Sangamo BioSciences, Inc. et al.

Patent Trials and Appeals Board

Jan 27, 2021

2020003547 (P.T.A.B. Jan. 27, 2021)

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.
14/706,747 05/07/2015 Steven Froelich 8325-0121 (S121-US1) 4789
20855 7590 01/27/2021
PASTERNAK PATENT LAW
1900 EMBARCADERO ROAD
SUITE 211
PALO ALTO, CA 94303
EXAMINER
HILL, KEVIN KAI
ART UNIT PAPER NUMBER
1633
MAIL DATE DELIVERY MODE
01/27/2021 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte STEVEN FROELICH, SEUNG KWAK, IGNACIO MUNOZ-
SANJUAN and H. STEVE ZHANG
____________

Appeal 2020-003547
Application 14/706,747
Technology Center 1600
____________

Before TAWEN CHANG, DEVON ZASTROW NEWMAN, and
MICHAEL A. VALEK, Administrative Patent Judges.

VALEK, Administrative Patent Judge.

DECISION ON APPEAL
Appellant1 submits this appeal under 35 U.S.C. § 134(a) involving
claims to methods of treating a subject with Huntington’s Disease (HD). We
have jurisdiction under 35 U.S.C. § 6(b).
We REVERSE.

1 We use the word “Appellant” to refer to “applicant” as defined in
37 C.F.R. § 1.42(a). Appellant identifies Sangamo BioSciences, Inc., and
CHDI Foundation, Inc. as the real parties in interest. Appeal Br. 2. Herein,
we refer to the Final Action mailed July 2, 2019 (“Final Act.”); Appellant’s
Appeal Brief filed January 2, 2020 (“Appeal Br.”); Examiner’s Answer
mailed February 12, 2020 (“Ans.”); and Appellant’s Reply Brief filed April
7, 2020 (“Reply Br.”).
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STATEMENT OF THE CASE
The Specification describes “methods and compositions for
diagnosing and/or treating Huntington’s Disease,” including “a method of
modifying a neuron in a subject with HD, the method comprising
administering a repressor of a mutant Htt allele to the subject such that the
neuron is modified.” Spec. ¶¶ 12–13.
Claims 1, 6–9, and 17 are on appeal and can be found in the Claims
Appendix of the Appeal Brief. Claim 1 is illustrative of the claims on
appeal. It reads as follows:
1. A method of reducing expression of a mutant Huntingtin
(mHtt) gene to reduce or prevent the formation of Htt
aggregates in a medium spiny neuron in a subject with
Huntington’s Disease (HD), the method comprising
administering to the striatum of the subject a
polynucleotide encoding a repressor of a mutant Htt (mHtt)
allele, the repressor comprising a zinc finger protein designated
30640, 30645 or 33074, wherein the polynucleotide comprises
an adeno-associated virus (AAV) vector administered at 2x1010
vector genomes, wherein the transcription factor repressor
reduces mHtt expression by at least 85% in HD neurons in the
striatum of the subject and reduces formation of Htt aggregates
in the medium spiny neuron by 20 to 50% as compared to an
untreated subject.
Appeal Br. 12.
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The following rejections are before us for review:
I. Claims 1 and 5–8 under 35 U.S.C. § 103 as unpatentable over
Miller,2 Gregory,3 and Harper;4
II. Claims 5–9 under 35 U.S.C. § 103 as unpatentable over Miller,
Gregory, Harper, and Garriga-Canut;5
III. Claim 17 under 35 U.S.C. § 103 as unpatentable over Miller,
Gregory, Harper, Garriga-Canut, and Perrin;6
IV. Claims 1 and 5–8 as unpatentable for obviousness-type double
patenting (“ODP”) over claims 1–7, 10, 11, and 19 of Miller in view
of Gregory and Harper;
V. Claims 5–9 as unpatentable for ODP over claims 1–7, 10, 11, and 19
of Miller in view of Gregory, Harper, and Garriga-Canut;
VI. Claim 17 as unpatentable for ODP over claims 1–7, 10, 11, and 19 of
Miller in view of Gregory, Harper, Garriga-Canut, and Perrin.
Appeal Br. 3–10; see Final Act. 3–23 (articulating rejections).

