Ex Parte Ostroff et al

Patent Trial and Appeal Board

Dec 8, 2017

12615040 (P.T.A.B. Dec. 8, 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.
12/615,040 11/09/2009 Gary R. Ostroff 2732.1047-012 9741
26813 7590 12/12/2017
MUETING, RAASCH & GEBHARDT, P.A.
P.O. BOX 581336
MINNEAPOLIS, MN 55458-1336
EXAMINER
FINN, MEGHAN R
ART UNIT PAPER NUMBER
1629
NOTIFICATION DATE DELIVERY MODE
12/12/2017 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):
ptodocketing @ mrgs .com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte GARY R. OSTROFF and GORDON D. ROSS
Appeal 2016-000477
Application 12/615,040
Technology Center 1600
Before JEFFREY N. FREDMAN, ULRIKE W. JENKS, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal1 under 35U.S.C. § 134 involving claims to a method
of suppressing or eliminating tumor cells. The Examiner rejected the claims
as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
Statement of the Case
Background
“Beta glucan is a complex carbohydrate” (Spec. 1:15). “Beta glucan’s
activity as an immune adjuvant and hemopoietic stimulator compares to that
of more complex biological response modifiers” {id. at 2:25—26). “The
potential antitumor activity of [3-glucans has been under investigation for
1 Appellants identify the Real Party in Interest as Biothera, Inc. {see App. Br.
3).
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Application 12/615,040
about 30 years” (id. at 3:21—22). Separately, “subtle changes associated
with cancer development can lead to different expression of surface proteins
. . . These changes in surface antigen expression also provide a target for
treatment using selective monoclonal antibodies (mAbs)” (id. at 4:12—15).
“The present application discloses a method of antitumor therapy in
which insoluble [3-glucan is used with complement activating antibodies
directed to tumor antigens to provide an antitumor effect” (Spec. 5:11—13).
The claims
Claims 1—9, 17, and 18 are on appeal.2,3 Claim 1 is representative and
reads as follows:
1. A method of suppressing or eliminating tumor cells,
comprising: administering to a subject that comprises tumor
cells a therapeutically effective amount of insoluble P( 1,3; 1,6)
whole glucan particles and at least one complement activating
anti-tumor antibody; wherein the glucan and antibody
suppresses or eliminates tumor cells.
2 We note that the Examiner required a species election on Sept. 14, 2011
and Appellants elected trastuzumab as the species for examination on Mar.
14, 2012. We therefore limit our consideration of the merits of the appealed
rejection to the elected species. See Ex parte Ohsaka, 2 USPQ2d 1460,
1461 (BPAI 1987).
3 The Examiner appears to have withdrawn the obviousness rejections
relying upon Jamas and Goldenberg (see Ans. 10-11), but then the Examiner
mailed a PTO-90 form indicating that every ground of rejection is
maintained (see Misc. Comm, dated Aug. 25, 2015). As Appellants’ Reply
Brief dated Oct. 9, 2015 appears to treat the Jamas and Goldenberg
rejections as withdrawn, and given the ambiguity engendered by the
Examiner, we will treat these rejections as withdrawn from appeal.
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Application 12/615,040
The issue
The Examiner rejected claims 1—9, 17, and 18 under 35 U.S.C.
§ 103(a) as obvious over Vetvicka,4 Asp,5 Mathiowitz,6 and Miller7 (Non-
Final Act.8 3—8).
The Examiner finds Vetvicka teaches “insoluble P(1,3;1,6) whole
glucan . . . inhibited the growth of cancer cells in vivo” (Non-Final Act. 5).
The Examiner finds Vetvicka teaches P(l,3;l,6) glucan “slowed down the
progression of tumor growth in a colon cancer model” {id. at 6). The
Examiner finds “a synergy between oral pi,3-glucan immunotherapy and
traditional chemotherapeutic treatments” {id. at 7).
The Examiner finds Asp teaches “a monoclonal antibody that has
been shown to inhibit the proliferation of tumor cells from sources
expressing HER2 as well as a synergist result with trastuzumab and several
chemotherapeutic agents” (Non-Final Act. 7). The Examiner finds
Mathiowitz teaches “treatment of cancer by targeting antigens specific to
that cancer (page 9, [0077]) including specifically identifying colon
carcinoma was having ‘HER2/neu’ as an antigen” (id. at 8). The Examiner
finds Miller teaches “antibody 4D5 was found to sensitize breast tumor cell
lines to the cytotoxic effects of TNFa” (id. at 8).
