UNITED STA 1ES p A 1ENT AND TRADEMARK OFFICE
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`Address: COMMISSIONER FOR PATENTS
`P.O. Box 1450
`Alexandria, Virginia 22313-1450
`www.uspto.gov
`
`APPLICATION NO.
`
`FILING DATE
`
`FIRST NAMED INVENTOR
`
`ATTORNEY DOCKET NO.
`
`CONFIRMATION NO.
`
`14/322,565
`
`07/02/2014
`
`Hans-Juergen Krause
`
`110222-0005-308
`
`6071
`
`7590
`118276
`Ropes & Gray, LLP
`1211 Avenue of the Americas
`New York, NY 10036
`
`09117/2014
`
`EXAMINER
`
`BUNNER, BRIDGET E
`
`ART UNIT
`
`PAPER NUMBER
`
`1647
`
`NOTIFICATION DATE
`
`DELIVERY MODE
`
`09/17/2014
`
`ELECTRONIC
`
`Please find below and/or attached an Office communication concerning this application or proceeding.
`
`The time period for reply, if any, is set in the attached communication.
`
`Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
`following e-mail address(es):
`USPatentMai1@ropesgray.com
`USPatentMai12@ropesgray.com
`
`PTOL-90A (Rev. 04/07)
`
`Ex. 2039-0001
`
`

`
`Application No.
`14/322,565
`
`Applicant(s)
`KRAUSE ET AL.
`
`Office Action Summary
`
`AlA (First Inventor to File)
`Status
`No
`-- The MAILING DATE of this communication appears on the cover sheet with the correspondence address -(cid:173)
`Period for Reply
`
`Examiner
`Bridget E. Bunner
`
`Art Unit
`1647
`
`A SHORTENED STATUTORY PERIOD FOR REPLY IS SET TO EXPIRE ;2 MONTHS FROM THE MAILING DATE OF
`THIS COMMUNICATION.
`Extensions of time may be available under the provisions of 37 CFR 1.136(a). In no event, however, may a reply be timely filed
`after SIX (6) MONTHS from the mailing date of this communication.
`If NO period for reply is specified above, the maximum statutory period will apply and will expire SIX (6) MONTHS from the mailing date of this communication.
`Failure to reply within the set or extended period for reply will, by statute, cause the application to become ABANDONED (35 U.S.C. § 133).
`Any reply received by the Office later than three months after the mailing date of this communication, even if timely filed, may reduce any
`earned patent term adjustment. See 37 CFR 1.704(b).
`
`Status
`1 )~ Responsive to communication(s) filed on 02 Julv 2014.
`0 A declaration(s)/affidavit(s) under 37 CFR 1.130(b) was/were filed on __ .
`2a)0 This action is FINAL.
`2b)~ This action is non-final.
`3)0 An election was made by the applicant in response to a restriction requirement set forth during the interview on
`__ ;the restriction requirement and election have been incorporated into this action.
`4)0 Since this application is in condition for allowance except for formal matters, prosecution as to the merits is
`closed in accordance with the practice under Ex parte Quayle, 1935 C.D. 11, 453 O.G. 213.
`
`Disposition of Claims*
`5)~ Claim(s) 1-30 is/are pending in the application.
`5a) Of the above claim(s) __ is/are withdrawn from consideration.
`6)0 Claim(s) __ is/are allowed.
`7)~ Claim(s) 1-30 is/are rejected.
`8)0 Claim(s) __ is/are objected to.
`9)0 Claim(s) __ are subject to restriction and/or election requirement.
`* If any claims have been determined allowable, you may be eligible to benefit from the Patent Prosecution Highway program at a
`participating intellectual property office for the corresponding application. For more information, please see
`http:ilvvww.uspto.gov!patents/init events/pph/index.jsp or send an inquiry to PPHfeedback(wuspto.oov.
`
`Application Papers
`1 0)0 The specification is objected to by the Examiner.
`11 )0 The drawing(s) filed on __ is/are: a)O accepted or b)O objected to by the Examiner.
`Applicant may not request that any objection to the drawing(s) be held in abeyance. See 37 CFR 1.85(a).
`Replacement drawing sheet(s) including the correction is required if the drawing(s) is objected to. See 37 CFR 1.121 (d).
`
`Priority under 35 U.S.C. § 119
`12)0 Acknowledgment is made of a claim for foreign priority under 35 U.S.C. § 119(a)-(d) or (f).
`Certified copies:
`a)O All b)O Some** c)O None of the:
`Certified copies of the priority documents have been received.
`1.0
`Certified copies of the priority documents have been received in Application No. __ .
`2.0
`Copies of the certified copies of the priority documents have been received in this National Stage
`3.0
`application from the International Bureau (PCT Rule 17.2(a)).
`** See the attached detailed Office action for a list of the certified copies not received.
`
`Attachment{s)
`1) 0 Notice of References Cited (PT0-892)
`
`2) ~ Information Disclosure Statement(s) (PTO/SB/08a and/or PTO/SB/08b)
`Paper No(s)/Mail Date 712114· 7117114.
`
`3) 0 Interview Summary (PT0-413)
`Paper No(s)/Mail Date. __ .
`4) 0 Other: __ .
`
`U.S. Patent and Trademark Off1ce
`PTOL-326 (Rev. 11-13)
`
`Office Action Summary
`
`Part of Paper No./Mail Date 20140825
`
`Ex. 2039-0002
`
`

