Ex Parte Bernstein

Patent Trials and Appeals Board

Mar 26, 2019

14095066 - (D) (P.T.A.B. Mar. 26, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
14/095,066 12/03/2013 Lawrence Richard Bernstein
74973 7590 03/28/2019
Lawrence R. Bernstein
285 Willow Road
Menlo Park, CA 94025-2711
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.
01-005.1 7979
EXAMINER
LAMBERSKI, JENNIFER A
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
03/28/2019 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):
LawrenceRBernstein@gmail.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte LAWRENCE RICHARD BERNSTEIN 1
Appeal2018-000368
Application 14/095,066
Technology Center 1618
Before DONALD E. ADAMS, ERIC B. GRIMES, and TA WEN CHANG,
Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of treating cancer, which have been rejected as obvious. We have
jurisdiction under 35 U.S.C. § 6(b). We affirm.
STATEMENT OF THE CASE
"Gallium radioisotopes, particularly 67 Ga, have been in widespread
use since about 1969 to help detect and localize cancer, infection, and
inflammation in the body. The detection and localization are typically
accomplished with a gallium scan." Spec. ~ 3. "If gallium-avid cancer tissue
1 Appellant identifies the Real Party in Interest as Lawrence R. Bernstein.
Appeal Br. 1.
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Application 14/095,066
is present, it will become more radioactive than healthy surrounding tissue .
. . . Decades of gallium scan results show that little gallium is taken up by
most healthy tissues, even by those containing rapidly multiplying cells." Id.
"Gallium, in its naturally occurring, non-radioactive form, is known to
be effective in treating many types of cancer." Id. ,r 4. "One mechanism of
action for gallium appears to be its ability to act as an irreducible mimic of
ferric iron (Fe3+) .... [I]n many cases, Ga3+ is avidly taken up by cancer
cells .... The gallium thus taken up may then interfere with the utilization of
iron within the cell, inhibiting DNA synthesis and cell division." Id.
The Specification states that
gallium scanning can identify those patients who have cancers
that are most likely to be susceptible to gallium therapy
(gallium-responsive cancers) .... The ability to screen for,
image, and then treat a disorder all with the same chemical
entity-in this case gallium----constitutes a powerful new
method of identifying and treating disease.
Id. ,I 5.
Claims 1-11, 13-19, and 21-23 are on appeal. Claim 1 is illustrative
and reads as follows:
1. A method of treating cancer in a patient in need thereof, comprising:
(1) administering to the patient a gallium radioisotope;
(2) performing a gallium scan on the patient;
(3) measuring the ratio of gallium radioisotope uptake in cancer tissue
to that in nearby healthy tissue from the gallium scan;
( 4) treating the patient with a therapeutically effective amount of a
pharmaceutically acceptable gallium compound if the measured uptake of
gallium radioisotope by the cancer tissue is greater than that of nearby
healthy tissue.
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Claims 13 and 23 are the only other independent claims, and are
directed to methods similar to that of claim 1, where the gallium
radioisotope is 67Ga-citrate in a specific range of dosages and the gallium
scan is performed 24--72 hours after 67 Ga-citrate administration. Claim 23
also recites treating specific types of cancer.
The claims stand rejected as follows:
Claims 1-3, 8-11, 13, 18, 19, 21, and 22 under 35 U.S.C. § I03(a) as
obvious based on Chitambar2 and Kaplan3 (Ans. 2);
Claims 4--7 and 14--17 under 35 U.S.C. § I03(a) as obvious based on
Chitambar, Kaplan, and Morton4 (Ans. 4); and
Claim 23 under 35 U.S.C. § I03(a) as obvious based on Chitambar,
Kaplan, and Bartold5 (Ans. 5).
I
The Examiner has rejected claims 1-3, 8-11, 13, 18, 19, 21, and 22 as
obvious based on Chitambar and Kaplan. The Examiner finds that
Chitambar teaches a method of treating lymphoma by "administering a
therapeutically effective amount of a gallium complex to the patient, e.g.,
gallium nitrate (GaN) if the lymphoma is GaN-sensitive, or gallium
2 US 2007/0231407 Al, published Oct. 4, 2007.
3 William D. Kaplan, etc., Gallium-67 Imaging: A Predictor of Residual
Tumor Viability and Clinical Outcome in Patients with Diffuse Large-Cell
Lymphoma, 8 Journal of Clinical Oncology 1966--1970 (1990).
