Ex Parte Cederholm-Williams

Board of Patent Appeals and Interferences

Feb 4, 2008

09334325 (B.P.A.I. Feb. 4, 2008)

UNITED STATES PATENT AND TRADEMARK OFFICE
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BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
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Ex parte STEWART A. CEDERHOLM-WILLIAMS
__________

Appeal 2008-1157
Application 09/334,325
Technology Center 1600
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Decided: February 4, 2008
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Before DONALD E. ADAMS, ERIC GRIMES, and JEFFREY N.
FREDMAN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of transforming cells, which the Examiner has rejected on grounds of lack of
enablement. We have jurisdiction under 35 U.S.C. § 6(b). We reverse.

Appeal 2008-1157
Application 09/334,325

BACKGROUND
The Specification notes that “a wide variety of viral vectors have been
selected or engineered for gene therapy. Moreover, nucleic acid can be
delivered successfully without the use of viral vectors” (Specification 12).
According to the Specification, “[s]imilarly, nucleic acid-based vaccines
seek to induce a percentage of cells to produce immune-reaction inducing
polypeptides, to induce an antibody-based or cellular-based immune
response” (Specification 1). Separately, the Specification teaches that
“[f]ibrin sealants are used to create solid formulations of polymerized fibrin
or other fibrin-related molecules” (Specification 1).
Appellant teaches “compositions of fibrin sealants that incorporate
recombinant vectors for delivery to a tissue or cell against which the sealant
will be polymerized and, typically, adhered” (Specification 2). Appellant
notes that with the use of fibrin sealants “the vectors can be maintained at a
locally at [sic] high concentration in the solid gel produced by the sealant,
thereby increasing the efficiency of transfection or transformation of cells”
(Specification 2).
STATEMENT OF THE CASE
The Claims
Claims 1 and 13-16 are on appeal. Claims 13-16 have not been
argued separately and therefore stand or fall with the representative claim.
37 C.F.R. § 41.37(c)(1)(vii). We will focus on claim 1 which is
representative and reads as follows:
1. A method of transforming a cell comprising, in order, the
steps of: applying a transformation effective amount of a
nucleic acid to the cell; and adhering a pliable, adhesive
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fibrin gel to the cell so as to entrap the transformation
effective amount of the nucleic acid in the fibrin gel adhered
to the cell and thereby transforming the cell with the nucleic
acid.

The Examiner has rejected claims 1 and 13-16 under 35
U.S.C. § 112, first paragraph based on:
Donovan U.S. Patent 5,833,651 November 10, 1998
Schek et al., Delivery and Protection of Adenoviruses using biocompatible
hydrogels for localized gene therapy, 9 Molecular Therapy 130-138 (2004)
(hereinafter “Schek”).

Deonarain, Ligand-targeted receptor-mediated vectors for gene delivery, 8
Expert Opinion on Therapeutic Pat. 53-69 (1998) (hereinafter “Deonarain”).

Verma and Somia, Gene therapy – promises, problems and prospects, 389
Nature 239-242 (1997) (hereinafter “Verma”).

Stephen L. Eck and James M. Wilson, Gene based Therapy, in The
Pharmacological Basis of Therapeutics, 77-101 (1996) (hereinafter “Eck”).

Gorecki, Prospects and problems of gene therapy: an update, 6 Expert
Opinion on Emerging Drugs 187-198 (2001)(hereinafter “Gorecki”).

The Issue
The Examiner’s position is that the
specification fails to provide adequate guidance and
evidence for transforming a cell in vitro or in vivo by
applying a nucleic acid, such as a vector or a virus carrying
the nucleic acid, to the cell first and then applying a pliable,
adhesive fibrin gel to said cell so as to transform the cell in
vitro or in vivo at any location of any subject via various
administration routes.

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(Answer 4.) The Examiner concedes that the “method as taught by
Don[o]van to transform a cell in vivo is enabled, however, the method to
transform a cell in vivo as claimed in the instant invention, which is different
from the method taught by Don[o]van and by the state of the art, is not
enabled” (Answer 12).
According to the Examiner, undue experimentation would be required
because the claimed invention “must provide such a high concentration of
the vector in order to increase the efficiency of the transformation of the
cells in vitro or in vivo in the claimed invention” (Answer 15).
Appellant responds that the
rejection suggests that Appellant's invention must “increase
or enhance cell transformation efficiency”. That is not a
requirement of the patent law either. The rejection further
indicates that Appellant must show every possible way to
administer his invention. And that is not a requirement of
the patent law. Accordingly, Appellant submits that this
rejection, whether under 35 U.S.C. §112 or §101, is without
merit.

