Ex Parte RANGES et al

Patent Trial and Appeal Board

May 20, 2016

12619913 (P.T.A.B. May. 20, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
12/619,913 11/17/2009
23599 7590 05/24/2016
MILLEN, WHITE, ZELANO & BRANIGAN, P,C
2200 CLARENDON BL VD.
SUITE 1400
ARLINGTON, VA 22201
Gerald RANGES
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.
BA YER-0002-D02 9542
EXAMINER
KANTAMNENI, SHOBHA
ART UNIT PAPER NUMBER
1627
NOTIFICATION DATE DELIVERY MODE
05/24/2016 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):
docketing@mwzb.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte GERALD RANGES, WILLIAM SCOTT,
MICHAEL BOMBARA, DEBORAH RAUNER, ANIKO REDMAN,
ROGER SMITH, HOLGER PAULSEN, DAVID GUNN, JINSHAN CHEN,
and JOEL RENICK1
Appeal2013-003060
Application 12/619,913
Technology Center 1600
Before JEFFREY N. FRED MAN, ULRIKE W. JENKS, and
CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
JENKS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims directed to a
method of treating p38-mediated disease with aryl urea compounds. The
Examiner rejects the claims for lack of enablement, obviousness, and on the
grounds of nonstatutory obviousness-type double patenting. We have
jurisdiction under 35 U.S.C. § 6(b ).
We AFFIRM.
1 According to Appellants, the Real Party in Interest is Bayer Healthcare
LLC. (Br. 1.)
Appeal2013-003060
Application 12/619,913
STATEMENT OF THE CASE
Claims 1-16 are on appeal, and can be found in the Claims Appendix
of the Appeal Brief. Claim 1 is representative of the claims on appeal, and
reads as follows:
1. A method for the treatment of a disease, other than cancer,
mediated by p3 8, comprising administering a pharmaceutical
composition comprising a pharmaceutically acceptable carrier
and a compound of Formula I
I
wherein
A is optionally substituted C6-12-aryl or Cs-12-heteroaryl;
R1 is Hor C1_4-alkyl;
R2 and R3 are each independently halogen, -COOR1, -CN, -
CONR7R8, or-CH2NHR9;
R5 is C3_5-alkyl;
R6 is C1-6-alkyl;
R7 is hydrogen;
R 8 is methyl;
R9 is hydrogen, methyl or -CO-R10; and
R 10 is hydrogen or methyl optionally substituted by NR62 or
COOR6.
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The following grounds of rejection are before us for review:
I. claims 1-16 under 35 U.S.C. § 112, first paragraph as failing to
meet the enablement requirement;
II. claims 1-3, 5, 7-11 under 35 U.S.C. § 103(a) as unpatentable
over Widdowson; 2 and
III. claims 1-16 are rejected under the judicially created doctrine of
nonstatutory obviousness-type double patenting.
I Issue: Enablement
The Examiner's position is that the Specification "while being
enabling for [a] method of treating a specific disease mediated by p38, does
not reasonably provide enablement for treating any disease mediated by p3 8
by administering a pharmaceutical composition comprising a compound of
Formula I." (Ans. 4.) "The specification does not provide sufficient
information that all diseases are treatable with pharmaceutical composition
comprising compound of Formula I described in the method claims." (Id.
at 5.) The Examiner finds that "[t]he claims would reasonably encompass
any disease mediated by p3 8 which could be the treatment of unknown
diseases." (Id. at 6.) "[T]he treatment of any disease using inhibitors of
p38 is highly unpredictable with regard to therapeutic effects." (Id. at 8.)
Appellants contend that the Examiner has not established that "there
are 'reasons or evidence' to doubt the objective enablement." (Br. 3.)
Appellants contend that "the use of p3 8 inhibitors to treat various indications
2 Katherine Lousia Widdowson et al., US 5,886,044, issued Mar. 23, 1999
("Widdowson"). We note that the Examiner consistently refers this
reference as "Louisa" (Ans. 10).
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Application 12/619,913
is established as noted in the background section of the application, and
would be well understood by one of skill in the art." (Id. at 5.)
The issue is: Does the preponderance of evidence of record support
the Examiner's conclusion that the claims are not enabled?
Findings of Fact
Breadth of the claims
FF 1. Claim 1 is directed to "[a] method for the treatment of a disease, other
than cancer, mediated by p3 8, comprising administering a
pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a compound of Formula I."
FF2. The Examiner finds that "[t]he claims would reasonably encompass
any disease mediated by p3 8 which could be the treatment of
unknown diseases." (Ans. 6 (emphasis removed).)
