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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Atty. Dkt. No. 016777-0454
`
`Applicant:
`
`Indu J. ISAACS
`
`Title:
`
`GLP-2 FORMULATIONS
`
`Appl. No.:
`
`09/750,022
`
`Filing Date: 12/29/2000
`
`Examiner:
`
`Chih Min KAM
`
`Art Unit:
`
`1653
`
`AMENDMENT AND REPLY UNDER 37 CFR § 1.111
`
`Mail Stop Amendment
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`This communication is responsive to the non-final Office Action dated October 4,
`
`2004, concerning the above-referenced patent application. As the shortened statutory period
`
`for response expires Tuesday, January 4, 2005, this response is timely filed.
`
`Amendments to the Claims are reflected in the listing of claims which begins on
`
`page 2 of this document.
`
`Remarks begin on page 12 of this document.
`
`CFAD Exhibit 1016
`
`1
`
`

`

`Appln. No. 09/750,022
`Atty. Dkt. No. 016777-0454
`
`Amendments to the Claims:
`
`This listing of claims will replace all prior versions, and listings, of claims in the application.
`
`Listing of Claims:
`
`1.
`
`(Previously Presented) A glucagon-like peptide 2 (GLP-2) formulation
`
`comprising:
`
`(a)
`
`(b)
`
`(c)
`
`( d)
`
`a medically useful amount of a naturally occurring GLP-2 or an analog thereof;
`
`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
`
`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 of the
`
`formulation is from about 7.3 to about 7.4.
`
`5.
`
`(Original) The GLP-2 formulation of claim I, 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.
`
`-2-
`
`2
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`

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`Appln. No. 09/750,022
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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 I 0, 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.
`
`-3-
`
`3
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`

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`Appln. No. 09/750,022
`Atty. Dkt. No. 016777-0454
`
`17.
`
`(Currently Amended) The GLP-2 formulation of claim 1, wherein the GLP-2
`
`peptide is an analog of natural GLP-2, the analog having:
`
`(a)
`
`one or more amino acid substitutions, additions, deletions, or modifications;
`
`and
`
`(b)
`
`GLP-2 receptor binding hiologieal 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.
`
`(Previously Presented) The GLP-2 formulation of claim 15, which is stable at
`
`ambient temperature for up to 6 months, as evidenced by GLP-2 peptide degradation of less
`
`than about 5% during this time period.
`
`26.
`
`(Previously Presented) The GLP-2 formulation of claim 25, wherein less than
`
`about 4% peptide degradation is observed after storage of the GLP-2 formulation during the
`
`time period.
`
`-4-
`
`4
`
`

`

`•
`
`Appln. No. 091750,022
`Atty. Dkt. No. 016777-0454
`
`27.
`
`(Previously Presented) The GLP-2 formulation of claim 26, wherein less than
`
`about 2% peptide degradation is observed after storage of the GLP-2 formulation during the
`
`time period.
`
`28.
`
`(Previously Presented) The GLP-2 formulation of claim 1, which is stable at a
`
`temperature of about 4°C for up to 18 months, as evidenced by GLP-2 peptide degradation of
`
`less than about 5% during this time period.
`
`29.
`
`(Previously Presented) The GLP-2 formulation of claim 28, wherein less than
`
`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.
`
`-5-
`
`5
`
`

`

`..
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`Appln. No. 09/750,022
`Atty. Dkt. No. 016777-0454
`
`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 of the 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 -1 ° 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.
`
`-6-
`
`6
`
`

`

`Appln. No. 09/750,022
`Atty. Dkt. No. 016777-0454
`
`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
`
`2 ° C/minute; and
`
`(b)
`
`maintaining the formulation at about -20 ° C for about 14 hours under a
`
`vacuum of about 150 mT 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 of about -80° C
`
`until there is less than about 5% of water remaining in the formulation.
`
`42.
`
`(Previously Presented) The method of claim 41, wherein the formulation is
`
`maintained at about +20°C, at a vacuum of about 150 mT and a condenser temperature of
`
`about -80°C, until there is about 2% or less 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.
`
`-7-
`
`7
`
`

