UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`PHIGENIX, INC.
`
`Petitioner
`
`IMMUNOGEN, INC.
`
`Patent Owner
`
`Case IPR2014—00676
`
`Patent 8,337,856 B2
`
`PETITIONER PHIGENIX, INC.’S REPLY TO PATENT OWNER
`IMMUNOGEN, INC’S PATENT OWNER RESPONSE TO THE PETITION
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`US. Patent and Trademark Office
`
`PO. Box 1450
`
`Alexandria, VA 223 13— 1450
`
`

`

`PETITIONER PHIGENIX, INC.’S REPLY TO PATENT OWNER IMMUNOGEN, INC.’S PATENT
`OWNER RESPONSE TO THE PETITION
`CASE IPR2014-00676
`
`TABLE OF CONTENTS
`
`Patent Owner (“PO”)’s Response Fails To Overcome The Strong Prima
`Facie Case Of Obviousness ............................................................................ 1
`
`II.
`
`1—8 of US. Patent No. 8,337,856 Are
`All Limitations Of Claims
`Disclosed In Chari 1992 In View Of The HERCEPTIN® Label And The
`
`Combination Renders The Claims Obvious ................................................... 3
`
`A.
`
`HERCEPTIN® Had Acceptable Toxicity Contrary To PO’s
`Arguments ............................................................................................. 4
`
`B.
`
`Pai-Scherf 1999 Is Not Relevant As It Discloses A Fusion Protein
`
`Not An Antibody-Drug Conjugate ....................................................... 4
`
`C. Mouse Xenograft Models Can Be Used Effectively To Study
`Antigen-Specific Drug Targeting ......................................................... 6
`
`D.
`
`E.
`
`F.
`
`Herceptin Resistance Would Not Discourage Use Of An Anti-
`HER2 Immunoconjugate ...................................................................... 8
`
`Reasonable Expectation Of Success For An Additive Effect
`Between huMAB4D5—8 And Maytansinoids ..................................... 11
`
`POSA Knows That A Maytansinoid Linked To Herceptin Via A
`Non-Cleavable Linker Is Highly Cytotoxic to ErbB2~Expressing
`Breast Cancer Cells As Shown In Chari 1992 ................................... 12
`
`G. Motivation Existed To Humanize The Antibody In The Conjugate
`Of Chari 1992 To Reduce Irnrnunogenicity As Chari 1992
`Expressly Teaches And PO’s Expert Admits ..................................... 17
`
`III.
`
`Alleged Secondary Considerations Of Non—Obviousness Lack A Nexus
`To The Claimed Features Of Claims 1—8 Of The ‘856 Patent ...................... 17
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`T11
`
`No Unexpected Results ...................................................................... 18
`
`The Alleged Unexpected Results Are Not Commensurate With
`The Scope Of The Claims .................................................................. 19
`
`The Alleged Unexpected Results Do Not Inherently Flow From
`The Original Disclosure ...................................................................... 20
`
`No Long—Felt, Unmet Need ................................................................ 20
`
`No Nexus Between Industry Praise And The Claimed Features ....... 21
`
`No Nexus Between Commercial Success And The Claimed
`
`Features ............................................................................................... 22
`
`ii
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`PETITIONER PHIGENIX, INC. ’8 REPLY TO PATENT OWNER IMMUNOGEN, INC. ’S PATENT
`OWNER RESPONSE TO THE PETITION
`CASE IPR2014-00676
`
`G.
`
`The Alleged Secondary Considerations Have No Nexus To The
`Claimed Invention Which PO Admitted Was Not Even Conceived
`
`As Of The Priority Date Of The ‘856 Patent...................................... 23
`
`IV.
`
`Conclusion .................................................................................................... 24
`
`iii
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`