Presence of Working Examples
FF3. The Specification provides "[t]he in vivo inhibitory properties of
selected compounds were determined using a murine LPS induced
TNFa production in vivo model. BALB/c mice ... in groups often
were treated with either vehicle or compound by the route noted ....
TNF a levels in sera were measured using a commercial murine TNF
ELISA kit." (Spec. 76-76; see Ans. 6 and 14.)
Amount of Direction or Guidance Presented
FF4. The Examiner finds that "[a]ll of the guidance given by the
specification is the in vitro inhibitory properties of the compounds
using a p3 8 kinase assay, and in vivo inhibitory properties of selected
compounds using a murine LPS induced TNF alpha production in
vivo model." (Ans. 6 (emphasis removed).)
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State of the Prior Art
FF5. The Examiner finds that "the state of the art with regard to treating
any disease mediated by p3 8 generally is underdeveloped. In
particular, there is no known compound which is effective against all
diseases." (Ans. 7 (emphasis removed).)
Unpredictability of the Art
FF6. The Specification explains that "[ s ]everal patents have appeared
claiming polyarylimidazoles and/or compounds containing
polyarylimidazoles as inhibitors of p38 .... It has been reported that
arylimidazoles complex to the ferric form of cytochrome P450cam ... ,
causing concern that these compounds may display structure-related
toxicity." (Spec. 6; see Ans. 8 ("these compounds may display
structure-related toxicity .... Thus the treatment of any disease using
inhibitors of p3 8 is highly unpredictable with regard to therapeutic
effects").)
Quantity of Experimentation
FF7. As explained by the Examiner, the quantity of experimentation
required to practice the claimed invention is high. First you start out
by envisioning the compound, then you choose appropriate carrier,
then you decide the route of administration and need to select the
appropriate animal model. Once all that is complete "[ o ]ne would
then need to test the combination in the model system to determine
whether or not the combination is effective for inhibiting TNFapha,
and then need to determine if the composition inhibits p38." (Ans. 8.)
If unsuccessful, further testing is required after modifications to both
compound and assay (id.). "[I]t would be necessary for one to
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conduct the preceding experimentation for each type of disease
because there is no known drug effective for treating all types of
diseases." (Id. at 9.)
FF8. The Examiner finds:
Since every disease and disorder has its unique chemical
pathway of expression, diagnosis and treatment of individual
diseases and condition cannot be predicted a priori but must be
determined from case to case by painstaking experimental study
and when the above factors are weighed together, one of
ordinary skill in the art would be burdened with undue
"painstaking experimentation study" to determine which
compounds of Formula I treats which diseases/ conditions."
(Ans. 9.)
Principle of Law
Factors to be considered in determining whether a disclosure
would require undue experimentation ... include (1) the
quantity of experimentation necessary, (2) the amount of
direction or guidance presented, (3) the presence or absence of
working examples, (4) the nature of the invention, (5) the state
of the prior art, ( 6) the relative skill of those in the art, (7) the
predictability or unpredictability of the art, and (8) the breadth
of the claims.
In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).
In order for a medical treatment claim to satisfy the enablement
requirement of Section 112, one of ordinary skill in the art must be able to
effectively use the claimed treatment method in order to achieve the desired
therapeutic result. See, e.g., In re '318 Patent Infringement Litig., 583 F.3d
1317, 1325-27 (Fed. Cir. 2009); Rasmusson v. SmithKline Beecham Corp.,
413 F.3d 1318, 1322-25 (Fed. Cir. 2005). When the claims are directed to a
treatment using a particular drug, "[ w ]hat is necessary to satisfy the how-to-
use requirement of§ 112 is the disclosure of some activity coupled with
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Application 12/619,913
knowledge as to the use of this activity." In re Cortright, 165 F.3d 1353,
13 60 (Fed. Cir. 1999) (citation omitted).
Analysis
Appellants contend that there is no "'reasons or evidence' to doubt the
objective enablement" of the claims (Br. 3), as "the use of p38 inhibitors to
treat various indications is established as noted in the background section of
the application." (Br. 5.)
We are not persuaded. As we balance the Wands factors, the breadth
of claim 1 that is directed to the treatment of any p3 8 mediated disease (FF 1
and FF2), the lack of working examples for treating any non-cancer disease
that is mediated by p38 (FF3), the lack of specific guidance on how to treat
any and all diseases when all the guidance is limited to testing the effect of
compounds on the production of TNFa (FF4), the underdeveloped state of
the art with respect to showing that there are compounds effective for all
diseases (FF5) and the unpredictability and quantity of experimentation
(FF6-FF8) combined with a high level of skill supports a finding of lack of
enablement with respect to the method of claim 1.
