Ex Parte Keimel

Patent Trial and Appeal Board

Feb 11, 2013

11124984 (P.T.A.B. Feb. 11, 2013)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte JOHN G. KEIMEL
__________

Appeal 2011-001176
Application 11/124,984
Technology Center 3700
__________

Before DEMETRA J. MILLS, MELANIE L. McCOLLUM, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to methods
of treatment of cardiac disorders. The Examiner rejected the claims as
obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm-in-part.

Appeal 2011-001176
Application 11/124,984

2
Statement of the Case
Background
“The present invention uses an implantable source and catheter to
deliver a therapeutic protein formulation containing a protein in a form that
is deficient in cardiac cells in a patient with a cardiac disorder. The protein
formulation is delivered by the catheter to a pericardial sac region of the
heart.” (Spec. 4 ¶ 0012.)
The Claims
Claims 18, 23, 25, and 32-36 are on appeal. Claims 18 and 34 are
representative and read as follows:
18. A method comprising:
diagnosing a patient as having a cardiac disorder
caused by a protein deficiency due to a gene mutation,
the disorder being selected from the group consisting of
glycogen storage disease Type II and Fabry disease;
injecting a therapeutic protein formulation into an
implantable source, the therapeutic protein formulation
comprising a protein in a form that is deficient in cardiac
cells in the patient with the cardiac disorder, the protein
being selected from lysosomal acid -glucosidase and -
galactosidase;
determining a rate for delivering the therapeutic
protein formulation based on the genetic sequence of the
patient‟s gene encoding the deficient protein or enzyme
level assessment of cardiac tissue; and
delivering the therapeutic protein formulation from
the source through an implantable catheter directly to a
pericardial sac region of a heart of a patient,
wherein the source is an implantable pump that
provides for a programmable delivery rate of the protein
formulation, and wherein the protein formulation is
delivered at the determined delivery rate.

Appeal 2011-001176
Application 11/124,984

3
34. The method of claim 18, wherein the rate for
delivering the therapeutic protein formulation is based on
the genetic sequence of a patient‟s gene encoding the
deficient protein.

The issues

A. The Examiner rejected claims 18, 23, 25, and 32-34 under 35 U.S.C. §
103(a) as obvious over LeBowitz,
1
Struijker-Boudier,
2
and Stafford
3
(Ans. 3-
5).
B. The Examiner rejected claims 18, 23, 25, 32, 33, 35, and 36 under 35
U.S.C. § 103(a) as obvious over LeBowitz, Struijker-Boudier, and Martinez
4

(Ans. 5-6).
We begin our analysis with claim interpretation. The “determining”
step in claim 18 recites two alternative modes of identifying “a rate for
delivering the therapeutic protein formulation”. The first mode is through
the “genetic sequence of the patient‟s gene”. The second mode is through an
“enzyme level assessment of cardiac tissue”. The Examiner addressed both
alternatives by applying two rejections, the first rejection including Stafford
to address the first “genetic sequence” mode and the second rejection
including Martinez to address the second “enzyme level” mode. We
therefore separately address these rejections consistent with the mode relied
upon by the Examiner.

1
LeBowitz et al, US 2005/0281805 A1, published Dec. 22, 2005.
2
Struijker-Boudier et al., US 2003/0009145 A1, published Jan. 9,
2003.
3
Stafford et al., US 2006/0240440 A1, published Oct. 26, 2006.
4
Martinez, G., US 6,592,519 B1, issued Jul. 15, 2003.
Appeal 2011-001176
Application 11/124,984

