Ex Parte McInnes et al

Patent Trial and Appeal Board

Apr 19, 2017

13851661 (P.T.A.B. Apr. 19, 2017)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/851,661 03/27/2013 Campbell Mclnnes USC-323 (829) 8074
22827 7590 04/19/2017
DORITY & MANNING, P.A.
POST OFFICE BOX 1449
GREENVILLE, SC 29602-1449
EXAMINER
REYNOLDS, FRED H
ART UNIT PAPER NUMBER
1675
MAIL DATE DELIVERY MODE
04/19/2017 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 CAMPBELL McINNES and SHU LIU
Appeal 2016-007915
Application 13/851,6611
Technology Center 1600
Before ELIZABETH A. LaVIER, JOHN E. SCHNEIDER, and
RYAN H. FLAX, Administrative Patent Judges.
LaVIER, Administrative Patent Judge.
DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellants seek review of the
Examiner’s rejections of claims 1—5 and 7. We have jurisdiction under 35
U.S.C. § 6(b). For the reasons set forth below, we AFFIRM.
BACKGROUND
The Specification describes methods using in silico models to develop
synthetic CDK/cyclin inhibitors, and the synthetic inhibitors generated
therefrom, which may offer promise as oncology targets. See Spec. 3:20—22,
1 Appellants state the real party in interest is the University of South Carolina.
Br. 1.
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Application 13/851,661
4:27—28; see generally id. at 1:21—3:18. Claim 1, the only independent
claim on appeal, is illustrative:
1. A method for developing a synthetic CDK/cyclin inhibitor for
a first CDK/cyclin complex formed between a first CDK protein
and a first cyclin protein, the method comprising:
developing a first fragment ligated inhibitor from a peptide
inhibitor, the peptide inhibitor including an arginine residue and
a phenylalanine residue, the arginine residue being closer to the
N-terminus of the peptide inhibitor than the phenylalanine
residue, the peptide inhibitor inhibiting a second CDK/cyclin
complex formed between a second CDK protein and a second
cyclin protein, the first fragment ligated inhibitor differing from
the peptide inhibitor by inclusion of a first substitute segment in
place of [[the]] [sic] a first fragment of the peptide inhibitor, the
first substitute segment being a non-peptide fragment, the first
substitute segment comprising a capping group bonded to the
arginine residue or comprising a replacement for the
phenylalanine residue;
determining an affinity of the first fragment ligated inhibitor for
the first cyclin protein from an in silico model of the first
fragment ligated inhibitor complexed with the first cyclin
protein;
based upon this affinity, modifying the first substitute segment
of the first fragment ligated inhibitor one or more times to
develop a second fragment ligated inhibitor comprising the
modified first substitute segment, the second fragment ligated
inhibitor exhibiting an increased affinity for the first cyclin
protein as compared to the first fragment ligated inhibitor based
upon in silico modeling of the second fragment ligated inhibitor
complexed with the first cyclin protein;
following development of the second fragment ligated inhibitor,
developing a third fragment ligated inhibitor, the third fragment
ligated inhibitor differing from the peptide inhibitor by inclusion
of the modified first substitute segment and also by inclusion of
a second substitute segment in place of a second fragment of the
peptide inhibitor, the second substitute segment being a non-
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Application 13/851,661
peptide fragment, the second substitute segment comprising a
capping group bonded to the arginine residue or comprising a
replacement for the phenylalanine residue;
determining an affinity of the third fragment ligated inhibitor for
the first cyclin protein from an in silico model of the third
fragment ligated inhibitor complexed with the first cyclin
protein;
based upon the affinity, modifying the second substitute segment
of the third fragment ligated inhibitor one or more times to
develop a fourth fragment ligated inhibitor comprising the
modified first substitute segment and the modified second
substitute segment, the fourth fragment ligated inhibitor
exhibiting an increased affinity for the first cyclin protein as
compared to the third fragment ligated inhibitor based upon in
silico modeling of the fourth fragment ligated inhibitor
complexed with the first cyclin protein;
forming the fourth fragment ligated inhibitor in vitro; and
carrying out an in vitro assay to determine the inhibitory effect
of the fourth fragment ligated inhibitor on the CDK/cyclin
complex formed between the first CDK protein and the first
cyclin protein.
Br. 14—15 (Claims Appendix).
REJECTIONS MAINTAINED ON APPEAL
1. Claims 1—5 and 7 stand rejected under 35 U.S.C. § 103 as
unpatentable over Liu,2 Andrews,3 and Sintchak.4 Ans. 3.
2 Liu et al., Structural and Functional Analysis of Cyclin D1 Reveals p27 and
Substrate Inhibitor Binding Requirements, 5 ACS Chem. Bio. 1169 (2010).
3 Andrews et al., REPLACE: A Strategy for Iterative Design of Cyclin-Binding
Groove Inhibitors, 7 ChemBioChem 1909 (2006).
4 Sintchak & Nimmesgem, The Structure of Inosine 5’-monophosphate
Dehydrogenase and the Design of Novel Inhibitors, 47 Immunopharm. 163
(2000).
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2. Claims 1, 2, 4, 5, and 7 stand rejected for non-statutory double
patenting as unpatentable over claims 1,3, 8—12 and 14 of the ’072
patent5 in view of Sintchak. Ans. 9.
DISCUSSION
A. Rejection 1
The Examiner relies on a combination of Liu, Andrews, and Sintchak
to reject claims 1—5 and 7 as unpatentable under § 103. See Non-Final
Action 3—8; Ans. 3—8. We adopt the Examiner’s findings and conclusions as
set forth in the Final Action and Answer, as further discussed below.
1. Teachings of the References Individually
Appellants argue generally that none of the references teaches or
suggests the type of iterative6 method, using successive rounds of in silico
modeling, recited in claim 1. See Br. 7—11. Specifically, Appellants argue
the modified inhibitors in Liu “were synthesized and were not modeled,” nor
