Ex Parte Hadden

Patent Trial and Appeal Board

Feb 5, 2018

13940558 (P.T.A.B. Feb. 5, 2018)

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.
13/940,558 07/12/2013 John W. Hadden U0157.70015US05 2575
23628 7590 02/07/2018
WOLF GREENFIELD & SACKS, P.C.
600 ATLANTIC AVENUE
BOSTON, MA 02210-2206
EXAMINER
WEN, SHARON X
ART UNIT PAPER NUMBER
1644
NOTIFICATION DATE DELIVERY MODE
02/07/2018 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
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JOHN W. HADDEN
(APPLICANTS: IRX Therapeutics, Inc.)
Appeal 2016-0083441
Application 13/940,55 82
Technology Center 1600
Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and
JOHN G. NEW, Administrative Patent Judges.
ADAMS, Administrative Patent Judge.
DECISION ON APPEAL
This Appeal3 under 35 U.S.C. § 134(a) involves claims 39-41 (App.
Br.4 5).5 Examiner entered a rejection under 35 U.S.C. § 103(a). We have
jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
1 Oral hearing held January 30, 2018.
2 Appellant identifies the real party in interest as “IRX Therapeutics, Inc.”
(August 13, 2015 App. Br. 3).
3 This Appeal is related to Appeal 2016-003340, Application 13/653,152.
4 Appellant’s August 13, 2015 Appeal Brief (see Appellant’s November 2,
2015 Response to Notification of Non-Compliant Appeal Brief).
5 Pending claims 30 and 32—37 stand withdrawn from consideration (see
App. Br. 5).
Appeal 2016-008344
Application 13/940,558
STATEMENT OF THE CASE
Appellant’s disclosure “relates to vaccine therapy for cancer patients.
More specifically, [Appellant’s disclosure]. . . relates to a vaccine
immunotherapy which immunizes cancer patients, having immune
suppression, to both endogenous and exogenous tumor peptides or proteins”
(Spec.6 71). Appellant’s claim 39 is representative and reproduced below:
39. A vaccine composition comprising:
a natural cytokine mixture[7] comprising the cytokines IL-
1 beta, IL-2, IL-6, IL-8, IFN gamma, and TNF-alpha; and
at least one exogenous tumor antigen, wherein the natural
cytokine mixture and the at least one exogenous tumor antigen
are present in amounts effective for administration to a subject
to stimulate an immune response to the at least one exogenous
tumor antigen, wherein the natural cytokine mixture is prepared
ex vivo by stimulating lymphocytes with a mitogen.
(Appellant’s November 3, 2015 Response 2.)
The claims stand rejected as follows:
Claims 39-41 stand rejected under 35 U.S.C. § 103(a) as unpatentable
over the combination of Simmons,8 Heath,9 and Hadden.10
6 Appellant’s September 20, 2013 Substitute Specification.
7 Appellant states that “[t]he natural cytokine preparation” is “also known as
NCM or IRX-2” (App. Br. 13).
8 S.J. Simmons et al., GM-CSF as a Systemic Adjuvant in a Phase II
Prostate Cancer Vaccine Trial, 39 The Prostate 291—297 (1999).
9 A.W. Heath et al., Cytokines as immunological adjuvants, 10 Vaccine 427—
434(1992).
10 Hadden, US 5,632,983, issued May 27, 1997.
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ISSUE
Does the preponderance of evidence relied upon by Examiner support
a conclusion that the combination of Simmons, Heath, and Hadden, makes
obvious a vaccine composition comprising a known natural cytokine
preparation (NCM) and a known tumor antigen, such as PSMA?
FACTUAL FINDINGS (FF)
FF 1. Appellant discloses that the art prior to Appellant’s filing date
recognized that a
fundamental problem in the effort to immunize cancer patients
is that the tumor-bearing state is associated with
immunosuppressive mechanisms derived from both the tumor
and the host’s disturbed immune system . . . thereby making
immunization difficult. . . . Immune suppression or depletion
involves a reduced capacity of the immune system to respond.
Such suppression can be drug or disease induced. The
condition can be drug induced by treatment, virus induced as in
AIDS, or induced by a disease state such as cancer. The
immune system in this condition is effectively turned off.
(Spec.11 2 (citations omitted).) See Hadden 2: 22—30:
The limited efficacy and significant toxicity associated with
high doses of rIL-2, rIFN-y, rTNF-a, and other monotherapies,
suggests reconsideration of natural combinations of cytokines
in therapeutic strategies. Furthermore, more than one-hundred
different cytokine activities have been identified, which raises
significant doubt as to whether immunotherapy, based upon
combining recombinant cytokines, has a reasonable probability
of success in the cancer clinic in the near future.