We additionally highlight some of the Examiner's reasons for finding
a lack of enablement. The Examiner's position is that "[ t ]here are no
working examples [in the Specification] for the treatment of a disease using
pharmaceutical compositions comprising compounds of Formula (I)." (Ans.
6.) The Examiner recognizes that the Specification teaches the effect of the
compounds on the production of TNFa in an animal model (FF3). However,
this particular animal model tests the use of the compounds for only a short
period of time in the animal and only asks what the effect of the compound
is on TNFa production. Additionally, the assay itself does not establish if
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there is any benefit to the animal over time as the animals are sacrificed 90
minutes after supplying the compound to the animal (FF3). Although the
experiments disclosed in the Specification can be used to test whether the
compounds have an effect on the production of TNFa, they do not establish
that they can treat any particular p3 8-mediated disease. Furthermore, the
background section of the Specification recognizes that some inhibitors of
p38, for example polyarylimidazoles, have been shown to be toxic (FF6).
Additionally, as pointed out by the Examiner, Appellants "have not
specifically described the compounds tested in the p38 assay or LPS induced
TNFa production mouse model, [and] they have not correlated the structure
of the compounds tested with their relative activity in said assays and they
have not tested the compounds in any specific assay, for example specific
rheumatoid arthritis assay or any other assays for specific diseases."
(Ans. 15.)
Accordingly, the experiments disclosed in the Specification are not
sufficient to establish that the compounds within the scope of the claims can
treat any p38-mediated disease. The Examiner cites Graninger3 and Herlaar4
to support the position that, at the time of filing the present Specification, the
prior art recognized that the ability to "treat[] disease by the inhibition of
p38 is still exploratory, and other mechanisms are also involved .... Note all
these references state that p38-mediated diseases/disorders in general are at
best in the early experimental stage and needs further exploratory studies."
3 Graninger and Smolen, One-year inhibition of tumor necrosis factor-a: a
major success or a larger puzzle? 13 Current Opinion in Rheumatology
209--213 (2001).
4 Herlaar and Brown, p38 MAPK signalling cascades in inflammatory
disease, 5. Mol. Med. Today 439-447 (1999).
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(Ans. 13.) Herlaar teaches that "[t]he pyridinyl imidazoles have shown
potent inhibitory effects on cytokine production both in vitro and in vivo"
and suggest that they may have use in the treatment of inflammatory
conditions. (Herlaar 446.) Graninger teaches "the effects of therapeutic
TNF blockade on the biology of the disease. The fact that inflammation is
not completely halted [in rheumatoid arthritis] and destruction is ongoing in
some patients suggests that other mechanisms may also be involved."
(Graninger, Abstract.) We agree with the Examiner, that the literature does
not provide sufficient evidence that the use of a compound that blocks TNF
would also be expected to inhibit a disease mediated by p38. Indeed,
Graninger tells us that the assay disclosed in the Specification is insufficient
to establish a correlation that an inhibitor of TNF production can be
extrapolated to include inhibition of all p38 (see Graninger, Abstract
"inflammation is not completely halted").
The preponderance of evidence of record supports the Examiner's
conclusion that the Specification fails to provide an enabling disclosure
commensurate with the scope of claim 1. Claim 2-16 were not separately
argued and fall with claim 1. 3 7 C.F .R. § 41.3 7 ( c )( 1 )(iv).
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II. Issue: Obviousness over Widdowson
Does the preponderance of evidence of record support the Examiner's
conclusion that formula III of Widdowson renders obvious a method of
treating a disease using a compound as represented by the claimed
formula I?
Findings of Fact
FF9. Widdowson formula III
wherein
X is oxygen or sulfur;
R is any functional moiety having an ionizable hydrogen
and a pKa of 10 or less;
R 1 is independently selected from hydrogen; halogen ....
Y is independently selected from ... halogen; ... cyano; ...
C1-10 alkyl; ... C(O)NRiRs [(Ri and Rs can be hydrogen); C(O)OR12
[(R12 can be hydrogen)]. .. ;
n is an integer having a value of 1 to 3;
or a pharmaceutically acceptable salt thereof.
