Ex Parte Taylor et al

Patent Trial and Appeal Board

Jun 22, 2016

12524398 (P.T.A.B. Jun. 22, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
12/524,398 0712412009 Douglas D. Taylor
24350 7590 06/24/2016
STITES & HARBISON, PLLC
400 W MARKET ST
SUITE 1800
LOUISVILLE, KY 40202-3352
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
UN024/0UN7 l-US 8515
EXAMINER
RAWLINGS, STEPHEN L
ART UNIT PAPER NUMBER
1643
NOTIFICATION DATE DELIVERY MODE
06/24/2016 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address( es):
PatLou@stites.com
mstofferahn@stites.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte DOUGLAS D. TAYLOR and CICEK GERCEL-TA YLOR
Appeal2014-005092
Application 12/524,398
Technology Center 1600
Before RICHARD M. LEBOVITZ, JEFFREY N. FREDMAN, and
RICHARD J. SMITH, Administrative Patent Judges.
LEBOVITZ, Administrative Patent Judge.
DECISION ON APPEAL
This appeal involves claims directed to a method for determining the
presence or absence of autoantibodies that are immunoreactive with a tumor
antigen in a subject. Appellants appeal from the Examiner's final rejection
of claims 1, 3, 5-12, and 14 as lacking written description and enablement
under 35 U.S.C. § 112 and as obvious under 35 U.S.C. § 103. We have
jurisdiction under 35 U.S.C. § 134(a). The§ 112 rejections are reversed.
The§ 103 rejections are affirmed.
STATEMENT OF CASE
The claims stand rejected by the Examiner as follows:
Appeal2014-005092
Application 12/524,398
1. Claims 1, 3, 5-12, and 14 under 35 U.S.C. § 112, first paragraph
(pre-AIA), for failing to comply with the written description requirement.
2. Claims 1, 3, 5-12, and 14 under 35 U.S.C. § 112, first paragraph
(pre-AIA), for failing to comply with the enablement requirement.
3. Claims 1, 3, 6-11, and 14 under 35 U.S.C. § 103(a) (pre-AIA) as
obvious in view of Kemp (Kemp et al., Autoantibodies to human melanocyte
specific protein Pmell 7 in the sera of vitiligo patients: a sensitive and
quantitative radioimmunoassay (RIA), 114 CLIN EXP IMMUNOL. 333-8
(1998)), and Andre (Andre et al., Tumor-derived exosomes: a new source of
tumor rejection antigens, 20 VACCINE A28-A3 l (2002)).
4. Claims 1, 3, 5-11, and 14 under 35 U.S.C. § 103(a) (pre-AIA) as
obvious in view of Graves (Graves et al., Malignancy-induced autoimmunity
to MUCJ: initial antibody characterization, 66 J PEPTIDE RES. 357-63
(2005)), Andre and Cho (Cho et al., Exosomes: a new delivery system for
tumor antigens in cancer immunotherapy, 114 INT J CANCER; 613-22
(2005)).
5. Claims 1, 3, 5-12, and 14 under 35 U.S.C. §103(a) (pre-AIA) as
obvious in view of Kim (Kim et al., Identification of Epithelial Cell
Adhesion Molecule Autoantibody in Patients with Ovarian Cancer, 9 CLIN
CANCER RES. 4782--4791 (2003)), Runz (Runz et al., Malignant ascites-
derived exosomes of ovarian carcinoma patients contain CD24 and EpCAM,
107 GYNECOL ONCOL. 563-571 (2007)), and Andre.
Claim 1 is the only independent claim on appeal. Claim 1 is
reproduced below:
2
Appeal2014-005092
Application 12/524,398
1. A method for determining the presence or absence of
autoantibodies that are immunoreactive to a tumor antigen in a
subject, comprising:
(a) providing a biological sample comprising or
suspected of comprising autoantibodies from the subject;
(b) isolating the tumor antigen from an exosome;
( c) contacting the tumor antigen with the sample; and
( d) detecting autoantibodies in the sample that are
immunoreactive to the antigen, thereby determining the
presence or absence of autoantibodies that are immunoreactive
to the tumor antigen in the subject.
Appeal Br. 86 (Claims Appendix).
