Ex Parte Kalish

Board of Patent Appeals and Interferences

Jul 31, 2003

08907783 (B.P.A.I. Jul. 31, 2003)

The opinion in support of the decision being entered today was not written
for publication and is not binding precedent of the Board.

Paper No. 28

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte RICHARD S. KALISH
__________

Appeal No. 2002-1355
Application No. 08/907,783
__________

ON BRIEF
__________

Before WILLIAM F. SMITH, GRIMES, and GREEN, Administrative Patent
Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL

This is a decision on appeal under 35 U.S.C. § 134 from the examiner’s
final rejection of claims 1, 3-15, 18-23, 25, 27-44, 47-52, and 54, all of the claims
remaining. Claim 1 is representative and reads as follows:
1. A method for screening a test compound for the ability of the
test compound to induce a response from human naive T-cells, the
method comprising:

obtaining a sample of human blood, wherein the sample of
human blood contains human naive T cells and
macrophages/monocytes;

admixing the sample of human blood with immortalized B
cells lacking class I and class II major histocompatibility antigens
Appeal No. 2002-1355 Page 2
Application No. 08/907,783

and with a test compound, wherein the B cells act as co-stimulatory
molecules; and

determining whether the test compound induces a response
from the human naive T cells.

The examiner relies on the following references:
Ho 5,106,746 Apr. 21, 1992
Engleman WO 94/02156 Feb. 3, 1994

Schwartz, “The Role of Gene Products of the Major Histocompatibility Complex
in T Cell activation and Cellular Interactions,” Fundamental Immunology, Chp.
15, pp.379-438 (1984)

Del Prete et al. (Del Prete), ”Purified Protein Derivative of Mycobacterium
tuberculosis and Excretory-Secretory Antigen(s) of Toxocara canis Expand In
Vitro Human T Cells with Stable and Opposite (Type 1 T Helper or Type 2 T
Helper) Profile of Cytokine Production,” J. Clin. Invest., Vol. 88, pp. 346-350
(1991)

ATCC Cell and Hybridoma on-line catalog (ATCC number CRL-1992); (1995)
Mehta-Damani et al. (Mehta-Damani), “Generation of antigen-specific CD4+ T
cell lines from naive precursors,” Eur. J. Immunol., Vol. 25, pp. 1206-1211 (1995)

Yokozeki et al. (Yokozeki), ”Experimental Study for the Development of an in
vitro Test for Contact Allergens,” Int Arch Allergy Immunol, Vol. 106, pp. 394-400
(1995)

Li et al. (Li), ”Evaluation of cross-sensitization among dye-intermediate agents
using a modified lymphocyte transformation test,” Arch Toxicol, Vol. 70, pp. 414-
419 (1996)

Krasteva et al. (Krasteva), In vitro primary sensitization of hapten-specific T cells
by cultured human epidermal Langerhans cells – a screening predictive assay for
contact sensitizers,” Clinical and Experimental Allergy, Vol. 26, pp. 563-570
(1996)

Goronzy et al. (Goronzy), ”Immunoregulatory Effects of Borrelia burgdorferi on T-
B Cell Interactions, Journal of Rheumatology, Vol. 19, No. 4, pp. 573-578 (1992)
Rietschel, “Occupational contact dermatitis,” Lancet, Vol. 349, pp. 1093-1095
(1997)

Appeal No. 2002-1355 Page 3
Application No. 08/907,783

The claims stand rejected under 35 U.S.C. § 103 as obvious in view of the
following combinations of references:1
• Claims 1, 15, 18, 19, 32, 44, 47, and 48 in view of Yokozeki, Goronzy,
Schwartz, and the ATCC catalog.
• Claims 3-5 and 33-35 in view of Yokozeki, Goronzy, Schwartz, the
ATCC catalog, Krasteva, and Rietschel.
• Claims 6-10, 14, 36-39, and 43 in view of Yokozeki, Goronzy,
Schwartz, the ATCC catalog, Engleman, and Ho.
• Claims 11-13 and 40-42 in view of Yokozeki, Goronzy, Schwartz, the
ATCC catalog, Krasteva, and Li.
• Claims 20-23, 49-52, and 54 in view of Yokozeki, Goronzy, Schwartz,
the ATCC catalog, and Mehta-Damani.
• Claims 27-31 in view of Yokozeki, Goronzy, Schwartz, the ATCC
catalog, and Del Prete.

We reverse all of the rejections.
Background
“There is a great need for in vitro methods for testing allergenicity of
compounds. . . . In particular, a method is needed to screen for potential
allergens in products intended for topical application, such as cosmetics.”
Specification, page 1. “Allergic contact dermatitis is mediated by T-
lymphocytes. . . . Allergens thus function as antigens to induce a T-lymphocyte
response.” Id., page 2.
“Primary in vitro sensitization is the sensitization of naive T-lymphocytes to
antigens which the donor has never encountered. Other investigators have been
unable to achieve primary in vitro sensitization without the use of dendritic cells.”