(Widdowson col. 13, 1. 11 to col. 14, 1. 8)
FFlO. Widdowson teaches "[c]ompounds of Formula (III) are also useful for
treating a chemokine mediated disease, wherein the chemokine is one
which binds to an IL-8 a or B receptor and which method comprises
administering an effective amount of a compound of Formula (III) or
a pharmaceutically acceptable salt thereof." (Widdowson col. 13,
11. 6-10)
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Principle of Law
[I]f an examiner considers that he has found prior art close
enough to the claimed invention to give one skilled in the
relevant chemical art the motivation to make close relatives
(homologs, analogs, isomers, etc.) of the prior art compound(s),
then there arises what has been called a presumption of
obviousness or a prima facie case of obviousness.
In re Dillion, 919 F.2d 688, 696 (1990), citing In re Henze, 181 F.2d
196 (CCPA 1950); In re Hass, 141F.2d122, 127, 130 (CCPA 1944).
[S]tructural similarity between claimed and prior art subject
matter, proved by combining references or otherwise, where the
prior art gives reason or motivation to make the claimed
compositions, creates a prima facie case of obviousness, and
that the burden (and opportunity) then falls on an applicant to
rebut that prima facie case.
Id. at 692.
Analysis
The Examiner's position is that "Widdowson clearly teaches the
presently claimed thienyl ring. . . . [and explains that] formula III taught by
... Widdowson is a subgenus of instant formula I." (Ans. 17.) The
Examiner acknowledges that Widdowson "does not specifically teach the
exact position of substitution on the thienyl ring, such as 3, 5 substituted
thienyl ring." (Ans. 17 .)
Appellants contend "that mere encompassment in a generic formula,
without more, is insufficient to render obvious a species or subgenus
claimed therein." (Br. 7, citing In re Jones, 21USPQ2d 1941 (Fed. Cir
1992) in support.)
The question is, how much picking and choosing would be required to
arrive at the claimed subject matter given Widdowson's disclosure?
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Application 12/619,913
The Specification explains that cytokines whose production is affected
by p38 "include, but are not limited to TNFa, IL-1 and IL-8." (Spec. 7.)
Widdowson teaches that compounds falling within the general formula III
are active as "treating a chemokine mediated disease, wherein the
chemokine is one which binds to an IL-8 a or B receptor" (FFlO).
As recognized by the Examiner, Widdowson does not teach the
production of a compound with "the exact position of substitution on the
thienyl ring, such as 3, 5 substituted thienyl ring." (Ans. 17; FF9.)
The similarity between Widdowson's Formula III and the present
claim 1 are shown below.
Widdowson's disclosure:
x
'~N-
H H
Widdowson discloses that X in
formula III can be either sulfur or
oxygen. (FF9)
Claim 1 formula I:
H
Widdowson requires a selection between and oxygen and a sulfur
group. Both structures, however, can be readily envisioned.
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Application 12/619,913
Widdowson's disclosure:
R
(Rl1)m
Claim 1 unit A:
"R is any functional moiety having A is optionally substituted C6--12-aryl
an ionizable hydrogen and a pKa of or CS--12-heteroaryl. (Claim 1) The
10 or less." (FF9.) Such ionizable C6--12-aryl can optionally be
hydrogen "groups include, but are substituted with an-OH. (Claim 3.)
not limited to, hydroxy, carboxylic
acid, thiol, ... More preferably R is
OH, SH, or NHS(0)2Rb."
(Widdowson col. 4, 11. 6-14
(emphasis added).)
"R1 is independently selected from
hydrogen; halogen" among others.
(FF9.)
Accordingly, Widdowson encompasses structures having a C6 aryl
that is substituted with an-OH moiety. Thus, Widdowson's structures
encompass the structures of "A" as claimed.
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Widdowson's disclosure:
(Yi•Yl
s
"n is an integer having a value of
1 to 3" (FF9.)
"Y is independently selected from
... halogen; ... cyano; ... C1-10
alkyl; ... C(O)NR4Rs [(~ andRs
can be hydrogen); C(O)OR12 [(R12
can be hydrogen)]." (Widdowson
col. 13, 11. 50.)