4
A. 35 U.S.C. § 103(a) over LeBowitz, Struijker-Boudier, and Stafford
The Examiner finds that “LeBowitz teaches a method of supplying a
lyosomal [sic] acid alpha-glucosidase . . . or alpha-galatosidase (Example
12, treatment of Fabry disease) to cells in the body, where the protein
formulation includes deficient proteins” (Ans. 4). The Examiner finds that
“LeBowitz does not specifically teach delivery to the heart or pericardial sac
with a drug pump or determining the drug delivery rate based on the
patient‟s genetic sequence” (id.).
The Examiner finds that “Strutjket-Boulder [sic] teaches a method and
device for treating a cardiac disorder, such as a cardiodegenerative disease
(P0113) using a source (pump, P0166-0184) for supplying a protein
formulation (P0185-0197) to the pericardial sac via a catheter” (Ans. 4).
The Examiner finds that “Stafford teaches delivering a drug (warfarin) to
treat a genetic variation (vitamin K epoxide reductase mutation) by varying
the drug delivery dosage and rate based on the patient‟s specific genetic
mutation” (id.).
The Examiner finds it obvious to
use the teachings of Stafford regarding relating treatment of
a genetic variation to the patient‟s genetic mutation to adjust
delivery of a protein formulation for treatment of GSD Type
II or Fabry disease, since both diseases are genetic disorders.
Applying the teachings of Stafford would involve only
routine skill in the art since it has been held that improving
similar methods (treatment of genetic variation) in the same
way is within the skill of an ordinary worker in the art

(id. at 4-5).
Appeal 2011-001176
Application 11/124,984

5
The issue with respect to this rejection is: Does the evidence of record
support the Examiner‟s conclusion that LeBowitz, Struijker-Boudier, and
Stafford render claim 18 obvious?
Findings of Fact
1. LeBowitz teaches “to evaluate the efficacy of GILT-modified
alpha-galactosidase A ( -GAL A) as an enzyme replacement therapy for
Fabry‟s disease” (LeBowitz 21 ¶ 0199).
2. LeBowitz teaches that “Fabry‟s disease is a lysosomal storage
disease resulting from insufficient activity of -GAL A, the enzyme
responsible for removing the terminal galactose from GL-3 and other neutral
sphingolipids. The diminished enzymatic activity occurs due to a variety of
missense and nonsense mutations in the X-linked gene” (LeBowitz 21 ¶
0200).
3. LeBowitz teaches that the “glycosylation independent
lysosomal targeting (GILT) technology of the present invention directly
targets therapeutic proteins to the lysosome via a different interaction with
the IGF-II receptor” (LeBowitz 21 ¶ 0203).
4. LeBowitz teaches that the “improved range of tissue
distributions could include delivery of GILT-modified -GAL A across the
blood-brain barrier since IGF proteins demonstrably cross the blood-brain
barrier” (LeBowitz 21 ¶ 0203).
5. LeBowitz teaches that an “enzyme dose can be about 1 mg/kg
body weight administered intravenously, and the enzyme concentration
about 1-3 mg/mL. As another example, a dose of about 5 mg/kg body weight
of . . . protein treated with periodate and sodium borohydride can be
Appeal 2011-001176
Application 11/124,984

6
administered. Injections can, for example, be weekly” (LeBowitz 23 ¶
0224).
6. Struijker-Boudier teaches that:
A drug can be administered into the pericardial fluid
using any of a number of delivery systems, including
sustained release devices. In some embodiments, the drug
delivery system will comprise a catheter operably attached
to a sustained release drug delivery device. A proximal end
of the catheter is operably attached to a sustained release
drug delivery device; and a distal end of the catheter may be
adapted for transpericardial delivery, or may be adapted for
intrapericardial delivery.

(Struijker-Boudier 12 ¶ 0168.)
7. Struijker-Boudier teaches that a “drug delivery device of the
invention may release drug in a range of rates of from about 0.01
microgram/hr to about 500 microgram /hr, and which can be delivered at a
volume rate of from about 0.01 microliter/day to about 100 microliter/day”
(Struijker-Boudier 13 ¶ 0174).
8. Struijker-Boudier teaches that “[d]rug release devices based
upon a mechanical or electromechanical infusion pumps can also be suitable
for use with the present invention” (Struijker-Boudier 13 ¶ 0177).
9. Struijker-Boudier teaches that “[c]ardiomyopathies include . . .
metabolic disorders . . . and idiopathic causes” (Struijker-Boudier 16 ¶
0219).
10. Stafford teaches “a method of correlating a single nucleotide
polymorphism in the VKOR gene of a subject with increased or decreased
sensitivity to warfarin” (Stafford 1 ¶ 0013).
Appeal 2011-001176
Application 11/124,984

