Ex Parte Tsuchiya

Patent Trials and Appeals Board

Apr 1, 2019

14228993 - (D) (P.T.A.B. Apr. 1, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
14/228,993 03/28/2014
51414 7590 04/03/2019
GOODWIN PROCTER LLP
PATENT ADMINISTRATOR
100 Northern A venue
BOSTON, MA 02210
UNITED ST A TES OF AMERICA
FIRST NAMED INVENTOR
Masakazu Tsuchiya
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.
CHR-OllDl 1032
EXAMINER
AFREMOVA, VERA
ART UNIT PAPER NUMBER
1653
NOTIFICATION DATE DELIVERY MODE
04/03/2019 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):
PA TENTBOS@GOODWINPROCTER.COM
PSOUSA-ATWOOD@GOODWINPROCTER.COM
GLENN .WILLIAMS@GOODWINPROCTER.COM
PTOL-90A (Rev. 04/07)
UNITED ST ATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte MASAKAZU TSUCHIYA
Appeal2018-001353
Application 14/228,993
Technology Center 1600
Before DEBORAH KATZ, JOHN G. NEW, and
TIMOTHY G. MAJORS, Administrative Patent Judges.
MAJORS, Administrative Patent Judge.
DECISION ON APPEAL
Appellant 1 submits this appeal under 35 U.S.C. § 134(a) involving
claims to a method of detecting (1 ~3)-P-D-glucan in a sample with the use
of a heat-treatedLimulusamebocyte lysate. The Examiner rejected the
claims as indefmite, anticipated, and obvious. We have jurisdiction under
35 U.S.C. § 6(b).
We REVERSE.
1 Appellant identifies the real party in interest as Charles River Laboratories,
Inc. App. Br. 2.
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Application 14/228,993
STATEMENT OF THE CASE
"Limulus Amebocyte Lysate (LAL) derived from the blood cells of
the American horseshoe crabs react with [bacterial] endotoxin ... or ( 1 ~ 3 )-
P-D-glucan ... forming a gel." Spec. ,r 2. As explained in the Specification,
"[ e ]ndotoxin and P-glucan trigger two distinct LAL pathways, activation of
either of which leads to gelation." Id. The Specification further explains
that a sample contaminated with endotoxin may be "lethally toxic," and that
"detection of endotoxin is important for confirming the safety of parenteral
drugs." Id.
"Because LAL reacts with either endotoxin or P-glucan, knowing
which of the two activators is present in a sample is not necessarily
straightforward." Id. ,r 3. Moreover, P-glucan, which is commonly found in,
inter alia, plants, "causes false positives in Bacterial Endotoxin Tests."
Accordingly, "detection of P-glucan contamination in parenteral drugs and
medical devices is useful to avoid unexpected rejection of a product that
should not be rejected." Id. The Specification explains, however, that "[t]he
challenge has been to develop reliable, cost-effective assays for P-glucan
detection that can distinguish the presence of P-glucan from the presence of
endotoxin." Id. ,r 5; see also id. ,r 10 ("despite efforts over the past two
decades to develop P-glucan assays, there remains a need for a simple
method for preparing LAL with a reduced sensitivity to endotoxin").
The Specification explains that it was known in the art that "heating
lysates from Asian horseshoe crabs ... to temperatures above 40°C quickly
inactivated the P-glucan-sensitive factor ('Factor G')." Id. ,r 11 ( citing a
publication by "Muta"). However, the Specification indicates that the
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Application 14/228,993
present inventor "discovered that the same is not true of lysates harvested
from the American horseshoe crab." Id. ,r 11. More specifically, "when
LAL is heated to a temperature above 40°C, sensitivity of the LAL to
endotoxin is lost more quickly than sensitivity of the LAL to P-glucan." Id.
