Ex Parte Lapierre et al

Patent Trial and Appeal Board

Mar 21, 2016

12631579 (P.T.A.B. Mar. 21, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO.
12/631,579
58249 7590
COOLEYLLP
ATTN: Patent Group
FILING DATE
12/04/2009
03/23/2016
1299 Pennsylvania Avenue, NW
Suite 700
Washington, DC 20004
FIRST NAMED INVENTOR
Jean-Marc Lapierre
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.
22596-621001US 2048
EXAMINER
HEYER, DENNIS
ART UNIT PAPER NUMBER
1628
NOTIFICATION DATE DELIVERY MODE
03/23/2016 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):
zpatdcdocketing@cooley.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JEAN-MARC LAPIERRE, Y ANBIN LIU,
MANISH TANDON, and MARK A. ASHWELL 1
Appeal2013-007697
Application 12/631,579
Technology Center 1600
Before LORA M. GREEN, JOHN G. NEW, and RICHARD J. SMITH,
Administrative Patent Judges.
NEW, Administrative Patent Judge.
DECISION ON APPEAL
1 Appellants state the real party-in-interest is ArQule, Inc. App. Br. 2.
Appeal2013-007697
Application 12/631,579
SUMMARY
Appellants file this appeal under 35 U.S.C. § 134(a) from the
Examiner's Final Rejection of claims 1--4, 6, 8-13, and 15 as unpatentable
under 35 U.S.C. § 103(a) as being obvious over the combination of Lapierre
et al. (WO 2007/123892 A2, November 1, 2007) ("Lapierre") and Valentino
J. Stella and Kwame W. Nti-Addae, Prodrug Strategies to Overcome Poor
Water Solubility, 59 ADV. DRUG DELIVERY REVIEWS 677-94 (2007)
("Stella").
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
NATURE OF THE CLAIMED INVENTION
Appellants' invention is directed to imidazooxazole and
imidazothiazole compounds and their syntheses. The compounds of the
present invention are capable of inhibiting the activity of Rapidly
Accelerated Fibrosarcoma ("RAF") kinase, such as B-RAFv600E. The
compounds are useful for the treatment of cell proliferative disorders such as
cancer. Abstract.
REPRESENTATIVE CLAIM
Claim 1 is representative of the claims on appeal and recites:
1. A compound of formula I, or pharmaceutically
acceptable salts thereof:
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App. Br. 18.
wherein
m is an integer from 1 to 3;
n is an integer from 1 to 3;
o is an integer from 0 to 2;
Ri is hydrogen, halogen, substituted or unsubstituted
alkyl, -CN, -COQR4, -OR4, or -NR4Rs,
R2 and R3 are independently hydrogen, substituted or
unsubstituted lower alkyl, -COQR4, or -C(O)NR4Rs;
each R4 and each Rs are independently hydrogen,
substituted or unsubstituted alkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted
heterocyclyl, or R4 and Rs, taken together, may form a
nng;
R6 is a (C1- Cs) alkyl-substituted heteroaryl group; and
R7 is (CH20)o -P(O)QR40Rs.
THE EXAMINER'S REJECTION
The Examiner has concluded it would have been prima facie obvious
to one of ordinary skill in the art, at the time the invention was made, to
select one of the most highly potent B-RAF inhibitor compounds of
Lapierre, compound 3 7 6, as a lead compound for further investigation.
Final Act. 9. The Examiner finds it would have been obvious to modify
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compound 376 and to modify the phenol hydrogen (R7) in compound 376 of
Lapierre with a phosphate ester (R7 = CH20)a-P(O)OR40Rs; in which o =O
or 1 and R4 =Rs= 0 or 1 and R4 = R5 =Hor Na; i.e., a prodrug wherein R7
is Hor CH20H after hydrolysis, instant Claim 9). Final Act. 9-10. The
Examiner finds one would have been motivated to do so because Stella
teaches that substituting the hydrogen of a drug containing an OH group
with an ionizable phosphate ester improves drug delivery because the
compound formed will function as a prodrug which provides the benefit of
increased solubility, rapidly dissolution in the gastrointestinal tract and
cleavage to the parent drug (ROH) by the enzyme alkaline phosphatase
allowing the parent to enter the systemic circulation. Id. at 10. Further, one
would have been motivated to modify compound 376 with a phosphate
group because Lapierre teaches an embodiment wherein when one or more
water solubilizing moieties (a promoiety), such as a phosphate group, is
covalently linked to said compound to form a prodrug said prodrug exhibits
the added benefit of increased aqueous solubility, improved stability,
bioavailability and/or in vivo delivery or uptake. Id.
