Ex Parte Albano et al

Patent Trial and Appeal Board

May 4, 2018

12544999 (P.T.A.B. May. 4, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
12/544,999 08/20/2009 Maria S. Albano
45200 7590 05/08/2018
K&L Gates LLP-Orange County
1 Park Plaza
Twelfth Floor
IRVINE, CA 92614
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.
1958427.00132 1463
EXAMINER
GOUGH, TIFFANY MAUREEN
ART UNIT PAPER NUMBER
1651
NOTIFICATION DATE DELIVERY MODE
05/08/2018 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):
uspatentmail@klgates.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte MARIA S. ALBANO,
WILLIAM ROTHMAN, and PABLO RUBINSTEIN
Appeal2017-005178
Application 12/544,999
Technology Center 1600
Before JEFFREYN. FREDMAN, RYAN H. FLAX, and DAVID COTTA,
Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal 1 under 35 U.S.C. § 134 involving claims to a
standardized colony forming unit assay. The Examiner rejected the claims
as obvious. We have jurisdiction under 35 U.S.C. § 6(b ). We affirm.
Statement of the Case
Background
"Umbilical cord blood (CB) is an increasingly accepted graft source"
and the quality of this source for use in grafting is determined by
"enumeration of total nucleated cells (TNC), CD34+ cells, and colony
1 Appellants identify the real party in interest as New York Blood Center,
Inc. (see App. Br. 3).
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Application 12/544,999
forming units (CPU)" because the "number of CPU before and after
freezing/thawing specimens is a strong independent predictor of CB cell
engraftment" (Spec. i-f 3). The Specification explains that currently "the 14
day CPU assay is the only assay that determines the functional state as well
as the number and repopulation capacity of hematopoietic progenitor cells"
but this assay "is time consuming, subjective, difficult to standardize and not
practical when a large number of samples have to be tested daily" because it
"is manually performed by phase contrast light microscopy" and requires
colonies to be classified and manually counted (Spec. i-f 22).
"The present disclosure provides a high throughput system for the
objective, standardized determination of colony forming units (CPU) in
populations of hematopoietic cells using colony staining and high resolution
digital imaging" (Spec. i-f 11 ).
The Claims
Claims 1-7, 11, 13-16, and 19-21 are on appeal. Independent claim 1
is representative and reads as follows:
1. A standardized colony forming unit assay comprising the
steps of:
obtaining a sample of a hematopoietic cell-containing
tissue or fluid;
culturing hematopoietic cells obtained from said sample
in a semi-solid medium which supports growth of
hematopoietic precursor cell colonies;
staining the colonies contained in the semi-solid medium
with 3-[ 4,5-dimethylthiazol-2y 1 ]-2,5-diphenyltetrazolium
bromide (MTT) in a single step without washing;
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imaging the colonies such that an image is obtained
which includes an entire culture dish; and
counting the colonies for multilineage colony forming
units (CFU-GM/E), granulocyte-macrophage colony forming
units (CPU-GM), erythroid colony forming units (CFU-E), and
combinations thereof;
wherein the assay is performed without a microscope.
The Issue
The Examiner rejected claims 1-7, 11, 13-16, and 19-21under35
U.S.C. § 103(a) as obvious over De Kreuk, 2 Velazquez, 3 Horowitz, 4
Putnam, 5 Bernard, 6 and Migliaccio 7 (Final Act. 3-7)8.
2 De Kreuk et al., A Single-Step Colony-Forming Unit Assay for
Unseparated Mobilized Peripheral Blood, Cord Blood, and Bone Marrow,
10 J. HEMATOTHERAPY & STEM CELL RES. 795-806 (2001).
3 Velazquez et al., Cytokine Signaling and Hematopoietic Homeostasis Are
Disrupted in Lnk-deficient Mice, 195 J. Exp. Med. 1599-1611 (2002).
4 Horowitz et al., Colorimetric determination of inhibition of hematopoietic
progenitor cells in soft agar, 244 J. IMMUNOLOGICAL METHODS 49-58
(2000).
5 Putnam et al., Simplified method to automatically count bacterial colony
forming unit, 302 J. IMMUNOLOGICAL METHODS 99-102 (2005).
