Ex Parte Kawai

Patent Trial and Appeal Board

Oct 27, 2017

13264280 (P.T.A.B. Oct. 27, 2017)

United States Patent and Trademark Office
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
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/264,280 01/03/2012 Megumi Kawai 0412.01PCT-US 3765
25871 7590 10/31/2017
SWANSON & BRATSCHUN, L.L.C.
8210 SOUTHPARK TERRACE
LITTLETON, CO 80120
EXAMINER
BADIO, BARBARA P
ART UNIT PAPER NUMBER
1628
NOTIFICATION DATE DELIVERY MODE
10/31/2017 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):
efspatents @ sbiplaw.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte MEGUMI KAWAI
Appeal 2017-0037081
Application 13/264,280
Technology Center 1600
Before RICHARD M. LEBOVITZ, RYAN H. FLAX, and DAVID COTTA
Administrative Patent Judges.
LEBOVITZ, Administrative Patent Judge.
DECISION ON APPEAL
This appeal involves claims directed to vitamin D3 derivatives and
their use to treat diseases and conditions. The Examiner rejected the claims
under 35 U.S.C. § 103 as obvious. We have jurisdiction under 35 U.S.C.
§ 6(b). The Examiner is affirmed-in-part.
1 The Appeal Brief (“Br.”) identifies Vidasym Inc., as the real-party-in-
interest. Br. 3.
Appeal 2017-003708
Application 13/264,280
STATEMENT OF THE CASE
Claims 1, 3, 4, 10-15, 17—19, 24, and 29 are pending. The claims
stand rejected by the Examiner as follows:
1. Claims 1, 3, 10-15, 17—19, and 24 under pre-AIA 35 U.S.C.
§ 103(a) as unpatentable and obvious in view of US 8,377,913 B2, iss. Feb.
19, 2013 (“Von Geldem”). Examiner’s Answer (“Ans.”) 2.
2. Claims 1, 3, 10-12, 18, 19, and 29 under pre-AIA 35 U.S.C.
§ 103(a) as unpatentable and obvious in view of EP 1 559 708 Al, publ.
Aug. 3, 2005 (“Yamada”). Ans. 5.
There are two independent claims on appeal, claims 1 and 19.
Claim 1, which is illustrative of the claimed subject matter, is
reproduced below:
1. A compound of Formula (I)
(1)
wherein
-R1 is =CH2; or
-R1 is
R6 is optionally substituted Cm2 alkyl or optionally substituted
aryl;
X is oxygen or sulfur; and
a is 0-1;
provided that when a is 1, then R6 is substituted aryl; and
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Application 13/264,280
when a is 0, R6 is optionally substituted Cm2 alkyl;
or a pharmaceutically acceptable salt thereof.
Independent claim 19 is a method of treating a disease or
condition with the same Formula (I) compound depicted above.
The Formula (I) compound is a vitamin D3 derivative and is described
in the Specification as a vitamin D receptor (VDR) agonist. Spec. H 2, 5, 6.
The endogenous VDR agonist is 1,25-dihydroxyvitamin D3, also known as
calcitriol. Id. 12. Calcitriol functions by activating VDR. Id. “The
activated VDR recruits cofactors to form a complex that binds to vitamin D
response elements in the promoter region of target genes to regulate gene
transcription.” Id.
PRINCIPLES OF LAW
To establish obviousness in cases involving new chemical
compounds, the accused infringer must identify some reason
that would have led a chemist to modify a known compound.
Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d
1350, 1357 (Fed. Cir. 2007). Generally, an obviousness inquiry
concerning such “known compounds” focuses on the identity of
a “lead compound.” Eisai Co. Ltd. v. Dr. Reddy’s Labs., Ltd.,
533 F.3d 1353, 1359 (Fed. Cir. 2008). A lead compound is a
compound in the prior art that would be “a natural choice for
further development efforts.” Altana Pharma AG v. Teva
Pharms. USA, Inc., 566 F.3d 999, 1008 (Fed. Cir. 2009). The
motivation to modify that lead compound can come from any
number of sources and need not necessarily be explicit in the
art. “[I]t is sufficient to show that the claimed and prior art
compounds possess a ‘sufficiently close relationship ... to create
an expectation,’ in light of the totality of the prior art, that the
new compound will have ‘similar properties’ to the old.”
Otsuka Pharm. Co., Ltd. v. Sandoz, Inc., 678 F.3d 1280, 1293
(Fed.Cir.2012) (quoting In re Dillon, 919 F.2d 688, 692 (Fed.
Cir. 1990) (en banc)). . . . [I]t is the possession of promising
useful properties in a lead compound that motivates a chemist
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Application 13/264,280
to make structurally similar compounds. . . . Accordingly,
proving a reason to select a compound as a lead compound
depends on more than just structural similarity, but also
knowledge in the art of the functional properties and limitations
of the prior art compounds. See Eli Lilly, 471 F.3d at 1377—79.
