Ex Parte Gillies et al

Patent Trial and Appeal Board

Feb 28, 2017

12395159 (P.T.A.B. Feb. 28, 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.
12/395,159 02/27/2009 STEPHEN D. GILLIES LEX-014C1 3823
51414 7590 03/02/2017
GOODWIN PROfTFR T T P
EXAMINER
PATENT ADMINISTRATOR NATARAJAN, MEERA
100 Northern Avenue
BOSTON, MA 02210 ART UNIT PAPER NUMBER
1643
NOTIFICATION DATE DELIVERY MODE
03/02/2017 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):
PATENTBOS @GOODWINPROCTER.COM
PSOUSA-ATWOOD@GOODWINPROCTER.COM
GLENN.WILLIAMS@GOODWINPROCTER.COM
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte STEPHEN D. GILLIES, YAN LAN, and
SYLVIA HOLDEN1
Appeal 2014-009451
Application 12/395,159
Technology Center 1600
Before ERIC B. GRIMES, ULRIKE W. JENKS, and RICHARD J. SMITH,
Administrative Patent Judges.
JENKS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims directed
to a method of treating a tumor in a mammal by administering a cytotoxic
agent before administering an immunocytokine to the mammal. The
Examiner rejects the claims as obvious. We have jurisdiction under
35 U.S.C. § 6(b).
We affirm.
1 According to Appellants, the Real Party in Interest is Merck Patent GmbH.
Appeal Br. 2.
Appeal 2014-009451
Application 12/395,159
STATEMENT OF THE CASE
The Specification explains that “cytotoxic therapy of cancer is
damaging to the immune system.” Spec. 2:10—11. However, “[effective
treatment of diseases such as cancer require robust immune responses by one
or more effector cell types such as natural killer (NK) cells, macrophage and
T lymphocytes.” Id. at 1:19—21. The Specification states that the uptake of
an antibody-cytokine fusion protein (immunocytokine) by a tumor results in
a more potent anti-tumor response in an animal if the animal is first treated
with an immunocytokine uptake enhancing agent. See id. at 2:29-3:25. The
immunocytokine uptake enhancing agent is administered either
simultaneously with or prior to the administration of the immunocytokine.
Id. “Immunocytokine uptake enhancing agents comprise alkylating
chemotherapeutic agents and taxanes such as paclitaxel.” Id. at 3:4—5.
Claims 1—3, 6—9, 11—16, and 28—30 are on appeal, and can be found in
the Claims Appendix of the Appeal Brief. Claim 1 is representative of the
claims on appeal, and reads as follows:
1. A method of enhancing the immune destruction of a tumor in
a mammal, the method comprising the steps of:
pre-treating a mammal with a cytotoxic agent; and
administering to the mammal an immunocytokine
comprising an antibody binding site and interleukin-12 wherein
the pre-treating step enhances the immune destruction of the
tumor.
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Appellants seek review of the following rejections:
I. claims 1—3, 6—9, 11, 12, and 30 under 35 U.S.C. § 103(a) as
unpatentable over Mullins2 and Peng3; and
II. claims 1—3, 6—9, 11—16, and 28—30 under 35 U.S.C. § 103(a) as
unpatentable over Mullins and Peng and further in view of Lentz.4
I. Obviousness over Mullins and Peng
The Examiner finds that Mullins suggests the “addition of paclitaxel
to tumors for 4-24 hours prior to administration of IL-12” reduces immune
suppression associated with paclitaxel treatment. Office Act. 35; Ans. 2; see
infra FF1—FF4. The Examiner acknowledges that Mullins does not
administer IL-12 to animals. Office Act. 3; Ans. 2. The Examiner relies on
Peng for teaching the in vivo administration of an IL-12 fusion protein.
Office Act. 4; Ans. 2. The Examiner concludes that based on the combined
teachings of Mullins and Peng it would have been obvious to use “an IL-12
antibody fusion protein, instead of recombinant IL-12, in the method taught
by Mullins et al., [and that] one of ordinary skill in the art would have
reasonable success in achieving effective antitumor activity while limiting
toxicity.” Ans. 3.
2 Mullins et al., Interleukin-12 overcomespaclitaxel-mediated suppression
of T-cellproliferation, 20 Immunopharmacology and Immunotoxicology
473-92 (1998) (“Mullins”).
3 Peng et al., A Single-Chain IL-12 IgG3 Antibody Fusion Protein Retains
Antibody Specificity and IL-12 Bioactivity and Demonstrates Antitumor
Activity, 163 J. Immunol. 250—58 (1999) (“Peng”).