WRITTEN DESCRIPTION AND ENABLEMENT REJECTIONS
The Examiner found that the claims did not meet the written
description and enablement requirements of 35 U.S.C. § 112.
The Examiner stated that the inventors did not describe the genus of
tumor antigens in exosomes. Final Rej. 12-13. The Examiner further stated
that it could not be predicted whether a given tumor antigen would be
present in an exosome. Id. at 13. Because the Examiner found the
Specification deficient, the Examiner concluded
Id.
[The] description by the specification of only a few of the
polypeptides that are present in the exosomes secreted by an
ovarian cancer cell line (e.g., "UL-1 ["]), for example, does not
entitle Applicant to claim the genus of such different
polypeptides, which are (or might be) present in the exosomes
produced by any of the large plurality of different types of cells
to which the claims are directed for use in practicing the
claimed invention.
3
Appeal2014-005092
Application 12/524,398
The Examiner cited University of California v. Eli Lilly & Co.
("Lilly"), 119 F.3d 1559 (Fed. Cir. 1997) and University of Rochester v.
G.D. Searle & Co., Inc., 358 F.3d 916, 928 (Fed. Cir. 2004) to support the
legal basis of rejection. Id. at 14-15.
We begin with the Specification. The following findings of fact are
pertinent:
FF 1. The Specification defines exosomes as "vesicles of endosomal
origin that are secreted in the extracellular milieu following fusion of late
endosomal multivesicular bodies with the plasma membrane." Spec. 14, 11.
6-8; Example 17 (at 41, 1. 25).
FF2. The Specification teaches that cells from various tissue types,
including tumor cells, have been shown to secrete exosomes. Id. at 14, 11. 8-
10. Thus, exosomes are not newly discovered by the inventors.
FF3. The Specification discloses that "exosomes derived from cancer
cells comprising cancer antigens have been shown to comprise
immunosuppressive polypeptides." Id. at 14, 11. 16-17.
FF4. The Specification provides an example of exosomes comprising
the tumor antigen EpCAM obtained from ovarian tumor cell lines. Id. at 15,
11. 13-24.
FF5. According to Appellants, Table 1 on page 39 of the
Specification lists 12 additional example tumor antigens "actually" isolated
from exosomes, and Table 2 on page 40 lists 20 from exosomes. Appeal Br.
33. The antigens were isolated from ovarian cancer cell lines. Spec. 39, 11.
24-26; 40, 11. 7-12.
FF6. The Specification teaches how the antigen is isolated and
utilized to detect autoantibodies. Id. at 41, 1. 31 to 43, 1. 26.
4
Appeal2014-005092
Application 12/524,398
The issue is whether the disclosure in the Specification is adequate to
satisfy the written description requirement for independent claim 1. Under
35 U.S.C. § 112, first paragraph (pre-AIA), the "specification shall contain a
written description of the invention." A specification adequately describes
an invention when it "reasonably conveys to those skilled in the art that the
inventor had possession of the claimed subject matter as of the filing date."
Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir.
2010)(en bane).
In this case, Appellants have described a generic invention using
tumor antigens isolated from exosomes in an immunoassay. While it
appears that only several ovarian cancer cell lines were utilized to identify
the tumor antigens disclosed in the Specification (FF4 and FF5), the
Specification teaches the exosomes were known (FF2), and known to
contain tumor antigens (FF3). The prior art cited in the obviousness
rejections also teaches that it was known that exosomes comprise tumor
antigens. See, e.g., Andre's teaching tumor-derive exosomes are source of
tumor antigens. Andre, A28 and A29 (Section 3); Runz (Abstract); Cho
(Abstract).
"[W]hat is needed to support generic claims to biological subject
matter depends on a variety of factors, such as the existing knowledge in the
particular field, the extent and content of the prior art, the maturity of the
science or technology, [and] the predictability of the aspect at issue." Capon
v. Eshhar, 418 F.3d 1349, 1359 (Fed. Cir. 2005). The evidence supports a
finding that there was "existing knowledge" about exosomes and tumor
antigens present in them. FF2, FF3, FF5. The "content of the prior art"
cited by the Examiner, namely Andre, Runz, and Cho, also provides
5
Appeal2014-005092
Application 12/524,398
evidence that exosomal tumor antigens were known prior to the invention.