`

`,,
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`Appln. No. 09/750,022
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`
`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.
`
`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.
`
`(Previously Presented) A method for treating a human or animal having a
`
`gastrointestinal 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.,.,
`
`thereby enhancing, maintaining, or promoting the growth or functioning of the gastrointestinal
`
`tract.
`
`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.
`
`-8-
`
`8
`
`

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`Appln. No. 09/750,022
`Atty. Dkt. No. 016777-0454
`
`51.
`
`(Original) The method of claim 50, wherein the pH of the formulation is from
`
`about 7.3 to about 7.4.
`
`52.
`
`(Previously Presented) The method of claim 49, wherein the GLP-2 treatment
`
`is for a 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:
`
`(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.
`
`(Canceled).
`
`57.
`
`(Canceled).
`
`58.
`
`(Previously Presented) 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.
`
`59.
`
`(Previously Presented) The GLP-2 formulation of claim 21, wherein the GLP-
`
`2 receptor antagonist has either (1) an amino acid substitution selected from the group
`, Phe22
`, Thr29
`, Thr32
`consisting of Asp 15
`, Asp33
`acid substitution of Ala at position 2 by an amino acid selected from the group consisting of
`
`, and combinations thereof; or (2) an amino
`
`Leu, Cys, Gglu, Arg, Trp and P03-Tyr.
`
`-9-
`
`9
`
`

`

`Appln. No. 09/750,022
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`60.
`
`(Previously Presented) 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.
`
`(Previously Presented) 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.
`
`(Previously Presented) 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.
`
`63.
`
`(Previously Presented) 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.
`
`(Previously Presented) The GLP-2 formulation of claim 1, wherein the GLP-2
`
`peptide is h(Gly2)GLP-2.
`
`65.
`
`(Previously Presented) The GLP-2 formulation of claim 2, wherein the GLP-2
`
`peptide is h(Gly2)GLP-2.
`
`66.
`
`(Previously Presented) The GLP-2 formulation of claim 3, wherein the GLP-2
`
`peptide is h(Gly2)GLP-2.
`
`67.
`
`(Previously Presented) The GLP-2 formulation of claim 4, wherein the GLP-2
`
`peptide is h(Gly2)GLP-2.
`
`68.
`
`(Previously Presented) The GLP-2 formulation of claim 5, wherein the GLP-2
`
`peptide is h(Gly2)GLP-2.
`
`69.
`
`(Previously Presented) The GLP-2 formulation of claim 6, wherein the GLP-2
`
`peptide is h(Gly2)GLP-2.
`
`-10-
`
`10
`
`

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`Appln. No. 09/750,022
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`
`70.
`
`(Previously Presented) The GLP-2 formulation of claim 7, wherein the GLP-2
`
`peptide is h(Gly2)GLP-2.
`
`71.
`
`(Previously Presented) The GLP-2 formulation of claim 8, wherein the GLP-2
`
`peptide is h(Gly2)GLP-2.
`
`72.
`
`(Previously Presented) The GLP-2 formulation of claim 9, wherein the GLP-2
`
`peptide is h(Gly2)GLP-2.
`
`73.
`
`(Previously Presented) The GLP-2 formulation of claim 10, wherein the GLP-
`
`2 peptide is h(Gly2)GLP-2.
`
`74.
`
`(Previously Presented) The GLP-2 formulation of claim 11, wherein the GLP-
`
`2 peptide is h(Gly2)GLP-2.
`
`75.
`
`(Previously Presented) The GLP-2 formulation of claim 12, wherein the GLP-
`
`2 peptide is h(Gly2)GLP-2.
`
`76.
`
`(Previously Presented) The GLP-2 formulation of claim 13, wherein the GLP-
`
`2 peptide is h(Gly2)GLP-2.
`
`77.
`
`(Previously Presented) The kit of claim 45, wherein the GLP-2 peptide is
`
`h(Gly2)GLP-2.
`
`78.
`
`(Previously Presented) The method of claim 50, wherein the GLP-2 peptide is
`
`h(Gly2)GLP-2.
`
`-11-
`
`11
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`