`
`Application/Control Number: 14/322,565
`Art Unit: 1647
`
`Page 2
`
`DETAILED ACTION
`
`The present application is being examined under the pre-AlA first to invent provisions.
`
`Status of Application, Amendments and/or Claims
`
`Claims 1-30 are pending and under consideration in the instant application.
`
`Information Disclosure Statement
`
`The information disclosure statements (IDS) submitted on 02 July 2014 and 17 July 2014
`
`are in compliance with the provisions of 37 CPR 1.97. Accordingly, the information disclosure
`
`statements are being considered by the Examiner. It is noted that on the IDS of 02 July 2014, the
`
`Salfeld abstract was cited twice. The duplicate citation has been crossed off by the Examiner.
`
`Claim Rejections - 35 USC § I 03
`
`The following is a quotation of pre-AlA 35 U.S.C. 103(a) which forms the basis for all
`
`obviousness rejections set forth in this Office action:
`
`(a) A patent may not be obtained though the invention is not identically disclosed or described as set
`forth in section 102 of this title, if the differences between the subject matter sought to be patented and
`the prior art are such that the subject matter as a whole would have been obvious at the time the
`invention was made to a person having ordinary skill in the art to which said subject matter pertains.
`Patentability shall not be negatived by the manner in which the invention was made.
`
`In the event the determination of the status of the application as subject to AlA 35 U.S.C.
`
`102 and 103 (or as subject to pre-AlA 35 U.S .C. 102 and 103) is incorrect, any correction of the
`
`statutory basis for the rejection will not be considered a new ground of rejection if the prior art
`
`relied upon, and the rationale supporting the rejection, would be the same under either status.
`
`Ex. 2039-0003
`
`

