Ex Parte Steiner et al

Patent Trial and Appeal Board

Mar 28, 2017

12715203 (P.T.A.B. Mar. 28, 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.
12/715,203 03/01/2010 Solomon S. Steiner SOLO 119 8284
23579 7590
Pabst Patent Group LLP
1545 PEACHTREE STREET NE
SUITE 320
ATLANTA, GA 30309
EXAMINER
HELLMAN, KRISTINA M
ART UNIT PAPER NUMBER
1675
MAIL DATE DELIVERY MODE
03/28/2017 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 SOLOMON S. STEINER, ROBERT HAUSER, MING LI,
ROBERT FELDSTEIN, and RODERIKE POHL1
Appeal 2015-003409
Application 12/715,203
Technology Center 1600
Before ERIC B. GRIMES, FRANCISCO C. PRATS, and KRISTI L. R.
SAWERT, Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a
stabilized glucagon formulation, which have been rejected for obviousness.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm-in-part.
STATEMENT OF THE CASE
“[Gjlucagon increases the concentration of glucose in the blood.”
(Spec. 1:15—16.) Glucagon is soluble in aqueous solution at low or high
pHs, but “has low solubility in the pH range of 4 to 8. ... It forms a gel in
1 Appellants identify the Real Party in Interest as Biodel, Inc. (Appeal Br.
2.)
Appeal 2015-003409
Application 12/715,203
acidic aqueous conditions (pH 3-4) and precipitates within an hour of
preparation in a neutral aqueous solution.” {Id. at 1:24—27.)
The Specification reports that the commercial preparation of glucagon
is a two-part vial, to be reconstituted immediately before use. {Id. at 1:28—
29.) An “artificial pancreas” for treatment of diabetes needs to be capable of
keeping a patient within ideal glucose levels, providing insulin or glucagon
as needed. {Id. at 2:24—3:7.) Thus, an artificial pancreas “requires a
glucagon that is stable in solution for at least seven days at 30-37°C.” (Id. at
3:9-10.)
Claims 1, 4, 5, and 10—20 are on appeal. Claims 1 and 19 are
illustrative and read as follows:
1. A stabilized glucagon formulation comprising
between 0.8 and 1.5 mg/mL of glucagon,
between 0.5 and 5 mg/mI. of lyso myristoyl phosphocholine (LMPC),
between 20 and 100 mg of a monosaccharide or disaccharide/ ml, and
between 0.2 and 3 mg/mL of a preservative,
having enhanced stability of the glucagon in an aqueous solution at
physiological temperature as compared to glucagon not
formulated with LMPC or the monosaccharide or disaccharide.
19. (Previously presented). The stabilized glucagon
formulation of claim 1 comprising between 36 and 72 mg/mI.
glucose.
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Application 12/715,203
DISCUSSION
The Examiner has rejected all of the claims on appeal under 35 U.S.C.
§ 103(a) as obvious based on Kaarsholm2 and Pedersen.3 (Ans. 3.) The
Examiner finds that Kaarsholm discloses stabilized compositions of a
peptide that can be glucagon comprising a detergent, which can be myristoyl
lysophosphatidylcholine,4 a preservative, and an isotonic agent, but where
the isotonic agent is mannitol rather than a monosaccharide as required by
the claims. {Id. at 3 4.) The Examiner finds that Pedersen suggests
glucagon formulations containing a variety of tonicity agents, including
mannitol and “other art-recognized agents: glucose, lactose, maltose,
sucrose, glycine, polyethylene glycol, arginine, inositol, propylene glycol,
dimethylsulfone, sorbitol and xylitol.” {Id. at 4.) The Examiner also finds
that the concentration ranges suggested by Kaarsholm and Pedersen for
peptides, LMPC, and preservative overlap the ranges recited in claim 1. {Id.
at 3—4.)
The Examiner finds that development of stabilized glucagon solutions
was a recognized problem in the art, and Pedersen teaches that use of
mannitol in peptide formulations improves their stability, but the mannitol
crystallizes and clogs injection devices. {Id. at 5.) The Examiner finds that
Pedersen teaches “a finite number of potential solutions to the problem of
finding an alternative to mannitol,” meaning the other isotonic agents, which
2 US 6,384,016 Bl, issued May 7, 2002.
3 US 2007/0010424 Al, published January 11, 2007.
4 Appellants do not dispute that Kaarsholm’s myristoyl lysophosphatidyl­
choline is the same as the lyso myristoyl phosphocholine (LMPC) recited in
claim 1.
3
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Application 12/715,203
include mono-and disaccharides. (Id. at 6.) The Examiner concludes that “it
would have been obvious to one of ordinary skill in the art to substitute the
isotonicity agents taught by Pedersen et al. for the mannitol in the
compositions taught by Kaarsholm.” (Id. at 6.)
We agree with the Examiner that the composition of claim 1 would
have been obvious based on Kaarsholm and Pedersen. Kaarsholm discloses
that “soluble and stable formulations of glucagon . . . may be prepared by
means of addition of detergents carrying multiple charges.” (Kaarsholm
2:58—61.) Kaarsholm states that “myristoyl derivatives of lysophosphatidyl-
choline ... are particularly useful.” (Id. at 5:6—8.) Kaarsholm discloses that
its compositions can contain excipients to adjust isotonic strength such as
NaCl, glycerol, or mannitol, and antibacterial agents. (Id. at 5:34—36, 48—
50.)
Pedersen states that including “isotonicity agents in peptide-
containing pharmaceutical formulations is widely known and one of the
more common isotonic agents used in such formulations is mannitol.”
(Pedersen 13.) Pedersen states, however, that “mannitol causes problems
during the production of peptide formulations as it crystallizes resulting in
deposits in the production equipment and in the final product.” (Id.)
