Ex Parte Robic

Patent Trial and Appeal Board

Aug 11, 2016

12089592 (P.T.A.B. Aug. 11, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/089,592 08/05/2008
24353 7590 08/15/2016
BOZICEVIC, FIELD & FRANCIS LLP
Bozicevic, Field & Francis
1900 UNIVERSITY A VENUE
SUITE 200
EAST PALO ALTO, CA 94303
FIRST NAMED INVENTOR
Srebrenka Robie
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.
IMMU-002 4539
EXAMINER
NOAKES, SUZANNE MARIE
ART UNIT PAPER NUMBER
1656
NOTIFICATION DATE DELIVERY MODE
08/15/2016 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):
docket@bozpat.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte SREBRENKA ROBIC 1
Appeal2013-008778
Application 12/089,592
Technology Center 1600
Before JEFFREY N. FREDMAN, JACQUELINE WRIGHT BONILLA,
and TA WEN CHANG, Administrative Patent Judges.
CHANG, Administrative Patent Judge.
DECISION ON APPEAL
Appellant appeals under 35 U.S.C. § 134(a) in relation to an
application involving claims to a pharmaceutical formulation comprising
prolyl endopeptidase (PEP) conjugated to at least one polyethylene glycol
(PEG) moiety, which have been rejected as obvious. We have jurisdiction
under 35 U.S.C. § 6(b ).
We AFFIRM.
1 Appellant identifies the Real Party in Interest as Alvine Pharmaceuticals,
Inc. (Appeal Br. 1.)
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Application 12/089,592
STATEMENT OF THE CASE
It has been recognized that gluten, a common dietary protein, may
cause celiac sprue and a related disease, dermatitis herpetiformis, in
sensitive individuals. (Spec. ,-i,-i 1-2.) According to the Specification, celiac
sprue is generally considered to be an autoimmune disease, and "[a]
promising new therapy ... involves the oral administration of a protease or
mixture of proteases that, together with endogenous enzymes of the stomach
and small intestine, can degrade gluten to amino acids and small peptides
unable to induce the autoimmune response." (Id. at ,-i,-i 3, 7.) Further
according to the Specification, however, "the harsh conditions of the
stomach and small intestine can degrade such proteases, and methods and
reagents for stabilizing them ... are needed." (Id. at ,-i 7.) The Specification
states that
[t]he present invention relates to the discovery that glutenases are
stabilized for enteric delivery by covalent addition of polyethylene
glycol to the glutenase, a process termed 'PEGylation', and that
PEGylation can increase the relative activity of the enzyme against
gluten oligopeptides and in any even makes the PEGylated glutenase
more resistant to degradation under physiological conditions.
(Id. at ,-i 9.)2
Claims 5, 6, 8, 10, and 13 are on appeal. Claim 6 is illustrative and
reproduced below:
6. A pharmaceutical formulation, comprising: a unit dose of
a prolyl endopeptidase conjugated to at least one polyethylene
2 Glutenase refers to "an enzyme ... that is capable, alone or in combination
with endogenous or exogenously added enzymes, of cleaving toxic
oligopeptides of gluten proteins of wheat, barley, oats and rye into non-toxic
fragments." (Spec. ,-i 25.) A glutenase may be a prolyl endopeptidase
(PEP). (Id. at ,-i,-i 27, 29.)
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Application 12/089,592
Issue
glycol (PEG) moiety; and a pharmaceutically acceptable
excipient for oral administration wherein said PEG moiety is at
least 5000 Da.
DISCUSSION
The Examiner has rejected claims 5, 6, 8, 10, and 13 under 35 U.S.C.
§ 103(a) as being unpatentable over Rausch,3 Gamez,4 and Roberts. 5 (Ans.
4.) The Examiner finds that Rausch teaches the oral administration of a
pharmaceutically acceptable formulation of glutenase, such as prolyl
endopeptidase (PEP) from F. meningosepticum, A. hydrophila, and S.
caplsulata, in a dose effective to treat celiac sprue and/or dermatitis
herpetiformis. (Final Act. 2-3.) The Examiner finds that Rausch teaches
that formulations are typically provided in a "unit dosage form," where
"each unit contain[ s] a predetermined quantity of glutenase in an amount ...
sufficient to produce the desired effect in association with a
pharmaceutically acceptable diluent, carrier or vehicle." (Id. at 3.) The
Examiner finds Rausch teaches that
(Id.)
[a]lso useful in the practice of [its] invention are proteins that have
been modified ... so as to improve their resistance to proteolytic
degradation and/or to acidic conditions such as those found in the
stomach ....
3 Rausch et al., US 2003/0215438 Al, published Nov. 20, 2003
4 Alejandra Gamez et al., Toward PKU Enzyme Replacement Therapy:
PEGylation with Activity Retention for Three Forms of Phenylalanine
Hydroxylase, 9 MOLECULAR THERAPY 124 (2004).
5 M.J. Roberts et al., Chemistry for peptide and protein PEGylation, 54
ADVANCED DRUG DELIVERY REVIEWS 459 (2002).
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Application 12/089,592
The Examiner finds that Hausch does not teach the attachment of
polyethylene glycol moieties. However, the Examiner finds that Gamez,
which relates to treating patients with phenylketonuria (PKU) by
administering an enzyme (i.e., "oral enzyme therapy"), discloses attaching
PEG molecules of 5,000 or 20,000 daltons to the enzyme phenylalanine
hydroxy lase (P AH), "with the aim [of] using this form of [PEGylated]
enzyme to protect the orally delivered enzyme from degradation by digestive
system protease." (Id. at 4.) The Examiner also finds that Roberts "teach
numerous different methods and strategies to [PEG]ylate any protein or
enzyme" and "cite multiple reasons one skilled in the art would want to
[PEGylate] a protein or enzyme[,] including preventing recognition and
degradation by proteolytic enzymes." (Id.)
The Examiner concludes that it would have been obvious to a skilled
artisan to PEGylate Hausch's PEP with PEG molecules that are, for
example, 5,000 to 20,000 daltons: Rausch teaches that it would be
advantageous to modify orally administered PEPs "so as to improve their
