Ex Parte Thakur et al

Patent Trial and Appeal Board

Aug 26, 2016

13615760 (P.T.A.B. Aug. 26, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/615,760 09/14/2012
27326 7590 08/30/2016
VANCE INTELLECTUAL PROPERTY, PC
P.O. Box 1224
CROZET, VA 22932-3167
FIRST NAMED INVENTOR
Ajit B. Thakur
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.
ATL-022-US2 6669
EXAMINER
DONOHUE, SEAN R
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
08/30/2016 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):
DA VID@V ANCEIP.BIZ
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Exparte AJIT B. THAKUR, DIANNE D. ZDANKIEWICZ, HSUN-WEN
HSU, JAMES F. CASTNER, and JAMES E. ANDERSON 1
Appeal2015-000457
Application 13/615,760
Technology Center 1600
Before ULRIKE W. JENKS, JOHN G. NEW, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
TOWNSEND, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a stable
composition for myocardial perfusion imaging, which have been rejected as
obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We reverse.
STATEMENT OF THE CASE
Adenosine "is known to be highly efficacious as a pharmacologic
stress agent for myocardial imaging in patients which are unable to exercise
adequately." (Spec. ,-i 5.) "Other adenosine-based analogs and derivatives
1 Appellants identify the Real Party in Interest as Adenosine Therapeutics,
LLC. (Appeal Br. 3.)
Appeal2015-000457
Application 13/615,760
have now shown great potential as possible coronary vasodilators for use in
medical imaging." (Spec. ii 6.) According to Appellants' specification
"many adenosine derivatives can be very difficult to solubilize in aqueous
media." (Spec. ii 7.) "[T]he skilled artisan has often turned to solvents like
glycerol, propylene glycol and other polar additives when preparing
injection solutions [of these derivatives]." (Id.) Appellants' invention is
directed to using a different solubilizing agent to provide an "improved
composition" of an adenosine derivative that is stable. (Spec. ii 9.)
Claims 1-10 and 17-18 are on appeal. Claim 1 is representative and
reads as follows:
1. A stable composition useful for myocardial perfusion
1magmg, compnsmg:
(a) an adenosine derivative, which is methyl trans-4-[3-
[ 6-amino-9-(N-ethyl-B-D-ribofuranosyluronamide )-9 H-purine-
2-yl]prop-2-ynyl]cyclohexane carboxylate or a
pharmaceutically acceptable salt thereof; and,
(b) a solvent consisting essentially of water and
hydroxypropy 1-B-cyclodextrin.
(Appeal Br. 15.)
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Application 13/615,760
The following ground of rejection by the Examiner is before us on
review:
Claims 1-10 and 17-18 under 35 U.S.C. § 103 as unpatentable over
Linden,2 Uekama,3 Gomori,4 Loftsson,5 and Li. 6
DISCUSSION
The Examiner finds that Li teaches a "pharmaceutical composition
comprising A2A adenosine agonists" that are "A2A adenosine receptor
modulator compounds," which may be "formulated ... using standard
pharmaceutically acceptable carriers, fillers, solubilizing agents and
stabilizers known to those of ordinary skill in the art." (Non-Final 7 6-7.)
The Examiner notes that Li "specifically defines pharmaceutically
acceptable carriers as hydroxypropyl-B-cyclodextrin [("HP-B-CD")] and
water" and teaches that the A2A adenosine agonist "may be methyl trans-4-
[3-[6-amino-9-(N-ethyl-/J-D-ribofuranosyluronamide)-(H-purine-2yl)]prop-
2-ynyl]cyclohexane carboxylate [("the claimed adenosine derivative")]."
(Non-Final 7.) The Examiner further finds that Li teaches that "various
2 Linden et al., US 6,322,771 B, issued Nov. 27, 2001.
3 Uekama et al., Cyclodextrin Drug Carrier Systems, 98 Chem. Rev. 2045-
207 6 (1988).
4 G. Gomori, [16} Preparation of Buffers for Use in Enzyme Studies,
1 Methods in Enzymol. 138-146 (1955).
5 Loftsson, US 7,115,586 B2, issued Oct. 3, 2006.
6 Li et al., US 2008/0064653 Al, published Mar. 13, 2008.
7 We refer to the Examiner's rejection set forth in the Non-Final Action
dated Dec. 20, 2012 ("Non-Final") because, in the Final Action, the
Examiner maintained the obviousness rejection set forth in the Non-Final,
but did not repeat the statement of rejection. (Final Action 3.)
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Application 13/615,760
types of wetting agents (also known as surfactants)" are pharmaceutical
carriers that could be included. (Ans. 9-10.)
