Ex Parte Schiller et al

Patent Trials and Appeals Board

Mar 26, 2019

14540563 - (D) (P.T.A.B. Mar. 26, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
14/540,563 11/13/2014
119489 7590
Vivex Biomedical Inc.
David L. King
5131 NE County Road 340
High Spring, FL 32643
03/26/2019
FIRST NAMED INVENTOR
Paul C. Schiller
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.
DN0215 8717
EXAMINER
FOX, ALLISON M
ART UNIT PAPER NUMBER
1653
MAIL DATE DELIVERY MODE
03/26/2019 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte PAUL C. SCHILLER and
GIANLUCA D'IPPOLIT0 1
Appeal2018-005564
Application 14/540,563
Technology Center 1600
Before RICHARD M. LEBOVITZ, JAMES A. WORTH, and
ROBERT A. POLLOCK, Administrative Patent Judges.
LEBOVITZ, Administrative Patent Judge.
DECISION ON APPEAL
This appeal involves claims directed to a method of collecting non-
expanded post-natal multilineage-inducible cells. The Examiner rejected the
claims as obvious under 35 U.S.C. § 103 and under non-statutory
obviousness-type double-patenting. Pursuant to 35 U.S.C. § 134, Appellants
appeal the Examiner's determination that the claims are unpatentable. We
have jurisdiction under 35 U.S.C. § 6(b). The Examiner's decision is
affirmed.
1 The Appeal Brief ("Br." entered Jan. 22, 2018) lists the University of
Miami and the Government of the United States of America as the real-
parties-in-interest. Br. 3.
Appeal2018-005564
Application 14/540,563
STATEMENT OF THE CASE
The Examiner rejected claims 1, 2, 9, 15-19, 25-28, 48-56, and
61-69 as follows:
1. Claims 1, 2, 9, 15-19, 25-28, 48-50, 54--56, and 65-67 under
35 U.S.C. § 103 as obvious in view of Gang et al. (Blood, 2007,
109(4):1743-1751) ("Gang"), Dawidowska (in Molecular Aspects of
Hematologic Malignancies, 2012, Chapter 19, 305-308), and Rojewski et al.
(Transfusion Medicine and Hemotherapy, 2008, 35: 168-184) ("Rojewski").
Ans. 3.
2. Claims 1, 2, 9, 15-19, 25-28, 48-56, and 65-57 under 35 U.S.C.
§ 103 as obvious in view of Gang, Dawidowska, Rojewski, and further in
view of Schiller et al. (U.S. Patent 7,807,458 B2, issued Oct. 5, 2015)
("Schiller '458"). Ans. 8-9.
3. Claims 1, 2, 9, 15-19, 25-28, 48-50, 54--56, and 61-69 under
35 U.S.C. § 103 as obvious in view of Gang, Dawidowska, Rojewski, and
further in view of Quirici et al. (Experimental Hematology, 2002,
30:783-791) ("Quirici"). Ans. 9.
4. Claims 1, 2, 9, 15-19, 25-28, 48-56, and 61-69 under 35 U.S.C.
§ 103 as obvious in view of Schiller '458, Furcht et al. (US 2005/0181502
Al, published Aug. 18, 2005) ("Furcht"), and Dawidowska. Ans. 12.
5. Claims 1, 2, 9, 15-19, 25-28, 48-56, and 61-69 on the ground of
non-statutory obviousness-type double patenting as being unpatentable over
claims 1-17 of Schiller' 458. Ans. 18.
Independent claim 1, which is illustrative of the appealed claims, is
reproduced below:
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Application 14/540,563
1. A method of collecting non-expanded post-natal
multilineage-inducible cells comprising:
obtaining bone marrow from a biological sample of an
animal;
isolating total nuclear cells (TNCs) from the bone
marrow;
incubating the TN Cs in the presence of an antibody,
wherein the antibody is directed to a cell surface marker
comprising SSEA-4;
separating non-expanded post-natal multilineage-
inducible cells that bind to the antibody from cells that do not
bind to the antibody; and
collecting the non-expanded post-natal multilineage-
inducible cells at a yield of 1.5% or greater of the TN Cs before
the number of cells obtained from bone marrow have increased
in number due to cell division in vitro.
OBVIOUSNESS BASED ON GANG
The Examiner found that Gang teaches that cell surface marker
SSEA-4 is present on human mesenchymal cells ("MSCs") in the bone
marrow. Ans. 3. The Examiner found that Gang performed fluorescent
activated cell separation (FACS) on the MSCs using a SSEA-4 antibody. Id.