7
11. Stafford teaches “correlating single nucleotide polymorphisms
in a subject with an increased or decreased sensitivity to warfarin, thereby
allowing for more accurate and rapid determination of therapeutic and
maintenance doses of warfarin at reduced risk to the subject” (Stafford 1 ¶
0006).
12. Stafford teaches that by “direct genomic DNA sequencing and
SNP realtime PCR detection, five SNPs were identified in the VKOR gene:
one in the 5'-UTR, two in intron 11, one in the coding region and one in the
3'-UTR” (Stafford 8 ¶ 0085).
Principles of Law
“In proceedings before the Patent and Trademark Office, the
Examiner bears the burden of establishing a prima face case of obviousness
based upon the prior art.” In re Fritch, 972 F.2d 1260, 1265 (Fed. Cir. 1992).
To establish a prima facie case of obviousness, the Examiner must
find “a reason that would have prompted a person of ordinary skill in the
relevant field to combine the elements in the way the claimed new invention
does.” KSR Int’l. Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007).
Analysis
Lebowitz inherently teaches diagnosis of Fabry disease and teaches
treatment of Fabry disease using an injectable therapeutic formulation of -
galactosidase (FF 1-5). Struijker-Boudier teaches delivering the protein
drug to the pericardial sac of a patient using a pump that provides for
programmed rates of delivery (FF 6-9). Stafford teaches “correlating single
nucleotide polymorphisms in a subject with an increased or decreased
sensitivity to warfarin, thereby allowing for more accurate and rapid
Appeal 2011-001176
Application 11/124,984

8
determination of therapeutic and maintenance doses of warfarin at reduced
risk to the subject” (Stafford 1 ¶ 0006; FF 11).
While this evidence might be sufficient to support a prima facie case
against a generic method of providing a delivery rate of a therapeutic drug
based upon single nucleotide polymorphisms, Claim 18 and all the
dependent claims are limited to either glycogen storage disease Type II or
Fabry disease.
The Examiner has provided no evidence that there are any known
mutations, in the prior art, which are associated with either glycogen storage
disease Type II or Fabry disease and which correlate with a requirement for
treatment with additional amounts of either lysosomal acid glucosidase or
-galactosidase. The Specification does not provide any discussion of such
mutations nor does the Specification disclose that the prior art was aware of
such mutations. In the absence of such evidence, the Examiner has not
established a prima facie case of obviousness since the prior art does not
demonstrate that any rate of protein level can be determined by any SNP or
genetic sequence encoding the deficient proteins in either glycogen storage
disease Type II or Fabry disease as required by the determining step of claim
18.
Conclusion of Law
The evidence of record does not support the Examiner‟s conclusion
that LeBowitz, Struijker-Boudier, and Stafford render claim 18 obvious.

Appeal 2011-001176
Application 11/124,984

9
B. 35 U.S.C. § 103(a) over LeBowitz, Struijker-Boudier, and Martinez
The Examiner finds that “LeBowitz teaches a method of supplying a
lyosomal [sic] acid alpha-glucosidase . . . or alpha-galatosidase (Example
12, treatment of Fabry disease) to cells in the body, where the protein
formulation includes deficient proteins” (Ans. 5). The Examiner finds that
“LeBowitz does not specifically teach delivery to the heart or pericardial sac
with a drug pump or determining the drug delivery rate based on the
patient‟s genetic sequence” (id.). The Examiner finds that “Strutjket-
Boulder [sic] teaches a method and device for treating a cardiac disorder,
such as a cardiodegenerative disease (P0113) using a source (pump, P0166-
0184) for supplying a protein formulation (P0185-0197) to the pericardial
sac via a catheter” (Ans. 5).
The Examiner finds that “Martinez teaches delivering a drug based on
the local enzyme level assessment of the drug delivery area” (Ans. 6). The
Examiner finds it obvious “to use the teachings of Martinez regarding
relating treatment using a smart drug delivery pump controlled by a sensor
with the pump of Strutijiket-Boulder to more finely control drug delivery (as
taught by Martinez)” (Ans. 6).
The issue with respect to this rejection is: Does the evidence of record
support the Examiner‟s conclusion that LeBowitz, Struijker-Boudier, and
Martinez render claim 18 obvious?
Findings of Fact
13. Martinez teaches that sensors “can facilitate the implementation
of „smart‟ devices that can monitor and control the concentration and
amount of drug delivery” (Martinez, col. 7, ll. 21-23).
Appeal 2011-001176
Application 11/124,984

