Ex parte Janaky et al.

Board of Patent Appeals and Interferences

Jul 28, 2000

08008186 (B.P.A.I. Jul. 28, 2000)

Application for patent filed January 25, 1993. According to appellants, this1
application is a continuation-in-part of Application 07/505,517, filed April 6, 1990, now
abandoned; which is a continuation-in-part of Application 07/404,667, filed September 7,
1989, now abandoned; which is a continuation-in-part of Application 07/260,994, filed
October 21, 1988, now abandoned.
1
THIS OPINION WAS NOT WRITTEN FOR PUBLICATION
The opinion in support of the decision being entered today (1) was not written for
publication in a law journal and (2) is not binding precedent of the Board.
Paper No. 26
UNITED STATES PATENT AND TRADEMARK OFFICE
__________
BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________
Ex parte TAMAS JANAKY, ATTILA JUHASZ, SANDOR BAJUSZ
and ANDREW V. SCHALLY
__________
Appeal No. 1996-2431
Application 08/008,186 1
__________
ON BRIEF
__________
Before WINTERS, ROBINSON and SCHEINER, Administrative Patent Judges.
SCHEINER, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 from the final rejection of claims 1
through 23, all the claims remaining in the application.
Appeal No. 1996-2431
Application 08/008,186
2
Claims 1, 2, 5, 13 and 14 are representative of the subject matter on appeal and
read as follows:
1. A peptide selected from the group of peptides having the formula:
X-R -R -R -Ser-R -R (Q)-Leu-Arg-Pro-R -NH 1 2 3 5 6 10 2
wherein
R is pGlu or D-Nal(2),1
R is His or D-Phe(4Cl),2
R is Trp, D-Trp or D-PAl(3),3
R is Tyr or Arg5
R is D-Lys or D-Orn6
R is Gly or D-Ala,10
X is a hydrogen or a lower alkanoyl group of 2-5 carbon atoms,
Q is a cytotoxic moiety having the formula
-Q or -A(Q ) or -B(Q ) or -B(AQ ) 4 3 1 22 2
wherein
A is -NH-(CH ) -CO- or -OH-(CH ) -CO- 2 n 2 n
where n is 2-6,
B is -HN-CH -(CH ) -CH(NH)-(CH ) -CO-2 2 m 2 n
where
m is 0 or 1,
n is 0 or 1,
the -CO moiety of A- and of B- being bonded to the epsilon or delta amino
group of R when R is Lys or Orn respectively, and in the group -B(AQ ) , the -CO moiety6 6 2 2
of A being bonded to an amino group on B,
Q is D or L-melphalanyl, cyclopropanecarbonyl, aziridine-2-carbonyl, epoxyalkyl or1
1,4-naphthoquinone-5-oxycarbonyl-ethyl,
Q is Q 2-anthraquinonyl-methylenoxy or doxorubicinyl,2 1,
Q is Q , mitomicinyl, esperamycinyl or methotrexoyl,3 2
Q is Q or methotrexoyl,4 1
and pharmaceutically acceptable salts thereof.
Appeal No. 1996-2431
Application 08/008,186
3
2. A peptide of Claim 1 wherein Q is Q .4
5. A peptide of Claim 1 wherein Q is A(Q ).3
13. A peptide according to Claim 2 wherein Q is D- or L-Mel, CPC or4
methotrexoyl.
14. A peptide according to Claim 5 wherein A is 6-aminohexanoyl or glutaryl, and
Q is 2-anthraquinonyl-methylenoxy, doxorubicinyl or methotrexoyl.3
The references relied on by the examiner are:
Sela et al. (Sela) 4,263,279 Apr. 21, 1981
Rivier et al. (Rivier) 4,652,550 Mar. 24, 1987
Stevens 4,713,366 Dec. 15, 1987
Anderson et al. (Anderson) 5,169,933 Dec. 8, 1992
Lin et al. (Lin), “2-Methylanthraquinone Derivatives as Potential Bioreductive Alkylating
Agents,” J. Med. Chem., Vol. 23, pp. 1237-1242 (1980).