F ACS separates cells based on expression of a cell surface marker, which in
this case is SSEA-4. Thus, the Examiner found that Gang accomplished the
claimed steps of "incubating" cells "in the presence of an antibody, wherein
the antibody is directed to a cell surface marker comprising SSEA-4" and
"separating non-expanded post-natal multilineage-inducible cells that bind to
the antibody from cells that do not bind to the antibody." Ans. 3--4. The
Examiner found that the cells isolated from the bone marrow using the
SSEA-4 would be the claimed "non-expanded post-natal multilineage-
inducible cells" because they are isolated by F ACS prior to expansion in
culture and were shown to be "multilineage" after expansion in culture.
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Application 14/540,563
Ans. 4. With respect to the claimed "yield of 1.5% or greater," the
Examiner identified Gang's disclosure of yields of 2--4% SSEA-4+ cells
from the bone marrow as meeting the limitation. Ans. 4--5.
The Examiner stated that Gang differs from the claim in not
disclosing the step of "isolating total nuclear cells (TN Cs) from the bone
marrow." Ans. 5. However, the Examiner found that it was routine at the
time of the invention to perform such a step as established by Dawidowska.
Id. The Examiner found it obvious to do so to reduce the "overall volume of
cellular material is reduced (by removing non-MNCs (e.g. red blood cells,
adipocytes)) and thus would permit for use of reduced quantities of antibody
and staining reagents, thereby saving money." Id.
Appellants argue that "Gang failed to establish that their non-
expanded SSEA-4+ cells have multilineage differentiation potential." Br. 13.
Appellants identify the disclosure in Gang of cells passaged in culture and
then differentiated (Gang, Fig. 6). Id. Based on this disclosure, Appellants
state that, in all the examples, "Gang's SSEA-4+ cells were never shown to
have multilineage differentiation potential without having previously been
expanded" in culture. Br. 14. Appellants that that "[t]here is no evidence of
record that one of ordinary skill would have reasonably expected that Gang's
SSEA-4+ cells have multilineage differentiation potential after their isolation
and before their expansion." Id.
This argument does not persuasively demonstrate error in the
Examiner's rejection. As found by the Examiner, Gang isolated SSEA-4+
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Application 14/540,563
cells in the same way as claimed, namely, using a SSEA-4 antibody. 2 The
cells "obtained from SSEA-4+ -sorted cells" by Gang were "prove[d]
conclusively" to be mesenchymal stem cells by their ability, after single-cell
cloning by F ACS and 2 or more passages, to differentiate into bone,
cartilage, and fat cells. Gang 17 48 ("Clonal analysis"). Gang thus
persuasively demonstrated that a single cell, separated using the SSEA-4
antibody, is a "multilineage-inducible" cells as required by claim 1.
Appellants did not identify a limitation in claim 1 that would require
the "non-expanded post-natal multilineage-inducible cells" obtained after the
F ACS sorting to have been induced to differentiate into adult lineages in the
non-expanded state. Nonetheless, to the extent the claim would be
interpreted this way, as found by the Examiner, Gang's cell were isolated
from the same source, and by the same technique which is claimed, and
therefore would be reasonably expected to possess the same characteristics.
Ans. 19.
Appellants argue that it is "well-known in the art that in vitro
treatment of cells by reprogramming them can change their phenotype. For
example, changing the expression of a limited number of genes in somatic
cells can tum them into induced pluripotent stem (iPS) cell." Br. 14--15.
Appellants, however, did not explain, why the same cell population isolated
in the claims and in Gang, from the same source, would behave differently.
Consequently, we find this argument unavailing. As held in In re Best, 562
F.2d 1252 (CCP A 1977):
2 "The SSEA-4 mouse monoclonal antibody recognizes the SSEA-4 antigen
expressed on human and mouse cells." Gang 17 44 (in section titled "Flow
cytometry and sorting of MS Cs.").
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Application 14/540,563
Where, as here, the claimed and prior art products are
identical or substantially identical, or are produced by identical
or substantially identical processes, the PTO can require an
applicant to prove that the prior art products do not necessarily
or inherently possess the characteristics of his claimed product.
Whether the rejection is based on "inherency" under 35 U.S.C.
§ 102, on "prima facie obviousness" under 35 U.S.C. § 103,
jointly or alternatively, the burden of proof is the same, and its
fairness is evidenced by the PTO' s inability to manufacture
products or to obtain and compare prior art products.