Potent and promising activity in the prior art trumps mere
structural relationships.
Daiichi Sankyo Co., Ltd. v. Matrix Laboratories, Ltd., 619 F.3d 1346, 1354
(2010
REJECTION BASED ON VON GELDERN
The Examiner found that Example 8 of Von Geldem falls within the
scope of claim 1. Ans. 3. Von Geldem’s Example 8, as shown in the
structural drawing below (left), differs, inter alia, from Appellant’s claim
17’s Vida-5 (below right) (claim 17 depends from claim 1) by having the
“natural” stereochemical configuration at position 20.
The drawing above on the left is the structure of the compound made
in Example 8 of Von Geldem. Von Geldem, col. 45. The drawing above on
the right is the stmcture of claim 17’s Vida-5 compound. Both compounds
have a methylene (the “I” group) at the R1 position of Formula (I) of claim 1,
both have an oxygen at the X group position of Formula (I), and both have a
hydroxy substituted alkyl group at R6 position of Formula (I). However, at
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Application 13/264,280
position-20, shown by the arrow in the images above, Example 8 is an
epimer having a “natural” stereochemistry of vitamin D (orientation
indicated by line with railroad tracks), which is the R-stereoisomer, while
Vida-5 has an “unnatural” stereochemistry (orientation indicated by solid
line), making it the S-stereoisomer. See Appeal Br. 7.
Von Geldem, however, teaches that its compounds may exist in both
orientations, namely as R or S stereoisomers:
Compounds of the invention may exist as stereoisomers
wherein asymmetric or chiral centers are present. These
stereoisomers are “R” or “S” depending on the configuration of
substituents around the chiral element. . . . The invention
contemplates various stereoisomers and mixtures thereof and
are specifically included within the scope of this invention.
Stereoisomers include enantiomers and diastereomers, and
mixtures of enantiomers or diastereomers. Individual
stereoisomers of compounds of the invention may be prepared
synthetically from commercially available starting materials
which contain asymmetric or chiral centers or by preparation of
racemic mixtures followed by resolution well-known to those
of ordinary skill in the art.
Von Geldem, col. 16,11. 14—29.
Appellant argues that Von Geldem made one unnatural epimer, but
did not pursue any others. Appeal Br. 13. Appellant summarized data in
Von Geldem on binding of the vitamin D derivative to the vitamin D
receptor. Id. at 14. Appellant states:
Von Geldem’s data show that the unnatural epimer has 2.7-fold
worse binding affinity than the corresponding natural epimer.
Thus, one of skill in the art would draw the same conclusion as
Von Geldem apparently did that it is the natural
stereochemistry at the 20 position, which provides more
desirable compounds (all but one (Example 3) of the
exemplified compounds in Von Geldem have the natural
stereochemistry at the 20 position).
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Application 13/264,280
Id.
This argument does not persuade us that the Examiner erred in finding
the stereoisomer at position 20 obvious to one of ordinary skill in the art.
First, while a 2.7 fold difference may have been observed with one
unnatural epimer, Appellant did not provide evidence that such a difference
would have been considered significant or undesirable by one of ordinary
skill in the art. An argument made by counsel in a brief does not substitute
for evidence lacking in the record. Estee Lauder, Inc. v. L ’Oreal, S.A., 129
F.3d 588, 595 (Fed. Cir. 1997).
Second, the reporter gene assay summarized by Appellant in Table 1
of the Brief showed that compound 1 (a natural epimer) and compound 3 (an
unnatural epimer) both had improved activity over calcitriol (0.4 nM and 0.9
nM, respectively, versus 5.9 nM). Appeal Br. 14. Appellant did not provide
evidence, such as testimony by one of ordinary skill in the art, that the lower
activity observed with the unnatural epimer (0.9 nM) as compared to the
natural epimer (0.4 nM) would have not have been considered useful and/or
would have dissuaded one of ordinary skill in the art from making other
epimers with the unnatural configuration at the 20-position.
Moreover, we further note that Table 4 (Von Geldem, cols. 84—85)
shows the calcitriol had an IC50 of 1.6 nM on renin mRNA expression, while
compounds 1 (natural epimer) and 3 (unnatural epimer) had IC50 values of
0.3 nM and 0.4 nM, respectively, again better than calcitriol and less of a
difference between the two epimers than observed in the binding studies
cited by Appellant.
