Ex Parte Avner

Board of Patent Appeals and Interferences

Apr 21, 2011

10295903 (B.P.A.I. Apr. 21, 2011)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte DAVID B. AVNER
__________

Appeal 2010-007973
Application 10/295,903
Technology Center 1600
__________

Before DEMETRA J. MILLS, ERIC GRIMES, and MELANIE L.
McCOLLUM, Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims “relate[d] to
transgenic cats wherein the gene sequences, coding for the major cat
allergen Fel d I, have been disrupted” (Spec. 1, ¶ 2). The Examiner has
rejected the claims as nonenabled. We have jurisdiction under 35 U.S.C.
§ 6(b). We affirm.
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STATEMENT OF THE CASE
Claims 21-32 are on appeal. The claims have not been argued
separately and therefore stand or fall together. 37 C.F.R. § 41.37(c)(1)(vii).
Claim 28 is representative and reads as follows:
28. A cat exhibiting a phenotype confererred by the reduction or lack
of a Fel d I protein in a cell of the cat, wherein the phenotype: (a) is a
reduced allergic response in a human to the cat, (b) is transmissible to
offspring of the cat, and (c) whose genome comprises a disrupted or
knocked-out Fel d I gene.
Issue
The Examiner has rejected claims 21-32 under 35 U.S.C. § 112, first
paragraph, as “not enabled because the art at the time of filing taught the
unpredictability in producing knockout mammals having a targeted
phenotype” (Answer 3). The Examiner finds that the Specification discloses
that the claimed transgenic cat can be made using either embryonic stem cell
technology or somatic cell nuclear transfer technology (id. at 4). The
Examiner concludes, however, that the Specification’s guidance and the
state of the art were inadequate to enable a skilled worker, as of the relevant
filing date, to use either approach to make the claimed transgenic cat without
undue experimentation (id. at 5-14).
Appellant contends that the Specification discloses detailed methods
for making the claimed transgenic cat through either embryonic stem cell
technology (Appeal Br. 15-16) or nuclear transfer techniques (id. at 16-17).
Appellant also contends that he has provided declaratory evidence showing
that the procedures set out in the Specification can be followed by those of
skill in the art to clone a cat (id. at 22-24) and showing that the amount of
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experimentation required to do so would be considered routine in the
relevant field (id. at 24-25).
The issue presented is: Does a preponderance of the evidence of
record support the Examiner’s conclusion that making the claimed
transgenic cat would have required undue experimentation?
Findings of Fact
1. The Specification discloses that “[u]sing, newly developed gene
targeting techniques it is possible to ‘knock-out’ the Fel d I genes in an
embryonic cell ie. Embryonic Stem (ES) Cells” (Spec. 2, ¶ 6).
2. The Specification reviews a variety of techniques that had been
described in the prior art that are relevant to generating and working with ES
cells (id. at 7, ¶ 38 to 32, ¶ 194).
3. The Specification states that “there are other cloning techniques
that can be used to create transgenic animals. One such technique that has
enjoyed recent success is nuclear transfer.” (Id. at 32, ¶ 196.)
4. The Specification describes in general terms the nuclear transfer
technique (id. at 33, ¶ 197).
5. The Specification does not provide any working examples.
6. The Examiner finds that making the claimed transgenic cat using
ES cell technology requires “germ line competent cat embryonic stem (ES)
cells” (Answer 5) because only germ line competent ES cells introduce
modified genetic information to the murine gene pool (id.).
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7. Gardner1 states that the “ability to form viable gametes . . . is the
key attribute of ES cells from the point of view of genetic manipulation”
(Gardner 235, right col.).
8. The Examiner cites Moreadith2 as evidence that, although putative
ES cells had been isolated from other species, “knockout technology in [ES
cells] was limited to mice” (id. at 6).
9. Moreadith states that the technology “to generate gain-of-function
and loss-of-function mutations in laboratory animals . . . is generally limited
only to the mouse at present” (Moreadith 214, left col.).
10. Moreadith states that “putative pluripotential ES cells” have been
derived from several other species; “[t]hus it seems likely the technology
will be advanced into these additional species over the next few years” (id.).
11. The Examiner cites Gardner as disclosing that ES cells from
several species other than mice showed no evidence of germ line
colonization (Answer 6).
12. Gardner states that “[a]s yet, it is only in the mouse that lines of
ES cells which retain the ability to form gametes following reintroduction
into the early conceptus have been obtained” (Gardner, abstract).
13. Gardner states:
That problems have been encountered in attempting to derive
ES lines in mammals other than the mouse is perhaps not
surprising since, in essence, what has been done is simply to
apply the strategy devised for deriving ES cells in the mouse to