`
`Application/Control Number: 14/322,565
`Art Unit: 1647
`
`Page 3
`
`This application currently names joint inventors. In considering patentability of the
`
`claims under pre-AlA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the
`
`various claims was commonly owned at the time any inventions covered therein were made
`
`absent any evidence to the contrary. Applicant is advised of the obligation under 37 CPR 1.56 to
`
`point out the inventor and invention dates of each claim that was not commonly owned at the
`
`time a later invention was made in order for the examiner to consider the applicability of pre-
`
`AlA 35 U.S.C. 103(c) and potential pre-AlA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AlA
`
`35 U.S.C. 103(a).
`
`2.
`
`Claims 1-9, 11-13, 16-18,22-26,28-30 are rejected under pre-AlA 35 U.S.C. 103(a) as
`
`being unpatentable over Lam et al. (U.S. Patent 6,171,586) and Salfeld et al. (U.S. Patent
`
`6,090,382).
`
`Lam et al. teach a stable aqueous pharmaceutical formulation comprising an antibody not
`
`subjected to prior lyophilization, a buffer maintaining the pH in a range from about 4.5 to about
`
`6.0, a surfactant, and a polyol (abstract; column 2, lines 25-33). Lam et al. disclose that the
`
`amount of antibody present in the formulation is, for example, from about 0.1 mg/ml to about 50
`
`mg/ml (column 22, lines 1-17). Lam et al. state that buffers that control the pH within the
`
`desired range include gluconate (column 22, lines 18-24; column 6, lines 61-67 through column
`
`7, lines 1-2). Lam et al. teach that the buffer concentration can be from about 1mM to about 50
`
`mM (column 22, lines 25-30). Lam et al. disclose that the polyol is a substance with multiple
`
`hydroxyl groups and includes sugars (such as the nonreducing sugar, trehalose), sugar alcohols
`
`(such as mannitol), and sugar acids (column 6, lines 38-52; column 22, lines 31-48). Lam et al.
`
`Ex. 2039-0004
`
`

`
`Application/Control Number: 14/322,565
`Art Unit: 1647
`
`Page 4
`
`disclose that the polyol may be in the range from about 1% to about 15% w/v (column 22, lines
`
`31-48). Lam et al. teach that the surfactant in the formulation may be polysorbate 20 or
`
`polysorbate 80 and may be present in an amount from about 0.001% to about 0.5% (column 22,
`
`lines 49-59). Lam et al. also state that the antibody in the formulation is directed against an
`
`antigen of interest, wherein the antigen is TNFa (column 9, lines 59-67 through column 10, lines
`
`1-19). Lam et al. mention that the formulation may be administered subcutaneously at one time
`
`or over a series of treatments (column 23, lines 32-54).
`
`Lam et al. does not disclose an aqueous pharmaceutical composition comprising an
`
`antibody that comprises the light chain variable region and the heavy chain variable region of the
`
`TNFa antibody, D2E7.
`
`Salfeld et al. teaches TNFa is implicated in the pathophysiology of a variety of human
`
`diseases, such as shock, sepsis, infections, autoimmune diseases, transplant rejection and graft-
`
`versus-host disease (column 1, lines 10-20). Salfeld discloses that therapeutic strategies have
`
`been designed to inhibit or counteract hTNFa activity, in particular antibodies that bind to and
`
`neutralize hTNFa (column 1, lines 23-27). Salfeld et al. teach a recombinant anti-hTNFa
`
`antibody, termed D2E7, neutralizes hTNFa activity (column 2, lines 50-67; column 9, lines 43-
`
`67 through column 5). Salfeld et al. teach that the antibody is of the IgG 1 subclass (column 30,
`
`lines 39-47; column 34, lines 44-56; column 2, lines 56-57). Salfeld et al. disclose administering
`
`an anti-hTNFa to a human subject suffering from a disorder in which TNFa activity is
`
`detrimental such that human TNFa activity in the human subject is inhibited (column 4, lines 32-
`
`48; columns 24-27).
`
`Ex. 2039-0005
`
`

