Ex Parte Dryden et al

Patent Trial and Appeal Board

Sep 7, 2016

12568443 (P.T.A.B. Sep. 7, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
12/568,443 09/28/2009 Daniel Dryden
69139 7590 09/09/2016
LOEB & LOEB, LLP
321 NORTH CLARK
SUITE 2300
CHICAGO, IL 60654-4746
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www .uspto.gov
ATTORNEY DOCKET NO. CONFIRMATION NO.
221886-30002 6380
EXAMINER
POPA, ILEANA
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
09/09/2016 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address( es):
CHPATENT@LOEB.COM
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte DANIEL DRYDEN and JAMES HARDY
Appeal2015-001425
Application 12/568,443
Technology Center 1600
Before DONALD E. ADAMS, JOHN G. NEW, and
RYAN H. FLAX, Administrative Patent Judges.
ADAMS, Administrative Patent Judge.
DECISION ON APPEAL 1
This appeal under 35 U.S.C. § 134(a) involves claims 24---61 (App. Br.
6). Examiner entered rejections under 35 U.S.C. § 103(a). We have
jurisdiction under 35 U.S.C. § 6(b ).
We AFFIRM.
1 Appellants identify "[t]he real party in interest [as] IN VITRO, INC."
(App. Br. 4.)
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Application 12/568,443
STATEMENT OF THE CASE
Appellants' claims 24, 32, and 34 are representative and reproduced
below:
24. A method comprising the steps of:
thawing cryopreserved hepatocytes; and
cryopreserving the thawed hepatocytes.
32. A method comprising the steps of:
thawing cryopreserved hepatocytes from a first source;
obtaining hepatocytes from a second source;
pooling the hepatocytes from the first source and the
hepatocytes from the second source; and
cryopreserving the pooled hepatocytes.
34. The method of claim 32, further comprising the step of recovering
viable hepatocytes from the pooled hepatocytes before
cryopreservmg.
GROUNDS OF REJECTION
Claims 24--31 and 41-50 stand rejected under 35 U.S.C. § 103(a) as
unpatentable over the combination of Ostrowska, 2 Kreamer, 3 and Chesne. 4
Claims 24--61 stand rejected under 35 U.S.C. § 103(a) as unpatentable
over the combination of Ostrowska, Kreamer, Chesne, and Shibata. 5
2 Alina Ostrowska et al., Investigation of functional and morphological
integrity of freshly isolated and cryopreserved human hepatocytes, 1 Cell
and Tissue Banking 55---68 (2000).
3 Bill L. Kreamer et al., Use of a Low-speed, !so-density Percoll
Centrifugation Method to Increase the Viability of Isolated Rat Hepatocyte
Preparations' 22 IN VITRO CELLULAR & DEVELOPMENT AL BIOLOGY 201-
211 (1986).
4 Christophe Chesne et al., Viability and Function in Primary Culture of
Adult Hepatocytes from Various Animal Species and Human Beings after
Cryopreservation, 18 HEPATOLOGY 406-414 (1993).
5 Yoshihiro Shibata et al., Prediction of Hepatic Clearance and Availability
by Cryopreserved Human Hepatocytes: an Application of Serum Incubation
Method, 30 DRUG METABOLISM AND DISPOSITION 892-896 (2002).
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Application 12/568,443
The rejection over the combination of Ostrowska, Kreamer, and
Chesne is cumulative to the rejection over the combination of Ostrowska,
Kreamer, Chesne, and Shibata. In this regard, we note that Examiner
incorporated Examiner's findings based on the combination of Ostrowska,
Kreamer, and Chesne into the rejection based on the combination of
Ostrowska, Kreamer, Chesne, and Shibata (see Ans. 5 ("The teachings of
Ostrowska [],Kreamer[], and [Chesne] are applied as above for claims 24--
31 and 41-50)). Therefore, we vacate the rejection over the combination of
Ostrowska, Kreamer, and Chesne in favor of the more comprehensive
rejection of Appellants' claimed subject matter over the combination of
Ostrowska, Kreamer, Chesne, and Shibata.