Varga, “Hormone-Drug Conjugates,” in Methods in Enzymology, Vol. 112, pp. 259-269
(1985).
Bajusz et al. (Bajusz), “Highly potent analogues of luteinizing hormone-releasing hormone
containing D-phenylalanine nitrogen mustard in position 6,” Proc. Natl. Acad. Sci. USA,
Vol. 86, pp. 6318-6322 (August 1989).
Channabasavaiah et al. (Channabasavaiah), “New Potent Agonist and Antagonist Analogs
of Luteinizing Hormone Releasing Hormone,” Peptides, Proceedings of the Sixth
American Pept. Symp., E. Gross and J. Meienhofer (eds.), pp. 803-806.
The claims stand rejected as follows:
I. Claims 1 through 4 and 13 under 35 U.S.C. § 103 as unpatentable over
Channabasavaiah, Bajusz and Rivier.
Appeal No. 1996-2431
Application 08/008,186
35 U.S.C. § 7(b): “The [board] shall . . . review adverse decisions of examiners2
upon applications for patents . . . “
4
II. Claims 5 through 7, 12 and 14 under 35 U.S.C. § 103 as unpatentable over
Channabasavaiah, Bajusz, Rivier, Sela and Varga.
III. Claims 8 through 10, 12 and 15 under 35 U.S.C. § 103 as unpatentable over
Channabasavaiah, Bajusz, Rivier and Stevens.
IV. Claims 16 through 18 under 35 U.S.C. § 103 as unpatentable over
Channabasavaiah, Bajusz, Rivier, Sela, Varga and Stevens.
Claims 11, 13, 14 and 19 through 23 under 35 U.S.C. § 103 as unpatentable
over Channabasavaiah, Bajusz, Rivier, Stevens, Lin and Anderson.
DISCUSSION
The present invention is directed to cytotoxic agonists and antagonists of luteinizing
hormone releasing hormone (LHRH). In each of the claimed LHRH decapeptide analogs,
a cytotoxic agent is conjugated directly or indirectly to the amino acid residue at position
six, and the amino acid at position six is always D-Lys or D-Orn. We note that both the
examiner and appellants have focused throughout the prosecution on those LHRH
agonists and antagonists wherein the cytotoxic moiety is D-melphalan (D-Mel),
anthraquinoyl or methotrexoyl. As this board functions as a board of review, not a de novo
examination tribunal, we shall do likewise. 2
Appeal No. 1996-2431
Application 08/008,186
5
There are five rejections under 35 U.S.C. § 103, and each is founded on the
combination of Channabasavaiah and Bajusz. We view the examiner’s proposed
combination of these two references as the dispositive issue in each of the rejections.
Channabasavaiah discloses a number of agonist and antagonist analogs of LHRH,
including “[DLys(Chlorambucil) ]-LRH,” wherein the amino acid at position six of the native6
decapeptide is replaced by D-Lys, and the D-Lys is conjugated in turn to the alkylating
agent, chlorambucil (Chl); and “[Dphe ,DLys(Chlorambucil) ]-LRH,” wherein the amino acid2 6
at position two is additionally replaced by D-Phe. According to the examiner,
“Channabasavaiah does not expressly teach other alkylating agents such as D-Mel as
claimed.” Examiner’s Answer, page 5.
Bajusz teaches that “highly potent alkylating analogues of LH-RH” were obtained
when “the D enantiomer of Mel was incorporated into position 6 of the native hormone and
some of its antagonistic analogues.” In addition, “[D-Mel ]LH-RH . . . showed high affinities6
for the membrane receptors of . . . human breast cancer cells, human prostate cancer cells,
and rat Dunning R-3327 prostate tumor cells” and “exerted cytotoxic effects on human and
rat mammary cancer cells in vitro.” Abstract.
