Ex Parte Uberti et al

Board of Patent Appeals and Interferences

Sep 22, 2010

10469835 (B.P.A.I. Sep. 22, 2010)

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.
10/469,835 04/20/2004 Ettore Ciro Degli Uberti 101P/PCT2/US 6688
37903 7590 09/22/2010
DAWN MACPHERSON AT
BIOMEASURE INC.
27 MAPLE STREET
MILFORD, MA 01757
EXAMINER
FETTEROLF, BRANDON J
ART UNIT PAPER NUMBER
1628
MAIL DATE DELIVERY MODE
09/22/2010 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 BOARD OF PATENT APPEALS
AND INTERFERENCES
____________

Ex parte ETTORE CIRO DEGLI UBERTI, MARIA CHIARA ZATELLI,
and MICHAEL DEWITT CULLER
____________

Appeal 2010-002569
Application 10/469,835
Technology Center 1600
____________

Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and
STEPHEN WALSH, Administrative Patent Judges.

Opinion for the Board filed by DONALD E. ADAMS, Administrative
Patent Judge

Opinion Concurring-in-part and Dissenting-in-part filed by JEFFREY N.
FREDMAN, Administrative Patent Judge

ADAMS, Administrative Patent Judge.

DECISION ON APPEAL1

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, or for filing a request for rehearing,
as recited in 37 C.F.R. § 41.52, begins to run from the “MAIL DATE”
(paper delivery mode) or the “NOTIFICATION DATE” (electronic delivery
mode) shown on the PTOL-90A cover letter attached to this decision.
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Application 10/469,835

2
This appeal under 35 U.S.C. § 134 involves claims 3-10 and 18-22.
We have jurisdiction under 35 U.S.C. § 6(b). Pending claims 1 and 2 were
withdrawn from consideration (App. Br. 3).
STATEMENT OF THE CASE
The claims are directed to a method of decreasing the rate of
proliferation of medullary thyroid carincoma (MTC2) cells (claims 3-10) and
a method of treating medullary thyroid carcinoma (claims 18-22). Claims 3
and 18 are representative and are reproduced in “Appendix A” of
Appellants’ Brief (see App. Br., Appendix A).
The rejections presented by the Examiner follow:
1. Claims 3-10 and 18-22 stand rejected under the enablement provision of
35 U.S.C. § 112, first paragraph.
2. Claims 3-10, 18, and 19 stand rejected under 35 U.S.C § 103(a) as
unpatentable over either Woltering ‘5513 or Woltering ‘0824 in combination
with Woltering5 and Coy.6
We reverse the rejection under the enablement provision of 35 U.S.C.
§ 112, first paragraph and affirm the rejections under 35 U.S.C § 103(a).

2 See Spec. 3: 4.
3 Woltering et al., WO 99/26551, published June 3, 1999.
4 Woltering et al., US 6,180,082 B1, issued January 30, 2001.
5 E.A. Woltering et al., Synthesis and characterization of multiply-
tyrosinated, multiply-iodinated somatostatin analogs, 53 J. PEPTIDE RES.
201-213 (1999).
6 Coy et al., US 5,597,894, January 28, 1997.
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Enablement:
ISSUE
Does the preponderance of evidence of record support the Examiner’s
conclusion that undue experimentation would be required to practice the
claimed invention?
FINDINGS OF FACT
FF 1. The Examiner finds that Appellants’ Specification provides an
enabling description of
[A]n in vitro method of decreasing the rate of proliferation of
[a] medullary thyroid carcinoma cells which comprises
contacting said medullary thyroid carcinoma cells with a
SSTR2 agonist alone or an in vivo method of treating
medullary thyroid carcinoma consisting of administering to said
patient in need thereof an effective amount of an SSTR2
agonist comprising a radioactive iodine isotope.

(Ans. 3.)

