r
`
`Atty. Dkt. No. 016777-0454
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicant:
`
`Indu J. ISAACS
`
`Title:
`
`GLP-2 FORMULATIONS
`
`Appl. No.:
`
`09/750,022
`
`Filing Date: December 29, 2000
`
`Examiner:
`
`ChihMinKam
`
`Art Unit:
`
`1653
`
`AMENDMENT AND REPLY UNDER 3 7 CFR 1.111
`
`Commissioner for Patents
`PO Box 1450
`Alexandria, Virginia 22313-1450
`
`Sir:
`
`This communication is responsive to the Non-Final Office Action dated September
`
`16, 2003, concerning the above-referenced patent application.
`
`Amendments to the Claims are reflected in the listing of claims which begins on
`
`page 2 of this document.
`
`Remarks/Arguments begin on page 12 of this document.
`
`Please amend the application as follows:
`
`03/17/2004 SDENBOB1 00000117 09750022
`01 FC:1202
`378.00 OP
`
`03/17/2004 SDENBOB1 00000117 09750022
`02 FC:1253
`950.00 OP
`
`CFAD Exhibit 1012
`
`1
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`

`

`.c'
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`(I
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`Amendments to the Claims:
`
`Atty. Dkt. No. 016777-0454
`Appln. No.: 09/750,022
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`- This listing of claims will replace all prior versions, and listings, of claims in the application:
`
`Listing of Claims:
`
`1.
`
`(Presently Amended) A glucagon-like peptide 2 CGLP-2} formulation
`
`comprising:
`
`(a)
`
`a medically useful amount of a naturally occurring gll:leagoa like
`
`peptiae 2 (GLP-21 or an analog thereof;
`
`(b)
`
`a phosphate buffer in an amount sufficient to adjust the pH of the
`
`formulation to a physiologically tolerable level;
`
`L-histidine; and
`
`a bulking agent selected from the group consisting of mannitol and
`
`(c)
`
`( d)
`
`sucrose.
`
`2.
`
`(Original) The GLP-2 formulation of claim 1, wherein the· pH of the
`
`formulation is greater than about 6.0.
`
`3.
`
`(Original) The GLP-2 formulation according to claim 2, wherein the pH of the
`
`formulation is from about 6.9 to about 7.9.
`
`4.
`
`(Original) The GLP-2 formulation of claim 3, wherein the.pH ofthe
`
`formulation is from about 7.3 to about 7.4.
`
`5.
`
`(Original) The GLP-2 formulation of claim 1, wherein the GLP-2 peptide or
`
`analog thereof is present at a concentration of about 0.1 to about 50 mg/ml.
`
`6.
`
`(Original) The GLP-2 formulation of claim 5, wherein the· GLP-2 peptide or
`
`analog thereof is present at a concentration of about 5 to about 40 mg/ml.
`
`7.
`
`(Original) The GLP-2 formulation of claim 6, wherein the GLP-2 peptide or
`
`analog thereof is present at a concentration of about 7 to about 30 mg/ml.
`
`8.
`
`(Original) The GLP-2 formulation of claim 7, wherein the. GLP-2 peptide or
`
`analog thereof is present at a concentration of about 10 to about 20 mg/ml.
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`Atty. Dkt. No. 016777-0454
`Appln. No.: 091750,022
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`9.
`
`(Original) The GLP-2 formulation of claim 8, wherein the· L-histidine is
`
`- present in an amount of about 0.5 to about 1 %.
`
`10.
`
`(Original) The GLP-2 formulation of claim 9, wherein the bulking agent is·
`
`mannitol.
`
`11.
`
`(Original) The GLP-2 formulation of claim 10, wherein the mannitol is
`
`present at a concentration of about 2 to about 5%.
`
`12.
`
`(Original) The GLP-2 formulation of claim 11, wherein the mannitol is
`
`present at a concentration of about 2.5 to about 3.5%.
`
`13.
`
`(Original) The GLP-2 formulation of claim 1, wherein the GLP-2 peptide is
`
`selected from the group consisting of a mammalian GLP-2 peptide, a vertebrate GLP-2
`
`peptide, and a human GLP-2 peptide.
`
`14.
`
`(Previously Presented) The GLP-2 formulation of claim 13, wherein the GLP-
`
`2 peptide has the sequence of a GLP-2 species from an animal selected from the group
`
`consisting of a primate, rat, mouse, porcine species, oxine species, bovine species, degu,
`
`hamster, guinea pig, fish, chicken, and human.
`
`15.
`
`(Previously presented) The GLP-2 formulation of claim 14, wherein the GLP-
`
`2 peptide is h(Gly2)GLP-2.
`
`16.