4 US 6,558,650 Bl, May 6, 2003.
5 Stephen P. Bartold, etc., Society of Nuclear Medicine Procedure Guideline
for Gallium Scintigraphy in the Evaluation of Malignant Disease, V3.0
(2001), http://snmmi.files.cms-plus.com/docs/pg_ch23_0403.pdf.
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maltolate ... if the lymphoma is GaN-resistant." Ans. 2. The Examiner finds
that Chitambar also teaches "a method of determining whether or not a
lymphoma cell line takes up (i.e., is sensitive to) a gallium complex in vitro"
by administering and measuring uptake of 67 Ga, but does not teach
"administering a 67Ga-radiolabeled gallium complex to the patient and
imaging the patient before treating the patient." Id.
The Examiner finds that "Kaplan teaches a method of imaging and
treating lymphoma" by "administering ... 67 Ga citrate to the patient; ...
performing 67 Ga scans of the patient; determining abnormal 67 Ga uptake as
... an indicator of residual tumor (reads on measuring tumor to background
ratio); and administering a therapeutically effective amount of
chemotherapy." Id. at 3. The Examiner concludes that it would have been
obvious to modify Chitambar's method to include Kaplan's steps of
administering a 67 Ga compound to a patient and performing a gallium scan
in order to image and treat lymphoma "because administering and imaging a
67Ga-radiolabeled gallium complex would provide the advantages of
determining tumor location in the patient, as suggested by Kaplan, and
tumor sensitivity to (i.e., uptake of) the gallium complex, as suggested by
Chitambar." Id.
We agree with the Examiner that the method of Appellant's claims 1
and 13 would have been obvious based on Chitambar and Kaplan. Chitambar
discloses that "[n]on-radioactive gallium compositions ... have been found
effective in treating some mammalian tumors .... It is known that Gallium
becomes concentrated in malignant tumors and sites of infection." Chitambar
,r 3. "Recent clinical trials have demonstrated that FDA approved GaN
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[gallium nitrate] ... has efficacy in the treatment of NHL [non-Hodgkin's
lymphoma]." Id. ,r 4.
However, "a significant fraction of lymphoma patients treated with
GaN fail to respond due to tumor cell resistance to this drug." Id. ,r 6.
Chitambar discloses "a method of inhibiting the growth of lymphoma cells,
suitably non-Hodgkin's lymphoma cells, that are not responsive to GaN by
contacting the cells with an effective amount of ... gallium maltolate
(GaM)." Id. ,I 8.
Chitambar discloses that " [ t] o evaluate cellular uptake of GaM and
GaN in ... gallium-sensitive and -resistant[ 6] CCRF-CEM [lymphoma]
cells," the cells were plated and incubated with "either GaM or GaN
containing 67Ga as a tracer." Id. ,r 79. Chitambar reports that "both gallium-
sensitive and -resistant cells incorporated greater amounts of 67Ga as GaM
than as GaN. These results suggest that the uptake of gallium is more
efficient when gallium is presented to cells as GaM." Id. ,r 80.
Kaplan "evaluated the ability of gallium-67 citrate (Ga-67) imaging to
define residual disease and predict outcome ... [in] patients with DLCL
[ diffuse large-cell lymphoma]." Kaplan 1966, abstract. Kaplan states that
"[t]he ability to further prognosticate outcome during early treatment might
lead to a change in therapy with potential improvement in survival of
patients with refractory lymphoma." Id. at 1966, bridging paragraph.
Kaplan administered multi-drug chemotherapy to 37 patients with
DLCL and, halfway through therapy, administered 296 to 370 MBq
6 In this context, "gallium-sensitive and -resistant" refers to sensitivity or
resistance, respectively, to GaN. See id. ,r 65.
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(megabecquerels) of Ga-67 as the citrate 7 and imaged the patients 72 hours
after Ga-67 administration. Id. at 1967, left col. and Table 1.