FF 2. Woltering ‘551 teaches the use of radiolabelled somatostatin or
somatostatin analogs for tumor imaging and therapy (id. at 5-6).
FF 3. Coy teaches “a method of treating and/or diagnosing conditions
associated with aberrant expression of a somatostain [sic] receptor
comprising administering a multi-tyrosinated somatostatin analogue” (id. at
6).
FF 4. “Short-term or long-term somatostatin analogue (octreotide [an
SSTR2] . . .) treatment in patients with persistent MTC or metastatic MTC
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did not result in any significant tumor response” (Kebebew7 364: 5-7; Ans.
6).
FF 5. Vitale8 demonstrates alleviation of the symptoms of MTC through
the administration of interferon α2b in combination with a somatostatin
analog, but fails to establish that this combination treatment decreases
cellular proliferation (Ans. 6).
FF 6. The Examiner finds that Appellants’ Specification fails to provide an
enabling disclosure of “an in vivo method of treating medullary thyroid
carcinoma consisting of administering to said patient in need thereof an
effective amount of an SSTR2 agonist alone, e.g., which does not comprise a
radioactive iodine isotope” (id. at 3).
FF 7. Freshney9 teaches that “there are many differences between cultured
cells and their counterparts in vivo” (Ans. 7).
FF 8. Dermer10 “teaches that, ‘petri dish cancer’ is a poor representation of
malignancy, with characteristics profoundly different from the human
disease” (id.).
FF 9. Gura11 teaches “the potential shortcomings of potential anti-cancer
agents including extrapolating from in-vitro to in-vivo protocols, the

7 Electron Kebebew, MD and Orlo H. Clark, MD, Medullary Thyroid
Cancer, 1 CURRENT TREATMENT OPTIONS IN ONCOLOGY 359-367 (2000).
8 Vitale et al., Slow Release Lanreotide in Combination with Interferon-α2b
in the Treatment of Symptomatic Advanced Medullary Thyroid Carcinoma,
85 J. CLIN. ENDOCRINOLOGY METAB. 983-988 (2000).
9 R. Ian Freshney, CULTURE OF ANIMAL CELLS, A MANUAL OF BASIC
TECHNIQUE, 4 (1983).
10 Gerald B. Dermer, Another Anniversary for the War on Cancer, 12
BIO/TECHNOLOGY 320 (1994).
11 Gura, Systems for Identifying New Drugs Are Often Faulty, 278 SCIENCE
1041-1042 (1997).
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problems of drug testing in knockout mice, and problems associated with
clonogenic assays” (id. at 7-8).
FF 10. Appellants rely on Schiff12 to teach that “Taxol stabilizes
microtubules in mouse fibroblast cells” (App. Br. 14; Schiff, Title).
FF 11. “[A]ll SSTR2 preferential compounds significantly inhibited [TT]
cell proliferation when compared with untreated control cells at each
concentration tested” (Spec. 27: 13-15).
FF 12. “There is evidence that SS [(somatostatin)] regulates cell
proliferation by arresting cell growth via SSTR1, 2, 4, and 6 subtypes”
(Spec. 1: 18-19).
FF 13. “[T]he human MTC cell line TT . . . displays MTC cell
characteristics” (Spec. 3: 18-19; see also Spec. 19: 22 - 20: 12).
FF 14. “Proliferation of the TT cell line can be reduced by SSTR2 selective
agonists, but not by SSTR5 agonists” (Spec. 4: 21-22).
FF 15. “The key inhibitory role of SSTR2 on MTC cell proliferation
demonstrates that analogues with enhanced SSTR2 affinity and selectivity
versus SSTR5 would be useful as antiproliferative agents in MTC treatment”
(id. at 23-26).
ANALYSIS
The Examiner finds that the prior art recognizes that labeled
somatostatin or somatostatin analogs are useful for tumor imaging and
therapy (FF 1-3). The Examiner finds, however, that the short/long-term
treatment of patients with the unlabeled somatostatin analogue (octreotide)
failed to result in a significant tumor response (FF 4). In addition, the