`
`Application/Control Number: 14/322,565
`Art Unit: 1647
`
`Page 5
`
`It would have been obvious to the person of ordinary skill in the art at the time the
`
`invention was made to modify the aqueous pharmaceutical composition as taught by Lam et al.
`
`by substituting the antibody with the anti-hTNFa antibody, D2E7, as taught by Salfeld et al. The
`
`person of ordinary skill in the art would have been motivated to make that modification to
`
`provide a stable liquid formulation of anti-TNFa that remains biologically active for
`
`administration to subjects suffering from a disorder in which TNFa activity is detrimental (see
`
`for example, Lam et al., column 1, lines 14-26; column 2, lines 25-33;; Salfeld et al. column 4,
`
`lines 32-48; columns 24-27). The person of ordinary skill in the art reasonably would have
`
`expected success because similar preparations were already being generated at the time the
`
`invention was made. Therefore, the claimed invention as a whole was clearly prima facie
`
`obvious over the prior art.
`
`3.
`
`Claims 10, 14, 15, 19-21, and 27 are rejected under pre-AlA 35 U.S.C. 103(a) as being
`
`unpatentable over Lam et al. (U.S. Patent 6,171,586) and Salfeld et al. (U.S. Patent 6,090,382) as
`
`applied to claims 1-9, 11-13, 16-18,22-26,28-30 above.
`
`The teachings of Lam et al. and Salfeld et al. are set forth above.
`
`Lam et al. and Salfeld et al. do not recite specific amounts (mg/ml) of surfactant
`
`(polysorbate) recited in claims 10, 14, 15, 19-21, and 27.
`
`However, it would have been obvious to one having ordinary skill in the art at the time
`
`the invention was made to modify the amounts of surfactant (i.e., polysorbate 80) utilized in the
`
`compositions as taught by Lam et al. and Salfeld et al. The person of ordinary skill in the art
`
`would have been motivated to make that modification to in order to improve upon what is
`
`Ex. 2039-0006
`
`

`
`Application/Control Number: 14/322,565
`Art Unit: 1647
`
`Page 6
`
`already known, thus determining the optimum combination amounts of reagents. The person of
`
`ordinary skill in the art reasonably would have expected success because optimization of
`
`conditions is routine in the art. See In re Aller 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA
`
`1955) "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive
`
`to discover the optimum or workable ranges by routine experimentation". See also In re
`
`Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes
`
`which fell within the broad scope of the references were held to be unpatentable thereover
`
`because, among other reasons, there was no evidence of the criticality of the claimed ranges of
`
`molecular weight or molar proportions.). Therefore, the claimed invention as a whole is clearly
`
`prima facie obvious over the prior art.
`
`Double Patenting
`
`The nonstatutory double patenting rejection is based on a judicially created doctrine
`
`grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or
`
`improper timewise extension of the "right to exclude" granted by a patent and to prevent possible
`
`harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate
`
`where the claims at issue are not identical, but at least one examined application claim is not
`
`patentably distinct from the reference claim(s) because the examined application claim is either
`
`anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg,
`
`140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d
`
`2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van
`
`Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619
`
`(CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
`
`A timely filed terminal disclaimer in compliance with 37 CPR 1.32l(c) or 1.32l(d) may
`
`be used to overcome an actual or provisional rejection based on a nonstatutory double patenting
`
`ground provided the reference application or patent either is shown to be commonly owned with
`
`Ex. 2039-0007
`
`

`
`Application/Control Number: 14/322,565
`Art Unit: 1647
`
`Page 7
`
`this application, or claims an invention made as a result of activities undertaken within the scope
`
`of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CPR
`
`1.32l(b).
`
`The USPTO internet Web site contains terminal disclaimer forms which may be used.
`
`Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what
`
`form should be used. A web-based eTerminal Disclaimer may be filled out completely online
`
`using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and
`
`approved immediately upon submission. For more information about eTerminal Disclaimers,
`
`refer to http://www .uspto.gov/patents/process/file/efs/ guidance/eTD-info-I.j sp.
`
`4.
`
`Claims 1-30 are rejected on the ground of nonstatutory double patenting as being
`
`unpatentable over claims 1-29 of U.S. Patent No. 8,802,101. Although the claims at issue are not
`
`identical, they are not patentably distinct from each other because both sets of claims are directed
`
`to a liquid aqueous pharmaceutical formulation comprising the same isolated human IgG 1 anti-
`
`human TNFa antibody in overlapping concentrations.
`
`Claim 1 of the instant application recites a liquid aqueous pharmaceutical formulation
`
`comprising a human IgG 1 anti-human TNFa antibody, or an antigen-binding portion thereof, at a
`
`concentration of 20-150 mg/ml, a polyol, a surfactant, and 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 of D2E7. Claim 22 of the instant application recites a liquid
`
`aqueous pharmaceutical formulation comprising (a) 20 to 150 mg/ml of a human IgG 1 anti-
`
`human 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 of D2E7.
`
`Ex. 2039-0008
`
`

