Ex Parte Trese et al

Board of Patent Appeals and Interferences

May 18, 2010

10068314 (B.P.A.I. May. 18, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________

Ex parte MICHAEL T. TRESE, GEORGE A. WILLIAMS, and
MICHAEL K. HARTZER
____________

Appeal 2009-007265
Application 10/068,314
Technology Center 3700
____________

Decided: May 19, 2010
____________

Before JOHN C. KERINS, STEVEN D.A. McCARTHY, and
MICAHEL W. O’NEILL, Administrative Patent Judges.

O’NEILL, Administrative Patent Judge.

DECISION ON APPEAL

STATEMENT OF THE CASE
Michael T. Trese et al. (Appellants) appeal under 35 U.S.C. § 134
from the Examiner’s decision finally rejecting claims 1-10, 13-21, and 24-28
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under 35 U.S.C. § 103(a). We have jurisdiction under 35 U.S.C. § 6(b). We
REVERSE.
The Invention
The claims on appeal relate to a process for liquefaction of human
vitreous.
Claim 1, reproduced below, is illustrative of the subject matter on
appeal.
1. A process for human vitreous liquefaction
comprising the steps of:
delivering a dose of plasmin in a range of less than 0.4
units to 0.1 units and in a volume of about 0.1 cubic centimeters
into a vitreous body of a subject human eye; and
incubating the plasmin in the vitreous body for a
predetermined amount of time to create a liquefied vitreous.

The Rejections
The following Examiner’s rejections are before us for review:
Claims 1-7, 9, 10, 13-18, 20, 21, and 24 stand rejected under 35
U.S.C. § 103(a) as unpatentable over Margherio1.
For this ground of rejection, the Examiner finds Margherio discloses
the delivery of autologous plasmin, at a dose of 0.4 units, into a vitreous
body and then incubating the plasmin in the vitreous. The Examiner
acknowledges that Margherio fails to disclose using smaller doses. The
Examiner finds that in the medical arts it is known to vary the dose size
dependent upon the patient size as well as the location of the injection of the
dose. The Examiner concludes based on these findings that a person of

1 Alan R. Margherio, MD et al., Plasmin enzyme-assisted vitrectomy in
traumatic pediatric macular holes, Ophthalmology, Vol. 105, Issue 9, 1617-
1620 (1998) (available online at http://www.sciencedirect.com).
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ordinary skill in the art would modify Margherio to have the dose less than
0.4 IU and bolsters this conclusion by finding the claimed range lacks
criticality. Ans. 3
Claims 8, 19, and 25-28 stand rejected under 35 U.S.C. § 103(a) as
unpatentable over Margherio and Trese2.
The Examiner relies on the findings utilized to conclude claims 1-7, 9,
10, 13-18, 20, 21, and 24 are rendered obvious by Margherio and further
finds Trese’s teachings use a plasmin inhibitor and the claimed needle
gauge. As such, the Examiner concludes that the combined teachings render
obvious claims 8, 19, and 25-28. Ans. 4.
Contentions
Appellants contend that the Examiner utilizes hindsight reconstruction
in order to extend Margherio’s teachings beyond the treatment of macular
holes. App. Br. 4. Appellants contend that Margherio is solely directed to
the belief that higher doses of plasmin might allow a less-traumatic
separation of the vitreous from the retina and the optic-nerve head. App. Br.
5. Appellants contend that, based on Margherio’s teachings, a person of
ordinary skill in the art would conclude that the disclosed plasmin enzyme at
the disclosed dose of 0.4 IU is only beneficial for promoting detachment of
the vitreous from the surrounding tissue. App. Br. 6.
Appellants also contend, contrary to the Examiner’s findings, that a
person of ordinary skill in the art would not reason that the dose of plasmin
would be adjusted according to different sizes of patients or location of
administration of the dose because the same dose amount of 0.4 IU was used

2 Michael T. Trese, MD et al., A new approach to stage 3 macular holes,
Ophthalmology, Vol. 107, Number 8, 1607-1611 (2000).
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in the eyes of all four patients ranging from ages 11 to 14. Id. Appellants
further bolster their contention that a person of ordinary skill in the art would
not reduce the disclosed dose based on the Examiner’s rationale because the
same dose of 0.4 IU was used in patients ranging in age from 61 to 82 years.
App. Br. 7. Appellants contend that the Examiner’s modification of
reducing the dose of plasmin to less than 0.4 IU as the claims set forth has
no reasonable expectation of success in human vitreous liquefaction because
Trese discloses that vitreous liquefaction is variable at a dose of 0.4 IU.
App. Br. 10.

OPINION
Issues
The determinative issue in this appeal is:
Whether Appellants have shown that the Examiner erred in
concluding that Margherio renders obvious the process of liquefaction of the
human vitreous by delivering a dose of plasmin into the human vitreous and
incubating the plasmin for a predetermined amount of time in order to create
a liquefied vitreous.
Pertinent Facts
Margherio
Margherio discloses a study to evaluate the benefit of plasmin
enzyme-assisted macular hole surgery on pediatric patients with traumatic
macular holes. In pediatric patients, Margherio explains that the vitreous is
adherent to the retina and optic nerve head. Margherio explains that a
publication reports plasmin enzyme has been helpful in separating the
vitreous from the retina in animals. From this publication, Margherio
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deduces that application of plasmin enzyme might allow a less-traumatic
separation of the vitreous from the retina and the optic nerve head.
In order for this study to proceed, patient consent was required.
Patient consent qualified the utilization of autologous plasmin only if the
posterior vitreous detachment3 (PVD) could not be achieved safely by
standard methods.
Margherio reports the procedure for one patient in depth. Margherio
reports a PVD was done mechanically with a vitrectomy instrument on
active suction only and reports that removal of the vitreous appeared
successful. Margherio reports that upon further procedures it became
apparent that the cortical vitreous remained attached to the posterior of the
eye and several mechanical attempts were made to remove the remaining
vitreous. The mechanical attempts failed.
Upon failure of the mechanical attempts to remove the remaining
vitreous, viz., the cortical vitreous, the study’s procedure was implemented
based on the patient’s consent. Margherio discloses that 0.4 IU of
previously made plasmin was injected into the vitreous cavity and incubated
for 15 minutes. Margherio discloses that while the remaining cortical
vitreous was separated from the underlying neurosensory retina after the
injection of plasmin, mechanical removal was required in order to remove
the cortical vitreous from the underlying neurosensory retina surrounding the
macular hole.
Margherio summarizes the procedure for subsequent patients. Instead
of injecting the plasmin enzyme into the vitreous cavity after removal of the