1 R. L. Gardner, Reflections on the Biology of Embryonic Stem (ES) Cells, 41
INT. J. DEV. BIOL., 235-243 (1997)
2 R. W. Moreadith et al., Gene Targeting in Embryonic Stem Cells: The New
Physiology and Metabolism, 75 J. MOLECULAR MED., 208-216 (1997)
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these other species. Even in the mouse . . . the present strategy
has proved successful in only a very limited number of strains.
(Id. at 235, right col.)
14. The Examiner finds that “there was little prediction in the art at
the time of filing that germ line competent cat ES cells could readily be
obtained without an undue amount of experimentation” (Answer 7).
15. With regard to nuclear transfer, the Examiner finds that “[a]t the
time of filing, the art taught that such methodology was generally
unpredictable, and while some species had been cloned, the particular
methodology for one species is not transferable to another species” (id.).
16. The Examiner cites Pennisi3 as evidence that “[a]ttempts to clone
pigs using techniques successful in sheep were not successful; indicating
that cross-species application of methodology is unpredictable” (id. at 8-9).
17. Pennisi discloses that “[i]n all species, the basic hurdles [to
successful cloning] are the same, but the details differ sufficiently that each
species has gotten sidetracked at different points along the way to becoming
a commercially or medically useful clone” (Pennisi 1722, right col.).
18. Pennisi discloses that “PPL spent more than a year trying to clone
pigs with the techniques . . . used for sheep. Each attempt failed. . . . Then 2
years ago, company scientists junked that approach and hit upon an entirely
new—and apparently successful—one.” (Id. at 1725, left-to-middle cols.)
19. The Examiner cites Pennisi as evidence that efforts to clone cats
had not been successful (Answer 9).

3 E. Pennisi et al., Clones: A Hard Act to Follow, 288 SCIENCE, 1722-1727
(2000),
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20. Pennisi reports that a Japanese team and several groups in the
United States were pursuing research to clone cats but no cloned cats had yet
been produced (Pennisi 1726 (box), right col.).
21. The Examiner finds that “the production of cloned mammals
whose genomes had been genetically modified, as the claimed cat’s genome,
were even more unpredictable for cloning success” (Answer 10).
22. Pennisi states that the “big problem” in gene targeting
was finding a way to insert the gene before the donor cells got
too old. Most cells can divide only a limited number of times
in culture, and gene targeting requires several steps in which
DNA is inserted and the few select cells that incorporate it into
their chromosomes are allowed to multiply until there are
enough for the next modification. “By the time you go through
and get a large enough population, it’s really pushing the limits
[of the cells’ ability to divide],” says Robl of UMass.
(Pennisi 1723, right col., bracketed insert in original.)
23. Denning4 states that “the lifespan of primary cells in culture is a
critical issue; unlike ES cells and transformed cell lines, primary somatic
cells have a limited proliferative capacity. Genetic modification and
subsequent preparation for NT [nuclear transfer] must be accomplished
before the cells senesce or enter crisis and transform.” (Denning 222, left
col.)
24. The Examiner finds that “the art at the time of filing teaches that
the phenotype of any knockout animal is unpredictable. That is the
phenotype sought might not be the one obtained. . . . Thus, it would have