`
`Application/Control Number: 14/322,565
`Art Unit: 1647
`
`Page 8
`
`Meanwhile, claim 1 of the '1 01 patent recites a stable liquid aqueous pharmaceutical
`
`formulation comprising (a) a human IgG 1 anti-human TNFa antibody, or an antigen-binding
`
`portion thereof, at a concentration of 45 to 105 mg/ml, (b) a polyol, (c) polysorbate at a
`
`concentration of 0.1 to 10 mg/ml, and (d) a buffer system comprising acetate and having a pH of
`
`4.5 to 7.0, wherein the antibody comprises the light chain variable region and the heavy chain
`
`variable region of D2E7.
`
`The claims of both the instant application and the '1 01 patent are directed to the same
`
`anti-human TNFa antibody in a liquid formulation. The main difference between the two claim
`
`sets is that in the instant application, the TNFa antibody is formulated with a buffer system
`
`comprising gluconate, while in the '1 01 patent, the TNF a antibody is formulated with a buffer
`
`system comprising acetate. Thus, the claims of the instant application are an obvious variation
`
`of the invention claimed in the ' 1 0 1 patent.
`
`Although the claims of the '1 01 patent do not recite that the buffer system comprises
`
`gluconate, it is well known in the art that several different buffers can be used in protein
`
`formulations for pH and protein stability (see for instance, Akers et al. Development and
`
`Manufacture of Protein Pharmaceuticals (Pharmaceutical Biotechnology), Chapter 2, 2002
`
`Kluver Academic/Plenum Pub., New York;; page 60, 63; Table Von page 64). The
`
`specification of the '1 01 patent even teaches that examples of buffers that control the pH in the
`
`range from about 4 to about 8 (preferably from about 4.5 to about 7 and most preferably about
`
`5.0 to about 6.5) include acetate (e.g. sodium acetate), succinate (such as sodium succinate),
`
`gluconate, histidine, citrate and phosphate, and other organic acid buffers (see column 8, lines
`
`25-33; column 13, line 67 through column 14, lines 1-3; Example 1, columns 21-23). Thus, it
`
`Ex. 2039-0009
`
`

`
`Application/Control Number: 14/322,565
`Art Unit: 1647
`
`Page 9
`
`would have been obvious to the person of ordinary skill in the art at the time the invention was
`
`made to modify the types of buffers used in the liquid aqueous formulations of the identical anti-
`
`human TNF a antibody of the instant application and the '1 01 patent. The person of ordinary
`
`skill in the art would have been motivated to make buffer modifications as an obvious variation
`
`for pH and protein stability.
`
`5.
`
`Claims 1-30 are rejected on the ground of nonstatutory double patenting as being
`
`unpatentable over claims 1-29 of U.S. Patent No. 8,795,670. Although the claims at issue are not
`
`identical, they are not patentably distinct from each other because both sets of claims are directed
`
`to a liquid aqueous pharmaceutical formulation comprising the same isolated human IgG 1 anti-
`
`human TNFa antibody in overlapping concentrations.
`
`Claim 1 of the instant application recites a liquid aqueous pharmaceutical formulation
`
`comprising a human IgG 1 anti-human TNFa antibody, or an antigen-binding portion thereof, at a
`
`concentration of 20-150 mg/ml, a polyol, a surfactant, and 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 of D2E7. Claim 22 of the instant application recites a liquid
`
`aqueous pharmaceutical formulation comprising (a) 20 to 150 mg/ml of a human IgG1 anti-
`
`human 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 of D2E7.
`
`Meanwhile, claim 1 of the '670 patent recites a stable liquid aqueous pharmaceutical
`
`formulation comprising (a) a human IgG 1 anti-human TNFa antibody, or an antigen-binding
`
`Ex. 2039-0010
`
`