We agree with the Examiner's findings and reasoning, except as noted
below, and conclude the Examiner has set forth a prim a facie case of
obviousness.
ISSUES AND ANALYSES
Issue 1
Appellants argue the Examiner erred in finding the combined cited
prior art references teach or suggest the oxazole moieties or the phosphate
moiety at R7 as recited in the compounds of claim 1. App. Br. 8.
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Application 12/631,579
Analysis
Appellants argue the claimed compounds are directed to compositions
that comprise an oxazole moiety and a phosphate moiety at R7 (as indicated
by the arrows below):
App. Br. 8. Appellants maintain the compound taught by Lapierre that is
closest to the claimed compound, as found by the Examiner, is compound
376, which differs from the claimed compounds in that it has a thioxazole
(S) moiety in place of an oxazole (0) and a phenolic moiety with R7 being H
(on the positions indicated by the arrows in the depiction above). Id.
According to Appellants, Lapierre provides no guidance that would
lead a person skilled in the art to make the two modifications asserted by the
examiner, viz., changing the S to an 0, and adding a phosphate group (R7) to
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Application 12/631,579
the hydroxyl group of the phenolic moiety, and have a reasonable
expectation of successfully obtaining satisfactorily active compounds to treat
tumors. App. Br. 9. Appellants assert the Examiner has ignored the fact that
Lapierre teaches four hundred ( 400) compounds, on the premise that a
skilled artisan would start its investigation at one of the most promising
compound (i.e., compound 376) with an ICso of 1 nM. Id. Appellants
contend the Examiner allegedly ignores Lapierre's most active compound,
compound 354 with an ICso of 0.3 nM, which differs from the claimed core
structure in that it has neither an oxazole, nor phosphate at R7, and no R6 -
substituted heteroaryl group. Id. For these alleged omissions, Appellants
argue the examiner is impermissibly using hindsight in allegedly "zeroing
in" on compound 376 to begin the analysis. Id.
Appellants next argue Lapierre does not suggest modifying the
thiazole moiety for an oxazole moiety in compound 376 because Lapierre
does not teach any oxazole compounds having a biological activity
comparable to that of compound 354. App. Br. 10-11. Appellants point out
that Lapierre teaches nine very active compounds having an ICso within the
same order of magnitude compound 376 (i.e.,< 5 nM). Appellants assert
that none of these compounds have an oxazole moiety, rather, all have a
thiazole moiety. Id. (citing compounds 121, 288, 353, 354, 367, 371, 372,
374, and 376).
Appellants contend that, of the compounds taught by Lapierre
possessing an oxazole moiety compound, compound 388 is almost an order
of magnitude less active than compound 3 7 6 and the rest are even less
potent, with Icsos of > 10 nM. App. 11. According to Appellants, Lapierre
teaches nine compounds with oxazole moieties among the forty-six most
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Application 12/631,579
active compounds, however, none of these compounds, Appellants contend,
reads on the claimed compounds, as R6 is not a (C 1-C8) alkyl substituted
heteroaryl moiety and all lack the phosphate moiety at R7. Id.
Finally, Appellants argue that, assuming a person of ordinary skill
elected to employ compound 354 (the most potent inhibitor) as lead
compound, there is no explicit teaching in Lapierre that would tend to lead
that person to the claimed compound. App. Br. 12. Appellants assert there
are simply too many possible variations to lead an artisan of ordinary skill to
the claimed compound without undue experimentation. Id. at 13.
The Examiner responds that an artisan of ordinary skill would have
been motivated to select compound 376 as a potential lead compound for
further investigation because compound 3 7 6 is taught by Lapierre as one of
the most highly potent B-RAF inhibitor compounds, having an ICso = 1 nM.