4 C. Denning et al., Gene Targeting in Primary Fetal Fibroblasts from Sheep
and Pig, 3 CLONING AND STEM CELLS, 221-231 (2001)
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been unpredictable that the cat claimed would be hypoallergenic.” (Answer
12-13.)
25. Appellant has filed a declaration under 37 C.F.R. § 1.132 of
David A. Avner (executed May 7, 2004).
26. Dr. Avner presents a “comparison of the protocols used by Mark
Westhusin, Ph.D. at Texas A&M University and the protocols used by
Transgenic Pets to produce cloned kittens through the process of nuclear
transfer” (Avner Declaration, ¶ 3).
27. Dr. Avner does not relate either of the protocols compared in the
declaration to protocols disclosed in the Specification or known in the art at
the time the instant application was filed.
28. Appellant has filed a declaration under 37 C.F.R. § 1.132 of Betsy
Dresser (executed Jan. 11, 2005).
29. Dr. Dresser states that she has been involved in the successful
cloning of African wildcats and that “the cloning of cats using nuclear
transfer techniques is both predictable and reproducible” (Dresser
Declaration, ¶¶ 1, 2).
30. Dr. Dresser states that the “basic steps used by our team . . . are
the same as those described by Dr. Avner in his published United States
patent application” (id. at ¶ 3).
31. Dr. Dresser states that the
steps are essentially the same steps as those that have been used
to clone other mammals and include:
A. Establishing a fibroblast or other diploid cell line . . .;
B. Synchronizing said diploid cells in cell line through
serum starvation . . .;
C. Collecting oocytes from donor female cats . . .;
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D. Removing the nucleus from an oocyte . . .;
E. Inserting or fusing the nucleus or cell . . . into/with
the enucleated oocyte;
F. Culturing oocytes . . . until they divide and become
blastocysts;
G. Transferring blastocysts . . . [into a] surrogate female
cat;
H. Allowing surrogate female to carry the pregnancy to
term;
I. Assisting in birth of cloned cat.
(Id.)
32. Appellant has filed a declaration under 37 C.F.R. § 1.132 of Mark
Westhusin (executed Jan. 19, 2004).
33. Dr. Westhusin states that he was “involved in the successful
cloning of a domestic cat” (Westhusin Declaration, ¶ 1).
34. Dr. Westhusin states that “[l]ike other mammals that are
successfully cloned using nuclear transfer techniques, it can take hundreds of
nuclear transfers to produce a single cloned cat. This number of nuclear
transfers is routine in the field.” (Id. at ¶ 2.)
35. The Examiner finds that “a clone is a copy or replica of a prior
existing animal. The presently claimed cats are not clones because they are
not a copy or a replica of a prior existing cat. While the presently claimed
cats can be produced by somatic cell nuclear transfer, they are not clones.”
(Answer 15.)
Principles of Law
“Patent protection is granted in return for an enabling disclosure of an
invention, not for vague intimations of general ideas that may or may not be
workable.” Genentech Inc. v. Novo Nordisk A/S, 108 F.3d 1361, 1366 (Fed.
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Cir. 1997). “It is the specification, not the knowledge of one skilled in the
art, that must supply the novel aspects of an invention in order to constitute
adequate enablement.” Id.
If mere plausibility were the test for enablement under section
112, applicants would obtain patent rights to “inventions”
consisting of little more than respectable guesses as to the
likelihood of their success. When one of the guesses later
proved true, the “inventor” would be rewarded the spoils
instead of the party who demonstrated that the method actually
worked. That scenario is not consistent with the statutory
requirement that the inventor enable an invention rather than
merely proposing an unproved hypothesis.
Rasmusson v. SmithKline Beecham Corp., 413 F.3d 1318, 1325 (Fed. Cir.
2005).
Analysis
Appellant claims as his invention a cat that has been genetically
modified to reduce or eliminate expression of the Fel d I antigen, thereby
reducing the allergic reaction caused by the cat in susceptible people.
Appellant’s Specification reviews techniques involving embryonic stem
(ES) cells and somatic cell nuclear transfer that were known in the art, and
discloses that these known techniques can be used to make the claimed
invention. The Specification does not provide any working examples
applying the disclosed techniques to successfully make a transgenic cat.
The Examiner, for her part, has provided substantial evidence that, as
of the effective filing date, a skilled worker would have had to carry out
undue experimentation to successfully apply the previously known
techniques to cats. Gardner states that it was “not surprising” that simply
applying the mouse techniques of deriving ES cells to other species was
