Ex Parte Laughlin et al

Patent Trial and Appeal Board

Jul 6, 2017

11658065 (P.T.A.B. Jul. 6, 2017)

United States Patent and Trademark Office
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
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
11/658,065 06/09/2008 Mary J. Laughlin CWR-019381US PCT 2186
68705 7590 07/10/2017
TAROLLI, SUNDHEIM, COVELL & TUMMINO, LLP
1300 EAST NINTH STREET
SUITE 1700
CLEVELAND, OH 44114
EXAMINER
KIM, TAEYOON
ART UNIT PAPER NUMBER
1651
NOTIFICATION DATE DELIVERY MODE
07/10/2017 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):
rkline @ tarolli. com
docketing@tarolli.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte MARY J. LAUGHLIN and VINCENT POMPILI
Appeal 2016-002778
Application 11/658,065
Technology Center 1600
Before JEFFREY N. FREDMAN, JOHN G. NEW, and
JOHN E. SCHNEIDER, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134(a) involving claims to a
method of inducing neovascularization by administering a specific human
cell composition. The Examiner rejected the claims as obvious. We have
jurisdiction under 35 U.S.C. § 6(b). We affirm.
Statement of the Case
Background
“Although catheter-based revascularization or surgery-based
treatment approaches have been successful in restoring blood flow to
ischemic myocardium in the majority of cases, the treatments are inadequate
1 Appellants identify the Real Party in Interest as Case Western Reserve
University (see App. Br. 2).
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Application 11/658,065
for a significant number of patients who remain incompletely
revascularized” (Spec. 1:13—16). “[Tjherapeutic angiogenesis has attracted
many researchers attempting to discover a way to circumvent the burden of
chronic myocardial ischemia” (Spec. 1:24—26).
“One aspect of the invention provides methods of inducing
neovascularization in subjects in need thereof, such as in subjects afflicted
with ischemia or vascular occlusion, by administering the novel cell
population alone or in conjunction with other cells or noncellular agents”
(Spec. 2:14—17).
The Claims
Claims 53, 55, 56, 71—74, 76, and 77 are on appeal.2 Claim 53 is
representative and reads as follows:
53. A method of inducing neovascularization in a subject in
need thereof, the method comprising administering to the
subject a therapeutically effective amount of a composition, the
composition comprising human cells, wherein at least 10% of
the cells are CD34', CD133', and CD73'; and wherein further
said cells express one or more of the surface markers: CD 14,
CD1 lb and CXCR4.
The issue
The Examiner rejected claims 53, 55, 56, 71—74, 76, and 77 under
35 U.S.C. § 103(a) as obvious over Eggermann,3 Finney,4 and Rafii5 (Ans.
2-5).
2 We note that claim 70 was rejected as obvious over the same prior art in
the Non-Final Rejection mailed Aug. 1, 2014 and in earlier actions but was
omitted in the Final Rejection mailed Feb. 3, 2015 and in the Examiner’s
Answer. The Examiner did not, however, specifically address this claim in
the rejection under appeal, so we treat claim 70 as not subject to rejection.
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The Examiner finds:
Eggermann et al. teach a cell population (putative EPC
(endothelial progenitor cell) derived from unselected
mononuclear cell (MNC)) derived from human umbilical cord
blood by culturing EtUCB on fibronectin-coated culture dishes
for 9 days (p.480, “Results”), and these cells are negative for
CD133 and CD34, but positive for CD14, CD105, and VEGFR-
2 . . .
While Eggermann et al. do not particularly teach that the
cell population is negative for CD73; or positive for CD1 lb or
CXCR4, however, it is expected that the unselected MNC
culture of Eggermann et al. would express the claimed surf ace
markers in the same way as the claimed cells since the process
steps of preparing the unselected UCB MNC culture of
Eggermann et al. are substantially similar, if not identical, to the
process steps and the starting material for the claimed cells in
light of disclosure of the specification (i.e. UCB adherent cells
cultured on fibronectin-coated plates for more than 16 hours).
(Ans. 3).
