Ex Parte Salamone et al

Patent Trial and Appeal Board

Jul 22, 2016

12767034 (P.T.A.B. Jul. 22, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
121767,034 04/26/2010
26345 7590 07/26/2016
GIBBONS P.C.
ONE GATEWAY CENTER
NEW ARK, NJ 07102
FIRST NAMED INVENTOR
Salvatore J. Salamone
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.
105529-52543 2ND DIV 2829
EXAMINER
HAQ, SHAFIQUL
ART UNIT PAPER NUMBER
1678
NOTIFICATION DATE DELIVERY MODE
07/26/2016 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):
IPDocket@gibbonslaw.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Exparte SALVATORE J. SALAMONE, JODI BLAKE COURTNEY,
and DENNIS STOCKER
Appeal2013-008011
Application 12/767,034
Technology Center 1600
Before JEFFREY N. FREDMAN, JOHN G. NEW, and
CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
PAULRAJ, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal1under35 U.S.C. § 134 involving claims drawn to an
immunogen. The Examiner rejected the claims for being indefinite and
obvious. We have jurisdiction under 35 U.S.C. § 6(b). We reverse both
pending rejections.
1 Appellants identify the Real Party in Interest as Saladax Biomedical Inc.
(see Appeal Br. 3).
Appeal2013-008011
Application 12/767,034
STATEMENT OF THE CASE
Background
According to the Specification, "[t]he invention relates to the field of
immunological assays for determining the presence and/or quantifying the
amount of 5-fluoro-uracil [ 5-FU] in human biological samples in order to
rapidly determine optimal drug concentrations during chemotherapy." Spec.
1: 8-11. 5-FU is a common cytotoxic agent used for treatment of breast and
colorectal cancer, with the following formula:
0
Spec. 1-2. 5-FU is a type ofhapten, a protein-free substance that is
incapable of stimulating antibody formation but can react with antibodies
formed by coupling the hapten to a high molecular weight immunogenic
carrier and injecting to a human or animal subject. Id. at 9-10.
The Specification notes that "5-FU can be administered in its pro-drug
form as tegafur," which, "when administered to a patient, is generally
absorbed and metabolized into 5-FU by the patient at different rates." Id. at
3--4. However, "in monitoring the level of 5-FU in patients by means of an
immunoassay, it is important that the immunoassay be able to distinguish
between tegafur, the inactive substance, and 5-FU, the active substance, into
5 which tegafur metabolizes," and "[t]he problem with antibodies to 5-FU is
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Application 12/767,034
that they could be cross-reactive with tegafur making these immunoassays
not useful." Id. at 4.
The Specification discloses that a new class of antibodies specific for
5-FU are produced by immunogens formed as conjugates of an
immunogenic polyamine polymer. Id. at 5. The Specification discloses that
the antibodies produced by using such immunogens "are substantially
selectively reactive to 5-FU so as to bind to 5-FU without any substantial
cross reactivity to tegafur, as well as, to other interfering pyrimidine bases,
uracil and cytosine." Id. at 4.
The Claims
Claims 37, 38, 42, 43, and 46 are under appeal, and are reproduced in
the Claims Appendix of the Appeal Brief. Independent claim 3 7 is
representative and reads as follows:
37. An immunogen containing an immunogenic carrier containing a
polyamine polymer linked to a compound of the formula:
0
F
H II-A
wherein Y is an organic spacing group;
X is a terminal functional group involved in the binding to said
polyamine polymer; and
p is an integer from 0 to 1.
Appeal Br. 21 (Claims App'x).
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Application 12/767,034
The Re} ections
The Examiner has rejected the claims as follows:
I. Claim 46 under 35 U.S.C. § 112 (pre-AIA), second paragraph,
as being indefinite;
II. Claims 37, 38, 42, 43, and 46 under 35 U.S.C. § 103(a) as being
unpatentable over the combination of Yoshida, 2 Fujiwara, 3
Nolli,4 Marunaka,5 and Pischel. 6
Final Office Action dated Nov. 15, 2012 ("Final Act.").
DISCUSSION
Rejection I -Indefiniteness
The Examiner finds that claim 46 is indefinite because "[t]he
definition for the R4 is missing and thus it is unclear what linkages is/are
intended to be encompassed by the linkage -NH-(C=R4)-." Final Act. 2-3.
