Ex Parte Atala et al

Patent Trial and Appeal Board

Dec 19, 2012

11048097 (P.T.A.B. Dec. 19, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte ANTHONY ATALA, AKIRA JORAKU,
CHRISTOPHER A. SULLIVAN, and JAMES YOO
____________

Appeal 2011-001084
Application 11/048,097
Technology Center 1600
____________

Before DONALD E. ADAMS, STEPHEN WALSH, and
ULRIKE W. JENKS, Administrative Patent Judges.

JENKS, Administrative Patent Judge

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to an
artificial glandular oral tissue construct and an artificial salivary gland
construct. The Examiner has rejected the claims as obvious. We have
jurisdiction under 35 U.S.C. § 6(b). We affirm.

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STATEMENT OF THE CASE
The Specification is directed to “the construction of artificial oral
tissue structures by seeding cultured cell populations of oral cells, e.g.,
salivary gland cells onto or into a biocompatible substrate. The invention is
particularly useful in constructing artificial salivary glands.” (Spec. 1.)
“Engineering new tissues from cultured cells represents another new
approach to treat patients suffering from the loss or malfunction of certain
tissues.” (Spec. 2.)
Claims 15-28 and 36-41 are on appeal, and can be found in the
Appendix A of the Appeal Brief (App. Br. A-C). Claims 15 and 23 are
independent claims. Claims 15 and 23 are representative of the claims on
appeal, and read as follows (emphasis added):
15. An artificial glandular oral tissue construct for use in a subject
comprising
a substrate seeded with a population of isolated, autologous,
oral tissue cells,
wherein the seeded oral tissue cells are glandular epithelial cells
that were isolated from the oral tissue, grown and expanded in culture
and further cultured following attachment to the substrate to produce
an oral tissue layer comprising a primitive salivary system capable of
secreting saliva.

23. An artificial salivary gland construct comprising
a substrate seeded with a population of isolated, autologous,
cultured noncancerous salivary gland cells,
wherein the salivary gland cells attach to the substrate to
produce a salivary gland tissue layer comprising a primitive salivary
system capable of secreting saliva, wherein the noncancerous salivary
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gland cells were isolated by sorting autologous cells to separate
noncancerous cells from cancerous cells.

The following grounds of rejection are before us for review:
I. claims 15-28 and 36-41 are rejected under 35 U.S.C. 103(a) as
being unpatentable over Grikscheit
1
in view of Baum;
2
and
II. claims 15-28 and 36-41 are rejected under 35 U.S.C. 103(a) as
being unpatentable over Mooney
3
in view of Baum.

I.
The Issue
The Examiner finds that Grikscheit teaches artificial tissue constructs,
including the use of salivary tissue, where the tissue is seeded onto a
biocompatible material such as polyglycolic acid (PGA), cellulose or
polyamide, and where the seeded cells are able to maintain secretory
function. (Ans. 4.) The Examiner finds that “Grikscheit clearly teaches
isolating autologous cells by the [same] isolation method disclosed by
appellant and seeding said cells onto the claimed biocompatible substrate to
produce a functional tissue construct. While Grikscheit discloses using cells
from tissues such as salivary gland (0083), such cells are not exemplified.”

1
Grikscheit et al., US 2003/0129751 A1, published Jul. 10, 2003.
2
Baum et al., US 2003/0031696 A1, published on Feb. 13, 2003. The
application issued as U.S. patent No. US 6,743,626 B2 on June 1, 2004. In
this opinion all Baum references are directed to the pre-grant publication.
3
Mooney et al., US 5,885,829, issued Mar. 23, 1999.
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(Ans. 5.) The Examiner concludes that it would have been obvious to “use
the isolated salivary epithelial cells of Baum in an artificial tissue construct
such as that produced by Grikscheit.” (Id. at 6-7.)
Appellants contend that “Grikscheit defines the organoid unit as a
„cluster of isolated tissue comprising all the cell types found in a cross-
section of the native tissue.‟ In addition, the „organoid units are loaded into
the polymer scaffold at high density.‟” (App. Br. 6.) In contrast, “Baum's
preferred embodiments, the monolayer of cells is a layer of genetically
engineered epithelial cells transduced with a water transport gene.” (Id.)
The issue with respect to this rejection is whether the Examiner
established by a preponderance of the evidence that the combination of
Grikscheit and Baum render obvious the composition directed to an artificial
glandular construct using isolated glandular epithelial cells?