4 Vetvicka et al., Pilot Study: Orally-Administered Yeast J31,3-glucan
Prophylactically Protects Against Anthrax Infection and Cancer in Mice, 5
J. Am. Nutraceutical Ass’n 5-9 (2002).
5 Asp et al., US 2003/0096823 Al, published May 22, 2003.
6 Mathiowitz et al., US 2001/0043914 Al, published Nov. 22, 2001.
7 Miller et al., US 2002/0004587 Al, published Jan. 10, 2002.
8 We refer to the Non-Final Action mailed Jan. 30, 2014.
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Application 12/615,040
The Examiner finds it obvious
to combine the whole glucan from Vetvicka with the Herceptin
of Miller or Asp to treat a patient with colon cancer that
overexpresses HER2. Those patients would have tumor cells
and read upon the claimed patient population and there is a
reasonable expectation of success in inhibiting the tumor
growth since both treatments have been individually shown to
be effective against that type of cancer.
(Non-Final Act. 9).
The issues with respect to this rejection are:
(i) Does the evidence of record support the Examiner’s conclusion
that Vetvicka, Asp, Mathiowitz, and Miller render claim 1 obvious?
(ii) If so, have Appellants presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness?
Findings of Fact
1. Vetvicka teaches a “highly purified particulate yeast-derived
P1,6-branched [31,3 glucan . . . was used in all experiments” (Vetvicka 6,
col. 1).
2. Vetvicka teaches “[o]ral WGP Beta Glucan treatment also
reduces the threat of cancer, slowing down the progression of tumor growth
in a preclinical colon cancer model” (Vetvicka 8, col. 1).
3. Vetvicka teaches a
large body of preclinical and clinical work done in Japan
demonstrating the oral anti-tumor activity of mushroom pi,3-
glucans to yeast pi,3-glucan. These published studies have
demonstrated that pi,3-glucan immunotherapy leads to the
activation of the innate immune cells (macrophages, neutrophils
(PMN) and natural killer (NK) cells), the stimulation of
tumoricidal activities, production of cytokines, and the
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generation of enhanced cell-mediated responses. Suzuki and
colleagues have reported the stimulation of activated
macrophages by the administration of SSG and NK-type
lymphokine-activated killer cells by the combined
administration of lentinan and IL-2. The stimulation of
tumoricidal activities in PMN by a linear bacterial [31,3-glucan
has also been reported.
(Vetvicka 8, col. 1; citations omitted).
4. Vetvicka teaches a “number of clinical studies have
demonstrated synergy between oral [31,3-glucan immunotherapy, and
traditional radiation and chemotherapeutic cancer treatment options”
(Vetvicka 8, col. 1).
5. Asp teaches: “Trastuzumab is a recombinant DNA-derived
humanized monoclonal antibody that selectively binds with a high affinity in
cell-based assays (Kd: 5 nM) to the extracellular domain of the human
epidermal growth factor receptor 2 protein, HER2” (Asp 12).
6. Asp teaches: “Trastuzumab has been shown, in both in vitro
assays and animal models, to inhibit the proliferation of human tumor cells
from different sources overexpressing HER2. Furthermore, nonclinical
studies have shown additive and synergistic effects of trastuzumab when
given in combination with several chemotherapeutic agents” (Asp 14).
7. Mathiowitz teaches: “Antibody-based immunotherapies may
function by binding to the cell surface of a cancer cell and thereby stimulate
the endogenous immune system to attack the cancer cell” (Mathiowitz 174).
8. Mathiowitz teaches “synergistic combinations of IL-12 and
cytokines that augment antigen processing and presentation” (Mathiowitz
189).
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9. Miller teaches “a panel of anti-HER2 antibodies . . . The
antibody 4D5 was further found to sensitize HER2-overexpressing breast
tumor cell lines to the cytotoxic effects of TNF-alpha” (Miller 130).