Appellants argue that the R4 in claim 46 is defined in claim 42
because "[c]laim 46 is dependent upon claim 42," and "[t]herefore, it
includes all of the limitations of claim 42 which not need be stated is claim
2 Yoshida et al., Clinical significance of monitoring serum levels of 5-
fluorouracil by continuous infusion in patients with advanced colonic
cancer, 26 Cancer Chemotherapy and Pharmacology 352-354 (1990)
("Yoshida").
3 Fujiwara et al., Enzyme Immunoassay for the Quantification of Mitomycin
C Using fJ-Galactosidase as a Label, 42 Cancer Research 1487-1491 (1982)
("Fujiwara").
4 Nolli and Parenti, Antibodies against the antibiotics: an overview, 27 Ann.
1st Super. Sanita 149-154 (1991) ("Nolli").
5 Marunaka, Mass Spectra of N-Substituted Derivatives of 5-Fluorouracil, 8
Biomedical Mass Spectrometry 105-110 (1981).
6 Pischel et al., Synthesis and Biological Activity of N-substituted 5-
Fluroruracil-1-Acetamides, 4 7 Collection Czechoslovak Chem. Commun.
2806-2813 (1982) ("Pischel").
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Application 12/767,034
46." Appeal Br. 7. In claim 42, R4 is defined as being oxygen or sulfur.
We are persuaded by Appellants' representation that the R4 in claim 46 is the
same R4 as recited in claim 42 as being either oxygen or sulfur.
Accordingly, we reverse the indefiniteness rejection.
Rejection II - Obviousness
A. Findings of Fact
FF 1. Yoshida teaches that 5-FU is an anticancer drug, and the
monitoring of serum concentrations of 5-FU using an HPLC method.
Yoshida, 352 (Summary).
FF2. Fujiwara teaches that a "mitomycin C (MMC) antibody
was produced following immunization of rabbits with a MMC-bovine
serum albumin conjugate, which was newly synthesized by coupling
MMC to mercaptosuccinylated bovine serum albumin via a cross-
linker, N-maleoyl aminobutyric acid." Fujiwara, 1487 (Abstract)).
"An antibody against MMC was produced in each of 3 rabbits
immunized with a MMC-BSA conjugate and was detected by the
reaction of diluted antiserum with MMC-B-gal conjugate." Id. at 1488
(Results, "Antibody Response").
FF3. Nolli teaches generally that small molecules, such as
antibiotic haptens, be made immunogenic by conjugation with carrier
proteins or synthetic polypeptides. Nolli, 151. Nolli further teaches
different immunogenic carriers and potential positions on the hapten
(e.g., carboxyl groups) for linking to the carriers. Id.; Table 3.
FF4. Marunaka discloses that 5-FU and its derivatives have
been widely used in cancer chemotherapy. Marunaka, 105
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Application 12/767,034
(Introduction). Marunaka further teaches a 5-FU derivative
compound 15 having reactive carboxylic acid ester substituent that
satisfies the requirements of formula II-A. Id. at 106.
FPS. Pischel discloses 5-FU and its derivatives are in clinical
use the chemotherapy of cancer. Pischel, 2806. Pischel further
teaches 5-FU derivative compound III having reactive carboxylic acid
group substituent that satisfies the requirements of formula II-A. Id.
at 2807.
B. Analysis
The Examiner asserts that:
given the fact that 5-fluoro-uracil is well-established as an
anticancer drug and its detection in blood is important for
establishing optimal effective dose in a patient (Yoshida et al),
one of ordinary skill in the art would be motivated to substitute
the [H]PLC detection of 5-flurouracil with an immunoassay
detection in view of the teaching of Fujiwara et al and Nolli et
al because both Fujiwara et al [and] Nolli et al teach that
immunogenic detection is advantageous for being possessing
reasonable sensitivity, accuracy, precision and significant
degree of specificity (Fujiwara et al and Nolli et al). As
evidenced by Fujiwara et al and Nolli et al, once a drug is
established, it is obvious to make corresponding antibody for
high sensitive detection/assay of the drug and thus it would be
obvious to one of ordinary skill in the art to consider providing
corresponding antibody to 5-fluorouracil drug in accordance
with the reasoning set forth in Ex parte Erlich, 3 USPQ2d 1011
(1987), in particular, paragraph [5] of page 1016.