`

`Appln. No. 09/750,022
`Atty. Dkt. No. 016777-0454
`
`REMARKS
`
`Applicant respectfully requests reconsideration of the present application in view of
`
`the foregoing amendments and in view of the reasons that follow.
`
`I.
`
`Status Of The Claims
`
`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 claim( s)
`
`remain under examination in the application, is presented, with an appropriate defined status
`
`identifier.
`
`Claims 1-54 and 58-78 are pending. Claims 1-8, 10-22, 43-46, 49-55, 58-71 and 73-
`
`78 were rejected. Claims 9, 23-30, 47-48 and 72 were objected to. The Examiner is thanked
`
`for indicating allowable subject matter.
`
`Claim 1 7 is amended. Exemplary support for this amendment can be found, e.g., at
`
`original claims 1 and 17, and page 6, lines 1-3, of the application.
`
`Upon entry of this amendment, claims 1-54 and 58-78 will be pending in the
`
`application. As the foregoing amendment does not introduce new matter, entry thereof by the
`
`Examiner is respectfully requested.
`
`II.'
`
`Claim Rejections -- 35 U.S.C. § 112, Second Paragraph
`
`A.
`
`Claims 17, 58 And 60-63 For Reciting "One Or
`More Substitutions, Additions, Deletions, Or Modifications"
`
`Claims 17, 58 and 60-63 were rejected under 35 U.S.C. § 112, second paragraph, for
`
`reciting the phrase "one or more substitutions, additions, deletions, or modifications." The
`
`Examiner stated that it was not clear where the substitutions, additions, deletions, or
`
`modifications occur in the sequence and how many amino acids are substituted, added,
`
`deleted or modified, or what the resulting sequence is. Applicant respectfully traverses this
`
`ground of rejection.
`
`-12-
`
`12
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`

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`Appln. No. 09/750,022
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`
`The breadth of a claim is not to be equated with indefiniteness. In re Miller, 441 F.2d
`
`689, 169 USPQ 597 (CCPA 1971); see also MPEP § 2173.4. If the scope ofthe subject
`
`matter embraced by the claims is clear, and if applicants have not otherwise indicated that
`
`they intend the invention to be of a scope different from that defined in the claims, then the
`
`claims comply with 35 U.S.C. § 112, second paragraph. See MPEP § 2173.4.
`
`The pending claims recite an analog of natural GLP-2 "having one or more
`
`substitutions, additions, deletions, or modifications." Applicant specifically teaches suitable
`
`substitutions, additions, deletions, or modifications for GLP-2 analogs, for example, at page
`
`6, lines 1-12, of the Application. Moreover, Applicant specifically teaches and claims the
`
`functional characteristics of GLP-2 analogs. See page 5, lines 24-33, and page 6, lines 24-28,
`
`of the application. As such, the pending claims should be given their broadest reasonable
`
`interpretation consistent with the specification. MPEP § 2111. Read in light of the
`
`specification, a skilled artisan would understand the subject matter of the claimed invention.
`
`Accordingly, Applicant's claims are definite and this ground of rejection should be
`
`withdrawn.
`
`B.
`
`Claim 59 For Reciting Amino Acid
`Substitutions Without Indicating A "SEQ ID NO:"
`
`Claim 59 was rejected under 35 U.S.C. § 112, second paragraph, for reciting amino
`
`acid substitutions at various positions without indicating the "SEQ ID NO:" of the reference
`
`sequence. Applicant respectfully requests reconsideration and withdrawal of the rejection.
`
`For compliance with the definiteness requirement of 35 U.S.C. § 112, second
`
`paragraph, the claim language must meet the threshold requirements of clarity and precision
`
`regardless "whether more suitable language or modes of expression are available." MPEP §
`
`2173.02. The essential inquiry is whether the claims set out their subject matter with a
`
`reasonable degree of clarity and particularity. See MPEP § 2173.02. This inquiry is analyzed
`
`in light of: (1) the content of the particular application, (2) the teachings of the prior art, and
`
`(3) the claim interpretation that would be given by one of ordinary skill in the art at the time
`
`the invention was made. See MPEP § 2173.02.
`
`-13-
`
`13
`
`