Findings of Fact
FF1. Grikscheit disclosed that “an „organoid unit‟ comprises a
cluster of isolated tissue comprising all of the cell types found in a cross-
section of the native tissue, including organ-specific stem cells.” (Grikscheit
¶ 0082.) Additionally, “[o]rganoid units can be derived from tissues
including . . . endocrine tissue . . . Examples of endocrine tissues include, but
are not limited to . . . salivary and adrenal glands.” (Grikscheit ¶ 0083;
Ans. 4.)
FF2. Grikscheit disclosed polymer scaffolds that “function in place
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of a connective tissue scaffold or matrix, and are designed to optimize gas,
nutrient, and waste exchange by diffusion until neovascularization occurs
from the host environment. Polymer scaffolds comprise, for example, a
porous, non-woven array of fibers. They preferably comprise polyglycolic
acid (PGA), tubular in shape.” (Grikscheit ¶ 0095.) “The polymer scaffold
can be shaped to maximize surface area, to allow adequate diffusion of
nutrients and growth factors to the cells.” (Grikscheit ¶ 0096.)
FF3. Grikscheit disclosed that “[t]he tissue can be minced
mechanically, or more preferably, digested with an enzyme or enzyme
mixture. . . . Following mincing or digestion, organoid units are purified by
washing and centrifugation, prior to reconstitution in media and seeding on
polymer scaffolds.” (Grikscheit ¶ 0102; Ans. 5.)
FF4. Grikscheit disclosed that transplantation tissue can be
heterologous engineered tissue derived from neonatal, juvenile or adult
donors; or “[t]he transplantation [tissue] can [also] be autologous, such that
the donor of the tissue from which organoid units are derived is the recipient
of the engineered-tissue.” (Grikscheit ¶ 0085; Ans. 5.)
FF5. Baum disclosed a “device [that] has a support, an attachment
surface joined to the support, and joined to the attachment surface are a
polarized monolayer of allogenic or autologous cells that are engineered to
secrete ions and water unidirectionally.” (Baum ¶ 0008.) Baum disclosed
that “[p]referred biodegradable supports 10 are poly-L-lactic acid [PLLA]
and polyglycolic acid [PGA].” (Baum ¶ 0032.) Baum further disclosed that
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the “support 10 is coated with an extracellular matrix protein such as,
Matrigel, Vitrogen, fibronectin, laminin, collagen I, collagen IV or another
protein such as, gelatin or poly-lysine so as to provide a water and ion
permeable surface 12 for the cells 14 to attach and form a polarized
monolayer.” (Baum ¶ 0030.)
FF6. Baum disclosed that
epithelial cells from the subject are removed by conventional
techniques and are cultured in vitro so as to produce a
population of autologous cells in culture. The cultured
autologous cells can then be manipulated using techniques in
molecular biology (e.g., transfection with an expression
construct) to express desired proteins such as water or ion
channel proteins. Subsequently, the autologous cells 14
expressing the desired protein are used to seed a support 10 and
thereby create an artificial salivary gland that is specific for the
subject from whom the epithelial cells were removed.

(Baum ¶ 0042; Ans. 7.)
FF7. Baum disclosed the seeding of a salivary epithelial cell
suspension onto a support constructed of denuded rat trachea that was coated
with a matrix molecule such as Matrigel, fibronectin, laminin, collagen I,
collagen IV, and gelatin. (Baum ¶ 0046; Ans. 6.) This coated support
promoted the formation of a polarized monolayer. (Id.)
FF8. Baum disclosed the use of a human submandibular gland cell
line as a “prototype graft cell 14 because their phenotype is highly
responsive to different extracellular matrix components 12 and HSG cells 14
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exhibit intact Ca
2+
signaling systems, such as required to regulate salivary
fluid secretion.” (Baum ¶ 0047.)

