Ex Parte Ren et al

Patent Trials and Appeals Board

Apr 18, 2019

14820210 - (D) (P.T.A.B. Apr. 18, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
14/820,210 08/06/2015 Zhongxu Ren
21968 7590 04/18/2019
NEKT AR THERAPEUTICS
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.
SHE0158.ll 1032
EXAMINER
455 Mission Bay Blvd., South, Suite 100 o DELL, DAVID K
San Francisco, CA 94158
ART UNIT PAPER NUMBER
1625
MAIL DATE DELIVERY MODE
04/18/2019 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte ZHONGXU REN, BO-LIANG DENG,
JENNIFER RIGGS-SAUTHIER, and MICAH HARVEY
Appeal 2018-001132
Application 14/820,210
Technology Center 1600
Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal 1,2 under 35 U.S.C. § 134 involving claims to a
specific compound that is a calcium channel blocker. The Examiner rejected
the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We
affirm.
1 Appellants identify the Real Party in Interest as Nektar Therapeutics (see
App. Br. 3).
2 We have considered refer to the Specification of Aug. 6, 2015 ("Spec.");
Final Office Action of Feb. 9, 2017 ("Final Action"); Appeal Brief of July 5,
2017 ("App. Br."); and Examiner's Answer of Sept. 11, 2017 ("Ans.").
Appeal 2018-001132
Application 14/820,210
Statement of the Case
Background
"Drugs currently known as calcium channel blockers (CCB) (also
called calcium antagonists), among other actions, inhibit calcium-evoked
contractions in depolarized smooth muscles" (Spec. ,r 3). "This
pharmacological property has, at a minimum, been one of the bases for the
use of CCBs in the management of hypertension and coronary heart disease"
(id.). "Although CCBs serve an important role in treating patients, their use
is sometimes associated with ( among other things) extensive metabolism,
often resulting in inactive metabolites and thus lower bioavailability. CCBs
also exhibit several side effects" (id. ,r 9).
The Claims
Claims 4, 21, 33, and 35 are on appeal. Claim 4 is the sole
independent claim, is representative and reads as follows:
4. A compound of Formula:
0
II
H:,c"'-....( ~o,. ~ .. /c
\-L2 "-/ 1r'":0 m .
NOi
and optical isomers, diastereomers, and enantiomers thereof,
wherein:
each n is independently an integer from 2 to 10; and
each m is independently an integer from O to 19.
2
Appeal 2018-001132
Application 14/820,210
The Re} ection
The Examiner rejected claims 4, 21, 33, and 35 under 35 U.S.C.
§ I03(a) as obvious over Cupka3 and Bentley4 (Final Act. 5-10).
The Examiner finds that Cupka teaches "a small genus of compounds
that includes the elected species of the instant claims as Formula I on
column 1" (Final Act. 5). The Examiner acknowledges that Cupka "does
not exemplify the species of claim 33. The elected species has all the
structural features of the compound j [ of Cupka] except it is the ester of 2-
(2-Methoxyethoxy) ethanol while the prior art is 2-ethoxyethanol ester"
(Final Act. 7).
The Examiner finds that Bentley evidences that polyethylene glycol
(PEG) "is a well-known conjugate ester moiety used to increase solubility
and bioavailability" (Final Act. 8). The Examiner finds "Example i of
[ Cupka] is an mPEG compound where n is 1, therefore further mPEG
compounds are within the teaching of [Cupka]. Using the mPEG analog of
the prior art PEG compound is an obvious variation" (Final Act. 10).
The issues with respect to this rejection are:
(i) Does a preponderance of the evidence of record support the
Examiner's conclusion that Cupka and Bentley suggest the compound of
claim 4?
(ii) If so, have Appellants presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness?
3 Cupka et al., AA 243591 Bl, published Sept. 17, 1985. We rely upon the
translation of Cupka with a 9/11/2017 receipt date in the file record.
4 Bentley et al., US 2003/0143185 Al, published July 31, 2003.
3
Appeal 2018-001132
Application 14/820,210
Findings of Fact
1. Cupka teaches compounds that "are used as anti-anginous and
antihypertensive substances" (Cupka 2).
2 Cupka teaches a generic compound of formula I, shown below,
'' J
where "R1 and R2 represent either aliphatic or branched alkyl residue with
the number of carbon atoms being 1 to 5, while the alkyl residue may be
interrupted in the chain by an oxygen atom and R1 and R2 may either be
identical or different" (Cupka 2).
3. Cupka teaches "j) bis-ethoxy-ethyl-ester of 2,6-dimethyl-4-(2'-
nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid" (Cupka 8). The
Examiner provides the structure as shown below:
4
Appeal 2018-001132
Application 14/820,210
4. Cupka teaches "i) bis-methoxy-ethyl-ester of 2,6-dimethyl-4-
( 4'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid" (Cupka 7). The
Examiner provides the structure as shown below:
Meo~0
;
0
~oMe
Example i
5. Bentley teaches "there is a need in the art for alternative
compounds, or for approaches for modifying or improving upon existing
compounds, that can maintain at least a certain degree or enhance the
therapeutic activity ... while increasing solubility and bioavailability"
(Bentley ,r 5).
6. Bentley teaches "[ s ]uitable polymers for covalent attachment to
a PKC inhibitor include poly(alkylene glycols) .... In one embodiment of
the invention, the polymer is a poly( ethylene glycol)" (Bentley ,r 7).
7. Bentley teaches "PEG has the formula
---CH2CH20-( CH2CH20)n---CH2CHz--- Formula II
wherein n is from about 2 to about 2,000" (Bentley ,r,r 61---62).
8. Bentley teaches "methoxy-PEG-OH, or mPEG in brief, is a
form of PEG wherein one terminus of the polymer is a methoxy group,
while the other terminus is a hydroxyl group that is subject to ready
chemical modification. The structure of mPEG is given below.
---CH30-(CH2CH20)n---CH2CHz--OH Formula III
wherein n is as described above" (Bentley ,r,r 63---64).
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Appeal 2018-001132
Application 14/820,210
Principles of Law
Under the lead compound analysis rubric, we must first "determine[]
whether a chemist of ordinary skill would have selected the asserted prior art
compounds as lead compounds, or starting points, for further development