"[I]t is not necessary that every permutation within a generally operable
invention be effective in order for an inventor to obtain a generic claim,
provided that the effect is sufficiently demonstrated to characterize a generic
invention. See In re Angstadt, 537 F.2d 498, 504 (CCPA 1976)." Capon,
418 F.3d at 1359. The inventors are not asserting to have invented tumor
antigens. Rather, as discussed above, tumor antigens were known in the art,
as were exosomes comprising tumor antigens. Thus, we find it unnecessary
for the Specification to have described every exosomal tumor antigen useful
in the claimed immunoassays. The examples in the Specification illustrate
how the claimed method is performed (e.g., FF6) and establish that the
inventors had possession of a generic invention.
The Examiner cited Lilly as requiring a representative number of
members of the claimed genus of tumor antigens present in exosomes, where
the genus is describe by a precise definition such as a structure, formula, or
drawing. Final Rej. 16.
We do not agree that the Examiner properly applied Lilly. The claims
in Lilly were to a cDNA comprising a nucleotide sequence. The Lilly court
held:
In claims to genetic material, however, a generic
statement such as "vertebrate insulin cDNA" or "mammalian
insulin cDNA," without more, is not an adequate written
description of the genus because it does not distinguish the
claimed genus from others, except by function. It does not
specifically define any of the genes that fall within its
definition. It does not define any structural features commonly
possessed by members of the genus that distinguish them from
others. One skilled in the art therefore cannot, as one can do
6
Appeal2014-005092
Application 12/524,398
with a fully described genus, visualize or recognize the identity
of the members of the genus.
Id. at 119 F.3d at 1568.
Thus, in Lilly, the claims were directed to a new genus of nucleotides
for a protein with a single function. In this case, however, the claims are to a
known class of proteins - tumor antigens - found on tumor cells. Tumor
antigens were well known in the prior art at the time of the invention, as well
as their presence in exosomes. Unlike in Lilly, the inventors are not
asserting to have invented a new class of proteins - but are rather using
known proteins for an allegedly new purpose. As discussed by Appellants,
there is no distinguishing structure to the claimed genus of tumor antigens.
To require Appellants to describe "distinguishing identifying characteristics"
of exosomal tumor antigens (Final Rej. 16-17) is like asking to see a
um com.
The Examiner's reference to University of Rochester v. G.D. Searle &
Co., Inc., 358 F.3d 916, 928 (Fed. Cir. 2004) is erroneous because in
Rochester there were no structures disclosed in the specification which
satisfied the claims; here, there are many structures disclosed in the
Specification. FF4 and FF5.
We reverse the written description rejection.
We also reverse the enablement rejection. The PTO has the burden of
providing a reasonable explanation as to why the claims are not enabled by
the specification. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). In this
case, the Examiner did not meet the burden.
7
Appeal2014-005092
Application 12/524,398
CLAIM INTERPRETATION
Before applying the prior art, we begin with claim interpretation. The
preamble of the claim recites that the method is "for determining the
presence or absence of autoantibodies that are immunoreactive to a tumor
antigen in a subject." In the body of the claim, step ( d) recites "detecting
autoantibodies in the sample that are immunoreactive to the antigen, thereby
determining the presence or absence of autoantibodies that are
immunoreactive to the tumor antigen in the subject."
An issue in this appeal is whether the phrase "presence or absence of
autoantibodies" limits the scope of the claim. Specifically, Appellants
contend that the assay must be conducted with the purpose of determining
the "presence or absence of autoantibodies." Appeal Br. 62-63.
We do not agree. There are numerous cases in which the preamble of
a method claim which stated the purpose for a method was to be performed
was not sufficient to distinguish prior art which carried out the same steps of
the method claim, albeit for a different purpose. In re Cruciferous Sprout
Litig., 301F.3d1343, 1351 (Fed. Cir. 2002); see also In re Woodruff, 919
F.2d 1575 (Fed. Cir. 1990); MEHL/Biophile Int'! Corp. v. Milgraum, 192
F.3d 1362, 1365 (Fed. Cir. 1999); Perricone v. Medicis Pharm. Corp., 432
F.3d 1368, 1378-79 (Fed. Cir. 2005); In re Omeprazole Patent Litig., 483
F.3d 1364, 1373 (Fed. Cir. 2007). While such cases were in the context of
inherent anticipation, they stand for the principle that a claim preamble
stating a purpose of a method does not alone distinguish it from prior art.