(App. Br. 4.)
In view of these conflicting positions, we frame the issue before us as
follows:
Would undue experimentation have been required to apply the nucleic
acid prior to application of the fibrin gel in order to result in transfection of
the nucleic acid into the cells?
FINDINGS OF FACT
1. Donovan teaches that a “stent can be loaded with virus by
mixing the monomer solution of the first polymer composition with virus or
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by directly applying the virus to the polymerized composition” (Donovan,
col. 13, ll. 10-13).
2. Donovan claims a “method for delivering nucleic acid to cells
. . . comprising the steps of: providing a stent comprising . . . a first polymer
composition comprising fibrin . . . and virus comprising nucleic acid
associated with the first polymer composition wherein the stent is capable of
delivering nucleic acid to cells” (Donovan, claim 21 and col. 20, ll. 36-45).
3. Donovan notes that over “14 days, the stents released
approximately 50% of the loaded titer with the greatest release from about 1
to about 3 days. The functionality of this virus was confirmed by infecting
aortic smooth muscle cells and demonstrating transgene function”
(Donovan, col. 18, ll. 22-26).
4. Donovan cites U.S. Patent 5,510,077 to Dinh on incorporation
of drugs into fibrin coated stents (see Donovan, col. 15, ll. 57-60).
5. Schek teaches “we implanted virus containing hydrogels in the
quadriceps muscles of mice. We also implanted virus suspended in liquid to
serve as a comparison.” (Schek, p. 134, col. 1 and 2).
6. Schek teaches that the “volume of the ossicles that were formed
using virus in fibrin was significantly larger than that of those formed using
either collagen or liquid” (Schek, p. 134, fig. 5 legend).
7. Schek teaches that “[i]n vitro infection data demonstrated that
virus released from either gel was at least as effective as virus suspended in
liquid medium at transducing cells” (Schek, p. 134, col. 2).
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8. Eck teaches “[a]s of 1995, three gene transfer systems
(retroviral vectors, adenoviral vectors, and liposomes) had been used in
human gene therapy” (Eck, p. 83, col. 1).
9. Eck identifies a number of factors relevant to gene therapy,
including efficiencies in distribution of vectors, uptake of vectors and
expression of nucleic acids and proteins once inside cells (see Eck, p. 82,
col. 1).
10. Verma teaches that as of 1997, there was no successful gene
therapy outcome (Verma, p. 239, col. 1).
11. Verma teaches that the “Achilles heel of gene therapy is gene
delivery . . . the problem has been an inability to deliver genes efficiently
and to obtain sustained expression” (Verma, p. 239, col. 3).
12. Deonarain recognizes that “this approach to gene delivery is
much less efficient than viral gene delivery. However, under optimal
conditions, enough gene product may be produced to give a therapeutic
benefit” (Deonarain, p. 65, col. 1).
Discussion
There is no dispute that both the Specification and prior art teach
mixtures of fibrin and nucleic acid which will function to transform cells (FF
1-7). One argument relates to the scope of the phrase “applying a
transformation effective amount of a nucleic acid to the cell” in claim 1.
The Examiner contends that the scope of “applying” in claim 1 will
“encompass transforming cells in vivo via various administration routes,
such as intravenous administration, intraperitoneal administration, oral
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administration, subcutaneous administration, and intramuscular
administration” (Answer 6).
In analyzing the phrase “applying a transformation effective amount
of a nucleic acid to the cell” in claim 1, our mandate is to give claims their
broadest reasonable interpretation. “During patent examination the pending
claims must be interpreted as broadly as their terms reasonably allow.” In re
Zletz, 893 F.2d 319, 321 (Fed. Cir. 1989).
Regarding the “applying” phrase, the Specification teaches that the
method can be performed ex vivo (see Specification 2, ll. 28-31). Among
the different ways to “apply” that might fall within the scope of the claims,
the Specification teaches that the method can be performed by “surgically
exposing the tissue to allow for the applying steps” (Specification 3, ll. 7-8).
The Specification teaches performing surgery on an animal and exposing the
tissue in order to perform the application step (see Specification 3, ll. 9-15).
The Specification teaches forming recombinant cells which are then
implanted into animals (Specification 4, ll. 8-13). Lastly, the Specification
contemplates spraying the nucleic acid and the sealant onto the recipient
surface (Specification 17, ll. 28-31). The Specification recognizes that the
sealant mixture is pliable for 30 seconds or less (Specification 17, ll. 16-17).
A reasonable construction of the “applying” phrase of claim 1 in light
of the teachings of the Specification is that there must be a direct application
of the nucleic acid and then the fibrin to a cellular target. One of the
Examiner’s concerns appears to be the indirect application of the nucleic
acid followed by subsequent administration of the fibrin, for example that
the nucleic acid is introduced intravenously and targeted to a cell type by
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known techniques and then the fibrin is introduced and is unable to target to
the same location to which the nucleic acid was addressed.
However, the Specification never teaches or contemplates indirect
application modes. Further, the ordinary practitioner would not interpret
“applying” as including intravenous administration since the practitioner
would recognize that introducing fibrin into the bloodstream would cause a
clot, which would be expected by the ordinary practitioner to result in