10
14. Martinez teaches that “[s]ensors 50 and 53 . . . can monitor the
physiological condition 60 of a local area of a patient based on local
chemistry, e.g. . . . enzymes, or other optically detectable biological species”
(Martinez, col. 7, ll. 29-33).
15. Martinez teaches that the “readings by sensor 53 at a second
location 55 can be converted to electrical signals and transmitted to a smart
electronics-actuator system 70 that can deliver the required therapy to the
patient based on the sensor reading” (Martinez, col. 7, ll. 34-38).
Principles of Law
The Supreme Court has emphasized that “the [obviousness] analysis
need not seek out precise teachings directed to the specific subject matter of
the challenged claim, for a court can take account of the inferences and
creative steps that a person of ordinary skill in the art would employ.” KSR
Int’l v. Teleflex Inc., 550 U.S. 398, 418 (2007).
As noted by the Court in KSR, “[a] person of ordinary skill is also a
person of ordinary creativity, not an automaton.” Id. at 421. “The
combination of familiar elements according to known methods is likely to be
obvious when it does no more than yield predictable results.” Id. at 416.
Analysis
Lebowitz inherently teaches a first step of diagnosis of Fabry disease
and explicitly teaches a second step of injecting a protein formulation into
patients for treatment of Fabry disease using a therapeutic formulation of -
galactosidase (FF 1-5). Martinez teaches determining a rate for delivery of
enzymes by measuring the enzyme level using sensors and transmitting that
information to an implantable device (FF 13-15). Struijker-Boudier teaches
Appeal 2011-001176
Application 11/124,984

11
delivering the protein drug to the pericardial sac of a patient using a pump
that provides for programmed rates of delivery with a drug delivery device
(FF 6-9).
Applying the KSR standard of obviousness to the findings of fact, we
agree with the Examiner that the ordinary artisan would have reasonably
found it obvious to diagnose and treat Fabry disease heart damage using the
delivery system of Struijker-Boudier as controlled by the enzyme sensors of
Martinez. Such a combination is merely a “predictable use of prior art
elements according to their established functions.” KSR, 550 U.S. at 417.
Appellants contend that “[b]ecause the sensors 50 and 53 of Martinez
discussed in the Final Action are not at the tissue to which the drug is being
delivered, the sensors 50 and 53 do not assess the local enzyme level of the
drug delivery area” (App. Br. 9).
We are not persuaded. Martinez teaches that “[s]ensors 50 and 53 . . .
can monitor the physiological condition 60 of a local area of a patient based
on local chemistry, e.g. . . . enzymes, or other optically detectable biological
species” (Martinez, col. 7, ll. 29-33; FF 14). This is an express focus on
monitoring enzymes in any specific location of interest.

Appeal 2011-001176
Application 11/124,984

12
SUMMARY
In summary, we reverse the rejection of claims 18, 23, 25, and 32-34
under 35 U.S.C. § 103(a) as obvious over LeBowitz, Struijker-Boudier, and
Stafford.
We affirm the rejection of claims 18, 23, 25, 32, 33, 35, and 36 under
35 U.S.C. § 103(a) as obvious over LeBowitz, Struijker-Boudier, and
Martinez.

AFFIRMED-IN-PART

cdc