Ex Parte Jia et al

Board of Patent Appeals and Interferences

Mar 23, 2009

10185758 (B.P.A.I. Mar. 23, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte QI JIA and MEI-FENG HONG
__________

Appeal 2009-1630
Application 10/185,758
Technology Center 1600
__________

Decided:1March 23, 2009
__________

Before ERIC GRIMES, RICHARD M. LEBOVITZ, and STEPHEN
WALSH, Administrative Patent Judges.

WALSH, Administrative Patent Judge.

DECISION ON APPEAL

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, begins to run from the decided date
shown on this page of the decision. The time period does not run from the
Mail Date (paper delivery) or Notification Date (electronic delivery).
Appeal 2009-1630
Application 10/185,758

This is an appeal under 35 U.S.C. § 134 involving patent application
claims to a method of separating natural product extracts into a “library” of
fractions. The Examiner rejected the claims as obvious. We have
jurisdiction under 35 U.S.C. § 6(b). We affirm.
STATEMENT OF THE CASE
The invention relates to a method aimed at discovering novel
therapeutic, nutraceutical and cosmetic agents. (Spec. 10:8-9.) The process
starts with a natural product extract from any natural source (animal,
vegetable, mineral, microbial or other). (Id. at 14-17.) The claimed method
separates the natural product extract into fractions, screens the fractions for
biological activity, and dereplicates the active fractions. Dereplicating refers
to recognizing the known and novel compounds among the fractions. (Id. at
20:13-17.)
Claims 2, 3, 15-18, 20, 26, 30, 33-37, 45, 46, 48, 51, 52, 60-67 and
70-75, which are all the pending claims, are on appeal.
The Examiner rejected the claims as follows:
• claims 2, 3, 15-18, 20, 26, 30, 33-37, 45, 46, 48, 51, 52, 60-67, and 70-75
under 35 U.S.C. § 103(a) as obvious over the combination of Strege2 and
Hook;3 and

2 Mark A. Strege, High-performance liquid chromatographic-electrospray
ionization mass spectrometric analyses for the integration of natural
products with modern high-throughput screening, 725 J. Chromat. B 67-78
(1999).
3 Derek J. Hook, Edward J. Pack, Joseph J. Yacobucci, and Jeffrey Guss,
Approaches to Automating the Dereplication of Bioactive Natural
Products—The Key Step in High Throughput Screening of Bioactive
Materials From Natural Sources, 2 J. Biomol. Screen. 145-52 (1997).
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• claims 2, 3, 15-18, 20, 26, 30, 33-37, 45, 46, 48, 51, 52, 60-67, and 70-75
under 35 U.S.C. §103(a) as obvious over the combination of Rosell4 and
Castor.5
The claims subject to each rejection have not been argued separately
and therefore stand or fall together. 37 C.F.R. § 41.37(c)(1)(vii). Claims 72
and 73 are representative and read as follows:
72. A method for generating a high throughput (HTP) fractionation
library comprising the steps of:

(a) separating in parallel and HTP mode natural product extracts;
wherein an amount of 100-2000 mg is separated per extract;

(b) collecting at least 88-96 fractions from each of said extracts;

(c) screening each fraction against multiple biological screening
targets to determine the biological activity of each fraction with
respect to each target; and

(d) dereplicating the biologically active fractions to identify a
component profile for each active fraction.

73. The method of claim 72 wherein said natural product extracts are
prepared by extracting a sample using a two solvent system extraction
procedure, wherein said two solvent system extraction procedure is
comprised of extracting with an organic solvent, followed by
extracting with an aqueous solvent.

4 Sune Rosell, A New effective Means of bioprospecting Entire Rain
Forests can be Screened at the Laboratory, 94 Läkartidningen 4938-41
(1997).
5 U.S. Patent No. 5,750,709, issued to Trevor P. Castor, May 12, 1998.
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OBVIOUSNESS
Principles of Law
A patent may not be obtained . . . if the differences between the
subject matter sought to be patented and the prior art are such
that the subject matter as a whole would have been obvious at
the time the invention was made to a person having ordinary
skill in the art to which said subject matter pertains.