1 None of the rejections set out in the Examiner’s Answer included claim 25. Since claim 25 was
rejected in the final Office action (Paper No. 14, mailed Jan. 27, 2000), it is unclear whether or not
the rejection of claim 25 was withdrawn. In view of our disposition of the rejections on appeal,
however, the issue is moot.
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Application No. 08/907,783

Id. “The ability of dendritic antigen presenting cells to induce a primary immune
response to a novel antigen is probably a function of the high expression of
co-stimulatory molecules by these cells.” Id. Such co-stimulatory signals are
essential for inducing T-cell proliferation. See id., pages 2-3. Dendritic cells,
however, “are difficult to isolate in significant numbers, which greatly limits their
application to a commercial assay.” Id., page 2.
The specification discloses a method for achieving “primary in vitro
sensitization without the use of dendritic cells. This is achieved, in one
embodiment, by adding Epstein Barr virus (EBV) transformed human B-cells as a
source of co-stimulatory molecules. The human B-cell line used as a source of
co-stimulatory molecules lacks the major histocompatibility transplantation
antigens HLA-DR, and HLA-A,B,C. This permits the use of these B-cells with
lymphocytes from unrelated donors. . . . Culture of these co-stimulatory B-cells
lacking transplantation antigens, with human lymphocytes, monocytes, and
allergen, induces primary in vitro sensitization of T-lymphocytes to the allergen.
Peripheral blood monocytes function as antigen presenting cells in this system,
since the co-stimulatory B-cells lack antigen presenting molecules. . . . This
culture system . . . can function as an in vitro screen for allergenic compounds.”
Page 9.
Discussion
The claims are directed to a method for screening a test compound (i.e., a
potential allergen) for the ability to induce a response in naive T-cells. The
claimed method comprises obtaining a sample of human blood that contains
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Application No. 08/907,783

naive T cells and macrophages/monocytes, mixing the blood sample with (1) a
test compound and (2) immortalized B cells lacking class I and class II major
histocompatibility (MHC) antigens, then determining whether the test compound
induces a response from the T-cells. See, e.g., claim 1.
The examiner rejected all of the claims as obvious. The Examiner’s
Answer sets out fifteen separate § 103 rejections, which are based on six
different sets of references. All of the rejections, however, rely (at least in part) in
the combination of Yokozeki, Goronzy, Schwartz, and the ATCC catalog. We will
start, therefore, with these references.
The examiner characterized Yokozeki as teaching “a method for screening
test compounds for the ability to induce a response from mouse naive T cells.”
Examiner’s Answer, page 3. According to the examiner, “[t]he claimed invention
differs from the reference only by the recitation of the addition of immortalized B
cells which lack class I and class II major histocompatibility complex antigens in
place of the keratinocyte cell line” used by Yokozeki. Id., page 4. The examiner
cited Goronzy, Schwartz, and the ATCC catalog to make up this difference.
According to the examiner,
• Goronzy “teaches a method of using purified human B cells
obtained from peripheral blood that act as antigen presenting cells
to stimulate naive T cells in the presence of Borrelia burgdorferi
antigen and monocytes,”
• “Schwartz teaches the high frequency of alloreactive T cells that
recognize major histocompatibility complex molecules,” and
• the ATCC catalog “lists an immortalized human B cell line (T2)
which . . . lacks HLA-DR (class II major histocompatibility complex
antigens) and does not express class I major histocompatibility
complex.” Id.
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Application No. 08/907,783

The examiner concluded that it would have been obvious to “use the
immortalized B cell line (T2) that lacks major histocompatibility complex antigens
taught by [the ATCC catalog], to avoid alloreactivity of T cells taught by
[Schwartz], in place of the B cells taught by [Goronzy] in the in vitro allergen
system taught by Yokozeki . . . in order to be able to reconstruct in vitro all the
necessary components to detect the presence of allergens without having to
purify B cells from health donors and to provide a reproducible source of antigen
presenting cells.” Examiner’s Answer, pages 4-5.
“In rejecting claims under 35 U.S.C. § 103, the examiner bears the initial
burden of presenting a prima facie case of obviousness.” In re Rijckaert, 9 F.3d
1531, 1532, 28 USPQ2d 1955, 1956 (Fed. Cir. 1993). “The consistent criterion
for determination of obviousness is whether the prior art would have suggested
to one of ordinary skill in the art that this process should be carried out and would
have a reasonable likelihood of success, viewed in the light of the prior art. Both
the suggestion and the expectation of success must be founded in the prior art,
not in the applicant’s disclosure.” In re Dow Chemical Co., 837 F.2d 469, 473, 5
USPQ2d 1529, 1531 (Fed. Cir. 1988) (citations omitted).
Appellant argues that the references do not support a prima facie case of
obviousness. Among other things, Appellant argues that even if the references
were “combined in the manner suggested by the PTO, the method would not
work to screen a test compound.” Appeal Brief, page 7. In particular, Appellant
argues that, if the references are combined as suggested by the examiner, “one
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Application No. 08/907,783