Appellant has not provided argument or evidence as to how an assay
for determining "presence or absence" is any different from one which
detects the presence of autoantibodies. In other words, the mental step of
8
Appeal2014-005092
Application 12/524,398
determining whether antibodies are present or absent does not change the
way in which the method is performed. Consistently, in Bristol-Myers
Squibb Co. v. Ben Venue Laboratories, 246 F.3d 1368, 1375-76 (Fed. Cir.
2001 ), the court treated a claim expression ("method for treating a cancer
patient to effect regression of a taxol-sensitive tumor, said method being
associated with reduced hematologic toxicity") as non-limiting because
"[t]he expression does not result in a manipulative difference in the steps of
the claim."
Our interpretation is not changed by the "thereby" clause in the body
of claim 1 reciting "thereby determining the presence or absence of
autoantibodies that are immunoreactive to the tumor antigen in the subject."
The "thereby" clause states the result of carrying out the method. Merely
appreciating the result of the method does not patentably distinguish it from
prior art because it does not change how the method is performed which is
the critical comparison to be made for the purposes of the patent statutes.
Generally, if a limitation only states the result of the claim limitations, it
does not constitute a limitation itself. Texas Instruments Inc. v. U.S. Intern.
Trade Com 'n, 988 F.2d 1165, 1172 (Fed. Cir. 1993).
GROUND 4. OBVIOUSNESS IN VIEW OF GRAVES, CHO, ANDRE
Rejection
The Examiner found that Graves describes the detection of
autoantibodies that specifically bind to MU Cl in the sera of patients with
breast cancer, meeting the steps of claim 1 except for utilizing MUC 1 from
exosomes. Final Rej. 25. The Examiner found that Graves teaches that the
autoantibodies react more strongly with the intact, naturally occurring tumor
9
Appeal2014-005092
Application 12/524,398
associated antigen isolated from subjects than with a recombinant peptide
fragment of the tumor associated antigen. Id. at 25-26. The Examiner cited
Andre, finding that Andre described exosomes as a source of native tumor
associated antigens. Id. Cho was also relied upon by the Examiner for its
teaching of "purification of the polypeptide [MUC 1] from exosomes for use
in immunoassays; see entire document (e.g., the abstract; and page 617,
Figure 3C)." Id.
Based on these disclosures, the Examiner determined that it would
have been obvious to have utilized intact MUCl from exosomes (as
described in Cho) for detecting autoantibodies in patients as taught by
Graves. Id. at 26-27. The Examiner found the skilled worker would have
had reason to have used intact native MUCl from exosomes because Graves
"teaches the full-length polypeptide is used advantageously to detect a larger
repertoire of autoantibodies, as opposed to the smaller set of autoantibodies
that might be detected using a recombinant peptide fragment of MUCl." Id.
at 27.
Appellants contend that none of the cited references teach, disclose, or
suggest the step of "detecting autoantibodies in the sample that are
immunoreactive to the antigen, thereby determining the presence or absence
of autoantibodies that are immunoreactive to the tumor antigen in the
subject" as required by independent claim 1. Appeal Br. 61. Appellants
argue that Graves' research is performed on subjects who are already known
to possess autoantibodies to MUC 1. Id. Thus, Appellants argue that Graves
was not making a determination as to whether the autoantibodies are present
or absent as required by the claim. Id. at 62-63. Appellants also contend
that Cho was not purifying MUCl from exosomes for use in immunoassays
10
Appeal2014-005092
Application 12/524,398
as found by the Examiner, but was rather characterizing the different
proteins in exosomes. Id. at 63-64. With regard to Andre, Appellants
contend that Andre is studying the biochemical properties of exosomes and
their use as cancer vaccines, and does not teach or suggest determining the
presence or absence of autoantibodies. Id. at 64.
Discussion
We begin with the pertinent findings of fact ("FF").
