06/25/2009 15:26 FAX 2062330644
`
`AMGEN
`
`~003
`RECEIVED
`CENTRAL FAX CENTER
`JUN 2 5 2009
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicant: Grace C. CHU
`
`Serial No.: 11/437,602
`
`May 18,2006
`
`Filed:
`
`For:
`
`Group Art Unit No.: 1644
`
`Examiner:
`
`Yunsoo Kim
`
`COMPOSITIONS AND METHODS FOR INCREASING
`THE STABILITY OF ANTIBODIES
`
`Docket No.: A-1012-US-NP
`
`AMENDMENT AND RESPONSE
`
`Mail Stop Amendment
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`This is written in response to the non-final action dated March 23, 2009
`(hereinafter, the Action). Accompanying this response is a transmittal sheet
`including a petition for a one month extension of time under 37 C.F.R. §
`1.136, as well as the requisite fee authorization. However, if the Examiner
`detennines .that additional fees are due at this or any other time during the
`prosecution of this application, she is hereby authorized to charge any such
`fees, or credit any overpayment, to Deposit Account Number 01-0519.
`
`Amendments to the claims begin on page 2.
`
`Remarks begin on page 8.
`
`CERTIFICATE OF FACSIMILE TRANSMI§SION
`I hereby certify thai this paper (along with any referred to as being attached or endosed) Is being
`transmitted to the United States Patent and Trademark Office via facsimile to facsimile number 571-273-8300 on
`the date indicated below, and is addressed to Mail Stop Amendment, Commissioner fOr Patents, P.O. Box 1450,
`Alexandria, VA 22313-1450.
`
`"9"'d ~~ Katlieen!Grldk
`
`Date:
`
`BJ/~~ ~ ~818519 v.t-4~
`PAGE 3f38' Rcvo AT 612512009 6:27:45 PM [Eastern oa~ight Time!' SVR:USPTO-EFXRF-515' DNIS:273830D ~~~o~orn3o644 * ouRATib~~!fiil-ss):OB·12
`
`86/26/2069 Jvotml
`01 FC:1251
`
`80800813 11437602
`130.80 DA
`
`Ex. 2016-0001
`
`

`
`06/25/2009 15:27 FAX 2062330644
`
`AMGEN
`
`laJ 004
`
`A-1012-US-NP
`Amendment and Response
`
`Listing of Claims:
`1-45. (cancelled)
`46.
`(currently amended) A pharmaceutical composition comprising
`a purified preparation of a monoclonal antibody and a buffering agent,
`wherein the composition is at a pH from 5.7 &.-6 to 6.5, and
`·wherein the purified preparation comprises at least three different
`
`isoforms of the antibody,
`wherein the antibody comprises
`a heavy chain variable region including a CDR 1 having the
`(a)
`amino acid sequence of SEQ ID N0:34, a CDR2 having the amino acid
`sequence of SEQ ID N0:35, and a CDR3 having the amino acid sequence of
`SEQ 10 N0:36 or SEQ ID N0:37 and
`(b) a light chain variable region including a CDR1 having the amino
`acid sequence of SEQ ID N0:38, SEQ ID N0:39, or SEQ ID N0:40, a COR2
`having the amino acid sequence of SEQ ID N0:41 or SEQ 10 N0:42, and a
`CDR3 having the amino acid sequence of SEQ ID N0:43 or SEQ 10 N0:44.
`47.
`(previously presented) The pharmaceutical composition of claim
`46, wherein the antibody comprises an N-glycan site in a heavy and/or a light
`chain variable region.
`48.
`(previously presented) The pharmaceutical composition of claim
`46, wherein the antibody is a human or humanized lgG antibody.
`(previously presented) The pharmaceutical composition of claim
`49.
`46, wherein the buffering agent is histidlne, sodium acetate, sodium
`phosphate, potassium phosphate, or sodium citrate.
`50.
`(previously presented) The pharmaceutical composition of claim
`· 46, wherein the composrtion further comprises a sugar, a carbohydrate,
`I and/or a salt.
`51.
`{previously presented) The pharmaceutical composition of claim
`· 50, wherein the composition comprises sorbitol.
`
`PAGE 4/38 1 RCVD AT 6125/2009 6:27:45 PM [Eastern Da~ight Time) 1 SVR:USPTO.fFXRF·5/5 1 DNIS:2738300 1 CSID:2062330644 1 DURATION (mm-ss):08·12
`
`2
`
`Ex. 2016-0002
`
`

`
`06/25/2009 15:27 FAX 2062330644
`
`A.I'IGEN
`
`141005
`
`A-1012-US-NP
`Amendment and Response
`
`(previously presented) The pharmaceutical composition of claim
`52.
