IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`110222-0005-308
`
`Applicant
`
`Abb Vie Biotechnology Ltd.
`
`Application No.
`
`14/322,565
`
`Confirmation No.
`
`6071
`
`Filed
`
`For
`
`July 2, 2014
`
`FORMULATION OF HUMAN ANTIBODIES FOR
`TREATING TNF-ALPHA ASSOCIATED DISORDERS
`
`Group Art Unit
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`1647
`
`Examiner
`
`Bridget E. Bunner
`
`New York, New York
`September 26, 2014
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-14 50
`
`REPLY TO SEPTEMBER 17, 2014 NON-FINAL OFFICE ACTION
`
`Madam:
`
`This responds to the September 17, 2014 Non-Final Office Action in the
`
`above-identified application. A response is due on or before December 17, 2014. Thus, this
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`response is timely filed.
`
`A Listing of Claims begins on page 2 of this paper.
`
`Remarks begin on page 7 of this paper.
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`Ex. 2013-0001
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`

`
`Application No. 14/322,565
`Reply dated September 26, 2014
`In Response to September 17, 2014 Office Action
`
`Docket No.: 110222-0005-308
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`LISTING OF CLAIMS
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`No amendment is being made. Applicant provides this Listing of Claims for the
`
`Examiner's convenience.
`
`Listing of Claims
`
`1.
`
`(Original) A stable liquid aqueous pharmaceutical formulation comprising
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`(a) a human IgG 1 anti-human Tumor Necrosis Factor alpha (TNFa) antibody, or an
`
`antigen-binding portion thereof, at a concentration of20 to 150 mg/ml,
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`(b) a polyol,
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`(c) a surfactant, and
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`(d) a buffer system comprising gluconate and having a pH of 4.0 to 8.0,
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`wherein the antibody comprises the light chain variable region and the heavy chain
`
`variable region ofD2E7.
`
`2.
`
`(Original) The formulation of claim 1, wherein the concentration of the antibody or
`
`antigen-binding portion is 50 to 100 mg/ml.
`
`3.
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`(Original) The formulation of claim 2, wherein the concentration of the antibody or
`
`antigen-binding portion is 50 mg/ml.
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`4.
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`(Original) The formulation of claim 1, wherein the antibody is D2E7.
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`5.
`
`(Original) The formulation of claim 1, wherein the polyol is a sugar alcohol.
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`-2-
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`Ex. 2013-0002
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`

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`Application No. 14/322,565
`Reply dated September 26, 2014
`In Response to September 17, 2014 Office Action
`
`Docket No.: 110222-0005-308
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`6.
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`(Original) The formulation of claim 5, wherein the sugar alcohol is mannitol.
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`7.
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`(Original) The formulation of claim 1, wherein the polyol is a sugar.
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`8.
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`(Original) The formulation of claim 7, wherein the sugar is a nonreducing sugar.
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`9.
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`(Original) The formulation of claim 8, wherein the nonreducing sugar is trehalose.
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`10.
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`(Original) The formulation of claim 1, wherein the surfactant is at a concentration ofO.l
`
`to 10 mg/ml.
`
`11.
`
`(Original) The formulation of claim 1, wherein the surfactant is a polysorbate.
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`12.
`
`(Original) The formulation of claim 11, wherein the polysorbate is polysorbate 20.
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`13.
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`(Original) The formulation of claim 11, wherein the polysorbate is polysorbate 80.
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`14.
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`(Original) The formulation of claim 13, wherein the polysorbate 80 concentration is from
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`0.5 to 5 mg/ml.
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`15.
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`(Original) The formulation of claim 13, wherein the polysorbate 80 concentration is 1
`
`mg/ml.
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`-3-
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`Ex. 2013-0003
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`

