IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`110222-0005-303
`
`Applicant
`
`Abb Vie Biotechnology Ltd.
`
`Application No.
`
`14/091,661
`
`Confirmation No.
`
`1026
`
`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 27, 2014 NON-FINAL OFFICE ACTION
`
`Madam:
`
`This responds to the January 27, 2014 Non-Final Office Action in the
`
`above-identified application. A response is due on or before April27, 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. 2036-0001
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`

`
`Application No. 14/091,661
`Reply dated April16, 2014
`In Response to January 27, 2014 Office Action
`
`Docket No.: 110222-0005-303
`
`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 150 45 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 having a pH of-4-to-8- 4.5 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 105 50 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.
`
`(Cancelled)
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`-2-
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`Ex. 2036-0002
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`

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`Application No. 14/091,661
`Reply dated April16, 2014
`In Response to January 27, 2014 Office Action
`
`Docket No.: 110222-0005-303
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`5.
`
`(Currently Amended) The formulation of claim 1, wherein the antibody comprises the
`
`light and heavy chain variable regions of D2E7 formulation 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.
`
`(Previously Presented) The formulation of claim 1, wherein the polyol is a sugar.
`
`10.
`
`(Previously Presented) The formulation of claim 9, wherein the sugar is trehalose.
`
`11.
`
`(Canceled)
`
`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.
`
`14.
`
`(Currently Amended) The formulation of claim 13, wherein the polysorbate 80
`
`concentration is from 0.1 to 10 0.5 to 5 mg/ml.
`
`-3-
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`Ex. 2036-0003
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`

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`Application No. 14/091,661
`Reply dated April16, 2014
`In Response to January 27, 2014 Office Action
`
`Docket No.: 110222-0005-303
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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]]
`
`17.
`
`(Currently Amended) The formulation of claim 16, wherein the pH is from 5.0 to 6.5 4.8
`
`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) 40 100 50-100 mg/ml of the antibody or antigen-binding portion,
`
`(b) 7.5-15 mg/ml of mannitol, 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) 40 100 50-100 mg/ml of the antibody or antigen-binding portion,
`
`(b) 7.5-15 mg/ml of mannitol, and
`
`(c) 0.5-5 mg/ml of polysorbate 80,
`
`-4-
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`Ex. 2036-0004
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`

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`Application No. 14/091,661
`Reply dated April16, 2014
`In Response to January 27, 2014 Office Action
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`wherein said buffer has a pH of 5.0 to 6.5.
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`Docket No.: 110222-0005-303
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`21.
`
`(Currently Amended) A stable liquid aqueous pharmaceutical formulation comprising
`
`(a) 20 to 150 45 to 105 mg/ml of a human IgG1 anti-human Tumor Necrosis Factor alpha
`
`(hTNFa) antibody, or an antigen binding portion thereof,
`
`(b) a polyol,
`
`(c) 0.1-10 mg/ml of polysorbate 80, and
`
`(d) a buffer system having a pH of -4-to--& 4.5 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.
`
`(Cancelled)
`
`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.
`
`-5-
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`Ex. 2036-0005
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`

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`Application No. 14/091,661
`Reply dated April16, 2014
`In Response to January 27, 2014 Office Action
`
`Docket No.: 110222-0005-303
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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
`
`(a) 40 100 50-100 mg/ml of the antibody or antigen binding portion,
`
`(b) 7.5-15 mg/ml of mannitol, 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 :2-1-, 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.
`
`(Previously Presented) The formulation of claim 21, wherein the polyol is mannitol or
`
`trehalose.
`
`32.
`
`(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. 2036-0006
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`

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`Application No. 14/091,661
`Reply dated April16, 2014
`In Response to January 27, 2014 Office Action
`
`Docket No.: 110222-0005-303
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`(c) 0.5-5 mg/ml of polysorbate 80, and
`
`(d) a buffer system having a pH of 4.5 to 6.0.
`
`-7-
`
`Ex. 2036-0007
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`

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`Application No. 14/091,661
`Reply dated April16, 2014
`In Response to January 27, 2014 Office Action
`
`Docket No.: 110222-0005-303
`
`Amendments to the Claims
`
`REMARKS
`
`Applicant has canceled claims 4 and 24; amended claims 1, 2, 5, 6, 12-14, 16, 17,
`
`19-23, and 25-29; and added new claim 32. Upon entry of these amendments, claims 1-3, 5-10,
`
`12-23, and 25-32 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 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. 2036-0008
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`

`
`Application No. 14/091,661
`Reply dated April16, 2014
`In Response to January 27, 2014 Office Action
`
`Docket No.: 110222-0005-303
`
`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.
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`Applicant has added new claim 32, 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
`
`22:4-8.
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`-9-
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`Ex. 2036-0009
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`