10. Miller teaches a “recombinant humanized IgGl version of the
murine anti-HER2 antibody 4D5 ... is clinically active in patients with
HER2-overexpressing metastatic breast cancers that have received extensive
prior anti-cancer therapy” (Miller 131).
Principles 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).
Analysis
We adopt the Examiner’s findings of fact and reasoning regarding the
scope and content of the prior art (Non-Final Act. 3—8; FF 1—10) and agree
that the claims are obvious over Vetvicka, Asp, Mathiowitz, and Miller. We
address Appellants’ arguments below.
Prima Facie Obviousness
Appellants contend the
Examiner provided no rationale unmotivated by hindsight bias
why a person having skill in the art would have selected these
two anti-cancer treatments. Given all of the treatments known
to be effective against colon cancer at the time of the invention,
this purported motivation is little more than an invitation to
experiment.
(App. Br. 10).
We are not persuaded. Vetvicka evidences that [31,6-branched pi,3
glucan (FF 1) was a known cancer chemotherapeutic agent (FF 2—3) and was
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combined with other traditional cancer treatment options (FF 4), while Asp,
Mathiowitz, and Miller each teach cancer treatments comprising anti-tumor
antibodies (FF 5, 7, 10) and each recognizes combinations of the anti-tumor
antibodies with other therapeutic agents (FF 6, 8, 9).
The flexible analysis set out by the Supreme Court in KSR recognizes
the obviousness of pursuing known options within the technical grasp of the
skilled artisan, e.g., known equivalents. See KSR, 550 U.S. at 421. Here, it
is fair to say that given the prior art teaches certain antibodies were known to
treat certain cancers, and to do so in concert with other known knowon
antitumor agents (FF 5—10), and that the claimed glucan was known to have
demonstrated anti-tumor activity (FF 1—4), the combination of two known
anit-tumor antibodies with the claimed glucan was the “product not of
innovation but of ordinary skill and common sense.” See Wm. Wrigley Jr.
Co. v. Cadbury Adams USALLC, 683 F.3d 1356, 1364—65 (Fed. Cir. 2012
{citing KSR, 550 U.S. at 421).
Appellants contend
the Examiner used the claims as a template by which to
assemble the invention and that “the ‘known options’ in the
prior art were not ‘finite, identified, and predictable’ ... and are
identified only with hindsight knowledge” of the inventors’
formulation and its properties. Abbott Laboratories v. Sandoz,
Inc., 544 F. 3d 1341 (Fed. Cir. 2008). Given the number of
cytokines [3-glucan affects and the number of treatments known
to affect cytokine sensitivity, Appellant respectfully submits
that the Examiner improperly used the claim to assist in finding
the rationale to combine its elements.
(App. Br. 10).
We are not persuaded. While we are fully aware that hindsight bias
may plague determinations of obviousness, Graham v. John Deere Co., 383
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U.S. 1,36 (1966), we are also mindful that the Supreme Court has clearly
stated that the “combination of familiar elements according to known
methods is likely to be obvious when it does no more than yield predictable
results.” KSR, 550 U.S. at 416.
In the instant case, Vetvicka teaches “synergy between oral pi,3-
glucan immunotherapy, and traditional radiation and chemotherapeutic
cancer treatment options” (FF 4); Asp teaches “additive and synergistic
effects of trastuzumab when given in combination with several
chemotherapeutic agents” (FF 6); and Miller teaches the “antibody 4D5 was
further found to sensitize HER2-overexpressing breast tumor cell lines to the
cytotoxic effects of TNF-alpha” (FF 9); the ordinary artisan would have
reasonably expected the combination of these known chemotherapeutic
agents to demonstrate at least additive effects for cancer treatment. See In re
Kerkhoven, 626 F.2d 846, 850 (CCPA 1980) (“It is prima facie obvious to
combine two compositions each of which is taught by the prior art to be
useful for the same purpose, in order to form a third composition which is to
be used for the very same purpose.”). These expected additive and
synergistic effects would have provided reasons for the ordinary artisan to
have chosen to combine these chemotherapy treatments.
Appellants contend “the Examiner failed to provide any evidence that
would have provided a skilled artisan would [sic] a reasonable expectation
that the combination would have worked in vivo” (App. Br. 11).
