Ex Parte Chait et al

Board of Patent Appeals and Interferences

Apr 30, 2009

10393190 (B.P.A.I. Apr. 30, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________

Ex parte EDWARD M. CHAIT and SEUNG-YONG CHOI
____________

Appeal 2009-0718
Application 10/393,190
Technology Center 1600
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Decided:1 April 30, 2009
____________

Before DONALD E. ADAMS, RICHARD M. LEBOVITZ, and
MELANIE L. McCOLLUM, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL

1 The two-month time period for filing an appeal or commencing a civil
action, as provided for 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 2009-0718
Application 10/393,190

This is a decision on appeal from the Examiner’s final rejection of
claims 2, 3, and 6-35 as obvious over prior art. Jurisdiction for this appeal is
under 35 U.S.C. § 6(b). The rejection is affirmed.

STATEMENT OF THE CASE
The claims are directed to methods of synthesizing a diacyl cyclic
nucleotide salt known as N6,2'-O-diacyl-adenosine-3',5'-cyclic
monophosphate salt. Adenosine 3',5'-cyclic monophosphate (cAMP), a
cyclic nucleotide, is an intracellular mediator of the action of a large number
of extracellular mammalian hormones (Spec. 1: 9-11). Because of their
physiological activity, cyclic nucleotides and cyclic nucleotide derivatives
are potential pharmacological targets (id. at 12-14). For instance, the cyclic
nucleotide derivative dibutyryl-adenosine- 3',5'-cyclic monophosphate
sodium salt (db-cAMP-Na) can be used for organ preservation and
maintenance (id. at 14-17).
Claims 2, 3, and 6-35 are pending and stand rejected by the Examiner
under 35 U.S.C. § 103(a) as obvious in view of Posternak (38 METHODS OF
ENZYMOLOGY 399-409 (1974)) and Yamaji (US 4,458,067, Jul. 3, 1984)
(Ans. 3).
Appellants did not provide separate arguments for the patentability of
any individual claim. Therefore, we select claim 20 as representative for the
purpose of deciding the issues in this appeal. 37 C.F.R. § 41.37(c)(1)(vii).
Claim 20 reads as follows:
20. A method for synthesizing a N6, 2’-O-diacyl-adenosine-3’,5’-
cyclic monophosphate salt comprising:
a) adding an alkyl acid anhydride or an alkyl acid halide to a solution
2
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comprising an ammonium salt of adenosine-3’,5’-cyclic
monophosphate and a pyridine solvent to produce a reaction
mixture comprising a N6,2’-O-diacyl-adenosine-3’,5’-cyclic
monophosphate salt,
b) concentrating the reaction mixture by evaporating the pyridine
solvent,
c) adding a dialkyl ether to the reaction mixture to produce an organic
solution,
d) adding a water solution to the organic solution to produce a two
phase system,
e) extracting the N6,2’-O-diacyl-adenosine-3’,5’-cyclic
monophosphate salt from the organic solution to produce an
aqueous solution of the a N6, 2’-O-diacyl-adenosine-3’,5’-
cyclic monophosphate salt, and
f) removing the aqueous solution of the a N6, 2’-O-diacyl-adenosine-
3’,5’-cyclic monophosphate salt from the organic solution,
wherein steps d), e) and f) are accomplished before complete
hydrolysis of any alkyl acid halide or alkyl carboxylic acid anhydride.

ISSUE ON APPEAL
There is one obviousness rejection on appeal. The rejection is based
on descriptions by Posternak and Yamaji of methods for synthesizing diacyl
cyclic nucleotides. The issue in this appeal is whether persons of ordinary
skill in the art would have had reason to combine the teachings of Posternak
and Yamaji to have made the claimed method for synthesizing a N6,2'-O-
diacyl-adenosine-3',5'-cyclic monophosphate salt.

PRINCIPLES OF LAW
The question of obviousness is resolved on the basis of underlying
factual determinations including: (1) the scope and content of the prior art;
(2) the level of ordinary skill in the art; (3) the differences between the
claimed invention and the prior art; and (4) secondary considerations of
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nonobviousness, if any. Graham v. John Deere Co., 383 U.S. 1, 17-18
(1966).
FINDINGS OF FACT
Scope and content of the prior art
In making an obviousness determination, we must first ascertain the
scope and content of the prior art. Graham, 383 U.S. at 17. The following
numbered findings of fact (“FF”) summarize the prior art relied upon by the
Examiner in setting forth the basis of the rejection (Ans. 3-4):
Posternak
1. Posternak describes methods of preparing derivatives of cyclic
nucleotides, such as by treating a cyclic nucleotide (cAMP or cGMP) salt
with anhydrous pyridine and an acid anhydride (401-402).
2. In one method of preparing a dibutyryl-cGMP derivative, Posternak
describes starting with ten grams of a cGMP free acid and converting it to an
ammonium salt (406-407).
3. The salt was treated with pyridine and butyric anhydride, an acid
anhydride (407).
4. After reflux, the solvent was removed by vacuum and, after addition of
water, the residue was re-evaporated to dryness (407).
5. Water was added to the residue (“taken up in . . . distilled water) and
extracted with ether (407).
6. “The organic phase was discarded” to leave an aqueous solution (“water
layer”) (407).
7. The aqueous solution was treated, filtered through a Dowex-50 column,
and freeze dried (407).
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8. Posternak also describes preparing an acyl derivative of cUMP by the
pyridine/acid anhydride method followed by addition of water and ether
extraction (407).