Final Act. 4-5; Ans. 3--4. The Examiner further asserts that:
One of ordinary skill in the art would also be motivated to
utilize the 5-fluorouracil derivatives of Marunaka and Pischel et
al because Marunaka and Pischel et al disclose derivatives
having reactive group, such as carboxylic acid group and
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Application 12/767,034
carboxylic acid e[ s ]ters, suitable for conjugating to a carrier in
view of the teaching ofNolli et al. Reasonable expectation of
success in obtaining monoclonal antibody against 5-fluoro-
uracil comes from Nolli et al's teaching of the conventional
preparation methods of immunogenic carrier to activated drug
haptens, immunogens, tracers, and corresponding antibodies
using reactive groups on the hapten (e.g. amine group) and
since the amino group on the 5-fluoro-uracil is a potential
reactive functional group for the drug, one of ordinary skill in
the art would be motivated to try the anime groups on the drug
for conjugation of immunogenic carrier. Further, once a
compound has been established as a potential drug for
therapeutic application, one of ordinary skill in the art would be
motivated to establish an [a ]ssay to monitor the drug
concentration in blood, urine and other body fluids and tissues
which are essential for studying pharmacology and
pharmacokinetics of the drug and to establish therapeutic level
of the drug in various body compartments.
Final Act. 5-6; Ans. 4.
We determine that the Examiner has not made a prima facie showing
of obviousness. Yoshida, Marunaka, and Pischel do not teach or suggest any
need to formulate an immunogenic conjugate of 5-FU with a polyamine
polymer, much less the particular conjugate of formula II-A recited in claim
37. In particular, we agree with Appellants that although "Marunaka and
Pischel disclose the compound of formula II-A" among other 5-FU
derivatives, "there is no disclosure or teaching in Marunaka and Pischel of
forming a conjugate with this compound," and "none of the references teach
any immunogen structurally related to 5-fluoro-uracil or the haptens of
formula II-A." Appeal Br. 7-8, 12; see also Reply Br. 4 ("Nothing in
Marunaka or Pischel teach selecting the specific 5-FU derivative from
among their many 5-FU derivatives they disclose for conjugating to an
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Application 12/767,034
immunogenic carrier to produce the claimed immunogenic conjugates.").
We further agree with Appellants' argument that "[n]either the Nolli nor
Fujiwara references teach that the hap ten of formula II-A disclosed in
Marunaka and Pischel could be conjugated in any manner with an
immunogen to produce a conjugate for making an antibody for use in a 5-
fluoro-uracil immunoassay." Appeal Br. 12-13. As further noted by
Appellants, "[w]hile Fujiwara and Nolli provide generalized teachings for
the production of antibodies to non antigenic drugs, their non-antigenic
drugs or immunogens for forming antibodies are no way structurally related
to 5-fluoro-uracil or the 5-FU derivatives of Marunaka and Pischel." Reply
Br. 3.
Ex parte Erlich, cited by the Examiner, is distinguishable insofar as
the large molecule human fibroblast interferon at issue in that case was a
known antigen, unlike the record established regarding the small molecule
hapten 5-FU. See Ex parte Erlich, 3 USPQ2d 1011, 1015 (BPAI 1986)
("From our analysis, we find that it would have been obvious to ... form
monoclonal antibodies specific for human fibroblast interferon since human
fibroblast interferon was a known antigen ... of unquestioned research
interest as an antiviral or antitumor agent.").
Moreover, the Examiner has not taken into account the data in the
Specification and Appellants' argument that the claimed "immunogen
provides a new class of antibodies which are selectively reactive with [ 5-FU]
without having any substantial cross-reactivity to tegafur as well as other
cross-interfering pyrimidine bases." Reply Br. 3. In particular, the
Specification includes data showing that "it is when the immunogen is
formed from the compound of formula II-A, rather than II-B, an antibody is
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Application 12/767,034
produced which does not cross-react with Tegafur," and "[i]t is through the
antibody provided from the immunogen of the compound of the formula II-
A and the reagent carrier provided from the compound of II-A or II -B, that
produces an accurate immunoassay for 5-FU to monitor patients being
treated with 5-FU." Spec. 51; Tables 1and2. These results show that not
all conjugates of 5-FU derivatives will function effectively in an
immunoassay.
We therefore reverse the obvious rejection.
SUMMARY
We reverse the rejection of claim 46 under 35 U.S.C. § 112 (pre-
AIA), second paragraph for indefiniteness;
We reverse the rejection of claims 38, 42, 43, and 46 under 35 U.S.C.
§ 103(a) as being unpatentable over the combination of Yoshida, Fujiwara,
Nolli, Marunaka, and Pischel.
REVERSED
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