We are not persuaded. Our reviewing Court has stated: “Responding
to concerns about uncertainty in the prior art influencing the purported
success of the claimed combination, this court [in O’Farrell] stated:
‘ [o]bviousness does not require absolute predictability of success ... all that
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is required is a reasonable expectation of success’”. In re Kubin, 561 F.3d
1351, 1360 (Fed. Cir. 2009) {citingIn re OTarrell, 853 F.2d 894, 902 (Fed.
Cir. 1988)).
Here, Vetvicka evidences efficacy of [31,6-branched [31,3 glucan in “a
large body of preclinical and clinical work” (FF 3) while Asp, Mathiowitz,
and Miller each teach efficacy of antibodies in cancer treatment (FF 5—9)
including a commercially available anti-HER2 antibody (FF 10). Moreover,
each reference suggests combination therapies (FF 4, 6, 8, 9). Consequently,
there is a reasonable expectation of success in applying these combined
therapies to cancer treatment. Appellants provide no evidence, as opposed
to attorney argument, rebutting this expectation of success. See In re
Pearson, 494 F.2d 1399, 1405 (CCPA 1974) (“Attorney’s argument in a
brief cannot take the place of evidence.”).
Appellants contend
In Takeda Chem. Indus, v. Alphapharm Pty., the Federal Circuit
noted the importance of a starting point for an obviousness
analysis. 492 F.3d 1350, 1358 (Fed. Cir. 2007). In Takeda,
Alphapharm asserted that “the prior art would have led one of
ordinary skill in the art to select “compound b as a lead
compound.” Id. at 1357. The court disagreed, holding that when
the “prior art disclosed a broad selection of compounds any one
of which could have been selected” and provided nothing to
“narrow the possibilities” to a particular compound, selection of
a compound b from that list was not obvious. Id. at 1359-60.
Similarly, at the time of the invention, the literature related to
cancer treatment - and even colon cancer treatment - identified
hundreds, if not thousands, of potential agents that have an
effect against cancer in vitro and provided nothing to narrow
the choice of agents to those identified by the Examiner.
(Reply Br. 3).
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We are not persuaded. First Takeda involves a wholly different
factual scenario concerning structurally similar compounds, where the
question was whether a compound having a particular chemical structure
was obvious from a chemically similar structure. Takeda Chem. Indus., Ltd.
v. Alphapharm Pty., Ltd, 492 F.3d 1350, 1353—54 (Fed. Cir. 2007). The
obviousness question turned on the selection of a lead compound that the
infringer contended would have been obvious to modify to arrive at the
claimed invention. Id. at 1357. The Federal Circuit agreed with the District
Court that there was no reason to select the lead compound because there
was no experimental data or test results in one reference for any of the fifty-
four compounds synthesized that included the “lead compound” that would
suggest its selection as a “target[] for modification to seek improved
properties.” Id. In the second reference that disclosed the “lead compound,”
that particular compound was “not identified as ont of the three most
favorable compounds,” and, in fact, was “singled out” as having negative
activities. Id. at 1358. The Court further noted that none of the species in
the prior art genus fell within the scope of the claim, since “[pjioglitazone
differs from compound b in two respects, and one would have to both
homologate the methyl group of compound b and move the resulting ethyl
group to the 5-position on the pyridyl ring in order to obtain pioglitazone.”
Id. at 1360.
To the extent that Takeda may be relevant here, at all, we find it
supports the Examiner’s conclusion of obviousness. In the instant case, all
of the prior art compounds of Vetvicka, Asp, Mathiowitz, and Miller fall
within the scope of the claim (FF 1, 5, 7, 9, 10), and each has positive data
and/or test results which would recommend their use in suppressing or
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eliminating tumor cells. See Merck & Co., v. Biocraft Labs., Inc., 874 F.2d
804, 807 (Fed. Cir. 1989) (“That the [prior art] discloses a multitude of
effective combinations does not render any particular formulation less
obvious.”)
Secondary Considerations
Appellants contend “the Examiner failed to give adequate weight to
the unexpected result9 reported by Appellant in the Specification that the
combination of [3-glucan and complement-activating monoclonal antibodies
is synergistic” (App. Br. 12). Appellants contend “Figures 9-11 of the
specification, [show] the combination of [3-glucan and monoclonal
antibodies is more efficient at suppressing or eliminating tumor cells than
either [3-glucan or monoclonal antibodies administered alone” (id.).