`46, wherein the antibody comprises the amino acid sequence of SEQ ID
`N0:6, SEQ ID N0:10, SEQ ID N0:14, or SEQ ID N0:30.
`53.
`(currently amended) The pharmaceutical composition of claim
`46, wherein the antibody Is produced in a CHO cell and wherein the antibody
`comprises SEQ ID N0:6 and SEQ ID NO:S.
`54.
`(currently amended) The pharmaceutical composition of claim
`53 4-S, wherein the composition is a liquid. and wherein the composition is at a
`g_H from 5.7 to 6.3.
`55.
`(currently amended) A pharmaceutical composition comprising
`a purified preparation of a monoclonal antibody and a buffering agent.
`wherein the composition is at a pH from 5.7 e.:.e to 6.5,
`wherein the buffering agent is histidine, and
`wherein the antibody comprises
`a heavy chain variable region including a CDR1 having the
`(a)
`amino acid sequence of SEQ ID N0:34, a CDR2 having the amino acid
`sequence of SEQ ID N0:35, and a CDR3 having the amino acid sequence of
`SEQ ID N0:36 or SEQ ID N0:37 and
`(b) a light chain variable region including a CDR1 having the amino
`acid sequence of SEQ ID N0:38, SEQ ID N0:39, or SEQ ID N0:40, a CDR2
`having the amino acid sequence of SEQ 10 N0:41 or SEQ ID N0:42, and a
`CDR3 having the amino acid sequence of SEQ ID N0:43 or SEQ 10 N0:44.
`56.
`(previously presented) The pharmaceutical composition of claim
`55, wherein the antibody is a human or humanized lgG antibody.
`(previously presented) The pharmaceutical composition of claim
`57.
`55, wherein the antibody comprises an N-glycan srte in a heavy and/or a light
`chain variable region and wherein the antibody is produced in a mammalian
`, celt.
`
`58.
`(currently amended) The pharmaceutical composition of claim
`57, wherein the antibody is produced in a CHO cell, wherein the composition
`is at a pH from 5.7 to 6.3. and wherein the antibody comprises SEQ ID N0:6
`· and SEQ ID N0:8.
`
`PAGE 5138 a RCVD AT 612512009 6:27:45 PM !Eastern Daylight Time]* SVR:USPTO-EFXRF·515 * ONIS:2738300 * CSID:2062330644 * DURATION (mm-ss):08·12
`
`3
`
`Ex. 2016-0003
`
`

`
`06/25/2009 15:27 FAX 2062330644
`
`AMGEN
`
`~006
`
`I A-1012-US-NP
`Amendment and Response
`
`(withdrawn- currently amended) A pharmaceutical composition
`59.
`comprising a purified preparation of a monoclonal antibody and a buffering
`agent,
`wherein the composition is at a pH from 5.7 ~to 6.5,
`wherein the buffering agent is sodium acetate, sodium phosphate,
`potassium phosphate, or sodium citrate, and
`wherein the antibody comprises
`(a)
`a heavy chain variable region including a CDR1 having the
`amino acid sequence of SEQ ID N0:34, a CDR2 having the amino acid
`sequence of SEQ ID N0:35, and a CDR3 having the amino acid sequence of
`SEQ 10 N0:36 or SEQ ID N0:37 and
`(b) a light chain variable region including a CDR1 having the amino
`acid sequence of SEQ ID N0:38, SEQ ID N0:39, or SEQ ID N0:40, a CDR2
`having the amino acid sequence of SEQ ID N0:41 or SEQ ID N0:42; and a
`CDR3 having the amino acid sequence of SEQ I D N0:43 or SEQ ID N0:44.
`60.
`(V'(ithdrawn - previously presented) The pharmaceutical
`composition of claim 59, wherein the antibody is a human or humanized lgG
`antibody.
`(withdrawn- previously presented) The pharmaceutical
`61.
`composition of claim 59, wherein the antibody comprises an N-glycan site in a
`heavy and/or a light chain variable region and wherein the antibody is
`produced in a mammalian cell.
`62.
`(withdrawn- currently amended) The pharmaceutical
`composition of claim 61, wherein the antibody is produced in a CHO cell.._
`wherein the composition is at a oH from 5.7 to 6.3. and wherein the antibody
`comprises SEQ ID N0:6 and SEQ 10 NO:B.
`63-70. (cancelled)
`71.