The rejection over the combination of Ostrowska, Kreamer, Chesne, and
Shibata:
ISSUE
Does the preponderance of evidence relied upon by Examiner support
a conclusion of obviousness?
FACTUAL FINDINGS (FF)
FF 1. Ostrowska discloses that "[t]he use of human hepatocytes, both for
basic research and clinical trials, has been hampered by the limited
availability of adequate numbers of fresh, viable cells due to the ongoing
shortage of liver donors," wherein "[a] practical solution to this problem is
cryopreservation and banking of hepatocytes" (Ostrowska 56: col. 1, first
and second full paragraphs; see Ans. 4).
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Application 12/568,443
FF 2. Ostrowska discloses hepatocyte cryopreservation and thawing
(Ostrowska 57: col. 2, last paragraph; Ans. 3--4).
FF 3. Ostrowska discloses that "[ t ]he yield and viability of freshly isolated
or thawed cells were determined ... [and] [p]reparations with greater than
80% viability were used for other applications[, such as metabolic function
and metabolite production assays,] without further purification" (Ostrowska
58: col. 1, first paragraph; id. at col. 2, second full paragraph; Ans. 3--4; see
also Ans. 5 (Shibata discloses "using their pooled preparations [of
hepatocytes] in a method of investigating drug metabolism")).
FF 4. Ostrowska discloses that
[ v ]iable hepatocytes, either freshly isolated or recovered
from cryopreservation, showed typical and intact morphology
as demonstrated by light microscopy. In suspensions, most of
the cells were binucleated and spherical in shape with some
signs of translucent blebbing of plasma membrane. Blebs, the
most characteristic abnormal feature of cryopreserved
hepatocytes, were mainly observed in the cells isolated from
fatty livers. Incubation at 37°C for 30 min resulted in
significant improvement of cell morphology and reversal of
blebbing. Routine PAS staining demonstrated the presence of
intracellular red granules of glycogen, to a similar degree, in
both fresh and cryopreserved hepatocytes. Electron microscopy
examination showed ... [t]he appearance of cryopreserved
hepatocytes was similar to that of normal cells. However,
moderate signs of cellular derangement were found in some
cells.
(Ostrowska 59: col. 1-2, bridging paragraph; Ans. 3--4.)
FF 5. The result of Ostrowska's "work show[s] that, in general,
cryopreservation maintains the functional and morphological integrity of
isolated hepatocytes in vitro ... [and] confirms the importance and
feasibility of human hepatocyte banking" (Ostrowska 66: col. 2, last
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paragraph; id. at 56: col. 1-2, bridging paragraph (Ostrowska's "results
show that cryopreserved/thawed hepatocytes stored in liquid nitrogen for
extended periods retained their morphological integrity and expressed
functional activities at levels close to the freshly isolated primary cells");
Ans. 7 and 10).
FF 6. Examiner finds that Ostrowska discloses the separation of viable
hepatocytes from non-viable hepatocytes through the use of "Percoll
gradient centrifugation" and relies on Kreamer to disclose that "Percoll
gradients are established by using stock Percoll diluted in buffer" (Ans. 3-
4).
FF 7. Examiner finds that Ostrowska does not disclose "testing xenobiotics
at a first and second later time and comparing the results" and relies on
Chesne to suggest that suggest that the use of the foregoing methodology to
"assess the effect of prolonged storage was routine in the prior art" (Ans. 4--
5).
FF 8. Examiner finds that Ostrowska does "not [disclose] pool[ing]
preparations of cryopreserved hepatocytes from multiple sources" and relies
on Shibata to disclose "pooling cryopreserved hepatocyte[] preparations
derived from multiple sources" (Ans. 5; see, e.g., Shibata 895: col. 1, first
full paragraph ("[i]t was found that the pooled preparations of two lots [of
hepatocytes] achieved the same extent of predictability for all seven standard
compounds as the averaged results from 10 individual preparations" of
hepatocytes) ).
FF 9. Examiner finds that Ostrowska does not disclose the
cryopreservation of a preparation of thawed, previously cryopreserved,
hepatocytes (Ans. 4).
