35 use 371 Filing of PCT/11320031004502!
`Preliminary Amendment
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`OHS Rec d PCT/PTO 1 6 FEB 2005
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`“NEEEZ‘PE
`
`Application of:
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`PCT Application No.
`PCT Filing Date:
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`Hans—Juergen Krause et a1.
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`PCT/[82003/004502
`15 August 2003
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`16 August 2002
`FORMULATION OF HUMAN
`ANTIBODIES FOR TREATING
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`TNF-oc ASSOCIATED DISORDERS
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`U.S. Serial No.:
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`(not yet assigned)
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`Filed:
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`(concurrently herewith)
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`Priority Date:
`Entitled:
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`ART UT ”1:
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`("m yet ass‘gned)
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`EXAMINER:
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`(not yet assigned)
`
`Attorney Docket No.: BBC-166
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`Mail Stop PCT
`Commissioner for Patents
`PO. Box 1450
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`Alexandria, VA 22313-1450
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`PRELIMINARY AMENDIVIENT
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`Sir:
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`Applicants are herewith submitting a Preliminary Amendment. The Examiner is
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`respectfully requested to enter the amendments prior to considering the application.
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`Amendments to the Specification begin on page 2 of this paper.
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`Amendments to the Claims are reflected in the listing of claims, which begin on page 3 of this
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`paper.
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`Remarks begin on page 7 of this paper.
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`‘
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`AMGEN INC.
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`
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`Exhibit 1048
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`Ex. 1048 - Page 1 of7
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`Ex. 1048 - Page 1 of 7
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`AMGEN INC.
`Exhibit 1048
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`35 USC 371 Filing of PCT/IBZOO3/004502
`Preliminary Amendment
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`Amendments to the Specification:
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`Please insert the following new paragraph on Page 1, line 5, before “Background of the
`Invention”:
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`CROSS-REFERENCE TO RELATED APPLICATIONS
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`This application is a National Stage Application under 35 USC. 371 of International
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`Application No. PCT/B2003/004502, with International Filing Date of August 15, 2003; which
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`claims the priority of US. Application No. 10/222,140, filed August 16, 2002.
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`Ex. 1048 - Page 2 of 7
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`Ex. 1048 - Page 2 of 7
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`35 USC 371 Filing of PCT/1B2003/004502
`Preliminary Amendment
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`Amendments to the Claims:
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`This listing of claims will replace all prior versions, and listings, of claims in the application:
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`Listing of Claims:
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`I (currently amended): A pharmaceutical formulation selected frrom the group consisting of:
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`(a)
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`a liquid aqueous pharmaceutical formulation comprising a therapeutically
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`effective amount of an antibody in a buffered solution, said formulation having a
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`pH between about 4 and 8 and having a shelf life of at least 18 months;
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`(b)
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`an aqueous pharmaceutical formulation comprising a therapeutically
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`effective amount of an antibody in a buffered solution, said formulation having a
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`pH between about 4 and 8 and having a shelf life of at least 18 months in the
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`liquid state;
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`(c)
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`a liquid aqueous pharmaceutical formulation comprising a
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`therapeutically effective amount of an antibody in a buffered solution, said
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`formulation having a pH between about 4 and 8 which maintains stability
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`following at least 3 freeze/thaw cycles of the formulation; and
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`(d)
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`a liquid aqueous pharmaceutical formulation comprising a therapeutically
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`effective amount of an antibody in a buffered solution, said formulation having a
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`pH between 4 and 8 and having enhanced stability of at least 12 months at a
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`temperature of 2 - 8°C.
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`2 (original):
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`The formulation of claim 1, wherein the antibody is directed to TNFoc.
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`3 (original):
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`The formulation of claim 1, wherein the concentration of the antibody is
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`between about 1-150 mg/ml.
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`4 (original):
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`The formulation of claim 1, wherein the concentration of the antibody is
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`about 50 mg/ml.
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`5 (original):
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`The formulation of claim 1, which further is suitable for single use
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`subcutaneous injection.
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`Ex. 1048 - Page 3 of 7
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`Ex. 1048 - Page 3 of 7
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`35 USC 371 Filing of PCT/IBZOO3/004502
`Preliminary Amendment
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`6 (currently amended): The formulation of claim 1, wherein the antibody is an human
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`antibody, or an antigen-binding portion thereof, that dissociates from human TNFOL with a Kd of l
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`x 10'8 M or less and a Koff rate constant of l x 10'3 s'1 or less, both determined by surface
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`plasmon resonance, and neutralizes human TNFOL cytotoxicity in a standard in vitro L929 assay
`with an IC50 of l x 10'7 M or less.
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`7 (original):
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`The formulation of claim 6, wherein the antibody, or antigen-binding
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`portion thereof, is a recombinant antibody, or anti gen-bindin g portion thereof.
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`8 (currently amended): The formulation of claim 1, wherein the antibody is an—t-he g
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`human antibody, or antigen-binding portion, thereof which with the following characteristics:
`a) dissociates from human TNFoc with a Koff rate constant of 1 x 10'3 s‘1 or less, as
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`determined by surface plasmon resonance;
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`b) has a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3,
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`or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8 or by
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`one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9;
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`c) has a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO:
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`4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10
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`or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11
`and/or 12.
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`9 (original):
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`The formulation of claim 1, wherein the antibody, or antigen-binding
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`portion thereof, has a light chain variable region (LCVR) comprising the amino acid sequence of
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`SEQ ID NO: 1 and a heavy chain variable region (HCVR) comprising the amino acid sequence of
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`SEQ ID NO: 2.