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`Application No. 14/322,565
`Reply dated September 26, 2014
`In Response to September 17, 2014 Office Action
`
`Docket No.: 110222-0005-308
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`16.
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`(Original) The formulation of claim 1, wherein the pH is from 4.5 to 6.0.
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`17.
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`(Original) The formulation of claim 16, wherein the pH is from 4.8 to 5.5.
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`18.
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`(Original) The formulation of claim 1, which is suitable for subcutaneous injection.
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`19.
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`(Original) The formulation of claim 1, comprising:
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`(a) 50 to 100 mg/ml of the antibody or antigen-binding portion,
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`(b) trehalose, and
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`(c) 0.5-5 mg/ml of polysorbate 80,
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`wherein said buffer system has a pH of 4.5 to 6.0.
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`20.
`
`(Original) The formulation of claim 4, comprising:
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`(a) 50 to 100 mg/ml of the antibody or antigen-binding portion,
`
`(b) trehalose, and
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`(c) 0.5-5 mg/ml of polysorbate 80,
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`wherein said buffer system has a pH of 4.5 to 6.0.
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`21.
`
`(Original) The formulation of claim 4, comprising
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`(a) 50 mg/ml ofD2E7,
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`(b) 7.5-15 mg/ml ofmannitol, and
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`(c) 0.5-5 mg/ml of polysorbate 80,
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`-4-
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`Ex. 2013-0004
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`Application No. 14/322,565
`Reply dated September 26, 2014
`In Response to September 17, 2014 Office Action
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`Docket No.: 110222-0005-308
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`wherein said buffer system has a pH of 4.8 to 5.5.
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`22.
`
`(Original) A stable liquid aqueous pharmaceutical formulation comprising
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`(a) 20 to 150 mg/ml of a human IgG1 anti-human Tumor Necrosis Factor alpha (TNFa)
`
`antibody,
`
`(b) a polyol,
`
`(c) a polysorbate, and
`
`(d) a buffer system comprising gluconate and having a pH of 4.0 to 8.0,
`
`wherein the antibody comprises the light chain variable region and the heavy chain
`
`variable region ofD2E7.
`
`23.
`
`(Original) The formulation of claim 22, wherein the concentration of the antibody is from
`
`50 to 100 mg/ml.
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`24.
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`(Original) The formulation of claim 22, wherein the concentration of the antibody is 50
`
`mg/ml.
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`25.
`
`(Original) The formulation of claim 22, wherein the polysorbate is polysorbate 80.
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`26.
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`(Original) The formulation of claim 22, wherein the antibody is D2E7.
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`27.
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`(Original) The formulation of claim 26, comprising
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`(a) 50 to 100 mg/ml of the antibody,
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`-5-
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`Ex. 2013-0005
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`Application No. 14/322,565
`Reply dated September 26, 2014
`In Response to September 17, 2014 Office Action
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`(b) trehalose, and
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`(c) 0.5-5 mg/ml of polysorbate 80.
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`Docket No.: 110222-0005-308
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`28.
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`(Original) The formulation of claim 22, wherein the pH is from 4.5 to 6.0.
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`29.
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`(Original) The formulation of claim 22, wherein the pH is from 4.8 to 5.5.
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`30.
`
`(Original) The formulation of claim 22, which is suitable for subcutaneous injection.
`
`-6-
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`Ex. 2013-0006
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`

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`Application No. 14/322,565
`Reply dated September 26, 2014
`In Response to September 17, 2014 Office Action
`
`Docket No.: 110222-0005-308
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`REMARKS
`
`Claims 1-30 are currently pending. Applicant respectfully requests
`
`reconsideration of the application in view of the following remarks.
`
`Rejections Under 35 U.S.C. § 103
`
`Rejection 1
`
`Claims 1-9, 11-13, 16-18, 22-26, and 28-30 stand rejected under 35 U.S.C. § 103
`
`as allegedly being obvious over Lam (U.S. Patent 6,171,586) in view of Salfeld (U.S. Patent
`
`6,090,382). The Examiner asserts that Lam discloses a stable aqueous formulation comprising
`
`(a) an antibody at a concentration of, e.g., about 0.1 mg/ml to about 50 mg/ml,
`(b) a buffer of pH from about 4.5 to about 6.0 at, e.g., 1-50 mM, including, e.g.,
`gluconate,
`(c) a surfactant such as polysorbate 20 or polysorbate 80 at, e.g., 0.001-0.5%, and
`(d) a polyol at, e.g., 1-15% w/v.
`
`The Examiner also avers that Lam recites that the antibody may be directed against an antigen of
`
`interest, e.g., TNFa. The Examiner acknowledges that Lam does not disclose the antibody
`
`D2E7, but contends that Salfeld discloses D2E7 and its administration to a human subject
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`suffering from a disorder in which TNFa activity is detrimental. On this basis, the Examiner
`
`concludes that a person of ordinary skill in the art would have been motivated to modify Lam's
`
`formulations using Salfeld's D2E7 and reasonably expected success. Applicant traverses.
`
`A. Lam Fails to Provide a Reasonable Expectation of Success
`
`At the priority date of this application, it was known in the art that formulating
`
`pharmaceutical compositions of proteins was a complex process that required extensive
`
`experimentation, and success with one type of protein could not be reasonably expected to lead
`
`-7-
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`Ex. 2013-0007
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`