stroke, cardiac arrest or other undesirable sequelae. With regard to the other
modes of administration listed by the Examiner, either surgical incision or
sequential spraying of the components with a spray head as envisioned by
the Specification would permit some forms of intraperitoneal administration,
oral administration, subcutaneous administration or intramuscular
administration, and the ordinary practitioner would immediately recognize
that some modes of administration would result in undesirable morbidity and
mortality (see Specification, p. 17, ll. 8-19). See Atlas Powder Co. v. E.I. du
Pont De Nemours & Co., 750 F.2d 1569, 1576 (Fed. Cir. 1984) (“Even if
some of the claimed combinations were inoperative, the claims are not
necessarily invalid. ‘It is not a function of the claims to specifically exclude
... possible inoperative substances....’”).
We have no reason to doubt the Examiner's assessment of the state of
the art in general, and we think it is fair to say that the field of gene therapy
is indeed recognized as highly unpredictable by those of skill in the art (see
Answer 8). However, we are not persuaded by the Examiner’s argument
that the “claims read on applying a nucleic acid to cells in vivo so as to
transform cells and the transformation of cells in vivo must have a use,
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which is to provide therapeutic effect in vivo” (Answer 8). We interpret the
Examiner’s argument as an attempt to interpret the claims to require an in
vivo therapeutic effect from the current claims. First, this argument would
be more properly raised as a scope of enablement issue. Second, both the
claim and the art cited by the Examiner do not support the conclusion drawn
in the rejection. The claim is broadly drawn to transforming cells and no
therapeutic benefit is required in the claim. The claim encompasses
transformations done in vitro, ex vivo and in vivo. While the Examiner does
not concede that the method would function in vitro or ex vivo, there is no
scientific reasoning or evidentiary support in the Answer for the proposition
that ordinary infection of tissue culture plates with viruses, or calcium
phosphate transformations, or other known in vitro or ex vivo transformation
methods would be negatively impacted by spraying fibrin on top of the
transformation mixture. There is evidence that fibrin will not impact
infection when premixed with the virus (FF 1-7). Therefore, we disagree
with the Examiner’s intimation that there is no use for the claimed invention.
The scope of the claimed invention encompasses in vitro and ex vivo
utilities that would be clearly expected to function according to the claimed
invention.
We also disagree with the Examiner’s argument that “[t]here is no
evidence of record that shows increased or enhanced efficiency of cell
transformation by the claimed method either in vitro or in vivo via various
administration routes” (Answer 12). This argument, repeated through the
Answer, presupposes that there is a requirement for the invention to have
improved or enhanced efficiency (see, e.g., Answer 14-15). However, the
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Federal Circuit has noted that “[f]inding that an invention is an
‘improvement’ is not a prerequisite to patentability. It is possible for an
invention to be less effective than existing devices but nevertheless meet the
statutory criteria for patentability.” Custom Accessories, Inc. v. Jeffrey-
Allan Industries, Inc., 807 F.2d 955, 960 (Fed. Cir. 1986).
Also, the art cited by the Examiner does not support a conclusion that
gene transfer will not occur during in vivo administrations following the
disclosure of the method (see FF 8-12). At best, the art cited demonstrates
that therapeutic gene therapy is unpredictable and would require undue
experimentation (see FF 10-11). If the claim were drawn to therapeutic gene
therapy, or included a step or steps which required some therapeutic benefit,
this argument might have some significant force. However, while the claims
broadly encompass therapeutic gene therapy and the Specification
contemplates in vivo therapeutic gene therapy, this is only one of the uses of
the claimed method (see Specification 3, ll. 3-25). Thus, while the claims
read on gene therapy methods, they do not require producing a clinically
effective therapeutic response. See In re Cortright, 165 F.3d 1353 (Fed. Cir.
1999) (claims to a method of “treating scalp baldness” could be enabled
even if the method did not produce a full head of hair).
In addition, the post filing date art cited by the Examiner
demonstrated some therapeutic effect, in that intramuscular injection of a
liquid containing a viral vector functioned to transform cells and induced
ossicle formation (see Schek, p. 134, col. 2). Schek also demonstrated that
when the liquid containing virus was premixed with fibrin, the level of bone
formation increased (see Schek, fig. 5). We find that the ordinary
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practitioner would therefore expect that if liquid containing the virus alone
functioned in transformation, and fibrin mixed with liquid functioned better,
that the method where liquid is injected first and the injection site is then
coated with fibrin would reasonably be expected to work at least as well as
liquid alone, even if not as well as when premixed with fibrin. This
evidence of Schek contradicts the Examiner’s enablement position, since it
shows that in vivo, the transformed virus functioned to cause a significant
biological effect (see Schek, p. 134, col. 2).
Based on the above, we conclude the Examiner has not made a prima
facie case of lack of enablement under 35 U.S.C. § 112, first paragraph (FF
1-12).
CONCLUSION
In summary, we reverse the rejection of claims 1 and 13-16 under 35
U.S.C. § 112, first paragraph.
REVERSED

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