Ex Parte Ingvoldstad

Board of Patent Appeals and Interferences

Feb 28, 2012

12566038 (B.P.A.I. Feb. 28, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte ODD EINAR INGVOLDSTAD
__________

Appeal 2012-000663
Application 12/566,038
Technology Center 1600
__________

Before DONALD E. ADAMS, LORA M. GREEN, and
JACQUELINE WRIGHT BONILLA, Administrative Patent Judges.

BONILLA, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving a claim directed to
a process for crystallizing a non-ionic X-ray contrast agent. The Examiner
has rejected the claim as obvious. We have jurisdiction under 35 U.S.C.
§ 6(b). We affirm.
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STATEMENT OF THE CASE
Claim 1 is the only claim on appeal. Claim 1 reads as follows
(emphasis added):
1. A process for crystallizing 5-amino-N, N'-bis(2,3-
dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide
(Compound B) to increase its crystallization yield comprising the
steps:
(a) reacting 5-amino-N,N' -bis-(2,3-dihydroxypropyl)
isophthalamide with iodine chloride in an aqueous medium to form a
crude product comprising Compound B;
(b) quenching excess iodine chloride from step (a) with sodium
bisulphate and forming low molecular weight salts;
(c) crystallizing Compound B from said crude product by
adding seeds of Compound B to form a crystallization suspension
comprising said Compound B and said low molecular weight salts;
(d) filtering the mother liquor of said crystallization suspension
of step (c) through a nanomembrane whereby said Compound B is
retained on the retentate side of the nanomembrane while said low
molecular weight salts pass through the nanomembrane;
(e) returning the retentate containing enriched concentration
of Compound B to said crystallization suspension of step (c); and
(f) repeating steps (d) and (e).
Claim 1 stands rejected under 35 U.S.C. § 103(a) as being obvious
over the combined teachings of Thieking et al (U.S. Pat. No. 6,137,006,
issued Oct. 24, 2000), Viscardi et al. (U.S. Pat. No. 5,447,635, issued Sep. 5,
1995), and Cervenka et al. (U.S. Publ. No. 2008/0214867 A1, Sep. 4, 2008).