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`Application No. 14/322,565
`Reply dated September 26, 2014
`In Response to September 17, 2014 Office Action
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`Docket No.: 110222-0005-308
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`to success with another type of protein. For example, Wang et al. (Int. J Pharmaceutics
`
`185:129-188, 1999; submitted in applicant's July 17,2014 IDS) observed:
`
`[a ]lthough significant progress has been made in recent years, there is still no single
`pathway to follow in formulating proteins due to their structural diversities and
`complexities. There are several stages that require careful consideration and extensive
`experimentation in formulating a stable protein product. (p. 175, left col.)
`
`This was true for antibody formulations. It was known then that the hydrophobicity of antibody
`
`CDRs is a key determinant of the propensity of antibodies to aggregate. See, e.g., Helms and
`
`Wetzel, Protein Science, 4:2073-2081 (1995); 1 Ewert et al., J Mol. Biol., 325:531-553 (2003);2
`
`and Perchiacca and Tessier, Annu. Rev. Chem. Biomol., 3:263-86 (2012? (submitted in
`
`applicant's July 2, 2014 IDS). Thus, formulations that can stabilize one antibody may very well
`
`not work with an antibody with totally different CDRs.
`
`Indeed, the two antibodies that Lam tested in its Examples are both humanized
`
`antibodies with non-human (e.g., murine) CDRs (rhuMab CD18 and rhuMab CD20) (col. 24,
`
`lines 29-36; col. 40, lines 29-31). By contrast, applicant's claims recite anti-TNFa antibodies
`
`whose sequences are fully human. Indeed, the six CDRs in Lam's anti-CD18 antibody,4 in total,
`
`are only 37.7% identical to the D2E7 CDRs. The most pronounced difference occurs in the
`
`heavy chain CDR2s, which are only 11.7% identical.
`
`1 The authors state: "Although canonical CDR structures are usually discussed in terms ofthe role ofCDRs in
`antigen binding, our results suggest an additional important role of CDR sequence and structure: their contribution
`to domain stability" (p. 2079, right col.).
`2 The authors note that hydrophobic regions in CDRs resulted in aggregation, and use of a 17 amino acid residue
`long CDR increased solubility, possibly by partially covering the hydrophobic interface region (p. 532, para.
`bridging right and left col.).
`3 The authors note that "the hydrophobicity of CDR loops is a key determinant of the propensity of antibodies to
`aggregate" (p. 280).
`4 Lam does not provide any sequence for its anti-CD20 antibody, so no sequence comparison could be performed.
`But since that antibody is directed to an antigen different than D2E7's (TNFa), it can be reasonably assumed that the
`CDRs between these two antibodies also are quite different.
`
`-8-
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`Ex. 2013-0008
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`

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`Application No. 14/322,565
`Reply dated September 26, 2014
`In Response to September 17, 2014 Office Action
`
`Docket No.: 110222-0005-308
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`Table 1: Summary of Sequence Comparison Between Lam's anti-CD18 Antibody and D2E7
`
`Heavy Chain CDR1
`
`Heavy Chain CDR2
`
`Heavy Chain CDR3
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`Light Chain CDR1
`
`Light Chain CDR2
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`Light Chain CDR3
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`6 CDR Total
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`3/5 (60%)
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`2/17 (11.7%)
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`2/12 (16.7%)
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`8/11 (72.7%)
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`4/7(57.1%)
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`4/9 (44.4%)
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`23/61 (37.7%)
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`5 Sequence identity was calculated using D2E7 sequences as a reference.
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`-9-
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`Ex. 2013-0009
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`