`
`(Original) The GLP-2 formulation of claim 1, wherein the GLP-2 analog is
`
`identified by a process comprising:
`
`(a)
`
`screening peptides against cells genetically engineered to produce the GLP-2
`
`receptor, and
`
`(b)
`
`identifying peptides which bind to the GLP-2 receptor, wherein such peptides
`
`are identified as GLP-2 peptides useful in the formulation of claim 1.
`
`17.
`
`(Original) The GLP-2 formulation of claim 1, wherein the GLP-2 peptide is
`
`an analog of natural GLP-2, the analog having:
`
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`(a)
`
`one or more amino acid substitutions, additions, deletions, or modifications;
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`Atty. Dkt. No. 016777-0454
`Appln. No.: 09/750,022
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`and
`
`(b)
`
`biological activity.
`
`18.
`
`(Original) The GLP-2 formulation of claim 1, wherein the GLP-2 peptide is
`
`an analog which has been altered to confer resistance to endogenous enzymes.
`
`19.
`
`(Original) The GLP-2 formulation of claim 18, wherein the alteration
`
`comprises substitution of the alanine residue at position 2 of GLP-2 with another suitable
`
`amino acid.
`
`20.
`
`(Original) The GLP-2 formulation of claim 19, wherein the alanine residue at
`
`position 2 is substituted with glycine or serine.
`
`21.
`
`(Original) The GLP-2 formulation of claim 1, wherein the GLP-2 analog is a
`
`GLP-2 receptor antagonist.
`
`22.
`
`(Original) The GLP-2 formulation of claim 1 in lyophilized form.
`
`23.
`
`(Original) The lyophilized formulations of claim 22, comprising less than.
`
`about 5% water by weight.
`
`24.
`
`(Original) The lyophilized formulations of claim 23, comprising 2% or less
`
`water by weight.
`
`25.
`
`(Presently Amended) The GLP-2 formulation of claim +.li, which is stable at
`ambient temperature for up to at least 6 months, as evidenced by GLP-2 peptide degradation
`
`of less than about 5% during this time period.
`
`26.
`
`(Original) The GLP-2 formulation of claim 25, wherein less than about 3 to
`
`about 4% peptide degradation is observed after storage of the GLP-2 formulation during the
`
`time period.
`
`002.1087354. 1
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`Atty. Dkt. No. 016777-0454
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`27.
`
`(Original) The GLP-2 formulation of claim 26, wherein less than about 1 to
`
`-. about 2% peptide degradation is observed after storage of the GLP-2 formulation during the
`
`time period.
`
`28.
`
`(Original) The GLP-2 formulation of claim 1, which is stable at a temperature
`
`of about 4 °C for up to at least 18 months, as evidenced by GLP-2 peptide degradation of less
`
`than about 5% during this time period.
`
`29.
`
`(Original) The GLP-2 formulation of claim 28, wherein less than about 3 to
`
`about 4% peptide degradation is observed after storage of the GLP-2 during the time period.
`
`30.
`
`(Original) The GLP-2 formulation of claim 29, wherein less than about 2%
`
`peptide degradation is observed after storage of the GLP-2 formulation during the time
`
`period.
`
`31.
`
`(a)
`
`(b)
`
`( c)
`
`( d)
`
`(Original) A GLP-2 formulation comprising:
`
`about 0.1 to about 50 mg/ml of a GLP-2 peptide or an analog thereof;
`
`a phosphate buffer in an amount sufficient to adjust the pH of the formulation
`
`to a pharmaceutically tolerable level;
`
`about 0.5 to about 1 % L-histidine; and
`
`about 2 to about 5% mannitol.
`
`32.
`
`(Previously Presented) The GLP-2 formulation of claim 31, wherein the GLP-
`
`2 is h(Gly2)GLP-2.
`
`33.
`
`(Original) The GLP-2 formulation of claim 32, wherein the formulation is
`
`lyophilized.
`
`34.
`
`(Original) The GLP-2 formulation of claim 32, wherein the pH of the
`
`formulation is selected from the group consisting of greater than about 6.0, and from about·
`
`6.9 to about 7.9.
`
`35.
`
`(Original) The GLP-2 formulation of claim 34, wherein the pH of the
`
`formulation is from about 7.3 to about 7.4.
`
`002. 1087354.1
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`Atty. Dkt. No. 016777-0454
`Appln. No.: 091750,022
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`36.
`
`(Original) A method for making a lyophilized formulation of GLP-2
`
`- comprising the following steps:
`
`(a)
`
`preparing a GLP-2 formulation comprising:
`
`(i)
`
`(ii)
`
`(iii)
`
`(iv)
`
`a GLP-2 peptide or an analog thereof;
`
`a phosphate buffer in an amount sufficient to adjust the pH of the
`
`formulation to a pharmaceutically tolerable level;
`
`L-histidine; and
`
`a bulking agent selected from the group consisting of mannitol and
`
`sucrose;
`
`freezing the formulation to -40°C;
`
`drying the formulation in a first drying step at -20°C; and
`
`drying the formulation in a second drying step at +20°C.
