Ex Parte Hansen

Board of Patent Appeals and Interferences

Jul 31, 2007

08577106 (B.P.A.I. Jul. 31, 2007)

The opinion in support of the decision being entered is not
binding precedent of the Board.

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte HANS J. HANSEN
__________

Appeal 2006-0701
Application 08/577,106
Technology Center 1600
__________

DECIDED: July 31, 2007
__________

Before TONI R. SCHEINER, ERIC GRIMES, and LORA M. GREEN,
Administrative Patent Judges.

SCHEINER, Administrative Patent Judge.

DECISION ON APPEAL
Appellant appeals under 35 U.S.C. § 134 from the final rejection of
claims 38-42, 44-48, 50, 53 and 54, all the claims remaining in the
application. The Examiner has rejected the claims as unpatentable under
35 U.S.C. § 103(a). We have jurisdiction under 35 U.S.C. § 6(b).
We reverse.

Appeal 2006-0701
Application 08/577,106

DISCUSSION
The present invention “provide[s] a method for inducing humoral
and cellular immune responses against tumor cells and infectious agents
using vaccines comprising an antibody that binds with the HLA-DR-
complex” (Spec. 3: 24-26), in particular, a “monoclonal antibody that binds
with the HLA-DR complex on the plasma membrane of macrophages,
monocytes, and B-lymphocytes and then, rapidly internalizes” (id. at 32:
29-32), conjugated to “an antigenic peptide that comprises at least one
epitope of a [tumor associated antigen] or an antigen associated with an
infectious agent” (id. at 3: 27-29).
Claims 38, 39 and 41 are representative of the claimed subject matter:
38. A method for inducing humoral and cellular immune responses
in a mammal against a tumor that expresses a tumor associated antigen
(TAA) or against a disease caused by an infectious agent, said method
comprising:

(a) administering a vaccine intradermally to the mammal, wherein
said vaccine comprises an immunoconjugate that comprises:

(i) an antibody component that binds with the invariant chain
(Ii) of the HLA-DR class-II complex on the plasma
membrane of a cell expressing said HLA-DR-complex and is
internalized into said cell, and

(ii) an antigenic peptide, wherein said antigenic peptide
comprises at least one epitope of a TAA or an antigen
associated with said infectious agent,

and

(b) optionally administering said vaccine intravenously to said
mammal.
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39. The method of claim 38, wherein said antibody component is
selected from the group consisting of:

(a) a murine monoclonal antibody;

(b) a humanized antibody derived from a murine monoclonal antibody;

(c) a human monoclonal antibody; and

(d) an antibody fragment derived from (a), (b) or (c).

41. The method of claim 38, wherein said method comprises step
(b) and said method further comprises:

(c) administering at least one cytokine prior to and during step (b).

OBVIOUSNESS
Carayanniotis in view of Roche, Machy, Van Kaer, and Roitt
The Examiner rejected claims 38 and 50 under 35 U.S.C. § 103(a) as
unpatentable over Carayanniotis1 in view of Roche,2 Machy,3 Van Kaer,4
and Roitt.5