FF7. Graves describes an immunoassay ELISA (enzyme-linked
immunosorbent assay) which comprises contacting purified MUCl antigens
with affinity purified human MUC 1 autoantibodies, and then detecting
antibody binding using anti-human antibody conjugated to a detectable
label. Graves 359 ("Antibody specificity").
FF8. The MUCl antigens are purified from serum, seroma fluid, and
urine, from normal subjects and subjects with cancer. Id. at 358 ("MUCl").
FF9. The steps described in Graves (FF7) correspond to the claimed
steps (a) ("providing a biological sample comprising ... autoantibodies from
the subject," namely the purified MUC 1 antibodies), ( c) "contacting tumor
antigen with the sample," namely, the purified MUCl antigen), and (d)
"detecting autoantibodies."
Graves, as found by the Examiner, does not describe "(b) isolating the
tumor antigen from an exosome" and then ( c) contacting the antigen isolated
from exosomes with a sample comprising autoantibodies. The issue in this
rejection is whether these steps would have been obvious to one of ordinary
skill in the art.
11
Appeal2014-005092
Application 12/524,398
Appellants attempt to distinguish Graves because Graves's assay is
not for the purpose of determining whether autoantibodies are presence or
absence in the sample as recited in the claim. However, as discussed in the
"Claim interpretation" section, the purpose for which the assay is
accomplished does not patentably distinguish it from the prior art.
Consequently, we find this argument unavailing.
The Examiner found that the skilled worker would have had reason to
use exosome isolated MUC 1 because Graves "teaches a greater range of
epitopes was defined by the autoantibodies purified by their specificity for
the whole, native antigen." Final Rej. 25. The Examiner cited Andre and
Cho for teachings that MUCl is present in exosomes. Id. at 27.
FF 10. Cho specifically teaches Western blot analysis of
immunoprecipitated exosomes. Cho 614 ("Immunoprecipitation").
FF 11. Fig. 3C, relied upon by the Examiner, shows "exosomal
protein ... resolved by SDA-PAGE and subjected to Western blotting
analysis using ... anti-MUCl ... antibodies." Id. at 618 (legend to Figure
3).
The claim does not require the MUCl to be isolated in a specific way,
form, or degree of purity. Accordingly, its separation from other proteins in
exosomes on an SDS-PAGE gel (FFlO and FFl 1) constitutes "isolating the
tumor antigen from an exosome" as required by claim 1. TE SDS-PAGE
isolated protein is used in Western blotting (FF 11 ), which is a type of
immunoassay. Appellants acknowledge Cho's teaching (Appeal Br. 64), but
provide no clear explanation as to why the Examiner was incorrect to find
that Cho teaches the isolated polypeptide MUCl used in an immunoassay,
12
Appeal2014-005092
Application 12/524,398
i.e., Western blot analysis of SDS-PAGE separated MUCl (FFl 1) (Final
Rej. 5).
The Examiner provide an express reason to adapt Cho' s teachings to
Graves: because the full-length naturally-occurring antigen would be
expected "to be suitable for use in detecting most, if not all autoantibodies
that are present in the serum of a subject because it is expected to comprise a
full repertoire of epitopes that could give rise to autoantibodies." Final Rej.
26. Graves, as found by the Examiner was concerned with characterizing
"the immune response of an individual towards MUC l" (Graves 3 61, col.
2), making exosomal MUC 1 a logical choice since Cho teaches it as capable
of inducing an immune response (Cho, Abstract), and thus comprising the
immunogenic epitopes of interest.
Appellants attempt to distinguish Cho and Andre by arguing the
differences between these publications and the claimed subject matter.
Appeal Br. 64. However, these differences are not disputed. The basis of
the rejection is the obviousness of utilizing exosomal MUC 1 to detect
autoantibodies. It is true that Andre and Cho are concerned with making
cancer vaccines utilizing exosomes. However, these publications are cited
for teaching one of ordinary skill in the art that exosomes contain
immunogenic MUCl, making exosomal MUCl useful in Graves's assay for
MUCl antibodies. Accordingly, while Andre's statements that tumor-
derived exosomes are a source of tumor antigens is in the context of delivery
in the form of an exosome, this disclosure does not disparage the rejection
because it is Graves's and Cho' s teachings which provide the reason to use
exosomal MUCl in Graves's ELISA. Appellants have not identified a
persuasive defect in this argument.