`
`(b)
`
`(c)
`
`(d)
`
`37.
`
`(Original) The method of claim 36, wherein the pH ofthe GLP-2 formulation
`
`prior to freezing is selected from the group consisting of greater than about 6.0, and from
`
`about 6.9 to about 7.9.
`
`38.
`
`(Original) The method of claim 37, wherein the pH of the formulation is from
`
`about 7.3 to about 7.4.
`
`39.
`
`(Original) The method of claim 36, wherein the freezing process of step (b)
`
`comprises:
`
`(a)
`
`cooling the formulation from ambient temperature to about -1°C at about
`
`2°C/minute, followed by maintaining the formulation at about-l°C for
`
`about 15 minutes; and
`
`(b)
`
`cooling the formulation from about-1°C to about-40°C at about
`
`2 ° C/minute, followed by maintaining the formulation at about -40 ° C for
`
`about 4 hours.
`
`40.
`
`(Original) The method of claim 36, wherein the drying process of step ( c)
`
`comprises:
`
`(a)
`
`raising the temperature from about-40°C to about-20°C at about
`
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`;
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`2 ° C/minute; and
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`Atty. Dkt. No. 016777-0454
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`(b)
`
`maintaining the formulation at about-20°C for about 14 hours under a
`
`vacuum of about 150 m T with a condenser temperature of about - 80 ° C.
`
`41.
`
`(Original) The method of claim 36, wherein the drying process of step (d)
`
`comprises:
`
`(a)
`
`warming the formulation from about-20°C to about +20°C at about
`
`2°C/minute;
`
`(b)
`
`maintaining the formulation at about +20°C for about 14 hours at a
`
`vacuum of about 150 mT and a condenser temperature ofabout-80°C
`
`until there is less than about 5% of water remaining in the formulation. ·
`
`42.
`
`(Original) The method of claim 41, wherein the formulation is maintained at
`
`about + 20°C, at a vacuum of about 150 m T and a condenser temperature of about -80°C,
`
`until there is no more than about 2% of water remaining in the formulation
`
`43.
`
`(a)
`
`(Original) A kit comprising:
`
`a lyophilized GLP-2 formulation comprising:
`
`(i)
`
`(ii)
`
`a GLP-2 peptide or an analog thereof;
`
`a phosphate buffer in an amount sufficient to adjust the pH of the
`
`formulation to a pharmaceutically acceptable level;
`
`(iii)
`
`(iv)
`
`L-histidine; and
`
`a bulking agent selected from the group consisting of mannitol and
`
`sucrose;
`
`(b)
`
`( c)
`
`a vial of sterile water for reconstitution; and
`
`instructions directing reconstitution.
`
`44.
`
`(Original) The kit of claim 43, wherein the pH of the GLP-2 formulation is
`
`selected from the group consisting of greater than about 5.5, greater than about 6.0, and from
`
`about 6.9 to about 7.9.
`
`45.
`
`(Original) The kit of claim 44, wherein the pH of the formulation is from
`
`about 7.3 to about 7.4.
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`002.1087354.1
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`Atty. Dkt. No. 016777-0454
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`46.
`
`(Original) The kit of claim 43 further comprising an injection device for
`
`~ administration.
`
`47.
`
`(Original) The kit of claim 43, wherein following reconstitution the GLP-2
`
`formulation is stable for at least about 12 hours.
`
`48.
`
`(Original) The kit of claim 43, wherein following reconstitution the GLP-2
`
`formulation is stable for up to about 24 hours.
`
`49.
`
`(Original) A method for treating a human or animal having a disorder, disease
`
`or condition for which treatment with GLP-2 is indicated, the method comprising the step of
`
`administering a therapeutically effective amount of a GLP-2 formulation comprising:
`
`(a)
`
`(b)
`
`( c)
`
`( d)
`
`a GLP-2 peptide or an analog thereof;
`
`a phosphate buffer in an amount sufficient to adjust the pH of the formulation
`
`to a pharmaceutically tolerable level;
`
`L-histidine; and
`
`a bulking agent selected from the group consisting of mannitol and sucrose:
`
`50.
`
`(Original) The method of claim 49, wherein the pH of the GLP-2 formulation
`
`is selected from the group consisting of greater than about 5.5, greater than about 6.0, and
`
`from about 6.9 to about 7.9.
`
`51.