6 Bernard et al., Model-based automated detection of mammalian cell
colonies, 46 PHYS. MED. BIOL. 3061-72 (2001).
7 Migliaccio et al., Cell dose and speed of engraftment in placental/umbilical
cord blood transplantation: graft progenitor cell content is a better
predictor than nucleated cell quantity, 96 BLOOD 2717-22 (2000).
8 We note the Board may rely on less than all of the references
applied by the Examiner in an obviousness rationale without
designating it as a new ground of rejection. In re Bush, 296 F .2d
491, 496 (CCPA 1961); In re Boyer, 363 F.2d 455, 458 n.2 (CCPA
1966).
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Application 12/544,999
The issue with respect to this rejection is: Does the evidence of
record support the Examiner's conclusion that the ordinary artisan would
have found claim 1 obvious over the cited prior art?
Findings of Fact
1. De Kreuk teaches a "single-step direct plating technique is a
reliable method that significantly decreases variability of the CPU assay for
PB, BM, and CB samples" (De Kreuk 805, col. 1 ).
2. De Kreuk teaches obtaining a hematopoietic cell containing
sample, specifically cord blood (CB) "was obtained from term newborns
after either delivery or elective caesarian section. Twenty to 25 ml of CB
was aspirated from the umbilical vein with a syringe containing 2.5 ml of
3.8% tri-sodium-citrate directly after birth of the placenta" (De Kreuk 796,
col. 1 ).
3. De Kreuk teaches culturing the cells where "the final cell
suspension was added to 1100 µl of CPU culture medium ... plated into 35-
mm petri dishes ... and incubated for 16 days at 37°C" (De Kreuk 796, col.
2).
4. De Kreuk teaches imaging the colonies where "the colonies
were scored under an inverted microscope" (De Kreuk 796, col. 2).
5. De Kreuk teaches counting the colonies where "[c]olony-
forming units-granulocyte-macrophage (CPU-GM) were scored as colonies
consisting of granulocytes and/or macrophages of 20 or more cells" (De
Kreuk 796, col. 2).
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6. The Examiner acknowledges that De Kreuk does "not teach
staining with MTT and imaging the colonies in the absence of a microscope"
(Final Act. 4).
7. Horowitz teaches a "microtiter colorimetric assay was
developed as an alternative to the standard CPU assay to address issues of
subjectivity and throughput inherent to the manual enumeration of CPU by
microscopy" (Horowitz 55, col. 2).
8. Horowitz teaches the "microtiter colorimetric assay described
herein measures MTT conversion after addition to growth factor-stimulated
hematopoietic colonies in soft agar" (Horowitz 55, col. 2).
9. Horowitz teaches in "the colorimetric assay, 50 µg of MTT ...
was added to each well ... Optical density was measured using a Biotek
Instruments EL-312 Biokinetic plate reader" (Horowitz 51, col. 2).
10. Horowitz teaches the "colorimetric assay could be utilized as a
rapid screening assay" and that the "colorimetric readout should also reduce
lab to lab variation seen in the CPU assay with the subjective read out of
colony identification" (Horowitz 57, col. 1 ).
11. Putnam teaches "these colony-counting methods are much
faster than the manual counting method" and that "the long-standing
technical hurdle of efficiently counting colonies has now been eliminated by
using common imaging devices and internet access" (Putnam 102, col. 1-2).
12. Putnam teaches "[t]o obtain images of the Petri dish
reproducibly with a digital camera, an imaging station was made" and the
"jpeg files were ... e-mailed to a remote computer ... The image file was
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opened with the ProtoCOL program, which estimated the number of
bacterial colonies in each spot" (Putnam 100, col. 1-2).
13. Bernard teaches "a novel model-based method for automated
detection of cell colonies" (Bernard 3062).
14. Bernard teaches
a colony-forming ability test is still the most consistent,
relevant and reproducible, especially for cytotoxic studies ....
