Ex Parte LI et al

Patent Trial and Appeal Board

Feb 17, 2017

12366321 (P.T.A.B. Feb. 17, 2017)

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.
12/366,321 02/05/2009 Yuhua Li 5507-16 7615
86012 7590
VLP Law Group LLP
555 Bryant Street
Suite 820
Palo Alto, CA 94301
EXAMINER
STANFIELD, CHERIE MICHELLE
ART UNIT PAPER NUMBER
1647
NOTIFICATION DATE DELIVERY MODE
02/22/2017 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):
patents @ vlplawgroup. com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte YUHUA LI, ANDREW GUARINO, and
BENJAMIN CHIEN1
Appeal 2016-001598
Application 12/366,321
Technology Center 1600
Before DONALD E. ADAMS, TAWEN CHANG, and
JOHN E. SCHNEIDER, Administrative Patent Judges.
CHANG, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
composition for sustained release of a protein or peptide, which have been
rejected as obvious and/or indefinite. We have jurisdiction under 35 U.S.C.
§ 6(b).
We AFFIRM.
1 Appellants identify the Real Party in Interest as Foresee Pharmaceuticals
Co., Ltd. (Br. 2.)
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Application 12/366,321
STATEMENT OF THE CASE
“Hydrophobic, non-polymeric materials, particularly . . . highly
viscous, nonpolymeric liquid materials[,] have been described as
biodegradable systems for controlled release delivery of bioactive
compounds.” (Spec. 12.) The Specification states that combining such
materials with a plasticizing solvent results in a lower viscosity mixture that
can be formulated with a bioactive compound and administered to a subject
to form a highly viscous depot in the subject’s body. (Id.) According to the
Specification, however, many bioactive agents, particularly hydrophilic
peptides and proteins, may not be compatible with the hydrophobic non-
polymeric carrier, resulting in an unstable formulation that, for instance,
undergoes phase separation. (Id. at 14.) Further according to the
Specification, an undesirable “high initial burst release of the protein or
peptide [may be] observed during the depot formation process,” and
nucleophilic proteins or peptides may interact with the carrier material to
expedite the degradation of the carrier and/or chemically alter the proteins or
peptides. (Id. at||4, 10.)
The Specification states that the present invention relates to a liquid
composition “suitable for in-situ formation of a depot system to deliver a
protein or peptide in a controlled, sustained manner,” comprising a
hydrophobic non-polymeric carrier, a water miscible biocompatible organic
solvent, and “a protein or peptide covalently conjugated with one or more
formulation performance-enhancing compound(s)” that “stabilize[] the
protein or peptide, increase[] the compatibility with non-polymeric carrier
material, and improve[] the release profile of the protein or peptide.” (Id. at
117-8.)
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Application 12/366,321
Claims 1—10, 16—21, and 23—27 are on appeal. Claim 1 is illustrative
and reproduced below:
1. A composition for sustained release of a protein or peptide,
comprising:
(a) a hydrophobic non-polymeric carrier material;
(b) a water miscible pharmaceutically acceptable solvent; and
(c) a protein or peptide covalently conjugated with one or more
amphiphilic molecule(s),
wherein (c) maintains the stability of the composition by
preventing phase separation.
(Br. 9 (Claims App’x).)
During prosecution, Applicants elected the following species for
prosecution on the merits: sucrose acetate isobutyrate (SAIB) as the
hydrophobic non-polymeric carrier material; methoxy polyethylene glycol
350 (MPEG350) as the water miscible pharmaceutically acceptable solvent;
octreotide as the protein or peptide, and monopalmityl polyethylene glycol)
or polyethylene glycol hexadecyl ether as the “formulation performance­
enhancing compound” such as an amphiphilic molecule. (Response2 1—2.)
The Examiner rejects claims 1—10, 16—21, and 23—27 under 35 U.S.C.
§ 103(a) as being unpatentable over Tipton3 and Li.4 (Ans. 6.)
The Examiner rejects claims 23 and 24 under 35 U.S.C. § 112, second
paragraph, as being indefinite. (Id. at 3.)5
2 Response to Requirement for Election of Species/Restriction (May 20,
2010).
3 Tipton et al., US Patent No. 5,747,058, issued May 5, 1998.
4 Li et al., US 2008/0020016 Al, published Jan. 24, 2008.
5 In the Answer, the Examiner also reiterates objections to claims 10 and 23—
27 for certain informalities. (Ans. 2—3). These objections constitute
petitionable (rather than appealable) matter. Thus, we do not address them.