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`Application No. 14/322,565
`Reply dated September 26, 2014
`In Response to September 17, 2014 Office Action
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`Docket No.: 110222-0005-308
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`Figure 1: Summary of Sequence Comparison Between Lam's anti-CD18 Antibody and D2E7
`(CDRs underlined and bolded6
`)
`
`121
`
`12~
`
`5D
`
`Given these amino acid sequence differences at the very least, a person of
`
`ordinary skill in the art would not have reasonably expected that any formulations Lam allegedly
`
`discloses for its antibodies would stabilize an antibody having significantly different sequences,
`
`especially in the CDRs.
`
`Thus, Lam's alleged teachings would have provided no reasonable expectation of
`
`success that the claimed formulations ofD2E7-related antibodies would be stable.
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`B. Salfeld Does Not Remedy Lam's Deficiencies
`
`The Examiner cites Salfeld for teaching the D2E7 antibody and its use in
`
`neutralizing TNFa. However, While Salfeld discloses D2E7, it does not evaluate the stability of
`
`6 Lam's CDR definitions are based on col. 8, lines 36-41 of Lam. D2E7's CDR definitions are based on Figs. 1 and
`2 of Salfeld.
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`-10-
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`Ex. 2013-0010
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`

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`Application No. 14/322,565
`Reply dated September 26, 2014
`In Response to September 17, 2014 Office Action
`
`Docket No.: 110222-0005-308
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`any D2E7 formulation. Salfeld does not teach or suggest that the claimed formulations can
`
`stabilize D2E7, much less at high antibody concentrations. In short, Salfeld does not cure the
`
`deficiencies of Lam. Thus, the skilled person in the art would not have reasonably expected that
`
`the claimed formulations can remain stable during storage.
`
`For at least these reasons, claims 1-9, 11-13, 16-18, 22-26, and 28-30 are not
`
`obvious over Lam in view of Salfeld. Applicant requests reconsideration and withdrawal of this
`
`obviousness rejection.
`
`Rejection 2
`
`Claims 10, 14, 15, 19-21 and 27 stand rejected under 35 U.S.C. § 103 as allegedly
`
`being obvious over Lam in view of Salfeld. The Examiner asserts the same alleged teachings by
`
`Lam and Salfeld as discussed above. While the Examiner acknowledges that Lam and Salfeld do
`
`not disclose the specific amounts of surfactant (polysorbate) recited in the claims, the Examiner
`
`is of the view that these amounts are the result of routine optimization of conditions and that the
`
`claims are prima facie obvious over Lam and Salfeld. Applicant traverses.
`
`Lam and Salfeld, alone or in combination, do not teach or suggest the claimed
`
`invention as discussed above. For at least those same reasons, the present claims are not obvious
`
`over Lam and Salfeld. Applicant requests reconsideration and withdrawal of this obviousness
`
`rejection.
`
`Obviousness-Type Double Patenting Rejections
`
`Claims 1-30 stand rejected under the judicially-created doctrine of obviousness-
`
`type double patenting over certain claims of the following U.S. patents and patent applications
`
`(provisional rejections):
`
`Patent 8,802,101,
`
`-11-
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`Ex. 2013-0011
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`

`
`Application No. 14/322,565
`Reply dated September 26, 2014
`In Response to September 17, 2014 Office Action
`
`Docket No.: 110222-0005-308
`
`Patent 8,795,670,
`Patent 8,802,102,
`Patent 8,216,583,
`Patent 8,802,100,
`Application 13/471,820,
`Application 14/170,026,
`Application 14/170,061,
`Application 14/322,581,
`Application 14/453,461, and
`Application 14/453,490.
`
`Solely to advance prosecution and without acquiescing to the merits of the
`
`rejections, applicant submits herewith terminal disclaimers in compliance with 37 C.P.R. §
`
`1.321 (c) with respect to each of these eleven patents and applications. The terminal disclaimers
`
`overcome these rejections.
`
`Applicant also submits herewith a terminal disclaimer in compliance with 3 7
`
`C.P.R.§ 1.321(c) with respect to United States Patent Application 12/772,595.
`
`CONCLUSION
`
`Applicant requests favorable consideration of the application and early allowance
`
`of the pending claims. To that end, the Examiner is invited to telephone the undersigned to
`
`discuss any issue pertaining to this reply.
`
`Respectfully submitted,
`
`/BRIAN M. GUMMOW/
`James F. Haley, Jr. (Reg. No. 27,794)
`Z. Ying Li (Reg. No. 42,800)
`Brian M. Gummow (Reg. No. 63,933)
`Attorneys for Applicant
`ROPES & GRAY LLP
`CustomerNo. 118276
`1211 Avenue of the Americas
`New York, New York 10036
`Tel.: (212) 596-9000
`Fax: (617) 235-9492
`
`-12-
`
`Ex. 2013-0012