efforts." Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1291 (Fed. Cir.
2012). "The second inquiry in the analysis is whether the prior art would
have supplied one of ordinary skill in the art with a reason or motivation to
modify a lead compound to make the claimed compound with a reasonable
expectation of success." Id. at 1292.
Prima facie obviousness can be rebutted by presenting evidence of
secondary considerations and when such evidence is submitted, all of the
evidence must be considered anew. In re Piasecki, 745 F.2d 1468, 1472-
1473 (Fed. Cir. 1984).
Analysis
We adopt the Examiner's findings regarding the scope and content of
the prior art (Final Act. 5-10) and agree that claim 4 would have been
obvious in view of Cupka and Bentley (FF 1-8). We address Appellants
arguments below.
Prima facie obviousness
Appellants contend "[b ]ecause the Office has attempted to use a lead
compound rationale to support an alleged finding of obviousness of the
claims on appeal, following lead compound analysis is proper" (App. Br. 7).
Following the lead compound analysis, Appellants contend that "[n]o proper
reasoning has been identified in the Office Action as to why one of skill in
the art would have modified Cupka Example i." (Id.).
Appellants also contend
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Appeal 2018-001132
Application 14/820,210
The only assertion made as to why one would have modified
the compounds of Cupka in the manner of Bentley is the
alleged teaching of increased solubility and bioavailability upon
incorporation of a PEG moiety. . . . Bentley does not disclose
this property of PEG. In addition, no rationale or factual
findings are provided as to why the compound of Example i of
Cupka would benefit from increased solubility and
bioavailability. That is, it is not even alleged in the Office
Action that the compound of Example i of Cupka suffers from
low solubility or low bioavailability, such that one of skill in
the art would have modified this compound to increase
solubility and/or bioavailability.
(App. Br. 8).
We are not persuaded. Cupka teaches a base compound for use in
anti-hypertensive treatment (FF 1-2) as well as fifteen specific variations of
that base compound including compounds (i) and U) (FF 3--4). Cupka's base
compound is, essentially nifedipine (cf Spec. 4, structure of nifedipine).
Under the lead compound analysis, the ordinary artisan would have had
reason to select anti-hypertensive compounds based on the generic structure
disclosed by Cupka, including the two disclosed species (i) and U), in order
to treat high blood pressure and angina in patients (FF 1 ).
As to the issue of modifying either the generic compound or
compounds (i) and U) from having one ethylene glycol group at the R1 or R2
positions as disclosed in Cupka (FF 2--4) to having two such groups (i.e. a
"polyethylene glycol"), Bentley specifically teaches that inclusion of
polyethylene glycol "can maintain at least a certain degree or enhance the
therapeutic activity ... while increasing solubility and bioavailability" (FF
5).
We agree with the Examiner that the ordinary artisan interested in
improving Cupka's compounds for treatment of high blood pressure and
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Appeal 2018-001132
Application 14/820,210
angina would have had reason and motivation to ensure the bioavailability of
these compounds to enhance therapeutic activity as taught by Bentley (FF 5;
cf Ans. 12). Thus, even under the lead compound analysis rubric, the prior
art of Bentley provides reasons to modify Cupka' s compounds to improve
their use in patient treatment (FF 5).
To the extent that Appellants are contending that Bentley does not
teach polyethylene glycol improves bioavailability and solubility, Bentley
teaches otherwise. Bentley's direct contrasting of the need for improving
these traits with the inventive use of polyethylene glycol to create "water-
soluble, polymer-modified PKC inhibitors" (Bentley ,r 6) supports the
Examiner's position that Bentley understands the addition of polyethylene
glycol to a compound to function to increase solubility and bioavailability.
Appellants provide no evidence, only attorney argument, rebutting this
understanding of Bentley. However, "attorney argument [is] not the kind of
factual evidence that is required to rebut a prima facie case of obviousness."
In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997).
Secondary Considerations
Appellants contend "[o]bjective evidence of non-obviousness is
provided in Example 3. Specifically, the results of a calcium channel
binding assay are provided for compounds of the instant claims. In this
assay, the compounds of the instant claims retain nanomolar inhibition (IC
so), which is comparable to the inhibition ofnifedipine" (App. Br. 5).
We are not persuaded for two reasons. First, the comparison with
nifedipine is not with the closest prior art, which would be the compounds
disclosed by Cupka. See In re Baxter Travenol Labs., 952 F.2d 388, 392
(Fed. Cir. 1991) ("[W]hen unexpected results are used as evidence of
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Appeal 2018-001132
Application 14/820,210
nonobviousness, the results must be shown to be unexpected compared with
the closest prior art.").
Second, Appellants provide no evidence that the result of Example 3
would have been unexpected, whether by way of a Declaration or citation to
a statement in the Specification that this result is unexpected or otherwise
surprising. "It is well settled that unexpected results must be established by
factual evidence. Mere argument or conclusory statements ... [do] not
suffice." In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995).
Conclusion of Law
(i) A preponderance of the evidence of record supports the
Examiner's conclusion that Cupka and Bentley suggest the compound of
claim 4.
(ii) Appellants have not presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness.
SUMMARY
We affirm the rejection of claims 4, 21, 33, and 35 under 35 U.S.C.
§ 103(a) as obvious over Cupka and Bentley.
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
9