Ex Parte Nakas et al

Board of Patent Appeals and Interferences

Sep 9, 2010

10528923 (B.P.A.I. Sep. 9, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
___________________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________________

Ex parte JAMES P. NAKAS,
STUART W. TANENBAUM,
and
THOMAS KEENAN,
Appellants1
____________________

Appeal 2010-000356
Application 10/528,923
Technology Center 1600
____________________

Before ERIC GRIMES, CAROL A. SPIEGEL, and
MELANIE L. MCCOLLUM, Administrative Patent Judges.

SPIEGEL, Administrative Patent Judge.

DECISION ON APPEAL2

1 The real party in interest is the RESEARCH FOUNDATION OF THE
STATE UNIVERSITY OF NEW YORK. (Brief of Appellant filed 15 April
2009 ("Br.") at 1). This decision also cites to the Examiner's Answer mailed
10 July 2009 ("Ans.").
2 The two-month period for filing an appeal or commencing a civil action, as
recited in 37 C.F.R. § 1.304, or for filing a request for rehearing, as recited
in 37 C.F.R. § 41.52, begins to run from the "MAIL DATE" (paper delivery
mode) or the "NOTIFICATION DATE" (electronic delivery mode) shown
on the PTOL-90A cover letter attached to this decision.
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Appellants appeal under 35 U.S.C. § 134(a) from an Examiner's final
rejection of claims 1, 3-7, 9, and 18. Claims 10-17, the only other pending
claims, stand withdrawn from consideration as directed to a non-elected
invention. We have jurisdiction under 35 U.S.C. § 134. We AFFIRM.
I. Statement of the Case
The subject matter on appeal is directed to a method of producing
polyhydroxyalkonates ("PHAs") by bacterial fermentation using xylose and
levulinic acid ("LA") as primary and secondary carbon sources, respectively.
Claims 1 and 9 are illustrative and read (Br. 8-9, emphasis added):
1. A process for producing a
polyhydroxyalkonate (PHA) co-polymer
comprising 3-OH-valeryl (3-HV) and 3-OH-
butyryl (3-HB) monomers which comprises
adding to a medium containing a
microorganism that converts carbon to PHA a
quantity of xylose as a primary carbon source and
a first quantity of levulinic acid as a secondary
carbon source;
adding a second quantity of levulinic acid to
the medium between about 16 hours and about
24 hours after the first quantity of levulinic acid
is added,
wherein the second quantity of levulinic
acid is greater than the first quantity of levulinic
acid.

9. The process of claim 1 in which the ratio of
xylose to levulinic acid in the medium after the
second quantity of levulinic acid is added ranges
from about 0.01 to about 1.0.

The Examiner rejected claim 9 as confusing under 35 U.S.C. § 112,
second paragraph, and claims 1, 3-7, 9, and 18 as obvious under 35 U.S.C. §
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103(a) over the combined teachings of Lee,3 Ramsay,4 Bertrand,5 Chung,6
and Jang7 (Ans. 3-8).8
As to the rejection of claim 9 under § 112, second paragraph, the
Examiner stated in the Final Rejection that
Claim 9 is confusing in the recitation of "the ratio
of xylose to levulinic acid in the medium after the
second addition of levulinic acid is from about
0.01 to 1.0" … It would appear that this should
recite the ratio of levulinic acid to xylose. This
rejection has been previously presented as an
objection since it appeared to be simply a
typographical error but as applicant has twice not
corrected the problem it is now made a rejection as