See in re Hengehold, 440 F.2d 1395, 1403-04 (CCPA 1971).
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I.
Issue
The Examiner has rejected claims 1—10, 16—21, and 23—27 under 35
U.S.C. § 103(A) as obvious over Tipton and Li. The Examiner finds that
Tipton teaches “a composition for sustained release of proteins comprising
sucrose acetate isobutyrate (SAIB), N-methylpyrrolidone [(NMP)],
biodegradable polymers, and PEG conjugated peptides and small molecule
compositions, including hormones, growth factors, and cytokines.” (Ans. 6.)
The Examiner finds that Tipton teaches “optional embodiments where the
protein or peptide of interest may be covalently conjugated.” (Id.)
The Examiner finds that Tipton does not specifically disclose the
elected species of octreotide or GLP-1 as the bioactive substance. (Id.)
However, the Examiner finds that Tipton teaches “generic generas of
hormones, growth factors, and cytokines.” (Id.) The Examiner further finds
that Li teaches the limitations of claim 1 and also teaches octreotide and
GLP-1. (Id. at 7, 10.) In particular, the Examiner finds that Li teaches
“various compositions including PAL-PEG-BA-OCT in a solution of
NMP”6 as well as “selective covalent conjugation of peptides to .. .
amphiphilic moieties,” including “amphiphilic molecule covalently
conjugated to octreotide.” (Id. at 7.)
The Examiner finds that “[t]he teaching of SAIB by Tipton meets the
limitation of instant claim 1(a),” “[t]he NMP taught by both Li and Tipton
meet the limitation of instant claims 1(b),” and “[t]he amphiphilic molecule
6 PAL-PEG-BA-OCT refers to the conjugated peptide resulting from the
conjugation of octreotide with monopalmityl polyethylene glycol). (Li |
77.)
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Application 12/366,321
covalently conjugated to octreotide” taught by Li meets the limitation of
claim 1(c). (Id. at 7—8.) The Examiner further finds that, “[ajbsent
evidence to the contrary, the compositions of Li meet the limitation of the
wherein clause of claim 1,” because “[t]he physical properties of the
composition where the amphiphilic molecules maintain the stability of the
composition by preventing phase separation are inherent properties of the
composition itself.” (Id.)
Finally, the Examiner finds that “[t]he sustained release compositional
formulations of both Tipton and Li substantially overlap in terms of their
components and also in their intended use/purpose,” and concludes that
“[o]ne of skill in the art would have recognized that the results of the
combination would have yielded nothing more than predictable results . . . .”
(Id. at 9.) The Examiner also finds that it would have been obvious to use
the octreotide taught by Li as the bioactive substance because “Tipton
teaches that any pharmaceutical bioactive protein would be useful in [its]
formulation” and because it would be prima facie obvious to substitute one
known element (i.e., Tipton’s genera of hormones, growth factors, and
cytokines) for another (Li’s octreotide or GLP-1) to obtain predictable
results. (Id. at 9—10.)
Appellants contend that there is no reason to combine Tipton and Li.
(Br. 4.) Appellants also argue that,
[e]ven if both the Tipton and Li references could be combined, there
would not have been a reasonable expectation that combining these
elements would yield a composition having the desired property of
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Application 12/366,321
preventing phase separation and maintaining the stability of the
formulation.
(Id. at 5.) Appellants further argue that the claimed subject matter exhibits
the unexpected results of increased stability and prevention of phase
separation. (Id. at 5—6.)
Appellants do not separately argue the claims. (Id. at 7.) We
therefore limit our analysis to claim 1. The issue with respect to this
rejection is whether the evidence of record supports the Examiner’s
conclusion that the cited references would have rendered the composition of
claim 1 obvious and, if so, whether Appellants have provided evidence of
unexpected results that outweighs the evidence supporting a conclusion of
obviousness.
Findings of Fact
1. Tipton teaches “[a] composition for the controlled release of
substances . . . that includes: (i) a non-polymeric, non-water soluble liquid
carrier material (HVLCM) of viscosity of at least 5,000 cP at 37- C. that
does not crystallize neat under ambient or physiological conditions; and (ii)
a substance to be delivered.” (Tipton Abstract; see also id. at claim 1.)