Id. at 1255 (footnote omitted) (citation omitted). Thus, once "the PTO
shows sound basis for believing that the products of the applicant and the
prior art are the same, the applicant has the burden of showing that they are
not." In re Spada, 911 F.2d 705, 708 (Fed. Cir. 1990). Appellants have not
demonstrated that the cells described in Gang would not inherently possess
the same characteristics as the claimed cells.
Appellants argue that the Examiner did not "did not provide a reason
for one of ordinary skill in the art to include such an isolation step [ as
described in Dawidowska] when trying to improve a method for collecting
non-expanded multilineage-inducible cells." Br. 15. We do not agree. As
stated above in the summary of the Examiner's rejection, the Examiner
explained it would have been obvious to obtain the TNC fraction to reduce
the volume and reagents necessary to accomplish the cell separation.
Non-Final Act. 11. Appellants did not identify a defect in this reasoning.
Appellants contend that "[t]he inventors of the present invention have
found a 3500-fold increase in yield over their previously disclosed method.
This improved result would not have been obvious Gang in view of
Dawidowska." Br. 15. This argument is not convincing because Appellants
did not provide objective evidence of this result. An argument made by
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Application 14/540,563
counsel in a brief does not substitute for evidence lacking in the record.
Estee Lauder, Inc. v. L 'Orea!, S.A., 129 F.3d 588, 595 (Fed. Cir. 1997).
Furthermore, the proper comparison is with the closest cited prior art
in the rejection, which in this case is Gang, not the inventor's "previously
disclosed method," which has not even been identified. To establish
unexpected results, the claimed subject matter must be compared with the
closest prior art. In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir.
1991) ("[W]hen unexpected results are used as evidence of nonobviousness,
the results must be shown to be unexpected compared with the closest prior
art.").
Appellants also dispute that that the limitation of "collecting the non-
expanded post-natal multilineage-inducible cells at a yield of 1.5% or greater
of the TN Cs before the number of cells obtained from bone marrow have
increased in number due to cell division in vitro" is met by Gang. Br. 15-
16. Appellants acknowledge that "Gang reported 2-4% of total bone
marrow is SSEA-4+," but they argue Gang "did not teach all of them were
mesenchymal stem cells (MSCs)." Br. 16. But Appellants provide no
evidence for this assertion and their argument, standing alone, does not
demonstrate error in the Examiner's rejection. As discussed above, Gang
performed single-cell cloning using F ACS separation of bone marrow cells
using the SSEA-4 marker and "prove[d] conclusively that cultures obtained
from SSEA-4+-sorted cells contained true mesenchymal stem cells." Gang
1748 ("Clonal analysis"). In view of this disclosure, one of ordinary skill in
the art would have had reason to believe that the SSEA-4+ cells identified as
being 2-4% of total bone marrow are mesenchymal cells which are
"multilineage-inducible" as required by the claim.
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Appellants also argue that there is no evidence that the disclosed
process would provide sufficient cells for direct therapeutic use. Br. 17, 18.
Appellants do not identify a deficiency in the rejection, but simply make this
statement. As explained by the Examiner, the purpose of Gang is to provide
cells for clinical application. Gang, Abstract. Gang isolates cell populations
with mesenchymal cells which differentiate into different lineages. Id.
Appellants have not explained why such isolated cell populations would not
be sufficient for a therapeutic application.
The Examiner cited additional publications to meet additional
limitations in the dependent claims. Appellants argued that these
publications do not make up for the deficiencies in Gang and Dawidowska.
Br. 16, 17, 18.
For the foregoing reasons, the obviousness rejection of claim 1 is
affirmed. Claims 2, 9, 15-19, 25-28, 48-50, 54--56, and 65----67 were not
argued separately and fall with claim 1. Rejections 2 and 3, also based on
Gang and Dawidowska, are affirmed for the same reasons. 37 C.F.R.
§ 4I.37(c)(l)(iv).
OBVIOUSNESS BASED ON SCHILLER '458
The Examiner found the Schiller '458 describes multilineage-
inducible cells ("MIAMI") which can be isolated using the SSEA-4 marker,
the same marker described in the claim. Ans. 12. The Examiner also found
that the Schiller '458 teaches that the cells can be isolated from bone
marrow, the same source recited in the claims. Id. The Examiner stated that
Schiller' 458 does not disclose the step of "isolating total nuclear cells
(TNCs) from the bone marrow," but found it obvious to do so because
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Application 14/540,563
Schiller '458 teaches partial purification of cells after collection and that
isolation of TN Cs was routine at the time of the invention as established by
Dawidowska. Ans. 11-12. The Examiner determined it would have been
obvious to one ordinary skill in the art to combine the teachings of
Dawidowska with Schiller '458' s method to reduce the volume of material
and the needed reagents to accomplish separation and "to save money by
using less reagents." Id. at 13.