And, by"[ e ]xploiting the differential heat-sensitivity of the endotoxin and P-
glucan pathways in LAL permits the preparation of lysates with reduced
reactivity to endotoxin while retaining reactivity to (1 ~3)-P-D-glucan." Id.;
see also id. ,r 12 ( describing methods that "include heating the LAL to
reduce Factor C activity [i.e., the endotoxin activation pathway] in the lysate
while retaining sensitivity to (1 ~3)-P-D-glucan").
Claims 14--23 are on appeal. Claim 14, the only independent claim on
appeal, is illustrative and reads as follows:
14. A method of detecting(! ~3)-P-D-glucan in a sample, the
method comprising:
combining the sample with a heat-treated Limulus
amebocyte lysate comprising (1 ~3)-P-D-glucan-sensitive
Limulus Factor G and having an endotoxin reactivity less than
0.1 % of the endotoxin reactivity of an untreated Limulus
amebocyte lysate and
detecting a change in an optical property of the sample.
(App. Br. 17 (Claims App'x).)
The claims stand rejected as follows:
I. Claims 15-18 under 35 U.S.C. § 112, second paragraph, as
indefmite.
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II. Claims 14--23under35U.S.C. § 102(b)asanticipatedby
Wainwright. 2
III. Claims 14--23 under 35 U.S.C. § 103(a) as obvious over
Finkelman, 3 Nachum, 4 Levin, 5 and Wainwright.
An oral hearing before the Board took place on March 7, 2019.
I - INDEFINITENESS
The Examiner rejected dependent claims 15-18 as indefinite. Final
Act. 2. Claim 15 depends from claim 14 and further recites "combining the
sample with a substrate for activated Limulus amebocyte lysate prior to
detecting the change in the optical property of the sample." App. Br. 17.
According to the Examiner, "[ c ]laim 15 as amended is rendered indefmite
by the term 'activated' lysate in the lack of clear defmitions in [the] as-filed
specification. It is unclear what makes the lysate being 'activated' and non-
activated. Final Act. 2. In the Examiner's Answer, the Examiner
supplements the indefmiteness rejection by suggesting there is also a "lack
of antecedent basis in the claims" for the "activated" claim term. Ans. 2.
2 Wainwright et al., US 7,329,538 B2, issued Feb. 12, 2008.
3 Malcolm A. Finkelman et al., Detection andMeasurementof (1~3)-/J-D-
Glucan with Li mulus Amebocyte L ysate-Based Reagents, Toxicology (1 ~ 3 )-
/J-Glucans 179-197 (2005)
4 Ronald Nachum et al., Inactivation ofEndotoxin by Limulus Amoebocyte
Lysate, 32 JOURNAL OF INVERTEBRATE PATHOLOGY 51-58 (1977).
5 J. Levin et al., Clottable Protein inLimulus:Its Localization and Kinetics
of Its Coagulation by Endotoxin, 19 THROMB. DIATH. HAEMORRH. 186-197
(1968).
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Application 14/228,993
Appellant argues "activated" as claimed means a lysate "in which a
pathway leading to gelation has been activated," and that this meaning is
reasonably clear from the Specification and consistent with the prior art of
record. App. Br. 3--4 (citing Spec. ,r,r 2-3, 84, Wainwright Fig. 1 (showing
activated Factor C and Factor G pathways). As for the alleged lack of
antecedent basis, Appellant contends claim 15 refers to a substrate for
activated LAL, and that there is no reference to "the" or "said" activated
LAL and, hence, no antecedent basis issue. Reply 3. 6
Appellant has the more persuasive position. As Appellant notes, the
term "activated" is reasonably clear based on the Specification, as referring
to activation of a pathway (via Factor C or Factor G), which leads to
gelation. See, e.g., Spec. ,r 2. And we conclude the skilled artisan would
reasonably understand this term from reading the Specification and based on
background knowledge in this field ( as reflected by the cited art, such as
Wainwright).
We are also unpersuaded that antecedent basis for the "activated" term
is missing in claim 15. Claim 15 recites, interalia, "combining the sample
with a substrate for activated Limulus amebocyte lysate." App. Br. 17
( emphasis added). We conclude this language merely further describes a
feature of the "substrate"-it must be a substrate for an activated LAL.
