Ex Parte Califano et al

Patent Trial and Appeal Board

Aug 29, 2016

12432579 (P.T.A.B. Aug. 29, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/432,579 0412912009
43850 7590 08/31/2016
MORGAN, LEWIS & BOCKIUS LLP (SF)
One Market, Spear Street Tower, Suite 2800
San Francisco, CA 94105
FIRST NAMED INVENTOR
Andrea Califano
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.
016161-5001-US 7376
EXAMINER
NEGIN, RUSSELL SCOTT
ART UNIT PAPER NUMBER
1631
NOTIFICATION DATE DELIVERY MODE
08/31/2016 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):
sfipdocketing@morganlewis.com
donald.mixon@morganlewis.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte ANDREA CALIF ANO, RICCARDO DALLA-FA VERA, and
OWEN A. O'CONNOR
Appeal2014-005117
Application 12/432,579
Technology Center 1600
Before RICHARD M. LEBOVITZ, ULRIKE W. JENKS, and
RICHARD J. SMITH, Administrative Patent Judges.
LEBOVITZ, Administrative Patent Judge.
DECISION ON APPEAL
This appeal 1 involves methods, an apparatus, and computer medium
which are used for searching for combinations of drugs of therapeutic
interest. Appellants appeal from the Examiner's final rejection of claims 1-
39, 42-81, 84--101, and 110-112 as obvious under 35 U.S.C. § 103. We
have jurisdiction under 35 U.S.C. § 134. The rejections are affirmed-in-part
and reversed-in-part. A new ground of rejection is set forth pursuant 37
C.F .R. § 41. 77 (b) over claims 1 and 17.
1 Appellants identify the Real Party in Interest as Therasis, Inc. App. Br. 4.
Appeal2014-005117
Application 12/432,579
STATEMENT OF CASE
The claims stand rejected by the Examiner as follows: 2
1. Claim 1-16, 21, 22, 29, 30, 32, 37-39, 42, 43, 48, 49, 52---68, 75-
77, 79-81, 84, 85, 88-101, and 110-112 under 35 U.S.C. § 103(a) as
obvious in view of O'Connor3 and Emili.4
2. Claims 17-20, 33, 46, 47, 50, and 51under35 U.S.C. §103(a) as
obvious in view of O'Connor, Emili, and Wang. 5
3. Claims 34--36 under 35 U.S.C. §103(a) as obvious in view of
O'Connor, Emili, and Mani.
4. Claims 23-25 and 69-71 under 35 U.S.C. § 103(a) as obvious in
view of O'Connor, Emili, and Michnick.
5. Claims 26-28 and 72-74 under 35 U.S.C. § 103(a) as obvious in
view of O'Connor, Emili, and Abrams.
6. Claims 31 and 78 under 35 U.S.C. § 103(a) as obvious in view of
O'Connor, Emili, and Gray.
7. Claim 44, 45, 86, and 87 under 35 U.S.C. § 103(a) as obvious in
view of O'Connor, Emili, and Lee.
2 The full citations for the prior art publications cited in Rejections 3-7 can
be found on pages 12-13 of the Appeal Brief.
3 O'Connor et al., The Combination of the Proteasome Inhibitor
Bortezomiband the Bcl-2 Antisense Molecule Oblimersen Sensitizes Human
B-Cell Lymphomas to Cyclophosphamide, 12 Clin. Cancer. Res.2902-2911
(2006).
4 Emili and Cagney, US 2005/0048564 Al, publ. Mar. 3, 2005.
5 Wang et al., Genome-wide Discovery of Modulators of Transcriptional
Interactions in Human B Lymphocytes, RECOMB 2006, LNBI 3909, pp.
348-362 (2006).
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Appeal2014-005117
Application 12/432,579
CLAIM INTERPRETATION
Step (D) of claim 1 recites determining a drug activity profile using (i)
a MAP and (ii) an "interaction network." The Examiner interpreted the
"interaction network" to be a network of drug interactions on cytotoxicity.
Final Rej. 6-7. The Examiner's interpretation of the term "interaction
network" is erroneous.
During patent prosecution, claim terms are given their broadest
reasonable interpretation, consistent with the specification, as they would be
understood by one of ordinary skill in the art. In re Buszard, 504 F.3d 1364,
1367 (Fed. Cir. 2007); In re Am. Acad. of Sci. Tech Ctr., 367 F.3d 1359,
1364 (Fed. Cir. 2004). The specification provides a specific definition of
"interaction network": "As used herein, the term interaction network is any
network of molecular interactions relevant to the phenotype of interest."