The Examiner finds because Finney3 4 5 6 and Eggermann use similar
culture processes “the unselected UCB MNC population of Eggermann et al.
would be identical to UCB MNC of Finney et al. and thus, would be
3 Eggermann et al., Endothelial progenitor cell culture and differentiation in
vitro: a methodological comparison using human umbilical cord blood, 58
Cardiovascular Res. 478-86 (2003).
4 Finney et al., Direct Comparison of Umbilical Cord Blood versus Bone
Marrow-Derived Endothelial Precursor Cells in Mediating
Neovascularization in Response to Vascular Ischemia, 5 Biol. Blood
Marrow Transplantation 585-93 (2006).
5 Rafii et al., US 2002/0051762 Al, published May 2, 2002.
6 Because Finney is post-filing date art and does not fully address the
inherency issues, we do not rely upon Finney’s disclosure consistent with
Appellants’ arguments (see App. Br. 8).
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inherently positive for CXCR4 but negative for CD73 in majority of the
cells” (Ans. 4).
The Examiner finds Rafii teaches “the cell population of AC 133-
/CD34-/FLK-1+ (VEGFR-2) that can be derived from umbilical cord blood
(see par. 31 and 35; claim 7 at p.8), and such cell population can be used in
the method for treating mammals in need of neovascularization” (Ans. 4).
The Examiner finds it obvious to “use the unselected MNC population
after plating onto fibronectin-coated dishes of Eggermann et al. for the
method of treating a subject in need of neovascularization as taught by Rafii
et al. with a reasonable expectation of success” (Ans. 4—5).
The issue with respect to this rejection is: Does the evidence of
record support the Examiner’s conclusion that the prior art renders the
claims obvious?
Findings of Fact
1. Rafii teaches “purified populations of endothelial progenitor
cells and their uses in promoting neovascularization in mammals” (Rafii
11).
2. Rafii teaches “a method for inducing neovascularization in a
mammal by treating the mammal with an effective amount of a purified
population of endothelial stem cells. Neovascularization refers to the
development of new blood vessels from endothelial stem cells by any
means” (Rafii 1 54).
3. Rafii teaches “source of cells from which purified endothelial
stem cells are derived may be any natural or non-natural mixture of cells that
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contain endothelial stem cells . . . Preferably, the source of cells is . . .
umbilical cord blood” (Rafii 131).
4. Rafii teaches the “preferred cells of the invention are . . . FLK-
1+ CD34- AC133-” (Rafii 135). Rafii teaches the “FLK-1 receptor is also
known as vascular endothelial growth factor receptor-2 (VEGFR-2)” (Rafii
17).
5. The Specification teaches the “cell surface marker CD133+ is
also known as AC 133” (Spec. 13:6).
6. Eggermann teaches: “Endothelial progenitor cells from bone
marrow or peripheral blood play an important role in various physiological
and pathophysiological processes. They participate in angiogenesis and
arteriogenesis [], thus being functionally important in vascular repair.
Animal studies revealed that neovascularisation of ischemic tissue can be
enhanced by autologous bone marrow transplantation” (Eggermann 478, col.
2).
7. Eggermann teaches “the therapeutic usefulness of precursor
cells for vascular repair” and that “[a]n important practical consideration is
the expandability of endothelial progenitors” (Eggermann 485, col. 1).
8. Example 1 of the Specification teaches “UCB-derived EGCs
were isolated by adherence of CD 133' cells remaining after CD133+
selection for 16 hours on fibronectin in EGM2 media (Clonetics). Surface
phenotyping was evaluated by incubation for 20 minutes at 4 °C with
fhiorochrome-conjugated mAbs and appropriate isotype controls” (Spec.
34:14—18).
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9. Eggermann teaches: “Mononuclear cells (MNC) were isolated
from human umbilical cord blood (HUCB). . . . Cells were either selected
for the surface marker CD34 using anti CD34-coupled magnetic microbeads
... or further treated without selection” (Eggermann 479, col. 2).
10. Eggermann teaches: “Unselected MNC were plated on culture
dishes coated with human fibronectin (Sigma, Deisendorf, Germany) and
cultured in endothelial cell growth medium (EGM, Clonetics, San Diego,
USA). . . After 3 days nonadherent cells were removed and fresh culture
medium was applied” (Eggerman 479, col. 2 to 480, col. 1).