See also Hadden 14: 10-12 (exemplifying “chemotherapeutic agents” as a
class of agents that “can damage cells, including T lymphocytes, involved in
11 Appellant’s September 20, 2013 Substitute Specification.
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the immune response”); cf. Hadden 1: 5—6 (Hadden “relates to an improved
method of treating cellular immune deficiencies”); Hadden 14: 4—10
(Hadden’s “composition [] potently promotes T lymphocyte function . . . and
development. . which is therapeutically relevant in any therapeutic
measures requiring stimulation of the immune system or restoring even
partial functioning of a damaged or defective immune system”).
FF 2. Appellant discloses a
method for overcoming immune depression by inducing
production of naive T cells and restoring T-cell immunity. That
is the present invention provides an immune restoration.
[Appellant’s disclosure] . . . further provides a method of
vaccine immunotherapy including the steps of inducing
production of naive T cells and exposing the naive T cells to
endogenous or exogenous antigens at an appropriate site ...[;]
a method for unblocking immunization at a regional lymph
node by promoting differentiation and maturation of immature
dendritic cells at a regional lymph node and allowing
presentation of processed peptides by resulting mature dendritic
cells, thus exposing tumor peptides to T cells to gain
immunization of the T cells[; and] a method of treating cancer
and other persistent lesions by administering an effective
amount of a natural cytokine mixture as an adjuvant to
endogenous or exogenously administered antigen of the cancer
or other persistent lesions.
(Spec. 4; cf Hadden 4: 3—8 (disclosing “a method to treat cellular immune
deficiency in ... a patient by the steps of determining the presence of a
cellular immune deficiency and coadministering to the patient an effective
amount of a thymic peptide such as Thymosin ai combined with an effective
amount of a natural cytokine preparation [(NCM)])”; see Hadden 3: 20-21;
see also Hadden 16: 39-52 (disclosing “[a] method of improving cellular
immune response in a patient comprising coadministering to [a] patient an
effective amount of,” i.e., “Thymosin af’ and NCM); Hadden 1: 8—11
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(disclosing that “in recent years it has become possible to modulate the
immune system to improve its response and, where components of the
system are non-functioning, to either partially or completely restore the
function of the component”); Hadden 1: 27—31 (disclosing that “[t]he use of
immunomodulators in clinical medicine includes the reconstitution of
immune function (or the correction of immunodeficiency) and the
suppression of normal or excessive immune function. A major class of
immunomodulators is cytokines”); see generally Ans. 3).
FF3. Appellant’s disclosure
provides for unblocking immunization at a regional lymph node
by promoting differentiation and maturation of immature
dendritic cells in a regional lymph node and thus allowing
presentation by resulting mature dendritic cells of small
peptides. . . . Additionally, induction of mature dendritic cells
is required. Finally, mobilization of peripheral blood T-
lymphocytes in T-lymphocytopoenic patients in the presence of
induction of naive T cells capable of responding to dendritic
cells presenting endogenous tumor peptides is desired. . . .
[Thus,] the key mechanistic features of [Appellant’s
disclosure] are the in vivo maturation of dendritic cells resulting
in effective peptide antigen presentation. . . . With antigen, this
leads to T and B cell clonal expansion, creating immunity in the
patient. The resulting infiltration into tumors by hematogenous
spread leads to robust tumor destruction. The result... is
increased survival due to immunologic memory. . . .
[D]endritic cell activation and maturation is to be considered a
key factor in cancer immunodeficiency as well as the well-
known defects in T cells such as a decreased number and
function with anergy and presumed apoptosis.
(Spec. 4—5 (emphasis added; citations omitted); cf. Hadden 1: 5—6, 1: 8—11,
1: 27-31, 3: 20-21, 4: 3-8, 14: ^10, and 16: 39-52; see Ans. 3.)
FF 4. Appellant “predicts] logically that exogenously provided synthetic
or extracted tumor peptides . . . can be delivered into the pre-primed or co-
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primed regional or distal lymph node and yield tumor antigen specific T
cells, with or without B cells” (Spec. 9 (emphasis added); cf. Ans. 5—6 (“it is
not only routine in the art but also [] common sense to have both the antigen
and the adjuvant in one vaccine [composition] for the obvious advantage of
reducing cost of production and convenience of administering one does as
opposed to two dose[s]”)).
FF 5. Appellant discloses
A method of enhancing the immune response of cancer patients
to a cancer by administering an effective amount of a
composition containing therein [a natural cytokine mixture
(NCM)] acting as an adjuvant to produce the immune response.
The tumor associated antigen can be either an endogenously
processed tumor peptide preparation resident in regional nodes
of patients with cancer or in conjunction with an exogenously
administered tumor antigen preparation in or near these nodes.