The Examiner further finds that Linden teaches a composition for use
"in detecting the presence of, and assessing the severity of myocardial
perfusion abnormalities" in which the preferred general formula of the active
compound described in Linden reads on the claimed adenosine derivative
and "[ s ]olutions of the active compounds or its salts can be prepared in
water, optionally mixed with non-toxic surfactant." (Non-Final 3--4; Final
4.) The Examiner further notes that "Linden teaches that proper fluidity [of
the active compound] can be maintained, for example, by the formation of
liposomes, by maintenance of the required particle size in case of
dispersions or by the use of surfactants." (Ans. 10.) The Examiner indicates
that Linden does not "teach a composition wherein the surfactant is selected
as hydroxypropyl-B-cyclodextrin." (Non-Final 4.)
The Examiner finds that U ekama teaches that "the most common
pharmaceutical application of cyclodextrins is to enhance the solubility,
stability, and bioavailability of drug molecules" and that, in fact, "one of the
most important applications of cyclodextrins in the pharmaceutical field is to
enhance aqueous solubility of drugs through inclusion complexation."
(Non-Final 5.) In this regard, the Examiner finds that Uekama teaches that
the inclusion complexes "alter physical, chemical, and biological properties
of guest molecules" and that this alteration is brought about through various
kinds of reaction including hydrolysis of the guest molecule. (Id.) The
Examiner finds that Uekama teaches"[ w ]hen an ester group of a guest
molecule is fixed in close proximity to the catalytic site of cyclodextrins,
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Application 13/615,760
i.e., secondary hydroxyl groups, it experiences an acceleration in hydrolysis
... [whereas] hydrolysis is decelerated when the ester group is included
deeply inside the cavity." (Id.) The Examiner further finds that Uekama
teaches that as a drug carrier "the principle advantages of cyclodextrins ...
are (1) well-defined chemical structure; (2) availability of cyclodextrins of
different cavity size; (3) low-toxicity and low pharmacological activity; (4)
certain water solubility; and (5) protection of included/conjugated drugs
from biodegradation." (Id.) The Examiner further finds that Uekama
specifically teaches the use of 2-hydroxypropyl-B-cyclodextrin, (id.), and
that it "outperforms HE-B-CD." (Ans. 12.)
The Examiner finds that Loftsson teaches "enhancing the solubility of
an active ingredient, such as a drug, which is insoluble or sparingly soluble
in water wherein the method comprises combining active ingredient with B-
cyclodextrin in aqueous complexation medium" and that "[i]n solubility
experiment[ s ], Loftsson ... teach[ es] 2-hydroxypropyl-B-cyclodextrin out
performs other cyclodextrin[ s] of interest." (Non-Final 6.) The Examiner
further finds that Loftsson "teaches that HP-B-CD has the highest solubility
in water relative to other cyclodextrins." (Ans. 12.) Thus, the Examiner
finds that "Uekama and Loftsson independently teach HP-B-CD improves
solubility of pharmaceuticals in aqueous solution and consequently maintain
fluidity." (Ans. 10.)
The Examiner contends that one of ordinary skill in the art "would
have inferred from the [foregoing] documents of record that cyclodextrins
are non-toxic surfactants," i.e., "'[a] substance that, when dissolved in water,
lowers the surface tension of the water and increases the solubility of
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Application 13/615,760
organic compounds."' (Adv. Act. 8 2.) According to the Examiner, it would
have been obvious to one of ordinary skill in the art to modify the
composition of Li (containing the claimed adenosine derivative) by
substituting in HP-B-CD (as a non-toxic surfactant) in water as the
pharmaceutically acceptable carrier "because it would provide the
advantages of low-toxicity and low pharmacological activity, certain water
solubility and protection of included/conjugated drugs from bi ode gradation."
(Non-Final 7; Ans. 7-8.) The Examiner finds that Linden's teaching that
"solutions of active compounds or salts can be prepared in water, optionally
mixed with non-toxic surfactant. .. reads on a suggestion to combine [an]
active compound, such as Apadenoson [,the claimed adenosine derivative,]
with [a] non-toxic surfactant." (Final Action 4.) In addition, the Examiner
contends that because "Li uses [the] term 'wetting agent' in conjunction with
HP-B-CD," it suggests that HP-B-CD and surfactants "are substitutes."
(Ans. 11.)
We disagree with the Examiner's conclusion that Li, Linden, U ekama
and Loftsson make obvious the composition of claim 1. The mere fact that
references can be combined or modified does not render the resultant
combination obvious unless the prior art, the nature of the problem, or
common sense suggests the desirability of the combination, KSR Int 'l Co. v.