11. Eggermann teaches:
After 6 days in culture, however, the expression pattern shifted
to an endothelial character. Thus, cells became positive for
VEGFR-2, VE-cadherin and the expression of CD105 also
increased. In addition, cells took up Ac-LDL and bound the
endothelial specific lectin UEA-1 (Fig. IB). Cells were
negative for progenitor cell associated markers CD34 and
CD 133, whereas CD 14 and CD45 continued to be expressed,
albeit at a decreased level, through day 9.
(Eggermann 480, col. 2 to 482, col. 1).
12. Eggermann teaches “more putative EPCs could be generated
from HUCB than from adult peripheral blood MNCs. Thus, HUCB may be
a useful source of putative EPC superior to adult peripheral blood”
(Eggermann 483, col. 1).
Principles of Law
The Examiner has the burden of providing reasonable proof that a
claim limitation is an inherent characteristic of the prior art. In re Best, 562
F.2d 1252, 1254—55 (CCPA 1977). The Examiner meets this “burden of
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Application 11/658,065
production by ‘adequately explaining] the shortcomings it perceives so that
the applicant is properly notified and able to respond.’” In re Jung, 637 F.3d
1356, 1362 (Fed. Cir. 2011) (quoting Hyatt v. Dudas, 492 F.3d 1365, 1370
(Fed. Cir. 2007)). The burden of proof then shifts to the applicant “to prove
that the subject matter shown to be in the prior art does not possess the
characteristic relied on.” Best, 562 F.2d at 1254—55; In re Schreiber, 128
F.3d 1473, 1478 (Fed. Cir. 1997) (holding that once the Examiner
established a prima facie case of anticipation, the burden of proof was
properly shifted to the inventor to rebut the finding of inherency).
Analysis
We adopt the Examiner’s findings regarding the scope and content of
the prior art (Ans. 2—5; FF 1—11) and agree that the claimed method would
have been obvious over the teachings of Rafii and Eggermann.
The Examiner finds “the CD 133- cells present in the unselected UCB
MNC that are grown on fibronectin-coated plates are considered the same
CD 133- cells as the claimed invention” (Ans. 6).
Appellants contend “the EGCs of the invention are not isolated in the
same process as UCB unselected mononuclear cells of Eggermann et al. . .
the process of preparing a population of EGCs of the invention includes
negatively selecting for CD133+ cells prior to isolating the remaining
CD133- cells by adherence” (App. Br. 6). Appellants contend “the
Examiner has failed to provide evidence of any kind that this process would
result in the same cell population compared to a process including negatively
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Application 11/658,065
selecting for CD133+ cells prior to isolating the of the remaining CD133[-]
cells by adherence” (App. Br. 7).
We find the Examiner has the better position. Eggermann and the
Specification both teach culture of cells from umbilical cord blood on
fibronectin in EGM media and retention of adherent cells (FF 8, 10).
Eggermann teaches that these adherent cells “were negative for progenitor
cell associated markers CD34 and CD 133, whereas CD 14 and CD45
continued to be expressed” (FF 11). We recognize Eggermann did not
determine the expression of CD73, CD1 lb, or CXCR4 in the adherent cells,
but the Examiner has established that Eggermann’s cultured and adherent
cells match those required by claim 1 for all tested characteristics (FF 11, cf.
claim 53).
Consequently, we conclude the Examiner has established a prima
facie case because “[wjhere, as here, the claimed and prior art products are
identical or substantially identical, or are produced by identical or
substantially identical processes, the PTO can require an applicant to prove
that the prior art products do not necessarily or inherently possess the
characteristics of his claimed product.” Best, 562 F.2d at 1255. The
Examiner has reasonably shifted the burden to Appellants to demonstrate,
with evidence, that cells generated by the method of Eggermann for use in
neovascularization as suggested by Eggermann and Rafii would not
inherently satisfy the requirements of claim 53. “Whether the rejection is
based on ‘inherency’ under 35 U.S.C. § 102, on ‘prima facie obviousness’
under 35 U.S.C. § 103, jointly or alternatively, the burden of proof is the
same, and its fairness is evidenced by the PTO’s inability to manufacture
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products or to obtain and compare prior art products.” Best, 562 F.2d at
1255.