`(withdrawn -currently amended) A method for making a stable
`composition comprising
`combining a purified preparation of a monoclonal antibody with a
`: buffering agent,
`
`PAGE 6138 ~ RCVD AT 6/2512009 6:27:45 PM (Eastern Da~ight Time] • SVR:USPTO-EFXRF·5/5 ~ DNIS:2738300- CSID:2062330644 *DURATION (mm-ss):08·12
`
`4
`
`Ex. 2016-0004
`
`

`
`06/25/2009 15:27 FAX 2062330644
`
`:\1\I'GEN
`
`1@007
`
`A-1012-US-NP
`Amendment and Response
`
`wherein the purified preparation comprises at least three different
`
`isofonns of the antibody,
`wherein the pH of the composition is from 5.7 &..a to 6.5, and
`wherein the antibody comprises
`(a)
`a heavy chain variable region including a CDR1 having the
`amino acid sequence of SEQ ID N0:34, a CDR2 having the amino acid
`sequence of SEQ ID N0:35, and a CDR3 having the amino acid sequence of
`SEQ ID N0:36 or SEQ ID N0:37 and
`(b) a light chain variable region including a CDR1 having the amino
`acid sequence of SEQ ID N0:38, SEQ ID N0:39, or SEQ ID N0:40, a CDR2
`, having the amino acid sequence of SEQ ID N0:41 or SEQ ID N0:42, and a
`': CDR3 having the amino acid sequence of SEQ ID N0:43 or SEQ ID N0:44.
`72.
`(withdrawn- previously presented) The method of clairn 71,
`wherein the antibody comprises an N-glycan site in a heavy and/or a light
`chain variable region.
`73.
`(withdrawn- previously presented) The method of claim 71,
`wherein the antibody is a human or humanized lgG antibody.
`74.
`(withdrawn - previously presented) The method of claim 71,
`wherein the buffering agent is histidine, sodium acetate, sodium phosphate,
`potassium phosphate, or sodium citrate.
`75.
`(withdrawn - previously presented) The method of claim 71,
`wherein the composition further comprises a sugar, a carbohydrate, and/or a
`salt.
`
`(withdrawn - previously presented) The method of claim 75,
`76.
`wherein the composition comprises sorbitol.
`77.
`(withdrawn- currently amended) The method of claim 71,
`. wherein the antibody is produced in a CHO cell and wherein the antibody
`: comprises SEQ ID N0:6 and SEQ 10 NO:B.
`78.
`(withdrawn- previously presented) The method of claim 71,
`wherein at least about 90% of the detectable antibody in the purified
`preparation is in the monomer peak as assessed by size exclusion
`· chromatography after two years storage at 4 oc.
`
`PAGE 7/38 1 RCVD AT 6/25/2009 6:27:45 PM [Eastern Da~ight Time] 1 SVR:USPTO.£FXRF·5/5 ~ DNIS:2738300 1 CSID:2062330644 *DURATION (mm-ss):08·12
`
`5
`
`Ex. 2016-0005
`
`

`
`06/25/2009 15:27 FAX 2062330644
`
`AMGEN
`
`~008
`
`A-1012-US-NP
`Amendment and Response
`
`(withdrawn - currently amended) The method of claim 7774,
`79.
`wherein the composition is a liquid, wherein the composition is at a pH from
`5.7 to 6.3, and wherein the antibody comorises SEQ 10 N0:6 and SEQ ID
`N0:8.
`
`(cancelled)
`80.
`(currently amended) A pharmaceutical composition comprising
`81.
`a purified preparation of a monoclonal antibody and a buffering agent,
`wherein the composition is at a pH from 5.7 M
`to 6.5, and
`wherein the purified preparation comprises at least three different
`isoforms of the antibody,
`wherein the antibody comprises the amino acid sequence of SEQ ID
`N0:6, SEQ 10 N0:10, SEQ 10 N0:14, or SEQ ID N0:30.
`82.
`(previously presented) The pharmaceutical composition of claim
`81, wherein the buffering agent is histidine, sodium acetate, sodium
`phosphate, potassium phosphate, or sodium citrate.
`83.
`(previously presented) The pharmaceutical composition of claim
`82, wherein the composition comprises sorbitol.
`84.
`(previously presented) The pharmaceutical composition of claim
`81, wherein the antibody further comprises the amino acid sequence of SEQ
`10 N0:8, SEQ ID N0:12, SEQ ID N0:16, or SEQ 10 N0:31.
`85.