obtains T2 cells of ATCC as antigen presenting cells, T cells depleted of
autoreactivity, and macrophages as co-stimulatory molecules. However, this
method could not be used to induce a response from T-cells, because the T2
cells CANNOT present antigen (because they lack MHC I and MHC II).” Id.,
pages 7-8. Appellant cites Example III from the present specification as
supporting this argument.
We agree with Appellant that the references cited by the examiner do not
support a prima facie case of obviousness. We note initially that the examiner
appears to overstate the similarities between the claimed method and that of
Yokozeki. The examiner characterizes the reference as disclosing all of the
limitations of the claimed method except that it uses keratinocyte cells instead of
B cells lacking MHC class I and class II antigens, but Yokozeki’s method also
differs by using purified T cells and macrophages, not a blood sample as in the
claimed method. Nonetheless, we can accept the examiner’s characterization of
the reference for present purposes, because we agree with Appellant that the
relied-upon combination of references has a more fundamental flaw.
The record supports Appellant’s position that cells that lack class I and
class II MHC antigens cannot function as antigen-presenting cells. See, e.g., the
specification’s Example III, which is headed “In vitro sensitization induced by T2
cells is mediated by T-cells, and is dependent upon non-T cells to present
antigen.” Page 14. The portion of the specification states that “T-cells admixed
with T2 cells in the absence of non-T cells gave no response, indicating that the
T2 cells are not sufficient for antigen presentation, and autologous non-T cells
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Application No. 08/907,783

(e.g. monocytes, macrophages) are required. The T2 cells are not functioning as
antigen presenting cells (which is to be expected since the T2 cells lack antigen
presenting Major Histocompatibility Complex antigens HLA-DR and HLA-A,B,C),
but rather function as accessory cells.” Page 14.
In Yokozeki’s assay system, by contrast, the keratinocytes function as
antigen-presenting cells. See Yokozeki, page 394: “We conducted a study on
the primary in vitro activation of T cells from non-sensitized mice by using
hapten-conjugated Pam 212 cells (keratinocyte cell line). . . . Monolayered Pam
212 cells were incubated with a variety of chemicals exhibiting allergic
potential. . . . T cells and macrophages . . . were cocultured for 5 days with those
monolayered Pam cells conjugated with chemicals.” See also page 399:
[W]e examined whether or not primary activation of T cells from
nonsensitized Balb/c mice can be induced by hapten-conjugated
Pam cells and macrophages instead of hapten-conjugated
Langerhans [dendritic] cells. . . .

The role of the Pam cells and macrophages in our system remains
unclear. . . . Fahr et al. recently suggested that keratinocyte (KC)-
derived protein but not 3T3-fibroblast-derived protein can serve as
antigenic carriers for hapten. Our data are consistent with those of
Fahr et al.

One possibility of the mechanism in our system is that
macrophages may play a role as antigen-processing cell and be
required as the source of a costimulatory signal (2nd signal) and
the Pam cell[s] may serve as antigen carriers for hapten. This
possibility is currently under investigation.

(Reference citations omitted.)
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Application No. 08/907,783

The examiner has not adequately explained what would have led those
skilled in the art to replace the prior art’s antigen-presenting cells with cells that
were known to be incapable of functioning as antigen-presenting cells. The
examiner’s response to Appellant’s argument on this point, as we understand it,
is that the assay resulting from the combined references would not be inoperable
because the sample of human blood used in the assay would contain
macrophages, which could function as antigen-presenting cells. See the
Examiner’s Answer, pages 24-25.
This response is inadequate. The examiner has not rejected the claims
under 35 U.S.C. § 101 or otherwise disputed that the assay defined by the claims
would be operable. The issue is whether those of skill in the art would have
expected that the assay resulting from the combined references would have
been operable. If not, there would have been no reason to combine those
teachings. The examiner states that “one of ordinary skill in the art at the time
the invention was made would have been motivated to use the immortalized B
cell line (T2) . . . in order to present antigen (Borrelia burgdorferi antigen) that is
present in very low concentrations, as taught by Goronzy.” The evidence of
record does not support this rationale. The rejection is therefore reversed.
Summary
The disclosures of Yokozeki, Goronzy, Schwartz, and the ATCC catalog
would not have made the method of claim 1 prima facie obvious to those of
ordinary skill in the art. All of the examiner’s other rejections also depend on this
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Application No. 08/907,783

same combination of references, and those rejections therefore fail for the same
reasons discussed above. The rejections under 35 U.S.C. § 103 are reversed.

REVERSED

William F. Smith )
Administrative Patent Judge )
)
)
) BOARD OF PATENT
Eric Grimes )
Administrative Patent Judge ) APPEALS AND
)
) INTERFERENCES
)
Lora M. Green )
Administrative Patent Judge )
Appeal No. 2002-1355 Page 11
Application No. 08/907,783

Susan J. Braman
Braman & Rogalskyi, LLP
P.O. Box 352
Canadaigua, NY 14424-0352

EG/jlb