(Spec. 10; cf. Hadden 1: 5-6, 1: 8-11, 1: 27-31, 3: 20-21, 4: 3-8, 14: ^10,
and 16: 39-52.)
FF 6. Appellant defines the term “adjuvant” as “a composition with the
ability to enhance the immune response to a particular antigen. To be
effective, an adjuvant must be delivered at or near the site of antigen. Such
ability is manifested by a significant increase in immune mediated
protection” (Spec. 10; cf. Hadden 6: 38-49 (disclosing that the combination
of NCM and Thymosin al “can be administered in various ways,” including
“[s]ite specific administration i.e., regional to a cancer is preferred if
possible so that adjuvant effects are realized”); see also Hadden 8: 14—15;
Ans. 8—9).
FF 7. Appellant defines the term “NCM” as “a non-recombinant cytokine
mixture ... as set forth in[, inter alia,] Hadden” (Spec. 11; see Ans. 5
(“Appellant has not challenged Examiner’s position that [Hadden] taught the
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same NCM prepared by the same process as what is recited in [Appellant’s]
claims”); Ans. 8 (Hadden “taught the same combination of cytokines as
claimed in [Appellant’s] application”); see generally Hadden 1: 38—45, 7: 5—
19, and 16: 39-52; Ans. 4—5 and 8—9).
FF 8. Appellant discloses that
[u]pon administration of [the] NCM to immunosuppressed
patients with head and neck cancer, it is demonstrated in this
application for the first time that the mobilization of T
lymphocytes in the blood of cancer patients treated with the
NCM produces an increase in immature, naive T cells bearing
both CD2 and CD45 RA.
(Spec. 11 (emphasis added); cf. Co-pending Application 13/653,152,
November 3, 2013 Substitute Specification, 14; Hadden 6: 36—37 (an
“[e]xample of the clinical use [of NCM] is exemplified by Hadden et al.,
[Interleukins and Contrasuppression Induce Immune Regression of Head
and Neck Cancer, 120 Int. Arch. Otolaryngol. 395^403] (1994) in head and
neck cancer”); see Hadden 15: 24—26.)
FF 9. Appellant defines the term “pharmaceutically ‘effective amount’” as
“determined by such considerations as are known in the art,” wherein “[t]he
amount must be effective to achieve immunization including but not limited
to improved tumor reduction, fragmentation and infiltration, survival rate or
more rapid recover, or improvement or elimination of symptoms” (Spec. 15:
2—6; cf Hadden 6: 27—37 (disclosing that the term “effective amount,” as
used in Hadden’s disclosure,
is thus determined by such considerations as are known in the
art. The amount must be effective to show improvement in
immune function in 25% of patients treated including, but not
limited to, improved responses in vitro measurements of
cellular immune function, increased T lymphocyte levels in
vivo, improved skin test response to recall antigens or NCM,
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improved survival rate, more rapid recovery, or improvement or
elimination of symptoms and in cancer reduction of tumor
mass.
(See generally Ans. 8—9.))
FF 10. Hadden discloses that “NCM may be used with other treatments to
improve immune function and treat cancer” (Hadden 6: 34—36; see Ans. 7
(citing Hadden 6—7) (Hadden discloses “that NCM can be administered
along with other treatments to improve immune function and treat cancer”)).
FF 11. Hadden discloses that “IL-2,” inter alia, “induces and supports
proliferation of antigen or mitogen stimulated T-cells” (Hadden 1: 47 49).
FF 12. Hadden does not disclose a composition comprising at least one
exogenous tumor antigen.
FF 13. Simmons discloses the administration of
[rjecombinant human granulocyte-macrophage colony-
stimulating factor (GM-CSF. ..)... to a subgroup of 44
patients in a phase II clinical trial for prostate cancer using
[dendritic cells (DC)] pulsed with HLA-A2-specific prostate-
specific membrane antigen (PSMA) peptides ... to determine if
GM-CSF caused any enhancement of patients’ immune
responses, including enhancement of clinical response to the
DC-peptide treatment.”
(Simmons, Abstract; id. at 292: col. 1, 8—10 (Simmons “included GM-CSF
as a systemic adjuvant in [their] phase II prostate cancer clinical trial”); see
Ans. 2).
FF 14. Simmons discloses that “GM-CSF as employed in [Simmons ] trial
did not detectably enhance clinical response to DC-peptide infusions, or
significantly enhance the measured immune response” (Simmons, Abstract
(emphasis added)); see also id. at 292: col. 1, first full paragraph (disclosing
the employment of GM-CSF in Simmons’ trial); see Ans. 2).
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FF 15. Simmons discloses that
[t]he absence of benefit in [Simmons’] study contrasts with
other reports that suggested significant improvements in
antigen-specific immune response following vaccination with
GM-CSF. These reports differed from [Simmons’] study in
GM-CSF dose, duration of dosing, and dosing relative to
vaccination. These may be variables that need to be evaluated
with dendritic cell-based vaccines as well.