`(currently amended) The pharmaceutical composition of claim
`84, wherein the antibody comprises the amino acid sequences of SEQ 10
`N0:6 and SEQ ID NO:B and wherein the composition is at a pH from 5.7 to
`6.3.
`
`(previously presented) The pharmaceutical composition of claim
`86.
`85, wherein the buffering agent is histidine.
`87.
`(withdrawn- currently amended) A pharmaceutical composition
`comprising a purified preparation of a monoclonal antibody and a buffering
`agent,
`to 6.5, and
`wherein the composition is at a pH from 5.7 M
`wherein the purified preparation comprises at least three different
`isoforms of the antibody, and
`
`PAGE 8138 • RCVD AT 612512009 6:27:45 PM [Eastern Daylight TimeJ• SVR:USPTO.£FXRF·515 • ONIS:2738300 • CSID:2062330644 *DURATION (mm-ss):08·12
`
`6
`
`Ex. 2016-0006
`
`

`
`06/25/2009 15:28 ~~ 2062330644
`
`A.MGEN
`
`~009
`
`A-1012-US-NP
`Amendment and Response
`
`wherein the antibody comprises the amino acid sequence of SEQ 10
`N0:8, SEQ 10 N0:12, SEQ ID N0:16, or SEQ 10 N0:31.
`88.
`(withdrawn- currently amended) The pharmaceutical
`composition of claim 87, wherein the buffering agent is histidine, sodium
`acetate, sodium phosphate, potassium phosphate. or sodium citrate and
`wherein the composition is at a pH from 5.7 to 6.3 ..
`89.
`(withdrawn - previously presented) The pharmaceutical
`composition of claim 88, wherein the composition comprises sorbitol.
`(withdrawn - previously presented) The pharmaceutical
`90.
`composition of claim 46,
`wherein the heavy chain variable region includes a COR3 having the
`amino acid sequence of SEQ 10 N0:36 and
`wherein the light chain variable region includes a CDR 1 having the
`amino acid sequence of SEQ 10 N0:38, a CDR2 having the amino acid
`sequence of SEQ ID N0:41, and a CDR3 having the amino acid sequence of
`SEQ 10 N0:43.
`91.
`(withdrawn- previously presented) The pharmaceutical
`composrtion of claim 59, wherein the buffering agent is sodium acetate.
`92.
`(withdrawn previously presented) The pharmaceutical
`composition of claim 91, further comprising sorbitol.
`93.
`(withdrawn- previously presented) The pharmaceutical
`composition of claim 59, wherein the buffering agent is sodium phosphate.
`94.
`(withdrawn- previously presented) The phannaceutical
`composition of claim 93, further comprising sorbitol.
`95.
`(withdrawn - previously presented) The pharmaceutical
`composition of claim 59, wherein the buffering agent is sodium citrate.
`96.
`(withdrawn - previously presented) The pharmaceutical
`composition of claim 95, further comprising sorbitol.
`97.
`(withdrawn - previously presented) The phannaceutical
`composition of claim 59, wherein the buffering agent is potassium phosphate.
`98.
`(withdrawn - previously presented) The pharmaceutical
`composition of claim 97. further comprising sorbitol.
`
`PAGE 9i38 1 RCVD AT 612512009 6:27:45 PM [Eastern Oa~ight Timej 1 SVR:USPTO-EFXRF·515 1 DNIS:2738300 t CSID:2062330644 *DURATION (mm-ss):08·12
`
`7
`
`Ex. 2016-0007
`
`

`
`06/25/200~ 15:28 FAX 2062330644
`
`Ill 010
`
`A-1012-US-NP
`Amendment and Response
`
`REMARKS
`
`Claims 46-62, 71-79, and 81-98 are pending. Claims 59-62, 71-79,
`and 87-98 have been withdrawn from consideration by the Examiner. Claims
`46-58 and 81-86 stand rejected on multiple grounds. Claims 46, 53, 54, 55,
`58, 59, 62, 71, 77, 79, 81, 85, 87, and 88 are currently amended.
`
`Telephone Interview
`Applicant thanks the Examiner for the telephone interview of June 11,
`2009. Examiner Yunsoo Kim and Applicant's representative Rosemary
`Sweeney participated In the interview. The withdrawal of claims 87-90 was
`discussed. The examiner thought it possible that claim 90, since it depends
`on claim 46, should be examined, and she agreed to consider whether claims
`87-89 might also be examined. Issues of anticipation were also discussed in
`light of proposed claim amendments. The propriety of the double patenting
`rejections was also discussed. The examiner informed Applicant that,
`contrary to what was said in the Action, US Patent No. 6,267,958 was meant
`as a secondary reference in the double patenting rejection stated in item 11
`on page 8 of the Action, not as a primary reference. The primary reference
`intended, but not stated, in this rejection was US Patent No. 7,335,743.