3 Sang Yup Lee, Poly(3-hydroxybutyrate) production from xylose by
recombinant Escherichia coli, 18 BIOPROCESS ENGINEERING 397-399 (1998)
("Lee").
4 Ramsay et al., Hemicellulose as a potential substrate for production of
poly(ß-hydroxyalkanoates), 41 (Suppl. 1) CANADIAN JOURNAL OF
MICROBIOLOGY 262-266 (1995) ("Ramsay").
5 Bertrand et al., Biosynthesis of Poly-ß-Hydroxyalkanoates from Pentoses by
Pseudomonas pseudoflava, 56 APPLIED AND ENVIRONMENTAL
MICROBIOLOGY 3133-3138 (October 1990) ("Bertrand").
6 Chung et al., Effect of Levulinic Acid on the Production of Poly(3-
hydroxybutyrate-co-3-hydroxyvalerate) by Ralstonia eutropha KHB-8862,
39 THE JOURNAL OF MICROBIOLOGY 79-82 (March 2001) ("Chung").
7 J.-H. Jang and P.L. Rogers, Effect of Levulinic Acid on Cell Growth and
Poly-ß-hydroxyalkanoate Production by Alcaligenes SP. SH-69, 18
BIOTECHNOLOGY LETTERS 219-224 (February 1996) ("Jang").
8 The Examiner entered a claim amendment filed with Appellants' Brief
which overcame the rejection of claims 1, 3-7, 9, and 18 under 35 U.S.C. §
112, second paragraph, set forth on pages 3-4 of the Office action mailed 16
January 2009 (Final Rejection or "FR"), but not the rejection of claim 9 set
forth on pages 4-5 (Ans. 3-4). To the extent Appellants may not have
appreciated that the latter rejection of claim 9 was maintained, Appellants
had the opportunity to file a Reply Brief in response to the Examiner's
Answer. No Reply Brief was filed.
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applicants [sic] lack of correction imply this is not
the case. [FR 4-5.].

Since Appellants have not requested review of this rejection (Br. 3),
we summarily sustain the rejection of claim 9 as unpatentable under 35
U.S.C. § 112, second paragraph.
As to the obviousness rejection, Appellants argue that the applied
prior art fails to teach or suggest adding a second quantity of LA in an
amount greater than the first quantity subsequent to the first quantity as
claimed (Br. 6). Appellants further argue Chung explicitly teaches away
from the claimed subject matter by maintaining the level of LA at a constant
amount (id.). Thus, Appellants contend that there is no reason to combine or
modify the teachings of the applied prior art based on either the prior art or
ordinary knowledge in the art (id. at 7).
Therefore, the dispositive issue is whether the evidence of record
supports a conclusion that it would have been obvious to one of ordinary
skill in the art to add a second, larger quantity of LA subsequent to the first
quantity in a fermentation process for producing a PHA copolymer as
claimed.
II. Findings of Fact
The following findings of fact ("FF") are supported by a
preponderance of the evidence of record.
[1] Chung teaches that
Poly-ß-hydroxyalkanoates (PHAs), a family of
polyesters produced by a variety of
microorganisms, have … potential application as
biodegradable and biocompatible thermoplastics.
In particular, a copolyester consisting of 3-
hydroxybutyrate (3HB) and 3-hydroxyvalerate
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(3HV) … has been of the greatest commercial
interest since this polyester exhibits a considerable
range of thermomechanical properties, which
depend on its 3HV content. Production of
poly(3HB-co-3HV) is usually achieved by
providing bacteria with a cosubstrate, such as
propionate and valerate, along with a main carbon
source. … [Chung 79, ¶ 1, endnotes omitted.]