For the above reasons, we reverse the Examiner's rejection of claims
15-18 as indefmite.
6 Appellant also contends that claim 15 is distinct, and narrower than, claim
14 by virtue of reciting the "substrate" on which the sample of claim 14 is
combined. Reply 3.
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II - ANTICIPATION
The Examiner has rejected claims 14--23 as anticipated by
Wainwright. Final Act. 3--4. TheExaminerfmds that Wainwright discloses
detecting P-glucan in a sample. Id. at 3. According to the Examiner,
Wainwright describes the claimed "heat-treated" LAL because Wainwright
teaches a mixture of LAL and other agents that may be dried onto a
conduit/ cartridge "in an environment having a temperature of about 4 ° C to
about40° C." Id.; Wainwright 4:64--5:1. Citing Example 4 ofWainwright,
the Examiner fmds that Wainwright further describes a P-glucan-sensitive
LAL having an endotoxin reactivity less than 0.1 %. Final Act. 3 ( citing
Wainwright 26:41-56andFig. 16a). TheExaminerfurtherfmds that
Wainwright describes the "detecting" step of claim 14. Final Act. 3 ( citing
Wainwright 5 :48).
We are unpersuaded the Examiner has made a prima facie showing
that claim 14 is anticipated by Wainwright. In re Oetiker, 977 F.2d 1443,
144 5 (Fed. Cir. 1992) (The Examiner "bears the initial burden ... of
presenting a primafacie case ofunpatentability. ").
Wainwright's disclosure of a potential drying step for a cartridge
embodiment, does not describe sufficiently a heat-treated LAL that
maintains Factor G (P-glucan) sensitivity, while reducing endotoxin
reactivity to less than 0.1 % of an untreated (i.e., unheated) LAL as claimed.
As an initial matter, Wainwright does not describe heat as having any effect
on the relative sensitivities of the lysate to P-glucan versus endotoxin. To
the contrary, Wainwright describes creating a P-glucan specific assay (where
the LAL is substantially free of Factor C activity, yet retains Factor G
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Application 14/228,993
activity) by lysing the amebocytes in particular molar concentrations of
salt, not by application of heat. See, e.g., Wainwright 6:32-59, 26:1-55
(Example 4). The Examiner, in attempting to show satisfaction of the
"endotoxin reactivity less than 0.1 %" limitation turns to Wainwright's
Example 4. Final Act. 3. But, even if that example described the requisite
reduction in endotoxin reactivity (itself questionable), it did so with use of
salt, not heat. See Wainwright Fig. 16A-B (rows A, B, and C reflect,
respectively, the lysate in water, IM NaCl, and 2M NaCl), 8:28--42, 26:41-
55, And, as Appellant points out, Example 4 does not describe any heating
or drying of the LAL-rather the supernatant including the LAL is harvested
directly following removal of cell debris by centrifugation. App. Br. 8.
Recognizing this deficiency, the Examiner's Answer turns to another
example in Wainwright, Example 5. Ans. 8. Putting aside the potential
problem of combining embodiments for a rejection based on anticipation, 7
as Appellant notes, this example too creates a P-glucan-specific LAL with
salt, not heat, and to the extent temperature is described at all for this
example, it indicates drying at slightly above room temperature (25°C).
Reply 5---6. There is no evidence cited by the Examiner to indicate that
drying at such relatively low temperatures would result in the P-glucan-
specific LAL as claimed. Indeed, the evidence of record suggests the
opposite. See, e.g., Spec. 22 (Tables 1 and 2 ( showing that incubating at
7 In re Arkley, 455 F.2d 586,587 (CCPA 1972) (explaining that anticipation
requires the art "clearly and unequivocally disclose the claimed [invention]
or direct those skilled in the art to the [invention] without any need for
picking, choosing, and combining various disclosures not directly related to
each other by the teachings of the cited reference").