Indeed, Appellants state “that a key distinction between the cited prior
art and the claimed composition is that the cited art, alone and/or in
combination, fails to recognize that the CD34-, CD133-, CD14+, CD105+
UCB MNC culture of Eggermann et al. would be expected to express CD73,
CD1 lb or CXCR4 in the same way as the claimed cells” (Reply Br. 3). This
argument impliedly acknowledges that the cells of Eggermann would, in
fact, inherently be identical to those claimed, but arguing that the prior art
was ignorant of the inherent properties of these cells.
In In re Wiseman, the CCPA rejected the argument
that a structure suggested by the prior art, and, hence,
potentially in the possession of the public, is patentable to them
because it also possesses an inherent, but hitherto unknown,
function which they claim to have discovered. This is not the
law. A patent on such a structure would remove from the
public that which is in the public domain by virtue of its
inclusion in, or obviousness from, the prior art.
In re Wiseman, 596 F.2d 1019, 1023 (CCPA 1979). See also In re Huai-
Hung Kao, 639 F.3d 1057, 1072 (Fed. Cir. 2011) (affirming finding of
obviousness even where “the only claim element not expressly disclosed in
the prior art was the previously-unknown, yet inherent. . . property.”)
Appellants contend “Figure 1 of the specification illustrates some of
the phenotypic differences between UCB unselected MNCs and EGCs and
even indicates that less than 10% of the cells in the UCB derived unselected
MNC population express CD14 (8%), KDR (7.4%) and CD105 (6.7%)”
(App. Br. 7).
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We find this argument unpersuasive because Figure 1 does not
directly compare the cells produced by the process of Eggermann, but rather
compares unselected cells that were not, apparently, selected for adherence
to fibronectin in EGM media as were the cells produced by Eggermann (see
Spec. 34:14—18; FF 11). Thus, the comparison is inapt because different cell
types were tested.
We recognize, but find unpersuasive, Appellants’ contention that
“Rafii et al. do not teach a composition comprising human cells, wherein at
least 10% of the cells are CD34-, CD133-, and CD73-; and wherein further
said cells express one or more of the surface markers: CD14, CD1 lb and
CXCR4” (App. Br. 9). “Non-obviousness cannot be established by
attacking references individually where the rejection is based upon the
teachings of a combination of references.” In re Merck & Co., 800 F.2d
1091, 1097 (Fed. Cir. 1986). A reference “must be read, not in isolation, but
for what it fairly teaches in combination with the prior art as a whole.” Id.
Here, Rafii teaches a method of inducing neovascularization with
umbilical cord-derived endothelial cells that are CD34- CD133- (FF 1—5),
whereas Eggermann teaches a process of expanding endothelial cells (FF 7—
11). It is the combination of these teachings, not Rafii alone, that the
Examiner relies upon to establish prima facie obviousness (see Ans. 4—5
“one skilled in the art would use the unselected MNC population after
plating onto fibronectin-coated dishes of Eggermann et al. for the method of
treating a subject in need of neovascularization as taught by Rafii et al. with
a reasonable expectation of success.”)
Appellants contend
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even if FLK-1 + CD34- AC133- cells of Rafii et al. could be
derived from human umbilical cord blood, neither Eggermann
et al., Rafii et al., nor the Examiner make clear that the UCB
derived unselected MNC population of Eggermann et al. would
be recognized by persons of ordinary skill as equivalent to the
CD 133 -/CD34-/FLK+ cells of Rafii et al.
(App. Br. 12).
We do not find this argument persuasive because, as already discussed
above, the issue is not whether the ordinary artisan would have recognized
the inherent properties of the cells of Eggermann, but rather whether the
ordinary artisan would have had reason to select those cells for use in
neovascularization as taught by Rafii. Eggermann teaches “the therapeutic
usefulness of precursor cells for vascular repair” and that “[a]n important
practical consideration is the expandability of endothelial progenitors” (FF
7). Moreover, Eggermann teaches expansion of umbilical cord cells that are
CD34- and CD133- as well as VEGFR-2+ (FF 11), where VEGFR-2 is an
alternate name for FLK (FF 4).