34: 15-16. The Examiner did not explain how the drugs constituted a
network of molecular interactions.
INDEPENDENT CLAIMS 1, 91, AND 93
The Examiner found that the teaching in 0' Connor of the effect of
drug interactions on cell cytotoxicity constituted an "interaction network" as
required by independent claim 1, 91, and 93. Final Rej. 6-7. Specifically,
the Examiner cited Fig. 1 of O'Connor as showing an interaction network.
Fig. 1, however, shows that the drugs interacted in cells by affecting the
exclusion of dye as compared to control cells in trypan blue exclusion
cytotoxicity assay. See O'Connor 2905 (Fig. 1 ), 2903 ("Material").
0' Connor teaches that a combination of three drugs interacted in cells to
produce the most cytotoxic effect (("What seems consistent in these studies
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Application 12/432,579
is that the most favorable treatment outcome, regardless of schedule, always
appeared in the 'triplet combination.' Id. 2909); see Figs. IA & IB)). The
Examiner did not explain how this drug interaction constituted "a network of
molecular interactions" as required by the claimed "interaction network."
Thus, the Examiner construed the term "interaction network" erroneously to
mean a network of drug interactions. This erroneous interpretation was
applied to all seven of the rejections. Since the interpretation was erroneous,
and so is the finding on which it is based, we are compelled to reverse all the
rejections of claims 1, 91, and 93, and dependent claims 2-39, 42-51, 92,
94, and 99-101.
CLAIMS 52, 95, and 97
Independent claims 52, 95, and 97 were not argued separately by
Appellants. Br. 17, 21. These claims, however, do not require an
"interaction network." For the reasons discussed above with respect to
O'Connor and Emili only, we conclude that the Examiner did not err in
finding the claims obvious. Consequently, we affirm the obviousness
rejections 1, 4, and 5-7 of independent claims 52, 95, and 97, and dependent
claims 53-81, 84--90, 96, 98, and 110-112.
NEW GROUND OF REJECTION OF CLAIMS 1 AND 17
We set forth the following new ground of rejection pursuant to
37 C.F.R. 41.77(b).
Claims 1 and 17 are rejected under 35 U.S.C. § 103(a) (pre-AIA) as
obvious in view of O'Connor, Emili, and Wang.
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Application 12/432,579
Findings of Fact
O'Connor
FF 1. 0' Connor teaches that the combination of the proteasome
inhibitor bortezomib and the Bcl-2 antisense molecule oblimersen sensitizes
human B-cell lymphomas to cyclophosphamide. O'Connor (Title).
FF2. O'Connor teaches that recently developed "novel targeted
drugs" to treat human malignancies may be used with conventional
cytotoxic agents to treat tumors. Id., 2902.
Id.
FF3. O'Connor states:
Hence, it is likely that many new drugs that target important
growth and survival signaling pathways will be synergistic with
less specific and broadly damaging conventional agents in a
schedule-dependent manner. The determination of these
relationships in preclinical development is essential in
exploiting and optimizing therapeutic benefit.
FF 4. 0' Connor teaches that "[p ]roteasome inhibitors (bortezomib)
and drugs targeting Bcl-2 family members ( oblimersen) represent two prime
examples of these principles" and performs experiments with them. Id.,
2903.
FF5. O'Connor describes a cytotoxicity assay using trypan blue
("trypan blue exclusion assay") in which trypan blue is excluded from viable
cells, but stains cells who experience cell death when exposed to a cytotoxic
compound because dead cells do not exclude the trypan blue stain. Id., 2902
(Abstract), 2903 ("Materials"). The phenotype is thus cell death as
determined by trypan blue staining.
FF6. O'Connor describes exposing cells to bortezomib ("Bor"),
oblimerson ("Obl"), 4-hydroxycyclophosphoamide ("4 HC"), and
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Application I2/432,579
LipofectAMINE. Id., 2903 ("Materials"). The cells were subjected to the
trypan blue exclusion assay and the cell death phenotypes were measured as
in step (A) of claim I. Id., 2904 ("Results"; Fig. IA). Fig. IA shows that
each of "Bor", "Obl", and "4 HC" displayed different amounts of
cytotoxicity to cells, and more than the "control".