The examiner believes that “it would have been obvious to one having ordinary skill
in the art at the time the invention was made to replace the alkylating agent, Chl in the
peptide sequence of Channabasavaiah with another alkylating agent [such] as D-Mel such
that a peptide with high affinity to cancer receptor cells is obtained as per the teachings of
Appeal No. 1996-2431
Application 08/008,186
6
Bajusz.” Examiner’s Answer, page 5. If we understand the examiner’s position correctly, it
is that it would have been obvious for one of ordinary skill in the art to conjugate D-Mel,
rather than Chl, to the amino acid at position six of one of Channabasavaiah’s analogs (for
example, [Dlys(Chlorambucil) ]-LRH)) to obtain a peptide with high affinity to cancer cells.6
Appellants point out that D-Mel replaces the amino acid at position six of Bajusz’s
“highly potent alkylating analogues,” rather than being conjugated to it. Brief, page 12.
Nevertheless, the examiner maintains that:
[T]he findings of Channabasavaiah i.e., conjugating an alkylating agent to D-
Lys at position 6 results in high bioactivity coupled with the teachings of
Bajusz that the presence of an alkylating agent, Mel or Chl, at position six . . .
of the LHRH sequence, even in an unconjugated form, results in increase in
bioactivity would certainly motivate a person skilled in the art to make the
modification called for by the claims (Examiner’s Answer, page 10).
In our view, Bajusz’s observations are of little relevance in establishing a nexus
between conjugating an alkylating agent to position six of an LHRH analog and replacing
position six of the LHRH analog with the same (or a related) alkylating agent. As
discussed above, Bajusz teaches that replacing amino acid position six with D-Mel
produces highly potent alkylating analogs of LH-RH with high affinities for cancer cell
membrane receptors. On the other hand, the reference teaches that compounds
“prepared by linking Chl, as an N-Acyl moiety, to the complete amino acid sequence of
agonistic and antagonistic analogues . . . showed much lower potency than their
Appeal No. 1996-2431
Application 08/008,186
Contrary to appellants’ arguments in the Brief (e.g., page 12), this portion of3
Bajusz appears to refer to the effects of conjugating Chl to the N-terminal amino acids of
LHRH agonist and antagonist analogs, not to the effects of conjugating Chl to position six
of LHRH analogs.
7
congeners carrying other acyl groups.” Abstract. Neither teaching suggests anything,3
negative or positive, about the effects of conjugating D-Mel to position six of the analogs.
It is well settled that the initial burden of establishing unpatentability rests on the
examiner, In re Oetiker, 977 F.2d 1443, 1446, 24 USPQ2d 1443, 1445 (Fed. Cir. 1992).
As stated in Pro-Mold & Tool Co. v. Great Lakes Plastics, Inc., 75 F.3d 1568, 1573, 37
USPQ 1626, 1629, (Fed. Cir. 1996) (citation omitted):
[B]efore a conclusion of obviousness may be made based on a combination
of references, there must have been a reason, suggestion, or motivation to
lead an inventor to combine those references.
In our judgment, the examiner’s proposed reasons for combining Channabasavaiah and
Bajusz are not sufficient to support a conclusion of obviousness. This insufficiency is not
remedied by any of the remaining references relied on by the examiner.
Appeal No. 1996-2431
Application 08/008,186
Having determined that a prima facie case of obviousness has not been4
established, we do not find it necessary to comment on the declaration of Dr. Tetsu Yano
(submitted July 31, 1995, under 37 CFR § 1.132), or appellants’ arguments regarding
unexpected results attributable to an embodiment of the present invention.
8
Accordingly, we find that the examiner’s initial burden of establishing a prima facie
case of obviousness has not been met. On this record, we reverse the rejections of the
claims under 35 U.S.C. § 103. 4
REVERSED
)
SHERMAN D. WINTERS )
Administrative Patent Judge )
)
)
) BOARD OF PATENT
DOUGLAS ROBINSON )
Administrative Patent Judge ) APPEALS AND
)
) INTERFERENCES
)
TONI R. SCHEINER )
Administrative Patent Judge )
Appeal No. 1996-2431
Application 08/008,186
9
Omri M. Behr
325 Pierson Avenue
Edison, NJ 08837