`Finally, the definrtion of "isoform" and unexpected results were discussed.
`
`Withdrawal of Claims
`With the response filed January 9, 2009, Applicants added new claims
`81-98. Claims 87-98 now stand withdrawn. Applicants submit that claims 87-
`, . 90 were improperly withdrawn and respectfully request that they be reinstated
`and examined on the merits for the reasons outlined below.
`Claim 90 depends on claim 46, which was examined on the merits in
`the Action. Therefore, Applicant believes that it was mistakenly withdrawn
`and respectfully request that it be examined on the merits in the next Office
`Action.
`
`'
`
`PAGE 10/38 * RCVD AT 6/25/2009 6:27:45 PM [Eastern Da~ight TimeJ- SVR:USPTO·EFXRF·515 1 DNIS:2738300t CSID:2062330644 • DURATION (mm-ss):08·12
`
`8
`
`Ex. 2016-0008
`
`

`
`06/25/2009 15:28 FAX 2062330644
`
`A.c'\!GEN
`
`l(l)Oll
`
`A-1012-US-NP
`Amendment and Response
`
`Applicants also submit that claims 87-89 should be reinstated for the
`reasons explained below. These claims are similar in scope to examined
`claim 81, except that claim 87 recites the sequences of light chain variable
`regions, whereas claim 81 recites the sequences of heavy chain variable
`regions. Both claims 81 and 87 plainly recite in the same words all limitations
`in claims 46 other than the sequence-based limitations. With regard to
`sequences, claim 87 specifies that the antibody must contain certain light
`chain variable region sequences (SEQ ID N0:8, SEQ ID N0:12, SEQ 10
`N0:16, or SEQ 10 N0:31), whereas claim 81 specifies that the antibody must
`contain certain heavy chain variable region sequences (SEQ ID N0:6, SEQ
`ID N0:10, SEQ ID N0:14, or SEQ ID N0:30). Claim 46 recites the
`sequences of the various CDR sequences contained within these variable
`region sequences. Thus, claim 87 and dependent claims 88-89 should be
`reinstated and examined on the merits.
`
`Rejections under 35 USC§ 102
`Claims 46-54, 81, 84, and 85 stand rejected under 35 USC§ 102(e) as
`anticipated by U.S. Patent No. 7,335,743 (hereinafter the '743 patent) as
`evidenced by WO 92/08348 (hereinafter the 1348 publication). The Action
`states that all the sequences recited In the claims are taught in the '743
`patent. The Action further states that the '743 patent teaches a liquid
`formulation at a physiological pH or slightly lower comprising a buffer and
`sorbitol. It is further asserted that the '348 publication says that the
`physiological pH is 7.4. Action, page 3. The Action states that the "about" in
`"about 5.5 to about 6.5" as recited, for example, in the claim 46, broadens the
`claim such that It reads on "physiological pH (=pH 7.4) or slightly lower" as
`' taught in the '743 patent and that the '743 patent teaches a pH of 5.5 at
`column 42, lines 19-20. Further, the Action states that claim 47 is included in
`the rejection because '743 patent describes "antibody variants comprising
`glycosylatlon variants, "which inherently result in N-glycan sites." Action,
`pages 3-4. The Action states that the term "isoform" is defined on page 14 of
`the specification as a structural variant that varies "by the degree of
`
`PAGE 11138* RCvD AT 6/25/2009 6:27:45 PM (Eastern Daylight Time! A SVR:USPTO·EFXRF·515 A DNIS:2738300 • CSID:206233D644 t DURATION (mm-ss):08-12
`
`9
`
`Ex. 2016-0009
`
`

`
`06/25/2009 15:28 FAX 2062330644
`
`AMGEN
`
`~012
`
`A-1012-US-NP
`AunendlnentandResponse
`
`glycosylations (sic] and folding patterns" and that the '743 patent teaches
`antibody variants comprising "the various glycosylations and cysteine variants
`which play [sic] in various protein folding. n Action, page 4. The Action
`concludes that the antibodies described in the '743 patent inherently comprise
`multiple isoforms. The Action states that Applicants' arguments filed January
`9, 2009 were fully considered but not found persuasi~e. Action, page 4.