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FF 10. Myhre6 "detail[s] the chemical and cytological changes which occur
in units of red blood cells which have been repeatedly frozen" (Myhre 199:
col. 2).
FF 11. Myhre establishes that "red blood cells can not only be thawed and
refrozen, but that they can be stored at 4[
0
J C for up to five days, refrozen,
thawed, and the cycle repeated" (Myhre 202: second column).
FF 12. Myhre
do[ es] not recommend this type of handling [(i.e., repetitive:
thawing, storing at 4 ° C, and refreezing)] as routine for a fragile
biological component, but nevertheless ... establish[ es] that
refreezing is a practical step which can be employed to save a
rare unit of blood, and that this refreezing will not seriously
damage the unit of blood nor endanger the life of its eventual
recipient.
(Myhre 202: second column.)
ANALYSIS
Claims 24 and 32:
Based on the combination of Ostrowska, Kreamer, Chesne, and
Shibata, Examiner concludes that, at the time Appellants' invention was
made, it would have been prima facie obvious, to cryopreserve hepatocytes
that were previously cryopreserved and thawed; and to add "hepatocytes
from other sources to the[] thawed hepatocyte[, preparation suggested by the
combination of Ostrowka, Kreamer, and Chesne,] to make and use pooled
preparations," which, as suggested by Shibata, "provide more reliable
predictions for [] human liver metabolism," wherein unused portions of the
6 B. A. Myhre et al., Studies on 4foJ C Stored Frozen-Reconstituted Red
Blood Cells III. Changes Occurring in Units Which Have Been Repeatedly
Frozen and Thawed, 18 Transfusion 199-203 (1978).
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thawed preparations are re-cyropreserved for use at a later time (Ans. 5---6;
see FF 1-8).
Appellants contend that the evidence of record fails to support a
conclusion that a person of ordinary skill in this art would have appreciated
that cryopreserved cells, once thawed, could be, again, cryopreserved (see
App. Br. 25-26; Reply Br. 4--5). 7 We are not persuaded. KSR Int'! v.
Teleflex Inc., 550 U.S. 398, 418 (2007) (A fact-finder "need not seek out
precise teachings directed to the specific subject matter of the challenged
claim [in an analysis of obviousness], for a court can take account of the
inferences and creative steps that a person of ordinary skill in the art would
employ").
The evidence of record establishes that hepatocytes, which are cells of
"limited availability" can be isolated from a liver, cryopreserved, and
thawed, wherein the thawed cells "maintain[] the functional and
morphological integrity of [the originally preserved] hepatocytes in vitro"
(FF 1-7; see Ans. 10). The evidence of record further establishes that
multiple populations of hepatocytes may be combined, cryopreserved and
thawed (see FF 1-8; see also Ans. 10). While some hepatocytes may be
damaged during the cryopreservation process, the same is true of
hepatocytes freshly isolated from a human liver (see FF 3 and 4).
Ostrowska, however, addresses the problem of cell populations that
7 Appellants contend that Examiner's Answer contained new assertions and
allegations (see Reply Br. 3). To the extent that Appellants would contend
that any such new assertion and allegation by Examiner rose to the level of a
new ground of rejection, we find that Appellants waived any argument with
regard to a new ground of rejection by failing to timely file a petition under
37 C.F.R. § 1.181. See 37 C.F.R. §§ 41.40 and 41.41.
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comprise damaged cells by disclosing a method of purifying viable cells,
which, in the absence of evidence to the contrary, may be applied to a cell
preparation that is directly isolated from a liver or recovered from
cryopreservation (FF 6). The recovery of viable hepatocytes from a
hepatocyte population prior to cryopreservation is disclosed by Ostrowska,
and would have been prima facie obvious to those of ordinary skill in this
art, so as to not cryopreserve dead cells (see generally FF 6; Ans. 10).
