acids in length that can be used to fingerprint circulating
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antibodies. Id. at 20-21. Examiner acknowledges that Andresen "do[es] not
teach wherein each distinct feature of the array comprises at least two
peptides of the same sequence (instant claim 55, in part); or the synthetic
amino acids omithine or norleucine (instant claim 94); or where the sample
is cerebrospinal fluid (instant claim 115)." Ans. 23. Examiner relies on Chu
for teaching ultra-high density arrays for high throughput screening.
Ans. 24. Examiner finds that Chu teaches "artificial peptides can include
randomly synthesized peptides; and peptide arrays with random peptide
sequences (corresponding to random peptides) (paragraphs [0095], lines 5-7;
and [0129])." Ans. 37.
Appellants contend that neither Andresen nor Chu disclose arrays
with targets that are not preselected (Appeal Br. 20), and that Chu's
substrates are selected form a peptidase database that contain cysteine
residues (id. at 21 ).
Andresen teaches peptide arrays including describing various ways of
covalent and non-covalent site-specific immobilization of peptide. Andresen
4 (see Figure 2). Andresen teaches that "short synthetic peptides can be
used as probes to specifically detect antibodies from complex biological
fluid." Id. at 5. Andresen teaches "peptide arrays for the identification of
antibody reactivities by using a relatively small library of 5520 random
peptides to identify epitopes of four monoclonal antibodies." Id.
Chu teaches that enzymatic substrates include "artificial peptides[,]
can include randomly synthesized peptides, peptides designed based on
physiological substrates, and peptides designed based on the structure or
known binding of enzymes. In some embodiments, the peptide array can be
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a mix of artificial and physiological substrates." Chu ,r 95. Chu teaches that
protease substrates are disclosed in peptide databases. Id. ,r 101.
On this record, we find Appellants have the better position. Examiner
has not directed us to teachings in the combination of Andersen and Chu that
would lead us to conclude that the peptide arrays disclosed in these
references necessarily omit cysteine from the peptides in their array.
Examiner has not articulated any other rationale explaining how the
combination of references discloses an array that does not contain cysteine
as claimed. Accordingly, we are constrained to reverse the rejection that
relies on the combination of Andresen and Chu.
SUMMARY
We reverse the rejection of all claims on all grounds.
REVERSED
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