2 US 8,841,260 B2, issued September 23, 2014 (“Miller”).
3 Scott Q. Harper et al., RNA Interference Improves Motor and
Neuropathological Abnormalities in a Huntington’s Disease Mouse Model,
Vol. 102 No. 16 PNAS 5820–5825 (2005) (“Harper”).
4 US 2011/0082093 A1, published April 7, 2011 (“Gregory”).
5 Mireia Garriga-Canut et al., Synthetic Zinc Finger Repressors Reduce
Mutant Huntingtin Expression in the Brain of R6/2 Mice, PNAS E3136–
E3145 (2012) www.pnas.org/cgi/doi/10.1073/pnas.1206506109 (“Garriga-
Canut”).
6 US 2010/0299768 A1, published November 25, 2010 (“Perrin”).
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I. OBVIOUSNESS REJECTIONS
Issue
The three obviousness rejections turn on common issues relating to
the teachings in Miller, Gregory, and Harper, and Examiner’s conclusion of
obviousness based on the same. See Final Act. 18, 21 (relying on the
combination of these references “as applied” to claim 1). Accordingly, we
consider these rejections together. The issue before us is whether a
preponderance of the evidence supports Examiner’s conclusion that the
method in Appellant’s claims would have been obvious over the teachings in
these references.
Analysis
Examiner finds that Miller discloses “a method of reducing expression
of a mutant Huntingtin gene to reduce or prevent the formation of Htt
aggregates . . . comprising the step of administering to said subject a zinc
finger protein [“ZFP”] designated 30650, 30645, or 33074,” which are
amongst the 48 ZFPs listed in Miller Table 1B. Final Act. 12. According to
Examiner, ten of the ZFPs in Table 1B, including 30650, 30645, and 33074,
“target the CAG trinucleotide repeat region,” and Gregory teaches that
“ZFPs may be designed to preferentially bind to the expanded CAG tracts.”
Id. Based on these teachings, Examiner concludes “a method of treating
Huntington’s disease in a subject using the instantly recited three ZFP
species” would have been “an obvious varia[tion] of the method of treating
Huntington’s disease using the ZFP genus” taught in Miller. Id.
Regarding the dosage limitation, Examiner relies on Miller Example
9, which teaches the delivery of a ZFP via an AAV vector at a dose of
3x1010 vector genomes into the striatum. Final Act. 12. Examiner further
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relies on Harper’s teachings involving the administration of an AAV
encoding a different “repressor of a mutant Htt (mHtt) allele, to wit, an
shRNA” at a dose of “2.5x10^10 viral vector genomes/striatum.” Id. at 12–
13. Examiner concludes it would have been obvious to optimize these doses
to arrive at the recited dose for the recited ZFPs. Id. at 13.
As for the second wherein clause in claim 1, which recites that the
repressor “reduces mHtt expression by at least 85%” and “reduces formation
of Htt aggregates . . . by 20 to 50%,” Examiner determines this clause
“merely describe[s] functional properties that naturally flow from the mHtt
repressor(s) of zinc finger proteins designated 30640, 30645 or 33074” and
are therefore “inherent” within Miller’s disclosure of those ZFPs. Final Act.
16. Examiner further determines that the second wherein clause does
not recite any additional active method steps or structural
additions to the ZFNs [i.e., zinc finger nucleotides], but simply
states a characterization or conclusion of the results of the
administration step. . . . Therefore, the ‘wherein’ clause is not
considered to further limit the method defined by the claim and
has not been given weight in construing the claims.
Id. at 16–17.
Appellant argues that Examiner’s determination that the second
wherein clause “is not considered to further limit the method defined by the
claims and has not been given weight in construing the claims is improper.”
Appeal Br. 4 (quotations omitted). According to Appellant, the limitations