FF7. Combinations of drugs were tested in the trypan blue exclusion
assay and the resulting phenotypes were measured. Id.
Emili
FF8. Emili describes the use of peptide profiling to identify,
characterize, and classify biological samples. Emili, Abstract.
FF9. Emili teaches that proteomics (patterns of protein expression) is
useful to reveal regulatory networks. Id., i-fi-14, I5.
FF I 0. Emili teaches that its peptide profiling can be used to identify
and quantitate the peptides present in the samples. Id., i-fi-140, 41.
FF I I. Emili teaches:
The methods of the invention may be used in toxicology analysis.
The methods optionally comprise administering a candidate
compound to a cell. As described above, samples suitable for
MS anaylsis [sic, analysis] are generated and a peptide profile is
produced. Relative abundance of peptides in samples is also
preferably determined. This candidate compound peptide profile
is compared to peptide profiles in a database or library (for
example, profiles showing the cell in a normal state and in varied
states of toxicity). If the candidate compound sample profile is
highly similar to (for example, greater than 90%, 95%, or 99%
similarity), or identical to a profile in the database or library, then
that similarity shows the amount of toxicity of the candidate
compound to the cell. If the candidate compound sample profile
is highly similar to a normal cell profile, than the candidate
compound is less likely to be toxic than if the candidate
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Application 12/432,579
compound sample profile is similar to the peptide profile of the
cell in state of toxicity. The relative abundance of the test sample
peptides is also preferably compared to other profiles to
determine the amount of toxicity of a candidate compound.
Id., i-f 57.
Wang
FF12. Wang measured microarray expression profiles of normal and
tumor related human B lymphocytes and applied the results to identify "key
modulators of MYC, an important transcription factor involved in
tumorigenesis of a variety lymphomas." Wang 348, 350. Wang identified a
network model of transistor-like regulatory logic involving genome-wide
discovery of modulators of transcriptional interactions. Id., 349 (Fig. 1 ),
350-354 (Section 2).
Discussion
Claim 1 comprises five steps, (A) through (E). Step (A) is a cell-
based assay in which cells are exposed to a compound and a phenotype
resulting from the compound is measured. Step (B) is determining a subset
of compounds that "implement a desired end-point phenotype." Step (C) is
measuring a molecular abundance profile (MAP) comprising cellular
constituents in a different sample of cells exposed to each respective
compound in the subset of compounds. Step (D) is determining a drug
activity profile for each compound based on (i) the measured MAP and (ii)
"an interaction network." Step (E) is "forming a filter set of compound
combinations comprising a plurality of compound combinations" which is
"based on a difference between a drug activity profile of the first compound
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Application 12/432,579
and a drug activity profile of the second compound" in the subset of
compounds.
O'Connor describes step (A) of claim 1 in which cells are exposed to
a compound and a phenotype is obtained. FF5. This is shown in Fig. IA
where each of "Bor" "Obl" and "4 HC" produced more cell death
' '
("cytotoxicity") than the "control". FF6. Cell death, or trypan blue
exclusion, corresponds to the phenotype.
0' Connor does not measure the claimed cellular constituents ( C) on a
subset of cells (B) who show a desired phenotype in response to a compound
of step (A). However, it would have been obvious to have picked claimed
subset (B) for further study for the following reasons. O'Connor teaches
combining novel targeted drugs with conventional agents to achieve
synergistic and less damaging drug treatments. FF1-FF3. While O'Connor
did not pick a subset of drugs for testing (Br. 17-18), the skilled worker
would have had reason to have selected only drugs eliciting the desired cell
death phenotype to determine whether they exhibit synergy when combined
with other agents (FF3). The level of skill in the art was of a Ph.D. or M.D.
as established by the scientific publications which have been cited in this
proceeding which are authored by Ph.D. or M.D. scientists. Such an
experienced and educated scientist would have had the knowledge, skill and
reason to choose those drugs for further study which had the desired cell
death phenotype (FF4-FF7).
We have considered Appellants' arguments but do not find them
persuasive in view of the level of skill in the art and reasons to have selected
those drugs with the desired phenotype for further study. See Br. 17-18.
