Ex Parte Yang

Patent Trial and Appeal Board

May 6, 2013

10939302 (P.T.A.B. May. 6, 2013)

UNITED STATES PATENT AND TRADEMARK OFFICE
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
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
10/939,302 09/10/2004 Demao Yang 3067.02US01 3447
62274 7590 05/06/2013
DARDI & HERBERT, PLLC
Moore Lake Plaza, Suite 205
1250 East Moore Lake Drive
Fridley, MN 55432
EXAMINER
PARAS JR, PETER
ART UNIT PAPER NUMBER
1632
MAIL DATE DELIVERY MODE
05/06/2013 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 DEMAO YANG
__________

Appeal 2011-011434
Application 10/939,302
Technology Center 1600
__________

Before FRANCISCO C. PRATS, MELANIE L. McCOLLUM, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

PRATS, Administrative Patent Judge.

DECISION ON APPEAL
This appeal under 35 U.S.C. § 134 involves claims to a process of
treating a severely myelosuppressed patient. The Examiner rejected the
claims as obvious.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
STATEMENT OF THE CASE
“Myelosuppression is a condition in which bone marrow cell activity
is decreased, and can result in fewer red blood cells, white blood cells,
and/or platelets. . . . Myelosuppression is probably the most common side
effect of chemotherapy in cancer patients” (Spec. 3).
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“Unfortunately, the four FDA-approved growth factors (GCSF, GM-
CSF, Interleukin-11 and Erythropoietin) that are routinely used to accelerate
recovery of blood production are often not effective for severe and/or
chronic myelosuppression, and the recovery of multilineage hematopoiesis”
(id. at 5).
Appellant’s invention is thus directed to “materials and methods using
cultured (activated) blood cells for treating myelosuppressed patients, and
patients with blood deficiencies, such as anemia, aplastic anemia and/or
thrombocytopenia. Such approaches include treatments for severe and/or
chronic myelosuppression, and the recovery of multilineage hematopoiesis”
(id. at 6).
The sole rejection before us for review is the Examiner’s rejection of
claims 1-7, 9-14, 16-19, 21, 23-25, 38, 41, 44-47, 49, and 50 under
35 U.S.C. § 103(a) as obvious over Hashimoto,1 Weaver,2 Bowers,3
Ragnhammar,4 and Erdahl5 (Ans. Br. 4-7). Claims 1 and 11 are
representative and read as follows:

1 S. Hashimoto et al., Mechanism of Calcium Ionophore and Phorbol Ester-
Induced T-cell Activation, Accessory Cell Requirement for T-cell Activation,
33 SCAND. J. IMMUNOL. 393-403 (1991).
2 C.H. Weaver et al., Syngeneic Transplantation With Peripheral Blood
Mononuclear Cells Collected After the Administration of Recombinant
Human Granulocyte Colony-Stimulating Factor, 82 BLOOD 1981-1984
(1993).
3 Daniel C. Bowers et al., Immune constitution of complete DiGeorge
anomaly by transplantation of unmobilised blood mononuclear cells, 352
THE LANCET 1983-84 (1998).
4 P. Ragnhammar et al., Cytotoxicity of white blood cells activated
by granulocyte-colony-stimulating factor, granulocyte/macrophage-colony-
stimulating factor and macrophage-colony-stimulating factor against tumor
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1. A process of treating a severely myelosuppressed patient
having a blood deficiency, the process comprising
administering ex vivo activated blood cells to the patient to
increase concentrations of blood components that are deficient in the
severely myelosuppressed patients through stimulation of
hematopoiesis,
wherein the blood cells comprise a mixed population of
peripheral blood mononuclear cells cultured for from about 20 hours
to about 80 hours, without preselecting CD34+ cells and without
preparing a purified preparation of stem cells or highly enriched
monocyte preparations, in the presence of a cytokine and a calcium
ionophore to form the ex vivo activated blood cells,
wherein the peripheral blood mononuclear cells [PMBCs]
comprise at least monocytes and lymphocytes, and
wherein the cytokine is chosen from a group consisting of
survival, growth and differentiation stimulators of myeloid cells,
T-cells, or combination of them.