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`PETITIONER PHIGENIX, INC.’S REPLY TO PATENT OWNER IMMUNOGEN, INC.’S PATENT
`OWNER RESPONSE TO THE PETITION
`CASE IPR2014-00676
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`Cases
`
`Asysz‘ Techs., Inc. v. Emz‘rak, Inc.,
`544 F.3d 1310 (Fed. Cir. 2008) .......................................................................... 19
`
`In re Grasselli,
`
`713 F.2d 731 (Fed. Cir. 1983) ............................................................................ 19
`
`In re Gurley,
`27 F.3d 551 (Fed. Cir. 1994) .............................................................................. 13
`
`In re Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .......................................................................... 22
`
`In re Khelghatian,
`364 F.2d 870 (1966) ........................................................................................... 20
`
`In re Kubin,
`
`561 F.3d 1351 (Fed. Cir. 2009) ............................................................................ 3
`
`Ormco Corp. v. Align Tech., Inc.,
`463 F.3d 1299 (Fed. Cir. 2006) .......................................................................... 22
`
`Perfect Web Techs., Inc. v. InfoUSA, Inc.,
`587 F.3d 1324 (Fed. Cir. 2009) .......................................................................... 21
`
`In re Peterson,
`
`315 F.3d 1325 (Fed. Cir. 2003) .......................................................................... 19
`
`Power-One, Inc. v. Artesyn Techs., Inc.,
`599 F.3d 1343 (Fed. Cir. 2010) .......................................................................... 21
`
`Proctor & Gamble Co. v. Teva Pharms, USA, Inc.,
`
`566 F.3d 989 (Fed. Cir. 2009) .............................................................................. 2
`
`.
`Tokai Corp. v. Easton Enters., Inc.,
`632 F.3d 1358 (Fed. Cir. 2011) .......................................................................... 22
`
`iv
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`

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`PETITIONER PHIGENIX, INC.’S REPLY TO PATENT OWNER IMMUNOGEN, INC.’S PATENT
`OWNER RESPONSE TO THE PETITION
`CASE IPR2014-00676
`
`1.
`
`Patent Owner (“PO”)’s Response Fails To Overcome The Strong Prima
`Facie Case Of Obviousness
`
`The combination of Chari 1992 (Ex. 1012) and the HERCEPTIN® Label
`
`(Ex. 1008) teaches or suggests each and every limitation recited in Claims 1—8 of
`
`US. Patent No. 8,337,856 (“the ‘856 Patent”). Chari 1992 discloses an
`
`immunoconjugate comprising a maytansinoid conjugated to an anti—ErbB2—
`
`antibody (Ex. 1012, Fig. 2) as recited in Claim 1. Chari 1992 also discloses that
`the maytansinoid is DM1 and that the antibody is chemically linked to the
`
`maytansinoid via a disulfide or thioether group (Ex. 1012, Fig. 2), as recited in
`
`Claim 2 of the ‘856 Patent. The immunoconjugate of Chari 1992 may comprise
`
`from 3—5 maytansinoid molecules per antibody molecule (Ex. 1012, p. 129, bottom
`
`right 001., Table 2), as recited in Claim 3 of the ‘856 patent. The antibody and the
`
`maytansinoid were conjugated by a chemical linker selected from SPDP or SMCC
`(Ex. 10112, p. 128, bottom right col., Fig. 2), as recited in Claims 4 and 6-8 of the
`
`‘856 Patent.
`
`While Chari 1992 expressly suggests humanizing the murine antibody, Chari
`
`1992 does not explicitly disclose huMAB4D5-8 (recited in Claim 1 of the ‘856
`
`Patent) or a pharmaceutically acceptable carrier (recited in Claim 5 of the ‘856
`
`Patent). However, the HERCEPTIN® Label describes the clinical use of
`
`huMAB4D5—8 (i.e., HERCEPTIN®), which is described as being indicated for the
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`