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`10 (original):
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`The formulation of claim 1, wherein the antibody, or antigen-binding
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`portion thereof, neutralizes the activity of human TNFOL, chimpanzee TNFU. and at least one
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`additional primate TNFOL selected from the group consisting of baboon TNFOL, marmoset TNFOL,
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`cynomolgus TNFoc and rhesus TNFoc.
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`11 (original):
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`The formulation of claim 1, wherein the antibody, or an antigen-binding
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`portion thereof, also neutralizes the activity of mouse TNFOL and/or pig TNFOL.
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`12 (original):
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`The formulation of claim 1, wherein the antibody, or antigen-binding
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`portion thereof, binds human TNFOL and is the antibody D2E7 or an antigen binding portion
`thereof.
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`Ex. 1048 - Page 4 of 7
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`Ex. 1048 - Page 4 of 7
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`35 USC 371 Filing of PCT/IB2003/004502
`Preliminary Amendment
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`13 (original): An aqueous pharmaceutical composition comprising a polyol, a
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`surfactant, and a buffer system comprising citrate and/or phosphate with a pH of about 4 to 8, in
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`amounts sufficient to formulate an antibody for therapeutic use at a concentration of greater than
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`about 45 myml.
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`14 (original):
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`The composition of claim 13, wherein the polyol is mannito] and the
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`surfactant is polysorbate 80.
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`15 (original):
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`The composition of claim 14, which contains 5-20 mg/ml of mannitol and
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`01-10 mg/ml of polysorbate 80.
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`16 (original):
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`The formulation of claim 13, which contains an antibody, or antigen-
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`binding portion thereof, which binds human TNFa and is the antibody D2E7 or an antigen
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`binding portion thereof.
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`17 (original): A liquid aqueous pharmaceutical formulation comprising
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`(a) 1-150 mg/ml of antibody,
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`(b) 5—20 mg/m] of mannitol,
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`(0) 0.1-10 mg/ml of Tween-80, and
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`(d) a buffer system comprising citrate and/or phosphate, with a pH of 4
`to 8.
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`18 (original):
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`The formulation of claim 17, wherein the pH is selected from the group
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`consisting of between about 4.5 to about 6.0, between about 4.8 to about 5.5, and between about
`5.0 to about 5.2.
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`19 (original):
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`The liquid aqueous pharmaceutical formulation of claim 17, which
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`contains
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`(a) about 50 mg/ml of antibody,
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`(b) about 12 mgml of mannitol,
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`(c) about 1 mg/ml of Tween-80, and
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`(d) a buffer system comprising citrate and/or phosphate with a pH of about 4 to
`about 8.
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`20 (original):
`The formulation of claim 17, wherein the buffer system comprises
`' (a) about 1.3 mg/ml of citric acid,
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`(b) about 0.3 mg/ml of sodium citrate,
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`(c) about 1.5 mg/ml of disodium phosphate dihydrate,
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`EX. 1048 - Page 5 of 7
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`Ex. 1048 - Page 5 of 7
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`35 USC 371 Filing of PCT/IBZOO3/004502
`Preliminary Amendment
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`(d) about 0.9 mg/ml of sodium dihydrogen phosphate dihydrate, and
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`(6) about 6.2 mg/ml of sodium chloride.
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`21 (original):
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`The formulation of claim 19, wherein the antibody is directed to TNFOL.
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`22 (original):
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`The formulation of claim 19, wherein the antibody, or antigen-binding
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`portion thereof, binds human TNFoc and is the antibody D2E7 or an antigen binding portion
`thereof.
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`23 (original):
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`The formulation of claim 22, which is administered to a subject suffering
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`from a disorder in which TNFOL activity is detrimental such that TNFOL activity in the subject is
`inhibited.
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`Ex. 1048 - Page 6 of 7
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`Ex. 1048 - Page 6 of 7
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`35 USC 371 Filing of PCT/lBZOO3/004502
`Preliminary Amendment
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`w T
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`he amendment to the Specification inserts the priority information of this application.
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`The amendments to the Claims reflect amendments that were submitted to the
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`International Bureau under PCT Article 34 in response to the Written Opinion. However, as of
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`today, February 16, 2005, Applicants have not received the [PER from the International Bureau
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`reflecting entry of the amended Claims in PCT Application No. PCT/B2003/004502.
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`The Examiner is respectfully requested to enter the amendments.
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`Respectfully subtted,
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`ohn D. Conway
`Registration No. 39,150
`Attorney for Applicant
`ABBOTT BIORESEARCH CENTER
`100 Research Drive
`
`Worcester, Massachusetts 01605-4314
`telephone: (508) 688-8046
`telefax: (508) 688—81 10
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`CERTIFICATE OF MAILING BY "EXPRESS MAIL"
`
`The undersigned hereby certifies that this correspondence listed above is being deposited with the United
`States Postal Service "Express Mail Post Office to Addressee" Service under 37 CFR §1. 10, postage prepaid,
`Express Mailing Label No.
`ED072003559US
`, in an envelope addressed to Mail Stop PCT,
`Commissioner for Patents, PO. Box 1450, Alexandria, VA 22313—1450 on the date indicated below.
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`M—Lisa Rasmussen
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`Ex. 1048 - Page 7 of 7
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`Ex. 1048 - Page 7 of 7
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