Principles of Law
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
If a person of ordinary skill can implement a predictable
variation, § 103 likely bars its patentability. For the same
reason, if a technique has been used to improve one device, and
a person of ordinary skill in the art would recognize that it
would improve similar devices in the same way, using the
technique is obvious unless its actual application is beyond his
or her skill.

(Id. at 417.) It is proper to “take account of the inferences and creative steps
that a person of ordinary skill in the art would employ.” Id. at 418. See also
id. at 421 (“A person of ordinary skill is also a person of ordinary creativity,
not an automaton.”).

Analysis
Appellants contend that there is no reason to combine Baum with
Grikscheit. (App. Br. 7; Reply Br. 5.) Appellants assert that “the only
reasoning the Examiner has provided for combining Grikscheit's organoid
units with Baum's cell lines or isolated gland cells, is that Baum teaches their
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use for artificial salivary glands.” (App. Br. 7.) Appellants further assert
that “Grikscheit's only mention of salivary glands is in a laundry list of
tissues capable of artificial construction.” (Id. at 8.) “[N]o reason has been
advanced for why one of ordinary skill in the art would replace Grikscheit's
organoid units with isolated, cultured cells of any type.” (Id.)
The Examiner‟s position is that “Baum teaches that isolated salivary
epithelial cells can be seeded onto a biocompatible substrate to produce a
fully functional secretory salivary gland (0028, 0041, 0042).” (Ans. 14.)
“Baum clearly teaches the importance of salivary glandular epithelial cells
which are known in the art as secretory cells (0005) as well as a long felt
need in producing an artificial fluid secreting construct for oral implantation
so as to treat individuals suffering from salivary gland hypofunction (0007)
such as cancer patients (0006).” (Id. at 15.)
We are not persuaded by Appellants‟ arguments. “In determining
whether obviousness is established by combining the teachings of the prior
art, the test is what the combined teachings of the references would have
suggested to those of ordinary skill in the art.” In re GPAC Inc., 57 F.3d
1573, 1581 (Fed. Cir. 1995) (internal quotations omitted). We find that
Baum disclosed “replacement of destroyed salivary gland tissue [and]
particularly focus[es] on the creation of a functional new tissue using
allogenic or autologous cells grown and appropriately organized on a
suitable biocompatible support.” (Baum ¶ 0011.) Baum disclosed the
seeding of a salivary cell suspension onto a coated support (FF6). In
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addition, Baum exemplified an allogeneic graft using a human
submandibular gland cell line (FF7). Grikscheit disclosed the production of
artificial glandular constructs, and suggested the production of salivary
glands (FF1). Grikscheit also disclosed the use of polymer scaffolds (FF2)
as well as the isolation of autologous cells and the seeding of these cells onto
the polymer scaffolds (FFs 3-4; Ans. 13). We agree with the Examiner‟s
conclusion that based on the references as a whole the ordinary artisan
would have been motivated to use “salivary epithelial cells in an artificial
oral tissue construct with a reasonable expectation for successfully
producing an functional secretory salivary gland because the art of record
clearly teaches functional tissue constructs comprising isolated tissue cells
seeded on a substrate to produce secretory constructs.” (Ans. 7.) “The
combination of familiar elements according to known methods is likely to be
obvious when it does no more than yield predictable results.” KSR, 550 U.S.
at 416.
Appellants contend that “Baum's only mention of collagen and
Matrigel is found in a list of potential coatings for the membrane-type
support. None of Baum's actual examples use gels as supports and there is
no suggestion that a gel would function as a water porous support.” (App.
Br. 9-10.)
We are not persuaded by this argument. Baum disclosed an artificial
salivary gland comprising a support that is coated with an extracellular
matrix protein (FF5). Baum provides a short list of extracellular matrix
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proteins that can be used in the device, one of the listed extracellular matrix
proteins is Matrigel (FFs 5, 7). A disclosure that allows one skilled in the art
to “at once envisage each member of [a] limited class” describes each
member of the class “as if [the reference] had drawn each structural formula
or had written each name.” In re Petering, 301 F.2d 676, 681-682 (CCPA
1962). Baum‟s list of extracellular matrix protein is small, the ordinary
artisan could at once envision all members of the disclosed class, including
Matrigel.
Appellants assert that “Grikscheit and Baum fail to teach or suggest
isolated, autologous, cultured noncancerous salivary gland cells, wherein
the noncancerous salivary gland cells are isolated by sorting autologous
cells to separate noncancerous cells from cancerous cells or to remedy the
deficiencies of Grikscheit.” (App. Br. 9.)
The Examiners position is that “Grikscheit's autologous cell isolation
method (0102, 0121, 0124) is the same as that disclosed and exemplified by
appellant, i.e. mincing (as taught in Examples 1 and 2 of appellant's
specification) as well as enzyme digestion.” (Ans. 13.) The Examiner
concludes that it would have been obvious to remove cancerous cells
because “[t]he ultimate goal of cancer treatment is rid[d]ing the body of
cancerous cells; therefore, it would be quite obvious to separate healthy cells
from the cancerous cells” before returning the cells into the patient. (Id. at
16.)
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We are not persuaded by Appellants‟ arguments. As discussed above
we agree with the Examiner‟s conclusion that the combination of Grikscheit
and Baum renders obvious the presently claimed artificial glandular
construct using isolated, autologous, glandular epithelial cells. The question
is whether it would have been obvious to one of ordinary skill in the art at
the time of the invention to remove cancerous autologous cells from the
artificial glandular construct. Here, the purpose for creating an artificial
glandular construct is to treat patients that have undergone therapeutic
irradiation due to head and neck malignancies and others that have lost the
ability to produce saliva (Baum ¶ 0006). We agree with the Examiner‟s
position that
it would have been obvious to one of ordinary skill in the art to
have separated cancerous from noncancerous cells when
making an artificial salivary gland or tissue to benefit those in
need of tissue/organ/gland replacement, such as cancer patients.
Clearly one of skill in the art would not want to use cancerous
cells in an artificial gland construct especially in hopes of using
the gland for treating cancer patients who suffer from loss or
malfunction of organs/glands.