requiring that “(1) mHtt expression is reduced by at least 85% in HD
neurons in the striatum of the subject and; (2) the formation of Htt
aggregates in the medium spiny neuron are reduced by 20 to 50%” are
“functional limitations” that “must be evaluated and considered, just like any
other limitation of the claim.” Id. at 5 (quoting MPEP § 2173.05(g)); see
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also id. at 8–9. Appellant contends that Examiner’s inherency finding is
flawed because the claims are not directed to “ZFP products 30640, 30645
and 33074 per se, but, rather, to particular methods of using these products,
with particular limitations admittedly not disclosed in Miller or the other
references used to achieve a particular result.” Reply Br. 10; see Appeal Br.
8–9 (arguing that Miller and Gregory do not disclose the recited dosage or
functional requirements in the second wherein clause).
Appellant further contends that the other references Examiner relies
upon do not cure the deficiencies in Miller and Gregory. See Appeal Br. 8–
9; Reply Br. 10–11. Appellant argues that teachings in Harper and Perrin
are inapplicable because they relate to RNA repressors “that act post-
transcriptionally,” and not ZFPs “that bind to genomic DNA to repress
transcription.” Reply Br. 11; see also Appeal Br. 9. Moreover, Appellant
contends that Garriga-Canut teaches the use of different ZFPs at different
dosages that achieved “a reduction of a mutant Htt transgenes by 40% on
average and only up to 60% at most.” Appeal Br. 9. Appellant, therefore,
urges that the combination of Garriga-Canut with Miller and Gregory “does
not in any way teach or suggest methods . . . resulting in the claimed mHtt
reduction of at least 85%.” Reply Br. 10–11.
Based on the present record, we determine that Appellant has the
better position. The limitations in the second wherein clause of claim 1 are
functional limitations, requiring the administration of a repressor that both
reduces mHtt expression by at least 85% and reduces formation of Htt
aggregates by 20 to 50% (collectively, the “recited reduction levels”).
Therefore, to meet the burden to present a prima facie showing of
obviousness, Examiner must demonstrate that one of ordinary skill in the art
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would have had a reasonable expectation that the recited reduction levels
could be successfully achieved by administration of the recited ZFP-
encoding repressor.
Examiner sought to meet this burden by finding that the recited
reduction levels are inherent properties of the recited ZFPs, but Examiner’s
inherency finding is not sufficiently supported on the record before us. As
Appellant points out, the present claims are not directed to the ZFPs
themselves. See Reply Br. 10. Instead, claim 1 requires the administration
of a polynucleotide comprising “an adeno-associated virus (AAV) vector”
that encodes the recited ZFPs. A skilled artisan would have recognized that
the AAV comprises additional features that affect expression of the ZFP
encoded therein. See Final Act. 15 (acknowledging that “the recited
functional properties are dependent upon the degree/amount of the ZFP
expressed from the vector”).
Thus, even accepting that, as a general matter, it might have been
obvious to optimize the dosage in Miller’s method, Examiner has not shown
that administration of the AAV construct taught in Miller would necessarily
have achieved the recited reduction levels. Compare Miller, 53:35–60 with
Spec. ¶ 157 (describing the use of vectors driven by different promoters to
achieve ZFP expression).7 To the extent Examiner interprets the repressor
of claim 1 to “encompass[] any generic, weak, promoter,” including those
whose administration would not achieve the recited reduction levels (see

