IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`110222-0005-305
`
`Applicant
`
`Abb Vie Biotechnology Ltd.
`
`Application No.
`
`14/091,888
`
`Confirmation No.
`
`6912
`
`Filed
`
`For
`
`November 27, 2013
`
`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 JANUARY 28, 2014 NON-FINAL OFFICE ACTION
`
`Madam:
`
`This responds to the January 28, 2014 Non-Final Office Action in the
`
`above-identified application. A response is due on or before April28, 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.
`
`Ex. 2011-0001
`
`

`
`Application No. 14/091,888
`Reply dated April16, 2014
`In response to January 28, 2014 Office Action
`
`Docket No.: 110222-0005-305
`
`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 surfaetaH-1: polysorbate at a concentration of 0.1 to 10 mg/ml, and
`
`(d) a buffer system comprising acetate and having a pH of 4-te--84.5 to 7.0,
`
`wherein the antibody comprises [[a]] the light chain variable region eom:)9risiRg the light
`
`ehaiR eoill:)9lem:eRtarity determ:iRiRg regioR (CDR) 1, CDR2, aad CDR3 ofD2B7; aRd a and the
`
`heavy chain variable region eoill:)9risiRg the heavy ehaiR CDR1, CDR2, aad 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)
`
`-2-
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`Ex. 2011-0002
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`

`
`Application No. 14/091,888
`Reply dated April16, 2014
`In response to January 28, 2014 Office Action
`
`Docket No.: 110222-0005-305
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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.
`
`(Original) The formulation of claim 1, wherein the polyol is a sugar alcohol.
`
`8.
`
`(Original) The formulation of claim 7, wherein the sugar alcohol is mannitol.
`
`9.
`
`(Currently Amended) The formulation of claim 1, wherein the the polyol is a sugar.
`
`10.
`
`(Previously Presented) The formulation of claim 9, wherein the sugar is nonreducing
`
`sugar.
`
`11.
`
`(Previously Presented) The formulation of claim 10, wherein the nonreducing sugar is
`
`trehalose.
`
`12.
`
`(Currently Amended) The formulation of claim 1, wherein the surfactant is a polysorbate
`
`is polysorbate 20.
`
`13.
`
`(Currently Amended) The formulation of claim 12claim 1, wherein the polysorbate is
`
`polysorbate 80.
`
`-3-
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`Ex. 2011-0003
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`

`
`Application No. 14/091,888
`Reply dated April16, 2014
`In response to January 28, 2014 Office Action
`
`Docket No.: 110222-0005-305
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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.
`
`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.
`
`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 to 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.
`
`20.
`
`(Currently Amended) The formulation of claim 6, comprising:
`
`(a) 40 10050 to 100 mg/ml of the antibody or antigen-binding portion,
`
`-4-
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`Ex. 2011-0004
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`

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`Application No. 14/091,888
`Reply dated April16, 2014
`In response to January 28, 2014 Office Action
`
`Docket No.: 110222-0005-305
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`(b) trehalose, and
`
`(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
`
`(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,
`
`(c) 0.1-10 mg/ml of polysorbate 80, and
`
`(d) a buffer system comprising acetate 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 to 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.
`
`(Canceled)
`
`-5-
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`Ex. 2011-0005
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`

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`Application No. 14/091,888
`Reply dated April16, 2014
`In response to January 28, 2014 Office Action
`
`Docket No.: 110222-0005-305
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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.
`
`26.
`
`(Currently Amended) The formulation of claim 25claim 21, wherein the antibody is
`
`D2E7.
`
`27.
`
`(Currently Amended) The formulation of claim 21, comprising
`
`(a) 40 10050 to 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.
`
`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. 2011-0006
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`

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`Application No. 14/091,888
`Reply dated April16, 2014
`In response to January 28, 2014 Office Action
`
`Docket No.: 110222-0005-305
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`(c) 0.5-5 mg/ml of polysorbate 80, and
`
`(d) a buffer system comprising acetate and having a pH of 4.5 to 6.0.
`
`-7-
`
`Ex. 2011-0007
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`

`
`Application No. 14/091,888
`Reply dated April16, 2014
`In response to January 28, 2014 Office Action
`
`Docket No.: 110222-0005-305
`
`REMARKS
`
`Applicant has canceled claim 4 and 24; amended claims 1, 2, 5, 6, 9, 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 9 to improve its form and to cancel recitation of the
`
`duplicate "the" in the claim.
`
`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.
`
`-8-
`
`Ex. 2011-0008
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`