4 Lentz, US 6,231,536 Bl, issued May 15, 2001.
5 Office Action mailed March 28, 2013 (“Office Act.”).
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Appellants contend that there is no motivation to combine the
references (Appeal Br. 6; Reply Br. 3) and even if such motivation were
found there is no reasonable expectation of success. Appeal Br. 8.
The issue is: Does the preponderance of evidence of record support
the Examiner’s conclusion that the combination of references teach treating
an animal with a cytotoxic agent followed by treatment with an
immunocytokine as claimed?
Findings of Fact
We adopt the Examiner’s findings of fact and reasoning regarding the
scope and content of the prior art (Ans. 2—3; Office Act. 3—5). For emphasis
only we highlight the following:
FF1. Mullins teaches the in vivo administration of paclitaxel to mice.
Paclitaxel was administered to twenty-day post-induction
TBHs [(tumor-bearing host)] by intraperitoneal injection
at doses of 15 or 30 mg/kg . . . , approximating human
chemotherapeutic regimens .... Parallel control animals
received an equivalent volume of vehicle or physiologic
saline only. Immune cells were collected 12 or 24 h post-
paclitaxel administration.
Mullins 475.
FF2. Mullins teaches that paclitaxel “treatment inhibited both normal host
and TBH T-cell proliferation.” Id. at 478, see 479, 481.
FF3. Mullins teaches that exposure of immune cells in vitro to “IF-12
reconstituted proliferation of T-cells from TBHs .... This suggests
that IF-12 would be a useful therapeutic for reversing tumor-induced
immune suppression.” Id. at 482.
FF4. Mullins teaches that “this experiment, which mimics the transient
paclitaxel exposure lymphocytes may encounter during in vivo
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treatments, IL-12 reconstituted and enhanced proliferation of normal
host T-cells pretreated with 0.1 and 1.0 pM paclitaxel and enhanced
TBH T-cell proliferative response following pretreatment with the low
dose of paclitaxel.” Id. at 482. “Paclitaxel could be used as an
antitumor chemotherapeutic and delivered in transient, temporally-
separated regimens; paclitaxel regimens would be followed by IL-12
therapy, which would both assist in the recovery of lymphocyte
populations following paclitaxel, as well as impart distinct and
independent antitumor activities.” Id. at 485—486.
FF5. Peng teaches that “systemic administration of IL-12 can be toxic.
Tumor-specific Abs provide a means to selectively target a
metastatic/residual nodule and deliver therapeutic quantities of an
immunostimulatory molecule like IL-12 with lower systemic levels
and ideally, toxicity.” Peng, Abstract.
FF6. Peng teaches that the goal of the fusion protein is to use it as an
antitumor agent. Id. at 256.
this Ab-IL-12 fusion protein may be an effective alternate
to systemic administration of IL-12 for the treatment of
metastatic breast cancer. Using the tumor-targeting ability
of the Ab, it should be able to achieve effective local IL-
12 concentration at the sites of tumors and metastases with
lower doses of IL-12, thus decreasing the risk of toxicity
associated with IL-12 treatment.
Id. at 257.
FF7. Peng teaches that
We observed better antitumor activity when treatment was
started after the tumors were established with a mean
diameter of 8-9 mm than when treatment was started the
day after inoculation with tumor cells. This lends support
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to previous studies by others ... in which better antitumor
activity of IL-12 was observed when tumors were
established.
Id. at 256.
FF8. Peng teaches that the IL-12 fusion protein “mscIL-12.her2.IgG3 had
in vitro biologic activity comparable to rIL-12, the in vivo antitumor
activity was investigated using a CT26/Her2 animal model.” Id. at
254.
Principle of Law
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
KSRInt’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). “The fact that
appellant has recognized another advantage which would flow naturally
from following the suggestion of the prior art cannot be the basis for
patentability when the differences would otherwise be obvious.” Ex parte
Obiaya, 227 USPQ 58, 60 (BPAI 1985).
Analysis
We have reviewed Appellants’ contentions that the Examiner erred in
rejecting claims 1—3, 6—9, 11, 12, and 30 as obvious over the cited art.
Appeal Br. 4—10; Reply Br. 2—5. We disagree with Appellants’ contentions
and adopt the findings concerning the scope and content of the prior art set
forth in the Examiner’s Answer and the Office Action dated March 28,
2013. For emphasis, we highlight and address the following:
Claim 1
Appellants contend “[n]one of the cited references speaks to the
problem of tumor penetration of immunocytokines or suggests that improved
tumor penetration by an immunocytokine would enhance immune
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destruction of a tumor.” Appeal Br. 4, see also 6 (“the presently claimed
invention solves the problem of tumor penetration by immunocytokines by
pretreating with a cytotoxic agent to increase penetration of an IL-12
immunocytokine into the tumor microenvironment, enhancing the immune
destruction of the tumor”).
