Ex Parte Schild et al

Patent Trial and Appeal Board

Aug 12, 2013

11664817 (P.T.A.B. Aug. 12, 2013)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte HANSJOERG SCHILD,
TOBIAS WARGER, MARKUS RADSAK,
and GERD RECHTSTEINER
__________

Appeal 2012-000463
Application 11/664,817
Technology Center 1600
__________

Before JENNIFER D. BAHR, FRANCISCO C. PRATS, and
GEORGIANNA W. BRADEN, Administrative Patent Judges.

PRATS, Administrative Patent Judge.

DECISION ON APPEAL
This appeal1 under 35 U.S.C. § 134 involves claims to compositions
that contain Toll-like receptor ligands and major histocompatibility complex
ligands. The Examiner entered rejections for indefiniteness, enablement,
and anticipation.

1 “The real party in interest in this appeal is JOHANNES-GUTENBERG-
UNIVERSITAET MAINZ of Mainz, Germany” (App. Br. 3).
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We have jurisdiction under 35 U.S.C. § 6(b).
We reverse the indefiniteness and enablement rejections, but affirm
the anticipation rejection.
STATEMENT OF THE CASE
The Specification discloses that a number of prior art attempts were
made to use adjuvants to potentiate cytotoxic T cell responses induced by
vaccines (see Spec. 4-5). The Specification discloses, however, that these
efforts were only moderately successful, and produced undesirable side
effects (see id. at 5).
Thus, the objective of Appellants’ invention is “to significantly
improve[] generation of cytotoxic T cells by way of efficient activation
without the drawbacks of the prior art occurring in the process. In particular
the aim is to achieve efficient activation of antigen-presenting cells via
activation of Toll-like receptors” (id. at 5).
Claims 23, 24, 26-36, and 47 stand rejected and appealed (App. Br. 3).
Claims 23, 24, 26, and 28 illustrate the appealed subject matter and read as
follows:
23. A pharmaceutical combination, wherein the combination
comprises (a) at least one Toll-like receptor ligand selected from
TLR7 ligands and (b) at least one peptide selected from (i) major
histocompatibility complex class I ligands, (ii) major
histocompatibility complex class II ligands, and (iii) peptides which
comprise one or more of these histocompatibility complex ligands and
are capable of being presented by at least one of a MHC class I
molecule and a MHC class II molecule.

24. The combination of claim 23, wherein the at least one Toll-like
receptor ligand is selected from compounds of at least one of natural
and synthetic origin which are capable of being recognized by at least
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one Toll-like receptor and are capable of contributing to a triggering
of one or more signals which promote an immune response.

26. The combination of claim 24, wherein the at least one Toll-like
receptor ligand comprises one or more of imiquimod, loxoribine, and
R-848.

28. The combination of claim 23, wherein the combination
comprises at least one synthetic Toll-like receptor ligand (a) and at
least one synthetic peptide (b) and is present as a single formulation
which comprises (a) and (b) for combined administration.

The following rejections are before us for review:
(1) Claims 24, 26, and 27, under 35 U.S.C. § 112, second paragraph,
as indefinite (Ans. 4);
(2) Claims 23, 24, 26-36, and 47, under 35 U.S.C. § 112, first
paragraph, for lack of enablement as to the full scope of the claimed subject
matter (Ans. 4-7); and
(3) Claims 23, 24, 26-28, and 47, under 35 U.S.C. § 102(b) as
anticipated by Braun2 (Ans. 8).
INDEFINITENESS
The Examiner contends that the language in claim 24
“. . . capable of contributing to a triggering of one or
more signals which promote an immune response”. . . renders
the claim vague and indefinite because it is unclear how the
claimed combination contributes to triggering of one or more
signals, how many signals exactly and which signals. It is also
unclear what immune response is promoted.

(Ans. 4.)