Viable hepatocytes, whether obtained directly from a liver or from a
prior cryopreservation step, are viable hepatocytes. Therefore, in sum,
obtaining viable hepatocytes directly from a liver or a prior cryopreserved
population of hepatocytes was known in the art, pooling hepatocytes was
known in the art, and cryopreserving pooled populations of viable
hepatocytes was known in the art (FF 1-8). Thus, the evidence relied upon
by Examiner supports a conclusion that cryopreserving, or re-
cryopreserving, a population of viable hepatocytes pooled from various
sources would have been prima facie obvious to a person of ordinary skill in
this art (see, e.g., FF 1-8; cf App. Br. 34--35; Reply Br. 5).
Appellants fail to provide persuasive evidence or argument to support
a conclusion that a population of viable hepatocytes, whether isolated
directly from a liver or recovered from cryopreservation, could not be
cryopreserved, using the methodology set forth in the combination of
Ostrowska, Kreamer, Chesne, and Shibata for any number of reasons
including "provid[ing] more reliable predictions for[] human liver
metabolism," wherein unused portions of the thawed preparations are re-
cyropreserved for use at a later time (Ans. 5---6; cf App. Br. 25-26). See
Perfect Web Techs., Inc. v. Info USA, Inc., 587 F.3d 1324, 1329 (Fed. Cir.
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2009) (explaining that the obviousness analysis "may include recourse to
logic, judgment, and common sense available to the person of ordinary skill
that do not necessarily require explication in any reference or expert
opinion").
Examiner's rationale for the rejection over the combination of
Ostrowska, Kreamer, Chesne, and Shibata does not relate to "obtain[ing]
reproducible results between experiments," therefore, we are not persuaded
by Appellants' contention that "Examiner did not provide any supporting
evidence for the second critical allegation of the rejection - that one would
re-cryopreserve 'unused hepatocytes for further use ... in order to obtain
reproducible results between experiments by providing the same pool of
cryopreserved hepatocytes" (App. Br. 26 (ellipsis original); see also id. at
29-30; see Reply Br. 5---6). The evidence of record does, however, establish
that hepatocytes are of "limited availability" (FF 1 ). Thus, a person of
ordinary skill in this art would have found it prima facie obvious to preserve,
i.e. cryopreserve, viable hepatocytes to conserve a resource of "limited
availability" (see id.).
To the extent that Appellants' contend that Myhre, an evidentiary
reference of record, does not disclose repetitive: cryopreservation, thawing,
storing at 4° C, and refreezing rare units of blood, we are not persuaded (FF
12; cf App. Br. 26 (Myhre "does not disclose freezing and storing 'unused
rare materials such as' rare red blood units for subsequent use. Myhre
clearly and explicitly limits its disclosure only to 'rare red blood units"');
App. Br. 35-36).
We are not persuaded by Appellants' reliance on Myhre to support
their contention that "Myhre contradicts the Examiner's" conclusion of
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obviousness based on the combination of Ostrowska, Kreamer, Chesne, and
Shibata (App. Br. 28; Reply Br. 6-8). Hepatocytes, like rare red blood units,
are biological components of "limited availability" (FF 1 ). In this regard,
we recognize Myhre's disclosure that repetitive: thawing, storing at 4° C,
and refreezing is not recommended for "fragile biological component[s],"
nevertheless, Myhre "establish[ es] that refreezing is a practical step which
can be employed[, as here,] to save a rare [biological component,] and that
this refreezing will not seriously damage the [biological component]" (see
FF 12; see also FF 5 ("cryopreservation [of hepatocytes] maintains
functional and morphological integrity of isolated hepatocytes in vitro")).
We recognize, but are not persuaded by Appellants' contention that
"prior to the present method, it was believed that cryopreserving hepatocytes
caused significant damage to the cells" (App. Br. 30; see id. at 32-33; cf FF
5 ("cryopreservation maintains the functional and morphological integrity of
isolated hepatocytes in vitro ... [and] confirms the importance and
feasibility of human hepatocyte banking"). While, as Appellants' point out,
"[n]one of the prior art[, relied upon by Examiner,] discloses any attempt to
re-cryopreserve previously cryopreserved hepatocytes," Appellants failed to
establish an evidentiary basis on this record to support a conclusion that a
person of ordinary skill in this art would not have recognized that viable
hepatocytes, whether freshly recovered from a liver or from
cryopreservation, could not be cryopreserved according to the methodology
set forth in the combination of Ostrowska, Kreamer, Chesne, and Shibata.