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`PETITIONER PHIGENIX, INC.’S REPLY TO PATENT OWNER IMMUNOGEN, INC.’S PATENT
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`CASE IPR2014-00676
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`treatment of patients with metastatic breast cancer (Ex. 1008, p.1, right col.).
`
`HERCEPTIN® Label also describes the injection of HERCEPTIN® with a
`
`pharmaceutically acceptable carrier (Bacteriostatic Water for Injection, Ex. 1008,
`
`p.1, left 001.). Chari 1992 teaches that the anti—ErbB2 antibody—maytansinoid
`
`conjugates exhibited high antigen—specific cytotoxicity for cultured human breast
`
`cancer cells (including with non-cleavable SMCC linkers as will be discussed
`
`below), low systemic toxicity in mice, and good pharmacokinetic behavior (Ex.
`
`1012, Abstract). Chari 1992 states that “[t]he development of ‘humanized’
`
`antibodies will offer an opportunity to produce drug conjugates that would be less
`
`immunogenic than similar conjugates of murine antibodies” (Ex. 1012 at 130, first
`
`001.). Therefore, it would have been obvious to an ordinarily skilled artisan, at the
`
`time of filing of the ‘856 Patent, to simply substitute the mouse mAb TA.1 in the
`
`anti—ErbB2 antibody—maytansinoid conjugate of Chari 1992 with the FDA—
`
`approved, humanized anti—ErbB2 mAb huMAB4D5—8 to produce a maytansinoid—
`
`huMAB4D5-8 conjugate based on the teachings of Chari 1992 and the
`
`HERCEPTIN® Label.
`
`As the Board stated (Paper 11 at 20), the validity of composition claims is
`
`assessed based on whether, “a person having ordinary skill in the art would have
`
`had ‘reason to attempt to make the composition’” .
`
`.
`
`. and
`
`6“
`
`a reasonable
`
`expectation of success in doing so.’” Proctor & Gamble Co. v. Teva Pharms,
`
`2
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`

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`PETITIONER PHIGENIX, INC.’S REPLY TO PATENT OWNER IMMUNOGEN, INC.’S PATENT
`OWNER RESPONSE TO THE PETITION
`CASE IPR2014-00676
`
`USA, Inc., 566 F.3d 989, 995 (Fed. Cir. 2009); see also In re Kubin, 561 F.3d
`
`1351, 1360-61 (Fed. Cir. 2009). Therefore, the question before the Board is
`
`whether an ordinary artisan would have had reason to make the recited antibody—
`
`drug conjugates of Claims 1-8 of the ‘856 Patent before the effective filing date,
`
`and reasonably expect success. PO’s attempt to overcome the primafacie case
`
`relies on strained arguments and flawed analysis, in particular its misinterpretation
`
`of Fig. 3C of Chari 1992 (EX. 1012), as discussed below. Furthermore, PO’s
`
`arguments regarding secondary considerations of obviousness fail as there is no
`
`nexus to the features of the claims.
`
`In light of the concrete, specific teachings of Chari 1992 and the
`
`HERCEPTIN® Label, in view of Rosenblum 1999 (Ex. 1018) and Pegram 1999
`
`(Ex. 1020), and other art before the Board, ordinarily skilled artisans in this field
`
`had every motivation to seek and expect success in making the antibody—drug
`
`conjugate of the Claims 1-8 of the ‘856 Patent.
`
`II.
`
`All Limitations Of Claims 1-8 of US. Patent No. 8,337,856 Are
`Disclosed In Chari 1992 In View Of The HERCEPTIN® Label And The
`
`Combination Renders The Claims Obvious
`
`As the Board stated (Paper 11 at 20), there is no dispute that Chari 1992
`
`discloses all limitations recited in Claims 1-8 of the ‘856 Patent, except for
`
`specifying huMAB4D5—8 or a pharmaceutically acceptable carrier, which are both
`
`

