`_____________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
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`BIOEQ IP AG
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`Petitioner
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`v.
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`GENENTECH, INC.
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`Patent Owner
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`_____________________
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`Case No. IPR2016-01608
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`U.S. Patent No. 6,716,602
`_____________________
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`PETITIONER'S REPLY TO PATENT OWNER'S PRELIMINARY
`RESPONSE
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`Mail Stop "PATENT BOARD"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`Petitioner’s Reply to Patent Owner’s
` Preliminary Response IPR2016-01608
`Petitioner submits this Reply to address corrections to claims 14, 16, 21, 25,
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`28, and 38 of the '602 patent (BEQ1001), newly introduced by Patent Owner's
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`December 1, 2016 Request for Certificate of Correction Under 35 U.S.C. § 254
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`(EX2009). Petitioner confirms that its Petition (Paper 3) challenges claims 14, 16,
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`25, 28, and 38 as-issued, and this Reply, authorized by the Board, demonstrates
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`how the claims as presented in EX2009 are unpatentable. Petitioner also seeks to
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`add claim 21 to its original Ground 1—but for Patent Owner's dilatory efforts to
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`file its Request, Petitioner would have challenged claim 21 in its Petition.
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`I.
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`Seeger anticipates claims 16, 25, and 28
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`Seeger anticipates claims 16, 25, and 28—amended or not. Amended claims
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`16 and 25 include the same step (b) and same terminal "wherein" clause recited in
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`claim 1, modified to refer to "antibody, growth factor, or protease" (claim 16) or
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`"mammalian polypeptide" (claim 25). (EX2009, 2, 3, 7; BEQ1001, 18:23-24.)
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`Claim 28 would depend from claim 25, not 27. (EX2009, 3, 7; BEQ1001, 20:1-2.)
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`As explained in the Petition and Declaration (BEQ1002), Seeger anticipates claims
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`16, 25, and 28. (Paper 3, 28-41; BEQ1002, ¶¶68-74; 88-89; 98-99; 103-104.)
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`Seeger discloses every element of claims 16, 25, and 28, arranged as claimed
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`and in a manner enabling to a POSA. (Paper 3, 28-41; BEQ1002, ¶¶68-74; 88-89;
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`98-99; 103-104.) The Petition and Declaration show that Seeger describes
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`inducible expression of mammalian growth factor bFGF in recombinant host cells,
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`1
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`by first culturing the cells "under conditions of high metabolic and growth rate,"
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`Petitioner’s Reply to Patent Owner’s
`Preliminary Response in IPR2016-01608
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`and then "reducing the metabolic rate of the host cells at the time of induction" by
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`reducing the amount of available glucose. (Paper 3, 29, 32-35; BEQ1010, 951:2:1,
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`950:2, Figure 3; BEQ1002, ¶¶4, 29, 52-57, 68-69, 71-72, 76). Dr. Rosenberg's
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`calculations show that reducing available glucose resulted in a reduction in the host
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`cells' specific glucose uptake rate (GUR). (Paper 3, 34-35; EX1002, ¶56.) Indeed
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`"a reduction in [] GUR represents a reduction in the metabolic rate." (Paper 3, 34-
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`35; BEQ1002, ¶71.) Thus, the Petition shows that Seeger reduced metabolic rate of
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`the cells at the time of induction.
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`Genentech posits that Dr. Rosenberg's GUR calculation "does not reflect the
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`true metabolic rate" of Seeger's cells because it "ignores the effects of the
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`temperature increase on the metabolic rate." (Paper 9, 27-28). Genentech is wrong.
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`As Dr. Rosenberg explains, "a metabolic rate of a bacterial cell is closely related to
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`a rate with which the cell consumes and oxidizes [] glucose," e.g., GUR.
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`(BEQ1002, ¶37; Paper 3, 8.) And, "a magnitude of change in GUR [] can serve as
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`a proxy for the magnitude of change in a metabolic rate." (BEQ1002, ¶81; Paper 3,
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`41.) Thus, GUR is a "read-out" of the cells' metabolic rate. It accounts for any
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`external factors that influence the metabolic rate—amount of supplied glucose,
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`oxygen, or temperature. Dr. Rosenberg calculated GUR throughout Seeger's fed-
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`batch phases, i.e., before and after the temperature change that induced bFGF
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`2
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`expression, thus accounting for temperature. (Paper 3, 34-35; BEQ1002, ¶56.)
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`Petitioner’s Reply to Patent Owner’s
`Preliminary Response in IPR2016-01608
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`Indeed, “when the temperature was raised from 30° to 42°C [in Seeger’s method],
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`there was a reduction in the actual growth rate.” (BEQ1020, 64.)
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`Seeger also teaches the added "wherein" clause of claims 16 and 25. (Paper
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`3, 36-37; BEQ1002, ¶¶43, 55, 57, 73.) This clause imparts no patentable weight—
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`it is an intended outcome. (Paper 3, 20-21, 36.) Indeed, Genentech itself admits
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`unequivocally that "a reduction in metabolic rate at the time of induction will result
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`in an increased yield of properly folded polypeptide." (Paper 9, 16, emphasis
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`added.) But even if considered a limitation, Seeger teaches the "wherein" clause.