`

`Appln. No. 09/750,022
`Atty. Dkt. No. 016777-0454
`
`Those skilled in the art would understand the metes and bounds of the claimed
`
`specific peptide analogs. The GLP-2 peptide was well-known to those skilled in the art at the
`
`time the invention was made. For example, a review article summarized much of the
`
`contemporaneous knowledge concerning the peptide:
`
`the GLP-2 sequence (Fig. 2) was detected in all isolated
`mammalian proglucagon cDNAs and genes (6, 7, 8, 9, 10) as a
`33 amino acid peptide located carboxyterminal to GLP-1 and
`intervening peptide 2 (Figs. 1 and 2). Subsequent studies
`demonstrated that fish, chickens, and lizards generate GLP-2 in
`the gut as a result of tissue-specific alternative RNA splicing of
`proglucagon RNA transcripts (11, 12).
`In mammals, tissue(cid:173)
`liberates GLP-2 from
`specific posttranslational processing
`proglucagon in the intestine and brain but not in pancreas, as a
`result of cell-specific expression of prohormone convertases in
`gut endocrine cells (13).
`Isolation and sequencing of GLP-2
`from the porcine and human intestine confirmed that GLP-2 is a
`33 amino acid peptide (Fig 2), corresponding to proglucagon
`126-158, ending in a carboxyterminal Asp residue (14, 15).
`
`D.J. Drucker, J Clin. Endocrinol. Metab. 86(4):1159-64 (2001). As exemplified by the
`
`above excerpt, those skilled in the art would recognize that naturally occurring GLP-2 is a 33
`
`amino acid peptide cleaved from proglucagon and ending in a specific residue. This
`
`recognition is consistent with the disclosure of the application. See, e.g., page 1, lines 20-25.
`
`In addition and as previously stated, those skilled in the art would have recognized a
`
`number of specific GLP-2 analogs. See pages 17-19 of the Paper of September 7, 2004; see
`
`also U.S. Patent Nos. 5,789,379 and 5,952,301. Likewise, Applicant specifically teaches
`
`suitable GLP-2 analogs, for example, at page 5, line 24, to page 6, line 34, of the application.
`
`In view of the disclosure of the application and the state of the art at the time the
`
`invention was made, those skilled in the art would recognize the subject matter recited as an
`
`"analog of natural GLP-2." Accordingly, Applicant respectfully requests reconsideration and
`
`withdrawal of the rejection.
`
`-14-
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`14
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`

