Ex Parte Neuberger et al

Board of Patent Appeals and Interferences

Sep 25, 2002

08469786 (B.P.A.I. Sep. 25, 2002)

1 Application for patent filed June 6, 1995. According to appellants, this
application is a continuation of application no. 08/185,440, filed January 24, 1994, now
abandoned, which is a continuation of application no. 07/994,078, filed December 17,
1992, now abandoned, which is a continuation of application no. 07/489,207, filed
March 6, 1990, now abandoned, which is a continuation of application no. 06/865,816,
filed May 2, 1986, now abandoned.
The opinion in support of the decision being entered today was not written
for publication and is not binding precedent of the Board.
Paper No. 45
UNITED STATES PATENT AND TRADEMARK OFFICE
__________
BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________
Ex parte MICHAEL S. NEUBERGER and TERRENCE H. RABBITTS
__________
Appeal No. 1999-1355
Application No. 08/469,7861
__________
ON BRIEF
__________
Before WINTERS, WILLIAM F. SMITH 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 35
through 47, all the claims remaining in the application.
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Claims 35 and 42 are representative of the subject matter on appeal and read as
follows:
35. A chimeric antibody comprising an Ig moiety having antigen binding activity
and a non-Ig protein moiety comprising a protein having biological activity or a
biologically active portion thereof, wherein said non-Ig protein moiety is carboxy
terminal to said Ig moiety, said chimeric antibody having said antigen binding activity
and said biological activity.
42. A process for the production of a chimeric antibody comprising an Ig moiety
having antigen binding activity and an non-Ig protein moiety comprising a protein having
biological activity or a biologically active portion thereof, wherein said non-Ig protein
moiety is carboxy terminal to said Ig moiety, said chimeric antibody having said antigen
binding activity and said biological activity, said process comprising;
i) preparing a replicable expression vector comprising a promoter operably linked
to a DNA sequence comprising a first part encoding at least a variable region of an
antigen-binding Ig polypeptide chain and a second part 3' of said first part encoding a
biologically functional non-Ig protein, or a biologically active portion thereof, wherein
said first and second parts are combined such that expression results in a product
possessing said variable region capable of binding antigen and said non-Ig protein
capable of exhibiting its biological function as expressed;
ii) transforming an immortalized mammalian cell line that secretes an Ig
polypeptide chain complementary to the variable region encoded in said DNA sequence
with said vector; and
iii) culturing the transformed cell line under conditions such that said DNA
sequence is expressed and such that assembly of said chimeric antibody is effected so
that said variable region is immunologically active and said non-Ig protein moiety is
biologically functional.
The references relied on by the examiner are:
Hopp et al. (Hopp) 4,703,004 Oct. 27, 1987
Cabilly et al. (Cabilly) 4,816,567 Mar. 28, 1989
Lehninger, in Biochemistry, Worth Publishers, Inc., New York, NY, page 125 (1970)
Neuberger, “Expression and Regulation of Immunoglobulin Heavy Chain Gene
Transfected into Lymphoid Cells,” The EMBO Journal, Vol. 2, No. 8, pp. 1373-1378
(1983)
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Claims 35-47 stand rejected under the first paragraph of 35 U.S.C. § 112 as not
enabled throughout their scope by the specification. In addition, claims 35-41 stand
rejected under 35 U.S.C. § 103 as unpatentable over Neuberger, Cabilly and Hopp,
while claims 42-47 stand rejected under 35 U.S.C. § 103 as unpatentable over
Neuberger and Hopp.
We reverse all three of the rejections.
DISCUSSION
Enablement
In its broadest aspect, the claimed invention is directed to a chimeric protein (and
methods of making it) comprising an immunoglobulin moiety “having antigen binding
activity” and a non-immunoglobulin protein moiety “having a biological activity,” wherein
the non-immunoglobulin moiety is “carboxy terminal to” the immunoglobulin moiety, and
the chimeric protein “[has] said antigen binding activity and said biological activity.”
Claim 1. According to the examiner, however, the specification “is enabling only for
claims limited to chimeric antibodies which comprise a biologically functional non-Ig
protein for which working examples are disclosed in the specification.” Answer, page 6.