In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974) ("Attorney's argument in
a brief cannot take the place of evidence").
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We recognize, but are not persuaded by, Appellants' reliance on
Celsis In Vitro, Inc. v. Cellzdirect, Inc., 664 F.3d 922, 928 (Fed. Cir. 2012),
wherein "the record[, therein,] show[ ed] that the prior art taught away from
multiple freezings [because,] [a] single round of freezing severely damages
hepatocyte cells and results in lower cell viability" (App. Br. 31 ). In
contrast to the record in Celsis In Vitro, Inc., on this record, Examiner
established, inter alia, that cryopreserving viable hepatocytes "maintains the
functional and morphological integrity of isolated hepatocytes in vitro ...
[and] confirms the importance and feasibility of human hepatocyte banking"
(FF 5). The Examiner further established that, to the extent that
cryopreservation did result in the damage of some cells, the isolation of fresh
hepatocytes from a liver also resulted in the damage of some cells, and that
viable cells could be purified by following the methodology outlined in the
combination of prior art relied upon by Examiner (see FF 1-8; see also Ans.
7-8). Thus, absent evidence to the contrary, if viable hepatocyes can be
obtained from a liver and through recovery from cryopreservation, one
would reasonably expect that these viable cells, isolated from either source,
could be cryopreserved (or re-cryopreserved) (see FF 1-8; see also Ans. 7-
8).
For the foregoing reasons, we recognize, but are not persuaded by,
Appellants' contention that Examiner failed to establish "what, if any, types
of experiments one might hypothetically expect to obtain reproducible
results with repeatedly cryopreserved hepatocytes" (App. Br. 32; see id. at
33; cf FF 3).
For the foregoing reasons, we recognize, but are not persuaded by
Appellants' contention that the combination of Ostrowska, Kreamer,
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Chesne, and Shibata fails to make obvious the subject matter of Appellants'
claim 1 because no reference relied upon by Examiner expressly discloses
cryopreserving viable hepatocytes recovered from a prior cryopreservation
step (see App. Br. 34; Reply Br. 6).
Claim 34:
Appellants contend that "Examiner has not articulated why one, who
hypothetically- according to the Examiner - would have re-cryopreserved
hepatocytes and then performed the steps of claims 34--40 and 52---60 prior
to attempting to obtain 'reproducible experiments'" (App. Br. 36). We are
not persuaded. Examiner's rationale with regard to the rejection over the
combination of Ostrowska, Kreamer, Chesne, and Shibata, does not relate to
obtaining reproducible results (see Ans. 5---6). To the contrary, Examiner's
rationale is that a person of ordinary skill in this art would pool hepatocyte
preparations to "provide more reliable predictions [of] human liver
metabolism" (Ans. 5 and 8; see FF 8). In this regard, Examiner finds that a
person of ordinary skill in this art would have found it prima facie obvious
to cryopreserve hepatocytes, which are a limited resource (Ans. 5-9; see FF
1-8).
Shibata teaches the advantage of pooled hepatocytes (FF 8). As
discussed above, cryopreserving viable hepatocytes was known in the art
(FF 1-8). Therefore, for the reasons discussed above, the evidence relied
upon by Examiner supports a conclusion that cryopreserving, or re-
cryopreserving, a population of viable hepatocytes pooled from various
sources would have been prima facie obvious to a person of ordinary skill in
this art.
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For the foregoing reasons, we are not persuaded by Appellants'
contentions regarding the subject matter of claim 34 (see App. Br. 36-37).
CONCLUSION OF LAW
The preponderance of evidence relied upon by Examiner supports a
conclusion of obviousness.
The rejection of claims 24, 32, and 34 under 35 U.S.C. § 103(a) as
unpatentable over the combination of Ostrowska, Kreamer, Chesne, and
Shibata is affirmed. Claims 25-31 and 41-50 are not separately argued and
fall with claim 24. Claims 33 and 51 are not separately argued and fall with
claim 32. Claims 35--40 and 52-61 are not separately argued and fall with
claim 34.
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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