We are not persuaded by Appellants’ argument that the references do
not address “tumor penetration” because this is not a limitation disclosed in
the claims. It is well established that limitations not appearing in the claims
cannot be relied upon for patentability. In re Self, 671 F.2d 1344, 1348
(CCPA 1982).
Claim 1 requires two active steps: the first requires “pre-treating” the
mammal with a cytotoxic agent and this is followed by the second step that
requires the administration of an “immunocytokine comprising an antibody
binding site and interleukin-12.” Although the Specification does not
specifically define “pre-treating” it does disclose an embodiment that
encompasses that “the immunocytokine uptake enhancing agent can be
administered prior to administration of the immunocytokine” and is distinct
from the simultaneous administration of the immunocytokine. Spec. 3:20-
23. The broadest reasonable interpretation of “pre-treating” is a time frame
before and up to the point of administering the immunocytokine. In order to
meet the claim limitation the administration of the cytotoxic agent is
followed by administering an immunocytokine.
Mullins expressly teaches that, based on their observations, it is
recommended that “paclitaxel regimens would be followed by IL-12
therapy.” FF4. Peng on the other hand recognizes that systemic
administration of IL-12 can be toxic (FF5) and that the use of fusion proteins
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that are able to target IL-12 activity to the tumor are an effective alternative
to systemic IL-12 administration (FF6). Thus, Peng suggests applying their
fusion protein in treatment applications that ordinarily use IL-12, and
suggests that the use of their fusion protein would reduce known toxicity.
FF6. Accordingly, based on the combined teachings of the references we
agree with the Examiner that one of ordinary skill in the art would have
found it obvious to substitute Peng’s IL-12 fusion protein for IL-12 in the
treatment protocol suggest by Mullins. See FF1—FF7.
Claim 1 also recites “wherein the pre-treating step enhances the
immune destruction of the tumor.” This limitation is a result of the active
method steps which are applying the cytotoxic agent before administering
the immunocytokine. Mullins teaches that “[pjaclitaxel could be used as an
antitumor chemotherapeutic and delivered in transient, temporally-separated
regimens; paclitaxel regimens would be followed by IL-12 therapy.” FF4.
Thus, the prior art teaches the protocol of administering cytotoxic agent
spatially separated in time from and prior to administering IL-12 therapy.
“[I]t is not required . . . that the prior art disclose or suggest the properties
newly-discovered by an applicant in order for there to be a prima facie case
of obviousness.” In re Dillon, 919 F.2d 688, 697 (Fed. Cir. 1990). Mere
recognition of latent properties in the prior art does not render nonobvious
an otherwise known invention. In re Prindle, 297 F.2d 251, 254 (CCPA
1962). Here, the limitation of enhancing the immune destruction of the
tumor is something that flows naturally from the suggestion in the art —
namely administering a cytotoxic agent followed by IL-12 therapy. FF4.
Mullins recognizes that paclitaxel inhibits T-cell proliferation in normal as
well as tumor bearing mammals, and this inhibition can be reversed by the
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administration of IL-12. FF3 andFF4. Mullins teaches “that IL-12 would
be a useful therapeutic for reversing tumor-induced immune suppression.”
FF3. Peng teaches that its fusion protein is a functional equivalent of IL-12.
FF6. Thus, substituting Peng’s fusion protein for IL-12 in the protocol
suggested by Mullins would result in enhancing the immune destruction of
the tumor as claimed. FF1—FF7. This would flow naturally from the
method that is taught by Mullins which is to treat with paclitaxel first
followed by IL-12 treatment. See Ex parte Obiaya, 227 USPQ at 60.
Appellants contend that even if there were a motivation to combine
the references there is “no reasonable expectation of successfully arriving at
[the] claimed method.” Appeal Br. 8; see also Reply Br. 3 (“The question,
of course, is whether a person of ordinary skill would have been motivated
to substitute the single-chain antibody IL-12 fusion protein of Peng for the
IL-12 of Mullins”).
We are not persuaded. As explained by the Examiner,
although Mullins may be performing the method of pretreatment
with paclitaxel followed by IL-12 to highlight different results
than the method instantly claimed, it is clear by the data provided
in Mullins (and Peng) that treatment with IL-12 is used for the
same reason of achieving enhanced T-cell proliferation which
would aid[] in tumor destruction.