(Simmons 295: first and second columns, bridging paragraph; see Ans. 2
(Examiner reasons that “[although GM-CSF was not found to detectably
enhance clinical response to the DC-PSMA infusion, one of ordinary skill in
the art would appreciate the suggestion of using cytokine as an adjuvant in
cancer vaccine”)).
FF 16. Heath discloses that “[v]arious cytokines have been shown to be
effective immunological adjuvants in a variety of model systems, . . .
increasing parameters of immunity in tumor immunization models and in
clinical trials,” which “can rival that of the adjuvants presently allowed for
human use and there are many possible routes to improvement. The use of
cytokines may allow for a choice of which immune parameters are enhanced
in order to further enhance protective effects and decrease the negative
effects of vaccines” (Heath, Abstract (emphasis omitted); see Ans. 2; see
also Ans. 3 (Examiner finds that Heath discloses that IL-1 beta, IL-2, IFN-
gamma and TNF-alpha are cytokines); Heath 427-429).
FF 17. Heath discloses:
As cytokine adjuvants may exert local effects, then a
logical means of increasing adjuvanticity might be to ensure the
presence of cytokine and antigen in the same area by physical
association. This may be achieved to a certain extent by the
emulsion procedure, or by producing antigen/cytokine
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liposomes . . [or] by creating direct physical links between the
two.
FF 18. (Heath 431: first column, third full paragraph; see generally Ans. 2
and 8.) Heath discloses that
[t]he cytokine network is complicated, and it is possible that
combinations of cytokines may have synergistic adjuvant
effects. As yet, however, there has been little success in our
limited studies on cytokine combinations. . . . Much work
remains to be done, and clearly the number of combinations to
be tested, even for pairs of cytokines, would be staggering.
(Heath 430: second column, last paragraph; see Ans. 3.)
ANALYSIS
Appellant recognized that it was known in the art, prior to the filing
date of Appellant’s claimed invention, that a “fundamental problem in the
effort to immunize cancer patients is that the tumor-bearing state is
associated with immunosuppressive mechanisms derived from both the
tumor and the host’s disturbed immune system” that makes “immunization
difficult” (FF 1). Thus, Appellant sought to overcome, or unblock, this
immunosuppression and, thereby, restore immunological function so that an
immune response to at least one exogenous tumor antigen can be stimulated
by immunizing a cancer patient with a vaccine composition comprising a
tumor antigen and an adjuvant, wherein the adjuvant is a natural cytokine
mixture comprising the cytokines IL-lbeta, LI-2, IL-6, IL-8, IFN-gamma,
and TNF-alpha (see FF 1—9; see also Appellant’s claim 39).
Vaccine compositions comprising an exogenous antigen and an
adjuvant were not new to Appellant’s disclosure. To the contrary, vaccine
compositions comprising an exogenous antigen and an adjuvant were well-
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known in the art at the time of Appellant’s claimed invention (see FF 17
(advocating a close association between cytokine adjuvant and antigen, such
as by associating the adjuvant and antigen in an emulsion, liposome, or “by
creating direct physical links between the two” to enhance adjuvanticity);
see also FF 4 (Examiner finds that “it is not only routine in the art but also []
common sense to have both the antigen and the adjuvant in one vaccine
[composition] for the obvious advantage of reducing cost of production and
convenience of administering one does as opposed to two dose[s]”); see
generally FF 13—16 and 18; Ans. 5 (“[a]t the time . . . [Appellant’] invention
was made, the state of the art [was] ripe with the teachings of cancer
vaccines in combination with cytokines as adjuvants for the purpose of
enhancing immune responses to the antigens in the vaccines”); App. Br. 14
(Appellant’s acknowledge that “multiple investigators” in this art were
exploring vaccine compositions comprising cytokines and exogenous
antigens)).
The use of a cytokine or cytokine mixture as an adjuvant was also not
new to Appellant’s disclosure, but was instead routine in this art prior to the
filing date of Appellant’s claimed invention (see FF 16 (“[vjarious cytokines
have been shown to be effective immunological adjuvants in a variety of
model systems, . . . increasing parameters of immunity in tumor
immunization models and in clinical trials”); FF 13 (Simmons “included
GM-CSF as a systemic adjuvant in [their] phase II prostate cancer clinical
trial”); FF 6 (Hadden discloses a preferred site for NCM administration to
realize NCM’s “adjuvant effects”); FF 2 (“A major class of
immunomodulators is cytokines”)). As Heath explains, “[a]s cytokine
adjuvants may exert local effects, then a logical means of increasing
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adjuvanticity might be to ensure the presence of cytokine and antigen in the
same area by physical association,” such as by co-administering exogenous
antigen together with cytokines (FF 17).