Third, while Appellant contends that Von Geldem did not pursue
unnatural epimers, as mentioned, Von Geldem expressly states that
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Application 13/264,280
“Compounds of the invention may exist as stereoisomers wherein
asymmetric or chiral centers are present” and therefore did not exclude
unnatural epimers. Id. at col. 16,11. 14—15. Thus, given the fact that Van
Geldem expressly teaches that both natural and unnatural epimers are within
the scope of its disclosure, one of ordinary skill in that art would have had
reason to make them. Appellant did not establish by objective evidence that
the difference in activity were so great, than one of ordinary skill in the art
would have been dissuaded from making them. Appellant cites to the lead
compound cases, but does not clearly identify their pertinence to Van
Geldem, where epimers are expressly disclosed in it. Appeal Br. 12. Thus,
this is not a case where a lead compound must be selected because Von
Geldem expressly teaches that stereoisomers are within the scope of the
disclosure, leading one of skill in the art to make such stereoisomers when
“asymmetric or chiral centers are present” as they are in the compound of
Example 8.
In addition, the data in Von Geldem for compounds 1 and 3 (Table 1
in Appeal Br. 14) establish that the different isomer configurations at the 20-
position retain activity, and in some cases are superior to calcitriol, and thus
other epimers would have been reasonably expected to have activity, as well.
For the foregoing reasons, we affirm the rejection of claims 1,17, and
19 as obvious in view of Von Geldem. Claims 3, 10-15, 18, and 24 were
not separately argued and therefore fall with claims 1 and 19. 37 C.F.R.
41.37(c)(l)(iv).
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REJECTION BASED ON YAMADA
The rejection focuses on compounds containing an oxygen at the X
position and a spiro cyclo-propyl at the R6 position of the claimed chemical
structure. We note, however, that Claim 29, which was included in the
rejection, also lists compounds with a methylene group at R6 that do not
appeared to have been examined by the Examiner.
The Examiner cited compounds 108a and 108b from Yamada as
constituting the closest prior art to the claims. Ans. 6.
Compounds 108a and 108b are reproduced below (as annotated
herein) from page 80 of Yamada:
position-2 2
side-chain
The compounds reproduced above have been annotated to label the spiro-
epoxy group in the A-ring and the oxygen at position 22 in the side-chain.2
The principal difference between the claimed subject matter and
compounds 108a and 108b, as identified by the Examiner, is the presence of
the spiro-epoxy group in compounds 108a/108b in contrast to the spiro-
cyclopropyl at position R1 of claim 1. The Examiner found, however, that
Yamada describes a genus of compounds that include spiro-epoxy and spiro-
2 Nomenclature from Sato et al., 40 Bone 293—304 (2007) (“Sato”).
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Application 13/264,280
propyl at the same position, making it obvious to one of ordinary skill in the
art to have modified the spiro-epoxy by replacing it with a spiro-
cyclopropyl, as required by the claim. Ans. 12—13.
Appellant contends that compounds 108a/108b are the intermediates
for making more stable compounds. Appeal Br. 15. Appellant states that
replacing -C- with -O- in the side chain is not desirable. Id. at 16. As
evidence of this, Appellant cites two publications from the same group of
authors as Yamada, published before the application filing date, which
Appellant states, “show that compounds with -O- in the side chain plus
spiro-epoxy and/or its final derivatives in the A-ring (110a/110b in the data
summary shown below) exhibit orders of magnitude weaker potency than
calcitriol).” Id. The data cited by Appellant includes an example in which
oxygen makes the compound 100-fold weaker and an example in which
oxygen makes the compound more than 1000-fold weaker in binding to the
VDR receptor as compared to the same compound without the oxygen. Id.
at 17. Transcription activity is also diminished by the oxygen modification.
Id. For this reason, Appellant contends that one of ordinary skill in the art
would not have selected the spiro epoxy compound with oxygen as the lead
compound for further modification. Id.
Consistent with Appellant’s argument, the Sato publication expressly
states that the “osteoclast-inhibiting activities of 2MD 22-oxa analogs
[containing oxygen at the 22-position] were much lower than those of the
2MD analogs [oxygen absent from the same position].” Sato 297 (Fig. 2
legend). Sato also discloses that in certain analogs “the replacement of a
methylene group (-CH2-) with an oxygen atom at carbon 22 lost the effect on
osteoclastogenesis in the co-cultures.” Id. at 300 (Discussion). Thus, there
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are data and clear statements in Sato that reasonably would have dissuaded
one of ordinary skill in the art from starting with a vitamin D derivative with
an oxygen in the side chain as proposed by the Examiner. While there is
structural similarity between compounds with and without the oxygen, the
detriment to the activity caused by the replacement of a carbon with an
oxygen “trumps mere structural relationships.” Daichhi, 618 F.3d at 1354.
One of ordinary skill in the art would therefore not have chosen a compound
containing an oxygen in the side chain as the lead compound for further
modification because compounds of more promising and potent activity are
present in Yamada/Sato and such oxygen-containing compounds were
expressly stated in Sato to lack activity in some cases. Otsuka, 678 F.3d at
1294—95, 1295-96.
For the foregoing reasons, the obviousness rejection of claims 1, 3,
10—12, 18, 19, and 29 is reversed.
TIME PERIOD
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)(iv).
AFFIRMED-IN-PART
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