12 Peter B. Schiff and Susan band Horwitz., Taxol stabilizes microtubules in
mouse fibroblast cells, 77 PROC. NATL. ACAD. SCI. USA 1561-1565 (1980).
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Examiner finds that while Vitale establishes that the symptoms of MTC can
be alleviated by the administration of interferon α2b in combination with a
somatostatin analog, Vitale failed to establish that this combination
treatment decreases cellular proliferation (FF 5).
Based on the foregoing facts the Examiner concludes that Appellants’
Specification fails to provide an enabling description of the use of a non-
radioactively labeled SSTR2 agonist or pharmaceutically acceptable salt
thereof to decrease the rate of proliferation of medullary thyroid carcinoma
cells in vivo (FF 6). We are not persuaded that the evidence supports the
Examiner’s conclusion.
Appellants contend that the Examiner’s reliance on Kebebew (FF 4) is
misplaced because “Kebebew fails to provide any data to allow such a
comparison and conclusion” (App. Br. 16). Appellants’ claims require a
decrease in the rate of proliferation of MTC or MTC cells (see Claims 3 and
18). The Examiner failed to establish that a decrease in the rate of
proliferation of MTC or MTC cells must result in “a significant tumor
response” (Cf. Claims 3 and 18 with FF 4). There is no limitation in
Appellants’ claimed invention that requires the method to produce a
significant tumor response. To the contrary, Appellants’ claims require only
some decrease in the rate of proliferation of MTC or MTC cells. The
Examiner failed to establish that the therapy reported by Kebebew failed to
achieve the claimed goal.
We recognize the Examiner’s reliance on Freshney, Dermer, and Gura
to suggest potential shortcomings in the correlation between in vitro and in
vivo results (FF 7-9). However, Appellants contend “that it is possible to
extrapolate results from in vitro work to in vivo success” (App. Br. 17). In
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support of their contention Appellants rely on Schiff’s teaching that taxol, an
unrelated chemotherapeutic drug, stabilizes microtubules in mammalian
fibroblast cells in vitro (FF 10) and “is currently approved for, prescribed for
and used for the treatment of a number of cancers” (App. Br. 14). Thus, the
evidence and argument presented on this record suggests that care must be
taken to select an appropriate in vitro model of an in vivo system. In this
regard, Appellants contend that the Examiner failed to establish that the “TT
cell system, an accepted model useful for studying MTC[,] . . . is an
insufficient model to extrapolate to in vivo findings” (App. Br. 17; FF 11-
15). We agree. We also agree with Appellants’ contention that the
Examiner failed to establish that Kebebew “teach that the somatostatin
analog octreotide performed differently in vitro than in vivo” (App. Br. 17).
CONCLUSION OF LAW
The preponderance of evidence of record fails to support the
Examiner’s conclusion that undue experimentation would be required to
practice the claimed invention.
The rejection of claims 3-10 and 18-22 under the enablement
provision of 35 U.S.C. § 112, first paragraph is reversed.
Obviousness:
ISSUE
Does the preponderance of evidence on this record support a
conclusion of obviousness?
FINDINGS OF FACT
FF 16. Appellants concede that Woltering ‘551 and ‘082 “are identical”
(App. Br. 22). Accordingly, the following factual findings with regard to
Woltering ‘551 are cumulative to Woltering ‘082.
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FF 17. Woltering ‘551 teaches “a method of selectively accumulating a
receptor-dependent radiolabelled compound inside a tumor cell[, which
includes medullary thyroid carcinomas,] in a patient comprising,
administering a dose of a radiolabeled compound to the patient” (Ans. 8).
FF 18. Woltering ‘551 teaches that “[r]adiolabeled somatostatin or
somatostatin analogs have been used for tumor imaging and therapy”
(Woltering ‘551 7: 1-2; Ans. 16).
FF 19. Woltering ‘551 teaches that the receptor-dependent radiolabelled
compound “is a somatostatin analog referred to as lanreotide” (Ans. 8).
FF 20. The Examiner finds that lanreotide falls within the scope of
Appellants’ claimed invention and is identical to the SSTR-2 selective
agonist consisting of the amino acid sequence of Appellants’ SEQ ID NO: 2
(id.).
FF 21. The Examiner finds that Woltering ‘551 does not “teach treating a
patient comprising a medullary thyroid carcinoma” (Ans. 9).
FF 22. Coy “teach[es] a method of treating a patient having a condition[,
including medullary thyroid carcinoma,] characterized by aberrant
expression of a somatostatin receptor comprising administering to a patient a
multi-tyrosinated somatostain [sic] analog” (id.).
ANALYSIS
Appellants present separate arguments for representative claims 3 and
18. 37 C.F.R. § 41.37(c)(1)(vii).
Based on the foregoing factual findings the Examiner concludes that
[I]t would have been prima facie obvious to one of ordinary
skill in the art at the time the invention was made to
. . . modify the method taught by Woltering et al. for the
treatment of medullary carcinoma in view of the teachings of
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Coy . . . because Coy et al. teaches the treatment of patients
having a condition characterized by aberrant expression of a
somatostatin receptor such as medullary thyroid carcinoma
comprising administering to a patient a multi-tyrosinated
somatostain [sic] analog.