`Applicants disagree with the assertion that the pH range recited in the
`claims reads on "physiological pH or slightly lowe~ as taught in the '743
`patent. First, Applicants point out that "a pH from about 5.5 to about 6.5"
`(emphasis added) in claims 46, 55, 59, and 71 was amended to read "a pH
`from 5.5 to 6.5" (emphasis added) with the amendment filed January 9, 2009.
`Claims 81-98 have similar wording. Further, this amendment was pointed out
`on page 9 of the Remarks filed January 9, 2009. Nonetheless, the Action
`states, "Given that the claimed pH is from "about 5.5 to about 6.5" and the
`term "about" broadens the pH range to Include more than 6.5, the referenced
`uphysiological pH (=pH 7.4) or slightly lower" reads on the claimed limitation."
`Emphasis added, Action page 3. This language clearly indicates that
`Applicants' amendment was D.Qtconsidered. Applicant submits that the
`removal of "about" eliminates this basis for rejection and requests that the
`rejections based on anticipation be withdrawn.
`The Action asserts that the '743 patent teaches a pH of 5.5. The '743
`patent states, "In preferred embodiments, pharmaceutical compositions
`comprise Tris buffer of about pH 7.0-8.5, or acetate buffer of about pH 4.0-5.5
`... "' Action, page 4. All claims are now limited to "a pH from 5.7 to 6.5.n This
`limitation, which applies to all claims, is not disclosed expressly or Inherently
`by the '743 patent, and Applicants therefore request that the rejection of
`claims 46-54, 81, 84, and 85 as anticipated by the '743 patent be withdrawn.
`Although the Action does not assert that the limitation "wherein the
`purified preparation comprises at least three different isoforrns of the
`antibody" is explicitly taught in the '743 patent, it does assert that this
`limitation is inherent in the disclosure of the '743 patent based on the following
`logic. SEQ ID N0:17, a heavy chain amino acid sequence, contains two N-
`
`PAGE 12/38 * RCVD AT 6/25/2009 6:27:45 PM (Eastern Da~ight runeJ 1 SVR:USPTO·EFXRF·5/5 1 DNIS:27383DO 1 CSID:206233D644 *DURATION (mm-ss):D8·12
`
`10
`
`Ex. 2016-0010
`
`

`
`06/25/2009 15:28 FAX 2062330644
`
`A~'llGEN
`
`~013
`
`A-1012-US-NP
`Amendment and Response
`
`glycan sites, one at amino acid 28 and the other at amino acid 297. The
`Action asserts that SEQ ID N0:17 "inherently has 3 potential isoforrns- a)
`sialylated at the residue 28, b) sialylated at the residue 297 and c) sialylated
`at the residues 28 and 297." Action, page 4.
`Since the Examiner'::> comments are not consistent with the teachings
`concerning N-glycans in the Specification, Applicant offers the following
`clarifications for the Examiner. TheN-glycan site at 297 is the conserved N(cid:173)
`glycan site within the CH2 domain and data indicates that such sites are rarely
`sialylated. Specification, page 20, lines 9-14. Thus, this N-glycan site likely
`does not substantially contribute to the formation of isoforms in the antibodies
`described in the instant application. The N-glycan at position 27 could be
`sialylated, and the evidence in the instant application suggests that it is. As
`described in the specification, N-glycans are complex and heterogeneous,
`and a single N-glycan may generally include from zero to four sialic acid
`residues. Specification page 19, !ine34 to page 20, line 8 and Figure 1.
`Hence, more than three isoforms of an antibody comprising SEQ ID N0:17
`could ·potentially exist. Moreover, the data in Example 1 and Figure 2 of the
`Specification indicate that appreciable quantities of five isoforrns were
`detected.