`
`Application No. 14/091,888
`Reply dated April16, 2014
`In response to January 28, 2014 Office Action
`
`Docket No.: 110222-0005-305
`
`Applicant has amended claim 13 to update its dependency in view of the
`
`amendments to claims 1 and 12.
`
`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 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 ofD2E7. 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 the
`
`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
`
`-9-
`
`Ex. 2011-0009
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`

`
`Application No. 14/091,888
`Reply dated April16, 2014
`In response to January 28, 2014 Office Action
`
`Docket No.: 110222-0005-305
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`comprising acetate 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 22:4-8.
`
`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.
`
`Information Disclosure Statement
`
`The Examiner points out that applicant's November 27, 2013 Information
`
`Disclosure Statement (IDS) was deficient because the Voight reference was not in English and
`
`no translation or explanation was provided. Applicant notes that it submitted an additional copy
`
`of the Voight reference, including an English translation, in its January 24, 2014 IDS. Applicant
`
`stands ready to provide an additional copy of the Voight reference with an English translation
`
`upon request from the Examiner.
`
`Rejections Under 35 U.S.C. § 103
`
`1. Gombotz and Salfeld
`
`Claims 1-30 stand rejected under 35 U.S.C. § 103 as allegedly being obvious over
`
`Gombotz (U.S. Patent Publication 2003/0180287) in view ofSalfeld (U.S. Patent 6,090,382).
`
`A. Claims 1-13 and 16-18
`
`Regarding claims 1-13 and 16-18, the Examiner asserts that Gombotz recites an
`
`aqueous pharmaceutical composition comprising
`
`(a) a TNF-recognizing antibody or Fe domain containing polypeptide at a
`concentration of about 10 to about 100 mg/ml,
`
`-10-
`
`Ex. 2011-0010
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`

`
`Application No. 14/091,888
`Reply dated April16, 2014
`In response to January 28, 2014 Office Action
`
`Docket No.: 110222-0005-305
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`(b) a buffer comprising ammonium acetate or various forms of acetate at a
`concentration of about 1 mM to about 1 M with a pH of about 6.0 to 7.0,
`(c) a tonicity modifier, such as mannitol, at a concentration of about 1 mM to
`about 1 M, and
`(d) one or more excipients, such as polysorbate 80, mannitol, and trehalose, at
`0.001 to 5 percent by weight, to stabilize the polypeptide in solution.
`
`The Examiner acknowledges that Gombotz does not recite 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 it would have
`
`been prima facie obvious to a skilled person in the art to modify Gombotz's aqueous
`
`pharmaceutical composition by using Salfeld's D2E7 antibody. The Examiner also concludes
`
`that the skilled person would have reasonably expected success because similar preparations
`
`were already being made at the time the invention was made, and the substitute of one known
`
`TNF antibody for another would have yielded predictable results. Claim 4 has been deleted.
`
`Applicant traverses the rejection of claims 1-3, 5-10, 12, 13, and 16-18.
`
`(i)
`
`Gombotz's TNFR:Fc Formulations Are Not Relevant to the Claimed
`D2E7 Formulations
`
`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 November 27,2013 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.)
`
`-11-
`
`Ex. 2011-0011
`
`

`
`Application No. 14/091,888
`Reply dated April16, 2014
`In response to January 28, 2014 Office Action
`
`Docket No.: 110222-0005-305
`
`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) (hereinafter, "Helms"); 1 Ewert et al., J Mol. Biol.,
`
`325:531-553 (2003) (hereinafter, "Ewert");2 and Perchiacca and Tessier, Annu. Rev. Chem.
`
`Biomol. Eng., 3:263-86 (2012) (hereinafter, "Perchiacca"? (submitted concurrently herewith in a
`
`Supplemental IDS). In other words, protein formulation is complex and success with one protein
`
`(e.g., one antibody) cannot predict success with another protein (e.g., an antibody having
`
`different CDRs ).
`
`Gombotz describes certain formulations that allegedly stabilize a TNFR:Fc fusion
`
`protein. Gombotz's Fe fusion protein does not have the CDRs ofD2E7. In fact, Gombotz's
`
`protein does not have any CDRs-it is not even an antibody. That protein is a fusion of a TNF
`
`receptor domain and an Fe domain. Given what was known about antibody stability, a skilled
`
`person in the art would not have reasonably expected that Gombotz's work on formulating
`
`TFNR:Fc was applicable to formulating D2E7 and related antibodies, which not only have an Fe
`
`domain, but also have heavy and light chain variable domains containing particular CDR
`
`sequences.
`
`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).
`
`-12-
`
`Ex. 2011-0012
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`