At the outset, we note that the examiner has applied this rejection to all of the
claims on appeal, even claims 38-41, which specify that the non-Ig portion of the hybrid
protein is RNase, the Klenow fragment of DNA polymerase I, ricin or c-myc. Inasmuch
as these claims correspond to the working examples, and the examiner has conceded
that the specification is enabling for “chimeric antibodies which comprise a biologically
functional non-Ig protein for which working examples are disclosed in the specification,”
the continued rejection of claims 38-41 on the ground of lack of enablement is illogical
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on its face. That being said, for reasons which follow, we find that the rejection is
without merit for the broader claims as well.
“When rejecting a claim under the enablement requirement of section 112, the
PTO bears an initial burden of setting forth a reasonable explanation as to why it
believes that the scope of protection provided by that claim is not adequately enabled
by the description of the invention provided in the specification of the application.” In re
Wright, 999 F.2d 1557, 1561-62, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993). “[T]o be
enabling, the specification of a patent must teach those skilled in the art how to make
and use the full scope of the claimed invention without ‘undue experimentation’” Id. at
1561, 27 USPQ2d at 1513. “That some experimentation may be required is not fatal;
the issue is whether the amount of experimentation is ‘undue.’” In re Vaeck, 947 F.2d
488, 495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991) (emphasis in original).
“Whether undue experimentation is needed is not a single, simple factual
determination, but rather is a conclusion reached by weighing many factual
considerations.” In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir.
1988). Among these considerations are the so-called Wands factors, including “(1) the
quantity of experimentation necessary, (2) the amount of direction or guidance
presented, (3) the presence or absence of working examples, (4) the nature of the
invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the
predictability or unpredictability of the art, and (8) the breadth of the claims.” Id.
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The examiner indirectly touches on a few of the Wands factors (Answer, pages 7
and 8), arguing that
[D]isclosure of three functional chimeric antibodies is insufficient evidence
to support the present claims as to all chimeric antibodies prepared from
all non-Ig proteins as being functional.
The specification examples, while differing structurally and functionally,
are not representative of all classes of non-Ig protein moieties nor that
when coupled to an Ig, that the chimeric protein would have retained the
properties of both parts of the chimeric protein . . .
[T]he biological activity [and] function of a protein are greatly dependent
upon its three-dimensional configuration . . . and [ ] even minor changes in
the sequence of a protein may adversely affect its ability to fold properly.
Changes in DNA sequence may alter the ability of a transfected cell to
express, secrete and properly assemble the protein. The present
application disclosure does not disclose nor guide one skilled in the art . . .
as to the parameters that affect and/or effect the predictability of the
retention of biological activity and function for both the non-Ig segment
and the Ig segment of the chimeric protein. The indicia of certainty is not
apparent in the application as filed. Thus, one of skill in the art . . . would
not have been able to predict with certainty or even a priori that
biologically active and functional chimeric antibodies would have been
produced from all expression constructs.
This argument is not persuasive for several reasons. To the extent that the
examiner requires “certainty” to demonstrate enablement, we note that no authority has
been cited in support of this requirement. On the contrary, a requirement for certainty
would be incompatible with any amount of experimentation and therefore incompatible
with the standard of enablement discussed above. Nor is it the function of the claims to
specifically exclude possibly inoperative embodiments - only if the number of
inoperative embodiments becomes significant, and in effect forces one of ordinary skill
in the art to experiment unduly in order to practice the claimed invention, might the
claims be invalid. See Atlas Powder Co. v. E.I. Du Pont De Nemours & Co., 750 F.2d
1569, 1576-77, 224 USPQ 409, 414 (Fed. Cir. 1984).
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We accept, for the sake of argument, that many chimeric proteins will not fold
properly, will not function properly, and may not be secreted properly, and that a certain
amount of experimentation would be required to identify those that will. But quantity of
experimentation is only one factor in determining whether the experimentation is undue.