`
`(Original) The method of claim 50, wherein the pH of the formulation is from
`
`about 7.3 to about 7.4.
`
`52.
`
`(Presently Amended) The method of claim 49, wherein the GLP-2 treatment
`
`is for!! gastrointestinal disorder, disease or condition.
`
`53.
`
`(Original) The method of claim 49, wherein the GLP-2 formulation is
`
`administered by injection.
`
`54.
`
`(Original) The method of claim 49, wherein the GLP-2 formulation is
`
`administered by infusion.
`
`55.
`
`(Previously Presented) A GLP-2 formulation comprising:
`
`002.1087354.1
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`,,
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`Atty. Dkt. No. 016777-0454
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`(a)
`
`a medically useful amount of a naturally occurring GLP-2 peptide or an analog
`
`thereof;
`
`(b)
`
`a phosphate buffer in an amount sufficient to adjust the pH of the formulation
`
`to a physiologically tolerable level;
`
`( c)
`
`( d)
`
`L-histidine in an amount sufficient to stabilize the formulation; and
`
`a bulking agent selected from the group consisting of mannitol and sucrose.
`
`56.
`
`(New) The kit of claim 45, wherein the GLP-2 peptide is h[Gly2]GLP-2.
`
`57.
`
`(New) The method of claim 50, wherein the GLP-2 peptide is h[Gly2]GLP-2.
`
`58.
`
`(New) The GLP-2 formulation of claim 1, wherein said GLP-2 analog has one
`
`or more amino acid substitutions, additions, deletions, or modifications and has GLP-2
`
`receptor binding activity.
`
`(New) The GLP-2 formulation of claim 21, wherein the GLP-2 receptor
`59.
`antagonist has (1) an amino acid substitution at any of the following positions: Asp 15
`, Phe22
`Thr29
`, Thr32 and/or Asp33
`; or (2) an amino acid substation at Ala2 by anyone of the following
`amino acids: Leu, Cys, glu, Arg, Trp and P03-Tyr2
`
`•
`
`,
`
`60.
`
`(New) The GLP-2 formulation of claim 31, wherein said GLP-2 analog has
`
`one or more amino acid substitutions, additions, deletions, or modifications and has GLP-2
`
`receptor binding activity.
`
`61.
`
`(New) The method of claim 36, wherein said GLP-2 analog has one or more
`
`amino acid substitutions, additions, deletions, or modifications and has GLP-2 receptor
`
`binding activity.
`
`62.
`
`(New) The kit of claim 43, wherein said GLP-2 analog has one or more amino
`
`acid substitutions, additions, deletions, or modifications, and has GLP-2 receptor binding
`
`activity.
`
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`Atty. Dkt. No. 016777-0454
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`63.
`
`(New) The method of claim 49, wherein said GLP-2 analog has one or more
`
`- amino acid substitutions, additions, deletions, or modifications and has GLP-2 receptor
`
`binding activity.
`
`64.
`
`(New) The GLP-2 formulation of claim 1, wherein the GLP-2 peptide is
`
`h(Gly2)GLP-2.
`
`65.
`
`(New) The GLP-2 formulation of claim 2, wherein the GLP-2 peptide is
`
`h(Gly2)GLP-2.
`
`66.
`
`(New) The GLP-2 formulation of claim 3, wherein the GLP-2 peptide is
`
`h(Gly2)GLP-2.
`
`67.
`
`(New) The GLP-2 formulation of claim 4, wherein the GLP-2 peptide is
`
`h(Gly2)GLP-2.
`
`68.
`
`(New) The GLP-2 formulation of claim 5, wherein the GLP-2 peptide is
`
`h(Gly2)GLP-2.
`
`69.
`
`(New) The GLP-2 formulation of claim 6, wherein the GLP-2 peptide is
`
`h(Gly2)GLP-2.
`
`70.
`
`(New) The GLP-2 formulation of claim 7, wherein the GLP-2 peptide is
`
`h(Gly2)GLP-2.
`
`71.
`
`(New) The GLP-2 formulation of claim 8, wherein the GLP-2 peptide is
`
`h(Gly2)GLP-2.
`
`72.
`
`(New) The GLP-2 formulation of claim 9, wherein the GLP-2 peptide is
`
`h(Gly2)GLP-2.
`
`73.
`
`(New) The GLP-2 formulation of claim 10, wherein the GLP-2 peptide is
`
`h(Gly2)GLP-2.
`
`002.1087354.1
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`Atty. Dkt. No. 016777-0454
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`74.
`
`(New) The GLP-2 formulation of claim 11, wherein the GLP-2 peptide is
`
`~ h(Gly2)GLP-2.
`
`75.
`
`(New) The GLP-2 formulation of claim 12, wherein the GLP-2 peptide is
`
`h(Gly2)GLP-2.