7 It may be the case that a skilled artisan would have found it obvious to
optimize both the AAV and the dosage in Miller to achieve the recited
reduction levels. Examiner, however, has not sufficiently articulated such
findings on the record before us.
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Final Act 15), Examiner has failed to give proper weight to the functional
limitations recited in the second wherein clause of that claim. See MPEP
2173.05(g) (explaining that a “functional limitation must be evaluated and
considered, just like any other limitation” because such limitations often
“define a particular capability or purpose that is served by the recited
element . . . or step”).
It is also true that “absolute certainty for success” is not required to
demonstrate obviousness. PAR Pharm., Inc. v. TWI Pharms., Inc., 773 F.3d
1186, 1198 (Fed. Cir. 2014). In this case, a prima facie showing could have
been made by demonstrating that the recited reduction levels would have
been reasonably expected from Miller or the other cited references.
Examiner, however, has not sufficiently presented such a showing on the
present record. Examiner cites Miller Example 9 as teaching “the ability to
achieve significant repression of mutant Htt transgene.” Final Act. 17. But
Examiner has not explained why a skilled artisan would have had a
reasonable expectation of achieving the recited reduction levels from the
results in Miller Example 9, i.e., “~35%” repression of mutant Htt following
administration of a higher (3x1010 viral genomes) dose of ZFP-encoding
AAV.
The other references Examiner relies upon do not overcome this
defect. As Appellant points out, Harper and Perrin describe the
administration of a substantially different type of repressor (i.e., shRNA and
siRNA), which acts “post-transcriptionally.” Reply Br. 11. Examiner has
not sufficiently explained why, in view of this distinction, one of ordinary
skill would have considered the dosages and results in Harper and Perrin to
apply to the ZFP repressors taught in Miller, Gregory, and Garriga-Canut.
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As for Gregory and Garriga-Canut, Examiner does not dispute Appellant’s
argument that these references fail to teach both the recited dosage and
recited reduction levels.
For these reasons, we determine that Examiner has not sufficiently
shown that a skilled artisan would have had a reasonable expectation of
achieving the recited reduction levels on the record before us. Accordingly,
the obviousness rejections of claim 1 (and dependent claims 6–9) are not
supported by a preponderance of the evidence.
Claim 17 is not limited to the recited reduction levels of claim 1, but
instead requires that administration of the repressor “increas[es] DARP32
expression in the medium spiny neuron of the subject.” Examiner finds that
this limitation would have been obvious because Perrin teaches that the
administration of “shRNA molecules dramatically reduced Huntingon’s
disease pathology and increased DARPP-32 expression levels.” Final Act.
23; Ans. 28; see also Final Act. 8–9 (acknowledging that Miller does not
disclose this element). However, as explained above, Examiner has not
sufficiently explained why one of skill in the art would have considered the
teachings regarding the administration of Perrin’s shRNA molecules to
likewise apply to the administration of an AAV encoding the recited ZFPs
such that one would have reasonably expected similar results (i.e., increased
DARPP-32 expression levels) from the ZFP-encoding AAV administered in
Miller’s method. For this reason, the rejection of claim 17 is not supported
by a preponderance of the evidence before us.
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II. ODP Rejections
Issue
Examiner’s three ODP rejections turn on common issues relating to
the differences between the claims of Miller and Appellant’s present claims.
Accordingly, we consider the ODP rejections together. The issue before us
is whether a preponderance of the evidence supports Examiner’s conclusion
that Appellant’s claims would have been obvious over claims 1–17, 10, 11,
and 19 of Miller in view of the other cited references.
Analysis
Examiner’s ODP rejections largely follow the logic of Examiner’s
obviousness, but focus on the claims of Miller as opposed to the overall
disclosure in that reference. Examiner finds that that claim 19 of Miller
“recites a method of treating Huntington’s Disease in a subject, the method
comprising the step of administering a nucleic acid molecule encoding a
ZFP” from Table 1B, which discloses 48 ZFPs, including ZFP’s 33074,
30645, and 30640. Final Act. 4. Examiner acknowledges that Miller does
“not claim the method comprising the step of administering 2x10^10 adeno-
associated viral vector genomes/striatum” or the recited reduction levels in
the second wherein clause of claim 1. Id. Examiner finds that Harper
teaches that “the functional efficacy of . . . shRNA to reduce mutant Htt
mRNA is dose-dependent” and from this teaching concludes that dosage “is
a result-effective variable” and, therefore, a skilled artisan would have
“optimize[d] the dosage administered to achieve a therapeutically
meaningful and effective result.” Ans. 10. Examiner again concludes that
the recited reduction levels in claim 1 are “inherent” properties of ZFPs
30640, 30645, and 33074 and/or need not be “considered to further limit the
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method” because the they “simply state[] a characterization or conclusion of
the results” of the administration step. Id. at 6–7.
Regarding present claim 17, Examiner acknowledges that Miller
“does not claim [that] DARPP32 expression is increased.” Final Act. 8. To
fill this gap, Examiner again relies on Perrin’s teachings regarding shRNA
molecules as evidence that this limitation would have been obvious from the
administration of the ZFP-encoding polynucleotides in Miller claim 19. See
id. 8–9.
Based on the present record, we determine that Examiner’s ODP
rejections are not supported by the preponderance of the evidence for the
same reasons noted above in our analysis of the analogous obviousness
rejections. Accordingly, we reverse both sets of rejections.
DECISION SUMMARY
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1, 6–8 103 Miller, Gregory,
Harper
1, 6–8
6–9 103 Miller, Gregory,
Harper, Garriga-Canut
6–9
17 103 Miller, Gregory,
Harper, Garriga-
Canut, Perrin
17
1, 6–8 Obviousness-type
Double Patenting
(Miller claims 1–17,
10, 11, 19, Gregory,
Harper)
1, 6–8
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Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
6–9 Obviousness-type
Double Patenting
(Miller claims 1–17,
10, 11, 19, Gregory,
Harper, Garriga-
Canut)
6–9
17 Obviousness-type
Double Patenting
(Miller claims 1–17,
10, 11, 19, Gregory,
Harper, Garriga-
Canut, Perrin)
17
Overall
Outcome
1, 6–9, 17

REVERSED