11. The process of claim 1 wherein the cytokine comprises
macrophage-colony stimulating factor.

DISCUSSION
The Examiner cited Hashimoto as teaching that culturing in the
presence of “the ionophore, ionomycin, stimulates cell proliferation in
peripheral blood mononuclear cells (PBMC) populations” and causes the
cultured PBMCs to produce the cytokine interleukin 2 (IL-2) (Ans. 5). The
Examiner thus reasoned that Hashimoto taught the culturing conditions
required by claim 1, but found that Hashimoto differed from claim 1 in that
Hashimoto did not teach that its PBMCs were “used in transplantation” (id.).

cells in the presence of various monoclonal antibodies, 39 CANCER
IMMUNOL. IMMUNOTHER. 254-262 (1994).
5 Warren L. Erdahl et al., Ca2+ Transport Properties of lonophores A23187,
lonomycin, and 4-BrA23187 in a Well Defined Model System, 66
BIOPHYSICAL JOURNAL 1678-1693 (1994).
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To address that deficiency, the Examiner cited Weaver as disclosing
that “PBMC transplants are used to treat patients that have undergone
myeloablative therapy” (id.).
Based on the references’ combined teachings, the Examiner
concluded that an ordinary artisan would have considered it obvious to “use
proliferating PBMCs cells in a cancer patient whose bone marrow is
depleted of immune cells in order to repopulate said cancer patient’s
immune cells quickly” (id. at 5-6). In particular, the Examiner contends:
Hashimoto et al. . . . provide guidance that PBMCs proliferate
in the presence of ionomycin . . . . This teaching would indicate
to an artisan that PBMCs can be expanded before being
administered to a patient who has no immune system (e.g. a
leukemia patient whose bone marrow has been irradiated to
remove cancerous cells). An artisan would know that PBMCs
can be administered to patients, as shown by Weaver et al. and
an artisan would understand that the advantage of using an
expanded population of cells would mean more cells can be
used to restore a patient’s immune system.

(Id. at 9 (citation omitted).)
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.

Appellant’s arguments do not persuade us that a preponderance of the
evidence fails to support the Examiner’s conclusion of obviousness as to
claim 1.
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As to claim 1’s actual treatment step, Weaver describes administering
PBMCs from syngeneic donors to cancer patients that had received
myeloablative treatments (see Weaver 1981 (abstract) (“Five syngeneic
transplants were performed in four patients following myeloablative therapy
using unmodified peripheral blood mononuclear cells (PBMCs) collected
after the administration of recombinant human granulocyte colony
stimulating factor (rhG-CSF) to normal donors.”)).
As Weaver explains, administering PBMCs to myeloablated patients
offers distinct advantages as compared to bone marrow transplantation:
PBMCs appear to result in faster engraftment of neutrophils and
platelets than does marrow, or marrow plus post-transplant
GM-CSF in the autologous setting. Additional advantages of
PBMCs include a decrease in platelet and red blood cell
transfusions, a decrease in the duration of hospital stay, and a
reduction in the cost of transplantation.