(Ans. 9-10; see also Ans. 11.)
Appellants contend that “neither independent Claim 3 . . . nor
independent Claim 18 call for the use of radiolabelled compounds” and that
“Appellants claims’ are directed to the surprising discovery that the
compounds of the present invention were able to reduce the proliferation of
medullary thyroid carcinoma cells by themselves, that is, without the need
for radiotherapy or radioisotopic compounds” (App. Br. 20). We are not
persuaded. Neither Claim 3 nor Claim 18 excludes the use of a radiolabelled
SSTR2 agonist, such as the compound having SEQ ID NO: 2, or a
pharmaceutically acceptable salt thereof. For the foregoing reasons we are
not persuaded by Appellants’ contentions regarding the use of non-
radiolabelled compounds.
We are also not persuaded by Appellants’ contention that Coy’s
teaching of the “radiolabeled multi-tyrosinated somatostatin analogs’ ability
to treat medullary thyroid carcinoma is found within a laundry list of
conditions/diseases known to be associated with aberrant expression of a
somatostatin receptor” (App. Br. 21). Not withstanding Appellants’
intimation to the contrary, Coy suggests the use of the somatostatin analog to
treat any one of the named diseases, including medullary thyroid carcinoma
(FF 22).
Appellants provide no persuasive evidence or argument to support a
finding that the method of treating medullary thyroid carcinoma suggested
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by the combination of Woltering ‘551 or ‘082 and Coy does not result in
decreasing the rate of proliferation of medullary thyroid carcinoma cells.
CONCLUSION OF LAW
The preponderance of evidence on this record supports a conclusion
of obviousness.
The rejection of claims 3 and 18 under 35 U.S.C § 103(a) as
unpatentable over either Woltering ‘551 or Woltering ‘082 in combination
with Woltering and Coy is affirmed. Claims 4-10 fall together with claim 3.
Claim 19 falls together with claim 18.

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-IN-PART

cdc

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CONCURRING AND DISSENTING OPINION

FREDMAN,
Administrative Patent Judge, concurring-in-part and dissenting-in-part.
I concur with the majority regarding the affirmance of the rejection of
obviousness rejections.
I respectfully dissent from the majority regarding the reversal of the
rejection of claim 3-10 and 18-22 under 35 U.S.C. § 112, first paragraph. I
would affirm the Examiner’s scope of enablement rejection, based upon the
Examiner’s reasoning and the following comments.
The majority opinion points to in vitro data in the Specification which
demonstrates that SSTR2 selective agonists may inhibit an MTC cell line
(FF 11-14).
Balanced against this evidence of efficacy in vitro, Freshney, Gura
and Dermer are cited by the Examiner to show that it is unpredictable
whether results obtained from cell culture studies apply to in vivo therapies
(FF 7-9).
If this were all the evidence of record, I might agree with the Majority
to reverse the rejection. However, the Examiner has also cited Kebebew, a
specific, targeted reference which states that “[s]hort-term or long-term
somatostatin analogue (octreotide [an SSTR2] . . .) treatment in patients with
persistent MTC or metastatic MTC did not result in any significant tumor
response” (Kebebew 364: 5-7; Ans. 6; FF 4).
Thus, the Examiner has provided specific evidence that an SSTR2
agonist alone (without radioactive iodine) does not treat medullary thyroid
carcinoma (FF 4). Appellants, in rebuttal, irrelevantly cite to data on taxol,
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an entirely unrelated compound which functions on an entirely unrelated
cancer (see App. Br. 14-15). Appellants’ only specific rebuttal of Kebebew
is that “Kebebew fails to provide any data to allow such a comparison and
conclusion” (App. Br. 16). However, Kebebew is a review, not an original
scientific paper, and summarizes the results of two different studies (see
Kebebew 364).
Appellants provide no rebuttal to Kebebew’s conclusion based on the
two studies, that a somatostatin analogue did not achieve the goals of
Appellants’ claims, of decreasing the rate of proliferation of MTC cells in an
in vivo, tumor, environment.
Balancing the Wands factors regarding in vivo enablement, I agree
with the Examiner that based on the express and specific teaching of
unpredictability in vivo by Kebebew, the unpredictable nature of cancer
therapy (see Ans. 4), the breadth of the claims to any SSTR agonist (see
Ans. 4), along with the generic teachings of unpredictability in transferring
in vitro data to in vivo use of Freshney, Gura, and Dermer, weighted against
the in vitro working examples, undue experimentation would have been
required to use the invention as claimed.
For these reasons, I respectfully dissent from the reversal of the scope
of enablement rejection.

DAWN MACPHERSON AT
BIOMEASURE INC.
27 MAPLE STREET
MILFORD, MA 01757