resistance to proteolytic degradation and/or the acidic conditions such as
those found in the stomach, which would ... make them more suitable as a
therapeutic agent," while Gamez teaches "the successful [PEGylation] of an
enzyme specifically utilized for oral enzyme therapy which affords said
enzyme not only protection of degradation in the stomach and intestinal tract
but ... also increases the stability and specific activity [of the enzyme] by
up to 30%." (Id. at 4-5.) The Examiner further finds that a skilled artisan
would have had a reasonable expectation of success in PEGylating PEP,
because Roberts details "step-by-step methods for [PEGylating] various
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Application 12/089,592
.. enzymes" and explains that PEGylation can lead to enzymes that are
resistant to recognition and proteolytic degradation. (Id. at 5.)
Appellant contends that Rausch does not teach either PEGylation of a
prolyl endopeptidase for oral administration or the benefits of modification
with PEG moieties greater than 5,000 daltons, and further contends that
Gamez and Roberts do not remedy these deficiencies. (Appeal Br. 4, 6.)
Appellant also appears to contend that there was neither reason for a skilled
artisan to combine the disclosures of the cited art nor a reasonable
expectation that such combination would be successful. (Id.) Finally,
Appellant argues that the claims are non-obvious because the claimed
subject matter exhibits unexpected results. (Appeal Br. 2-5; Reply Br. 1-5.)
Appellant does not argue the claims separately. Thus, we focus our
analysis on claim 6. The issues with respect to this rejection are (1) whether
the evidence of record supports the Examiner's conclusion that claim 6 is
prima facie obvious and (2) whether Appellant has provided evidence of
unexpected results that, when considered together with evidence of
obviousness, is sufficient to support a conclusion of non-obviousness.
Findings of Fact
1. Rausch teaches that "[a ]dministering an effective dose of
glutenase to a Celiac or dermatitis herpetiformis patient reduces levels of
toxic gluten oligopeptides, thereby attenuating or eliminating the damaging
effects of gluten." (Rausch Abstract.)
2. Rausch teaches providing "pharmaceutical formulations
containing one or more glutenases and a pharmaceutically acceptable
carrier," including "formulations in which the glutenase is contained within
an enteric coating that allows delivery of the active agent to the intestine and
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Application 12/089,592
formulations in which the active agents are stabilized to resist digestion in
acidic stomach conditions." (Id. at iJ 11.)
3. Rausch teaches that "[f]ormulations are typically provided in a
unit dosage form, where the term 'unit dosage form[]' refers to physically
discrete units suitable as unitary dosages for human subjects, each unit
containing a predetermined quantity of glutenase in an amount calculated
sufficient to produce the desired effect in association with a
pharmaceutically acceptable diluent, carrier or vehicle." (Id. at iJ 73.)
4. Rausch teaches that administration of glutenase can be achieved
in various ways, usually by oral administration. (Id. at iii! 66, 80.)
5. Rausch teaches an embodiment where the glutenase is a PEP.
(See, e.g., id. at iii! 32, 51, 94, 111.)
6. Rausch teaches that "useful in the practice of [its] invention are
proteins that have been modified using molecular biological techniques
and/or chemistry so as to improve their resistance to proteolytic degradation
and/or to acidic conditions such as those found in the stomach, and to
optimize solubility properties or to render them more suitable as a
therapeutic agent." (Id. at iJ 58.)
7. Gamez teaches using PEGylation to produce protected forms of
the enzyme phenylalanine hydroxy lase (P AH) for potential therapeutic use.
(Gamez Abstract.)
8. Gamez teaches PEGylating P AH with PEGs of molecular
weight 5,000 or 20,000 daltons. (Id.; see also id. at 126.)
9. Gamez teaches that its goal is to "develop a stable form of
P AH, or other enzymes that are known to degrade phenylalanine, that will
be stable against degradation caused by the gastrointestinal environment or,
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Application 12/089,592
alternatively, resistant to rapid removal from the circulatory system via
action of the immune system." (Id. at 124; see also id. at 126 (describing
aim as using PEGylation to protect "an orally delivered or injected enzyme
from degradation by digestive system proteases or clearance from
circulation").)
10. Gamez teaches that "[a ]11 PEG-derivatized P AH species
retained catalytic activity, and, at low numbers of PEG molecules attached,
these PEGylated P AH proteins were found to be more active and more
stable than their nonderivatized PAH counterparts." (Id. at Abstract; see
also id. at 126 (stating that Gamez "provides the first report of successful
PEGylation for three different recombinant P AHs, for which improved
activity and presumably stability are provided by the covalent PEG
derivatization"), 127-128.)
11. Roberts teaches the chemistry of PEGylation (Roberts 461-
474 ), and teaches that "[r]easons for PEGylation ... of peptides and proteins
are numerous and include ... preventing recognition and degradation by
proteolytic enzymes" (id. at Abstract; see also id. at 460).
12. The Specification discloses reacting PEPs from Flavobacterium
menningosepticum (FM) and Myxococcus xantus (MX) with activated PEGs
with molecular weights of 2,000, 5,000, 20,000, and 30,000 daltons. (Spec.
,-i 86.)
13. The Specification describes cleaving chromogenic substrates
with the PEGylated PEPs described in FF12. (Id. at ,-i,-i 89, 95-96.) The
results of this assay are set forth in Table 1, reproduced below:
[ . "" "·-·:::··----] u.r1ir~Odiful