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problematic (FF 13). Gardner states that, as of 1997, germ-line competent
ES cells – the key to genetic manipulation (FF 7) – had been successfully
produced only in mice (FF 12).
In addition, Moreadith discloses that using ES cells to generate
animals with expression of a specific gene knocked-out was successful only
in mice, at least as of 1997 (FF 9). While Moreadith stated that “it seems
likely” that the technology would be successful in other species “over the
next few years” (FF 10), Appellant cites no evidence showing that the
prediction of other transgenic animals with knocked-out genes proved to be
correct.
With regard to nuclear transfer techniques, the Examiner has provided
evidence showing that cloning cats was not a simple matter of applying the
same technique used to clone sheep. Pennisi discloses that applying cloning
techniques to different species faced “the same basic hurdles . . . but the
details differ sufficiently that each species has gotten sidetracked at different
points” (FF 17) and that the sheep techniques did not work to clone pigs (FF
18). Pennisi also discloses that efforts to clone cats had been unsuccessful
as of 2000 (FF 20). Finally, Pennisi and Denning provide evidence that,
even if cloning techniques were successfully applied to cats, genetically
modifying a cat cell, as required to make the claimed transgenic cat, before
transferring its nucleus into an enucleated egg required overcoming a further
hurdle, in that somatic cells will divide only a limited number of times
before dying (FFs 22, 23). Appellant has provided no evidence to show that
skilled workers in this field had successfully addressed this problem.
For his part, Appellant cites evidence tending to show that the somatic
cell nuclear transfer technique is enabled by the Specification. The
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Specification provides some guidance on the technique, albeit only a single
paragraph reviewing cloning that had been done in other animals (FF 4).
The Avner Declaration discusses a protocol that is similar to one that was
successfully used to clone a cat (FF 26), although it does not relate either
protocol to anything that was disclosed in the Specification (FF 27).
The Dresser Declaration states that its cat-cloning procedure uses the
“basic steps . . . described by” the instant application (FF 30). However, the
Dresser Declaration describes those steps in very general terms and as
“essentially the same steps as those that have been used to clone other
mammals” (FF 31), but the evidence of record shows that those “same steps”
cannot routinely be applied to different species (FF 17), and that the method
successfully used in sheep ultimately failed in pigs (FF 18).
The Westhusin Declaration states that a large number of nuclear
transfers can be required to produce a cloned cat, as with other animals
(FF 34). The experimentation described, however, presumes the existence
of a working cat-cloning protocol, and Dr. Westhusin does not address the
amount of experimentation required to adapt the known techniques reviewed
in the Specification to cats.
Finally, and critically, the Examiner has pointed out that the claims
are not directed simply to a cloned cat (FF 35); making the claimed
transgenic cat by somatic cell nuclear transfer would also require carrying
out genetic manipulation on somatic cells and selecting the cells with the
desired genetic modification (FF 22; Spec. 33, ¶ 197), before using those
cells or their nuclei in a nuclear transfer technique like that used in cloning.
The Examiner has provided evidence that such genetic manipulation is
inherently problematic, because somatic cells will only divide a limited
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number of times before they die (FFs 22, 23). None of Appellant’s evidence
addresses this additional problem that must be overcome, in addition to the
experimentation required for cloning, in order to make the claimed
transgenic cat.
Although Appellant cites several prior art references (Appeal Br. 18-
22) in support of his position, he does not adequately explain how the
disclosures of those references remedy the deficiencies of the Specification
or overcome the problems that are discussed in the references relied on by
the Examiner.
Conclusion of Law
When we weigh the evidence cited by the Examiner and the evidence
provided by Appellant, we conclude that a preponderance of the evidence of
record favors the Examiner’s conclusion that undue experimentation would
have been required to make the claimed transgenic cat as of the effective
filing date of the instant application.
SUMMARY
We affirm the rejection of claims 21-32 based on nonenablement.
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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