First, a certain number of cells is plated onto petri dishes where
each cell that remains viable after a certain treatment divides
and eventually gives rise to a colony of daughter cells; second,
the cells are fixed and stained; third, cell colonies are counted;
and finally, the relative survival rate is calculated from the
number of colonies obtained from treated and untreated cells
Counting cell colonies manually is a time-consuming,
eye-straining and tedious task in which consistent objectivity is
hard to achieve. Computer vision methods, which in many
applications have proven to be accurate, reliable, robust and
fast, may overcome the deficiencies of manual counting.
(Bernard 3061-2).
15. Bernard teaches the "automated method gives not only the
number, but also the size and intensity of each colony ... the proposed
method is relatively fast, as it employs optimization to precisely estimate the
model parameters" (Bernard 3071-2).
Principles of Law
When there is a design need or market pressure to solve a
problem and there are a finite number of identified, predictable
solutions, a person of ordinary skill has good reason to pursue
the known options within his or her technical grasp. If this
leads to the anticipated success, it is likely the product not of
innovation but of ordinary skill and common sense. In that
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instance the fact that a combination was obvious to try might
show that it was obvious under § 103.
KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007).
Analysis
We adopt the Examiner's findings of fact and reasoning regarding the
scope and content of the prior art (Final Act. 3-7; FF 1-15) and agree that
the claims are obvious over the cited prior art. We address Appellants'
arguments below.
Appellants separately address each of the references (see App. Br. 10-
14) and contend "none of these references disclose, teach, or suggest a
method of performing a CPU assay and determining the types of CPUs
without a microscope" and "neither Putnam nor Bernard teach or suggest an
actual count of number and types of cell colonies without a microscope as is
currently claimed" (App. Br. 15).
We find this argument unpersuasive because Putnam teaches
"automated detection of cell colonies" (FF 13) and Bernard teaches "the
"automated method gives not only the number, but also the size and intensity
of each colony" (FF 15).
Thus, we agree with the Examiner that the ordinary artisan would
have had reason to improve De Kreuk's manual, microscope based CPU
assay by applying Horowitz's colorimetric MTT dye in the CPU assay in
order to "address issues of subjectivity and throughput inherent to the
manual enumeration of CPU by microscopy" as suggested by Horowitz (FF
7). The ordinary artisan would have had further reason to apply automated
counting of the colonies in the CPU assay as suggested by Putnam because
computerized "colony-counting methods are much faster than the manual
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Application 12/544,999
counting method" (FF 11) and as suggested by Bernard because "[ c ]omputer
vision methods ... have proven to be accurate, reliable, robust and fast" (FF
14 ). Such a combination is merely a "predictable use of prior art elements
according to their established functions." KSR, 550 U.S. at 417.
Appellants contend "[n]one of the prior art references teach or suggest
imaging and counting different types ofhematopoietic colony forming units
without the use of a microscope" (App. Br. 16). Appellants contend: "In
Putnam, pneumococcal colonies were estimated while in Bernard, DC3F
colonies, were estimated; the claimed colony types are not present in
pneumococcal bacteria or in DC3F cells" (App. Br. 16).
We find this argument unpersuasive because it fails to address the
references in combination, but rather attacks each reference individually. De
Kreuk teaches that hematopoietic colonies may be separately counted (FF
5); Horowitz demonstrates that hematopoietic colonies may be stained with
MTT to avoid subjectivity and throughput issues associated with microscopy
(FF 7-8); and Putnam and Bernard teach that colonies may be counted
automatically without a microscope including counting mammalian cells (FF
11-15). It is the combination of these teachings, not any single reference
alone, that renders claim 1 obvious. "Non-obviousness cannot be
established by attacking references individually where the rejection is based
upon the teachings of a combination of references." In re Merck & Co., 800
F.2d 1091, 1097 (Fed. Cir. 1986).
The Examiner reasons
one would expect success in imaging any cell types on a petri
dish including bacterial or mammalian cells using the disclosed
imaging system to obtain digital images for colony counting,
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i.e. one would have a reasonable expectation of successfully
taking a picture of a petri dish no matter what was present in the
dish.
(Final Act. 9). Appellants provide no evidence rebutting this reasonable
expectation of success based on the teachings of Putnam and Bernard (FF
11-15).
Appellants contend "in Horowitz, the CPU and the colorimetric assays
were performed separately from one another and each result was compared
to validate the colorimetric assay while the currently claimed assay and
method incorporate a staining step as part of a CPU assay" (App. Br. 17).