2 Braun, U.S. Patent App. Pub. No. 2003/0185835 A1 (published Oct. 2,
2003).
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Appellants argue, for a number of reasons, that an ordinary artisan
would understand the metes and bounds of the subject matter claimed (see
App. Br. 5, 9-11).
We find that Appellants have the better position.
Under § 112, second paragraph, “[a] claim is indefinite if, when read
in light of the specification, it does not reasonably apprise those skilled in
the art of the scope of the invention.” Amgen Inc. v. Hoechst Marion
Roussel, Inc., 314 F.3d 1313, 1342 (Fed. Cir. 2003).
As the Specification explains, Toll-like receptors, including the TLR7
receptor recited in the claims, were known in the art, as were ligands
recognized by the receptors (see Spec. 2-3 (citing Akira3)). As also
explained in the Specification, Toll-like receptors, when stimulated, activate
antigen-presenting cells (see id. at 2).
Thus, we are not persuaded that an ordinary artisan viewing claim 24
in light of the Specification would fail to understand that the claimed
combination, which includes a TLR7 ligand, contributes to triggering signals
that promote an immune response, as the claim requires. We acknowledge
that claim 24’s recitation of any TLR7 ligand “capable of contributing to a
triggering of one or more signals which promote an immune response” very
broadly encompasses any such ligand that initiates any signal that promotes
any immune response to any degree.
It is well settled, however, that “breadth is not to be equated with
indefiniteness.” In re Miller, 441 F.2d 689, 693 (CCPA 1971).

3 Shizuo Akira and Kiyoshi Takeda, Toll-Like Receptor Signalling, 4
NATURE REVIEWS IMMUNOLOGY 499-510 (2004).
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Thus, as we are not persuaded the Examiner has shown that an
ordinary artisan would fail to understand the metes and bounds of claim 24,
we reverse the Examiner’s indefiniteness rejection of that claim, and its
dependent claims 26 and 27.
ENABLEMENT
The Examiner contends:
[T]he specification, while being enabling for a
pharmaceutical combination comprising the MHC class I
ligand, SGPSNTPPEI peptide (SGP), and the TLR7 ligand,
imiquimod, does not reasonably provide enablement for
pharmaceutical compositions comprising at least one TLR-7
ligand, and at least one MHCI ligand or at least one MHCII
ligand or at least one peptide which comprises one or more of
the MHC ligands.

(Ans. 5.)
The Examiner finds the claims encompass compositions containing
“numerous TLR7 ligands together with . . . numerous MHC I ligands or
numerous MHC II ligands or numerous MHC I peptides or MHC II
peptides” (id.).
In contrast, the Examiner finds that the Specification “only teaches a
pharmaceutical composition which comprises the MHC class I ligand,
SGPSNTPPEI peptide (SGP) and the TLR7 ligand, imiquimod, (see bottom
of page 22 to top of page 23)” which is shown to be “superior to
conventional immunization with CFA [complete Freund’s] adjuvant for the
expansion of the specific cytotoxic T cells, (see page 26 and table 2 on page
7)” (Ans. 5-6).
Because the Specification only presents a single working example, the
Examiner finds that a skilled artisan “would not be able to determine,
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without undue experimentation, whether pharmaceutical compositions
comprising all of the encompassed TLR7 ligands and MHC I or MHC II
peptide ligands would trigger one or more signals which promote an immune
response” (id. at 7).
In this regard, the Examiner notes that, “[a]s is acknowledged by
Applicants, it is known that vaccination methods are still associated with
significant side effects due to toxicity” (id. (citing Spec. 5)). Thus, the
Examiner reasons, the “invitation to prepare pharmaceutical compositions
that comprise the recited molecules and to test them for their ability of
contributing to a triggering of one or more signals which promote an
immune response, does not provide a predictable result” (id.).
As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992):
[T]he examiner bears the initial burden . . . of presenting a
prima facie case of unpatentability. . . .
After evidence or argument is submitted by the applicant
in response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.