`Applicant submits that an antibody preparation comprising at least
`three isoforms is not disclosed, explicitly or inherently, in the '743 patent. The
`Examiner has not asserted that the '743 patent explicitly discloses a purified
`preparation containing at least three isoforms. lnherency requires that the
`inherent characteristic necessarily be present in the thing described in the
`reference. Continental Can v. Monsanto, 948 F.2d 1264, 1268-1269 (CAFC
`· 1991). Adjustment of cell culture conditions can have profound effects on
`protein glycosylation, generally, and sialylation in particular. For example,
`Stark and Heath report that a kappa type light chain, which is normally
`glycosylated, is produced primarily in a nonglycosylated form when cells
`producing the light chain are cultured in a medium using pyruvate, rather than
`glucose or mannose, as a primary source of carbon and energy. Stark and
`Heath (1979), Arch. Biochem. Blophys. 192(2): 599-609 (in Information
`
`PAGE 13/38 * RCVD AT 6/25/2009 6:27:45 PM [Eastern Da~ight runej 3 SVR:USPTO·EFXRF·5/5 3 DNIS:2738300 * CSID:2062330644 *DURATION (mm-ss):08·12
`
`11
`
`Ex. 2016-0011
`
`

`
`06/25/2009 15:28 FAX 2062330644
`
`AMGEN
`
`!il~014
`
`A·1012.US-NP
`Amendment and Response
`
`Disclosure Statement submitted herewith). Thus, the addition of any sort of
`glycan to a protein produced by cultured cells can be substantially inhibited by
`changes in the culture medium. Similarly, Etcheverry and Ryll observed very
`substantial differences in the sialylation of proteins in response to various
`alterations of culture conditions. U.S. Patent No. 5,705,364, Examples I and
`Ill and accompanying figures and tables (in the Information Disclosure
`Statement submitted herewith). They comment, "Sialic acid content could be
`controlled over a wide range of values by adjusting the process parameters."
`U.S. Patent No. 5,705,364, col. 21, lines 11-13. Hence, variations in culture
`conditions can cause profound changes in the glycosylation, particularly
`sialylation, of proteins produced by cultured cells. Thus, it is not the case that
`every preparation of the antibodies as recited in the claims would necessarily
`include at least 3 isoforms. Moreover, Applicant's ability to produce purified
`preparations containing primarily one isoform clearly demonstrates that it is
`not a foregone conclusion that any purified preparation of the disclosed
`antibodies will surely contain at least three isoforms. Therefore, the '743 does
`not inherently disclose an antibody preparation comprising at least three
`different isoforms of an antibody. Thus, the '743 patent does not anticipate
`claims 46-54, 81, 84, and 85. Applicants therefore request withdrawal of
`these rejections.
`Applicants agree with the Examiner that the ?43 patent does disclose
`antibody variants with different numbers of N-glycan sites, which, necessarily,
`must have different amino acid sequences at column 24, but assert that these
`antibody variants are not "isoforms" as defined in the instant application. The
`Examiner has not pointed to any explicit discussion of isoforms in the '743
`patent, and, as discussed above, the '743 patent does not inherently disclose
`"at least three isoforms." An "isoform" is defined in the instant specification as
`subset of the term "structural variant." Specification, page 14, lines 1-24. A
`' purified preparation may contain plural "structural variants" even though
`"substantially all of the molecules of the antibody in the purified preparation
`have identical amino acid sequences." Specification, page 14, lines 9-10.
`Further. "[n]ot included among "structural variants," as meant herein, are
`
`PAGE 14/38 * RCVO AT 6/25/2009 6:27:45 PM [Eastern Da~ight TimeJ• SVR:USPTO·EFXRF·515 ~ DNIS:2738300 ~ CSID:2062330644 ~DURATION (mm-ss):0&-12
`
`12
`
`Ex. 2016-0012
`
`

`
`06/25/2009 15:28 FAX 2062330644
`
`Ac'\fGEN
`
`l(l)015
`
`A-1012-US-NP
`Amendment and Response
`
`variants with drfferent amino acid sequences such as, for example, variants
`lacking C-terrninallysines or cyclized N-terrninal glutamines." Specification,
`page 14, Jines 12-14. Structural variants having different charges due to
`differential sialylation are termed ''isoforms." Specification, page 14, fine 24.
`Thus, the "isoforms• described in the instant application are not amino acid
`sequence variants like the glycosylation variants described in the '7 43 patent
`at column 24, lines 3-33.
`The Action concludes, "As Applicant differentiates an isoform from an
`antibody variant, one aspect of generating antibody variants as in col. 24 of
`the '743 patent cannot be presented as a general method of producing
`isoforrns." Action, page 5. Applicants are uncertain how to interpret this
`statement and request clarification, as it seems to be the basis for concluding
`that the '743 patent does meet the limitation: "wherein the purified preparation
`comprises at least three different isoforrns of the antibody." In any event,
`Applicants request the withdrawal of the rejection under 35 USC §102
`because the '743 patent does not disclose, expressly or inherently, purified
`preparations of antibodies comprising at least three isoforms.
`
`Rejections under 35 USC § 103
`Claims 55-58 and 81-83 stand rejected as obvious over the '743 patent
`in view of U.S. Patent No. 6,267,958 (hereinafter the '958 patent). The Action
`states that the '958 patent teaches that a histidine buffer at pH 6 stabilizes a
`monoclonal antibody, which may bind to various targets and may be
`humanized. The Action states that it would be obvious to stabilize an
`antibody having a sequence recited in the Instant claims with histidine buffer
`because the '958 patent teaches that a histidine buffer stabilizes any
`antibody.