Ans. 9. IL-12 is known to have an antitumor effect. Peng, Abstract. Peng
teaches that the goal of the IL-12 fusion protein is to ultimately use the agent
as an antitumor agent. Peng 256. Peng teaches that the IL-12 fusion protein
“had in vitro biologic activity comparable to rIL-12, the in vivo antitumor
activity was investigated using a CT26/Her2 animal model.” FF8. Peng
established that their IL-12 fusion protein is as effective as recombinant IL-
12 when used in vivo, in other words it is a functional equivalent. Further,
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“in vivo studies [of Peng] demonstrate that this fusion protein has significant
antitumor activity in immunocompetent BALB/c mice.” Peng 256. Because
Peng discloses that the IL-12 fusion protein is functionally equivalent to IL-
12 (FF6) we find that substituting the IL-12 fusion protein of Peng in the
treatment protocol suggested by Mullins would reasonably lead the ordinary
artisan to conclude that the protocol would reasonably work as suggested by
Mullins. See In re O’Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988)
(“[ojbviousness does not require absolute predictability of success ... all
that is required is a reasonable expectation of success.”); see also Hoffmann-
La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014)
(“Conclusive proof of efficacy is not necessary to show obviousness.”).
As Appellants do not argue claims 2, 3, 6—9, 11, and 12 separately, we
focus our analysis on claim 1, and claims 2, 3, 6—9, 11, and 12 fall with
claim 1. 37 C.F.R. § 41.37 (c)(l)(iv).
Claim 30
Appellants contend that none of the references teach that “the
pretreating step enhances uptake of the immunocytokine by the tumor.”
Appeal Br. 10.
We are not persuaded, as already explained above it is not required
that the combination of references discloses or suggest the properties as
recognized by Appellants in order to find a prima facie case of obviousness.
See In re Dillon, 919 F.2d at 697. Mullins teaches “that IL-12 would be a
useful therapeutic for reversing tumor-induced immune suppression.” FF3.
Both IL-12 and IL-12 fusion proteins are shown to be functional equivalents
and are known to be effective to treat tumors. See FF6-FF8. Because
Mullins suggests reducing the effects of paclitaxel treatment by the
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administration of IL-12 after the administration of paclitaxel, the effect of
this combination is that the paclitaxel treatment would “enhance[] uptake of
the immunocytokine by the tumor” as claimed. “The fact that appellant has
recognized another advantage which would flow naturally from following
the suggestion of the prior art cannot be the basis for patentability when the
differences would otherwise be obvious.” Ex parte Obiaya, 227 USPQ at
60. Because the IL-12 fusion protein is shown to be a functional equivalent
of rIL-12 the ordinary artisan would expect that the IL-12 fusion protein
would have the same effect as IL-12 in Mullin’s treatment protocol.
We conclude that the preponderance of the evidence of record
supports the Examiner’s conclusion that the combination of Mullins and
Peng renders claim 30 obvious.
II. Obviousness over Mullins, Peng, and Lentz
The Examiner recognizes that Mullins and Peng “do not teach
pretreatment with an alkylating agent or radiation. These deficiencies are
made up for by Lentz.” Office Act. 5.
Appellants contend that Lentz fails to “cure the deficiencies of
Mullins and Peng.” Appeal Br. 11. Specifically, that “Lentz does not teach
pre-treatment with a cytotoxic agent, or administration of an
immunocytokine comprising IL-12.” Appeal Br. 11—12.
Does the preponderance of evidence of record support the Examiner’s
conclusion that the combination of references teach treating an animal with a
cytotoxic agent followed by treatment with an immunocytokine as claimed?
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Findings of Fact
FF9. Lentz teaches an ultrafiltration method for the “removal of inhibitors
of immune mediators, in combination with anti-angiogenic
compounds, cytokines, compounds inducing a procoagulant state,
chemotherapeutics and/or radiation.” Lentz 1:10—13.
FF10. Lentz describes that “the presumed mechanism that the process is
removing immune inhibitors produced by the tumors, especially
inhibitors of cytokines and other immune mediators, it is possible to
treat the patients with adjuvant or combination therapies, that enhance
the results achieved with the ultrapheresis.” Lentz 5:40-45.
FF11. Lentz teaches the use of ultrafiltration in combination with
antiangiogenic compounds, for example paclitaxel (see id. 5:54—67),
procoagulant compounds, cytokines, anti-cytokine receptor molecules,
as well as chemotherapeutic agents “for example, alkylating agents,
doxyrubicin, carboplatinum, cisplatinum, andtomoxifen [sic].” Lentz
7:20-23.