2. Tipton discloses SAIB as a preferred embodiment of a non-
polymeric, non-water soluble liquid carrier material. (See, e.g., id. at 5:64—
6:19; see also id. at claim 2.)
3. Tipton teaches that,
[i]n one embodiment, the HVLCM is mixed with a viscosity lowering
water soluble or miscible solvent such as . . . N-methylpyrrolidone
[(NMP)] . . . , to form a lower viscosity liquid carrier material
(LVLCM), which is mixed with the substance to be delivered, prior to
administration. . . . On administration, the composition is placed into
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Application 12/366,321
the body or on a surface, and the solvent dissipates or diffuses away
from the LVLCM, forming in-situ a highly viscous implant or
composition that releases the substance over time.
(Id. at 2:47—63; see also id. at 5:50—57, 10:12—15, 10:23—25, 10:52—57,
claims 5, 6, 16.)
4. Tipton teaches that “[a] variety of additives can optionally be
added to the HVLCM or LVLCM to modify the properties of the material as
desired.” (Id. at 8:53—55; see also id. at claim 8.)
5. Tipton teaches that “[o]ne category of additives are
biodegradable polymers and oligomers,” which “can be used to alter the
release profile of the substance to be delivered, to add integrity to the
composition, or to otherwise modify the properties of the composition.” (Id.
at 9:8—12; see also id. at claims 9, 56.)
6. Tipton teaches that “[i]n humans the composition can be used
for the delivery of a wide range of biologically active substances,” such as
proteins, peptides, and hormones. (Id. at 3:11—13, 6:50-65 (biological active
substance includes peptide, protein, and hormone), claims 11, 37, 40.)
7. Tipton suggests that use of its non-polymeric, non-water
soluble high-viscosity liquid carrier material provides “more simple systems
with low toxicity for the controlled delivery of substances.” (Id. at 2:20—29.)
8. Li’s invention “relates to the field of controlled release delivery
of therapeutic peptides and to compositions and methods useful for
controlled release delivery of therapeutic peptides covalently modified with
one or more lipophilic or amphiphilic molecules.” (Li 14; see also id. at
11 12, 20, 60.)
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9. More particularly, Li teaches
methods of forming a solid, biodegradable implant in-situ in a body
by administering a liquid pharmaceutical composition comprising an
effective amount of a biocompatible, water-insoluble, biodegradable
polymer and an effective amount of a therapeutic peptide covalently
modified with one or more lipophilic or amphiphilic moieties, which
are dissolved or dispersed in a biocompatible, water-soluble organic
solvent.
(Id. at Abstract; see also id. at || 12—13, 21—22, 25—29, 49—50, claims 24,
40.)
10. Li teaches that “[pjharmaceutically acceptable organic solvents
include, but are not limited to, N-methyl-2-pyrrolidone . . . .” (Id. at | 54.)
Li also teaches embodiments having MPEG350 as the solvent. (Id. at || 16,
17, 69, 74.)
11. Li teaches that “[w]hen the liquid composition is injected into
the body, the solvent dissipates into the surrounding aqueous environment,
and the polymer precipitates to form a solid or gel depot from which the
bioactive agent is released over a long period of time as the polymer
degrades.” (Id. at 17; see also id. at || 49-50, claim 24.)
12. Li teaches that, “[f]or many therapeutic peptides, acylation
and/or degradation of the peptides encapsulated in [certain polymer]
microspheres have been observed during the release process.” (Id. at | 8.) Li
further teaches that “[t]he nucleophilic functional groups on peptides can . . .
react with the biodegradable polymer [and] also can catalyze the degradation
of the biodegradable polymer.” (Id.)
13. Li additionally teaches that,
during the formation of the implant, the rate of diffusion of the
peptide from the coagulating polymeric composition may be much
more rapid than the rate of release that occurs from the subsequently
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Application 12/366,321
formed solid implant. This initial “burst” release of peptide during
implant formation may result in the loss or release of a large amount
of the therapeutic peptides. If the peptide is particularly toxic or has a
narrow therapeutic window, this initial release or burst is likely to lead
to toxic side effects and may damage adjacent tissues.
(Id. at 19.)