Yamaji patent
9. Yamaji states that it was known to produce diacyl-cAMP salts by
reacting a cAMP triethylamine salt with n-butyric anhydride, an akyl acid
anhydride, in a pyridine solvent, adding water, and then extracting with ether
(col. 1, ll. 29-39).
10. Yamaji describes a method of producing diacyl-cAMP by method which
uses a carboxylic anhydride, but does not require a solvent such as pyridine
(col. 1, l. 54 to col. 2, l. 52).
11. After the reaction, the resulting diacyl-cAMP can be separated and
purified “in a usual way” (col. 3, ll. 16-17). For example, Yamaji describes
adding diethyl ether to the rejection mixture and extracting with water (id. at
col. 4, ll. 33-36; see also col. 3, ll. 17-20).

Claim 20
12. Claim 20 is a method of synthesizing “a N6, 2'-O-diacyl-adenosine-
3'-,5'-cyclic monophosphate salt” comprising, inter alia, the following steps:
13. a) adding an alkyl acid anhydride or halide to an ammonium salt of
cAMP and pyridine solvent;
14. b) evaporating the pyridine solvent;
15. c) adding dialkyl ether to produce an organic solution;
16. d) adding water to the organic solution to produce a two phase system;
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17. e) extracting the diacyl salt from the organic solution to produce an
aqueous solution of the diacyl salt; and
18. f) removing the aqueous solution of the diacyl salt from the organic
solution.
Differences between the prior art and the claimed invention
Once the scope and content of the prior art has been determined, the
next step is to identify the differences between the prior art and the claimed
invention. Graham, 383 U.S. at 17. The following numbered findings of
fact are pertinent to this issue:
19. Both Posternak and Yamaji teach that it was conventional to produce
diacyl cAMP by reacting a cAMP salt with an alkyl acid anhydride (such as
n-butyric anhydride) with pyridine (FF1, 3, & 9) as in step a) of claim 20
(FF13).
20. Posternak further describes a method of synthesizing a diacyl cGMP salt
comprising removing the pyridine solvent (FF4), the same step as in b) of
claim 20 (FF14).
21. The resulting residue is taken up in water by Posternak and ether is
added (FF5) which correspond to steps c) and d) of claim 20 (FF15 & 16),
but in the opposite order.
22. Posternak’s diacyl cGMP salt is extracted into the water or aqueous
layer as in claim 20’s step e) and the aqueous layer is removed, meeting the
limitation of step f) of claim 20 (FF6, 7, 17, & 18).
23. Posternak does not describe an example of synthesizing a diacyl-cAMP
salt following the claimed steps b) through f) as in claim 20, but rather
Posternak synthesizes a diacyl-cGMP salt (FF1 & 2) following these steps.