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`Application No. 14/091,661
`Reply dated April16, 2014
`In Response to January 27, 2014 Office Action
`
`Docket No.: 110222-0005-303
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`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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`Obviousness-Type Double Patenting Rejections
`
`1. U.S. Patent 8,216,583
`
`Claims 1-10 and 12-31 stand rejected under the judicially-created doctrine of
`
`obviousness-type double patenting over claims 1-19 ofU.S. Patent 8,216,583. Solely to advance
`
`prosecution and without acquiescing to the merit of the rejection, applicant has cancelled claims
`
`4 and 24, and submits herewith a terminal disclaimer in compliance with 37 C.P.R. § 1.321(c).
`
`The claim cancellation and the terminal disclaimer overcome the instant rejection.
`
`2. U.S. Patent Application 13/471,820
`
`Claims 1-10 and 12-31 stand provisionally rejected under the judicially-created
`
`doctrine of obviousness-type double patenting over claims 1, 3-5, 9, 12, and 14-31 of copending
`
`U.S. Patent Application 13/471,820. Solely to advance prosecution and without acquiescing to
`
`the merit of the rejection, applicant has cancelled claims 4 and 24, and submits herewith a
`
`terminal disclaimer in compliance with 37 C.P.R.§ 1.321(c). The claim cancellation and the
`
`terminal disclaimer overcome this rejection.
`
`3. U.S. Patent Applications 14/091,888, 14/091,938, and 14/147,287
`
`Claims 1-10 and 12-31 stand provisionally rejected under the judicially-created
`
`doctrine of obviousness-type double patenting over claims 1-30 of copending U.S. Patent
`
`Application 14/091,888 ("the '888 Application"); over claims 1-31 of copending U.S. Patent
`
`-10-
`
`Ex. 2036-0010
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`

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`Application No. 14/091,661
`Reply dated April16, 2014
`In Response to January 27, 2014 Office Action
`
`Docket No.: 110222-0005-303
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`Application 14/091,938 ("the '938 Application") and over claims 1-30 of copending U.S. Patent
`
`Application 14/147,287 ("the '287 Application"). Applicant has cancelled claims 4 and 24.
`
`Applicant requests that the provisional rejection of the remaining claims be held
`
`in abeyance until such time as the pending claims in the instant application are otherwise in
`
`condition for allowance. Applicant will address the obviousness-type double patenting rejection
`
`in an appropriate way then, e.g., by argument or the filing of an appropriate terminal disclaimer
`
`under 37 C.P.R. § 1.321(c).
`
`Rejections Under 35 U.S.C. § 103
`
`1. Gombotz and Salfeld
`
`Claims 1-10 and 12-31 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 1-10, 12, 13, and 16-18
`
`Regarding claims 1-10, 12, 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,
`(b) a buffer comprising potassium phosphate, sodium citrate or potassium citrate
`at a concentration of about 1mM 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
`
`-11-
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`Ex. 2036-0011
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`

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`Application No. 14/091,661
`Reply dated April16, 2014
`In Response to January 27, 2014 Office Action
`
`Docket No.: 110222-0005-303
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`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.)
`
`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
`
`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.).
`
`-12-
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`Ex. 2036-0012
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`

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`Application No. 14/091,661
`Reply dated April16, 2014
`In Response to January 27, 2014 Office Action
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`Docket No.: 110222-0005-303
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`and Perchiacca and Tessier, Annu. Rev. Chem. Biomol. Eng., 3:263-86 (2012)3 (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.
`
`(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 a 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.
`
`3 The authors note that "the hydrophobicity of CDR loops is a key determinant of the propensity of antibodies to
`aggregate" (p. 280).
`
`-13-
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`Ex. 2036-0013
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`

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`Application No. 14/091,661
`Reply dated April16, 2014
`In Response to January 27, 2014 Office Action
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`B. Claims 14, 15, and 19-31
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`Docket No.: 110222-0005-303
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`Regarding claims 14, 15, and 19-31, 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-
`
`10, 12-23, and 25-31 prima facie obvious. New claim 32 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.
`
`2. Heavner and Salfeld
`
`Claims 1-10 and 12-31 stand rejected under 35 U.S.C. § 103 as allegedly being
`
`obvious over Heavner (U.S. Patent 7,250,165) in view ofSalfeld.
`
`A. Claims 1-10, 12, 13, and 16-18
`
`Regarding claims 1-10, 12, 13, and 16-18, the Examiner asserts that Heavner
`
`recites a stable liquid formulation of an anti-TNFa antibody that can have an IgG 1 isotype. The
`
`Examiner contends that Heavner discloses that the anti-TNFa antibody may be administered at
`
`about 0.01 to 500 mg/kg per dose. The Examiner also asserts that Heavner disclose that the
`
`-14-
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`Ex. 2036-0014
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`