13
Appeal2014-005092
Application 12/524,398
The rejection of claim 1 is affirmed. Claims 3, 5-11, and 14 fall with
claim 1 because separate arguments for their patentability were not provided.
37 C.FR. § 41.37(c)(iv).
GROUND 5. OBVIOUSNESS IN VIEW OF KIM, RUNZ, AND ANDRE
Rejection
The Examiner found that Kim describes detecting EpCAM
autoantibodies in the serum of a normal subject and subjects with ovarian
cancer. Final Rej. 28. EpCAM is a tumor antigen within the scope of claim
1. Id. The Examiner found that Kim describes contacting the serum
samples with purified recombinant EpCAM. Id. Thus, Kim describes the
recited steps (a) of providing a biological sample (serum) with
autoantibodies; ( c) contacting the tumor antigen EpCAM with the
autoantibodies, and ( d) detecting the autoantibodies. However, Kim does
not describe step (b) of "isolating the tumor antigen from an exosome." To
meet this deficiency, the Examiner further cited Andre and Runz.
Andre was relied upon by the Examiner for its teaching that exosomes
are secreted by tumor cells and are a source of intact, native tumor
associated antigens. Id. The Examiner cited Runz for teaching that
exosomes which are isolated from the ascites of patients with ovarian cancer
contain EpCAM. Id.
Based on the teachings in Kim, Andre, and Runz, the Examiner
determined that it would have been obvious to have utilized the EpCAM in
Runz's exosomes in Kim's assay because it would have been expected that
"the polypeptide purified from exosomes secreted by ovarian cancer cells"
would "comprise the full repertoire of the antigenic determinants of
14
Appeal2014-005092
Application 12/524,398
EpCAM, which would give rise to autoantibodies in a patient atllicted by
ovarian cancer," making it "more suitable for detection of autoantibodies
against the native polypeptide." Id. at 29.
Appellants contend that none of the cited publications "teach,
disclose, or suggest" step (b) of "isolating the tumor antigen from an
exosome" as required by independent claim 1. Appeal Br. 74. Appellants
state that "[p ]roteins generated using cDNA are artificially synthesized and,
therefore, are clearly not isolated from an exosome. Thus, Kim clearly fails
to teach or suggest 'isolating the tumor antigen from an exosome' as
required by claim l ." Id. at 75. Appellants further argue that Runz does not
teach or suggest isolating EpCAM from exosomes. Id. With regard to
Andre, Appellants contend that Andre is studying the biochemical properties
of exosomes and their use as cancer vaccines. Id. at 76. Appellants state
that Andre's statement that exosomes are a source of a tumor antigen is a
reference to when the exosomes are used in a cancer vaccine, not as a source
which to isolate the antigen, itself. Id.
Discussion
The Examiner's findings that Kim describes steps (a), ( c ), and ( d) of
claim 1 is supported by a preponderance of the evidence. The following
findings of fact support this determination:
FF12. Kim describes an ELISA assay utilizing purified Ep-CAM
purified with a monoclonal antibody and using it to detect Ep-CAM
autoantibody in serum samples. Kim 4784-85 ("ELISA").
15
Appeal2014-005092
Application 12/524,398
FF13. Figures 5 and 6 of Kim show the Ep-CAM levels in normal
subjects and subjects with ovarian cancer. Id. at 4788 and 4789,
respectively.
FF14. Kim teaches:
Using an established ELISA, we evaluated the potential of
using Ep-CAM autoantibody levels to detect ovarian cancer.
Ep-CAM autoantibody levels proved to be significantly higher
in ovarian cancer than normal and benign ovarian disease.
Id. at 4789.