R2 and R3 are each independently
halogen, -COOR1, -CN, -CONR7Rs
(R7 and Rs can be hydrogen), or -
CH2NHR9;
Rs is C3--s-alkyl;
Widdowson discloses the same substitutions for Y as represented by
R2, R3, and Rs of the present claim with the exception of the CH2NHR9
substituent which does not appear disclosed as a potential Y substituent in
Widdowson. As recognized by the Examiner, Widdowson "does not
specifically teach the exact position of substitution on the thienyl ring, such
as 3, 5 substituted thienyl ring." (Ans. 17.) We note however, that the
thienyl ring of Widdowson can accept at most three substituents because
there are only three open positions on the thienyl ring, "n is an integer
having a value of 1 to 3" (Widdowson col. 13, 1. 63). Thus, picking and
choosing a position for a Y substituent in the thienyl ring of Widdowson
does not present an infinite number of possibilities, and if you are to add two
substituents the available options to choose from are even less. As noted in
Arkley, "picking and choosing may be entirely proper in the making of a
103, obviousness rejection, where the applicant must be afforded an
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Application 12/619,913
opportunity to rebut with objective evidence any inference of obviousness
which may arise from the similarity of the subject matter which he claims to
the prior art." In re Arkley, 455 F.2d 586, 587-588 (CCPA 1972).
Additionally, we find that the list of substituents for Y in Widdowson is not
so great as to make it impossible to envision all members of the subgenus.
We note that the compounds of Formula III in Widdowson are active
at "treating a chemokine mediated disease, wherein the chemokine is one
which binds to an IL-8 a or B receptor" (FFlO). "[B]ecause structurally
similar compounds will have similar properties, and thus would have same
or substantially similar beneficial therapeutic effects. It is pointed out that if
the claimed invention and the structurally similar prior art species share any
useful property, that will generally be sufficient to motivate an artisan of
ordinary skill to make the claimed species. In fact, similar properties may
normally be presumed when compounds are very close in structure." (Ans.
18, citing Dillon, 919 F.2d at 693, and MPEP 2144.)
We recognize, but are not persuaded by, Appellants' contention that
"mere encompassment in a generic formula, without more, is insufficient to
render obvious a species or subgenus claimed therein." (Br. 7). We find
that the Examiner has reasonably established that the compounds of Formula
III of Widdowson are sufficiently close in structure to the claimed
compound and are disclosed in Widdowson to effect a similar target, namely
IL-8 a target identified in the Specification as being affected by p3 8 (see
Spec. 6-7), to have met the burden of establishing a prima facie case.
Having considered all of Appellants' arguments and having found
them to be unpersuasive, we affirm the Examiner's rejection of claim 1 as
described above in conjunction with the reasons of record (see Ans. 10-11,
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16-18). Claim 2, 3, 5, and 7-11 have not been separately argued and fall
with claim 1.
III. Issue: Obviousness-Type Double Patenting
Does the preponderance of the evidence of record support the
Examiner's conclusion that the recitation of "a pharmaceutical composition
comprising a pharmaceutically acceptable carrier" in conjunction with the
compound of formula I as recited in the present claims are obvious in light
of the claims in Ranges?
Findings of Fact
FF 11. Claim 1 of Ranges reads, in pertinent part, as follows:
A method for the treatment of a disease, other than cancer,
mediated by p38, comprising administering a compound of Formula I
0
II
A....._ A /B
N N
! I
H H
wherein, ....
(Ranges, claim 1.)
Analysis
Appellants contend that rejection is conclusory and "without more,
do[ es] not establish motivation necessary to support a finding of
obviousness." (Br. 7 .)
The Examiner's position is that the Ranges claims are written in open
claim format and encompass additional ingredients such as pharmaceutical
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carriers. (Ans. 12.) Because Ranges' claims "do[] not exclude other
ingredients as in the pharmaceutical composition of [the] instant invention,
... the instant claims and the method of treating a disease comprising
administering pharmaceutical composition claimed in ... [Ranges] are
substantially overlapping" (id.), and thereby obvious.
Furthermore, the Examiner explains that "water is pharmaceutically
acceptable carrier" and that the instant compounds "with the urea linkage
would readily absorb moisture" and therefore the pharmaceutical
composition for the purpose of administering treatment is obvious (see
Ans. 18). We agree with the Examiner's position that one of ordinary skill
in the art would have recognized that formulating the compounds as claimed
in Ranges with a pharmaceutical carrier, such as water, would be obvious for
the purpose of administering the compound to a patient.
On the record before us, we conclude the Examiner did not err in
rejecting claim 1 on the ground of nonstatutroy obviousness-type double
patenting over the claims of Ranges. Claims 2-16 have not been separately
argued and fall with claim 1.
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SUMMARY
We affirm the rejection of claims 1-16 under 35 U.S.C. § 112, first
paragraph as failing to meet the enablement requirement.
We affirm the rejection of claims 1-3, 5, 7-11under35 U.S.C.
§ 103(a) as unpatentable over Widdowson.
We affirm the rejection of claims 1-16 are rejected under the
judicially created doctrine of nonstatutory obviousness-type double
patenting.
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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