(Ans. 15-16.)
The question of obviousness cannot be approached on the basis that
an artisan having ordinary skill would have known only what was read in the
references, because such artisan must be presumed to know something about
the art apart from what the references disclose. See In re Jacoby, 309 F.2d
513, 516 (CCPA 1962).
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We are not persuaded by Appellants‟ arguments that “[c]ontrary to the
Examiner's suggestions that one skilled in the art would inherently know to
separate cancerous cells, Grikscheit specifically recites the advantageous of
retaining „all of the cell types found in a cross-section of the native tissue.‟”
(App. Br. 8.) Appellants appear to argue that it would not have been
obvious to remove cancerous cells from an autologous tissue sample before
treating a patient with the artificial glandular constructs made up of the
autologous cells. Without removing cancerous cells from the autologous
tissue sample would result in the introduction of tumor cells back into a
patient after the patient has already been treated for that tumor. The law
presumes skill on the part of the artisan rather than the converse. See In re
Sovish, 769 F.2d 738, 742-43 (Fed. Cir. 1985).
We conclude that the preponderance of the evidence of record
supports the Examiner‟s conclusion that Grikscheit and Baum render
obvious the artificial salivary gland construct recited in claims 15 and 23.
We thus affirm the rejection of claims 15 and 23 under 35 U.S.C. § 103(a) as
being obvious, as claims 16-22, 24-28, and 36-41 fall with those claims, we
affirm the rejection of those claims as well. 37 C.F.R. § 41.37(c)(vii).

II.
The Issue
Appellants contend that there is no reason to combine Mooney with
Baum. (App. Br. 12.) Appellants assert that “Mooney's use of gingival
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tissue samples to seed the muscle and connective tissue constructs is to
regenerate specific oral tissues, i.e. periodontal tissue or tongue.” (Id. at 10.)
Appellants further assert that Mooney teaches a three dimensional oral
structure, and therefore, “Mooney effectively teaches away from Baum's use
of two-dimensional monolayers of cultured cells.” (Reply Br. 8.)
The Examiner finds that Mooney disclosed an artificial oral tissue
construct, that seeds isolated oral tissue cells onto, for example, PGA to
form new function tissue. (Ans. 9.) “The tissues used for [sic] form the oral
construct comprise tissue from the submucosa which includes lingual, labial,
buccal and palatine glands (col.7 lines 1-25) as well as salivary gland (col.
12, lines 41-43).” (Id.) The Examiner concludes that “it would have been
obvious to one of ordinary skill in the art to substitute the isolated salivary
epithelial cells of Baum in an artificial tissue construct such as that produced
by Mooney to produce an artificial glandular oral tissue construct.” (Id. at
10-11.)
The issue with respect to this rejection is whether the Examiner
established by a preponderance of the evidence that the combination of
Mooney and Baum render obvious the composition directed to an artificial
glandular construct using isolated glandular epithelial cells?