35 U.S.C. § 103(a).
Obviousness is a question of law based on fact findings. The scope
and content of the prior art are determined; differences between the prior art
and the claims at issue are ascertained; the level of skill in the art is resolved;
and objective record evidence of nonobviousness is considered. Graham v.
John Deere Co., 383 U.S. 1, 17-18 (1966). Against that background, the
obviousness or nonobviousness of the subject matter is determined. Id.; In
re Kahn, 441 F.3d 977, 985 (Fed. Cir. 2006).
The determination of obviousness is made with respect to the subject
matter as a whole, not separate pieces of the claim. See KSR Int’l Co. v.
Teleflex Inc., 550 U.S. 398, ___, 127 S. Ct. 1727, 1734 (2007). “The
combination of familiar elements according to known methods is likely to be
obvious when it does no more than yield predictable results. . . . [I]f a
technique has been used to improve one device, and a person of ordinary
skill in the art would recognize that it would improve similar devices in the
same way, using the technique is obvious unless its actual application is
beyond his or her skill.” KSR, 550 U.S. at ___, 127 S. Ct. at 1739-40.
“It is axiomatic that, in proceedings before the PTO, claims in an
application are to be given their broadest reasonable interpretation consistent
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with the specification, . . . and that 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 Bond, 910 F.2d 831, 833 (Fed. Cir. 1990). Prior art references
may be “indicative of what all those skilled in the art generally believe a
certain term means ... [and] can often help to demonstrate how a disputed
term is used by those skilled in the art.” Vitronics Corp. v. Conceptronic,
Inc., 90 F.3d 1576, 1584 (Fed. Cir. 1996).

Issues
The Rejection Based on Strege and Hook
The Examiner found that Strege taught that biological samples were
analytically characterized with various kinds of high performance liquid
chromatography in a process labeled “high throughput screening” or “HTS.”
(Ans. 5-6.) The Examiner found that Appellants’ claims differ from Strege’s
process “in that [Appellants’ step (d) specifies] identifying a component
profile for each active fraction which may require some sort of database.”
(Ans. 6.) However, the Examiner found that Hook taught analyzing natural
product extracts with a process similar to Strege’s, and Hook also taught
identification and biological profiling of the bioactive compounds in the
fractions obtained. (Id.) The Examiner concluded that it would have been
obvious to one of ordinary skill in the art at the time to apply Hook’s
identification and biological profiling in place of Strege’s activity analysis
because both aimed at identifying the active fractions. (Id. at 6.)
Appellants contend that Strege merely described the conventional
preparation of a single extract but did not disclose or suggest generating an
extract library. (App. Br. 7.) Their own method is said to differ from
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Strege’s by using “high throughput fractionation (HTP)” rather than Strege’s
high throughput screening (HTS). (Id.) According to Appellants, Hook
“does not cure this defect.”
The issues with respect to this rejection are:
Is there is a difference between Strege’s extraction, purification, and
collection steps and steps (a) through (c) in claim 72?; and
Would it have been obvious to adopt Hook’s identification and
biological profiling in place of Strege’s activity analysis step?

The Rejection Based on Rosell and Castor
Focusing on dependent claim 73, the Examiner found that Rosell’s
method of screening natural products differed from Appellants’ by not
disclosing a two solvent extraction procedure and reverse phase
chromatography. (Ans. 7-8.) Castor taught how to extract and isolate
naturally occurring therapeutic compositions using extraction and
chromatography, and specifically taught using a two solvent extraction
system and reverse phase chromatography. (Id. at 8.) The Examiner
concluded that one of ordinary skill in the art at the time would have found it
obvious to use Castor’s steps in Rosell’s process because one would select
known extraction and chromatographic procedures for their expected results.
(Id.)
Appellants argue that Rosell’s term “high throughput screening” is
different from “high throughput purification.” (App. Br. 9.) They argue that
Rosell offered no solution to the problem of false positive hits. (App. Br.
10.) They argue that Castor teaches away from extraction with organic
solvents. (App. Br. 11.)
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Appellants’ issue for this rejection is: Whether Rosell’s high
throughput screening is different from the claimed high throughput process?
A second issue is: Whether Rosell and Castor combined teach or
suggest all elements of the claimed process?