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40°C for up to 30 minutes has little effect on lysate reactivity to endotoxin
and P-glucan)).
As for Wainwright's disclosure of a range of potential drying
temperatures, from about 4--40°C, we are not persuaded that disclosure is
adequate to show anticipation of the heat-treated LAL with the specificity
claimed. 8 The Examiner cites this broad temperature range in Wainwright
and compares to Appellant's Specification, which describes heating the LAL
to between40-80°C. Ans. 7; Spec. ,r 16. It, thus, appears to be the
Examiner's position that, because the upper-bound drying temperature in
Wainwright marginally overlaps or touches the lower-bound temperature in
the Specification, Wainwright describes the recited heat treatment and
anticipates the claims. The problems with this position are several-fold. We
discuss below.
First, the Federal Circuit has emphasized caution when anticipation is
based on ranges disclosed in the prior art, even when a claimed range is
wholly encompassed within a broad range recited in the prior art, which is
not the case here. See Atofina v. Great Lakes Chemical Corp., 441 F.3d 991,
998-1000 (Fed. Cir. 2006) ("Given the considerable difference between the
claimed range [330-450°CJ and the range in the prior art [100-500°CJ, no
reasonable fact fmder could conclude that the prior art describes the claimed
range with sufficient specificity to anticipate this limitation of the claim.").
8 The relevant disclosure in Wainwright describes drying at a "temperature
of about 4 °C. to about 40° C., more preferably, from about 10° C. to about
35° C., more preferably, from about 15° C. to about30° C .... Preferably,
the temperature is about 25° C." Wainwright 4:66-5:6.
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Second, there is no actual species described in Wainwright, where the lysate
is heated or dried at 40°C. Merely a range is disclosed, and the preferred
and exemplified temperature ofWainwright is 25°C. SeeAtofina, 441 F.3d
at 1000 (holding "the disclosure of a range of 150 to 350 °C does not
constitute a specific disclosure of the endpoints of that range, i.e., 150 ° C
and 350 ° C"). Third, claim 14 does not recite a particular temperature or
range for the heat treatment, yet it recites the result of that heat treatment-
the LAL remains sensitive to P-glucan while endotoxin reactivity is reduced
to less than 0.1 %. The Specification does describe a heat treatment range of
between 40-80° C, but the time at which the LAL must be treated at 40° C
to reach the reactivity recited in claim 14 exceeds any drying time at 40° C
specifically described in Wainwright. As discussed above, incubating the
LAL at 40° C for up to 30 minutes had little effect on the respective
reactivity to P-glucan and endotoxin. Spec. ,r 86. 9
For the reasons above, we are unpersuaded the preponderance of the
evidence cited by the Examiner establishes anticipation of claim 14, or
dependent claims 15-23 by Wainwright.
9 Wainwright, here too, describes a broad range of drying times ( from about
10 minutes to 8 hours), and "preferably for about 1 hour." Wainwright 5 :7-
8. Even if one interpreted Wainwright as specifically describing drying at
40° C for 8 hours, the Specification indicates that would not result in a LAL
with an endotoxin reactivity less than 0.1 %. Indeed, at 40° C and heating
for 12.5 hours, the endotoxin reactivity was estimated to be at 0.108%, and
0.0% when heated for over220 hours. Spec. ,r 106 (Table 7).
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III-OBVIOUSNESS
The Examiner has rejected claims 14--23 as obvious over Finkelman,
Nachum, Levin, and Wainwright. Final Act. 4---6.
The Examiner fmds that Finkelman teaches detecting (1 ~3)-P-D-
glucan in a sample, where the LAL is specific for P-glucan, and has no
endotoxin reactivity. Final Act. 5. The Examiner fmds further that
Finkelman describes detecting changes in optical properties of the sample.
Id. Because Finkelman is "silent about heat treatment" of the LAL, the
Examiner turns to Nachum, Levin, and Wainwright. Id. at 5---6.