Ans. 10 (citing Final Act. 9; Adv. Act. 2-3 (August 22, 2012)). The
Examiner finds a selection of any compound as a suitable "lead" requires
recognizing that, of the total number of compounds for which IC so data is
disclosed, compound 376 is one of the most potent. Id. The Examiner
acknowledges that compound 354 is somewhat more potent than compound
376 (ICso of 0.3 vs 1 nM) and could also be reasonably viewed as an
alternative choice for a lead compound that one of ordinary skill could have
selected for further investigation. Id. However, the Examiner finds
compound 3 7 6, as the second most potent compound of the 400 disclosed by
Lapierre, also qualifies as a reasonable choice of a lead compound. Id. at 11.
Furthermore, the Examiner points out that any obviousness analysis
necessarily employs a degree of hindsight reasoning, but as long as it takes
into account only knowledge which was within the level of ordinary skill at
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the time the claimed invention was made, and does not include knowledge
gleaned only from the applicant's disclosure, such a reconstruction is proper.
Ans. 11-12 (citing In re McLaughlin, 443 F.2d 1392, 1395 (C.C.P.A. 1971).
In the present case, the Examiner's findings relied exclusively on the
teachings of Lapierre, which teaches compound 3 7 6 as the second most
potent of 400 B-RAF inhibitor compounds. Id. at 12.
The Examiner finds Lapierre teaches examples of oxazole moiety
compounds having potency that is either greater than, or comparable to, the
corresponding thiazole moiety compounds (e.g. compound 322 v. compound
266 or compound 111 v. compound 320).2 The Examiner further finds that
compound 388, which has the oxazole moiety and an ICso of 9 nM, is one of
the ten most potent of the 400 compounds disclosed by Lapierre. Ans. 13.
Finally, the Examiner admits that although a large number of
structural modifications are theoretically possible, as argued by Appellants,
one of ordinary skill in the art, reading the teachings of Lapierre, would have
been motivated to substitute the thiazole moiety with an oxazole moiety
because the feature of an oxazole moiety is, 1) disclosed by Lapierre in 150
of 400 compounds, 2) is present in 20% of the 46 most potent compounds,
and; 3) in some examples, confers potency comparable to, or more potent
than, the corresponding thiazole compound. Ans. 18. The Examiner
therefore concludes it would have been obvious, not only to select
2 In this particular instance, however, we partially disagree with the
Examiner's findings. Compound 322, with an oxazole substitution, has an
ICso of 46, whereas compound 266, with a thiazole substitution, has an ICsO
of 29, making it the more potent inhibitor. However, we agree that
compound 111 (thiazole substitution, ICso = 28) is less potent than
compound 320 ( oxazole substitution, ICso = 10).
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compound 376 (i.e., a single compound) as a lead compound for further
investigation, but also to preferentially modify the thiazole moiety with an
oxazole moiety with a reasonable expectation of obtaining a compound with
similar properties. Id.
We are not persuaded by Appellants' arguments. Appellants contend
that the appropriate lead compound should be compound 354 because it has
the most potent inhibitory capability (ICso = 0.3 nM). However, compound
376 is the second most potent inhibitor (ICso = 1.0 nM) and our reviewing
court has warned that to treat only the most potent species of a given genus
as a lead compound would be to adopt too restrictive a test upon which to
base an obviousness analysis:
[T]o the extent ... that the prior art must point to only a single lead
compound for further development efforts, that restrictive view of
the lead compound test would present a rigid test similar to the
teaching-suggestion-motivation test that the Supreme Court
explicitly rejected in KSR. Cf. [KSR Int'! Co. v. Teleflex Inc., 550
U.S. 398, 419 (2007)] ("The obviousness analysis cannot be
confined by a formalistic conception of the words teaching,
suggestion, and motivation, or by overemphasis on the importance
of published articles and the explicit content of issued patents. The
diversity of inventive pursuits and of modem technology counsels
against limiting the analysis in this way").
Altana Pharma AG v. Teva Pharms. USA, Inc., 566 F.3d 999, 1008 (Fed.
Cir. 2009). We agree that a person of ordinary skill in the art could well
select compound 376 as a lead component for further development due to its
strong inhibitory capability.
Moreover, we also agree with the Examiner's conclusion that a person
of ordinary skill would find it obvious to substitute an oxazole moiety for the
thiazole moiety to arrive at the claimed compound. Of the 400 compounds
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taught by Lapierre, all have either a thiazole or an oxazole at the same
location, 150 of these being an oxazole. Moreover, although the most potent
compounds are generally those with the thiazole moiety, there are examples
in which the oxazole-substituted compound is a more potent inhibitor than
the identical molecule with a thiazole substitution (e.g., compound 320 v.
compound 111 ). Moreover, the compounds show a wide variation in
potency, and thus the ordinary artisan would have had a reason to substitute
the oxazole for the thiazole with an expectation that the modified compound
may have similar or increased potency. We consequently agree with the
Examiner's conclusion that it would have been obvious to one of skill in the
art to substitute an oxazole moiety for a thiazole moiety in compound 367.
