IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`110222-0005-306
`
`Applicant
`
`Abb Vie Biotechnology Ltd.
`
`Application No.
`
`14/147,287
`
`Confirmation No.
`
`2290
`
`Filed
`
`For
`
`January 3, 2014
`
`FORMULATION OF HUMAN ANTIBODIES FOR
`TREATING TNF-ALPHA ASSOCIATED DISORDERS
`
`Group Art Unit
`
`1647
`
`Examiner
`
`Bridget E. Bunner
`
`New York, New York
`April16, 2014
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-14 50
`
`REPLY TO FEBRUARY 7, 2014 NON-FINAL OFFICE ACTION
`
`Madam:
`
`This responds to the February 7, 2014 Non-Final Office Action in the
`
`above-identified application. A response is due on or before May 7, 2014. Thus, this response is
`
`timely filed.
`
`Amendments to the Claims are reflected in the Listing of Claims, which begins
`
`on page 2 of this paper.
`
`Remarks begin on page 8 of this paper.
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`Ex. 2012-0001
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`

`
`Application No. 14/147,287
`Reply dated April16, 2014
`In response to February 7, 2014 Office Action
`
`Docket No.: 110222-0005-306
`
`AMENDMENTS TO THE CLAIMS
`
`This Listing of Claims will replace all prior versions, and listings, of claims in the
`
`application.
`
`Listing of Claims
`
`1.
`
`(Currently Amended) A stable liquid aqueous pharmaceutical formulation comprising
`
`(a) a human IgG 1 anti-human Tumor Necrosis Factor alpha (TNFa) antibody, or an
`
`antigen-binding portion thereof, at a concentration of20 to 15045 to 105 mg/ml,
`
`(b) a polyol,
`
`(c) a surfactant polysorbate at a concentration of 0.1 to 10 mg/ml, and
`
`(d) a buffer system comprising succinate and having a pH of 4 to 84.5 to 7 .0,
`
`wherein the antibody comprises [[a ]]the light chain variable region comprising the light
`
`chain complementarity determining region (CDR) 1, CDR2, and CDR3 ofD2E7; and a and the
`
`heavy chain variable region comprising the heavy chain CDR1, CDR2, and CDR3 ofD2E7.
`
`2.
`
`(Currently Amended) The formulation of claim 1, wherein the concentration of the
`
`antibody or antigen-binding portion is 45 to 10550 to 100 mg/ml.
`
`3.
`
`(Original) The formulation of claim 2, wherein the concentration of the antibody or
`
`antigen-binding portion is 50 mg/ml.
`
`4.
`
`(Canceled)
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`-2-
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`Ex. 2012-0002
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`

`
`Application No. 14/147,287
`Reply dated April16, 2014
`In response to February 7, 2014 Office Action
`
`Docket No.: 110222-0005-306
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`5.
`
`(Currently Amended) The formulation of claim 1, wherein the antibody comprises the
`
`light and heavy chain variable regions of D2E7formulation has a shelf life of at least 18 months.
`
`6.
`
`(Currently Amended) The formulation of claim 5claim 1, wherein the antibody is D2E7.
`
`7.
`
`(Currently Amended) The formulation of claim 1, wherein the polyol is a sugar alehel
`
`alcohol.
`
`8.
`
`(Original) The formulation of claim 7, wherein the sugar alcohol is mannitol.
`
`9.
`
`(Original) The formulation of claim 1, wherein the polyol is a sugar.
`
`10.
`
`(Original) The formulation of claim 9 wherein the sugar is a nonreducing sugar.
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`11.
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`(Original) The formulation of claim 10, wherein the nonreducing sugar is trehalose.
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`12.
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`(Currently Amended) The formulation of claim 1, wherein the surfactant is a polysorbate
`
`is polysorbate 20.
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`13.
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`(Currently Amended) The formulation of claim 12claim 1, wherein the polysorbate is
`
`polysorbate 80.
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`-3-
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`Ex. 2012-0003
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`