According to the Examiner, Nachum teaches "heating for 20 min
at 60 °C, 80 °C, and 100 °C ... provided for reduc [ ed] endotoxin
reactivity," and Levin teaches "heating for about30 min at about 56 °C
causes total reduction of lysate reactivity to endotoxin." Id. at 6. As above,
the Examiner fmds that Wainwright discloses drying the LAL up to 40°C.
Id.
The Examiner, thus, concludes it would have been obvious "to use the
'heat-treated' Limulus amebocyte lysate in order to provide for reduced
biological activities of endotoxin-reactive proteins in the lysate and, thereby,
to relatively change activities of various proteins including Factor C and
Factor Gin the Limulus amebocyte lysate preparation." Id.
We are unpersuaded. There is simply no teaching in the prior art on
this record, or other persuasive scientific reasoning provided, to explain why
heating the LAL would have been expected to decrease the reactivity of the
lysate to endotoxin (below 0.1 % of an untreated lysate) while maintaining
sensitivity to P-glucan. The evidence here is, in fact, to the contrary.
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Nachum and Levin describe heating the lysate to above 60°C and 56°C for
20 and 30 minutes respectively. Final Act. 5---6. Indeed, both references
specifically heated the lysate to inactivate the clotting enzyme in the LAL.
Nachum 53 ("heating whole LAL to 60°C for 20 min .... inactivated the
clotting enzyme in LAL ... , rendering the LAL incapable of gel formation
in the presence of endotoxin. "); Levin 192 ("Heating the cell lysate for 30
min at 56° C ... rendered the lysate incoagulable. "). But, heating at those
temperatures and times would not only inactivate the lysate to endotoxin, but
to P-glucan as well. 10 Tables 1 and 2 of the Specification, for example,
provide data showing that heating to 50°C for even 20 minutes renders the
lysate unreactive to both the endotoxin and P-glucan. Spec. ,r 86. The
lysate, heated as in N achum and Levin is, thus, not specific to one
compound versus the other, contrary to the claims and the whole point of
Appellant's invention. The deficiencies of Wainwright are discussed above.
Moreover, as Appellant argues persuasively, the ordinarily skilled
person, attempting to design a P-glucan-sensitive LAL assay would not have
been motivated to heat the LAL to temperatures greater than 40°C. App. Br.
13-14. According to Appellant, evidence of record (particularly the Muta
reference) shows that when amebocyte lysates from Asian horseshoe crabs
are heated to temperatures above 40°C, Factor G becomes unstable and is
quickly inactivated. Id. at 14--15; Spec. ,r 11 ( discussing Muta). As
10 The Examiner has not shown, in N achum, how the presence of another
enzyme, the endotoxin-inactivating factor ( 60C-S), which is apparently not
destroyed at temperatures at or above 60°C is germane to the activation of
either Factor G or Factor C pathways, which are the basis of the differential
heat-treatment, and lysate-specificity of the claimed invention.
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explained in the Specification, Factor G is required for the lysate's
sensitivity to (1 ~3)-P-D-glucan. Spec. ,r,r 11, 20, 34. Based on this
evidence, had the skilled person heated the lysate to above 40°C ( especially
at temperatures such as those described in Levin and Nachum), they would
not have reasonably expected retention of P-glucan sensitivity as claimed.
App. Br. 14--15.
The Examiner responds that Appellant's reliance on Muta, as
evidencing a lack of a reasonable expectation of success, is flawed because
Muta studied amebocyte lysates from a different species than is claimed-
the Asian horseshoe crab versus the American horseshoe crab. Ans. 9-10.
We disagree with this ex-post reasoning. Without evidence, we are
unpersuaded the skilled person would so readily dismiss and distinguish
Muta's teachings at the time of the invention, as the Examiner has done now.
For the above reasons, we determine that the preponderance of the
evidence cited by the Examiner on this record does not support a conclusion
that claim 14 ( or its dependent claims) would have been obvious.
SUMMARY
We reverse the rejections for indefmiteness, anticipation, and
obviousness on appeal.
REVERSED
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