`

`PETITIONER PHIGENIX, INC.’S REPLY TO PATENT OWNER IMMUNOGEN, INC.’S PATENT
`OWNER RESPONSE TO THE PETITION
`CASE IPR2014-00676
`
`V disclosed in the HERCEPTIN® Label (Ex. 1008). PO’s many strained attempts to
`
`cloud this indisputable fact should be rejected for the reasons discussed below.
`
`A.
`
`HERCEPTIN® Had Acceptable Toxicity Contrary To PO’s
`Arguments
`
`PO argues that HERCEPTIN® somehow had associated toxicity concerns.
`
`(PO’s Response, pp. 3-14). However, as an FDA approved antibody,
`
`HERCEPTIN® had already been subject to substantial FDA clinical trials to test its
`
`toxicity in humans. As a result, the FDA had already determined that any potential
`
`toxic effects related to HERCEPTIN® occurred at a clinically acceptable level.
`
`Thus, the skilled artisan would be directly led to combine Chari 1992 and the
`
`HERCEPTIN® label to obtain Claims 1~8. Moreover, to the extent that PO raises
`
`toxicity concerns related to maytansine, these concerns are related to unconjugated
`
`maytansine, and not relevant to the use of maytansine as a component of antigen—
`
`specific antibody—drug conjugates. Similarly, as discussed below, PO’s arguments
`
`regarding toxicity concerns related to HERZ immunoconjugates also rely on
`
`reports that are not relevant to the action of antibody-drug conjugates.
`
`B.
`
`Pai-Scherf 1999 Is Not Relevant As It Discloses A Fusion Protein
`
`Not An Antibody-Drug Conjugate
`
`PO’s Response relies on Pai—Scherf 1999 (Ex. 2029) to suggest some
`
`unacceptable hepatotoxicity (PO’s Response, pp. 4—7, 9, 13). However, Pai—Scherf
`
`1999 discusses toxic effects associated with a single-chain recombinant
`
`4
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`

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`PETITIONER PHIGENIX, INC.’S REPLY TO PATENT OWNER IMMUNOGEN, INC.’S PATENT
`OWNER RESPONSE TO THE PETITION
`CASE IPR2014-00676
`
`immunotoxin, not an antibody-drug conjugate. Pai~Scherf 1999 concerns “a
`
`single—chain immunotoxin (erb—38) that contains the FV portion of monoclonal
`
`antibody e23 fused to a truncated form of Pseudomonas exotoxin A” (Ex. 2029,
`
`Abstract). According to Pai—Scherf 1999, “[t]he gene encoding PE38 was fused to
`
`a gene encoding the FV portion of MAb e23 to form erb~38” (Ex. 2029 at 2311,
`
`col. 2). By contrast, as PO’s expert Dr. Pietersz admitted, antibody—drug
`
`conjugates are formed by “a chemical reaction, you would have the antibody in a
`
`solution or a buffer, and then you would react - - you’ve got SMCC, a chemical
`
`you can buy, and you would react [maytansine]” (Ex. 1036 at 2029-13). Thus, the
`
`immunotoxin discussed in Pai—Scherf 1999 has a fundamentally different chemical
`
`structure to an antibody-drug conjugate. Furthermore, for the single—chain
`
`recombinant immunotoxin discussed in Pai-Scherf 1999, the antibody fragment
`
`had been altered so that “the inherently unstable FV heterodimer (composed of VH
`
`and V1) is stabilized by a disulfide bond engineered between structurally conserved
`
`framework positions of VH and VL” (Ex. 2046, Abstract). Therefore, the single—
`
`chain recombinant immunotoxin used in Pai—Scherf 1999 owes its properties to
`
`unique structural features introduced into its design.
`
`PO makes no showing that an antibody-drug conjugate formed by
`
`chemically linking a whole humanized antibody to a small molecule cytotoxic drug
`
`would be expected to perform in the same manner as a recombinant protein that
`
`5
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`