Others factors are the amount of direction or guidance presented, and the presence or
absence of working examples. Here, the fact that the specification demonstrates the
successful production of several different hybrid proteins comprising antibodies joined
to members of several different protein classes (Specification, Examples 1-5, pages 12-
28) weighs heavily in favor of a finding of enablement for claims broader than the
working examples. The examiner’s summary dismissal of the examples as “not
representative of all classes of non-Ig protein moieties” is not evidence, and does not
provide a reasonable basis to question the adequacy of the disclosure provided for the
claimed invention.
In our judgment, the reasons cited in support of the examiner’s rejection are
insufficient to support the examiner’s conclusion that “the present specification does not
enable the scope of the claims” (Answer, page 10).
Accordingly, the rejection of claims 35-47 under the first paragraph of 35 U.S.C.
§ 112 is reversed.
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2 The examiner’s wording here is somewhat misleading - Hopp does not disclose
antibody-toxin hybrids, rather, the reference describes hybrids between “selected
proteins” and “identification peptides.” The selected protein portion of the hybrid may
be an antibody or a toxin, but the reference does not describe an antibody connected to
a toxin - instead, each is connected to an identification peptide. See, e.g., column 5,
lines 9-15 and column 6, lines 55-58.
Obviousness
All of the claims on appeal stand rejected under 35 U.S.C. § 103. With respect
to claims 35-41, the examiner relies on Neuberger, Cabilly and Hopp as evidence of
obviousness; with respect to claims 42-47, the examiner relies on Neuberger and Hopp.
Neuberger and Cabilly are cited principally to establish that recombinant
antibodies were known in the art at the time of the invention. Neither reference
describes antibody-non-antibody hybrid proteins, and the examiner relies on Hopp as
evidence that “the production of hybrid proteins was known in the art.” Answer, page
11. According to the examiner, Hopp “teach[es] the synthesis of hybrid proteins
including antibodies . . . and for example, toxic proteins . . . by recombinant DNA
techniques” and “also disclose[s] vectors encoding identification peptides and cleavable
linker sequences that facilitate[ ] purification of desired proteins.” Id.2
In the examiner’s opinion, it would have been obvious “to have modified the
teachings of either [Neuberger or Cabilly] by transfecting cells with vectors containing
hybrid immunoglobulin genes as taught by [Hopp] in order to obtain bifunctional
chimeric antibodies containing as part of that antibody, an identification peptide where
any peptide protein is an identification peptide.” Answer, page 11.
“[T]he examiner bears the initial burden of presenting a prima facie case of
obviousness. Only if that burden is met does the burden of coming forward with
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evidence or argument shift to the applicant.” In re Rijckaert, 9 F.3d 1531, 1532, 28
USPQ2d 1955, 1956 (Fed. Cir. 1993). “Measuring a claimed invention against the
standard established by section 103 requires the oft-difficult but critical step of casting
the mind back to the time of the invention, to consider the thinking of one of ordinary
skill in the art, guided only by the prior art references and the then-accepted wisdom in
the field.” In re Dembiczac, 175 F.3d 994, 999, 50 USPQ2d 1614, 1617 (Fed. Cir.
1999).
On this record, we find that the examiner’s initial burden of presenting a prima
facie case of obviousness has not been met. Hopp describes “[a] hybrid molecule
composed of a selected . . . protein and an identification or marker peptide,” wherein
“[t]he identification peptide ideally includes two primary components: a highly antigenic
N-terminal portion; and, a linking portion to connect the identification peptide to the
protein . . . [which] is characterized by being cleavable at a specific amino acid residue
adjacent the protein molecule by use of a sequence specific proteolytic agent.” Column
2, lines 53-63. The “selected protein” portion of Hopp’s hybrid “may be . . . substantially
any . . . protein that can be expressed by a vector in a transformed host cell,” including
an enzyme, a storage protein, a transport protein, an antibody, a hormone, a toxin, etc.
Column 6, line 55 to column 7, line 25.
Whether or not Hopp’s hybrid molecule can be considered to be a hybrid
between a biologically functional non-immunoglobulin protein and an immunoglobulin is
an open question, and one we need not answer here. It is enough to note that the
examiner has failed to come to grips with fact that all of the claims on appeal require
that the non-immunoglobulin protein moiety of the hybrid protein be connected to the
carboxy terminus of the immunoglobulin moiety.