Appellants contend that it would not have been obvious to have
isolated EpCAM from exosomes and utilized it in Kim's assay. Appellants
distinguish Runz and Andre, stating that neither reference teaches isolating
EpCAM from exosomes. Appeal Br. 75-76. Appellants focus on the
teachings in Runz that "merely describes that EpCAM was among the
proteins that can be identified on an exosomes of cultured cell lines and
malignant ascites" (id. at 83) and in Andre of biochemically characterizing
exosomes and in teaching that exosomes comprising tumor antigens can be
used as cancer vaccines (id. at 76). However, the Examiner's rationale for
the rejection is that the skilled worker would have had reason to have
utilized isolated EpCAM in Kim's immunoassay because a naturally-
occurring EpCAM would have been expected to "comprise the full
repertoire of the antigenic determinants of EpCAM" and be suitable for
detection of autoantibodies. Final Rej. 29. The Examiner is relying upon
Andre and Kim for teaching the EpCAM would be suitable in Kim's
immunoassay because it is native and immunogenic. The Examiner's
positon is reasonable and factually supported. The following facts are
consistent with the Examiner's determination:
16
Appeal2014-005092
Application 12/524,398
FF15. Fig. 4 of Runz specifically shows Western blots of gel
separated proteins from exosomes. EpCAM was detected using a
monoclonal antibody. Runz 568 (legend to Fig. 4).
FF 16. Andre teaches that "tumor-derived exosomes induced potent
anti-tumor immune Responses." Andre A29 (Section 3.2).
Thus, one of ordinary skill in the art would have reasonably expected
that EpCAM would be effective to detect autoantibodies based on the
showing in Runz's Western blot (FF15) and Andre's teaching that it is
potent in eliciting an immune response (FF 16), consistent with the
Examiner's determination exosomal EpCAM would comprise the full
repertoire of the antigenic determinants of EpCAM. Appellants distinguish
the publications individually, but did not identify a defect in the Examiner's
fact-based rationale for combining the teachings in Kim, Andre, and Runz.
With regard to Appellants' argument that the references do not
described isolating EpCAM from exosomes (Appeal Br. 52), as found by the
Examiner, it would be routine to do so. Answer 69. Specifically, Kim
teaches purifying EpCAM with an antibody (FF12) and Runz also teaches an
EpCAM antibody (FF15). Thus, the Examiner's finding about the
obviousness of purifying EpCAM is supported by a preponderance of the
evidence. In addition, Runz shows EpCAM isolated from other proteins on
a gel (FF 15).
Appellants state that Kim teaches synthesizing proteins (presumably
they mean EpCAM) from cDNA (Appeal Br. 75) and "replacing the array of
artificially-synthesized proteins in Kim" with EpCAM (id. at 82). However,
Appellants did not identify support for these statements or direct our
17
Appeal2014-005092
Application 12/524,398
attention to an array of artificially synthesized proteins. At page 4784 of
Kim, under the section titled "ELISA," Kim states:
ELISA performed Immunodetection of EpCAM autoantibody,
as described (15). Flat-bottomed microtiter ELISA plates (a
Diagnostic, San Antonio, TX) were incubated at 4 °C overnight
with 100 µl purified Ep-CAM (2.5 µg/ml), purified with
monoclonal antibody GA 733 as described (16), in 0.05 M
carbonate buffer (pH 9. 7).
This section of Kim does not characterize the EpCAM as
artificially synthesized.
In sum, we have considered Appellants' arguments, but do not find
them supported by a preponderance of the evidence. The Examiner made a
cogent fact-based argument as to why it would have been obvious to have
isolated EpCAM from the exosomes of Runz and used it in Kim's assay.
Appellants did not identify a persuasive defect in this argument, but rather
focused on the differences between the teachings in the publications and the
claimed method.
We affirm the rejection of claim 1. Claims 3, 5-11, and 14 fall with
claim 1 because separate arguments for their patentability were not provided.
37 C.FR. § 41.37(c)(iv).
GROUND 3. OBVIOUSNESS BASED ON KEMP AND ANDRE
The Examiner found that Kemp describes detecting autoantibodies to
the tumor antigen Pmel 17 (gp 100) in the sera of patients with vitiligo. Final
Rej. 22. Pmell 7 (gplOO) is found on the surface of melanoma cells. Kemp
333-334. The Examiner found that Kemp contacted recombinant Pmell 7
(gp 100) with a patient sample comprising autoantibodies and then detecting
the antibodies in a radioimmunoassay (RIA). Final Rej. 22. Thus, the
18
Appeal2014-005092
Application 12/524,398
described in Kemp meets the recited steps (a) of providing a biological
sample (serum) with autoantibodies; ( c) contacting the tumor antigen
EpCAM with the autoantibodies, and ( d) detecting the autoantibodies.