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`PETITIONER PHIGENIX, INC.’S REPLY TO PATENT OWNER IMMUNOGEN, INC.’S PATENT
`OWNER RESPONSE TO THE PETITION
`CASE IPR2014-00676
`
`fuses an antibody fragment with a truncated bacterial toxin, as disclosed by Pai—
`
`Scherf 1999. The single-chain immunotoxin of Pai-Scherf 1999 does not use a
`
`chemical linker, whether a disulfide linker or an SMCC linker, to join its antibody
`
`fragment to its bacterial toxin fragment. Although the “PE toxin contains ‘an
`
`internal disulfide bond within the toxin itself’” (PO’s Response, p. 33), this
`
`disulfide bond is an internal structural feature of the PE toxin, and therefore cannot
`
`and does not serve as a chemical linker. In this respect, in discussing the effects of
`
`the structural features of PE toxins, Vitetta 1993 (Ex. 2144) states that “[b]locked
`
`immunotoxins consisting of ricin, DT and Pseudomonas exotoxin routinely cause
`
`hepatotoxicity” (Ex. 2144, p. 255, col. 2). Accordingly, the results of Pai-Scherf
`
`1999 are in line with known problems regarding the hepatotoxicity of PE
`
`immunotoxins. PO has not shown any relevance to the performance of a
`
`maytansinoid—antibody drug conjugate.
`
`C. Mouse Xenograft Models Can Be Used Effectively To Study
`Antigen-Specific Drug Targeting
`
`PO alleges that mouse xenograft models could not be used to study
`
`antibody-dependent drug targeting because mouse cells do not express HERZ
`
`(ErbB2) (PO’s Response, pp. 10—13). However, this ignores the teachings of
`
`references like Rosenblum 1999 (Ex. 1018), which elegantly address the issue by
`
`looking at cytotoxic effects in tumor cells expressing different levels of ErbB2.
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`

`

`PETITIONER PI-IIGENIX, INC.’S REPLY TO PATENT OWNER IMMUNOGEN, INC.’S PATENT
`OWNER RESPONSE T0 THE PETITION
`CASE IPR2014-00676
`
`Rosenblum 1999 states that for an ErbB2 targeted antibody—drug conjugate “tumor
`
`cells expressing HER-Z/neu [ErbB2] at levels less than 500,000 sites/cell were
`
`relatively insensitive to the cytotoxic effects of immunotoxin .
`
`.
`
`. Therefore,
`
`normal tissues expressing relatively low levels of HER-2/neu should not be
`
`affected by this construct, whereas overexpressing tumor cells should remain
`
`sensitive” (Ex. 1018, p. 871). Therefore, contrary to PO’s assertions, one of
`
`ordinary skill would have been well aware that an antibody—drug conjugate
`
`targeted at ErbB2 could target tumor cells, while normal cells expressing low
`
`levels of the receptor would be left unharmed in vivo.
`
`Given that HERCEPTIN® had already been approved by the FDA, one of
`
`ordinary skill could reasonably expect that a HERCEPTIN®-maytansinoid
`
`antibody-drug conjugate would be effective in targeting tumor cells and that such a
`
`conjugate could be satisfactorily tested in mouse xenograft models. PO’s own
`
`expert, Dr. Pietersz admitted that mouse models are used because they “give[] you
`
`an idea that it has to penetrate the tumor. It has to be able to survive in the serum.
`
`So you don’t want to spend a lot of money doing clinical trials without getting
`
`some idea. And that’s what it’s used for” (Ex. 1036 at 55:17—22). Indeed, in
`
`criticizing xenograft models PO ignores that the disclosure of the ‘856 Patent itself
`
`relies on work done in mouse xenograft models (Ex. 1001, col. 46, 11. 39—42).
`
`