`
`Application No. 14/091,888
`Reply dated April16, 2014
`In response to January 28, 2014 Office Action
`
`Docket No.: 110222-0005-305
`
`(ii)
`
`Salfeld Does Not Cure Gombotz'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
`
`any D2E7 formulation, much less the stability of any D2E7 formulation having high antibody
`
`concentration. In short, Salfeld does not cure the deficiencies of Gombotz. Thus, a skilled
`
`person would not have arrived at the claimed invention with a reasonable expectation of success
`
`by combining Gombotz and Salfeld. For at least these reasons, claims 1-3, 5-10, 12, 13, and 16-
`
`18 are not obvious over Gombotz in view ofSalfeld.
`
`B. Claims 14, 15, and 19-30
`
`Regarding claims 14, 15, and 19-30, the Examiner asserts the same alleged
`
`teachings of Gombotz and Salfeld as discussed above. While the Examiner acknowledges that
`
`these two documents do not disclose the specific amounts of mannitol and polysorbate 80, 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 Gombotz and Salfeld.
`
`Applicant has cancelled claim 24. Regarding claims 14, 15, 19-23, and 25-31,
`
`applicant submits that Gombotz and Salfeld do not teach or suggest the claimed invention as
`
`discussed in Part A, supra. For at least those same reasons, the present claims are not obvious
`
`over Gombotz and Salfeld.
`
`C. Summary
`
`For the above reasons, Gombotz and Salfeld together fail to render claims 1-3, 5-
`
`23, and 25-30 prima facie obvious. New claim 31 depends from claim 21 and incorporates all of
`
`the patentable features of that base claim. Thus, the new claim is patentable over Gombotz and
`
`Salfeld as well for at least the same reasons.
`
`-13-
`
`Ex. 2011-0013
`
`

`
`Application No. 14/091,888
`Reply dated April16, 2014
`In response to January 28, 2014 Office Action
`
`2. Lam and Salfeld
`
`Docket No.: 110222-0005-305
`
`Claims 1-30 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).
`
`A. Claims 1-13 and 16-18
`
`Regarding claims 1-13 and 16-18, 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.,
`acetate,
`(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.
`
`(i) 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 November 27,2013 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
`
`-14-
`
`Ex. 2011-0014
`
`

`
`Application No. 14/091,888
`Reply dated April16, 2014
`In response to January 28, 2014 Office Action
`
`Docket No.: 110222-0005-305
`
`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; Ewert;
`
`and Perchiacca, supra. 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, in total,
`
`are only 37.7% identical to the D2E7 CDRs. 4 The most pronounced difference occurs in the
`
`heavy chain CDR3s, which are only 11.7% identical.
`
`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
`
`3/5 (60%)
`
`2/17 (11.7%)
`
`2/12 (16.7%)
`
`8/11 (72.7%)
`
`4/7(57.1%)
`
`4/9 (44.4%)
`
`4 Lam does not provide a 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.
`5 Sequence identity was calculated using D2E7 sequences as a reference.
`
`-15-
`
`Ex. 2011-0015
`
`

`
`Application No. 14/091,888
`Reply dated April16, 2014
`In response to January 28, 2014 Office Action
`
`Docket No.: 110222-0005-305
`
`6 CDR Total
`
`23/61 (37.7%)
`
`Figure 1: Summary of Sequence Comparison Between Lam's anti-CD18 Antibody and D2E7
`(CDRs underlined and bolded6
`)
`
`~. [:
`
`-~ ~-· ·:._;
`
`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 different sequences, including
`
`significant differences 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.
`
`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.
`
`-16-
`
`Ex. 2011-0016
`
`

`
`Application No. 14/091,888
`Reply dated April16, 2014
`In response to January 28, 2014 Office Action
`
`Docket No.: 110222-0005-305
`
`(ii)
`
`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
`
`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.
`
`B. Claims 14, 15, and 19-30
`
`Regarding claims 14, 15, and 19-30, 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.
`
`-17-
`
`Ex. 2011-0017
`
`

`
`Application No. 14/091,888
`Reply dated April16, 2014
`In response to January 28, 2014 Office Action
`
`Docket No.: 110222-0005-305
`
`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
`
`-18-
`
`Ex. 2011-0018