Hadden, however, recognized the “limited efficacy” of prior cytokine
therapies, potential “toxicity” associated with the use of cytokines, and the
number of potential cytokine combinations (see FF 1). Heath also
recognized the complexity of the cytokine network, their own limited
success, and the “staggering” number of cytokines and potential cytokine
combinations (FF 18). Hadden, therefore, set out to overcome these prior art
hurdles in the use of cytokine mixtures as adjuvants and successfully
developed a specific mixture of cytokines, NCM, that overcomes the prior
art problems with cytokine therapy, overcomes the immunosuppressive state
of cancer patients, and exhibits adjuvant effects (see FF 1—3 and 5—9). There
is no dispute on this record that Hadden’s NCM is the natural cytokine
mixture and is prepared by the same process required by Appellant’s claim
39 (see FF 7).
Although Hadden discloses an effective mixture of cytokines for use
in, inter alia, the treatment of cancer, Hadden does not disclose a vaccine
composition that comprises NCM and an exogenous antigen (FF 1—12).
Nonetheless, Hadden does disclose “that NCM can be administered along
with other treatments to improve immune function and treat cancer,” such as
those known in this art and disclosed by Simmons and Heath (see FF 1—18).
There is no dispute on this record that the prior art suggests amounts of
antigen and NCM that are effective for administration to a subject to
stimulate an immune response to the antigen as is required by Appellant’s
claim 39 or that such amounts could not have been “determined by such
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considerations as are known in the art” (see e.g., FF 9; see generally 1—18).
In re Geisler, 116 F.3d 1465, 1470, (Fed. Cir. 1997) (“‘[I]t is not inventive
to discover the optimum or workable ranges by routine experimentation.’”)
(quoting In reAller, 220 F.2d 454, 456 (CCPA 1955)).
Therefore, we find no error in Examiner’s conclusion that, at the time
of Appellant’s claimed invention, a person of ordinary skill in this art would
have found it prima facie obvious, based on the combination of Simmons,
Heath, and Hadden, to prepare a vaccine composition comprising Hadden’s
natural cytokine mixture and at least one exogenous tumor antigen, such as
Simmons’ PSMA (see Ans. 3; FF 1—18; see Ans. 3). In this regard, we note
that Heath suggests co-administration of a cytokine adjuvant and antigen,
and Hadden discloses the combination of NCM “with other treatments to
improve immune function and treat cancer” (FF 10 and 13). Thus, on this
record, the combination of Simmons, Heath, and Hadden suggest their
combination.
In sum, the combination of Simmons, Heath, and Hadden suggest the
combination of familiar elements according to known methods to yield a
predictable result. See KSRInt’l Co. v. Teleflex Inc., 550 U.S. 398, 416
(2007) (“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results”).
More specifically, as Examiner and Appellant appreciate, and the
combination of Simmons, Heath, and Hadden disclose, those of ordinary
skill in this art have prepared vaccine compositions comprising exogenous
antigen and cytokines with limited success and were searching for what may
have been the missing link — a cytokine mixture that would be an effective
adjuvant for an exogenous antigen for use, in combination with an
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exogenous antigen, in the treatment of cancer (see Ans. 3 and 5). As this
record makes clear, Hadden’s disclosure of an effective cytokine mixture
provides that missing link. Stated differently, Hadden ‘“puts the key in the
lock of the door of success’. All that remains for a person having ordinary
skill is to turn the key and, in so doing, open the lock. That, in our
judgment, does not give rise to a patentable invention.” See Ex parte
Goldgaber, 41 USPQ2d 1172, 1175 (Bd. Pat. App. & Int. 1995). See
Naylor121 8b (“it is the natural composition of the [NCM, disclosed by
Hadden] and its biologic nature that makes it unique” and “it is the
production and unique activity of the natural cytokine compositions^
disclosed by Hadden,] that is relevant”). Thus, on this record, the
combination of Simmons, Heath, and Hadden provides a person of ordinary
skill in this art with a reasonable expectation of successfully preparing a
vaccine composition within the scope of Appellant’s claim 39. See In re
O'Farrell, 853 F.2d 894, 903—904 (Fed. Cir. 1988) (“Obviousness does not
require absolute predictability of success ... all that is required is a
reasonable expectation of success”).
For the foregoing reasons, we are not persuaded by Appellant’s
contention that the combination of Simmons, Heath, and Hadden “does not
teach or suggest each and every limitation of claim 39 (App. Br. 10; see id.
at 12; cf. FF 1-18).