Findings of Fact
Strege
1. According to the Strege review article, “[t]he goal of a contemporary
natural products HTS [high throughput screening] program is to
rapidly identify novel biologically active chemical structures which
can be developed as pharmaceutical compounds, an objective highly
dependent upon analytical chemistry methodology.” (70:left col.)
2. Strege showed a flowchart overview of a drug discovery program for
analyzing natural product samples with high throughput screening and
dereplication. (69:Fig. 1)
3. Strege explained that dereplication referred to identifying compounds
already known, so that novel “hits” could be further studied. (69:left
col.)
4. Strege’s review “focus[ed] on the influence HPLC-ESI-MS [high
performance liquid chromatography with electrospray ionization mass
spectrometry detection] has had upon the effective integration of
natural products with HTS and drug discovery.” (70:left col.)
5. Strege reported that HPLC-ESI-MS had been used to analyze for
compounds present in a variety of natural products, in which the
extracts for chromatography were typically prepared by solid-liquid or
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liquid-liquid extraction, and Strege listed a number of examples of
fractionation done on plant extract examples. (70-72.)
6. According to Strege, the HPLC-ESI-MS “method proved useful for
the detection of both previously reported and novel molecules [i.e.,
dereplication] during a search for bioactive compounds, and
facilitated focused identification of selected compounds targeted for
re-isolation and biological evaluation.” (70:right col.)
7. The chromatography methods Strege reported on included reverse
phase and normal phase. (72:right col.-73:left col.)
8. According to Strege, the dereplication process has great impact by
focusing resources on extracts that have a high probability of
containing novel compounds. (74.)
9. Strege’s Fig. 4 illustrated the fractionation stream of an HPLC
purification divided into three parallel parts to facilitate dereplication.
(74:left col.-75:left col.)
10. Strege’s Fig. 5 is said to be a reproduction of data from analysis of a
fermentation broth sample as reported in Ref. 29, “Tandem Mass
Spectrometry in Natural Products Discovery.” (76: left col.; figure
legend.) Fig. 5B showed a “biological assay signal plotted vs. fraction
number for a series of fractions collected during the separation.” (Id.)
The plot in Fig. 5B appears to show four fractions collected per
minute for more than 20 minutes (totaling about 91 fractions as
estimated by counting the fraction lines), and that each fraction was
assayed for activity. (Id.)

Hook
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11. Hook reviewed “[t]he effective use of automated procedures and
databases in the isolation, identification and biological profiling of
bioactive compounds.” (Abstract.)
12. Hook emphasized the importance of dereplication in a section entitled
“Why do we need dereplication and why do we need to improve it?”
(146-47.)
13. Hook disclosed re-assay of HPLC [high performance liquid
chromatography] fractions. (147:left col.)
14. Hook developed an automated HPLC dereplication and fractionation
system to improve the process. (147:right col.)
15. Hook described sample extraction before HPLC. (147:right col.)
16. According to Hook, automated fraction collectors can use more than
one fractionation microplate, but single-plate manual operation is
usual; 96-well microplates are used to collect the fractions. (148-49.)

Rosell
17. Rosell disclosed that chemical analysis of natural product extracts,
robotic handling, molecular biology and data manipulation were used
in high throughput screening to purify active herbal substances from
plants by fractionation (e.g., “bioassay-guided fractional procedures”),
steps that correspond to steps (a), (b) and (c) in claim 72. (pp. 1-3.)
18. Rosell did not describe dereplicating biologically active fractions.

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Castor
19. Castor described methods and apparatus for extracting and purifying
therapeutic compounds from source material including plants, marine
life-forms, animals, and other biomass. (Col. 1, ll. 11-17.)
20. Castor collected fractions and analyzed them for activity, but did not
describe dereplicating biologically active fractions.