`

`PETITIONER PHIGENIX, INC.’S REPLY TO PATENT OWNER IMMUNOGEN, INC.’S PATENT
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`Moreover, as PO’s expert stated, a successful antibody—drug conjugate
`
`requires “a balance of anticancer efficacy versus toxicity” (Ex. 1036 at 62: 12-13).
`
`In this respect, Morgan 1990 (Ex. 1021) specifically disclosed that the use of an
`
`SMCC—linked conjugate “proved to have .
`
`.
`
`. favorable in vivo properties compared
`
`to disulfide conjugates: (1) a longer half-life in serum; (2) increased tumor
`
`localization: and (3) reduced toxicity” (Ex. 1021, Abstract). Accordingly, one of
`
`ordinary skill would have been directly motivated to use an SMCC—linked
`
`conjugate as claimed as this was disclosed by Chari 1992 (Ex. 1012) for reduced
`
`toxicity and other favorable in vivo properties.
`
`D.
`
`Herceptin Resistance Would Not Discourage Use Of An Anti-
`HERZ Immunoconjugate
`
`PO heavily relies on its expert’s theories that (1) an extracellular domain
`
`shed from the ErbB2 receptor would somehow interfere with HERCEPTIN®
`
`binding; or (2) that a naturally occurring variant of the ErbB2 receptor would not
`
`enable HERCEPTIN® binding (PO’s Response, pp. 14—15). As discussed below,
`
`neither theory has empirical or any other proper support.
`
`PO’s first theory relies on Christianson 1998 (Ex. 2048), however, it fails to
`
`discuss HERCEPTIN ®., much less provide any nexus between its observations and
`
`HERCEPTIN ® resistance. In particular, Christianson 1998 does not show any
`
`competition assays. Therefore, PO’s contentions are not supported by Christianson
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`

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`PETITIONER PHIGENIX, INC.’S REPLY TO PATENT OWNER IMMUNOGEN, IN C.’S PATENT
`OWNER RESPONSE TO THE PETITION
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`1998, since it shows no evidence for in vitro or in vivo competition between a shed
`
`extracellular domain and HERCEPTIN ® (or any other ErbB2-targeted antibody).
`
`Zabrecky 1991 (Ex. 2050), also relied upon by P0, shows a p105 extracellular
`
`product released from the surface of SK—BR—3 cells. This p105 product is also
`
`shown to compete with TA.1 against the extracellular domain of HER2. However,
`
`Zabrecky 1991 states: “it was difficult to prepare sufficient quantities of labeled
`
`p105 at high enough concentration to perform this experiment, so a capture ELISA
`
`format was used instead” (Ex. 2050, p. 1718). In other words, the amount of
`
`extracellular product is extremely low in the SK~BR-3 cell culture without taking
`
`steps to artificially enrich its concentration. Moreover, Chari 1992, also used SK-
`
`BR—3 cells to demonstrate the effective cytotoxicity of the maytansinoid antibody-
`
`drug conjugates. The cytotoxicity of anti-ErbB2 antibody-drug conjugates in SK-
`
`BR—3 cells in Chari 1992 undermines PO’s suggestion that the p105 product
`
`creates some resistance problem.
`
`PO speculates that I-IERCEPTIN® resistance reflects a problem of antibody
`
`binding to the ErbB2 receptor. However, nowhere in the HERCEPTIN® Label is
`
`there any discussion or data concerning the notion that any patient non—
`
`responsiveness has anything to do with lack of binding by HERCEPTIN® per se.
`
`To the contrary, Ex. 1008 merely conveys that 86% of HER2-overexpressing
`
`breast cancer patients did not respond clinically to HERCEPTIN®. As a matter of
`
`9
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`