`
`Application/Control Number: 14/322,565
`Art Unit: 1647
`
`Page 10
`
`portion thereof, at a concentration of 45 to 105 mg/ml, (b) a polyol, (c) a polysorbate at a
`
`concentration of 0.1 to 10 mg/ml, and (d) a buffer system comprising histidine and having a pH
`
`of 4.5 to 7.0, wherein the antibody comprises the light chain variable region and the heavy chain
`
`variable region of D2E7.
`
`The claims of both the instant application and the '670 patent are directed to the same
`
`anti-human TNFa antibody in a liquid formulation. The main difference between the two claim
`
`sets is that in the instant application, the TNFa antibody is formulated with a buffer system
`
`comprising gluconate, while in the '670 patent, the TNFa antibody is formulated with a buffer
`
`system comprising histidine. Thus, the claims of the instant application are an obvious variation
`
`of the invention claimed in the '670 patent.
`
`Although the claims of the '670 patent do not recite that the buffer system comprises
`
`gluconate, it is well known in the art that several different buffers can be used in protein
`
`formulations for pH and protein stability (see for instance, Akers et al. Development and
`
`Manufacture of Protein Pharmaceuticals (Pharmaceutical Biotechnology), Chapter 2, 2002
`
`Kluver Academic/Plenum Pub., New York;; page 60, 63; Table Von page 64). The
`
`specification of the '670 patent even teaches that examples of buffers that control the pH in the
`
`range from about 4 to about 8 (preferably from about 4.5 to about 7 and most preferably about
`
`5.0 to about 6.5) include acetate (e.g. sodium acetate), succinate (such as sodium succinate),
`
`gluconate, histidine, citrate and phosphate, and other organic acid buffers (see column 8, lines
`
`25-33; column 13, line 67 through column 14, lines 1-3; Example 1, columns 21-22). Thus, it
`
`would have been obvious to the person of ordinary skill in the art at the time the invention was
`
`made to modify the types of buffers used in the liquid aqueous formulations of the identical anti-
`
`Ex. 2039-0011
`
`

`
`Application/Control Number: 14/322,565
`Art Unit: 1647
`
`Page 11
`
`human TNFa antibody of the instant application and the '670 patent. The person of ordinary
`
`skill in the art would have been motivated to make buffer modifications as an obvious variation
`
`for pH and protein stability.
`
`6.
`
`Claims 1-30 are rejected on the ground of nonstatutory double patenting as being
`
`unpatentable over claims 1-29 of U.S. Patent No. 8,802,102. Although the claims at issue are not
`
`identical, they are not patentably distinct from each other because both sets of claims are directed
`
`to a liquid aqueous pharmaceutical formulation comprising the same isolated human IgG 1 anti-
`
`human TNFa antibody in overlapping concentrations.
`
`Claim 1 of the instant application recites a liquid aqueous pharmaceutical formulation
`
`comprising a human IgG 1 anti-human TNFa antibody, or an antigen-binding portion thereof, at a
`
`concentration of 20-150 mg/ml, a polyol, a surfactant, and 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 of D2E7. Claim 22 of the instant application recites a liquid
`
`aqueous pharmaceutical formulation comprising (a) 20 to 150 mg/ml of a human IgG 1 anti-
`
`human 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 of D2E7.
`
`Meanwhile, claim 1 of the '1 02 patent recites a stable liquid aqueous pharmaceutical
`
`formulation comprising (a) a human IgG 1 anti-human TNFa antibody, or an antigen-binding
`
`portion thereof, at a concentration of 45 to 105 mg/ml, (b) a polyol, (c) polysorbate at a
`
`concentration of 0.1 to 10 mg/ml, and (d) a buffer system comprising succinate and having a pH
`
`Ex. 2039-0012
`
`