`A proper prima facie case of obviousness has not been made because
`the two cited references do not disclose, expressly or inherently, the limitation
`""wherein the purified preparation comprises at least three different isoforms
`of the antibody," which applies to all claims. As discussed above, the '743
`patent does not disclose this limitation either expressly or inherently, and the
`
`PAGE 15/38 * RCVD AT 6/2512009 6:27:45 PM (Eastern Da~ight TimeJ• SVR:USPTO·EFXRF·515 • DNIS:2738300 • CSID:2062330644' DURATION (mm-ss):08·12
`
`13
`
`Ex. 2016-0013
`
`

`
`06/25/200~ 15:29 FAX 2062330644
`
`AMGEN
`
`~016
`
`A-1012-US-NP
`Amendment and Response
`
`Action does not assert that the '958 patent discloses this limitation.
`Therefore, a proper prima facie case of obviousness has not been made, and
`Applicants therefore request withdrawal of these rejections.
`Moreover, the claims 55-58 and 81-83 are a narrow species with
`regard to pH with respect to the entire disclosures of the cited references and
`are therefore are patentably distinct from the cited references. A species is
`patentable over a previously disclosed genus that encompasses the species.
`In re Baird, 16 F.3d 380 (CAFC 1994). The cited references disclose many
`different pHs for pharmaceutical compositions, including pH 7.0-8.5 and pH
`4.0-5.5, as well as pH 5, 6, 7, 4-8, and 5-7. The '743 patent col. 42, lines 17-
`19; the '958 patent col. 4, line 4 to col. 5, line 59, col. 15, lines 1-3. Given this
`broad array of pHs disclosed in the references, the selection of the particular.
`claimed range, that is, 5.7-6.5, is patentably distinct, especially in view of the
`unexpected results discussed below. Thus, a pharmaceutical composition
`comprising ~ particular purified preparation containing at least three lsoforms
`at a pH from 5.7 to 6.5 is nonobvious over the cited references, and
`Applicants therefore request the withdrawal of the obviousness rejection.
`Also, claims 55-58 and 81-83 are nonobvious over the cited references
`because numerous references teach away from the claimed invention.
`Applicants submit that the Examiner must consider such references because
`rebuttal evidence, including references that teach away from the claimed
`invention, must be considered. See, e.g., In re Sullivan, 498 F.3d 1345, 1351
`(CAFC 2007). There are many references disclosing antibody formulations at
`pH~s other than the range recited In the Instant claims. For example, U.S.
`Patent No. 6,171,586 (of record) teaches that pH 5 is preferable to pH 6 for
`stabilizing two antibodies that were tested fairly extensively. Its claims are
`directed to formulations of any antibody having a pH of 5 or a pH from 4.8-5.5.
`U.S. Patent No. 6,171,586, Examples 1 and 2 (col. 24, line 28 to col. 46, line
`32), claims 1, 23, and 24. Similarly, U.S. Patent No. 5,237, 054 (of record)
`teaches the use of a broad pH range between 5.0 and 9.0 and a narrower
`range between 7.0 and 8.5. U.S. Patent No. 5,237,054, col. 2, lines 49-51.
`This narrower range teaches away from the range of 5.7 to 6.5, and the range
`
`I
`I
`
`14
`
`PAGE 16138 1 RCVD AT 6125/2009 6:27:45 PM [Eastern Da~ight Time]~ SVR:USPTO·EFXRF·5/5 1 DNIS:2738300 ~ CSID:2062330644 1 DURATION (mm-ss):08·12
`
`Ex. 2016-0014
`
`

`
`06/25/2009 15:29 FAX 2062330644
`
`A.'IGEN
`
`~017
`
`A-1012-US-NP
`Amendment and Response
`
`of 5.7 to 6.5 is a patentable species over the broad range of pH 5 to 9,
`especially in view of the unexpected results discussed below. Thus, these
`references teach away from the claimed pH range. In fact, since a variety of
`references teach a huge range of pHs for antibody formulations generally (see
`Information Disclosure Statement filed November 19, 2007), one of skill in the
`art would have no meaningful direction in selecting the optimal pH for
`stabilizing the particular antibodies whose sequences are recited in the instant
`claims. Thus, the claimed pH range for these particular antibodies is
`nonobvious.
`Further, claims 55-58 and 81-83 are nonobvious over the cited
`references because there was no expecta