Issue 2
Appellants argue the Examiner erred because Lapierre teaches away
from the claimed composition. App. Br. 13.
Analysis
Appellants argue Lapierre teaches away from selecting oxazole
derivatives having a C1-Cs alkyl substituted heteroaryl group for R6. App.
Br. 13. According to Appellants, although Lapierre teaches compounds
(oxazole and thiazole derivatives) with unsubstituted heteroaryl groups with
very good activities (e.g., compounds 367, 371, and 388), all of the oxazole
derivatives with a C1-Cs alkyl substituted heteroaryl group for R6 have very
poor activities (e.g., compounds 64, 65, 66, 228, 230, and 248). Id.
Appellants contend a person skilled in the art would not have been
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motivated from the teachings of Lapierre to prepare the compounds as
presently claimed with any reasonable expectation of success. Id.
Appellants argue further that Lapierre presents seven sites where such
a phosphate moiety could be potentially introduced; however, Appellants
assert Lapierre does not suggest the Ri or R2 positions (which corresponds to
R7 of claim 1) for such phosphate group, but rather teaches a substitution at
R4 (which corresponds to R3 in present claim 1). App. Br. 13-14.
Appellants allege the Examiner ignores the fact that Lapierre also suggests
making other types of derivatives, such as amino acid moieties, without any
discussion of the resulting effects on the physical properties of such
modified compounds. Id. at 14. Appellants contend a skilled artisan,
reading the teachings of Lapierre, would not consider the R 7 position for
preparing the phosphate derivative, or if so, such an artisan would also have
to consider a number of possible sites for introducing a solubilizing moiety
other than R7. Id.
The Examiner responds that none of the oxazole moiety compounds
pointed to by Appellants (i.e., compounds 64, 65, 66, 228, 230, and 248) as
having a C1-Cs alkyl substituted heteroaryl group at R6, were compared in
Lapierre to an otherwise structurally identical thiazole moiety compound.
Ans. 19. The Examiner finds, given that Lapierre teaches 150 oxazole-
substituted compounds, many of which are very potent, one of ordinary skill
would not have reasonably concluded that the poor activity of compounds
64, 65, 66, 228, 230, and 248 was necessarily due to the presence of an
ozaxole moiety combined a C 1-C8 alkyl substituted heteroaryl group at R6.
Id.
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The Examiner also finds it is well-recognized in the pharmaceutical
art that the activity of any particular compound is determined by a complex
interaction between the entire structure of the compound and its biological
host (e.g., a receptor or enzyme active site). Ans. 19. The Examiner
therefore concludes a person of ordinary skill would not necessarily
conclude that the poor activity of compounds 64, 65, 66, 228, 230, and 248
was due to the presence of the oxazole moiety per se, in view of the potent
activity observed in Lapierre for numerous alternative oxazole compounds.
Id. at 19-20.
The Examiner finds further that, although Lapierre teaches the very
potent compound 376, which contains a thiazole moiety and a C1-Cs alkyl
substituted heteroaryl group for R6, Lapierre does not disclose the
corresponding oxazole moiety analogue. The Examiner therefore finds one
of ordinary skill would not have necessarily concluded that substituting the
thiazole moiety for an oxazole moiety in lead compound 376 would lead to a
compound with poor activity. Id.
With respect to phosphate substitution, the Examiner finds Lapierre
explicitly teaches that B-RAF inhibitor compounds can be covalently linked
to one or more water solubilizing moieties (a promoiety) to form a prodrug.
Ans. 21 (citing Final Act. 7-8 (citing Lapierre pp. 14--15, 11. 25-5)). The
Examiner finds Lapierre teaches the active compound can be released from
the promoiety by hydrolytic, oxidative and/or enzymatic release mechanisms
and adds benefit of increased aqueous solubility, improved stability,
bioavailability and/or in vivo delivery or uptake. Id.