It is well settled that, when making an enablement rejection, “it is
incumbent upon the Patent Office . . . to explain why it doubts the truth or
accuracy of any statement in a supporting disclosure and to back up
assertions of its own with acceptable evidence or reasoning which is
inconsistent with the contested statement.” In re Marzocchi, 439 F.2d 220,
224 (CCPA 1971).
We agree with Appellants that a preponderance of the evidence does
not support the Examiner’s prima facie case of lack of enablement.
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We note that the Specification’s sole working example of stimulating
an immune response uses the combination of Appellants’ preferred TLR7
ligand, imiquimod, with the SGP antigen from adenovirus 5 being the MHC
class I ligand (see Spec. 21). As noted above, however, the Specification
discloses that the TLR7 receptor was known in the art, as were ligands for
the receptor (see Spec. 2-3).
We also note that stimulation of Toll-like receptors was known to
result in immune responses (see id. at 2; see also Akira 499 (“Stimulation of
different TLRs induces distinct patterns of gene expression, which not only
leads to the activation of innate immunity but also instructs the development
of antigen-specific acquired immunity.”))
Because a skilled artisan would have expected that stimulation of
Toll-like receptors through ligand binding would generate an immune
response, we are not persuaded that the Examiner has adequately explained
why a single working example is insufficient to demonstrate that the claimed
combination, which expressly includes a TLR7 ligand, would be useful for
stimulating an immune response. Moreover, given the presence of an
immune-response-generating TLR7 ligand in the claimed composition, we
are not persuaded that an ordinary artisan would have expected that the
inclusion of additional ligands, either TLR receptors or MHC-binding
molecules, would render the composition incapable of generating an
immune response to a desired antigen, as the Examiner argues.
In that regard, we note that the Examiner has not advanced any clear
or specific evidence, in the prior art or otherwise, suggesting any degree of
unpredictability with respect to the capacity of TLR7 ligands to generate
immune responses. Absent such evidence, we are not persuaded that, in and
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of itself, the presentation of only a single working example demonstrates
that undue experimentation would have been required to practice the full
scope of the invention, as the Examiner seems to suggest.
Accordingly, as we are not persuaded that a preponderance of the
evidence supports the Examiner’s conclusion that practicing the full scope of
the claimed subject would have required undue experimentation, we reverse
the Examiner’s enablement rejection of claims 23, 24, 26-36, and 47.
ANTICIPATION
Appellants argue that the Examiner failed to make out a prima facie
that Braun anticipates claim 23 because the Examiner
has not explained why, let alone has provided any evidence
which would support an allegation that, the antigen mentioned
in paragraph [0331] of BRAUN presumably relied upon by the
Examiner in this respect necessarily is or comprises a major
histocompatibility complex class I ligand, a major
histocompatibility complex class II ligand, and/or a peptide
which comprise one or more of these histocompatibility
complex ligands and is capable of being presented by at least
one of a MHC class I molecule and a MHC class II molecule.

(App. Br. 15-16.)
Appellants further argue that “BRAUN is confusing and contradictory
in that it on the one hand calls for the sequential administration of the
adjuvant and the antigen/polynucleotide and on the other hand seems to
suggest that adjuvant and antigen/polynucleotide are present (contained) in
the same composition” (id. at 16; see also Reply Br. 6-7).
In this instance, we find that a preponderance of the evidence supports
the Examiner’s finding of anticipation.
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Claim 23 recites a pharmaceutical combination that contains two
ingredients: (a) at least one TLR7 ligand and (b) at least one peptide, which
may either be an MHC class I ligand, an MHC class II ligand, or a peptide
that contains one or more of those ligands and which is capable of being
presented by either an MHC class I molecule or an MHC class II molecule.
As to ingredient (a), the Specification explains that the compound
imiquimod is a TLR7 ligand (see Spec. 3 (“Documents WO-A 00/040,228,
WO-A 01/015,698 and WO-A 045,494 also describe the recognition of
different viral structures, which occur in connection with human and animal
diseases, by TLR7, i.e. the substance imiquimod . . . .”); see also Spec. 9
(imiquimod is “most particularly preferred” Toll-like receptor ligand)).
As to ingredient (b), the Specification explains that antigenic peptide
fragments of 8 to 10 amino acids are capable of being presented by a class I
MHC molecule (see id. at 1 (“Protein fragments (from peptides consisting of
8 to 10 amino acids, what are known as MHC class I ligands) are presented
on the cell surface by MHC I molecules.”) (emphasis added)).
Braun discloses that an “imidazo quinolone amine compound acts as
an effective adjuvant when administered topically 12 to 36 hours after a
primer or booster immunisation. In addition the compound was found to be
effective in stimulating cell-mediated immunity” (Braun ¶ [0003]). Braun
discloses that a “preferred compound of the invention is imiquimod” (id. at ¶
[0319]).
Braun discloses that, when generating an immune response, the
antigen “may be in the form of a vaccine composition. The term ‘vaccine
composition’ intends any pharmaceutical composition containing an antigen
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(e.g. polynucleotide encoding an antigen), which composition can used to
prevent or treat a disease or condition in a subject” (id. at [0322]).
Braun describes the antigens useful in its methods:
The antigen typically comprises one or more T cell
epitopes. “T cell epitopes” are generally those features of a
peptide structure capable of inducing a T cell response. In this
regard, it is accepted in the art that T cell epitopes comprise
linear peptide determinants that assume extended conformations
within the peptide-binding cleft of MHC molecules . . . . As
used herein, a T cell epitope is generally a peptide having about
8-15, preferably 5-10 or more amino acid residues.