[2] According to Bertrand, "the accumulation of the polymer is triggered
by limitation of a nutrient such as oxygen or nitrogen", e.g., after
about 15 to 20 hours of culture (Bertrand 3133, ¶ 2, endnotes omitted;
Fig. 2).
[3] Further according to Bertrand, poly(3HB-co-3HV) can be produced
by adding propionic acid and glucose to nitrogen-limited cultures of
Alcaligenes eutrophus (id. at ¶ 3) and that PHA production cost
largely depends on the carbon source used (id. at ¶ 4).
[4] Thus, replacing the traditional carbon sources with an inexpensive
substrate could significantly reduce production cost (id.).
[5] Bertrand teaches that when Pseudomonas pseudoflava was grown on
xylose, an inexpensive hemicellulosic sugar, as the sole carbon
source, the specific growth and poly(3-hydroxybutyrate) ("PHB")
production rate was four times slower than with glucose but the final
PHB content was similar to that measured for the glucose
fermentation (id. at 3133, ¶ 4; 3135, ¶ 3; Fig. 2; 3137, ¶¶ 3-4).
[6] Similarly, Ramsay teaches that Pseudomonas cepacia can use xylose
to produce PHAs (Ramsay abstract).
[7] According to Ramsay, "[w]hen grown on xylose, P. cepacia exhibited
similar behaviour to that on hexoses [e.g., glucose or fructose] with no
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detectable PHB accumulated until the NH4+ concentration had fallen
to less than 0.18 g·L-1 (Fig. 1)," in approximately 20 hours (id. at 264,
last full sentence; Fig. 1).
[8] Ramsay concluded that use of xylose as the main carbon source would
reduce the substrate cost by more than half compared to glucose to a
level comparable to that of molasses (id. at 265, last ¶).
[9] Lee teaches using a recombinant Escherchia coli bacteria transformed
with the A. eutrophus PHA biosynthesis genes to produce PHA,
specifically PHB, from xylose (Lee abstract).
[10] Jang discloses a two stage continuous culture with controlled
substrates feeding wherein Alcaligenes sp. SH-69 was cultured in the
first stage with glucose, followed by supplementing the glucose with
LA in the second stage (Jang 220, ¶ 5).
[11] "Depletion of nitrogen source in the medium in the second stage
fermentation in the presence of excess carbon was allowed to occur …
[in view of previous reports] that these conditions would enhance
accumulation of PHA" (id. at 223, ¶ 1).
[12] Jang concludes not only that LA can be used as a precursor of 3HV,
but also that LA has a larger stimulatory effect on PHA synthesis than
propionic acid (id. at 222, ¶ 2; 224 ¶ 2).
[13] Jang also concludes that the composition and concentration of the
copolymer can be manipulated by varying the LA/glucose ratio in the
feed to the second stage, thereby producing biopolymers with a range
of characteristics (id. at 224, ¶ 2).
[14] Similarly, Chung teaches that "… LA is a better cosubstrate for cell
growth as well as for poly(3HB-co-3HV) production than the
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conventionally used cosubstrates such as propionate and valerate"
(Chung 81, ¶ 1).
[15] Both Jang and Chung teach that relatively low concentrations of
cosubstrates inhibit bacterial growth (Jang 219, ¶ 1; Chung 80, ¶ 5).
[16] Chung also teaches that adding LA repeatedly into a fermentor culture
to maintain its concentration resulted in significantly higher
copolyester content and 3HV yield than when the same concentration
of LA was supplied all at once (id. abstract; 81, ¶ 3).
[17] "However, in the case of repeated addition of LA, the final 3HV
mol% in the copolyester decreased to 28 mol%, which was due to the
remarkable increase of cell and PHA content during the cultivation"
(id.).
III. Discussion
A. Legal principles
"The consistent criterion for determination of obviousness is whether
the prior art would have suggested to one of ordinary skill in the art that this
process should be carried out and would have a reasonable likelihood of
success, viewed in the light of the prior art." In re Dow Chem. Co., 837 F.2d
469, 473 (Fed. Cir. 1988). In determining whether obviousness is
established by combining the teachings of the prior art, "the test is what the
combined teachings of the references would have suggested to those of
ordinary skill in the art." In re Keller, 642 F.2d 413, 425 (CCPA 1981).
Furthermore, the "[obviousness] analysis need not seek out precise teachings
directed to the specific subject matter of the challenged claim, for a court
can take account of the inferences and creative steps that a person of
ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 550
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U.S. 398, 418 (2007). A person of ordinary skill must be presumed to have