The Examiner therefore concludes one of ordinary skill in the art
would have been motivated to a lead compound by covalently attaching a
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phosphate promoiety to the phenol group of compound 376 (R7), as opposed
to the other positions suggested by Appellants, to form the instantly claimed
compounds, because: ( 1) Lapierre makes an explicit suggestion to form a
phosphate prodrug in order to improve properties such as solubility,
stability, bioavailability, etc. and; (2) the formation of a phosphate at a
phenol position, wherein said phosphate improves water solubility and
functions as a prodrug, is well known in the art (as discussed with reference
to Stella, infra).
We are not persuaded by Appellants' arguments. A reference may be
said to teach away when "a person of ordinary skill, upon reading the
reference, would be discouraged from following the path set out in the
reference, or would be led in a direction divergent from the path that was
taken by the applicant." In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994).
Appellants point to no explicit teaching or suggestion of Lapierre that would
necessarily discourage or divert a person of ordinary skill from attaching a
(C1- Cs) alkyl-substituted heteroaryl group at R6. Lapierre does teach
compounds with this substitution as having low activity but Appellants do
not point to any teachings of Lapierre demonstrating that these compounds
would have improved activity if that substitution were not made. Nor do
Appellants show that highly active compounds, such as compound 376
would have significantly poorer activity if such a substitution (with or
without an oxazole substitution) were made. In short, Appellants point to no
clear teaching or suggestion of Lapierre that teaches away from substituting
a (C1- Cs) alkyl-substituted heteroaryl group at R6.
Nor are we persuaded by Appellants' argument that Lapierre would
discourage or divert an artisan of ordinary skill from attaching a phosphate
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group at the R7 position. Lapierre teaches that adding a phosphate group is
useful in improving the qualities of the resultant prodrug. See Lapierre 14--
15. Moreover, as we discuss infra, Stella teaches the attachment of a
phosphate group to a phenol moiety is well-known in the art and is useful in
improving the qualities of the prodrug. We consequently affirm the
Examiner's findings on this ground.
Issue 3
Finally, Appellants argue the Examiner erred because Stella fails to
cure the alleged defects of Lapierre, argued supra.
Analysis
Appellants argue ( 1) Stella does not teach or suggest the modification
of a thiazole to an oxazole; and (2) Stella does not teach or suggest the
modification of the phosphate group onto position R7. App. Br. 15.
However, we have related supra our reasons for finding that Lapierre
teaches these limitations.
The Examiner also finds Stella teaches prodrugs improve oral and
parenteral delivery of drugs with poor water solubility, that phosphate ester
prodrugs are well known in the art, and have been shown to be very effective
at improving drug delivery. Ans. 25. The Examiner further finds Stella
teaches several examples of structurally diverse phosphate prodrugs which
show enhanced oral delivery where the phosphate promoiety corresponds to
R7 = (CH20)a-P(O)(OH)2 where o = 0 or 1). Id. (citing Final Act. 9 (citing
Stella Table 1 )). The Examiner finds Stella teaches how structurally diverse
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compounds bearing a hydroxyl or phenol group can be successfully
modified as a phosphate ester and function as prodrugs. Id.
In response to Appellants contention that Stella does not suggest to
select phosphate moieties over a variety of other moieties (App. Br. 15), the
Examiner finds that modifying the oxazole analogue of lead compound 376
is based on the explicit teaching of Lapierre, proposing two classes of
promoieties for a prodrug; amino acids and phosphates. Ans. 25.
We agree with the Examiner. As related supra, Lapierre teaches a
phosphate group provides benefits when employed as a promoiety of a
prodrug and Stella explicitly teaches phosphate promoieties are effective
when attached to a phenol group. We therefore conclude that a person of
ordinary skill in the art would find it obvious to combine the teachings of
Lapierre and Stella to arrive at the claimed compound, and we consequently
affirm the Examiner's rejection of the claims.
CONCLUSION
For the reasons set forth supra, we conclude that the Examiner has
demonstrated by a preponderance of the evidence that claims that claims 1-
4, 6, 8-13, and 15 are rendered obvious by the combination of Lapierre and
Stella ..
DECISION
The Examiner's rejection of claims 1--4, 6, 8-13, and 15 as
unpatentable under 35 U.S.C. § 103(a) is affirmed.
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No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l). See 37 C.F.R.
§ 1.136(a)(l )(iv).
AFFIRMED
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