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`Dr. Rosenberg explains that shifting the exponential glucose feeding rate at
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`the time of induction resulted in an increased bFGF expression in a soluble
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`fraction—from zero without the shift. (Paper 3, 37; BEQ1002, ¶¶43, 57, 73.) A
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`POSA would have understood that the soluble fraction contained properly-folded
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`bFGF. (Paper 3, 37; BEQ1002, ¶73.) And Genentech agrees: "a POSA would have
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`understood that the soluble fraction of a cell lysate would contain properly folded
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`polypeptide of interest." (Paper 9, 15, emphasis added.) Indeed, Seeger’s goal was
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`to “optimize the production of soluble and thus biologically active bFGF.”
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`(BEQ1020, 80.) Claims 16 and 25 do not require a percentage of properly-folded
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`polypeptide—any increase in properly folded polypeptide is within the scope of
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`claims 16 and 25.
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`3
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`II.
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`Petitioner’s Reply to Patent Owner’s
`Preliminary Response in IPR2016-01608
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`Seeger renders obvious claims 14 and 38
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`The proposed corrections to claims 14 and 38 leave intact the phrase "the
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`polypeptide is selected from the group consisting of an Fab'2 antibody and an Fab
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`antibody." (EX2009, 7; BEQ1001, 18:52-54, 20:27-29; BEQ1002, ¶¶18:52-54,
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`20:27-29.) The Petition and Dr. Rosenberg's Declaration confirm that a POSA
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`reading Seeger and Cabilly, would have had a reason to produce Fab antibody
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`fragments as recited in claims 14 and 38, with a reasonable expectation of success.
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`(Paper 3, 53-57; BEQ1002, ¶¶144-163.) Genentech does not dispute these
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`teachings, and instead argues that Seeger teaches away. (Paper 9, 37.) But it does
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`not. Teaching away is measured in the art as a whole. Medichem, S.A. v. Rolabo,
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`S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2016). And Seeger clearly describes
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`decreasing the exponential feeding rate—and thus the metabolic rate—at the time
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`of induction to produce soluble, properly-folded bFGF protein.
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`III. Seeger anticipates claim 21
`Amended claim 21 would depend from claim 20 instead of claim 19.
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`(EX2009, 3, 4, 7; BEQ1001, 19:11-12.) The Petition did not challenge claim 19
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`but did challenge claim 20. (Paper 3, 40.) Because Patent Owner now seeks to
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`amend claim 21, Petitioner requests that the Board also institute IPR of claim 21.
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`Claim 21 states that "the carbon/energy source is glucose." (EX2009, 3, 4;
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`BEQ1001, 19:11-12.) Seeger teaches a glucose carbon/energy source, anticipating
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`4
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`claim 21. (Paper 3, 28; BEQ1002, ¶¶77-78, 103-104.) And Petitioner challenged
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`Petitioner’s Reply to Patent Owner’s
`Preliminary Response in IPR2016-01608
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`the same limitation in claims 4 and 28 (Paper 3, 40-41; BEQ1002, ¶¶77-78):
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`Challenged
`dependent claim
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`Depends from
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`Depends from
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`4
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`3
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`1
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`21
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`28
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`20
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`27
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`16
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`25
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`Seeger (BEQ1010) describes each element:
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`949:1:1, 950:2, Figure 3 legend, 952:1, Table 2
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`951:2:1-2, 950:2, Figure 3 legend
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`947, Abstract, 948:1:3, 948, Table 1, 948:2:1-3,
`950:2, 951:2:1-2, 952:1:1-952:2:2, 953:1:2
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`The Board has discretion to find claim 21 unpatentable in view of the prior
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`art and information provided in the Petition.[1] Cuozzo Speed Techs, LLC v. Lee,
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`136 S. Ct. 2131, 2140 (2016). Any prejudice to Patent Owner by such a finding is
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`minimal because the Petition provided notice that a glucose carbon source is in the
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`art. The same cannot be said for Petitioner. Had Patent Owner corrected claim 21
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`in the more than 12 years since issuance, the Petition would have included the
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`claim. It is manifestly unjust to reward Patent Owner’s delay by not adding claim
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`21 here.
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`Respectfully submitted,
`STERNE, KESSLER, GOLDSTEIN & FOX P.L.L.C.
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`Date: December 9, 2016
`1100 New York Avenue, N.W.
`Washington, DC 20005-3934
`(202) 371-2600
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`[1] The excess claim fee ($600) for claim 21 is paid with this filing.
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`l
`Deborah A. Sterling
`Registration No. 62,732
`Lead Attorney for Petitioner
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`5
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`Petitioner’s Reply to Patent Owner’s
` Preliminary Response IPR2016-01608
`CERTIFICATION OF SERVICE (37 C.F.R. §§ 42.6(e), 42.105(a))
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`The undersigned hereby certifies that the above-captioned "Petitioner’s
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`Reply to Patent Owner’s Preliminary Response" was served in its entirety on
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`December 9, 2016, upon the following counsel of record via electronic mail:
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`jengordon@paulweiss.com
`sbalcof@paulweiss.com
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`PAUL, WEISS, RIFKIND,
`WHARTON &
`GARRISON LLP
`1285 Avenue of the Americas
`New York, NY 10019
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`
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`Respectfully submitted,
`STERNE, KESSLER, GOLDSTEIN & FOX P.L.L.C.
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`l
`Deborah A. Sterling
`Registration No. 62,732
`Lead Attorney for Petitioner
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`dball@paulweiss.com
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`
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`PAUL, WEISS, RIFKIND,
`WHARTON &
`GARRISON LLP
`2001 K Street, NW
`Washington, DC 20006-1047
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`
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`Date: December 9, 2016
`1100 New York Avenue, N.W.
`Washington, DC 20005-3934
`(202) 371-2600