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`Application No. 14/147,287
`Reply dated April16, 2014
`In response to February 7, 2014 Office Action
`
`Docket No.: 110222-0005-306
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`14.
`
`(Currently Amended) The formulation of claim 13, wherein the polysorbate 80
`
`concentration is from 0.1 to 100.5 to 5 mg/ml.
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`15.
`
`(Original) The formulation of claim 13, wherein the polysorbate 80 concentration is 1
`
`mg/ml.
`
`16.
`
`(Currently Amended) The formulation of claim 1, wherein the pH is from 4.5 to
`
`[[7.0]]6.0.
`
`17.
`
`(Currently Amended) The formulation of claim 16, wherein the pH is from 5.0 to 6.54.8
`
`to 5.5.
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`18.
`
`(Original) The formulation of claim 1, which is suitable for single use subcutaneous
`
`injection.
`
`19.
`
`(Currently Amended) The formulation of claim 1, comprising:
`
`(a) 40 10050-100 mg/ml of the antibody or antigen-binding portion,
`
`(b) trehalose, and
`
`(c) 0.5-5 mg/ml of polysorbate 80,
`
`wherein said buffer has a pH of 5.0 to 6.5.
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`20.
`
`(Currently Amended) The formulation of claim 6, comprising:
`
`(a) 40 10050-100 mg/ml of the antibody or antigen-binding portion,
`
`-4-
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`Ex. 2012-0004
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`

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`Application No. 14/147,287
`Reply dated April16, 2014
`In response to February 7, 2014 Office Action
`
`Docket No.: 110222-0005-306
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`(b) trehalose, and
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`(c) 0.5-5 mg/ml of polysorbate 80,
`
`wherein said buffer has a pH of 5.0 to 6.5.
`
`21.
`
`(Currently Amended) A stable liquid aqueous pharmaceutical formulation comprising
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`(a) 20 15045 to 105 mg/ml of a human IgG 1 anti-human Tumor Necrosis Factor alpha
`
`(hTNFa) antibody, or an antigen binding portion thereof,
`
`(b) trehalose,
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`(c) 0.1-10 mg/ml of polysorbate 80, and
`
`(d) a buffer system comprising succinate succinte and having a pH of 4-te--84.5 to 7.0,
`
`wherein the antibody comprises [[a ]]the light chain variable region comprising the light
`
`chain complementarity determining region (CDR) 1, CDR2, and CDR3 ofD2E7; and a and the
`
`heavy chain variable region comprising the heavy chain CDR1, CDR2, and CDR3 ofD2E7.
`
`22.
`
`(Currently Amended) The formulation of claim 21, wherein the concentration of the
`
`antibody or antigen binding portion is from 45 to 10550-100 mg/ml.
`
`23.
`
`(Currently Amended) The formulation of claim 21, wherein the concentration of the
`
`antibody or antigen binding portion is 50 mg/ml.
`
`24.
`
`(Cancelled)
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`-5-
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`Ex. 2012-0005
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`

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`Application No. 14/147,287
`Reply dated April16, 2014
`In response to February 7, 2014 Office Action
`
`Docket No.: 110222-0005-306
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`25.
`
`(Currently Amended) The formulation of claim 21, wherein the antibody comprises the
`
`light and heavy chain variable regions of D2E7formulation has a shelf life of at least 18 months.
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`26.
`
`(Currently Amended) The formulation of claim 25claim 21, wherein the antibody is
`
`D2E7.
`
`27.
`
`(Currently Amended) The formulation of claim 21, comprising
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`(a) 40 10050-100 mg/ml of the antibody or antigen binding portion,
`
`(b) trehalose, and
`
`(c) 0.5-5 mg/ml of polysorbate 80.
`
`28.
`
`(Currently Amended) The formulation of claim 21, wherein the pH is from 4.5 to
`
`[[7.0]]6.0.
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`29.
`
`(Currently Amended) The formulation of claim 21, wherein the pH is from 5.0 to 6.54.8
`
`to 5.5.
`
`30.
`
`(Original) The formulation of claim 21, which is suitable for single use subcutaneous
`
`injection.
`
`31.
`
`(New) The formulation of claim 21, comprising
`
`(a) 50 mg/ml ofD2E7,
`
`(b) 7.5-15 mg/ml ofmannitol,
`
`-6-
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`Ex. 2012-0006
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`

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`Application No. 14/147,287
`Reply dated April16, 2014
`In response to February 7, 2014 Office Action
`
`Docket No.: 110222-0005-306
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`(c) 0.5-5 mg/ml of polysorbate 80, and
`
`(d) a buffer system comprising succinate and having a pH of 4.5 to 6.0.
`
`-7-
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`Ex. 2012-0007
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`