`
`Application/Control Number: 14/322,565
`Art Unit: 1647
`
`Page 12
`
`of 4.5 to 7.0, wherein the antibody comprises the light chain variable region and the heavy chain
`
`variable region of D2E7.
`
`The claims of both the instant application and the '1 02 patent are directed to the same
`
`anti-human TNFa antibody in a liquid formulation. The main difference between the two claim
`
`sets is that in the instant application, the TNFa antibody is formulated with a buffer system
`
`comprising gluconate, while in the '1 02 patent, the TNF a antibody is formulated with a buffer
`
`system comprising succinate. Thus, the claims of the instant application are an obvious variation
`
`of the invention claimed in the '1 02 patent.
`
`Although the claims of the '1 02 patent do not recite that the buffer system comprises
`
`gluconate, it is well known in the art that several different buffers can be used in protein
`
`formulations for pH and protein stability (see for instance, Akers et al. Development and
`
`Manufacture of Protein Pharmaceuticals (Pharmaceutical Biotechnology), Chapter 2, 2002
`
`Kluver Academic/Plenum Pub., New York;; page 60, 63; Table Von page 64). The
`
`specification of the '1 02 patent even teaches that examples of buffers that control the pH in the
`
`range from about 4 to about 8 (preferably from about 4.5 to about 7 and most preferably about
`
`5.0 to about 6.5) include acetate (e.g. sodium acetate), succinate (such as sodium succinate),
`
`gluconate, histidine, citrate and phosphate, and other organic acid buffers (see column 8, lines
`
`25-33; column 13, line 67 through column 14, lines 1-3; Example 1, columns 21-22). Thus, it
`
`would have been obvious to the person of ordinary skill in the art at the time the invention was
`
`made to modify the types of buffers used in the liquid aqueous formulations of the identical anti-
`
`human TNFa antibody of the instant application and the '102 patent. The person of ordinary
`
`Ex. 2039-0013
`
`

`
`Application/Control Number: 14/322,565
`Art Unit: 1647
`
`Page 13
`
`skill in the art would have been motivated to make buffer modifications as an obvious variation
`
`for pH and protein stability.
`
`7.
`
`Claims 1-30 are rejected on the ground of nonstatutory double patenting as being
`
`unpatentable over claims 1-19 of U.S. Patent No. 8,216,583. Although the claims at issue are not
`
`identical, they are not patentably distinct from each other because both sets of claims are directed
`
`to a liquid aqueous pharmaceutical formulation comprising the same isolated human IgG 1 anti-
`
`human TNFa antibody in overlapping concentrations.
`
`Claim 1 of the instant application recites a liquid aqueous pharmaceutical formulation
`
`comprising a human IgG 1 anti-human TNFa antibody, or an antigen-binding portion thereof, at a
`
`concentration of 20-150 mg/ml, a polyol, a surfactant, and 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 of D2E7. Claim 22 of the instant application recites a liquid
`
`aqueous pharmaceutical formulation comprising (a) 20 to 150 mg/ml of a human IgG 1 anti-
`
`human 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 of D2E7.
`
`Meanwhile, claim 1 of the '583 patent recites a stable liquid aqueous pharmaceutical
`
`formulation comprising (a) a human IgG1 anti-human TNFa antibody, or an antigen-binding
`
`portion thereof, at a concentration of between about 20 and about 150 mg/ml, a polyol, a
`
`surfactant, and a buffer system comprising citrate and phosphate, wherein said formulation has a
`
`pH of about 4 to about 8, and wherein the antibody, or antigen-binding portion thereof,
`
`Ex. 2039-0014
`
`

