Ex Parte Miller et al

Patent Trial and Appeal Board

May 10, 2016

12542556 (P.T.A.B. May. 10, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/542,556 08/17/2009
63467 7590
Ramey & Schwaller, LLP
5020 Montrose Blvd.
Suite 750
Houston, TX 77006
05/12/2016
FIRST NAMED INVENTOR
Dwight W. Miller
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.
20027.0003.NPUSOO 5712
EXAMINER
MCDOWELL, BRIAN E
ART UNIT PAPER NUMBER
1624
NOTIFICATION DATE DELIVERY MODE
05/12/2016 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):
uspto@rameyfirm.com
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte DWIGHT W. MILLER, NEIL C. MITCHELL,
and BILL W. MASSEY1
Appeal2014-000425
Application 12/542,556
Technology Center 1600
Before ERIC B. GRIMES, LORA M. GREEN,
and TIMOTHY G. MAJORS, Administrative Patent Judges.
MAJORS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to
compounds useful for treatment of psychosis. The claims have been rejected
as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
STATEMENT OF THE CASE
"A number of different types of antipsychotics have been developed,
particularly for treating schizophrenia." (Spec. i-f 3.) Per the Specification,
1 Appellants identify the Real Party in Interest as Litmus, L.L.C. (Appeal
Br. 4.)
Appeal2014-000425
Application 12/542,556
"identification of more effective antipsychotic drugs for treating
schizophrenia and related psychotic conditions would be of substantial
value .... [particularly] drugs having reduced incidence of side effects,
especially agranulocytosis, would be of particular benefit." (Id. at i-f 6.)
Claims 31-33 are on appeal.2 (Appeal Br. 6.) Claim 31 is illustrative:
31. A compound having the structure of:
The remainder of claim 31 defines the constituents that comprise Z, X, R3-
R9, and R27. (Appeal Br. 28-32 (Claims App'x).) For example, X may
2 (Appellants state the grounds to be reviewed on appeal include "[ w ]hether
Claim 35 is unpatentable under 35 U.S.C. § 103(a) over Craig." (Reply Br.
6.) Appellants, however, cancelled claim 35. (Appeal Br. 6.) Claim 34,
which Appellants identify only in the Reply Brief (p. 5) as subject to this
appeal, remains objected to (4/25/2013 Adv. Act. 2, 8 ("Claims 31-33 are
rejected. Claim 34 is objected to")), but does not appear to be subject to the
obviousness rejection that is the subject of this appeal. (12/7/2012 Final
Act. 4 (in discussion of obviousness rejection, stating that the "rejection of
claims 31-33 is maintained); see also 4/25/2013 Adv. Act. 3 (same).)
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Application 12/542,556
comprise H, F, Cl, or Br. R27 may comprise H, a C 1-C4 alkyl (such as
methyl, ethyl, propyl, butyl), or phenyl. (Id.)
The Examiner rejected claims 31-33 under 35 U.S.C. § 103(a) as
being unpatentable over Craig3 in view of Hegde. 4
DISCUSSION
Issue
The Examiner finds, and Appellants do not dispute, that the only
structural difference between a species of the claimed compound and the
prior art is the number of methylene (CH2) units in the spacer linking two
ring structures.
(Ans. 3--4.) As depicted in the boxes overlaying the chemical structures, the
claimed compound has two methylene groups linking a piperazine ring to
tricyclic rings, while the prior art compound has three methylene groups.
3 Craig et al., U.S. 3,043,842 ("Craig").
4 Ravi Hegde et al., Anti-calmodulin acridone derivatives modulate
vinblastine resistance in multidrug resistant (MDR) cancer cells, 39
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 161-177 (2004).
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Appeal2014-000425
Application 12/542,556
The Examiner finds that these compounds are homologs, and that the
addition or deletion of a single methylene group in the spacer is an obvious
modification that the skilled person would expect produces compounds
having similar properties. (Id. at 5---6.)
Appellants respond with a declaration from a co-inventor on the
present application, which Appellants argue rebuts the Examiner's
obviousness rejection.
The issue is whether, on this record, the Examiner has established by a
preponderance of the evidence that claims 31-33 would have been obvious.
Findings of Fact
1. Craig teaches "substituted acridans of this invention have utility as
mild sedative agents and tranquilizers and can be used, for example, to abate
mental disturbances, such as anxiety, confusion or physical excitation
without any concomitant physical incapacitation. They are also useful as
antiemetics. Further, their utility is greatly enhanced by their low
toxicities." (Craig col. 1, 11. 9-17.) Craig discloses the following structure:
G1I~
-~l \ ~
l (l Joi
'V . 11/ "'-<./l .-~----------,
l . "(_.'Y- • ".._i . . ~"<;,." ' "-.,.. ...~ "
CkfaC.U.~(~Ji~'""'"'"'.N .N-cu~
""'-"\, ................ -..................... ·
(Id. at col. 10, claim 4.)
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Application 12/542,556
2. Hegde discloses acridans with a spacer linking the piperazine ring
to a fused tricyclic ring like the claimed compounds. 5 (See, e.g., Hegde p.