Findings of Fact
FF9. Mooney disclosed oral tissue that “will preferably be
„autologous‟ cells and tissues, which are intended for return to the animal or
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human from which they were obtained.” (Mooney, col. 5, ll. 56-59, see also
col. 25, ll. 1-21.) Mooney disclosed a culture method that is applicable for
the regeneration of a variety of oral tissues, including “dental pulp tissue,
dentin, periodontium, bone, cementum, gingival submucosa, oral
submucosa, salivary gland tongue and taste bud tissues.” (Mooney, col. 12,
ll. 38-43.)
FF10. Mooney disclosed that “[g]rowth factors and regulatory factors
need not be added to the media since these types of factors are elaborated by
the three-dimensional cells. However, the addition of such factors, or the
inoculation of other specialized cells may be used to enhance, alter or
modulate proliferation and cell maturation in the cultures.” (Mooney, col. 8,
ll. 48-43.)

Analysis
We are not persuaded by Appellants‟ arguments. “[T]he test [for
obviousness] is what the combined teachings of the references would have
suggested to those of ordinary skill in the art.” In re GPAC Inc., 57 F.3d
1573, 1581 (Fed. Cir. 1995). Baum disclosed the production of an artificial
salivary gland (FF5) for implantation into a patient (Baum ¶ 0011). Mooney
disclosed a method for culturing autologous cells for the regeneration of a
variety of oral tissues, including salivary gland tissues (FFs 9-10.) We agree
with the Examiner‟s conclusion that the ordinary artisan would have been
motivated to combine Mooney and Baum to produce a
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functional secretory salivary gland because the art of record
clearly teaches functional tissue constructs comprising isolated
tissue cells seeded on a substrate to produce secretory
constructs. Baum clearly teaches the importance of salivary
glandular epithelial cells which are known in the art as
secretory cells (0005) as well as a long felt need in producing
an artificial fluid secreting construct for oral implantation so as
to treat individuals suffering from salivary gland hypofunction
(0007) such as cancer patients (0006)

(Ans. 19).
We are also not persuaded by Appellants‟ argument that the
combination of references does not disclose “sorting autologous cells to
separate noncancerous cells from cancerous cells.” (Reply Br. 9.)
Although, Mooney does not disclose sorting cancerous cells from non-
cancerous cells, Mooney does recognize that in order to regenerate oral
tissue that is to be transplanted back to the patient, it is important to obtain
healthy viable cells (Mooney, col. 28, l. 61 to col. 29, l. 22). Appellants
appear to argue that it would not have been obvious to remove cancerous
cells from an autologous tissue sample before treating a patient with the
artificial glandular constructs made up of those autologous cells. We agree
with the Examiner‟s conclusion that “one of skill in the art would not want
to use cancerous cells in an artificial gland construct especially in hopes of
implanting the gland for treating cancer patients who suffer from loss or
malfunction of organs/glands.” (Ans. 19.) Without removing cancerous
cells from the autologous tissue sample would result in the introduction of
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tumor cells back into a patient after the patient has already been treated for
that tumor. The law presumes skill on the part of the artisan rather than the
converse. See In re Sovish, 769 F.2d at 742-43.

SUMMARY
We affirm the rejection of claims 15-28 and 36-41 under 35 U.S.C.
103(a) as being unpatentable over Grikscheit in view of Baum.
We affirm the rejection of claims 15-28 and 36-41 under 35 U.S.C.
103(a) as being unpatentable over Mooney in view of Baum.

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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