Pedersen discloses tests of formulations containing different isotonic
agents, including: formulation 1 (glucose monohydrate, 38 mg/ml),
formulation 2 (lactose monohydrate, 65 mg/ml), formulation 3 (maltose,
67.2 mg/ml), and formulation 13 (sucrose, 79.1 mg/ml). (Id. 1181 and
Table 1.) Pedersen concludes that:
In the simulated filling experiment xylitol, glycerol, glucose,
maltose, PEG 400, propylene glycol, sorbitol, sucrose and
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Application 12/715,203
glycine were found to be suitable replacements candidates for
mannitol. However, as glucose is a reducing saccharide, and
therefore is able to initiate unwanted degradation in the
formulation, this tonicity modifier is ruled out. Furthermore,
maltose is ruled out due to clogging of needles. This leads to the
following candidates: glycerol, xylitol, sorbitol, sucrose, glycine,
propylene glycol and PEG 400, which are found to have suitable
properties as replacements candidates for mannitol in peptide
formulations with regards to drop test, clogging of needles and
simulated filling.
(Id. 1192, emphasis added.) Pedersen also discloses that lactose
monohydrate was found to cause worse deposits on filling equipment than
mannitol. (Id. 1 191.)
In summary, then, Pedersen discloses that the mono- or disaccharides
glucose, maltose, and lactose are unsuitable as substitutes for mannitol in
peptide formulations, but sucrose (a disaccharide) has suitable properties.
Therefore, we agree with the Examiner that it would have been obvious to
modify Kaarsholm’s glucagon formulation by replacing mannitol with a
mono- or disaccharide, specifically sucrose. Pedersen provides a reason to
make this substitution, because it discloses that mannitol causes problems
during production because it crystallizes, whereas sucrose does not.
The Examiner has calculated that Kaarsholm discloses a range of
concentrations for glucagon and LMPC, and Pedersen discloses a range of
concentrations for preservatives, that overlap those recited in claim 1. (Ans.
7—8.) Appellants do not dispute this finding. Pedersen discloses a
composition comprising 79.1 mg/ml sucrose, which is within the range
recited in claim 1. The cited references therefore support a prima facie case
of obviousness.
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Application 12/715,203
Appellants argue that
Pederson expressly directs one not to use some of the agents
listed . . ., either because they will initiate unwanted degradation
(glucose) in the formulation, or because, like mannitol or worse
than mannitol, they would cause deposits in equipment and/or
the formulation (glycine, lactose, arginine, etc.). See Pederson,
para. [0191] and [0192],
(Appeal Br. 8.)
We agree with Appellants that Pedersen discloses that certain mono-
and disaccharides, including glucose and lactose, are not suitable
replacements for mannitol in peptide formulations. We therefore reverse the
rejection as it is applied to claims 5, 19, and 20, which are limited to either
glucose or lactose in the claimed glucagon formulation.
However, claim 1 recites a monosaccharide or disaccharide generally,
and Pedersen discloses that sucrose is a suitable replacement for mannitol in
peptide formulations. Kaarsholm and Pedersen therefore make obvious a
formulation that is encompassed by claim 1.
The Examiner pointed out that “Pederson expressly states that
sucrose, another disaccharide, was ‘found have suitable properties as [a]
replacement candidate[] for mannitol in peptide formulations with regards to
drop test, clogging of needles and simulated filling (para. [0192]).” (Ans.
13.) In response, Appellants argued that Pedersen excluded glucose and
lactose as mannitol replacements. (Reply Br. 9.) Appellants did not,
however, point to any evidence to show that an ordinarily skilled artisan
would not have had a reason to replace mannitol with sucrose, based on the
cited references.
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Application 12/715,203
Appellants also argue that the cited references would not have led a
skilled artisan to combine LMPC and an isotonicity agent in order to
enhance stability of glucagon. (Appeal Br. 9-12.)
“In determining whether the subject matter of a patent claim is
obvious, neither the particular motivation nor the avowed purpose of the
patentee controls. . . . [A]ny need or problem known in the field of endeavor
at the time of invention and addressed by the patent can provide a reason for
combining the elements in the manner claimed.” KSR Int 7 Co. v. Teleflex
Inc., 550 U.S. 398, 419-20 (2007). Here, Pedersen provides a reason to
modify Kaarsholm’s composition by substituting sucrose for mannitol. The
Examiner has calculated that Kaarsholm discloses a range of LMPC that
overlaps that of claim 1, and Pedersen discloses using an amount of sucrose
that is encompassed by claim 1. It is reasonable, therefore, to expect that the
formulation made obvious by the prior art will have the same properties as
the claimed formulation, including enhanced stability.
Claims 4 and 10-18 have not been argued separately and therefore fall
with claim 1. 37 C.F.R. § 41.37(c)(l)(iv).
SUMMARY
We affirm the rejection of claims 1, 4, and 10—18 under 35 U.S.C.
§ 103(a) based on Kaarsholm and Pedersen. However, we reverse the
rejection as applied to claims 5, 19, and 20.
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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-IN-PART
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