Kaplan states that, of the 3 7 patients, "17 ( 46%) showed persistent
abnormal Ga-67 uptake halfway through chemotherapy .... Twenty patients
(54%) were Ga-67-negative halfway through chemotherapy." Id. at 1967,
right col. Kaplan reports that "13 of the 17 patients (76%) who were Ga-67-
positive halfway through chemotherapy either failed to achieve a CR
[complete remission] or relapsed at the completion of therapy." Id. at 1968,
left col. By contrast, "[ o ]f the 20 patients who were Ga-67-negative after
four cycles of chemotherapy, only five (25%) have died .... One patient is
alive with active tumor, and 14 (70%) are alive without evidence of
disease." Id.
Kaplan concludes that "Ga-67 imaging is a better predictor of residual
tumor viability than are net changes in tumor mass as defined by chest x-ray
or CT scan. Persistent Ga-67 uptake after four cycles of combination
chemotherapy for DLCL predicts for a poor outcome and may justify a
change in treatment regimen." Id. at 1970, bridging paragraph.
Based on the disclosures of Chitambar and Kaplan, it would have
been obvious to a person of ordinary skill in the art to administer a 67Ga
compound (e.g., 67Ga citrate) to lymphoma patients and carry out a gallium
scan halfway through chemotherapy in order to identify patients with
7 Appellant does not dispute that the dosage range of 67Ga-citrate disclosed
by Kaplan overlaps, or otherwise would have made obvious, the
approximately 1 to 5 MBq per Kg of body weight recited in claim 13. See
Appeal Br. 4--9.
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residual tumor and therefore a poor prognosis, as taught by Kaplan. It would
also have been obvious to change the treatment regimen of such patients to
include gallium maltolate. Both of the references provide a reason to
combine their teachings, because Kaplan expressly suggests changing the
treatment regimen of patients showing abnormal 67 Ga uptake halfway
through chemotherapy and Chitambar discloses that gallium maltolate is
taken up efficiently by lymphoma cells and inhibits their growth, even if the
cells are resistant to the FDA-approved gallium nitrate.
Appellant argues that the cited references do not teach or suggest "the
claim element of identifying a patient who is suitable for anticancer therapy
with a gallium compound (part ( 4) of claims 1, 13, and 23 ... ). " Appeal Br.
4. "No evidence has been presented in this case that, prior to the disclosures
of the instant application, it was known that the results of a Ga-67 scan could
be correlated with the efficacy of gallium therapy for cancer." Id. at 5.
Similarly, Appellant argues that "even if the teachings from the cited prior
art are combined, they do not lead to the instant invention, which
comprises the identifying of a patient suitable for anticancer gallium
therapy by use of a gallium scan." Id. at 9.
We disagree with Appellant's reading of Chitambar and Kaplan. As
discussed above, Kaplan suggests changing a chemotherapy regimen for
patients with lymphoma if, halfway through chemotherapy treatment, a
gallium scan carried out after administration of 67 Ga shows abnormal uptake
of 67 Ga by residual tumor cells; i.e., "if the measured uptake of gallium
radioisotope by the cancer tissue is greater than that of nearby healthy
tissue," as recited in the claims on appeal. In addition, Chitambar teaches
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that gallium maltolate is effective in inhibiting the growth of lymphoma
cells. In our view, these teachings reasonably suggest including gallium
maltolate as a chemotherapeutic agent for treating lymphoma if a gallium
scan shows 67 Ga uptake by cancer tissue that is greater than the uptake of
nearby healthy tissue, which meets the requirements of the claims on appeal.
Appellant also argues that the anticancer efficacy of a gallium
compound would not be predictable based on the results of a 67 Ga scan of a
patient. Appeal Br. 5. Appellant points to Morton's discussion of the "well-
recognized" limitations of 67Ga for imaging tumors. Id. at 5---6. Appellant
acknowledges Morton's statement that "no other gamma-emitting
radiopharmaceutical used for tumor imaging in nuclear medicine ... has
surpassed Ga-67 in cost-effectiveness, general availability, broad
applicability and ease of imaging" but argues that "[t]his statement is
irrelevant, because it has no bearing on the already stated 'well recognized'
limitations of Ga-67 scans for oncologic imaging." Id. at 6. Appellant also
argues that "Bartold ... states, 'Well differentiated lymphocytic lymphoma
usually does not accumulate Ga-67' ." Id.