FF12. “Ultrapheresis allows [for] the use of lower doses of radiation to kill
residual tumor cells and spare normal tissue. In a preferred method,
ultrapheresis is used as the initial therapy, followed by radiation at
approximately one-half of the normal dosages.” Lentz 7:34—36.
Analysis
We are not persuaded by Appellants’ contention that Lentz fails to
“cure the deficiencies of Mullins and Peng.” Appeal Br. 11. As explained
above (/.) we find no error with the Examiner’s reliance on the combination
of Mullins and Peng to establish that treating a mammal first with a
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cytotoxic agent followed by treatment with an IL-12 fusion protein would
have been obvious. See FF1—FF7.
We are also not persuaded by Appellants’ contention that “Lentz does
not teach pre-treatment with a cytotoxic agent, or administration of an
immunocytokine comprising IL-12.” Appeal Br. 11. “Non-obviousness
cannot be established by attacking references individually where the
rejection is based upon the teachings of a combination of references. . . .
[The reference] must be read, not in isolation, but for what it fairly teaches
in combination with the prior art as a whole.” In re Merck & Co., 800 F.2d
1091, 1097 (Fed. Cir. 1986).
Claim 1 recites a method comprising two active steps. “The transition
‘comprising’ in a method claim indicates that the claim is open-ended and
allows for additional steps.” Invitrogen Corp. v. Biocrest Mfg., L.P., 327
F.3d 1364, 1368 (Fed. Cir. 2003) (citations omitted). Thus, the claim is
open to include additional steps.
Lentz explains that by removing inhibitors of immune mediators in
conjunction with applying other therapies the combined result is improved.
FF9—FF12. Specifically, the Examiner explains that
[t]hose of skill in the art would have reasonable motivation and
could have expected a reasonable expectation of success in
performing the instantly claimed method based on the references
cited above because Lentz et al. teach the enhancement of an
immune response by using a combined approach of
administering an alkylating agent or radiation prior to treatment
which enhances cytokine activity against tumors.
Office Act. 6. The Examiner concludes that there would have been “a
reasonable expectation of success [based on the combination of references],
to use a variety of different ‘cytotoxic agents’ (all disclosed in Lentz) in the
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pretreatment step in the instantly claimed method.” Ans. 10. We find no
error in the Examiner’s reliance on Lentz to teach combination therapies that
can be applied in conjunction with those disclosed in Mullins and Peng.
Claims 13—16, 28, and 29
Appellants contend that Lentz does not teach treatment with an
alkylating agent, or administration of IL-12 (Appeal Br. 15, claims 13 and
14); two or more different cytotoxic agents, or administration of IL-12
(Appeal Br. 15, claim 15); administering two or more different
immunocytokines (Appeal Br. 16, claim 16); a radiation, or administration
of IL-12 (Appeal Br. 16, claim 28); or gamma radiation (Appeal Br. 16,
claim 29). Here, Appellants merely state that Lentz does not disclose the
recited limitations allegedly missing from the combination of Mullins and
Peng but do not otherwise address the Examiner’s combination. Because the
Board has “reasonably interpreted Rule 41.37 to require more substantive
arguments in an appeal brief than a mere recitation of the claim elements and
a naked assertion that the corresponding elements were not found in the
prior art,” we consider this argument unpersuasive. See In re Lovin, 652
L.3d 1349, 1357 (Led. Cir. 2011).
Claim 30
Appellants contend that none of the references teach that “the
pretreating step enhances uptake of the immunocytokine by the tumor.”
Appeal Br. 10.
Lor the same reasons discussed above (/.) we are not persuaded that
the combination of references does not meet the limitation of “enhances
uptake of the immunocytokine by the tumor.” Here, the enhancing step
flows naturally form the combination disclosed in Mullins and Peng. We
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find that the Examiner has established a prima facie showing of obviousness
with respect to claim 30, which Appellants have failed to rebut.
Accordingly, we affirm the rejection of this claim.
SUMMARY
We affirm the rejection of claims 1 and 30 under 35 U.S.C. § 103(a)
over Mullins and Peng. Claims 2, 3, 6—9, 11, and 12 were not argued
separately and fall with claim 1.
We affirm the rejection of claims 1 and 30 under 35 U.S.C. § 103(a)
over Mullins, Peng, and Lentz. Claims 2, 3, 6—9, 11—16, 28, and 29 were not
argued separately and fall with claim 1.
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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