(Id. at ¶ [0331].)
In addition to describing methods whereby a compound of its
invention, such as imiquimod, is administered topically 12 to 36 hours after
a primer or booster immunization, Braun also discloses that combining a
compound of the invention with an antigen produces a composition with
increased immunogenicity:
A composition which contains a selected antigen and an
adjuvant (such as the compound of the invention), or a vaccine
composition which is co-administered with an adjuvant,
displays “enhanced immunogenicity” when it possesses a
greater capacity to elicit an immune response than the immune
response elicited by an equivalent amount of the antigen
administered without the adjuvant.

(Id. at ¶ [0335] (emphasis added).)
Therefore it may be true, as Appellants argue, that Braun primarily
focuses on administering the imiquimod adjuvant after administering the
antigen. However, given the disclosure in Braun at paragraph [0335], we are
not persuaded that Braun is ambiguous in its description of an embodiment
where the adjuvant compound of the claimed invention, which is most
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preferably imiquimod, is directly combined with an antigen, as required by
claim 23.
Moreover, as also noted above, Braun describes its antigens as peptide
epitopes of 5 to 10 amino acids that are presented within the peptide-binding
cleft of MHC molecules (Braun ¶ [0331]). This conforms not only to the
description of an MHC I antigen Appellants’ Specification (see Spec. 1), but
also meets the functional requirement of claim 23 of being a peptide ligand
which is capable of presentation by either an MHC class I molecule or an
MHC class II molecule.
Thus, given Braun’s characterization of the antigens in its
compositions, we agree with the Examiner that when Braun describes a
composition that contains an antigen according to the invention, an ordinary
artisan would understand that Braun is referring to an antigen encompassed
by Appellants’ claim 23. As Braun describes a discrete composition that
contains a peptide antigen encompassed by claim 23, as well as a TLR7
ligand encompassed by claim 23, Appellants’ arguments do not persuade us
that the Examiner erred in finding that Braun anticipates claim 23. The fact
that In re Fulton, 391 F.3d 1195 (Fed. Cir. 2004), cited by the Examiner
(Ans. 22-23) might pertain to obviousness, rather than anticipation, does not
change our view.
In sum, because Appellants’ arguments do not persuade us, for the
reasons discussed, that the Examiner erred in finding that Braun describes a
composition having all of the features required by claim 23, we affirm the
Examiner’s anticipation rejection of that claim over that reference. Because
they were not argued separately, claims 24, 26, and 27 fall with claim 23.
See 37 C.F.R. § 41.37(c)(1)(vii).
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Further, because Braun expressly discloses that both ingredients
required by the claims are present in a single composition (see Braun
[0335]), Appellants’ arguments do not persuade us that Braun fails to
describe a single formulation containing both ingredients, as required by
claim 28. We, therefore, affirm the Examiner’s rejection of claim 28 over
Braun as well. Claim 47 was argued in the same grouping as claim 28 (see
App. Br. 18), thus claim 47 falls with claim 28.
SUMMARY
We reverse the Examiner’s indefiniteness rejection of claims 24, 26,
and 27, under 35 U.S.C. § 112, second paragraph.
We also reverse the Examiner’s enablement rejection of claims 23, 24,
26-36, and 47, under 35 U.S.C. § 112, first paragraph, for lack of
enablement as to the full scope of the subject matter claimed (Ans. 4-7); and
We affirm the Examiner’s anticipation rejection of claims 23, 24, 26-
28, and 47 over Braun.
TIME PERIOD
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED-IN-PART

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