164, Table 1.) The Hegde compounds have three or four methylene units in
the spacer. (Id. (Comp. No. 3A and Comp. No. 9A).) Hegde teaches the
biological activity (inhibition of P-glycoprotein-mediated multi-drug
resistance as shown by vinblastine accumulation in cells) between these
compounds is substantially similar despite having either three or four
methylene units in the spacer (619% and 680%, respectively, of the control).
(Id. at pp. 161-162, 164--165, Table 1.)
Principles of Law
"[H]omologs are presumptively obvious over known compounds." In
re Basel! Poliolefine Italia SP.A., 547 F.3d 1371, 1378 (Fed. Cir. 2009).
"To be particularly probative, evidence of unexpected results must
establish that there is a difference between the results obtained and those of
the closest prior art, and that the difference would not have been expected by
one of ordinary skill in the art at the time of the invention." Bristol-Myers
Squibb Co. v. Teva Pharma USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014).
5 The compounds of Hegde relied upon by the Examiner include a C=O at
the Z position, H at the X position, and a single methyl group at R27. (Hegde
p. 164, Table 1.)) Each of these positional constituents is within the scope of
claim 31. Thus, the only structural difference from the claimed compound is
Hegde has either three or four methylene units in the spacer, not two as in
the claims.
5
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Application 12/542,556
Analysis
The Examiner contends that claims 31-33 would have been obvious at
the time of the invention. More specifically, the Examiner finds
"[ s ]ubstituted acridans similar to the claimed [] species have been shown in
the art to treat mental disturbances at the time the invention was conceived."
(Ans. 3 (citing Craig).) According to the Examiner,
[t]he only difference between Applicant's compound and the
prior art compound is that the spacer linking the piperazine ring
to the fused tricyclic ring contains 2 methylene units instead of
3 methylene units, respectively .... Compounds that differ
only by the presence or absence of an extra methyl group or two
are homologues. Homologues are of such close structural
similarity that the disclosure of a compound renders prima facie
obvious its homologue ... The homologue is expected to be
preparable by the same method and have generally the same
properties. This expectation is then deemed the motivation for
preparing homologues.
(Id. at 3--4 (citations omitted).) The Examiner also cites Hegde as teaching
"analogous acridans ... wherein the spacer linking the piperazine ring to the
fused tricyclic ring was changed from 4- to 3-methylene units; consequently
affording compounds possessing near identical biological activity." (Id. at
5---6.) The Examiner concludes "the skilled artisan would have expected any
homologous change with respect to this spacer would afford a compound
with similar activity. Thus based on the art and known relevant case law, at
the time the invention was conceived the claimed compound would have
been considered prima facie obvious." (Id.)
Appellants respond with the declaration of William Massey, Ph.D.
(the "Declaration"), which Appellants argue "rebuts the Examiner's alleged
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Application 12/542,556
prima facie rejection and requires the Examiner to submit further evidence."
(Appeal Br. 19.) Appellants contend the Examiner has "not provided any
evidence showing that a decrease in methylene linkers, per the instant
claims would be biologically equivalent to either Craig or Hedge [sic]"
while the Declaration "clearly explains why a decreased linker of 2-
methylene groups is used and the problem that it solves." (Id. at 20 (citing
Deel. i-f 6).) Appellants also argue that "even minor variations of the
structure of the chemical compound can have dramatic effects." (Id. at 24.)
Appellants again cite the Declaration for support, which states
As a skilled pharmacologist, I would not consider the
compound in [Craig] a functional homologue of the claimed
compound of the present invention. There are too many
variables. First, the compounds listed in [Craig] are thought to
function as mild sedative agents whereas the compounds of the
present application are thought to function as antipsychotics for
the treatment of schizophrenia. Second, our research has
demonstrated that even the deletion of a single methyl group
can result in surprisingly unexpected differences in binding
properties. Even a 1 carbon difference in such a linkage chain
dramatically changes the overall molecular shape and steric
properties that can affect the molecules receptor affinities. For
instance, Table 1 of the present invention demonstrates that the
simple deletion of a methyl group in otherwise identical
compounds can result in three fold differences in binding to a
number of receptors.
(Id. at 24--25; Deel. i-f 5.) Appellants conclude they have "presented
substantial evidence that anti-psychotics are not a degree of improvement
over sedatives and vice versa ... [and] also supplied substantial evidence
that even minor changes in structure of the compound can result in different
receptor binding properties." (Appeal Br. 26-27.)
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Application 12/542,556
Appellants' arguments and evidence are unpersuasive. The prior art
differs from the claims merely due to the presence of an additional
methylene unit in the spacer linking two identical ring structures. (FF 1-2.)
Craig discloses such a compound is suitable for treatment of "mental
disturbances." (FF 1.) The Examiner has supplied further evidence that
modifying the number of methylene units in the spacer had little to no
impact on biological activity. (FF 2.) And the Examiner explained why,
based on this evidence and substantial case law, the claims would have been
prima facie obvious. See e.g., In re Basel! Poliolefine Italia SP.A., 547 F.3d
at 1378. For the reasons discussed below, Appellants' evidence and
argument does not overcome the Examiner's rejections.