3 Posterior vitreous detachment is the detachment of the vitreous from the
retina.
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vitreous core, 0.4 IU of autologous plasmin was injected into the vitreous
cavity at the beginning of the procedure. Fifteen minutes elapsed for
enzymatic cleavage to occur on the vitreoretinal interface. Then a standard
vitrectomy was performed with peeling of the posterior cortical vitreous
using a technique described in the medical literature.
Trese
Trese discloses an experimental surgical technique where 0.4 IU of
autologous plasmin enzyme in a volume of 0.12 ml was injected into the
midvitreous cavity through the pars plana. After waiting 15 minutes, Trese
discloses two wounds were made through the pars plana and a light pipe and
vitreous cutter were placed into the midvitreous cavity. Trese discloses the
amount of liquefaction present in the vitreous cavity was graded using the
light pipe to assess the amount of optically empty space. Trese discloses
that liquefaction was graded as small, medium, or large. Trese reports after
the assessment of PVD and vitreous liquefaction, the vitreous cutter
positioned in the midvitreous cavity was engaged and suction cutting
proceeded. After a period of suction cutting, Trese reports that the anterior
retinal surface of the posterior pole was checked to see whether any vitreous
remained.
Trese provides a discussion of this study and other studies utilizing
autologous plasmin enzymes. Trese discusses that previously it has been
demonstrated in rabbits that autologous plasmin enzyme in a dose-dependent
fashion contributes to liquefaction of the vitreous. Concerning human eyes,
Trese discusses that autologous plasmin could give a spontaneous or easy-
to-create posterior vitreous separation. Trese discusses after injecting the
eye with 0.4 IU of the autologous plasmin enzyme and waiting 15 minutes,
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the enzyme reaches a peak activity on the substrates of the laminin and
fibronectin. Trese discusses that the enzyme digesting the laminin and
fibronectin allows for an atraumatic posterior separation spontaneously or a
relatively atraumatic peeling of the posterior hyaloid from the anterior
retinal surface. Trese discloses that liquefaction features of plasmin enzyme
are prominent in animal eyes using 0.1 units of plasmin; however, a dose of
0.4 IU of autologous plasmin enzyme, while producing a PVD in humans,
does not show the reliable liquefaction of vitreous that was seen in animal
subjects. Accordingly, Trese concludes that a vitreous cutter is still
necessary to safely remove the partially liquefied vitreous and while the dose
of 0.4 IU can achieve spontaneous posterior separation of the vitreous,
liquefaction of the vitreous at such a dose is variable in human eyes.
Analysis
Based on the record, we agree with Appellants that Margherio’s
disclosure fails to render obvious the subject matter set forth in claim 1.
From our finding above, Margherio discloses a study to evaluate the benefit
of plasmin enzyme when performing macular hole surgery. Margherio
discloses one of the difficulties with this surgery is detaching the vitreous
from the posterior of the eye, i.e., the neuroretinal area. While Margherio
discloses 0.4 IU of plasmin enzyme was injected into all patients, for one
patient this was done after the vitreous was already removed, and only upon
discovery that the cortical vitreous remained attached was the injection of
plasmin enzyme performed. Even after injection of the plasmin enzyme,
Margherio discloses that separating the cortical vitreous from the retinal area
required mechanical removal of the tissue for this patient. The other patients
had the plasmin enzyme injected prior to removal of the vitreous. However,
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Margherio discloses that a standard vitrectomy was performed and the
posterior cortical vitreous still had to be peeled away according to known
surgical techniques. As such, Margherio does not expressly disclose that
liquefaction of the human vitreous occurred prior to the macular hole
surgery.
Appellants’ contentions along with the submitted declarations provide
a convincing line of reasoning that a person of ordinary skill in the art would
not consider that Margherio renders obvious delivering a dose of plasmin to
create a liquefied vitreous. Margherio fails to expressly mention
liquefaction of the vitreous. At most, Margherio’s express disclosure can be
fairly read as teaching the utilization of plasmin enzyme to assist in peeling
away the remaining cortical vitreous from the vitreoretinal interface. It is
speculative to find that liquefaction occurs at this interface after delivery of
the dose of plasmin based on Margherio. Based on a reading of Margherio’s
disclosure as it would be understood by persons of ordinary skill in the art,
and Appellants’ arguments and declaratory evidence, the Examiner’s factual
basis is deficient with respect to being able to conclude that liquefaction of
the vitreous occurs at the vitreoretinal interface, much less any other location
within the vitreous.
The Examiner does not utilize Trese to cure the aforementioned
deficiency of Margherio.

CONCLUSION
Appellants have shown that the Examiner erred in concluding that
Margherio and Trese render obvious the process of liquefaction of the
human vitreous by delivering a dose of plasmin into the human vitreous and
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incubating the plasmin for a predetermined amount of time in order to create
a liquefied vitreous.

DECISION
The decision of the Examiner to reject the claims as obvious is
reversed.

REVERSED

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