`
`76.
`
`(New) The GLP-2 formulation of claim 13, wherein the GLP-2 peptide is
`
`h(Gly2)GLP-2.
`
`002.1087354.1
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`Atty. Dkt. No. 016777-0454
`Appln. No.: 09/750,022
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`- I.
`
`Status of the Claims
`
`REMARKS
`
`Applicant respectfully requests reconsideration of the present application in view of
`
`the foregoing amendments and in view of the reasons that follow.
`
`Claims 1, 25 and 52 are currently amended, and claims 56-76 are added.
`
`This amendment adds, changes and/or deletes claims in this application. A detailed
`
`listing of all claims that are, or were, in the application, irrespective of whether the claims
`
`remain under examination in the application, is presented, with an appropriate defined status
`
`identifier.
`
`Exemplary support for the claim amendments and newly added claims is found the
`
`specification as indicated below. The amendments were made and the new claims were
`
`added to more clearly define claim scope.
`
`Exemlllan'. SUililOrt
`
`Page 1, line 20
`Page 8, lines 1-2
`Page 6, line 33, through page 7, line 2
`
`Claim#
`1
`52
`56-57
`(new)
`58 (new) Original claims 1 and 17; page 6, lines 1-3
`59 (new) Page 6, lines 16-19
`60-63
`Original claims 1 and 17; page 6, lines 1-3
`(new)
`64-76
`(new)
`
`Page 6, line 33, through page 7, line 2
`
`Upon entry of this Amendment, claims 1-76 will be pending in the application.
`
`Because the foregoing amendments do not introduce new matter, entry thereof by the
`
`Examiner is respectfully requested.
`
`II.
`
`October 30, 2003 Teleconference
`
`002.1087354.1
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`Atty. Dkt. No. 016777-0454
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`Applicants would like to thank Examiner Kam for clarifying the correct date on which
`
`- Paper No. 8 was filed. On page 3 of the outstanding Office Action dated September 16, 2003,
`
`the Examiner refers to Paper 8 filed on November 27, 2002. During an October 30, 2003
`
`teleconference with Applicant's representative, Examiner Kam confirmed that Paper No. 8 is
`
`Applicant's Amendment Under 37 C.F.R. § 1.111, dated June 10, 2002, a copy of which was
`
`faxed to the Examiner on November 1, 2003 and November 15, 2003. Applicant refers to
`
`this paper as "Paper No. 8" in the discussion provided below.
`
`III.
`
`Claim Objections
`
`Claim 1 is objected to because the amended claim in the response filed on July 9,
`
`2003 (Paper No. 12) is allegedly not based on the previously amended claim 1 filed in Paper
`
`No. 8. Applicant has amended claim 1 to be based on the previously amended claim 1 (Paper
`
`No. 8). This ground for objection is now moot.
`
`IV.
`
`Claim Rejections - 35 U.S.C. § 112, Second Paragraph
`
`Claims 2-4, 17, 23-30, 34, 35, 37, 38, 41, 42, 44, 45 and 47-54 are rejected under 35
`
`U.S.C. § 112, second paragraph, as being allegedly indefinite. Applicant respectfully requests
`
`reconsideration and withdrawal of the rejection.
`
`A.
`
`The Examiner asserts that in claims 2-4, 34, 35, 37, 38, 44, 45, 50 and 51, the
`
`terms "greater than about 6.0" and "greater than about 5.5'' are allegedly indefinite.
`
`B.
`
`The Examiner asserts that in claims 23-25, the terms "less than about 5%,"
`
`"for up to at least 6 months," and "less than about 3 to about 4%" are allegedly indefinite.
`
`C.
`
`The Examiner asserts that in claim 42, the term "no more than about 2%" is
`
`allegedly indefinite.
`
`D.
`
`The Examiner asserts that in claim 48, the term "up to about 24 hours" is
`
`allegedly indefinite.
`
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`Atty. Dkt. No. 016777-0454
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`E.
`
`The Examiner asserts that in claim 1 7, the terms "one or more amino acid
`
`· substitutions, additions, deletions or modifications" and "biological activity" are allegedly
`
`indefinite.
`
`F.
`
`The Examiner asserts that in claims 49-54 the terms "a disorder, disease or
`
`condition" and "gastrointestinal disease" are allegedly indefinite.
`
`G.
`
`Finally, the Examiner asserts that claims 49-54 are indefinite because the
`
`claims allegedly lack essential steps. The Examiner states that the omitted step is the
`
`outcome for the treatment.
`
`All of the above-noted rejections were made by the Examiner in the Office Action
`
`dated March 8, 2002 (Paper No. 7), and were successfully overcome by Applicant's
`
`arguments recited in Paper No. 8.