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`PETITIONER PHIGENIX, INC.’S REPLY TO PATENT OWNER IMMUNOGEN, INC.’S PATENT
`OWNER RESPONSE TO THE PETITION
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`fact, 2% responded completely and 12% responded partially. The HERCEPTIN®
`
`Label does not suggest any reason for non—responsiveness, and PO provides no
`
`evidence to support the notion that at the time of the alleged invention, or any time
`
`since then, that failure of HERCEPTIN® binding to HER2 overexpressing cells
`
`causes non—responsiveness.
`
`PO’s second theory that a natural variant in the ErbB2 receptor somehow
`
`interferes with binding is likewise absent empirical foundation. Sliwkowski 1999
`
`(Ex. 2049) is cited to show that the epitope for murine 4D5 antibody lies between
`
`amino acids 529 to 627 of the extracellular domain of the ErbB2 receptor (Ex.
`
`2049, p. 61). Kwong 1998 (Ex. 2051) is also cited to show the existence of a
`
`natural deletion of 16 amino acids in the extracellular domain of the ErbB2
`
`receptor in some instances (Ex. 2051, Fig.1). However, neither cited reference nor
`
`Koski 19981 (Ex. 2052) shows that this deletion is actually located within the
`
`epitope for 4D5. Of course, if any deletion is outside the epitope for 4D5, it cannot
`
`interfere with binding. Accordingly, PO’s contention is not supported by the
`
`references or in its expert testimony by either Dr. Pietersz or Dr. O’Shaughnessy
`
`(who relies on the same flawed theory). Therefore, PO’s theory regarding the
`
`lKoski 1998 (US Patent No. 5,783,404) states that Domain IV of the ErbB2 (HER—
`2/neu) receptor runs from amino acids 503—649 (Ex. 2052, col. 7, 11. 49—50), but
`PO notably fails to show where the natural deletion actually falls within that
`domain and whether it falls within the alleged 4D5 epitope.
`
`10
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`

`

`PETITIONER PHIGENIX, INC.’S REPLY TO PATENT OWNER IMMUNOGEN, INC.’S PATENT
`OWNER RESPONSE TO THE PETITION
`CASE IPR2014-00676
`
`effect of the natural deletion is unsupported by the cited (or any other) references
`
`and is, at best, speculative.
`
`Of note, these unsupported theories regarding HERCEPTIN® resistance are
`
`also relied on in PO’s Response to argue for “unexpected superiority”‘of T‘DMl
`
`over the conjugates disclosed in Chari 1992 (PO’s Response, p. 43). Since these
`
`theories lack any sound basis, those arguments based on them, including regarding
`
`“unexpected superiority” should be similarly discounted.
`
`E.
`
`Reasonable Expectation Of Success For An Additive Effect
`Between huMAB4D5-8 And Maytansinoids
`
`PO contends that it would not have been expected that anti-tubulin agents,
`
`such as maytansinoids, would have been effective when combined with
`
`HERCEPTIN® (PO’s Response, pp. 23—26). PO’s response ignores key findings of
`
`Pegram 1999 (Ex. 1020), which teaches that not only is there an additive effect /
`
`between humanized 4D5 antibody (“rhuMAb HER2”) and anti—tubulin agents, but,
`
`furthermore, the use of rhuMAb HER2 showed “no deleterious effect on
`
`chemotherapeutic drug efficacy” (Ex. 1020, p. 2248). If the use of rhuMAb HER2
`
`had a deleterious effect on an anti—tubulin agent then Pegram 1999 would have
`
`reported such an effect, as it expressly did for the antimetabolite drug S—FU, stating
`
`it “is the only drug which demonstrated antagonism when used in combination
`
`with rhuMAb HER2 in vitro” (Ex. 1020, p. 2248).
`
`11
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`