were the modified inhibitors subsequently optimized via in silico affinity
determination. Br. 7. Appellants further assert that Andrews’ iterative
method amounts to a “plug-and-chug” approach, in which each of 4,500
potential capping groups were modeled and scored in each of 10 different
poses, resulting in 45,000 virtual screenings. Id. at 7—8. In contrast,
Appellants describe their claimed method as utilizing “an in silico affinity
determination in order to modify and thus optimize a single non-peptide
5 Mclnnes et al., US 8,566,072 B2, issued Oct. 22, 2013.
6 Claim 1 does not use the word “iterative.” However, both Appellants and
the Examiner use this term in describing the claimed method and in comparing
it to the prior art, as discussed herein.
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Application 13/851,661
fragment.” Id. at 8. Appellants also distinguish Sintchak’s iterative method
as being one that “simply looks at the structure and activity information of
each of these multiple different compounds one by one in an iterative
fashion.” Id. at 10.
The Examiner agrees that Liu does not disclose “an iterative method
where a modified peptide is modeled in silico for binding, and iteratively
changed based on the modeling,” and further acknowledges that Andrews
“does not provide an example of an iterative technique (testing thousands of
modifications to a peptide individually, as noted by applicants).” Ans. 7.
However, the Examiner finds that Andrews suggests an iterative
methodology based on rounds of in silico modeling, as “the authors [of
Andrews] explicitly state that the best compounds they had discovered could
be further modified using similar techniques to provide improved
properties.” Ans. 7; see also id. at 5 (citing Andrews 1913). We discern no
error in this interpretation of Andrews. In the paragraph cited by the
Examiner (see Ans. 5), Andrews suggests that compounds designed through
its strategy “could be considered as fragment starting points for further
discovery and optimization by using REPLACE[7] and/or traditional
medicinal chemistry/structure-guided design in order to improve potency”
(Andrews 1913).
7 REPLACE (REplacement with Partial Ligand Alternatives) is the drug-
design strategy described in Andrews “in which nonpeptidic surrogates for
specific determinants of known peptide ligands are identified in silico by
using a core peptide-bound protein structure as a design anchor.” Andrews
Abstract.
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As to Sintchak, the Examiner considers Appellants’ reading to be
overly strained, as Sintchak describes not only “the in silico modeling of
representative commercially available compounds, identifying lead
compounds,” but also synthesis, testing, and modeling of lead compound
analogs in silico “to guide further rounds of ligand design in an iterative
process.” Ans. 8 (discussing Sintchak 178). We agree with the Examiner
that Sintchak thus discloses “a repetitive method where analogs are made,
modeled in silico for insights into binding, and modified based on those
insights, with the method repeated as needed until analogs with desired
properties are arrived at.” Id.
2. Motivation to Combine
Appellants also argue that the Examiner fails to provide a rationale for
combining Sintchak with either Liu or Andrews. See Br. 11. Appellants
note that Sintchak focuses on discovery of potential inhibitors that are
“structurally unrelated to” known inhibitors for its target, IMPDH (Br. 12
(citing Sintchak 167)), in contrast to the approaches in Liu and Andrews,
which start with known CDK/cyclin inhibitors (id.). Appellants also point
out that the known inhibitors for IMPDH are not peptide inhibitors, as they
are for CDK/cyclin, but rather non-polymeric molecules. Id. at 11 (citing
Sintchak 165). Thus, according to Appellants, based on Liu and Andrews,
“in which only a fragment of a known polymeric peptide inhibitor is
modified in development of a new inhibitor,” it would not have been
obvious for the skilled artisan to look to Sintchak, “in which a library of
non-polymeric molecular compounds unrelated to known inhibitors are
examined for potential use as an inhibitor. Br. 12.
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These arguments are unpersuasive. At the outset, Appellants’ detailed
distinctions regarding the types of molecules modeled in Sintchak are not
salient given the very general purpose for which the Examiner relies on
Sintchak, i.e., to “show[] that an iterative design methodology using
computer modeling, similar to the process described by the instant claims,
can accelerate the drug discovery process.” Non-Final Action 5. Further,
we agree with the Examiner that:
None of the differences pointed out by applicants call into
question the teachings of Fiu et al and Andrews et al that specific
modifications to peptides binding to the various cyclin proteins
can improve their properties, the suggestion to iteratively model
and modify these compounds, presented in Andrews et al, or the
teachings of Sintchak et al that such methods are important (and
thus well known) in the art of drug design (leading to a
reasonable expectation of success). Nor do they contradict the
motivation to combine, which was given by both Fiu et al and
Andrews et al.
Ans. 8.
3. Conclusion
Having considered each of Appellants’ arguments, we are
unpersuaded that the Examiner erred in rejecting claim 1 as unpatentable
over Fiu, Andrews, and Sintchak. Accordingly, we affirm the rejection of
claim 1. Claims 2—5 and 7 are not argued separately, and fall with claim 1.
See 37 C.F.R. § 41.37(c)(l)(iv).
B. Rejection 2
Appellants do not dispute the Examiner’s non-statutory double
patenting rejection of claims 1, 2, 4, 5, and 7. See Br. 13. We summarily
affirm this rejection.
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CONCLUSION
The rejections of claims 1—5 and 7 are affirmed. 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
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