`
`In the March 8, 2002 Office Action (Paper No. 7), items 7-12 recited rejections under
`
`35 U.S.C. § 112, second paragraph, which are nearly identical to the rejections under 35
`
`U.S.C. § 112, second paragraph, recited in the outstanding Office Action. In response to
`
`Applicant's arguments recited in Paper No. 8, the Examiner stated: "[t]he previous rejection
`of claims 1-54, under 35 u.s.c. 112, second paragraph, is withdrawn in view of applicants'
`amendment to the claims, and applicants' response at pages 3-5 in Paper No. 8." (See page 2
`
`of the Examiner's Office Action dated February 5, 2003 (Paper No. 10), under the heading
`
`"Rejections Withdrawn"). Therefore, Applicant respectfully requests reconsideration and
`
`withdrawal of the rejections.
`
`V.
`
`Claim Rejections - 35 U.S.C. § 103
`
`A.
`
`Rejection of Claims 1-10, 22 and 49-55 as Being Obvious
`over Knudsen et al. in view of Yamazaki et al.
`
`Claims 1-10, 22 and 49-55 are rejected under 35 U.S.C. § 103 as being allegedly
`
`obvious over Knudsen et al. (WO 99/43361, "Knudsen") in view of Yamazaki et al. (USP
`
`6,120,761, 102(e) date: December 16, 1998, "Yamazaki"). Applicant respectfully traverses
`
`and requests reconsideration and withdrawal of the rejection.
`
`002.1087354.1
`
`-14-
`
`14
`
`

`

`1.
`
`The Examiner's Basis for the Rejection
`
`Atty. Dkt. No. 016777-0454
`Appln. No.: 09/750,022
`
`The Examiner asserts that it would have been obvious to a person of ordinary skill in
`
`.
`
`the art to prepare a pharmaceutical composition ofGLP-2 as indicated by Knudsen with the
`
`addition of histidine as a stabilizing agent as taught by Yamazaki to treat a gastrointestinal
`
`disease because using histidine as a stabilizing agent is safe without the risk of viral
`
`contamination and is also economically advantageous.
`
`2.
`
`There is no Motivation to Combine the Teachings of Knudsen and
`Yamazaki Because Yamazaki Relates to Erythropoietin, Which is
`Significantly Different Than Applicant's Claimed GLP-2
`
`A proper rejection for obviousness under§ 103 requires consideration of two factors:
`
`( 1) whether the prior art would have suggested to those of ordinary skill in the art that they
`
`should make the claimed composition, or device, or carry out the claimed process, and
`
`(2) whether the prior art would also have revealed that in making or carrying out the claimed
`
`invention, those of ordinary skill would have a reasonable expectation of success. Both the
`
`suggestion and the reasonable expectation of success must be found in the prior art. and not in
`
`the applicant's disclosure. In re Vaeck, 947 F.2d 488, 493, 20 USPQ2d 1438 (Fed. Cir.
`
`1991 ). In the present case, the examiner has failed to establish a prima facie case of
`
`obviousness for the following reasons.
`
`There is no teaching or suggestion in the cited art to combine the teachings of
`
`Knudsen with the teachings of Yamazaki to obtain the claimed invention.- Yamazaki is
`
`directed to a composition comprising erythropoietin, while the present invention is directed to
`
`a formulation comprising a naturally occurring GLP-2 or analog thereof. Erythropoietin and a
`
`naturally occurring GLP-2 or an analog thereof are not interchangeable, and have different
`
`properties and characteristics. The physical properties of each protein are so dramatically
`
`different that it is not intuitive that excipients and formulations that stabilize erythropoietin
`
`would have the same effect on naturally occurring GLP-2 or an analog thereof.
`
`The chart provided below shows some of the different properties between GLP-2 and
`
`ALX-0600, an exemplary GLP-2 analog.
`
`002.1087354.1
`
`-15-
`
`15
`
`

`

`Prol!er!I
`
`ALX-0600
`
`En::throl!oietin
`
`Atty. Dkt. No. 016777-0454
`Appln. No.: 09/750,022
`
`Molecular
`weight (Da)
`Isoelectric
`point
`structure
`
`Amino acid
`sequence
`
`3752.1
`
`4.3
`
`30,400 (fully glycosylated protein)
`
`8.99
`
`essentially random coil, very
`little structure, no glycosylation,
`no disulfide bridging
`HGDGSFSDEMNTILDNLAAR
`DFINWLIQTKITD
`
`glycoprotein, 4-helix bundle·
`structure, one disulfide bridge
`
`APPRLICDSRVLER YLLEAKEAE
`NITTGCAEHCSLNENITVPDTKV
`NFYAWKRMEVGQQAVEVWQG
`LALLSEAVLRGQALLVNSSQPW
`EPLQLHVDKA V
`SGLRSL TTLLRALRAQKEAISPP
`DAASAAPLRTITADTFRKLFRV
`YSNFLRGKLKLYTGEACRTGDR
`
`Erythropoietin is a large glycoprotein (eight times the size of ALX-0600), with
`
`significant conformational structure. At a neutral pH, this protein will be positively charged.