Appellants argue that Schiller '458 has in vitro culture and expansion
steps are that are not recited in claim 1. Br. 1 7. Appellants state that "there
is no evidence of a reasonable expectation that multilineage-inducible cells
can be isolated without in vitro expansion." Id.
As discussed above for the rejections based on Gang, the claimed
method of using an SSEA-4 antibody to isolated cells from the bone marrow
is the same method as disclosed in Schiller '458 3 and thus would have
reasonably been expected to result in the isolation of the same cells.
Appellants have the burden in such circumstances to prove that the claimed
cells are different, but did not provide objective evidence to establish a
difference. Best, 562 F.2d at 1255.
Appellants argue that the cells isolated "by Appellant's invention and
Schiller's previous process are also different." Br. 19. Appellants state that
3 "In other embodiments, MIAMI cells are isolated from a biological sample
based on the physical properties of the MIAMI cells. For example, several
techniques are known in the art by which MIAMI cells may be isolated
based on the unique set of markers expressed by MIAMI cells, including, for
example, fluorescence-activated cell sorting (F ACS), immobilized marker-
specific antibodies (such as, antibody-coupled beads), or magnetic-activated
cell sorting (MACS)." Schiller '458, col. 17, 11. 41--49.
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"[ s ]urprisingly, the claimed process can isolate about 3,500 times more
multilineage-inducible cells than the inventors' previous process (i1 [131] of
the specification as filed and corresponding ,r [0130] of the US
2015/0132266 publication)." Br. 19.
Paragraph 131 from the Specification is reproduced below:
In one embodiment, the isolation of ne-MIAMI cells was
performed on fresh human BM. After Ficoll gradient
separation total nuclear cells (MNCs) were incubated for 30
minutes at 4 degrees C in the presence of anti-SSEA-4 antibody
phycoerythrin conjugated (SSEA-4-PE). At the end of the
incubation time anti-PE microbeads (Miltenyi Biotech) were
added to cells. FACS analysis demonstrated that 3.5% of TNCs
are SSEA-4+ cells, as shown in figure lB, which is about 3,500
times more cells than the number of marrow stromal cells
(MSCs) isolated from BM using the empirical isolation
procedure used in the inventor's prior patented invention.
We do not find Appellants' argument persuasive. First, there are steps
described in paragraph 131 which do not appear in the claim, such as the
incubation time and temperature, specific antibody, and the use anti-PE
microbeads. To the extent the results are "surprising," it has not been
established that the "surprising" results would be obtained for the full scope
of the claim, for example, using different incubation times, temperatures,
antibody, and no beads. Unexpected results must be commensurate with the
full scope of the claim. In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005).
Second, Appellants did not identify the "empirical isolation procedure
used in the inventor's prior patented invention." Thus, it is not evident to
what the comparison is being made. Indeed, no comparative data has been
provided to determine whether such evidence is sufficient to establish
surprising results for the full scope of the claim.
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OBVIOUSNESS-TYPE DOUBLE PATENTING
The Examiner rejected the claims under obviousness-type4 double-
patenting as obvious in view of claims of 1-17 of Schiller' 458. Ans. 18.
The Examiner stated "[a]lthough the claims at issue are not identical, they
are not patentably distinct from each other because the patented claims are to
the cells which are produced via the method of the instant claims." Id.
We reverse the rejection. An obviousness-type double-patenting
rejection requires the determination of whether the claimed method would
have been obvious based the claims of the patent. In this case, the patented
claims are directed to a composition comprising multilineage-inducible cells
"which (i) express at least CD29, CD 81, CD90, CD122, and CD164; and
(ii) do not express CD13." The Examiner did not explain how the claimed
method of collecting multilineage-inducible cells using an SSEA-4 antibody
would have been obvious based on a composition of cells claimed in Schiller
'458. Because the Examiner did not establish that the claimed method
would have been obvious to one of ordinary skill in the art based on the
claimed composition of Schiller' 458, the rejection is reversed.
4 The Examiner did not state the double-patenting was of the "obviousness-
type." While the rejection is characterized as being non-statutory, it is based
on 35 U.S.C. § 103 that the same inventions cannot be patented nor obvious
variations thereof.
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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)(l)(iv).
AFFIRMED
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