These arguments are also unpersuasive. "When prior art contains
apparently conflicting references, the Board must weigh each reference for
its power to suggest solutions to an artisan of ordinary skill." In re Young,
927 F.2d 588, 591 (Fed. Cir. 1991). "In reviewing the examiner's decision
on appeal, the Board must necessarily weigh all of the evidence and
argument. ... [T]he ultimate determination of patentability is made on the
entire record." In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992).
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Here, Appellant accurately cites Morton for its disclosure that "[t]he
limitations of Ga-67 for oncologic imaging are well-recognized." Morton
1:38-39. Appellant also accurately cites Bartold for its statement that "[w]ell
differentiated lymphocytic lymphoma usually does not accumulate Ga-67."
Bartold 7, IV.K.10.
Those statements, however, must be weighed against the rest of the
disclosures of Morton and Bartold, as well as those of Chitambar and
Kaplan. In addition to the disclosure relied on by Appellant, Morton states
that "[ d]espite its drawbacks, no other gamma-emitting radiopharmaceutical
used for tumor imaging in nuclear medicine ... has surpassed Ga-67 in cost-
effectiveness, general availability, broad applicability and ease of imaging."
Morton 1 :49-54. In addition, Morton states that its invention "improve[ s]
the use of gallium" by "improv[ing] tumor imaging" and "improv[ing] the
use of gallium as an adjunct to chemotherapy." Id. at 3: 18-21.
Similarly, Bartold states that, as of 2001, "Ga-67 ... ha[ d] been used
for imaging a variety of solid neoplasms for more than 25 years," that "Ga-
67 imaging of neoplastic disease has shown the greatest utility in imaging
lymphoma," and "Ga-67 has proven useful in the management of patients
with lymphoma." Bartold 1, II.A-II.C. And, as noted above, Kaplan
concludes that "Ga-67 imaging proved to be an excellent indicator of
residual viable tumor." Kaplan 1966, abstract.
Thus, when we consider the prior art as a whole and weigh the
statements indicating that Ga-67 imaging is effective against the statements
indicating that Ga-67 imaging has limitations, we conclude that the
teachings of the prior art as a whole would not have led a skilled artisan to
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doubt the efficacy of combining the Ga-67 imaging taught by Kaplan with
the gallium maltolate treatment taught by Chitambar. Appellant's argument
to the contrary is therefore unpersuasive.
Appellant argues that "[t]he Chitambar patent application by itself
provides robust evidence that the instant invention would not have been
obvious to one of ordinary skill in the art" because Chitambar "teaches the
use of gallium nitrate and gallium maltolate to treat cancer ... and yet never
even suggests using a 67Ga-scan to predict the efficacy of a gallium
compound against cancer." Appeal Br. 8.
This argument is also unpersuasive, because the test of obviousness is
"whether the teachings of the prior art, taken as a whole, would have made
obvious the claimed invention." In re Gorman, 933 F.2d 982, 986 (Fed. Cir.
1991 ). See also In re Young, 927 at 591 ("The test for obviousness is what
the combined teachings of the references would have suggested to one of
ordinary skill in the art."). Here, although Chitambar does not suggest
combining its gallium maltolate treatment with administration of 67Ga and a
gallium scan, that combination reasonably follows from Kaplan's disclosure
of identifying lymphoma patients with a poor prognosis using 67Ga and a
gallium scan. Thus, Appellant's claimed method would have been obvious
based on the cited references as a whole.
Appellant argues that "[t]he performing of at least one Ga-67 scan
on a patient partway through treatment is essential to Kaplan's
procedure," but modifying Chitambar "to administer to a patient a
therapeutic, non-radioactive gallium compound ... , with the performing of
the Ga-67 scans on a patient ... would result in the Ga-67-scans performed
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during treatment not functioning properly," because the radioactive Ga-67
would be diluted in the body by the non-radioactive gallium compound to
the point of being undetectable. Appeal Br. 9.