`
`Application No. 14/147,287
`Reply dated April16, 2014
`In response to February 7, 2014 Office Action
`
`Docket No.: 110222-0005-306
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`REMARKS
`
`Applicant has canceled claims 4 and 24; amended claims 1, 2, 5-7, 12-14, 16, 17,
`
`19-23, and 25-29; and added new claim 31. Upon entry of these amendments, claims 1-3, 5-23,
`
`and 25-31 will be pending.
`
`Applicant has amended claim 1 to recite that the antibody or antigen-binding
`
`portion thereof is at a concentration of 45 to 105 mg/ml, that the formulation comprises
`
`polysorbate at a concentration of0.1 to 10 mg/ml, that the pH is 4.5 to 7.0, and that the antibody
`
`comprises the light chain variable region and the heavy chain variable region of D2E7. Support
`
`for these amendments may be found in the specification, e.g., at 7:6-8 and 13-15; 10: 12-14;
`
`15:23-31; 17:3-8; 18:30-33; and 22:4-8.
`
`Applicant has amended claims 2, 19, 20, 22 and 27 to recite that the concentration
`
`of the antibody or antigen-binding portion is 50 to 100 mg/ml. Support for these amendments
`
`may be found in the specification, e.g., at 17:3-8 and 22:4-8.
`
`Applicant has amended claims 5 and 25 to recite that the formulation has a shelf
`
`life of at least 18 months. Support for these amendments may be found in the specification, e.g.,
`
`at 3:17-23 and 32-33; 14:31-34; and 17:16-17.
`
`Applicant has amended claim 6 to update its dependency in view of the
`
`amendments to claims 1 and 5.
`
`Applicant has amended claim 7 to correct a misspelling of alcohol.
`
`Applicant has amended claim 12 to recite that the polysorbate is polysorbate 20.
`
`Support for this amendment may be found in the specification, e.g., at 18:21-23.
`
`Applicant has amended claim 13 to update its dependency in view of the
`
`amendments to claims 1 and 12.
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`-8-
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`Ex. 2012-0008
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`

`
`Application No. 14/147,287
`Reply dated April16, 2014
`In response to February 7, 2014 Office Action
`
`Docket No.: 110222-0005-306
`
`Applicant has amended claim 14 to recite that the polysorbate 80 concentration is
`
`from 0.5 to 5 mg/ml. Support for this amendment may be found in the specification, e.g., at
`
`18:30-32.
`
`Applicant has amended claims 16 and 28 to recite that the pH is from 4.5 to 6.0.
`
`Support for these amendments may be found in the specification, e.g., at 7:23-24 and 17:20-22
`
`and 30-32.
`
`Applicant has amended claims 17 and 29 to recite that the pH is from 4.8 to 5.5.
`
`Support for these amendments may be found in the specification, e.g., at 7:24-25 and 17:20-22
`
`and 30-32.
`
`Applicant has amended claim 21 to correct a misspelling of succinate and to recite
`
`that the antibody is at a concentration of 45 to 105 mg/ml, that the pH is 4.5 to 7.0, and that the
`
`antibody comprises the light chain variable region and the heavy chain variable region of D2E7.
`
`Support for these amendments may be found in the specification, e.g., at 7:6-8 and 14-15; 10:12-
`
`14; 15:23-31; 17:3-8; and 22:4-8.
`
`Applicant has also amended claims 21-23 and 27 to cancel recitation of an
`
`antigen-binding portion of the antibody.
`
`Applicant has amended claim 26 to update its dependency in view of the
`
`amendments to claims 21 and 25.
`
`Applicant has added new claim 31, which recites a formulation comprising 50
`
`mg/ml ofD2E7, 7.5-15 mg/ml of mannitol, 0.5-5 mg/ml of polysorbate 80, and a buffer system
`
`comprising succinate and having a pH of 4.5 to 6.0. Support for these amendments may be
`
`found in the specification, e.g., at 7:6-8 and 13-15; 10:12-14; 15:23-31; 17:3-8; 18:30-33; and
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`22:4-8.
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`-9-
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`Ex. 2012-0009
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`