We find these arguments unpersuasive. As indicated above, due to
the election of species, the claims are limited to the antibody trastuzumab,
identified by the Specification as Herceptin™ (see Spec. 23:21), an antibody
targeted to extracellular domain of the human epidermal growth factor
receptor 2 protein, HER2 (FF 5). However, the data presented in figures 9 to
11 of the Specification is drawn to the anti-GD2 ganglioside antibody, 3F8
(see Spec. 30:18—19) or anti murine mammary tumor virus membrane
antigen antibody, 11C1 (see Spec. 37:13—14).
Neither antibody tested shares the same binding to the target antigen
as trastuzumab or the same structure as trastuzumab, and therefore the
evidence of figures 9-11 was not compared to the closest prior art of Asp
who teaches trastuzumab (FF 5—6) or even Miller who teaches a more
9 We note that the Examiner found, in the Answer, that unexpected results
“is a new argument that appellant did not raise previously” (Ans. 14).
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general anti-HER2 antibody that sensitizes tumor cells to TNF-a (FF 9).
See In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) (“when
unexpected results are used as evidence of nonobviousness, the results must
be shown to be unexpected compared with the closest prior art.”).
In addition, to the extent that Appellants are ignoring the species
election and reading claim 1 to encompass any complement activating anti­
tumor antibody, the evidence is not commensurate in scope with this broad
genus because only two species were tested. Unexpected results must be
“commensurate in scope with the degree of protection sought by the claimed
subject matter.” In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005). Here,
to the extent that any results are unexpected, they are not commensurate in
scope with the much broader recitations of claim 1.
Finally, we find unpersuasive, Appellants’ contention that “none of
the cited documents, either alone or in combination, teach or suggest a
synergistic effect would be achieved when treating with trastuzumab and a
[3-glucan” (Reply Br. 6). In contrast, Vetvicka teaches “synergy between
oral pi,3-glucan immunotherapy, and traditional. . . chemotherapeutic
cancer treatment options (FF 4); Asp teaches “synergistic effects of
trastuzumab when given in combination with several chemotherapeutic
agents” (FF 6); and Miller teaches that the anti-HER2 antibody 4D5 was
“found to sensitize HER2-overexpressing breast tumor cell lines to the
cytotoxic effects of TNF-alpha” (FF 9).
Thus, three separate references provide some evidence that the
ordinary artisan would have expected synergistic results between P-glucan
therapy and other known therapies and between trastuzumab and other
known therapies, thereby providing support for the Examiner’s finding that
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“there is teaching that one agent would increase the effectiveness of the
other agent and thus the prior art directly suggests the synergistic effect.”
(Ans. 17). See In re Skoner, 517 F.2d 947, 950 (CCPA 1975) (“Expected
beneficial results are evidence of obviousness of a claimed invention. Just
as unexpected beneficial results are evidence of unobviousness”).
Therefore, as we balance the evidence as a whole, including the
Examiner’s prima facie case of obviousness, Appellants’ rebuttal arguments,
and Appellants’ asserted unexpected results, we conclude that the method of
claim 1 is obvious over the teachings of Vetvicka, Asp, Mathiowitz, and
Miller (FF 1—10). In particular, we find that even if the Specification
evidence demonstrates some unexpected results for two antibodies other
than trastuzumab, that showing does not support the breadth of claim 1 or
the election to trastuzumab and is insufficient to overcome the Examiner’s
showing of obviousness in this case, where Vetvicka teaches synergies in
tumor cell treatment with a [3-glucan and other chemotherapeutic agents (FF
4) and similar teachings in Asp (FF 6), Mathiowitz (FF 8), and Miller (FF
9).
Conclusions of Law
(i) The evidence of record supports the Examiner’s conclusion that
Vetvicka, Asp, Mathiowitz, and Miller render claim 1 obvious.
(ii) Appellants have not presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness.
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SUMMARY
In summary, we affirm the rejection of claim 1 under 35 U.S.C.
§ 103(a) as obvious over Vetvicka, Asp, Mathiowitz, and Miller. Claims 2—
9, 17, and 18 fall with claim 1.
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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