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`Application No. 14/091,661
`Reply dated April16, 2014
`In Response to January 27, 2014 Office Action
`
`Docket No.: 110222-0005-303
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`formulation may comprise a buffer with a pH of about 4 to 1 0; carbohydrate excipients, such as
`
`mannitol or trehalose; and non-ionic surfactants, such as polysorbate 80. The Examiner
`
`acknowledges that Heavner does not disclose antibodies having the CDRs ofD2E7, but states
`
`that Salfeld discloses D2E7 and its administration to a human subject suffering from a disorder
`
`in which TNFa activity is detrimental. The Examiner concludes that the skilled person in the art
`
`would have been motivated to modify Heavner's formulation using Salfeld's D2E7 with a
`
`reasonable expectation of success. Claim 4 has been cancelled. Applicant traverses the rejection
`
`of claims 1-3, 5-10, 12, 13, and 16-18.
`
`(i)
`
`Heavner Provides No Specific Teachings on Antibody Formulations
`
`Heavner relates to an anti-TNF antibody having specific heavy and light chain
`
`sequences (See, e.g., claim 1 ). Heavner does not teach or evaluate how to stabilize this antibody
`
`in an aqueous pharmaceutical solution suitable for long term storage. In fact, Heavner does not
`
`provide any specific pharmaceutical formulations at all for its antibody. The biological studies
`
`shown in Heavner were all done in mice, and the document merely notes that the mice were
`
`"treated with a single intraperitoneal bolus dose ofDulbecco's PBS (D-PBS) or an anti-TNF
`
`antibody of the present invention" (Example 5, col. 71, lines 12-14; see also Examples 6-8; col.
`
`71-74).
`
`The alleged formulation language in Heavner cited by the Examiner is boilerplate
`
`at best, and provides no guidance for any specific formulations, much less the ones applicant
`
`presently claims. In evaluating a composition claim, the obviousness analysis begins with the
`
`closest prior art composition, i.e., the "reference composition," see, Unigene Laboratories, Inc.
`
`v. Apotex Inc., 655 F.3d 1352, 1361-1362 (Fed. Cir. 2011). The Examiner has not identified a
`
`reference composition in Heavner. Indeed, Heavner does not provide any "reference"
`
`-15-
`
`Ex. 2036-0015
`
`

`
`Application No. 14/091,661
`Reply dated April16, 2014
`In Response to January 27, 2014 Office Action
`
`Docket No.: 110222-0005-303
`
`composition or formulation. Rather, at 31:18-64, 42:54-66, and 43:15-29, Heavner generically
`
`describes a laundry list of preservatives and a list of formulation types (solution, emulsion
`
`colloid, suspension, or power formulation) for administration by about 40 routes or modes. The
`
`cited dosage language at 41:26-65 and 42:4-9 does not provide more particularity-it recites
`
`wide ranges of dosages in mg/kg body weight, and does not refer to the antibody concentration
`
`in a pharmaceutical formulation. The cited language at 30:13-62 and 32:28-49 also is extremely
`
`generic. It states that the composition can include "at least one of any suitable auxiliary, such as
`
`... diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the
`
`like," and useful pharmaceutical excipients and additives "include but are not limited to proteins,
`
`peptides, amino acids, lipids, and carbohydrates", and "pharmaceutically acceptable
`
`solubilizers." Each type of these potential "excipients and additives" is in tum exemplified by
`
`another long list of potential compounds. In all, there are hundreds of thousands of potential
`
`combinations of formulation ingredients allegedly "taught" in these selected passages. A person
`
`of ordinary skill in the art would have seriously doubted that all these hundreds of thousands of
`
`combinations would provide a stable formulation for an anti-TNF antibody. In other words,
`
`Heavner provides no guidepost for one of ordinary skill in the art to follow, such that he/she
`
`could select any particular combination of excipients for formulating a stable pharmaceutical
`
`composition of an anti-TNF antibody, with a reasonable expectation of success.
`
`(ii)
`
`The Sequence Differences Between Heavner's and Applicant's
`Antibodies Are a Key Determinant in the Formulation Art
`
`What is more, Heavner's antibody has significantly different heavy and light
`
`chain variable domain sequences, especially the CDR sequences, from D2E7. For example,
`
`Heavner's heavy and light chain variable regions are only 72.7% and 69.2% identical,
`
`-16-
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`Ex. 2036-0016
`
`