Appellants contend the "Office cannot merely pick and choose amongst the
disclosures of a prior art document using the benefit of hindsight and
combine the disclosures to reconstruct the claimed invention without regard
to the context in which they were used" (Id.). Appellants contend "that the
Office is using the claimed invention as an instruction manual to piece
together the teachings of the prior art so that the claimed invention is
rendered obvious" (App. Br. 18).
We are not persuaded. While we are fully aware that hindsight bias
may plague determinations of obviousness, Graham v. John Deere Co., 383
U.S. 1, 36 (1966), we are also mindful that the Supreme Court has clearly
stated that the "combination of familiar elements according to known
methods is likely to be obvious when it does no more than yield predictable
results." KSR, 550 U.S. at 416.
Here, the Examiner has provided specific reasons based on evidence
disclosed in the prior art for obtaining the obvious combination. In
particular, the Examiner's reason to modify De Kreuk's manual microscopic
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CPU assay with Horowitz's MTT colorimetric assay is "because Horowitz
teaches that MTT can effectively stain hematopoietic colonies and provides
advantages including successful correlation to microscopically counted
colonies and can help reduce lab to lab variation in CPU assays with the
subjective read out of colony identification" (Ans. 13-14; cf FF 10 (the
"colorimetric readout should also reduce lab to lab variation seen in the CPU
assay with the subjective read out of colony identification")).
Similarly, the Examiner reasons that further modification of the assay
rendered obvious by De Kreuk and Horowitz with automatic, non-
microscopic imaging as disclosed by Putnam and Bernard would have been
obvious because "previous colony counting methods such as microscopy are
known in the art to be tedious and have become a technical hurdle, thus,
skilled artisans have opted to use digital imaging systems to overcome these
hurdles and difficulties in colony counting methods" (Ans. 14; cf FF 11
("these colony-counting methods are much faster than the manual counting
method") and FF 15 ("[ c ]omputer vision methods, which in many
applications have proven to be accurate, reliable, robust and fast, may
overcome the deficiencies of manual counting.")).
Thus, the Examiner has provides specific reasons grounded in direct
suggestions by the cited prior art of Horowitz, Putnam, and Bernard for
modifying the CPU assay of De Kreuk to include the MTT colorimetric
assay as well as computer vision colony counting processes (FF 7-15).
Appellants "submit[] there is no reason to combine the cited prior art
references" (App. Br. 19) and "[t]here could not have been a teaching or
suggestion to combine the cited prior art because a person of skill in the art
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would have to have selected a different element from each of the cited
references as an unknown variable and which differed from the other
references, with an unknown expectation of success, and with the prior art
still not disclosing every element of the claim." (App. Br. 20).
We find this argument unpersuasive because, as discussed above, the
Examiner provides specific reasons grounded in direct suggestions by the
cited prior art of Horowitz, Putnam, and Bernard for modifying the CPU
assay of De Kreuk to include the MTT colorimetric assay as well as
computer vision colony counting processes (FF 7-15). We also agree with
the Examiner that the prior art provides a reasonable expectation of success
because "one would have a reasonable expectation of successfully taking a
picture of a petri dish no matter what was present in the dish" (Ans. 10).
"Obviousness does not require absolute predictability of success ... all that
is required is a reasonable expectation of success." In re Kubin, 561 F.3d
1351, 1360 (Fed. Cir. 2009) (citation omitted). Appellants provide no
rebuttal evidence to the Examiner's finding.
Appellants reiterate their arguments regarding teaching or suggestion,
reasonable expectation of success, teaching of the claim limitations, and
reason to combine (see App. Br. 21-22). We remain unpersuaded for the
reasons already given.
Conclusion of Law
The evidence of record supports the Examiner's conclusion that the
ordinary artisan would have found claim 1 obvious over the cited prior art.
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SUMMARY
In summary, we affirm the rejection of claim 1 under 35 U.S.C.
§ 103(a) as obvious over De Kreuk, Velazquez, Horowitz, Putnam, Bernard,
and Migliaccio. Claims 2-7, 11, 13-16, and 19-21 fall with claim 1.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).
AFFIRMED
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