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Issue
Issues regarding claim 1 are (1) whether it would have been prima
facie obvious to one of skill in the art to engage in the process recited in
claim 1 by modifying the process of Thieking in light of teachings in
Viscardi and Cervenka, and if so, (2) whether the record presents evidence
of secondary considerations, such as unexpected results, that when weighed
with the evidence of obviousness, are sufficient to rebut the prima facie case.
Findings of Fact
1. Claim 1 recites a process for crystallizing a non-ionic X-ray contrast
agent, Compound B. (Spec. 3, ll. 5-14.) The process comprises reacting a
specific starting compound with iodine chloride, quenching excess iodine
chloride with sodium bisulfate and forming low molecular weight salts, and
crystalizing Compound B by adding seeds of Compound B to form an initial
crystallization suspension comprising Compound B and the low molecular
weight salts. (See also Spec. 3, 6.)
2. The process of claim 1 also comprises filtering the “mother liquor” of
the crystallization suspension through a nanomembrane. The nanofiltering
step retains Compound B and some of the mother liquor on the retentate side
of the membrane and allows the salts in liquid to pass through. (Claim 1;
Spec. 3.) The process further involves returning the retentate (containing
Compound B and mother liquid) to the crystallization suspension, and then
repeating the steps of nanofiltering and returning the retentate to the
crystallization suspension. (Claim 1; Spec. 3-4.)
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3. The instant Specification states that the inventors “have surprisingly
found that in the instant process the solubility of Compound B depends on
the salt concentration.” (Spec. 4, ll. 6-15.)
4. Examples in the Specification describe the production of Compound
B via methods disclosed in Example 1 (comparative), Example 2 and
Example 3.
5. Example 2 is similar to Example 1, but differs in that the “seeded
mixture is slowly cooled to 35ºC” (rather than 32ºC as disclosed in Example
1) and then “subjected to nanofiltration followed by diafiltration with
water.” (Spec. 5, ll. 2-4.) In addition, “[t]he mother liquor is decanted from
the slurry and concentrated in the nanofiltration unit to about 60 % of its
original volume before it is returned to the crystallization vessel” where
crystal growth proceeds for 12 hours before filtering and washing the filter
cake with water. (Id. at ll. 4-7.)
6. Example 3 is similar to Example 2, except that the procedure of
nanofiltering, diafiltering with water, concentrating and returning to the
crystallization vessel is repeated twice before proceeding with final crystal
growth for 12 hours. (Id. at ll. 16-21.)
7. The Specification states that yields of Compound B via the processes
of Example 2 and 3 are about 3.5% higher and about 4% higher,
respectively, than via the process of comparative Example 1. (Id. at ll. 7-8,
21.)
8. Thieking discloses “a process for the preparation of compounds
containing triiodinated benzene rings, e.g., iodinated X-ray contrast agents.”
(Thieking, col. 1, ll. 11-18.)
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9. Thieking teaches that the “2,4,6-unsubstituted starting reagent for the
triiodination is preferably a 5-amino-benzamide,” such as 5-amino-N,N’bis-
(2,3-dihydroxypropyl)-isophthalamide, which is “[e]specially prefer[red].”
(Id. at col. 2, ll. 47-65.)
10. Thieking teaches a process that comprises (a) reacting the 5-amino-
benzamide with iodine halide, such as iodine chloride, to yield a triiodinated
product (id. at col. 1, ll. 49-61; col. 2, ll. 64-65; col. 3, ll. 4-5, 39-42); (b)
quenching excess iodine chloride with sodium bisulphate (id. at col. 3, ll. 44-
45; col. 4, l. 9); and (c) crystallizing the triiodinated product using seed
crystals of the compound, thereby creating a “reaction mixture” (id. at col. 4,
ll. 19-31).
11. Thieking also describes filtering the reaction mixture, which generates
a “cake” of the triiodinated product. Thieking further states that “[g]iven the
high initial salt content of the reaction medium following addition of the
aqueous base … it is very surprising that such low salt contents can be
achieved with such little washing and without requiring recrystallization.”
(Id. at col. 4, ll. 57-61.) In other words, Thieking discloses that the filtering
membrane retains the triiodinated product, and salts in the initial reaction
mixture pass through the membrane.
12. Viscardi teaches a method of concentrating and purifying iodinated X-
ray contrast agents via nanofiltration. (Viscardi, col. 1, ll. 5-22, col. 3, ll. 42-
56.) Viscardi states that the nanofiltration “process of this invention has
provided excellent and fully unexpected degrees of purification and recovery
of the desired products.” (Id. at col. 3, ll. 49-57.)
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13. Viscardi also discloses that “[i]t is known that organic impurities with
low relative mass and/or inorganic salts can be removed from aqueous dilute
solutions through tangential filtration processes by using ultrafiltration
(U.F.) or nanofiltration (N.F.) membranes.” (Id. at col. 2, ll. 17-21.) In this
context, Viscardi teaches that: “Water, salts, organic compounds at relative
mass lower than 200 and solvents, if any, permeate through the membranes
and the retentate, partially concentrated and purified as to the contrast agent,
is recycled at the first stage after dilution with a little amount of deionized
make-up water.” (Id. at col. 4, ll. 57-62.)
14. Cervenka discloses a process for purifying iodinated X-ray contrast
agents by continuous crystallization. (Cervenka, 1, [0009] – [0010].)
Cervenka states that the process “allows for purification in an efficient and
safe manner at a low cost.” (Id. at [0001].)
15. As disclosed by Cervenka, “[b]y performing the crystallisation
process as a continuous crystallisation process the yield per volume and time
unit of the equipment is increased while the purity level of the crystallised
iodinated compounds are maintained and may even be increased.” (Id. at
[0010].)
16. Cervenka also teaches the concept of seeding, or preloading, with
crystals before repeated crystallization, and states that the “use of seed
crystals will enhance the initial crystallisation process and promote the
establishment of steady state conditions.” (Id. at 2, [0027].)
17. Cervenka further describes a filtering step between the repeated
crystallization steps when it teaches that “crystallisers will usually be
coupled in series, optionally with partial recycling of the product stream and