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ANALYSIS
Posternak describes a method of synthesizing a diacyl-cyclic
nucleotide which incorporates steps a) through f) of claim 20, but adds the
water and ether in a different order than claimed (FF21) and produces a
diacyl-cGMP, rather than a diacyl-cAMP as claimed (FF23). The Examiner
finds that Yamaji teaches that “diacyl cAMP’s are the ones that are useful in
pharmaceutical and biochemical research (Yamaji, col. 1, lines 6-15). . . .
The process of Posternak, which is similar to the instant method, uses an
ammonium salt [of a cGMP], gives good yield” (Ans. 7), providing reason to
have applied Posternak’s method to an ammonium salt of cAMP as recited
in claim 20.
Appellants contend that the Examiner erred in combining Yamaji and
Posternak. Appellants argue: 1) lack of motivation to combine Yamaji and
Posternak (App. Br. 13); and 2) modifying Yamaji with Posternak would
render Yamaji unsatisfactory for its intended purpose (App. Br. 16).
As to the motivation argument, Appellants focus on the
incompatibility of the two references because Posternak is said to utilize
pyridine as a solvent in the production of diacyl nucleotide, while Yamaji is
said to teach that pyridine should not be used as a solvent in the synthetic
method (App. Br. 14).
It is correct that Yamaji teaches a method for synthesizing diacyl-
cAMP which does not require a pyridine solvent (FF10). However, Yamaji
recognizes that diacyl-cAMP derivatives were conventionally synthesized
with alkyl acid anhydride and pyridine solvent (FF9) as in step a) of claim
20. Yamaji also teaches that it was conventional to purify a diacyl-cAMP
derivative by water/ether extraction as in claim 20, steps c) through of e),
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whether produced in the presence (FF9) or absence of pyridine (FF10-11).
Yamaji performs the extraction by first adding the dialkyl ether and then
adding water (FF11), the same order recited in claim 20 (FF15 & 16).
In addition to distinguishing Yamaji because of its teaching of an
alternative synthesis method that leaves out pyridine, Appellants also
contend that it is incompatible with Posternak because the reaction
temperatures used in the two references are different (App. Br. 14).
However, Yamaji’s teaching about carrying out the reaction above
70°C as cited by Appellants (App. Br. 15) is with respect to the synthesis
method which omits pyridine, not the more conventional method which
includes it (FF9). Yamaji’s teaching is therefore not incompatible with
Posternak.
Finally, Appellants point to differences between Posternak and
Yamaji in how a sodium salt is prepared from the diacyl cyclic nucleotide
derivative, stating that the former uses a Dowex exchange column while the
latter specifically indicates that columns can be dispensed (App. Br. 16;
Reply Br. 7). First, we note the claim 20 is not limited to a particular salt
type, nor does the claim exclude column chromatography. Second, once
again, Yamaji’s discussion about columns relates to the pyridine-free
synthetic methods, not the more general conventional synthesis methods
which use pyridine.
Appellants have focused their arguments on Yamaji’s apparent
pyridine-free synthetic method. However, while the Examiner referred to
this method in the Answer, the Examiner did not rely on it exclusively to
reach the principal manipulation steps of claim 20, but rather quite clearly
cited Posternak for teaching substantially all the claimed method steps
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(paragraph spanning pages 3-4 of the Answer; Ans. 7: 3-10). The Examiner
also recognized that Posternak differed from the claimed process because it
used a cGMP derivative, and cited Yamaji for its teaching of cAMP
derivatives as cited in claim 20 (Ans. 3). Thus, the Examiner did not ignore
this difference as asserted by Appellants (Reply Br. 6).
In sum, Yamaji’s teachings are not incongruous with Posternak since,
despite its teaching that pyridine may be omitted from the synthesis method,
it describes a more conventional synthesis method for diacyl cAMP which
incorporates many of the same steps as in claim 20.
Appellants also contend that the combination of Yamaji and Posternak
“would render the prior art invention being modified unsatisfactory for its
intended purpose” (App. Br. 16). Appellants argue that adding pyridine to
the reaction mixture would frustrate Yamaji’s goal in providing an
alternative pyridine free synthetic method (id. at 17).
For the reasons already discussed, this argument is not persuasive
since this portion of Yamaji is unnecessary to reach the conclusion that
claim 20 would have been obvious to persons of ordinary skill in the art.
Appellants also argue that Yamaji “is unlikely to suggest to one of
ordinary skill in the art that a process for preparing and/or separating cAMP
can be efficiently performed using pyridine as a solvent” (Reply Br. 7).
This argument is not supported by the evidence. Both Posternak and
Yamaji teach that it was conventional to produce diacyl cAMP with a
pyridine solvent (FF19). Claim 20 does not require a particular degree of
efficiency or cAMP yield.
Appellants also argue that Posternak “only discloses processes for
separating non-cAMP based compounds that are salts of tetrabutyl
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ammonium hydroxide, compounds IV-VI, using pyridine and ether/water”
(Reply Br. 7).
Again, this argument is not persuasive. Yamaji clearly teaches that it
was known to make and separate cAMP derivatives using pyridine (FF9)
followed by water/ether extraction (FF9, 11), the same order specified in
claim 20 (FF15 & 16). Based on these teachings, persons of ordinary skill in
the art would have reasonably expected that Posternak’s cGMP synthesis
method using the same pyridine and water/ether extraction steps would also
work for cAMP. Appellants have not provided adequate evidence to rebut
this reasonable expectation.

CONCLUSION OF LAW
Persons of ordinary skill in the art would have had reason to combine
the teachings of Posternak and Yamaji to have made the claimed synthesis
method. The rejection of claim 20 as obvious in view of Posternak and
Yamaji is therefore affirmed. Claim 2, 3, 6-19, and 21-35 fall with claim 20
because separate reasons for their patentability were not provided. 37 C.F.R.
§ 41.37(c)(1)(vii).

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).

AFFIRMED

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cdc

Charles W. Calkins, Esq.
Kilpatrick Stockton LLP
1001 West Fourth Street
Winston-Salem NC 27101-2400