Appellants fail to address the key issue: whether the claimed
compound having two methylene units in the spacer versus the applied prior
art with three methylene units would be expected to exhibit, or that it indeed
exhibits, material and nonobvious differences in biological activity.
Appellants have not pointed to any evidence that the claimed compounds
show any unexpected results over the closest prior art. Bristol-Myers
Squibb, 752 F.3d at 977; In re Baxter Travenol Labs., 952 F.2d 388, 392
(Fed. Cir. 1991) ("when unexpected results are used as evidence of
nonobviousness, the results must be shown to be unexpected compared with
the closest prior art."). Likewise, Appellants do not direct us to any
evidence that the prior art compound disclosed in Craig would not exhibit
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Application 12/542,556
antipsychotic activity or that it would carry any side effects relative to the
claimed compounds. 6
Rather than addressing the prior art compound applied by the
Examiner, Appellants focus on another prior art compound that has a
structure further away from the invention. Appellants' Declaration explains
why the inventors created a compound with a methylene spacer compared to
prior art clozapine - a compound having no spacer and a different tricyclic
ring structure. (Deel. i-f 6; Reply Br. 8-9 (depicting clozapine ).) The
addition of a methylene spacer may help isolate the ring structures and avoid
harmful agranulocytosis, which the Declaration theorizes is due to the
absence of a spacer linking the rings in clozapine. (Id.) But the prior art that
forms the basis of the present rejections, like the claimed compound,
includes a methylene spacer. And Appellants' evidence does not explain
why otherwise identical compounds that include two versus three methylene
units in a spacer would have been expected to have dissimilar properties.
Appellants critique the Examiner for showing how an "increase"
rather than a "decrease" in the number of methylene units in a spacer would
produce a biologically equivalent compound. (Appeal Br. 20.) The
Examiner has, however, shown prior art compounds with three or four
methylene units in the spacer with equivalent biological activity. (FF 2;
Ans. 5---6.) Whether this is characterized as an increase from three to four or
a decrease from four to three is immaterial. Although Appellants contend
that adding a spacer where none existed (e.g., clozapine) may avoid side
6 The claims are to the compounds alone, not methods of treating psychosis.
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Application 12/542,556
effects, Appellants have supplied no evidence showing that the number of
methylene units in the spacer significantly changes the compound's
biological activity.
Appellants argue that "even minor variations of the structure of the
chemical compound can have dramatic effects." (Appeal Br. 24.) In
support, Appellants cite the Declaration and Table 1 of the Specification,
which shows testing of two embodiments of the claimed compound for
receptor affinity. (Id. at 24--25.) Here too, Appellants' evidence misses the
mark. As the Examiner correctly points out, the structural difference
between the two compounds in Table 1 is at position R27 and "the data does
not reveal any nexus" between variable R27 and the spacer linking the two
rings together. 7 (Ans. 8.) Moreover, these embodiments, which differ by
having either a methyl or an ethyl group at R27, are both within the scope of
the claim. At best this shows Appellants are claiming species with
"surprisingly unexpected differences in binding properties" for some
receptors.8 (Deel. i-f 5.) Yet it reveals nothing surprising or unexpected
relative to the closest prior art cited in the rejection.
7 The Declaration states "[ e ]ven a 1 carbon difference in such a linkage
chain dramatically changes the overall molecular shape and steric properties
that can affect the molecules receptor affinities." (Deel. i-f 5.) Table 1 of the
Specification, which the Declaration relies upon for this proposition, relates
to molecular changes unrelated to the "linkage chain." (Spec. i-fi-1196-197.)
8 The data in Table 1 shows that for many receptors - including 5-HT 2a and
D2, which are of special interest in the Specification - there was little to no
effect on receptor affinity despite the structural change. (Id. at i-fi-1 64, 196-
197.) Thus, Appellants' evidence may also be interpreted as showing that,
in many cases, the addition or deletion of a single methylene unit at R27 had
little impact on biological activity.
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Finally, we are unpersuaded by the Declaration's assertion that
persons of skill in the art would not consider Craig a functional homolog of
the claimed compound. (Id.; Appeal Br. 24.) The Declaration states that
there are "too many variables" and that Craig's compounds are "thought to
function as mild sedative agents whereas the compounds of the present
application are thought to function as antipsychotics." (Deel. i-f 5.) But no
detail or data is provided to explain why a person of skill in the art would
conclude that compounds differing by only a single methylene unit in the
spacer would have dissimilar properties.
Conclusion of Law
The claims have not been argued separately and, therefore, fall
together. 37 C.F.R. § 41.37(c)(l)(iv). We conclude the Examiner
established by a preponderance of the evidence that claims 31-33 would
have been obvious under 35 U.S.C. § 103(a) over Craig, in view ofHegde.
SUMMARY
We affirm the rejections of claims 31-33 under 35 U.S.C. § 103(a)
over Craig, in view of Hegde.
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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