For the foregoing reasons, we are also not persuaded by Appellant’s
contention that “a reasonable expectation of success is not present in this
case in view of the cited art and the knowledge available to one of ordinary
skill in the art at the time of the filing of. . . [Appellant’s] application” (App.
12 Declaration of Paul H. Naylor, Ph.D., signed July 16, 2014.
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Br. 10; cf. FF 1—18). We recognize that Simmons’ disclosure that “GM-CSF
as employed in [Simmons ] trial did not detectably enhance clinical response
to DC-peptide infusions, or significantly enhance the measured immune
response” (FF 14; see also App. Br. 10; Reply Br. 5 (“Simmons discloses
that the GM-CSF ‘did not directly enhance clinical response to DC-peptide
infusions, or significantly enhance the measured immune response’”)).
Simmons, however, acknowledges that their results contrasted “with other
reports that suggested significant improvements in antigen-specific immune
response following vaccination with GM-CSF” and concedes that their study
deviated, in a number of ways, from the protocols of the prior successful
results obtained in this art (see FF 15). Thus, rather than detracting from a
person of ordinary skill’s reasonable expectation of success, Simmons
focuses the attention of a person of ordinary skill in this art to developing a
vaccine composition based on prior art success as is provided in and guided
by the combination of Simmons, Heath, and Hadden (see FF 1—18). In
addition, we are not persuaded by Appellant’s contention that
Simmons did not disclose a vaccine containing GM-CSF and
exogenous tumor antigen. The GM-CSF was administered
separately. For this reasons alone [] Examiner has not made out
a prima facie case for combining the pulsed dendritic cells of
Simmons with the cytokine mixture of Hadden to generate a
vaccine containing both,
which fails to account for Heath’s disclosure of formulating exogenous
antigen and cytokine in the same composition (FF 17). Therefore, we are
not persuaded by Appellant’s contentions regarding Simmons, which fails to
consider the disclosures of Simmons, Heath, and Hadden in combination
(see App. Br. 10; id. at 14 (“[i]f anything, Simmons teaches away from using
a cytokine treatment to enhance a dendritic cell treatment”); Reply Br. 5).
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See In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986) (Each
reference “must be read, not in isolation, but for what it fairly teaches in
combination with the prior art as a whole”).
We are also not persuaded by Appellant’s contention that Heath’s
disclosure, when viewed in isolation, fails to provide a person ordinary skill
in this art with a reasonable expectation of success in formulation a vaccine
composition within the scope of Appellant’s claim 39 (App. Br. 11). In this
regard, Appellant directs attention to Heath’s disclosure “that there is ‘much
work to be done, and clearly the number of combinations to be tested, even
for pairs of cytokines, would be staggering’” (App. Br. 11 (citing Heath 430:
right column, last paragraph)). Hadden, however, specifically addresses
Heath’s concern, acknowledging that “more than one-hundred different
cytokine activities have been identified, which raises significant doubt as to
whether immunotherapy, based upon combining recombinant cytokines, has
a reasonable probability of success in the cancer clinic in the near future”
(FF 1). Nevertheless, Hadden rose to the challenge, performed the necessary
work, and disclosed a specific combination of cytokines, NCM, that
exhibited the desired effects and, is the same natural cytokine mixture now
required by Appellant’s claim 39 (see FF 1—10). Thus, notwithstanding
Appellant’s contention to the contrary, Hadden not only directs a person of
ordinary skill in this art to the use of Hadden’s NCM, Hadden suggests
combining NCM with other cancer therapies, and recognized and overcame
the prior art, e.g., Heath’s, concerns about a reasonable expectation of
success. Therefore, we are not persuaded by Appellant’s contentions
regarding a reasonable expectation of success in the context of Heath’s
disclosure, which fails to consider the disclosures of Simmons, Heath, and
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Hadden in combination (see App. Br. 11). See In re Merck & Co., 800 F.2d
at 1097 (Fed. Cir. 1986).
As discussed above, Simmons and Heath disclose the use of cytokines
as adjuvants for exogenous antigen (see FF 13—18). In addition, Hadden
discloses the use of NCM as an adjuvant (FF 6). Thus, in combination,
Simmons, Heath, and Hadden suggest the use of NCM as an adjuvant for an
exogenous antigen. Therefore, we are not persuaded by Appellant’s
contention that, when viewed in isolation, Hadden “does not disclose that the
natural cytokine preparation can induce an enhanced immune response to an
exogenous tumor antigen” (App. Br. 11). See In re Merck & Co., 800 F.2d
at 1097 (Fed. Cir. 1986). We are also not persuaded by Appellant’s
contention that Hadden’s NCM, which is the same natural cytokine mixture
required by Appellant’s claim 39, exhibits different properties than
Appellant’s natural cytokine mixture (see App. Br. 11; id. ; cf. FF 1—10).