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mother liquor or crystals after filtration from a crystalliser to a previous
crystalliser in the series.” (Id. at 3, [0032].)
Principles of Law
“An examiner bears the initial burden of presenting a prima facie case
of obviousness.” In re Huai-Hung Kao, 639 F.3d 1057, 1066 (Fed. Cir.
2011). “Once the examiner establishes a prima facie case of obviousness,
the burden shifts to the applicant to rebut that case.” Id. If the applicant
presents rebuttal evidence, such as unexpected results or that the prior art
teaches away from the claimed invention, the Examiner must consider the
totality of the evidence to determine whether the obviousness rejection
should stand. Id.
Analysis
We agree with the Examiner that it would have been prima facie
obvious to one of skill in the art to engage in the process recited in claim 1
by modifying the process of Thieking to include nanofiltration as taught by
Viscardi as well as continuous crystallization as taught by Cervenka. (Ans.
5.)
Thieking taught a process for crystallizing a 5-amino-benzamide
compound comprising (a) reacting 5-amino-N,N’bis-(2,3-dihydroxypropyl)-
isophthalamide with iodine chloride to form the compound; (b) quenching
excess iodine chloride with sodium bisulphate (and thereby forming low
molecular weight salts); (c) crystallizing the compound by adding seed
compounds to form a crystallization suspension comprising the compound
and salts; and (d) filtering the crystallization suspension. (FF 10, 11.) Thus,
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as noted by the Examiner (Ans. 5), the difference between the Thieking and
the process of claim 1 is that Thieking does not teach nanofiltering or
continuous crystallization by returning the retentate from the nanofiltering
step to the crystallization suspension for crystallization, and then repeating
the nanofiltering and returning steps.
Viscardi and Cervenka both provided clear motivation to add such
steps to the process described in Thieking. Both references, similarly to
Thieking, describe methods for purifying non-ionic iodinated X-ray contrast
agents. Viscardi teaches that nanofiltration “provided excellent and fully
unexpected degrees of purification and recovery of the desired products.”
(FF 12.) Cervenka teaches that continuous crystallization “allows for
purification in an efficient and safe manner at a low cost,” and “the yield …
is increased while the purity level … are maintained and may even be
increased.” (FF 14, 15.) Thus, as stated by the Examiner, “absent evidence
to the contrary” (Ans. 5), it would have been obvious to modify the Thieking
process to include nanofiltration and continuous (repeated) crystallization to
increase yield and purity.
The question then becomes whether the record before us presents
evidence of secondary considerations, such as unexpected results, that when
weighed with the evidence of obviousness, are sufficient to rebut the prima
facie case. In the first instance, Appellant asserts that Thieking, Viscardi,
and Cervenka do not teach or suggest that use of nanofiltration and
continuous crystallization would increase the yield of Compound B. (App.
Br. 4, 8.) For the reasons discussed above, however, we conclude otherwise.
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Viscardi and Cervenka expressly teach that nanofiltration and continuous
crystallization, respectively, would increase yield.
Appellant also argues (App. Br. 4), as also stated in the instant
Specification (Spec. 4, ll. 6-15), that they “have surprisingly found that in
the instant process the solubility of Compound B depends on the salt
concentration.” (FF 3.) In response to the Examiner’s assertion that “it is
well known in the chemical art that the solubility of a compound increases in
the salt form” (Ans. 6), Appellant “submit[s] that it is not always the case”
and “it is not common knowledge that the solubility of a large molecule like
Compound B would decrease with lower salt concentration or increase in the
presence of salts” (App. Br. 5 (emphasis in original).)
In support, Appellant provides attorney argument, but no evidence of
what one skilled in the art would have known or expected regarding the
solubility of Compound B in relation to salt concentration. In any event, the
issue here is whether a skilled artisan would have been motivated to modify
the Thieking process to include the steps of nanofiltration as taught by
Viscardi and continuous crystallization as taught by Cervenka. Regardless
of the salt solubility issue, Viscardi and Cervenka taught that such steps
would increase yield, as discussed above.
Appellant also argues unexpected or surprising results. In support,
Appellant presents Table 1, which “compares side by side, Comparative
Example 1 against Example 2 and Example 3.” (App. Br. 6-7.) Appellant
states that “the increased yield of 3.5% and 4% recited in Example 2 and
Example 3, respectively, reflects that 3.5% and 4% more Compound B was
isolated when using nanofiltration and repeated crystallization … than when
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only a single crystallization step without nanofiltration was performed ….”
(Id. at 7.) Appellant asserts that these increases in yield are “unexpected
results.” (Id.)
In light of the fact that Viscardi and Cervenka taught that
nanofiltration and continuous crystallization would increase yield (as
discussed above), we agree with the Examiner that “an increase of 3 to 4%
yield is definitely not [] unexpected and one of ordinary skill in the art
would expect much more higher yield” than the yields presented in the
instant Specification and Table 1. (Ans. 6.) Appellant has not provided
persuasive evidence or reasoning to refute the Examiner’s conclusion. In
sum, Appellant has not shown sufficient evidence of unexpected results or
any other secondary considerations in support of non-obviousness.
Conclusion of Law
We agree with the Examiner that, based on the cited references, it
would have been prima facie obvious to combine the teachings of Thieking
with those of Viscardi and Cervenka to engage in the process recited in
claim 1. We also conclude that the record before us does not provide
sufficient evidence of secondary considerations, when weighed with the
evidence of obviousness, to rebut the prima facie case.
SUMMARY
We affirm the rejection of claim 1 under 35 U.S.C. §103(a) as
unpatentable over the combined teachings of Thieking, Viscardi, and
Cervenka.

Appeal 2012-000663
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TIME PERIOD FOR RESPONSE
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)(iv).

AFFIRMED

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