`
`In contrast, the GLP-2 analog ALX-0600 is considered to be a small peptide, i.e., it has very
`
`little structure. At neutral pH (the pH of the formulation), the GLP-2 analog ALX-0600 will
`
`be negatively charged.
`
`002. 1087354.1
`
`-16-
`
`16
`
`

`

`Atty. Dkt. No. 016777-0454
`Appln. No.: 09/750,022
`
`3.
`
`There is no Motivation to Combine the Teachings of Knudsen
`and Yamazaki Because Many Problems may be Encountered in
`Designing Peptide/Protein Formulations
`·
`
`Additionally, a person of ordinary skill in the art would know that there are several
`
`problems that may be encountered when designing peptide/protein formulations, as each
`
`protein is unique and the formulation depends on the physiochemical properties of the protein
`
`among other things.
`
`Attached are Pikal et al., Pharmaceutical Research, 8(4):427-436 (1991) (Exhibit 1)
`
`and Cleland, J.L. and Langer, R. (1994) "Formulation and delivery of proteins and peptides:
`
`design and development strategies" in J.L. Cleland and R. Langer (Eds.), Formulation and
`
`Delivery of Proteins and Peptides. American Chemical Society, Washington D.C., p. 1-19
`
`(Exhibit 2). These references detail the difficulties that may be involved with designing
`
`peptide/protein formulations. For example, Pikal et al. describe the difficulties that were
`
`encountered in determining a formulation for human growth hormone. See e.g., Abstract ..
`
`Cleland et al. describe the many variables that must be considered when designing a
`
`protein/peptide formulation, such as the isoelectric point, molecular weight, glycosylation or
`
`other post-translational modification, and overall amino acid composition (see e.g., page 4,
`
`third full paragraph of Cleland et al.). Cleland et al. also note that "one parameter that
`
`impacts all the major degradation pathways is the solution pH." (See e.g., page 5, first full
`
`paragraph). Additionally, in the paragraph bridging page I of Cleland et al. it states"
`
`The design and production of protein and peptide drug
`formulations is not well developed and many of the mechanisms
`for stabilization and delivery of these drugs have not been
`determined ... Each molecule has its own unique physical and
`chemical properties which determine its in vitro stability.
`
`Because of the inherent difficulties in designing peptide/protein formulations, one of
`
`skill in the art at the time the claimed invention was made would not have been motivated to
`
`attempt to make Applicant's claimed invention, given the teachings of Knudsen and
`
`Yamazaki.
`
`002.1087354.1
`
`-17-
`
`17
`
`

`

`Atty. Dkt. No. 016777-0454
`Appln. No.: 09/750,022
`
`4.
`
`One of Ordinary Skill in the Art Would Not Have had a
`Reasonable Expectation of Success in Obtaining the Claimed
`Invention by Combining the Teachings of Knudsen and Yamazaki
`
`A person of ordinary skill in the art would not have had a reasonable expectation of
`
`success in adding a stabilizing agent known to stabilize erythropoietin to a pharmaceutical
`
`formulation comprising a naturally occurring GLP-2 or analog thereof.
`
`As discussed above, erythropoietin and GLP-2 have different properties and
`
`characteristics. Additionally, a person of ordinary skill in the art would know that there are
`
`several problems that may be encountered when designing peptide/protein formulations, as
`
`each protein is unique and the formulation depends on the physiochemical properties of the
`
`protein among other things. Thus, a person of ordinary skill in the art would not expect a.
`
`naturally occurring GLP-2 or analog thereof to be stable under the same conditions as
`
`erythropoietin. At best, the examiner is using an improper "obvious to try" standard.
`
`However, "'obvious to try' has long been held to not constitute obviousness." In re Deuel, 51
`
`F.3d 1552, 1559, 34 USPQ2d 1210 (Fed. Cir. 1995).
`
`B.
`
`Rejection of Claims 11, 12, 31 and 33 as Being Obvious over
`Knudsen in view of Yamazaki and Further In View of Hora
`et al.
`
`Claims 11, 12, 31 and 33 are rejected under 35 U.S.C. § 103 as being allegedly
`
`obvious over Knudsen in view of Yamazaki as applied to claims 1-10, and further in view of
`
`Hora et al. (USP 5,997 ,856; "Hora"). Applicant respectfully requests reconsideration and
`
`withdrawal of the rejection.