We are not persuaded by Appellant’s contention “that if one were to
make the suggested combination one could only ‘hope’ that it would work
... as the Simmons combination did not itself work, it would have been a
wish and a hope at best that a new combination would work” (App. Br. 13).
As discussed above, Simmons acknowledges that the protocol used in their
study deviated from known successful protocols (FF 15). In addition, and as
discussed above, the combination of Simmons and Heath suggest that those
of ordinary skill in this art were searching for an effective cytokine or
mixture of cytokines that would serve as an effective adjuvant for an
exogenous antigen (see FF 13—18; see also Ans. 5); Heath suggests a
composition comprising an exogenous antigen and a cytokine adjuvant (FF
17); and Hadden, after recognizing the deficiencies in the art, disclosed an
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effective NCM for use as an adjuvant in combination with other cancer
therapies (see FF 6 and 10). Thus, when viewed in combination, Simmons,
Heath, and Hadden established that there was a design need or market
pressure to solve a problem, specifically, to identify or develop a cytokine or
cytokine mixture that would be an effective adjuvant for an exogenously
administered tumor antigen (FF 1—18). Hadden provided such an effective
cytokine mixture and, thereby, identified a predictable solution to the prior
art problem (FF 1—10).
When there is a design need or market pressure to solve a
problem and there are a finite number of identified, predictable
solutions, a person of ordinary skill has good reason to pursue
the known options within his or her technical grasp. If this
leads to the anticipated success, it is likely the product not of
innovation but of ordinary skill and common sense. In that
instance the fact that a combination was obvious to try might
show that is was obvious under § 103.
KSR, 550 U.S. at 416.
As discussed above, there is no dispute on this record that Hadden’s
NCM is the same natural cytokine mixture as is required by Appellant’s
claim 39. Hadden appears to be the inventor of the subject matter in this
Appeal. Appellant and Hadden both disclose similar features and/or benefits
associated with NCM (see FF 1—10). Nevertheless, Appellant contends that
“[t]he mechanism of action of the natural cytokine preparation^ was not
understood at the time [prior to Appellant’s claimed invention]” and “[t]his
mechanism of action of NCM and, therefore, the ability to predict that it
should enhance the immune response against an exogenous antigen was not
revealed until the present application” (App. Br. 13). Stated differently,
subsequent to Appellant’s earlier Hadden Patent, Appellant discovered new
properties and/or benefits associated with the combination of NCM with
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other cancer therapies. Hadden, however, discloses the combination of
NCM with other cancer therapies that were known in the art, such as those
disclosed by the combination of Simmons and Heath (see FF 10 and 13—18).
Thus, Hadden disclosed, what was at the time of Appellant’s filing date, an
old process and composition. Cf. King Pharmaceuticals, Inc. v. Eon Labs,
Inc., 616 F.3d 1267, 1275—76 (Fed. Cir. 2010) (“[MJerely discovering and
claiming a new benefit of an old process cannot render the process again
patentable.”); In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990). See In
re Kubin, 561 F.3d 1351, 1357 (Fed. Cir. 2009) (“[e]ven if no prior art of
record explicitly discusses the [limitation or benefit], [Applicant’s]
application itself instructs that [the limitation or benefit] is not an additional
requirement imposed by the claims on the [claimed invention], but rather a
property necessarily present in [the claimed invention]”). Therefore, we are
not persuaded by Appellant’s contention that the observation and further
characterization of the NCM composition alone or in combination with other
therapies, as disclosed by Hadden, renders Appellant’s old vaccine
composition newly patentable. See also In re Papesch, 315 F.2d 381, 391
(CCPA 1963) (“From the standpoint of patent law, a compound and all of its
properties are inseparable; they are one and the same thing”).
We are not persuaded by Appellant’s contention that the combination
of Simmons, Heath, and Hadden fails to make obvious Appellant’s claimed
invention, because Hadden’s disclosure, of cancer reduction of tumor mass
and treating cancer, when viewed in isolation, “does not teach that the
natural cytokine preparation can induce an enhanced immune response to an
exogenous tumor antigen” (App. Br. 11; see also id. at 12—13; Naylor | 8a
(Hadden does not disclose the production of “antigen-specific T cells
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capable of eliciting an enhanced immune response to an exogenous
antigen”); cf. FF 17 (Heath suggests co-administration of cytokine and
exogenous antigen); FF 2 (Hadden discloses “[a] method of improving
cellular immune response in a patient comprising coadministering to [a]
patient an effective amount of,” e.g., “Thymosin ai” and NCM).