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Application 12/432,579
Emili teaches that peptide profiling can be utilized to characterize
whether a compound is toxic to a cell. FFl 1. Because O'Connor's assay
measures cytotoxicity (FF5, FF6), one of skill in the art would have had
reason to apply Emili's peptide profiling to O'Connor's assay to meet step
(C) of claim 1 to further characterize the results. As stated in KSR Int 'l Co.
v. Teleflex Inc., 550 U.S. 398, 417 (2007),
[I]f a technique has been used to improve one device, and a
person of ordinary skill in the art would recognize that it would
improve similar devices in the same way, using the technique is
obvious unless its actual application is beyond his or her skill .
. . . [A] court must ask whether the improvement is more than the
predictable use of prior art elements according to their
established functions.
Appellants did not identify a fact-based reason as to why this rationale
is erroneous. Br. 20-21.
Moreover, Emili teaches that patterns of protein expression can be
used to reveal regulatory networks (FF9), providing further reason to apply
Emili to O'Connor because O'Connor broadly discusses exploiting signaling
pathways and relationships between conventional and targeted drugs (FF3)-
implicating network concepts.
Claim 1 also requires "(D) determining a drug activity profile of each
respective compound in the subset of compounds using (i) measured MAPs
from the measuring (C) in which a sample of cells was exposed to the
respective compound and (ii) an interaction network."
Emili teaches that protein profiling can be used to classify biological
samples and reveal regulatory networks. FF8-FF10. As mentioned, Emili
specifically teaches utilizing protein profiling of a cell in a state of toxicity.
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Application I2/432,579
FI I. Consequently, the skilled worker would have had reason to have used
both parameters in O'Connor's cytotoxicity phenotype assay.
Wang describes an interaction network model for lymphocytes and
lymphomas (FFFI2), the same cell type as studied in O'Connor (FFI).
Thus, it would have been obvious to one of ordinary skill in the art to apply
Wang's teaching to O'Connor based on Emili's suggestions.
Step (E) of claim I recites "forming a filter set of compound
combinations comprising a plurality of compound combinations" which is
based on the drug profiles of (D). O'Connor expressly teaches combinations
of drugs to optimize drug effects and to determine whether synergy occurs.
FF3. While O'Connor does not teach choosing combinations "based on a
difference between a drug activity profile of the first compound and a drug
activity profile of the second compound" as recited in step (E), it is
reasonable to believe that any two drugs selected would have different drug
profiles. See, e.g., O'Connor, Fig. IA where Bor, Obl, and 4 HC each have
different cytotoxicity values in the trypan dye exclusion assay. Each of
O'Connor, Emili, and Wang quantitated and measured compounds (drugs,
peptides, expression levels) (FF6, FFIO, FFI2). Consequently, one of
ordinary skill in the art would have had reason to have selected drug activity
profiles based on quantitative values because each of O'Connor, Emili, and
Wang teach measuring and quantitating compounds.
For the foregoing reasons, we conclude that claim I and I 7 (reciting
"the interaction network comprises one or more transcriptional targets of
each of one or more expressed transcription factors") would have been
obvious to one of ordinary skill in art in view of O'Connor, Emili, and
Wang.
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Appeal2014-005117
Application 12/432,579
With respect to the remaining claims, we leave it to the Examiner to
make the appropriate rejections, e.g., based on the prior art publications and
findings already of record.
TIME PERIOD
When the Board designates a new ground of rejection under 37 C.F.R.
§ 41. 50(b ), the appellant, as to each claim so rejected, has the option of:
( 1) Reopen prosecution. Submit an appropriate amendment of the
claims so rejected or new evidence relating to the claims so rejected, or both,
and have the matter reconsidered by the examiner, in which event the
proceeding will be remanded to the examiner ....
(2) Request rehearing. Request that the proceeding be reheard under
37 C.F.R. § 41.52 by the Board upon the same record .... The amendment
and/ or new evidence under 3 7 C.F .R. § 41. 50(b )( 1 ), or the request for
rehearing under 37 C.F.R. § 41.50(b)(2), must be filed within 2 months from
the date of the Board's decision. In accordance with 37 C.F.R. § 41.50(±),
this 2-month time period may not be extended by the filing of a petition and
fee under 3 7 C.F .R. § 1.13 6( a), but only under the provisions of 3 7 C.F .R.
§ 1.136(b).
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-IN PART; REVERSED-IN-PART;§ 41.50(B)
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