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Hopp explicitly states that “[t]he identification peptide is . . . a linear sequence of
amino acids bonded to the N-terminus of the protein of interest” (emphasis added) and
“is composed of two basic portions: an antigenic N-terminus or ‘head’ portion; and a
linking or ‘tail’ portion to link the identification peptide to the selected protein molecule.”
Column 5, lines 9-15. The linking portion of the identification peptide is “composed of a
sequence of amino acids ending with either Lys, Arg, Met or Asn, so that “a proteolytic
enzyme that cleaves after the Arg or Lys residue can be used . . . or an appropriate
chemical agent that cleaves after [Met or Asn] may be employed to sever the
identification peptide from the protein molecule” (Column 6, lines 4-12), “ideally at the
residue adjacent the N-terminus of the protein molecule” (Column 5, lines 51-55).
“By this particular construction of the identification peptide, the hybrid . . . molecules
expressed by the transformed host cells can be isolated by affinity chromatography
techniques . . . [and] the identification peptide [can be] cleaved from the protein
molecule . . . releasing the desired, highly purified protein.” Column 2, line 63 to
column 3, line 7. Clearly, the orientation of the two moieties of the protein-peptide
hybrid is dictated by Hopp’s ultimate goal: isolation and purification of the selected
protein.
In responding to appellants’ comments on this issue, the examiner argues
(Answer, page 24) that
One of ordinary skill in the art would have known that the genetic material
encoding the immunoglobulin constant region is 3' to the genetic material
encoding the variable region of an antibody chain . . . [and] would have
constructed the gene of the Ig-protein chimera analogous to the structure
of the Ig gene constructs containing the variable and constant region gene
segments . . . since anyone of ordinary skill in the art would also have
known that a functional antibody has a variable region domain in the
protein that is antigen specific and [Hopp] as well as each of [Neuberger]
or [Cabilly] teach maintenance of that variable region antigen binding
domain.
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. . . It is also known in the art that linkage of the polynucleic acid segment
encoding the non-Ig protein moiety to the 5' end of the genetic construct
encoding the variable segment . . . would have been expected to interfere
with the antigen binding site . . .

The examiner concludes that “no one of ordinary skill in the art having the references
would have put the identification peptide where appellant asserts especially where the
combined references are directed to producing and disclosure of bifunctional
antibodies.” Answer, page 24. This presupposes that one would have had a reason to
modify Hopp (or Neuberger or Cabilly) in the first place - something the examiner has
not established.
“It is impermissible to use the claimed invention as an instruction manual or
‘template’ to piece together the teachings of the prior art so that the claimed invention is
rendered obvious.” In re Fritch, 972 F.2d 1260, 1266, 23 USPQ2d 1780, 1784 (Fed.
Cir. 1992), citing In re Gorman, 933 F.2d 982, 987, 18 USPQ2d 1885, 1888 (Fed. Cir.
1991). The examiner may establish a case of prima facie obviousness based on a
combination of references “only by showing some objective teaching in the prior art or
that knowledge generally available to one of ordinary skill in the art would lead that
individual to combine the relevant teachings of the references.” Id., 972 F.2d 1260,
1265, 23 USPQ2d 1780, 1783 (Fed. Cir. 1992).
On this record, the only reason or suggestion to combine the references in the
manner claimed comes from appellant’s specification. Accordingly, the rejection of
claims 35-47 under 35 U.S.C. § 103 is reversed.
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CONCLUSION
On consideration of the record, we have reversed the rejection of the claims
under the first paragraph of 35 U.S.C. § 112, as well as the rejections of the claims
under 35 U.S.C. § 103.
REVERSED
)
Sherman D. Winters )
Administrative Patent Judge )
)
)
) BOARD OF PATENT
)
William F. Smith ) APPEALS AND
Administrative Patent Judge )
) INTERFERENCES
)
)
)
Toni R. Scheiner )
Administrative Patent Judge )
Appeal No. 1999-1355
Application No. 08/469,786
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Doreen Yatko Trujillo
Woodcock, Washburn, Kurtz,
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