14. Li teaches that
covalently modified peptides with one or more lipophilic and/or
amphiphilic molecules could be formulated with biodegradable
polymers resulting in significantly improved stability and sustained
release profiles relative to non-conjugated peptides. Lipophilically
and/or amphiphilically modified peptides could not only prevent the
uncontrolled random acylation and degradation of the peptides during
the formulation, storage and subsequent in vivo release processes, but
could also reduce the undesired initial burst release of peptides. Such
delivery systems allow higher concentrations of a therapeutic peptide
to be safely incorporated into a biodegradable polymer delivery
system. The efficacy of such products is also improved, since a much
greater percentage of intact active peptide remains in the delivery
system for sustained release and is not lost by degradation during the
formulation, storage, administration and subsequent release in vivo.
(Id. at 111; see also id. at || 12—13, 48, 80 (teaching that “covalently
conjugated octreotide . . . prevented . . . acylation reaction [on the octreotide]
and significantly reduced the degradation rate of the polymer relative to the
unmodified octreotide”), claim 24.)
15. Li teaches that,
[pjreferably, a therapeutic peptide is covalently conjugated to one or
more amphiphilic molecules comprising (a) a hydrophilic moiety and
(b) a lipophilic moiety, wherein the balanced hydrophilic and
lipophilic characteristics of the amphiphilic molecule impart the
conjugate with suitable solubility in biological fluid or aqueous
solution.
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Application 12/366,321
More preferably, a therapeutic peptide is covalently conjugated
to one or more amphiphilic molecules comprising (a) a linear
polyethylene glycol moiety and (b) a lipophilic moiety, wherein the
therapeutic peptide, the polyethylene glycol and the lipophilic moiety
are conformationally arranged to have the lipophilic moiety exteriorly
available for interaction with lipophilic environment or cell
membranes.
(Id. at 1139-40.)
16. Li teaches that “[pjeptides useful in the preparation of the
formulation of the invention include, but are not limited to . . . glucagon-like
peptide (GLP-1). . . .” (Id. at 125.) Li teaches embodiments where the
therapeutic peptide is octreotide. (Id. at H 18—19, 33—34, 65—67, 77.) Li
further teaches an embodiment where an amphiphilic molecule is covalently
conjugated to octreotide. (Id. at H 42, 84 (teaching that “covalent
conjugation of the peptide with an amphiphilic moiety such as monopalmityl
poly(ethylene glycol) can prevent or significantly reduce the interaction
and/or reaction between peptides and biodegradable polymers”).)
Analysis
We agree with the Examiner that claim 1 is rendered obvious by the
combination of Tipton and Li. Tipton teaches a composition for controlled
release of biologically active substances such as proteins and peptides (FF1,
FF6), comprising (a) a non-polymeric, non-water soluble (i.e., hydrophobic)
liquid carrier material such as SAIB (FF1, FF2), (b) a water soluble or
miscible solvent such as NMP (FF3), and (c) the substance to be delivered
(FF1). Fi teaches a composition for controlled release delivery of
therapeutic peptides such as octreotide, where the peptides are covalently
modified with one or more amphiphilic molecules. (FF8, FF9, FF13—16.)
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Li further teaches that the therapeutic peptides are dissolved or dispersed in
a biocompatible, water-soluble organic solvent and further teaches NMP and
MPEG350 as examples of such solvent. (FF8, FF9.)
Tipton suggests that using non-polymeric, non-water soluble high-
viscosity liquid carrier material provides “more simple systems with low
toxicity for the controlled delivery of substances.” (FF7.) Fi teaches that
covalently modifying the therapeutic peptide with one or more amphiphilic
molecules reduce acylation and/or degradation of the peptides, the
degradation of the polymer in the formulation, and the undesired initial burst
release of the peptides. (FF12—FF15.) Accordingly, we find that it would
have been obvious to a skilled artisan to combine the disclosures of Tipton
and Fi to arrive at the claimed invention: Given the teachings in Tipton and
Fi regarding the advantages of a non-polymeric carrier and a peptide
covalently modified with amphiphilic molecule(s), it would have been
obvious to a skilled artisan to use Tipton’s non-polymeric, non-water soluble
high viscosity liquid carrier material in place of Fi’s biocompatible, water-
insoluble, biodegradable polymer and/or to use Fi’s octreotide covalently
modified with one or more amphiphilic molecules and MPEG350 as the
bioactive substance and solvent, respectively, in Tipton’s formulation.