1 George Carayanniotis et al., Delivery of Synthetic Peptides by Anti-Class
II MHC Monoclonal Antibodies Induces Specific Adjuvant-Free IgG
Responses In Vivo, 25 Molecular Immunology 907-911 (1988).
2 Paul A. Roche et al., Cell Surface HLA-DR-Invariant Chain Complexes
are Targeted to Endosomes by Rapid Internalization, 90 Proc. Natl. Acad.
Sci. USA 8581-8585 (1993).
3 Patrick Machy et al., Endocytosis and Recycling of MHC-Encoded Class
II Molecules by Mouse B Lymphocytes, 145 J. Immunol. 1350-1355 (1990).
4 Luc van Kaer, Accessory Proteins that Control the Assembly of MHC
Molecules with Peptides, 23 Immunologic Research 205-214 (2001).
5 Ivan M. Roitt et al., IMMUNOLOGY, Third Ed., Mosby, St. Louis, 6.9, 6.13-
6.14 (1993).
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Carayanniotis describes an “approach to protein antigen delivery in
vivo that circumvents the need for adjuvant by using [monoclonal
antibodies] to target foreign proteins onto cells of the immune system
bearing class II MHC antigens” (Carayanniotis at 907, right-hand col.), i.e.,
antigen-presenting cells. Synthetic peptide vaccines were constructed based
on potential neutralizing epitopes from herpes simplex virus glycoprotein D
(id.). The synthetic peptides were coupled to avidin, and then conjugated to
biotinylated monoclonal antibodies specific for a class II MHC determinant
(id. at 908, left-hand col.). According to Carayanniotis, results “indicate that
Mab-mediated delivery of peptide antigens is able to prime for good
secondary antibody responses in the absence of adjuvant” (id. at 910, right-
hand col.), i.e., a humoral response, but “[i]t will also be of interest to
determine whether or not peptides corresponding to T-cell determinants can
be delivered by anti-MHC MAbs and used to elicit specific T-cell response
in vivo” (id.), i.e., a cellular response.
We note that the reference does not mention the possibility that the
vaccine conjugate, or any part of the vaccine conjugate, is internalized into
the cells and processed for presentation in the context of class II MHC.
Rather, Carayanniotis explains that “[t]he assumption underlying this
approach [to peptide antigen delivery] is that coupling antigens to MAbs
specific for class II determinants of the MHC serves to focus antigen onto
antigen-presenting cells . . . , thereby enabling efficient triggering of an
immune response in the absence of adjuvant” (Carayanniotis at 909, right-
hand col.).
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Carayanniotis differs from the present invention in that the antibody
portion of the vaccine conjugate is specific for I-Ak, and binds the MHC
class II α-β dimer, rather than the invariant chain (Ii) of the HLA-DR
class II-Ii complex (i.e., the αβIi complex).
Roche teaches that “[p]rocessing of antigen for presentation to
CD4+ T cells involves its delivery to an acidic endosomal or lysosomal
compartment, where antigen can be unfolded and cleaved into peptides that
bind to class II major histocompatibility complex (MHC) molecules. . . .
Newly synthesized molecules appear to be the relevant population of MHC
class II molecules for antigen presentation [ ], and their targeting to
endosomes is dependent on their association with the invariant chain (Ii)”
(Roche at 8581, left-hand col.). “Although mostly intracellular, Ii has also
been detected at the surface of human B cells [ ], and at least some of the
surface Ii is associated with class II α and β chains” (id. at 8581, right-hand
col.). “The number of [HLA-]DR molecules and Ii molecules on the surface
of [human B-cells] was determined” (id. at 8582, right-hand col.).
“[A]nalysis revealed that there were >500,000 surface [HLA-]DR molecules
and only 23,500 [ ] surface Ii molecules” and it was “demonstrated that most
[ ] of the surface Ii was bound to HLA-DR molecules” (id.).
“Internalization assays [using prebound radiolabled mAb] were
performed to determine the fate of surface αβIi complexes” (id. at 8583,
left-hand col.), and it was confirmed that “αβIi molecules were rapidly
internalized[,]” but “the vast majority of [HLA-]DR molecules remained
stably at the cell surface” (id.).
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Roche concludes that “retrieval of αβIi complexes from the cell
surface is a viable mechanism for the targeting of a large number of class II
molecules to endosomes” (id. at 8585, left-hand col.), and suggests that
“gradual Ii dissociation from internalized αβIi complexes . . . may allow
newly liberated class II αβ heterodimers to bind peptides [already] in
different compartments along the endocytic route, thus extending the range
of peptides presented to CD4+ T cells” (id.).
As discussed above, the present invention is directed to a method of
inducing humoral and cellular immune responses in a mammal by
administering an immunoconjugate vaccine, wherein the immunoconjugate
comprises an antibody specific for the invariant chain (Ii) of the HLA-DR
class II-Ii complex and an antigenic peptide. The issue raised by this appeal,
then, is whether it would have been obvious for one skilled in the art to
substitute Roche’s antibody (which is specific for the invariant chain (Ii) of
the HLA-DR class-II complex) for Carayanniotis’ antibody (which is
specific for I-Ak, and binds the MHC class II α-β dimer), in Carayanniotis’
vaccine conjugate.
The Examiner reasoned that it would have been obvious for one of
ordinary skill in the art “to replace the antibody component of the anti-MHC
II immunoconjugates of Carayanniotis [ ] with the anti-Ii chain antibodies
taught by Roche [ ], in order to target the population of MHC II complex (Ii-
alpha-beta chain) . . . because [Roche teaches] said population of class MHC
II molecule has an important role in efficient antigen presentation, and [is]
rapidly internalized” (Answer 9).
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Nevertheless, as explained in the Declaration of Dr. Alice P. Taylor,6
“Carayanniotis’ study . . . did not disclose that the [antigen presenting cell]-
targeting complex was internalized, processed or presented in the context of
class II MHC” (Decl. 2). Moreover, according to Dr. Taylor, Roche “does
not address antigen presentation, antigen processing, or even the function of
this cell surface-to-endosome pathway in antigen presentation” (id. at 3).
Dr. Taylor points out that the “anti-Ii antibody has no function in Roche’s
experimental study other than as an indicator of the presence and location of
the Ii chain” (id. at 3), and “this study did not establish whether the HLA-
DR/Ii molecules are loaded with peptide after internalization or whether the
HLA-DR/Ii molecules eventually return to the surface bearing peptides” (id.
at 2-3). In Dr. Taylor’s opinion, “Roche does not establish that anti-Ii
antibodies will deliver peptide to the antigen-processing pathway” (id. at 2).
Finally, in Dr. Taylor’s opinion, the experiments of Carayanniotis and Roche
“provide no evidence that targeting surface HLA-DR/Ii will result in
internalization, processing and presentation of a peptide in the context of
HLA-DR (or any other class II molecule)” (id. at 3).
That being the case, Appellant argues that there is no reason for one
skilled in the art “to combine Carayanniotis and Roche because
Carayanniotis is concerned with stable cell surface display of an intact
complex of an antibody bound to an antigenic peptide where the antibody
binds the MHC Class II α-β dimer, whereas Roche is concerned merely with