`

`Appln. No. 09/750,022
`Atty. Dkt. No. 016777-0454
`
`III. Claim Rejections -- 35 U.S.C. § 103
`
`A.
`
`Rejection Of Claims 1-8, 10, 22, 49-55, 58, 63-71, 73
`And 78 As Being Obvious Over Knudsen In View Of Kornfelt
`
`Claims 1-8, 10, 22, 49-55, 58, 63-71, 73 and 78 were rejected under 35 U.S.C.
`
`§ 103(a) as being allegedly obvious over Knudsen et al. (WO 99/43361, "Knudsen") in view
`
`of Komfelt et al. (U.S. Patent No. 5,652,216, "Komfelt"). Applicant respectfully traverses
`
`and requests reconsideration and withdrawal of the rejection.
`
`1.
`
`The Examiner's Basis for the Rejection
`
`The Examiner asserts that it would have been obvious to a person of ordinary skill in
`
`the art to prepare a pharmaceutical composition of GLP-2 as indicated by Knudsen with the
`
`addition of histidine as a stabilizing agent as taught by Komfelt because histidine had been
`
`shown to stabilize glucagon and GLP-2 is a glucagon-like peptide.
`
`2.
`
`There is no Motivation to Combine the Teachings of
`Knudsen and Kornfelt Because Kornfelt Relates To Glucagon,
`Which is Significantly Different Than Applicant's Claimed GLP-2
`
`A proper rejection under 35 U.S.C. § 103(a) requires 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 carrying out the claimed invention, 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. See In re Vaeck, 947 F.2d 488, 493, 20 USPQ2d 1438, 1442 (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 Komfelt to obtain the claimed invention. Komfelt is directed
`
`to a pharmaceutical composition comprising glucagon and a stabilizing amount of a
`
`pharmaceutically acceptable ampholyte including, for instance, histidine. Despite similarities
`
`-15-
`
`15
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`Appln. No. 09/750,022
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`in their names, glucagon and a naturally occurring GLP-2, or an analog thereof, are not
`
`interchangeable and have different properties, characteristics, and functionality.
`
`For example, the physical properties of each protein are so different that it is not
`
`intuitive that excipients and formulations that stabilize glucagon would have the same effect
`
`on naturally occurring GLP-2, or an analog thereof. The following figure shows that there is
`
`very little structural equivalence between glucagon and GLP-2.
`
`hGLP-2
`
`Glucagon
`
`HADGSFSDEMNTILDNLAARDFINWLIQTKITD
`+ + +
`++
`+ ++
`++
`+
`HSQGTFTSDYSKYLDSRRAQDFVQWLMNT
`
`Although the origin of the sequences are related, GLP-2 possesses only 33% sequence
`
`homology to glucagon - which is equivalent to 11 of 33 amino acid residues. Moreover, the
`
`chart provided below shows some of the properties, characteristics, and functionality which
`
`are different between glucagon and ALX-0600, an exemplary GLP-2 analog.
`
`Pronertv
`
`Soluble In HiO?
`
`ALX-0600
`
`Gluca2on
`
`Yes
`
`No
`
`Soluble At pH?
`
`Above About 5 .5
`
`About 2.8
`
`High Affinity Binding to GLP-2 Receptor?
`
`In Vivo Intestinotrophic Activity?
`
`Yes
`
`Yes
`
`No
`
`No
`
`As shown above, the solubility glucagon and GLP-2 are dramatically different.
`
`Applicant teaches that [Gly2]hGLP-2 precipitates from solution below about pH 5.5. See
`
`page 7, lines 3-6, of the Application. In contrast, Kornfelt teaches that the preferred pH for
`
`glucagon is pH 2.8. See col. 3, lines 9-12, ofKornfelt. Likewise, glucagon is practically
`
`insoluble in water. See European Pharmacopoeia Commission, The European Pharmacopeia
`
`(2nd Ed.), page 612 (1989).
`
`-16-
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`16
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`Appln. No. 09/750,022
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`Moreover, glucagon and GLP-2 are functionally distinct. GLP-2 analogs that activate
`
`GLP-2 receptor signal transduction in vitro display intestinotrophic activity in vivo. See, e.g.,
`
`Munroe et al., Proc. Natl. Acad. Sci. U.S.A. 96(4):1569-73 (1999) ("Munroe"). Glucagon
`
`does not. See page 1573, Table 2, of Munroe. Likewise, GLP-2, but not glucagon, is capable
`
`of high affinity binding to the GLP-2 Receptor. See page 1573, Table 2, of Munroe.
`
`Accordingly, glucagon and a naturally occurring GLP-2, or an analog thereof, are not
`
`interchangeable as each peptide has different properties, characteristics, and functionality.
`
`3.
`
`There is no Motivation to Combine