For the foregoing reasons, we are not persuaded by the Naylor or
Appellant’s reliance thereon (see Naylor || 4—8; App. Br. 13—16). As
discussed above, we are not persuaded by Appellant’s contention and
Naylor’s statement that “[wjithout the knowledge of the mechanism of
action of [NCM], one of ordinary skill in the art would not have been able to
predict that a T cell response to exogenous antigens would be the result of
administering the exogenous antigen in a composition with [NCM]” (App.
Br. 13 (citing Naylor | 8e)). Notwithstanding Appellant’s contention to the
contrary, Hadden discloses the same NCM required by Appellant’s claim 39
and its use as an adjuvant in combination with other cancer therapies, such
as those disclosed by the combination of Simmons and Heath (FF 6, 10, and
13—18). The observation and further understanding of NCM’s mechanism of
action, which are properties of NCM itself, does not support a conclusion of
non-obviousness on this record. See In re Papesch, 315 F.2d at 391.
Further, on this record, Appellant failed to provide persuasive evidence or
argument to support a conclusion that the administration of the vaccine
composition suggested by the combination of Simmons, Heath, and Hadden,
to a patient in need thereof would not have achieved the same result as
obtained from administering a vaccine composition within the scope of
Appellant’s claim 39 (see FF 1—18). Therefore, we are not persuaded by
Appellant’s contention that “prior to the filing of the instant application, one
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o[f] ordinary skill in the art would not have had any reasonable expectation
of success that the composition of [] claim 39 would have the properties of
stimulating an immune response against an exogenous tumor antigen” (App.
Br. 14; see also App. Br. 13—14; Naylor || 8d—f; Reply Br. 1—6).
Notwithstanding Appellant’s contention to the contrary, Hadden discloses
the stimulation of an immune response, discloses that NCM is an adjuvant,
and suggests NCM’s use in combination with other cancer therapies, such as
those involving an exogenous antigen and a cytokine adjuvant for the
purpose of stimulating an immune response against the exogenous antigen
{see FF 1-18).
We are not persuaded by Appellant’s contentions and Naylor’s
statements regarding “that ‘natural biologies can vary and their exact
composition is often critical to their action’” (App. Br. 14 (citing Naylor
1 8b)). On this record, Hadden provides a NCM that overcomes the
deficiencies in the prior art as discussed in Hadden, Heath, and Simmons
(FF 1-18).
We are not persuaded by Appellant’s contentions and Naylor’s
statements regarding Cavaillon13 and other publications cited by Naylor
(App. Br. 15—16; see also Naylor | 8). At best, these contentions and
statements reflect the concerns expressed by Hadden and Heath regarding
the complexity of the cytokine network and number of potential cytokine
combinations. As discussed above, however, these concerns were overcome
by Hadden’s disclosure of NCM and its combination with other cancer
therapies {see FF 1—10 and 16—18; see generally Ans. 6—9).
13 Jean-Marc Cavaillon, Pro-versus Anti-Inflammatory Cytokines: Myth or
Reality, 47 Cellular and Molecular Biology 695—702 (2001).
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Appellant’s claimed invention does not require a synergistic mixture
of cytokines and at least one exogenous tumor antigen (see Appellant’s
November 3, 2015 Response 2). Therefore, we are not persuaded by
Appellant’s contention and Naylor’s statements regarding synergism (App.
Br. 14; Naylor Deck 1 8b). Nor does Naylor provide comparative evidence
showing unexpected results or demonstrating another secondary
consideration (Naylor Decl. 1 8).
We are not persuaded by Naylor’s statement that “Simmons does not
teach the use of cytokines, and certainly not the claimed complex cytokine
mixture, in combination with exogenous antigens either as peptides, proteins
or peptide-conjugates, all antigen compositions relevant to the claimed
composition,” which fails to consider the combination of Simmons with
Heath and Hadden (see Naylor Decl. 1 8d; cf. FF 1—18). Heath suggests a
composition comprising exogenous antigen and cytokines, therefore, we are
not persuaded by Naylor’s statement that Simmons, when viewed in
isolation, fails to suggest such a composition because Simmons makes use of
DC-cells to carry the exogenous antigen and “[s]uch a distinction is critical
to using exogenous antigens, as exogenous antigens act via different
pathways than endogenous antigens and dendritic cells presenting antigen”
(Naylor | 8c—d). In addition, we note that Appellant’s claim 39 does not
exclude exogenous antigen carried by DC-cells.
CONCLUSION OF LAW
The preponderance of evidence relied upon by Examiner supports a
conclusion that the combination of Simmons, Heath, and Hadden, makes
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obvious a vaccine composition comprising a known natural cytokine
preparation (NCM) and a known tumor antigen, such as PSMA.
The rejection of claim 39 under 35 U.S.C. § 103(a) as unpatentable
over the combination of Simmons, Heath, and Hadden is affirmed. Claims
40 and 41 are not separately argued and fall with claim 39.
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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