Finally, we agree with the Examiner that, given the substantial
identity of the claimed composition and the composition rendered obvious
by Tipton and Fi, the functional limitation in the wherein clause of claim 1
(i.e., covalently conjugated peptide maintaining the stability of the
composition by preventing phase separation) is inherently met absent
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Application 12/366,321
evidence to the contrary. The predecessor to our reviewing court has
counseled that,
[w]here ... the claimed and prior art products are identical or
substantially identical ... the PTO can require an applicant to
prove that the prior art products do not necessarily or inherently
possess the characteristics of his claimed product. . . . [The]
fairness [of the burden-shifting] is evidenced by the PTO’s
inability to manufacture products or to obtain and compare prior
art products.
In re Best, 562 F.2d 1252, 1255 (CCPA 1977).
Appellants first contend that there is no reason to combine Tipton and
Li. We disagree for the reasons discussed above. More particularly,
Appellants argue that, whereas Tipton teaches “mov[ing] away from
delivery systems that require the preparation of polymers and loaded
polymeric matrices” and using a non-polymeric high viscosity liquid as the
carrier, “Li teaches the use of biodegradable polymeric carriers, whereby the
polymer coagulates or solidifies to produce the biodegradable solid
implant.” (Br. 4.) We are not persuaded. A prior art reference is relevant
for all that it teaches to those of ordinary skill in the art. In re Fritch, 972
F.2d 1260, 1264 (Fed. Cir. 1992). The fact that the formulations of Tipton
and Li use different types of carriers does not render non-obvious the
combination of the relevant disclosures of each reference to arrive at the
claimed invention. Neither do the references teach away from the claimed
combination, because neither Tipton nor Li discredits or otherwise
discourages the combination of non-polymeric carrier and bioactive
substance conjugated with amphiphilic molecules. In re Gurley, 27 F.3d
551, 553 (Fed. Cir. 1994) (“A reference may be said to teach away when a
person of ordinary skill, upon reading the reference, would be discouraged
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Application 12/366,321
from following the path set out in the reference, or would be led in a
direction divergent from the path that was taken by the applicant.”).
Appellants also contend that,
[e]ven if both the Tipton and Li references could be combined, there
would not have been a reasonable expectation that combining these
elements would yield a composition having the desired property of
preventing phase separation and maintaining the stability of the
formulation.
(Id. at 5.) Appellants argue that Tipton does not suggest that there are phase
separation problems with its formulation and Li also does not suggest
maintaining the stability of its composition by preventing phase separation.
(Id. at 4—5.) These arguments are also not persuasive. As an initial matter,
“the statement that a prima facie obviousness rejection is not supported if no
reference shows or suggests the newly-discovered properties and results of a
claimed structure is not the law.” In re Dillon, 919 F.2d 688, 692—93 (Fed.
Cir. 1990, en banc). Furthermore, Li suggests that covalently conjugating
therapeutic peptides with amphiphilic molecules stabilizes the formulation,
including by, e.g., imparting the conjugate with suitable solubility. (FF14,
FF15.)
Finally, we note but are not persuaded by Appellants’ argument that
the claimed subject matter exhibits the unexpected results of increased
stability and prevention of phase separation. (Id. at 5—6.) Appellants have
not shown that increased stability and prevention of phase separation are
unexpected in the claimed formulation, particularly given Li’s teaching that
conjugating peptides with amphiphilic molecules imparts suitable solubility
to the conjugate. (FF15.)
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Accordingly, we affirm the Examiner’s rejection of claim 1. Claims
2—10, 16—21, and 23—27, which were not separately argued, fall with claim
1. 37C.F.R. §41.37(c)(l)(iv).
II.
Issue
The Examiner rejects claims 23 and 24 under 35U.S.C. § 112, second
paragraph, as being indefinite. Appellants do not argue this rejection, stating
only that, “upon the allowability of claim 1 . . . , amendments will be made
to claims 10 [and] 23—27 to overcome the rejection under 35U.S.C. [§] 112,
second paragraph.” (Br. 7—8.) Accordingly, we summarily affirm the
rejection. See Manual of Patent Examining Procedure § 1205.02 (“If a
ground of rejection stated by the examiner is not addressed in the appellant's
brief, . . . the Board may summarily sustain it.”)
SUMMARY
For the reasons above, we affirm the Examiner’s decision rejecting
claims 1—10, 16—21, and 23—27.
TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).
AFFIRMED
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