Analysis
The claimed method starts at steps (a) and (b) with a natural product
extract, separating it and collecting the separated fractions. Although not
recited in the claim, separation can typically be by chromatography. In steps
(c) and (d), the method screens the fractions for activity and identifies the
fractions containing already known components (dereplication). Strege and
Hook both reviewed prior art methods of generating high throughput
fractionation libraries from natural product extracts. We agree with the
Examiner that both references teach steps (a), (b) and (c); and that Hook’s
dereplication step is the same as step (d).
Strege and Hook both reviewed methods in use for preparing natural
product extracts to be separated into active fractions. (FF2; FF11.) Both
reviewed the methods then in use for fractionating the extracts with
chromatography. (FF4-5; FF13-14.) Both included a description of
collecting the fractions. (FF5, 9, 10; FF14.) Both reviewed various methods
used to screen the fractions for biological activity. (FF6; FF13.) Both
reviewed the importance of dereplicating the active fractions. (FF8; FF14.)
Both touted the advantages of the high throughput methods then in use.
(FF1; FF2.)
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We interpret “fractionation library” as recited in claim 72 to mean the
collection of fractions generated by fractionation. Strege and Hook both
surveyed a variety of chromatographic techniques for fractionating natural
product extracts. In their reports, the fractions collected after passage of
extracts through chromatography columns constituted fractionation libraries.
We find no difference between the collections of fractions that Strege and
Hook describe and the fractionation library of claim 72.
Appellants argue that claim 72 uses a “novel high throughput
fractionation method of purification.” (App. Br. 5.) Step (a) is the only step
that can be construed as a “purification” step. We do not agree that step (a)
is novel. Step (a) simply recites “separating in parallel and HTP mode,” and
the preamble defines HTP as simply the acronym for “high throughput.” As
both references taught high throughput chromatography for generating
fractionation libraries from natural product extracts, we find nothing novel in
step (a). See, e.g., Strege 69, Fig. 1 (showing a flow chart with HTS
representing both fractionation and screening.) Appellants refer to the
Specification at page 21, lines 16-19 for a definition of “high throughput
purification” as “a method designed to simultaneously perform multiple
column separations.” However, the claim does not use the phrase “high
throughput purification.” “During patent examination the pending claims
must be interpreted as broadly as their terms reasonably allow.” In re Zletz,
893 F.2d 319, 321 (Fed. Cir. 1989). We decline to change the preamble’s
definition of HTP from “high throughput” to “high throughput purification.”
We also decline to narrow the claim by importing “simultaneous multiple
column separations” from the specification into the claim. Phillips v. AWH
Corp., 415 F.3d 1303, 1323 (Fed.Cir.2005) (en banc) (limitations are not
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imported from the specification into the claims, and it is improper to confine
the claims to embodiments in the specification). Strege and Hook both
disclosed column chromatography, i.e., purification. Strege disclosed
separating the fractions in parallel mode to facilitate dereplication. (FF9.)
Strege and Hook both used the term “high throughput” as descriptive of the
fractionation and screening methods they described. We interpret “HTP” in
Appellants’ step (a) to mean the same thing that Strege and Hook meant.
Vitronics, 90 F.3d at 1584. We find that the claim does not distinguish over
the chromatographic purification techniques that Strege and Hook disclosed
for fractionating natural product extracts.
Appellants argue that claim 72 is “a method to generate natural
product libraries themselves,” but that in contrast Strege starts with a natural
product library to be analyzed and then uses high throughput screening to
identify individual compounds. (App. Br. 7.) Relabelling claim 72 as a
method to generate a natural product library does not distinguish the prior
art. A fractionation process that starts with natural product extracts yields
natural products in the fractions. Step (a) requires natural product extracts as
the starting material. According to step (b), a natural product extract is
separated into “at least 88-96 fractions.” The fractions collected contain
compounds or mixtures of compounds which are also fairly labeled “natural
products.” See Spec. 20:11-12 (“fractions that contain a single or a mixture
of natural products”). Strege and Hook described the same process, and
when applied to a starting material containing more than one natural
product, would result in a library of fractions containing different natural
products. Even if Strege or Hook chose their natural products for extraction
from a natural product library (i.e., a collection of natural products), the
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claim simply requires natural product extracts, without limitation as to
source. Like Appellants’ fractions, Strege’s or Hook’s fractions contained
single or a mixture of natural products. We find that the fractionation
library, or fraction collection, that claim 72 generates is not distinguished
from prior art fractionation libraries or collections that were generated by
separating natural product extracts into fractions as reviewed in Strege or
Hook.
Appellants argue that the quantity of material that can be fractionated