6 Declaration of Dr. Alice P. Taylor, dated August 27, 2002, submitted
under the provisions of 37 C.F.R. § 1.132 (hereinafter “Decl.”).
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describing how the complex of the invariant chain Ii bound to HLA-DR is
internalized in an extremely rapid fashion” (Br. 8).
We agree with Appellant that the Examiner has not established that
one skilled in the art would have had a reason to combine the teachings of
these two references, for the reasons discussed immediately above. We are
not persuaded otherwise by the Examiner’s additional reliance on Machy.
Apparently in response to Dr. Taylor’s declaration, the Examiner points to
Machy as evidence that “both antibodies to Class II MHC molecules and
antibodies to the invariant Ii chain of the HLA-DR-Ii complex are
internalized” (id. at 7), and that “intact protein originating outside of antigen
processing cells (APC) must be endocytosed and denatured or partially
degraded to associate with either newly synthesized or endocytosed-recycled
class II molecules” (id. at 8).
If we understand the Examiner’s implication, it is that one skilled in
the art, at the time of the invention, would have recognized that
Carayanniotis’ vaccine conjugate must also have been internalized,
(otherwise Carayanniotis would not have observed an IgG response), and
therefore, it would have been obvious to substitute one internalizing
antibody for another in Carayanniotis’ vaccine delivery method.
We disagree. As discussed above, Roche teaches that most MHC
class II α-β dimers on the surface of a cell are not bound to the Ii chain, and
remain stably at the surface. In addition, we note that Carayanniotis’
conjugates contained short peptide fragments representing neutralizing
epitopes of HSV, rather than intact protein antigens (Carayanniotis at 907,
right-hand col.). Machy does not appear to add anything to the Examiner’s
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case. Machy teaches that “3.5% of surface class II molecules are
internalized” (Machy at 1350, left-hand col.), but does not distinguish
between MHC class II α-β dimers and αβIi complexes. In any case, Machy
teaches that antibody that enters the cell already bound to MHC class II
molecules is recycled to the surface, apparently unprocessed (id. Abstract).
The Examiner further relies on Van Kaer as evidence that “class II
molecules bind with peptides” and “unstable MHC molecules are retained in
peptide-loading compartments until they bind with high-affinity peptides”
(Answer 8). Finally, the Examiner cites Roitt as evidence that αβIi
complexes are transported to endosomal compartments “where dissociation
of Ii occurs, and the swapping of antigenic peptide [already in the
compartment] for Ii generates a stable class II molecule that is transported to
the cell surface for antigen presentation” (id. at 9). Again, we fail to see
how this information adds anything to the Examiner’s case.
The question of obviousness is resolved on the basis of underlying
factual determinations including: (1) the scope and content of the prior art;
(2) the level of ordinary skill in the art; (3) the differences between the
claimed invention and the prior art; and (4) secondary considerations of
nonobviousness, if any. Graham v. John Deere Co., 383 U.S. 1, 17-18, 148
USPQ 459, 467 (1966). “Often, it will be necessary . . . to look to
interrelated teachings of multiple [references] . . . and the background
knowledge possessed by a person having ordinary skill in the art, all in order
to determine whether there was an apparent reason to combine the known
elements in the fashion claimed” (KSR Int’l Co. v. Teleflex Inc., 127 S. Ct.
1727, 1740-41, 82 USPQ2d 1385, 1396 (2007)), taking into account “the
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inferences and creative steps that a person of ordinary skill in the art would
employ” (id. at 1741, 82 USPQ2d at 1396). That being said, “this analysis
should be made explicit” (id.), and it “can be important to identify a reason
that would have prompted a person of ordinary skill in the relevant field to
combine the elements in the way the claimed new invention does” (id.).
In this case, we find that the Examiner has not established that one of
ordinary skill in the art, at the time of the invention, would have had a reason
to combine the references relied on in the manner claimed. Accordingly, the
rejection of claims 38 and 50 as unpatentable over Carayanniotis in view of
Roche, Machy, Van Kaer, and Roitt is reversed.