Therefore, Eggermann’s cells satisfy all of the specific requirements
identified by Rafii as preferred, because they are FFK (VEGFR-2)+, CD34-
and CD 133- (FF 11), providing additional reasons to select these cells of
Eggermann for use in the neovascularization process of Rafii.
Appellants contend “Eggermann et al. expressly teach away from
using their UCB unselected MNCs derived cells in the method of treating
mammals in need of neovascularization of Rafii et al. for fear of
immunological incompatibilities” (App. Br. 13). Appellants contend
“Eggermann et al. teach away from the use of unselected MNC cells in favor
of CD34 selected cultures considered closer to putative EPCs. Eggermann
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et al. expressly state in the Abstract that their objective was to compare
methods for purification of EPC from human umbilical cord blood” (Id.).
We do not find this argument persuasive. While Eggermann
recognizes the well-known fact that immunological incompatibility may
exist for some patients, Eggermann also teaches “more putative EPCs could
be generated from HUCB than from adult peripheral blood MNCs. Thus,
HUCB may be a useful source of putative EPC superior to adult peripheral
blood” (FF 12). We also agree with the Examiner that “this does not teach
away of the putative EPC of Eggermann et al. for the use within the
limitations” (Ans. 9).
[Ojbviousness must be determined in light of all the facts, and
there is no rule that a single reference that teaches away will
mandate a finding of nonobviousness. Likewise, a given course
of action often has simultaneous advantages and disadvantages,
and this does not necessarily obviate motivation to combine.
See [WinnerInt7 Royalty Corp. v. Wang, 202 F.3d 1340, 1349
n. 8 (Fed. Cir. 2000)] (“The fact that the motivating benefit
comes at the expense of another benefit, however, should not
nullify its use as a basis to modify the disclosure of one
reference with the teachings of another. Instead, the benefits,
both lost and gained, should be weighed against one another.”).
Where the prior art contains “apparently conflicting” teachings
(i.e., where some references teach the combination and others
teach away from it) each reference must be considered “for its
power to suggest solutions to an artisan of ordinary skill. . . .
considering] the degree to which one reference might
accurately discredit another.” In re Young, 927 F.2d 588, 591
(Fed. Cir. 1991).
Medichem, S.A. v. Rolabo, S.L. ,437 F.3d 1157, 1165 (Fed. Cir. 2006).
Apply the Medichem analysis to the instant facts, we find that while
the Eggermann cells would not necessarily work for every patient, the
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ordinary artisan would have had reason to select this “useful source of
putative EPC” for use in the neovascularization treatments of Rafii in
appropriate patients because more cells can be generated from Eggermann’s
HUCB and because Eggermann’s cells share the same specific requirements
identified by Rafii as preferred, because they are FLK (VEGFR-2)+, CD34-
and CD133- (FF 11). Moreover, Rafii expressly recognized that umbilical
cord blood cells (HUCB) are a preferred cell source (FF 3).
Claim 76
Appellants contend in “regard to a pharmaceutically-acceptable
medium, Eggermann et al. do not teach a composition comprising a
pharmaceutically-acceptable medium or any composition intended for
therapeutic use in a subject” (App. Br. 15). Appellants contend “the
Examiner has not provided a rational basis to include a pharmaceutically-
acceptable medium in a composition consisting of a population of human
cells” (App. Br. 16).
We find this argument unpersuasive because we agree with the
Examiner that “the culture medium of Eggermann et al. would meet the
limitation” (Ans. 5) and we agree with the Examiner that “it would have
been obvious to a person skilled in the art to use a suitable culture medium
for in vivo application with a reasonable expectation of success” (Ans. 10).
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that the
prior art renders the claims obvious.
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SUMMARY
In summary, we affirm the rejection of claims 53 and 76 under
35 U.S.C. § 103(a) as obvious over Eggermann and Rafii. Claims 55, 56,
71—74, and 77 that were not separately argued fall with claims 53 and 76.
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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