`
`Application/Control Number: 14/322,565
`Art Unit: 1647
`
`Page 14
`
`comprises a light chain variable region comprising a CDRl domain comprising the amino acid
`
`sequence set forth in SEQ ID NO: 7; a CDR2 domain comprising the amino acid sequence set
`
`forth in SEQ ID NO: 5; and a CDR3 domain comprising the amino acid sequence set forth in
`
`SEQ ID NO: 3 or a modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4,
`
`5, 7, or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 an/or
`
`9; and a heavy chain variable region comprising a CDR1 domain comprising the amino acid
`
`sequence set forth in SEQ ID NO: 8; a CDR2 domain comprising the amino acid sequence set
`
`forth in SEQ ID NO: 6; and a CDR3 domain comprising the amino acid sequence set forth in
`
`SEQ ID NO: 4 or modified from SEQ ID NO: 4 by a single alanine substitution at positions 2, 3,
`
`4, 5, 6, 7, 8, 10, or 11, or by one to five conservative amino acid substitutions at positions 2, 3, 4,
`
`5, 6, 8, 9, 10, 11, and/or 12. (It is noted that the anti-TNFa antibody, D2E7, comprises a light
`
`chain variable region comprising a CDR1 domain comprising the amino acid sequence set forth
`
`in SEQ ID NO: 7; a CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO:
`
`5; and a CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 3; and a
`
`heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence set
`
`forth in SEQ ID NO: 8; a CDR2 domain comprising the amino acid sequence set forth in SEQ ID
`
`NO: 6; and a CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 4, as
`
`recited in the claims of the '583 patent (see Salfeld et al. U.S. Patent 6,090,382, Figures 1A-1B,
`
`2A-2B).)
`
`The claims of both the instant application and the '5 83 patent are directed to the same
`
`anti-human TNFa antibody in a liquid formulation. The main difference between the two claim
`
`sets is that in the instant application, the TNFa antibody is formulated with a buffer system
`
`Ex. 2039-0015
`
`

`
`Application/Control Number: 14/322,565
`Art Unit: 1647
`
`Page 15
`
`comprising gluconate, while in the '583 patent, the TNFa antibody is formulated with a buffer
`
`system comprising citrate and phosphate. Thus, the claims of the instant application are an
`
`obvious variation of the invention claimed in the '583 patent.
`
`Although the claims of the '583 patent do not recite that the buffer system comprises
`
`gluconate, it is well known in the art that several different buffers can be used in protein
`
`formulations for pH and protein stability (see for instance, Akers et al. Development and
`
`Manufacture of Protein Pharmaceuticals (Pharmaceutical Biotechnology), Chapter 2, 2002
`
`Kluver Academic/Plenum Pub., New York;; page 60, 63; Table Von page 64). The
`
`specification of the '5 83 patent even teaches that examples of buffers that control the pH in the
`
`range from about 4 to about 8 (preferably from about 4.5 to about 7 and most preferably about
`
`5.0 to about 6.5) include acetate (e.g. sodium acetate), succinate (such as sodium succinate),
`
`gluconate, histidine, citrate and phosphate, and other organic acid buffers (see column 8, lines
`
`16-24; column 13, line 67 through column 14, lines 1-3; Example 1, columns 21-22). Thus, it
`
`would have been obvious to the person of ordinary skill in the art at the time the invention was
`
`made to modify the types of buffers used in the liquid aqueous formulations of the identical anti-
`
`human TNFa antibody of the instant application and the '583 patent. The person of ordinary
`
`skill in the art would have been motivated to make buffer modifications as an obvious variation
`
`for pH and protein stability.
`
`8.
`
`Claims 1-30 are rejected on the ground of nonstatutory double patenting as being
`
`unpatentable over claims 1-29 of U.S. Patent No. 8,802,100. Although the claims at issue are not
`
`identical, they are not patentably distinct from each other because both sets of claims are directed
`
`Ex. 2039-0016
`
`

`
`Application/Control Number: 14/322,565
`Art Unit: 1647
`
`Page 16
`
`to a liquid aqueous pha