Carayanniotis in view of Roche, Machy, Van Kaer, and Roitt, and further in
view of Elliott, Becker, and Scott
Claims 41, 42, 44, 53, and 54 stand rejected under 35 U.S.C. § 103(a)
as unpatentable over Carayanniotis, Roche, Machy, Van Kaer, Roitt,
Elliott,7 Becker,8 and Scott.9
The Examiner cited Elliott, Becker, and Scott as evidence that it was
known in the art to administer various cytokines to enhance T cell
proliferation.

7 U.S. Patent 5,478,556 to Elliot et al., issued December 26, 1995.
8 Susanne Becker, Interferon-γ Accelerates Immune Proliferation via Its
Effect on Monocyte HLA-DR Expression, 91 Cellular Immunology 301-307
(1985).
9 U.S. Patent 5,571,515 to Scott et al., issued November 5, 1996.
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None of these references cures the underlying deficiency in the
Examiner’s proposed combination of Carayanniotis and Roche.
Accordingly, we reverse the rejection of claims 41, 42, 44, 53, and 54
under 35 U.S.C. § 103(a).

Carayanniotis in view of Roche, Machy, Van Kaer, and Roitt, and further in
view of Losman, Helstrom, Queen, Burnett, and Hefta.
Claims 39, 40, and 45-48 stand rejected under 35 U.S.C. § 103(a) as
unpatentable over Carayanniotis, Roche, Machy, Van Kaer, Roitt, Losman,10
Helstrom,11 Queen,12 Burnett,13 and Hefta.14
The Examiner cited Losman and Helstrom as evidence that anti-
idiotypic antibodies that mimic tumor associated antigens were known in the
art; Queen and Burnett as evidence that humanized antibodies were known
in the art; and Hefta as evidence that various domains of carcinoembryonic
antigen (CEA) were known in the art.

10 Michele J. Losman et al., Human Response Against NP-4, a Mouse
Antibody to Carcinoembryonic Antigen: Human Anti-Idiotype Antibodies
Mimic an Epitope on the Tumor Antigen, 88 Proc. Natl. Acad. Sci. USA
3421-3425 (1991).
11 U.S. Patent 5,614,610 to Helstrom et al., issued March 25, 1997.
12 U.S. Patent 5,530,101 to Queen et al., issued June 25, 1996.
13 Karen G. Burnett et al., Human Monoclonal Antibodies to Defined
Antigens, HUMAN HYBRIDOMAS AND MONOCLONAL ANTIBODIES, Engleman
et al., eds., Plenum Press, New York (1985).
14 Laura J.F. Hefta et al., Expression of Carcinoembryonic Antigen and Its
Predicted Immunoglobulin-Like Domains in HeLa Cells for Epitope
Analysis, 52 Cancer Research 5647-5655 (1992).
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Again, none of these references cures the underlying deficiency in the
Examiner’s proposed combination of Carayanniotis and Roche.
Accordingly, we reverse the rejection of claims 39, 40, and 45-48
under 35 U.S.C. § 103(a).

SUMMARY
Because the examiner has not established prima facie case that the
claimed invention would have been obvious over the cited prior art, we
reverse all three of the rejections of the claims under 35 U.S.C. § 103(a).

REVERSED

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