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`Application No. 14/147,287
`Reply dated April16, 2014
`In response to February 7, 2014 Office Action
`
`Docket No.: 110222-0005-306
`
`The claim amendments are made without prejudice or waiver of applicant's rights
`
`to file for and obtain claims to the canceled subject matter in this application or in other
`
`applications that claim priority and benefit of this application. None of the claim amendments or
`
`additions adds new matter. Applicant respectfully requests reconsideration of the application in
`
`view of the above amendments and the following remarks.
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`Information Disclosure Statement
`
`The Examiner points out that applicant's January 24, 2014 Information Disclosure
`
`Statement (IDS) was deficient because (1) the EP-0453898 and Fielder documents were not in
`
`English and no translation or explanation was provided, and (2) the Salfeld abstract was blurry
`
`and illegible.
`
`Applicant submits herewith a supplemental IDS, in which an English translation
`
`has been provided for EP-0453898 and a clearer copy of the Salfeld abstract has been provided.
`
`Regarding the Fiedler document, a concise explanation of the relevance of the
`
`Fiedler document may be found on page 19, lines 8-10 of the instant application. Specifically,
`
`Fiedler is cited to establish that Tween 80 is a term used to describe polyoxyethylene (20)
`
`sorbitanmonooleate. Additionally, applicant submits herewith a 2002 English-language version
`
`of the Fiedler document in the supplemental IDS. Applicant stands ready to provide a direct
`
`translation of the "Tween®, entry in the 1996 German version of Fiedler upon request from the
`
`Examiner.
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`-10-
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`Ex. 2012-0010
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`

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`Application No. 14/147,287
`Reply dated April16, 2014
`In response to February 7, 2014 Office Action
`
`Rejections Under 35 U.S.C. § 103
`
`Docket No.: 110222-0005-306
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`Rejection 1
`
`Claims 1-13 and 16-18 stand rejected under 35 U.S.C. § 103 as allegedly being
`
`obvious over Lam (U.S. Patent 6,171,586) in view ofSalfeld (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.,
`succinate,
`(c) a surfactant such as 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
`
`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. Claim 4 has been
`
`cancelled. Applicant traverses the rejection of claims 1-3, 5-13, and 16-18.
`
`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
`
`to success with another type of protein. For example, Wang et al. (Int. J Pharmaceutics
`
`185:129-188, 1999; submitted in applicant's January 3, 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
`
`-11-
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`Ex. 2012-0011
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`

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`Application No. 14/147,287
`Reply dated April16, 2014
`In response to February 7, 2014 Office Action
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`Docket No.: 110222-0005-306
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`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
`
`concurrently herewith in a Supplemental 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.
`
`-12-
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`Ex. 2012-0012
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`

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`Application No. 14/147,287
`Reply dated April16, 2014
`In response to February 7, 2014 Office Action
`
`Docket No.: 110222-0005-306
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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
`
`Light Chain CDR1
`
`Light Chain CDR2
`
`Light Chain CDR3
`
`6 CDR Total
`
`3/5 (60%)
`
`2/17 (11.7%)
`
`2/12 (16.7%)
`
`8/11 (72.7%)
`
`4/7(57.1%)
`
`4/9 (44.4%)
`
`23/61 (37.7%)
`
`5 Sequence identity was calculated using D2E7 sequences as a reference.
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`-13-
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`Ex. 2012-0013
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`

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`Application No. 14/147,287
`Reply dated April16, 2014
`In response to February 7, 2014 Office Action
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`Docket No.: 110222-0005-306
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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.
`
`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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`-14-
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`Ex. 2012-0014
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`Application No. 14/147,287
`Reply dated April16, 2014
`In response to February 7, 2014 Office Action
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`Docket No.: 110222-0005-306
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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 1-3, 5-13, and 16-18 are not obvious over Lam
`
`in view of Salfeld. Applicant requests reconsideration and withdrawal of this obviousness
`
`rejection.
`
`Rejection 2
`
`Claims 14, 15, and 19-30 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 polysorbate 80 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 has cancelled claim 24. Regarding claims 14, 15, 19-23, and 25-30,
`
`applicant submits that Lam and Salfeld 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. New claim 31 depends from claim 21 and is also patentable over the cited art for
`
`the same reasons discussed herein.
`
`-15-
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`Ex. 2012-0015
`
`

`
`Application No. 14/147,287
`Reply dated April16, 2014
`In response to February 7, 2014 Office Action
`
`Docket No.: 110222-0005-306
`
`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)
`Attorney/ Agent 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
`
`-16-
`
`Ex. 2012-0016