by the claimed method is “incomparable” to other methods available in that
it allows for the collection of up to 96 individual fractions. (App. Br. 6.)
The Examiner found there is no criticality associated with the amount of
extract to be fractionated (Ans. 11), and Appellants do not dispute that
finding. Appellants provide no evidence that collecting up to 96 fractions
means “incomparable” results. Hook discussed the commercially available
96-well collection plates typically used to collect fractions. (FF16.) Strege
also described collecting multiple fractions. (FF10.) We do not find a
factual basis to conclude that separating any amount of extract into at least
88-96 fractions is “incomparable” to the prior art, because that is what was
reported in the prior art.
Appellants argue that Strege “merely describes the conventional
preparation of a single extract from a natural product source.” (App. Br. 7.)
Claim 72 recites nothing about extract preparation, and is open to the use of
conventionally prepared extracts. Step (a) in claim 72 assumes the existence
of any kind of natural product extracts, whether prepared from a fresh
specimen, prepared after selection from a natural products library, or
selected from a previously prepared library of extracts. The evidence
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contradicts Appellants’ assessment that Strege described merely a single
extract. Strege reviewed numerous articles that reported the preparation of
numerous different natural product extracts which were then fractionated by
chromatography into fractions that were collected and screened for
biological activity. (FF5.) Nor did Strege advise fractionating merely a
single extract. See Strege 69 (Fig. 1, showing as a first step the selection of
a library, i.e. multiple extracts, for analysis). Strege reported that crude plant
extracts yielded acetogenins; plant extracts yielded paclitaxel and related
diterpenoids; kava roots yielded cavalactones and flavokavains; Salvia plant
material yielded aldose reductase (Strege 70-72); and a set of 88 crude
fungal extracts were fractionated (Strege 73-74, Fig. 3). Claim 73 requires
an organic then aqueous extraction in sequence. The Examiner pointed to
Strege’s reports of aqueous and organic mobile phases for chromatography
and the diversity of samples studied. (Ans. 5-6.) Strege taught both reverse
phase and normal phase chromatography. (FF7.) We agree with the
Examiner that a two solvent extraction would have been obvious as a
preparation for subjecting a sample to the kinds of chromatography that
Strege reported.
Appellants argue that Strege teaches away from the claimed method
by “emphasizing the use of crude chemical libraries that have not been
fractionated in any manner.” (App. Br. 8.) First, Strege’s emphasis was on
natural product fractionation, not crude chemicals. E.g., Strege 68 (“natural
products (i.e. samples of biological origin) are believed to present the
greatest source of chemical diversity on the earth.”) Second, claim 72 does
not recite starting with something that has been “fractionated in any
manner.” Strege reviewed a variety of prior art references that separated the
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same kind of natural product extracts recited in the claim. (FF5.) Finally,
Strege did not teach away from the claimed method. A prior art reference is
said to teach away from an applicant’s invention “when a person of ordinary
skill, upon reading the reference, would be discouraged from following the
path set out in the reference, or would be led in a direction divergent from
the path that was taken by the applicant.” In re Gurley, 27 F.3d 551, 553
(Fed. Cir. 1994). Rather than leading those in the art in a direction divergent
from Appellants’ path, Strege advocated the fractionation of natural product
extracts. A review article reporting a variety of successes in fractionating a
variety of natural product extracts into a variety of fractionation libraries
does not discourage those of skill in the art from repeating the work
disclosed, applying the teachings, or combining the teachings with other
references. “The prior art’s mere disclosure of more than one alternative
does not constitute a teaching away from any of these alternatives because
such disclosure does not criticize, discredit, or otherwise discourage the
solution claimed.” In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004).
We note Appellants’ comments on the problem of preventing or
minimizing “false negative results,” the enrichment of “minor active
components in the plant extracts,” and the problem of synergistic effects and
non-specific interference. (App. Br. 6-7.) These concerns are not based on
express claim language, nor do Appellants explain how these concerns are
related to the prima facie case of obviousness. We are not persuaded of
Examiner error because the prior art, taken together, teaches all the elements
of claim 72. It is undisputed that Hook’s dereplication method meets step
(d). The Examiner’s finding of motivation to improve Strege’s dereplication
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method with Hook’s improvements to dereplication is supported by the
evidence, and Appellants do not dispute it.
Similarly, Appellants’ comment about extracts prepared with organic
solvent and with aqueous solvent (App. Br. 8), is not persuasive of error
because, as pointed out by the Examiner, Strege teaches on page 70, column
1, last paragraph, the use of volatile buffers and aqueous/organic mobile
phases (Ans. 5), and thus the extraction procedure of claim 73 would have
been commensurate with the exercise of conventional skill in the art.