This argument is also unpersuasive, for two reasons. First, Appellant
does not support the argument regarding the degree of dilution and
consequent ineffectiveness of a gallium scan by citation to any evidence. See
In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992) ("After evidence or
argument is submitted by the applicant ... , patentability is determined on
the totality of the record, by a preponderance of evidence with due
consideration to persuasiveness of argument."). Second, Kaplan administers
its chemotherapeutic agents at discrete times, not continuously. See Kaplan
1966, abstract ("Patients .... were imaged prior to, following cycles 4 to 6,
and at completion of intensive chemotherapy."). Appellant has not pointed
to evidence showing that interrupting treatment with the gallium maltolate
taught by Chitambar, in order to perform Kaplan's gallium scan, would
result in the effect described in the Appeal Brief.
For the reasons discussed above, we affirm the rejection of claims 1
and 13 under 35 U.S.C. § 103(a) based on Chitambar and Kaplan. Claims 2,
3, 8-11, 18, 19, 21, and 22 were argued separately and therefore fall with
claims 1 and 13. 37 C.F.R. § 4I.37(c)(l)(iv).
II
The Examiner has rejected claims 4--7 and 14--17 as obvious based on
Chitambar, Kaplan, and Morton. The Examiner has rejected claim 23 as
obvious based on Chitambar, Kaplan, and Bartold. The Examiner cites
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Chitambar and Kaplan for the disclosures that are discussed above with
regard to the§ 103(a) rejection of claims 1 and 13.
The Examiner finds that Chitambar and Kaplan do not teach
"abnormal 67Ga uptake over background, e.g., 10%, 2X, lOX, or lOOX
higher than background, as required by" claims 4--7 and 14--17. Ans. 4. The
Examiner finds that "Morton teaches a method for improving tumor cell
uptake of gallium compounds, e.g., 67Ga, by exposing cells to an uptake
enhancer," which allows tumors to be imaged more quickly and results in
67Ga uptake ofup to 1000-fold greater than basal levels. Id. The Examiner
concludes that it would have been obvious "to incorporate administering the
uptake enhancer of Morton into the method of Chitambar in view of Kaplan"
in order to "improv[ e] localization and uptake efficiency of 67 Ga selectively
in tumors ... and reduc[ e] the time needed between administering and
imaging 67Ga, as suggested by Morton." Id. at 5.
With regard to claim 23, the Examiner finds that "Bartold teaches that
67Ga has been used for imaging a variety of solid neoplasms," including
multiple myeloma. Id. at 6. The Examiner concludes that it would have been
obvious to apply the method made obvious by Chitambar and Kaplan to the
types of tumors recited in claim 23, because "imaging a variety of solid
neoplasms using 67Ga was known in the art, as taught by Bartold." Id. at 7.
We agree with, and adopt, the Examiner's findings, reasoning, and
conclusion that claims 4--7, 14--1 7, and 23 would have been obvious to a
person of ordinary skill in the art based on the cited references.
With regard to the rejection of claims 4--7 and 14--17, Appellant
argues that the "[t]he instant invention is predicated on the surprising and
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unexpected discovery that the results of a gallium scan can be used to
identify a patient who will likely respond to gallium therapy" and "this
element of the instant invention is nowhere present in any of the cited
literature and is not suggested by it." Appeal Br. 10. That is, Morton does
not "cure the deficiencies of Chitambar and Kaplan." Id.
This argument is unpersuasive because, as discussed above with
regard to the rejection based on Chitambar and Kaplan, we conclude that the
broadest reasonable interpretation of the claim language reads on the method
made obvious by Chitambar and Kaplan, and Morton provides a reason to
include an uptake enhancer in that method. With regard to the rejection of
claim 23, Appellant argues that Bartold's teachings "do not address the
fundamental deficiencies of Chitambar and Kaplan." Appeal Br. 10. This
argument is unpersuasive for the reasons discussed above with regard to the
rejection based on Chitambar and Kaplan.
We therefore affirm the rejections under 35 U.S.C. § 103(a) of claims
4--7 and 14--17 based on Chitambar, Kaplan, and Morton, and of claim 23
under 35 U.S.C. § 103(a) based on Chitambar, Kaplan, and Bartold.
SUMMARY
We affirm all of the rejections on appeal.
TIME PERIOD FOR RESPONSE
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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