Teleflex Inc., 550 U.S. 398, 401 (2007); In re Fritch, 972 F.2d 1260, 1266
(Fed. Cir. 1992), and a person of ordinary skill in the art would have had a
reasonable expectation of success, Merck & Cie v. Gnosis S.P.A., 808 F.3d
8 Advisory Action, mailed Nov. 21, 2013.
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829, 833 (Fed. Cir. 2015). The Examiner has not provided sufficient
evidence as to why one of ordinary skill in the art would have had a
reasonable expectation of success in substituting HP-B-CD from among the
pharmaceutically acceptable carriers identified in Li or the generally
mentioned surfactants in Linden.
We agree with the Examiner that Li includes the claimed HP-B-CD as
a possible "pharmaceutically acceptable carrier" that might be used with the
claimed adenosine derivative. (Li ,-i 46.) However, as Appellants note, Li
"does not recommend HP-B-CD over other carriers" (Appeal Br. 10), or as a
"'go to' surfactant" (Appeal Br. 12). Indeed, Li does not provide any
examples in which HP-B-CD is used with any of the described active
ingredients (see Li ,-i,-i296-301), nor is HP-B-CD mentioned as one of the
potential ingredients in forming a pharmaceutical formulation for
intravenous or intraperitoneal infusion or injection (as a surfactant or
otherwise) (see Li ,-i,-il95-202). Furthermore, in the exemplified injection
formulations that include the claimed adenosine derivative, Li discloses the
use of dibasic and monobasic sodium phosphate, and when a surfactant is
included, polyethylene glycol 400 was selected. (Li ,-i,-i 299-300.) As
Appellants' note (Appeal Br. 10), Li, thus, discloses that HP-B-CD is "no
different" from PBS as a potential pharmaceutically acceptable carrier and
nothing more. There is nothing in Li suggesting the desirability of using
HP-B-CD or that one would have a reasonable expectation of success in
combining HP-B-CD with the claimed adenosine derivative and obtain a
stable composition. And we agree with Appellants (Appeal Br. 11-12,
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Reply Br. 7) that the additional references relied upon by the Examiner do
not establish the foregoing either.
Linden, as Appellants note, does not mention "what surfactants out of
all known surfactants might be useful, or what surfactant properties would
be desirable" (Appeal Br. 8-9), for use with the disclosed adenosine
derivatives in Linden. And neither Uekama, nor Linden establish that HP-B-
CD would be expected, a priori, to solubilize the claimed adenosine
derivatives. Indeed, Uekama teaches that the solubilization ability of
cyclodextrins has to be "quantitatively evaluated by the phase solubility
method" and that it is possible for cyclodextrins to form insoluble complexes
in water. (Uekama 205l(referring to Br and Bs type phase solubility
diagrams).) Loftsson teaches that not all "guest" compounds form a
complex with cyclodextrins. (Loftsson 4:30-36.) If one does not know
whether the guest will complex with a particular cyclodextrin, one cannot
know that the cyclodextrin will provide solubilization to that guest. There is
nothing in U ekama, or any rationale provided by the Examiner, that teaches
or suggests that one can predict whether the claimed cyclodextrin will be
capable of forming an inclusion complex with the claimed adenosine
derivative.
Moreover, as Appellants also note, Uekama teaches that cyclodextrins
can both increase and decrease stability dependent upon the location of the
ester being either "near the surface (increase) of the cyclodextrin or deeper
in the pocket (decrease)." (Appeal Br. 11; Uekama 2053; see also Reply Br.
7.) There is nothing in Uekama, or any rationale provided by the Examiner,
that teaches or suggests that one can predict whether a particular
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cyclodextrin will increase or decrease stability of any particular drug a
priori, much less the claimed adenosine derivative or the claimed
cyclodextrin.
In KSR, the Supreme Court acknowledged the importance of
identifying "a reason that would have prompted a person of ordinary skill in
the relevant field to combine the elements in the way the claimed new
invention does" in an obviousness determination. KSR, 550 U.S. at 418.
After reviewing the evidence, we agree with Appellants, that the Examiner
has failed to identify a reason, i.e., a desirability, that would have prompted
a person of ordinary skill in the art to use "HP-B-CD when selecting either a
pharmaceutical carrier or a surfactant" for use with the claimed adenosine
derivative. (Appeal Br. 12.) The Examiner has also not pointed to
predictability of using cyclodextrins in general to stabilize or solubilize the
claimed adenosine derivative, much less using the claimed HP-B-CD.
For the foregoing reasons, we reverse the rejection of claim 1-10 and
17-18 under 35 U.S.C. § 103 as unpatentable over Linden, Uekama,
Gomori, Loftsson, and Li.
SUMMARY
We reverse the Examiner's rejection of claims 1-10 and 17-18 under
35 U.S.C. § 103 as unpatentable over Linden, Uekama, Gomori, Loftsson,
and Li.
REVERSED
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