`
`As discussed above, the Examiner has failed to establish a prima facie case of
`
`obviousness for the rejection of the claims over Knudsen in view of Yamazaki. Hora does
`
`not remedy the deficiencies of Knudsen and Yamazaki. Hora discloses a method for the
`
`solubilization and/or stabilization of polypeptides using cyclodextrin. The claims of Hora are
`
`directed to a method for formulating IL-2. Hora fails to disclose the presently claimed
`
`combination of GLP-2, histidine, phosphate buffer, and a bulking agent. Therefore, claims
`
`11, 12, 31 and 33 are not obvious over Knudsen in view of Yamazaki and further in view of
`
`002 .1087354. 1
`
`-18-
`
`18
`
`

`

`Atty. Dkt. No. 016777-0454
`Appln. No.: 09/750,022
`
`Hora. Applicant respectfully traverses and requests reconsideration and withdrawal of the
`
`- rejection.
`
`C.
`
`Rejection of Claims 13-15, 17-20 and 32 as Being Obvious
`over Knudsen et al. In View of Yamazaki et al., and Hora et
`al., and Further In View of Drucker et al. (WO 97/39031)
`
`Claims 13-15, 17-20 and 32 are rejected under 35 U.S.C. § 103 as being allegedly
`
`obvious over Knudsen in view of Yamazaki and Hora as applied to claim l, and further in
`
`view of Drucker et al. (WO 97/39031; "Drucker A"). Applicant respectfully requests
`
`reconsideration and withdrawal of the rejection.
`
`As discussed above, the Examiner has failed to establish a prima facie case of
`
`obviousness for the rejection of the claims over Knudsen in view of Yamazaki and Hora.
`
`Drucker A does not remedy the deficiencies of Knudsen, Yamazaki and Hora. Drucker A
`
`discloses analogs of GLP-2, formulations comprising the analogs, and uses thereof.
`
`However, Drucker A fails to disclose the presently claimed combination of GLP-2, histidine,
`
`phosphate buffer, and a bulking agent. Therefore, claims 13-15, 17-20 and 32 are not ?bvious
`
`over Knudsen in view of Yamazaki and Hora and further in view of Drucker A. Applicant
`
`respectfully traverses and requests reconsideration and withdrawal of the rejection.
`
`D.
`
`Rejection of Claims 16 and 21 as Being Obvious over
`Knudsen In View of Yamazaki, and Further In View of
`Thim
`
`Claims 16 and 21 are rejected under 35 U.S.C. § 103 as being allegedly obvious over
`
`Knudsen in view of Yamazaki as applied to claim 1, and further in view of Thim et al. (USP
`
`5,912,229; "Thim"). Applicant respectfully requests reconsideration and withdrawal of the
`
`rejection.
`
`As discussed above, the Examiner has failed to establish a prima facie case of
`
`obviousness for the rejection of the claims over Knudsen in view of Yamazaki. Thim does
`
`not remedy the deficiencies of Knudsen and Yamazaki. Thim relates to use of a
`
`pharmaceutical composition comprising GLP-2 or an analog thereof. However, Thim fails to
`
`disclose the presently claimed combination of GLP-2, histidine, phosphate buffer, and a
`
`002.1087354.1
`
`-19-
`
`19
`
`

`

`Atty. Dkt. No. 016777-0454
`Appln. No.: 091750,022
`
`bulking agent. Therefore, claims 16 and 21 are not obvious over Knudsen in view of
`
`- Yamazaki and further in view of Thim. Applicant respectfully traverses and requests
`
`reconsideration and withdrawal of the rejection.
`
`E.
`
`Rejection of Claims 43-46 as Being Obvious over Knudsen
`In View of Yamazaki, and Further In View of Drucker· et
`al. (USP 5,952,301; "Drucker B")
`
`Claims 16 and 21 are rejected under 35 U.S.C. § 103 as being obvious over Knudsen
`
`in view of Yamazaki as applied to claim 1, and further in view of Drucker et al. (USP
`
`5,952,301; "Drucker B''). Applicant respectfully requests reconsideration and withdrawal of
`
`the rejection.
`
`As discussed above, the Examiner has failed to establish a prima facie case of
`
`obviousness for the rejection of the claims over Knudsen in view of Yamazaki. Drucker B
`
`does not remedy the deficiencies of Knudsen and Yamazaki. Drucker B discloses
`
`pharmaceutical compositions of GLP-2 with at least one other peptide hormone, and uses.
`
`thereof. However, Drucker B fails to disclose the presently claimed combination of GLP-2,
`
`histidine, phosphate buffer