`
`Application No. 14/091,661
`Reply dated April16, 2014
`In Response to January 27, 2014 Office Action
`
`Docket No.: 110222-0005-303
`
`respectively, to the D2E7 heavy and light chain variable regions. See, Table 1 and Figure 1,
`
`infra. The differences between Heavner's variable regions and the D2E7 variable regions are
`
`even more pronounced in the CDR sequences. !d. Indeed, Heavner's six CDRs, in total, are
`
`only 40.9% identical to the D2E7 CDRs. The most pronounced difference occurs in the heavy
`
`chain CDR3s, which are only 8.3% identical.
`
`Table 1: Summary of Sequence Comparison Between Heavner's anti-TNF Antibody and D2E7
`
`Heavy Chain CDR1
`
`Heavy Chain CDR2
`
`Heavy Chain CDR3
`
`Light Chain CDR1
`
`Light Chain CDR2
`
`Light Chain CDR3
`
`6 CDR Total
`
`4/5 (80%)
`
`6/17 (35.2%)
`
`1/12 (8.3%)
`
`7/11 (63.6%)
`
`2/7 (28.5%)
`
`5/9 (55.5%)
`
`25/61 (40.9%)
`
`4 Sequence identity was calculated using D2E7 sequences as a reference. Due to additional amino acids in
`Heavner's heavy chain CDR3, light chain CDR2, and light chain CDR3, the percentage identities of those CDRs
`would be lower, i.e., 6.3% (1/16), 25% (2/8) and 50% (5/10), respectively, if the Heavner sequences were used as
`the reference.
`
`-17-
`
`Ex. 2036-0017
`
`

`
`Application No. 14/091,661
`Reply dated April16, 2014
`In Response to January 27, 2014 Office Action
`
`Docket No.: 110222-0005-303
`
`Figure 1: Summary of Sequence Comparison Between Heavner's anti-TNF Antibody and D2E7
`(CDRs underlined and bolded5
`)
`
`-;
`
`,""'.(">
`
`~·._, .. ,_ ..
`
`Thus, even if Heavner's purported antibody formulations (if any) were stable, the
`
`skilled worker would not have reasonably expected that they would be applicable to D2E7. As
`
`discussed at subsection 1(A)(i), supra, at the priority date of this application, skilled artisans had
`
`experienced difficulties in developing a unified strategy for developing stable liquid
`
`pharmaceutical formulations of proteins, due to protein structural diversities and complexities.
`
`Also as discussed above, antibody CDRs were known to play a key role in the propensity of
`
`antibodies to aggregate. Thus, even if Heavner had provided a stable liquid pharmaceutical
`
`formulation for its antibody, the skilled worker would not have reasonably known whether that
`
`formulation would also work for D2E7 or an antibody having its variable region sequences.
`
`5 Heavner's CDR definitions are based on Figs. 4 and 5 of Heavner. D2E7's CDR definitions are based on Figs. 1
`and 2 of Salfeld.
`
`-18-
`
`Ex. 2036-0018
`
`

`
`Application No. 14/091,661
`Reply dated April16, 2014
`In Response to January 27, 2014 Office Action
`
`Docket No.: 110222-0005-303
`
`(iii)
`
`Salfeld Does Not Remedy Heavner's Deficiencies
`
`Salfeld does not remedy the deficiencies of Heavner. While Salfeld discloses
`
`D2E7, it does not evaluate the stability of any D2E7 formulation. Thus, given Heavner and
`
`Salfeld, a person of ordinary skill in the art would not have arrived at the claimed stable aqueous
`
`liquid pharmaceutical composition, let alone with a reasonable expectation of success. For at
`
`least these reasons, claims 1-3, 5-10, 12, 13, and 16-18 are not obvious over Heavner in view of
`
`Salfeld.
`
`B. Claims 14, 15, and 19-31
`
`Regarding claims 14, 15, and 19-31, the Examiner asserts the same alleged
`
`teachings of Heavner and Salfeld. While the Examiner acknowledges that Heavner and Salfeld
`
`do not disclose the specific amounts of mannitol and polysorbate 80 recited in the claims, the
`
`Examiner contends that these amounts are the result of routine optimization of conditions.
`
`Applicant has cancelled claim 24. With respect to claims 14, 15, 19-23, and 25-
`
`31, applicant submits that they are patentable over Heavner and Salfeld for the same reasons as
`
`discussed above.
`
`C. Summary
`
`For the above reasons, Heavner and Salfeld together fail to render claims 1-3, 5-
`
`10, 12-23, and 25-31 primafacie obvious. New claim 32 depends from claim 21 and
`
`incorporates all of the patentable features of that base claim. Thus, the new claim is patentable
`
`over Heavner and Salfeld as well for at least the same reasons.
`
`-19-
`
`Ex. 2036-0019
`
`

`
`Application No. 14/091,661
`Reply dated April16, 2014
`In Response to January 27, 2014 Office Action
`
`Docket No.: 110222-0005-303
`
`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
`
`-20-
`
`Ex. 2036-0020