(Id. at 1982 (citations omitted).)
While it is undisputed that Weaver differs from claim 1 in failing to
subject the PBMCs to the culturing steps recited in the claim, as the
Examiner pointed out, Hashimoto discloses that culturing PBMCs in the
presence of an ionophore causes the cells to proliferate (see Hashimoto 393-
94 (“When peripheral blood mononuclear cells (PBMC) (approximately
80% lymphocytes and 20% monocytes) are stimulated with either calcium
ionophore or phorbol ester, lymphocyte proliferation does occur.”)).
As the Examiner also pointed out, Hashimoto discloses that the
proliferation effect was detectable in PBMCs cultured for 68 hours (see id. at
394), and that the presence of IL-2 was detected in PBMCs cultured in the
presence of ionomycin after 48 hours (see id. at 398 (Table 5)). We are
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therefore not persuaded that Hashimoto fails to describe claim 1’s culturing
steps, including culturing the PBMCs in the presence of a cytokine, as
Appellant argues (see App. Br. 10; see also Reply Br. 4).
Moreover, given the references’ teachings, we are not persuaded that
the Examiner’s position is contrary to the references’ teachings, as Appellant
further argues (see App. Br. 11). Rather, we agree with the Examiner that an
ordinary artisan, advised by Weaver of the therapeutic efficacy and
advantages of PBMCs in myeloablated patients, would have been prompted
to administer those cells to patients suffering from severe myelosuppression,
and would also have been prompted to culture those cells under the
proliferative conditions described by Hashimoto, so as to increase the
number of cells available for transplantation.
While Hashimoto might not have expressly stated that increasing the
number of PBMCs had any clinical application, given Weaver’s disclosure
of the therapeutic efficacy of that very same population of cells, i.e. PBMCs,
we agree with the Examiner that an ordinary artisan would have reasoned
that it would be useful to culture the cells under the conditions described in
Hashimoto before transplanting them. As the Supreme explained in KSR,
“the [obviousness] analysis need not seek out precise teachings directed to
the specific subject matter of the challenged claim, for a court can take
account of the inferences and creative steps that a person of ordinary skill in
the art would employ.” KSR Int’l v. Teleflex Inc., 550 U.S. 398, 418 (2007);
see also id. at 421 (“A person of ordinary skill is . . . a person of ordinary
creativity, not an automaton.”).
We acknowledge Appellant’s argument that a number of prior art
treatments using growth factors had failed to provide adequate results in
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severely myelosuppressed patients, and that this art should therefore be
considered unpredictable (see App. Br. 8 (citing Spec. 5); see also Reply Br.
5-6). In particular, we note claim 1’s requirement that the treatment is “to
increase concentrations of blood components that are deficient in the
severely myelosuppressed patients through stimulation of hematopoiesis”
(App. Br. 13 (claim 1)).
However, given the success and advantages described in Weaver that
result from PBMC administration, we are not persuaded that an ordinary
artisan lacked a reasonable expectation that administering PMBCs would
result in the claimed patient improvement, even if those cells were subjected
to the proliferative culture conditions described in Hashimoto. Moreover,
given that Weaver describes administering the same population of cells to a
very similar, if not the same, patient population, we conclude that the
Examiner had an adequate basis for finding that the patient improvement
recited in claim 1 would necessarily occur when administering PBMCs
cultured in the manner taught by Hashimoto. As stated in In re Best, 562
F.2d 1252, 1255 (CCPA 1977) (citations omitted):
Where . . . 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.