`the Teachings of Knudsen and Kornfelt Because
`of the Empirical Nature of Peptide/Protein Formulations
`
`Additionally, a person of ordinary skill in the art would know that there are several
`
`problems that may be encountered in designing peptide/protein formulations due to their
`
`empirical nature.
`
`In Applicant's previous response, several references were cited that detail the
`
`difficulties that may be involved with designing peptide/protein formulations. See e.g., Pikal
`
`et al., Pharm. Res. 8(4):427-436 (1991) ("Pikal") and Cleland et al., "Formulation and
`
`delivery of proteins and peptides: design and development strategies" in Cleland et al. (Eds.),
`
`Formulation and Delivery of Proteins and Peptides, American Chemical Society, Washington
`
`D.C., p. 1-19 (1994) ("Cleland"), Cleland prominently noted that "one parameter that
`
`impacts all the major degradation pathways is the solution pH." (See e.g., page 5, first full
`
`paragraph). Additionally, Cleland states that:
`
`[t] he 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.
`
`Page l. Because these 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 Komfelt.
`
`-17-
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`17
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`Appln. No. 09/750,022
`Atty. Dkt. No. 016777-0454
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`For at least these reasons, this ground for rejection should be withdrawn.
`
`B.
`
`Rejection Of Claims 11-12 And 74-75 As Being Obvious Over
`Knudsen In View Of Kornfelt And Further In View Of Hora
`
`Claims 11-12 and 74-75 were rejected under 35 U.S.C. § 103(a) as being obvious over
`
`Knudsen in view ofKornfelt and further in view of Hora et al. (U.S. Patent No. 5,997,856,
`
`"Hora"). Applicant respectfully traverses 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 ofKornfelt. Hora does not
`
`remedy the deficiencies of Knudsen and Kornfelt. Hora discloses a method for the
`
`solubilization and/or stabilization of polypeptides using cyclodextrin. Hora fails to disclose
`
`the presently claimed combination of GLP-2, histidine, phosphate buffer, and a bulking agent.
`
`Accordingly, claims 11-12 and 74-75 are not obvious over Knudsen in view ofKornfelt and
`
`further in view of Hora. Applicant respectfully requests withdrawal of the rejection.
`
`C.
`
`Rejection Of Claims 13-15, 17-20 And 76 As
`Being Obvious Over Knudsen In View Of Kornfelt And
`Further In View Of Drucker (WO 97/39031, "Drucker A")
`
`Claims 13-15, 17-20 and 76 were rejected under 35 U.S.C. § 103(a) as being obvious
`
`over Knudsen in view ofKornfelt and further in view of Drucker et al. (WO 97/39031,
`
`"Drucker A"). Applicant respectfully traverses 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 ofKornfelt. Drucker A
`
`does not remedy the deficiencies of Knudsen and Kornfelt. 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 76 are not obvious over Knudsen in view
`
`of Kornfelt and further in view of Drucker A. Applicant respectfully requests withdrawal of
`
`the rejection.
`
`-18-
`
`18
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`Appln. No. 09/750,022
`Atty. Dkt. No. 016777-0454
`
`D.
`
`Rejection Of Claims 16 And 21 As Being Obvious Over
`Knudsen In View Of Kornfelt And Further In View Of Thim
`
`Claims 16 and 21 were rejected under 35 U.S.C. § 103(a) as being obvious over
`
`Knudsen in view ofKornfelt and further in view of Thim et al. (U.S. Patent No. 5,912,229,
`
`"Thim"). Applicant respectfully traverses and requests 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 ofKornfelt. Thim does not
`
`remedy the deficiencies of Knudsen and Kornfelt. 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 bulking agent.
`
`Therefore, claims 16 and 21 are not obvious over Knudsen in view ofKornfelt and further in
`
`view of Thim. Applicant respectfully requests withdrawal of the rejection.
`
`E.
`
`Rejection Of Claims 43-46 And 77 As Being
`Obvious Over Knudsen In View Of Kornfelt And Further
`In View Of Drucker (U.S. Patent No. 5,952,301, "Drucker B")
`
`Claims 43-46 and 77 were rejected under 35 U.S.C. § 103(a) as being obvious over
`
`Knudsen in view ofKornfelt and further in view of Drucker et al. (U.S. Patent No. 5,952,301,
`
`"Drucker B"). Applicant respectfully traverses and requests withdrawal of the rejection.
`
`As discussed above, the Examiner has failed to establish a prima facie case of