The Rejection over Rosell and Castor
The Examiner found that Rosell taught separating natural product
extracts, collecting fractions, and screening the fractions, which accounted
for steps (a), (b), and (c) of the claimed method. (Ans. 7-8.) According to
the Examiner there was only one difference between Rosell’s method and
the claims: a two solvent extraction procedure and reverse phase
chromatography. (Ans. 8.) The Examiner found Castor taught those
procedures in high throughput purification of natural product extracts, and
concluded the claimed method would have been obvious. (Id.)
Appellants argue that the references did not teach a two-step extract
preparation comprising organic then aqueous solvent extraction. (App. Br.
10.) The Examiner cited Castor’s chromatographic procedures as teaching a
two solvent extraction system. (Ans. 8.) It is not clear that Castor
performed a two-solvent extraction and then submitted the extract to
separation as required by the claims. Appellants also argue that Rosell does
not recognize the problem of “false positive hits.” (App. Br. 10.)
Appellants do not explain how this “problem” is addressed by the claim, but
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it appears to be related to dereplication. Claim 72 includes step (d),
dereplicating biologically active fractions. The Examiner did not point to a
dereplicating step in Rosell or Castor, nor did the Examiner address how a
dereplicating step would have been an obvious addition to the fractionation
method of the two references. We do not find dereplicating discussed in
either reference. (FF18, FF20.) We conclude that the Office did not
establish a prima facie case of obviousness over Rosell and Castor, because
the Office’s case did not account for every step in the claimed method.

CONCLUSIONS OF LAW
There is no difference between Strege’s natural product extract
purification and collection steps generating a fractionation library and
Appellants’ steps (a) through (c);
one of skill in the art at the time of the invention would have been
motiovated to modify Strege’s dereplication step with Hook’s dereplication
method because Hook described it as improved; and
the combined teachings of Rosell and Castor do not suggest all the
steps of claim 72 because they do not address dereplication step (d).

SUMMARY
We the affirm rejection of claims 2, 3, 15-18, 20, 26, 30, 33-37, 45,
46, 48, 51, 52, 60-67 and 70-75 under 35 U.S.C. § 103(a) as obvious over
the combination of Strege and Hook; and
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we reverse the rejection of claims 2, 3, 15-18, 20, 26, 30, 33-37, 45,
46, 48, 51, 52, 60-67 and 70-75 under 35 U.S.C. §103(a) as obvious over the
combination of Rosell and Castor.

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

Ssc:

SWANSON & BRATSCHUN, L.L.C.
8210 SOUTHPARK TERRACE
LITTLETON, CO 80120
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