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We are also not persuaded that culturing PBMCs before administering
them to a patient would have required an ordinary artisan to discard the
teachings in Weaver, as Appellant argues (see App. Br. 9-10). In particular,
claim 1 does not contain any language limiting the donor of the PMBCs to
any particular population of individuals, nor does claim 1 exclude culturing
PBMCs obtained from donors which have received rhG-CSF prior to cell
donation, as taught in Weaver. Moreover, while the rationale for culturing
the cells in vivo – increasing cell number as taught by Hashimoto – might
not be taught or suggested in Weaver, Appellant directs us to no clear or
specific evidence of record suggesting that the therapeutic properties of
PBMCs taught in Weaver would be lost upon culturing as described in
Hashimoto.
In sum, for the reasons discussed, Appellant’s arguments do not
persuade us that the Examiner erred in concluding that the process recited in
claim 1 would have been obvious to an ordinary artisan. We therefore
affirm the Examiner’s rejection of that claim, as well as claims 2-7, 9, 10,
12-14, 16-19, 21, 23-25, 38, 41, 44-47, 49, and 50, which were not argued
separately. See 37 C.F.R. § 41.37(c)(1)(vii).
Claim 11, which Appellant did argue separately, recites “[t]he process
of claim 1 wherein the cytokine comprises macrophage-colony stimulating
factor [M-CSF].” (App. Br 14.)
In rejecting claim 11, in addition to relying on Hashimoto and
Weaver, the Examiner cited Ragnhammar as teaching that “M-CSF and GM-
CSF can be used to activate PBMCs in antibody-dependent cellular
cytotoxicity (ADCC) to lyse cancer cells” (Ans. 6). Based on this teaching,
the Examiner reasoned that an ordinary artisan would have considered it
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obvious to “have included M-CSF or GM-CSF to a media that comprises
ionomycin to arrive at NK cells that are activated to lyse tumor cells” (id. at
6-7).
Appellant argues that the Examiner’s rationale does not find a basis in
the prior art or in the “evidence in the record. Neither Weaver no[r]
Hashimoto teach or suggest a need to make NK cells or lyse tumor cells.
Nor does Ragnhammar provide any such suggestions. Nor is there any
suggestion to undertake all of the particularly claimed cell culture conditions
using M-CSF” (App. Br. 11; see also Reply Br. 7-8 (also arguing
unpredictability in the art (citing Spec. 5)).
We are not persuaded.
Specifically, Ragnhammar discloses an in vitro study whereby
PBMCs acted as effector cells in the monoclonal antibody-mediated killing
of cancer cells, also known as antibody-dependent cellular cytotoxicity or
ADCC (see Ragnhammar 254). As Ragnhammar explains “[t]he killing
capacity of PBMC as well as of granulocytes was statistically significantly
enhanced when mAbs [monoclonal antibodies] were added. M-CSF and
GM-CSF were the best CSF for augmenting the lytic capacity of PBMC in
ADCC” (id.). Ragnhammar thus ultimately advised that “[o]n the basis of
the present evaluation, clinical trials in tumor patients are warranted,
combining mAbs with GM-CSF or M-CSF. Preference might be given to
GM-CSF as this cytokine activates both PBMC and granulocytes” (id.).
While it may be true that neither Weaver nor Hashimoto discloses the
cancer cell killing capacity of PMBCs, Weaver does disclose that its patients
suffered from a number of different cancers (see Weaver 1982 (Table 1)).
Thus, we detect no error in the Examiner’s finding that an ordinary artisan
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would have reasoned that the cancer cell killing properties of M-CSF-
activated PBMCs would have been useful for targeting any cancer cells
remaining in Weaver’s patients after myeloablation (see Ans. 15).
Accordingly, Appellant’s arguments do not persuade us that the cited
references failed to provide a reason why an ordinary artisan, advised by
Ragnhammar that M-CSF boosted the cancer cell-killing ability of PMBCs,
would have cultured PMBCs in M-CSF before administering them to cancer
patients. Moreover, given the express teaching in Weaver regarding the
therapeutic effect of PBMCs, as well as the express teaching in
Ragnhammar that M-CSF-stimulated PBMCs were useful for killing cancer
cells, we are not persuaded that an ordinary artisan lacked a reasonable
expectation of success in treating cancer patients with M-CSF-treated
PBMCs.
We note the teaching in Ragnhammar, pointed to by Appellant (Reply
Br. 8), that the cell-killing effect occurred after as little as 6 hours (see
Ragnhammar 254 (abstract)), whereas claim 11, through its dependency on
claim 1, requires culturing for from about 20 hours to about 80 hours. As
the Examiner found, however (Ans. 16), Ragnhammar discloses that the
improvement in cancer cell-killing capacity in PBMCs was observed up to
18 hours after growth factor stimulation (see id. at 259 (“Fc receptors did not
increase in vitro on the cell surface of effector cells after stimulation with
CSF during short (3-18 h) culture periods but the cytotoxic capability
increased . . . .”) (emphasis added)).
Thus, as Appellant points to no clear or specific evidence of record
suggesting that the lower limit of the claimed range, about 20 hours, fails to
encompass the 18 hour culture period taught by Ragnhammar as achieving
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the improvement in the cancer cell-killing capacity of PBMCs, we are not
persuaded that the Examiner lacked an evidentiary basis for concluding that
an ordinary artisan would have been prompted to culture PBMCs under the
claimed conditions, before transplanting them as taught by Weaver. We
therefore affirm the Examiner’s rejection as to claim 11 as well.
SUMMARY
We affirm the Examiner’s obviousness rejection of claims 1-7, 9-14,
16-19, 21, 23-25, 38, 41, 44-47, 49, and 50 over Hashimoto, Weaver,
Bowers, Ragnhammar, and Erdahl.

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

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