some skill, In re Sovish, 769 F.2d 738, 743 (Fed. Cir. 1985), and ordinary
creativity, KSR, 550 U.S. at 418.
"A reference may be said to teach away 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).
B. Analysis
Bertrand, Ramsay, and Lee all teach using xylose as a primary carbon
source (substrate) for bacterial production of PHAs (FF 5, 6, 9). Bertrand
and Ramsay also teach that accumulation of PHAs is triggered by decreased
nitrogen content in the culture media at about 15 to 20 hours (FF 2, 7).
Bertrand and Ramsay expressly teach that xylose is a cost effective
alternative to conventional substrates, e.g., glucose (FF 3-5, 8). Jang and
Chung both teach that LA is a better cosubstrate than conventionally used
substrates, e.g., propionate and valerate, for production of a PHA copolymer
of great commercial interest because of its range of thermochemical
properties, poly(3HB-co-3HV) (FF 1, 12, 14). Chung also teaches that
adding LA to the bacterial fermentation culture over time results in a
significantly higher copolyester content and 3HV yield (FF 16). Both
Chung and Jang teach that the ratio of 3HV to 3HB in the copolymer can be
modulated by adjusting the ratio of primary and secondary carbon sources
(FF 13, 17). Both Chung and Jang teach that relatively low levels of
cosubstrates inhibit bacterial growth (FF 15). However, Chung suggests that
when LA is repeatedly added over time to maintain a constant LA level
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(rather than adding the same amount of LA all at once), the final 3HV and
copolyester concentrations decrease due to increased cell and PHA content
during the cultivation (FF 17).
Thus, it would have been obvious to one of ordinary skill in the art to
produce poly(3HB-co-3HV) by bacterial fermentation using xylose as the
primary carbon source (Bertrand, Ramsay, Lee) because it is cheaper than
other conventionally used substrates of 3HB (Bertrand, Ramsay) and LA as
a secondary carbon source of 3HV (Jang and Chung). It would have been
further obvious to add a small amount of LA initially followed by a larger
amount about 16 to 24 hours later to minimize inhibition of bacterial growth
in the first stage of fermentation (Jang and Chung) and to stimulate PHA
production in the second stage of production and/or provide a desired level
of 3HV for producing a copolymer with desired thermochemical properties
(Jang and Chung). Appellants' arguments do not persuade us otherwise.
The Examiner has provided sound reasoning for combining the
teachings of the references, i.e., xylose is a cheap primary carbon source, LA
is a more effective cosubstrate than propionate or valerate, and adjusting the
amount of LA added in the first and second fermentation stages to maximize
PHA production (Ans. 8-10). We also note that Chung teaches that, in the
case of repeated addition of LA, the final 3HV mol% in the copolyester
decreased to 28 mol% (FF 17); and, both Jang and Chung teach that the
relative ratio of cosubstrate/primary carbon source is a result effective
variable vis-à-vis the composition of the resulting copolymer (FF 13, 17).
Finally, Appellants' argument that Chung teaches away by maintaining a
constant level of LA during fermentation is not persuasive. Chung suggests
that it is undesirable to add the total amount of LA as a single, initial
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addition. Chung does not say that it is undesirable to add increasing
amounts of LA over time or that this approach will not work, and so does
not teach away. Gurley, 27 F.3d at 553. Silence cannot be interpreted as a
teaching away.
C. Conclusion
We will sustain the rejection of claims 1, 3-7, 9, and 18 as obvious
under § 103(a) over Bertrand, Ramsay, Lee, Jang, and Chung. The evidence
of record supports a conclusion that it would have been obvious to a skilled
artisan to add a second, larger quantity of LA subsequent to the first quantity
in a fermentation process for producing a PHA copolymer as claimed.
IV. Order
Upon consideration of the record, and for the reasons given, it is
ORDERED that the decision of the Examiner to reject claim 9 as
unpatentable under 35 U.S.C. § 112, second paragraph, is AFFIRMED;
FURTHER ORDERED that the decision of the Examiner to reject
claims 1, 3-7, 9, and 18 as obvious under 35 U.S.C. § 103(a) over the
combined teachings of Lee, Ramsay, Bertrand, Chung, and Jang is
AFFIRMED; and,
FURTHER ORDERED that no time period for taking any subsequent
action in connection with this appeal may be extended under 37 C.F.R. §
1.136(a)(1)(vi).
AFFIRMED

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