However, Kemp does not describe step (b) of "isolating the tumor antigen
from an exosome." To meet this deficiency, the Examiner further cited
Andre. The Examiner found that Andre teaches that exosomes are secreted
by tumor cells and are a source of intact, native tumor associated antigens,
including Pmell 7 (gp 100). Id.
Based on the teachings in Kemp and Andre, the Examiner determined
that it would have been obvious to have utilized the Pmell 7 (gp 100) in
Andre's exosomes in Kemp's assay because it would have been expected
that "the polypeptide purified from exosomes secreted by melanomas"
would "comprise the full repertoire of the antigenic determinants of Pmel 1 7
(gp 100), which would give rise to autoantibodies in a subject," making it
"more suitable for detection of autoantibodies against the native
polypeptide." Id. at 23.
Appellants contend the neither of the publications describe isolating
tumor antigens from exosomes. Appeal Br. 50-51. With regard to Andre,
Appellants contend that Andre is studying the biochemical properties of
exosomes and their use as cancer vaccines. Id. at 51. Appellants state that
Andre's statement that exosomes are a source of a tumor antigen is when the
exosomes are used in a cancer vaccine, not as a source in which to isolate
the antigen, itself. Id.
19
Appeal2014-005092
Application 12/524,398
Discussion
Appellants do not dispute that Kemp describes steps (a), ( c ), and ( d)
of independent claim 1. As found by the Examiner, Kemp describes an
immunoassay for Pmel 17 (gp 100) autoantibodies utilizing a recombinant
Pmell 7 (gp 100). Kemp 334. The issue is whether it would have been
obvious to have utilized exosomal Pmell 7 (gplOO) in Kemp's assay.
With regard to Appellants' arguments about Andre, we note these
arguments are the same as those made for the other obviousness rejections
and thus refer to our discussion above. Appellants further contend:
In this regard, the modification of the prior art elements being
proffered by the Examiner of replacing the 35S-labelled
recombinant human Pmel 17 of Kemp with the tumor antigens
described in Andre for the function of analyzing vitiligo sera for
the presence of antibodies to Pmel 17 is quite clearly "more than
the predictable use of prior art elements according to their
established functions" and, therefore, insufficient to establish a
prima facie case of obviousness.
Appeal Br. 57.
Appellants have not provided adequate evidence to support this
argument. The recombinant Pmell 7 (gp 100) produced by Kemp is not
naturally-occurring, but is produced in an in vitro system. Kemp 334. This
system apparently does not glycosylate because Kemp teaches that an
additional step was performed in "some experiments" to glycosylate the
recombinant Pmell 7 (gp 100). Id. at 334. Because recombinant Pmell 7
(gplOO) is not naturally-occurring, e.g., lacks glycosylation, the Examiner
reasonably found that one skilled in the art would have had reason to replace
it with a native naturally-occurring Pmell 7 (gp 100) because the native
polypeptide "purified from exosomes secreted by melanomas" would have
been expected "to comprise the full repertoire of the antigenic determinants
20
Appeal2014-005092
Application 12/524,398
of PMell 7/gplOO." Final Rej. 23. Appellants have not identified a
deficiency in the Examiner's finding nor reasoning.
Kemp teaches that its study is concerned with studying autoantibodies
present in subjects:
In the present study we aimed to analyse vitiligo sera for the
presence of antibodies to Pmel 1 7 using an RIA with 35S-
labelled recombinant human Pmel 1 7. This type of assay is
sensitive, quantitative, allows the detection of conformational
epitopes and has been widely used to identify various
autoantigens.
Kemp 334. Consequently, one of skill in the art, as found by the Examiner,
would have had reason to use the exosomal native form to detect the full
repertoire of autoantibodies expressed by a subject with vitiligo or
melanoma ("Pmel 1 7 has also recently been identified as an important
antigen on the surface of melanoma tumour cells recognized by cytotoxic T
lymphocytes.") Id. at 333-334.
We affirm the rejection of claim 1. Claims 3, 5-11, and 14 fall with
claim 1 because separate arguments for their patentability were not provided.
37 C.FR. § 41.37(c)(iv).
TIME PERIOD
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § l .136(a)(l )(iv).
AFFIRMED
21