`

`PETITIONER PHIGENIX, INC.’S REPLY TO PATENT OWNER IMMUNOGEN, INC.’S PATENT
`OWNER RESPONSE TO THE PETITION
`CASE IPR2014-00676
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`Notably, Pegram 1999 states that the antagonism between 5—FU and
`
`rhuMAb HER2 may be due to “alterations in cell cycle distribution caused by
`
`rhuMAb HER2” (Ex. 1020, p. 2248), but does not discuss any such issue
`
`connected to cell cycle distribution with the use of anti—tubulin agents. Therefore,
`
`one of ordinary skill would have had a reasonable expectation that the conjugation
`
`of huMAB4D5-8 with maytansinoids would have had an additive effect and be
`
`independent of any cell cycle conditions. Furthermore, while Drewinko 1981 (Ex.
`
`1031) states that methotrexate is ineffective against non—proliferating cells, it also
`
`discloses that maytansine is one of a group of mitotic inhibitors that retains
`
`cytotoxicity against non-proliferating cells, albeit at a relatively lower level to its
`
`effectiveness against proliferating cells (Ex. 1031, p. 2330). This provides further
`
`empirical support that a skilled artisan understands that a highly cytotoxic
`
`maytansinoid conjugate, such as disclosed in Chari 1992, would retain efficacy
`
`against both proliferating and non—proliferating cells.
`
`F.
`
`POSA Knows That A Maytansinoid Linked To Herceptin Via A
`Non-Cleavable Linker Is Highly Cytotoxic to ErbB2-Expressing
`Breast Cancer Cells As Shown In Chari 1992
`
`PO relies on its expert Dr. Pietersz’s understanding of Chari 1992 (Ex.
`
`1012) to contend that a skilled artisan would believe that a maytansinoid conjugate
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`using a non-cleavable linker would somehow be ineffective (PO’s Response, pp.
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`27-34). As discussed below, Dr. Pietersz misunderstands Chari 1992.
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`12
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`

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`PETITIONER PHIGENIX, INC.’S REPLY TO PATENT OWNER IMMUNOGEN, INC.’S PATENT
`OWNER RESPONSE TO THE PETITION
`CASE IPR2014-00676
`
`Chari 1992 states that the IC50 (M) for its disulfide linker antibody—drug
`
`conjugate (denoted in Chari 1992 as TA.1(—SS-May)4) is 3 x 10'12 M based on Fig.
`
`3C (Ex. 1012, p. 129, first 001.). Notably, the text of Chari 1992 also enables the
`
`calculation of the IC50 for the TA.1 antibody linked by a noncleavable linker to
`
`four maytansinoid molecules (denoted in Chari 1992 as TA.1(non-cleavable linker—
`
`May)4), since the text states that it is “200-fold less potent” than the conjugate with
`
`the cleavable linker (Ex. 1012, p. 129, first 001.). Thus, the IC50 of the non—
`
`cleavable linker conjugate is 6 x 10'10 M (3 x 10'12 M x 200 = 6 x 10'10 M). In this
`
`respect, it is well-established that “[a] known or obvious composition does not
`
`become patentable simply because it has been described as somewhat inferior to
`
`some other product for the same use.” In re Gurley, 27 F.3d 551, 553 (Fed. Cir.
`
`1994). By way of comparison, an IC50 of 6 x 10‘10 M makes TA.1(non—cleavable
`
`linker—May)4 more toxic than every cytotoxin (actinomycin D, colchicine,
`
`daunomycin, vinblastine, methotrexate and mitomycin C) shown in Fig. 1 of Chari
`
`1992 apart from maytansine itself. Therefore, one of ordinary skill understands
`
`based on reading the data of Chari 1992 that the noncleavable linker—antibody drug
`
`conjugate is a highly effective antigen-specific cytotoxin against breast cancer
`
`cells.
`
`13
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`

`

`PETITIONER PHIGENIX, INC.’S REPLY TO PATENT OWNER IMlVIUNOGEN, INC.’S PATENT
`OWNER RESPONSE TO THE PETITION
`CASE IPR2014-00676
`
`As further discussed below, PO’s failure to correctly understand Fig. 3C is
`
`rooted in Dr. Pietersz’s mistake in interpreting the negative control as being
`
`precisely 300-fold less potent and then using that as the baseline for his analysis.
`
`Petitioner respectfully directs the Board’s attention to Fig. 3C of Chari 1992
`
`(see Ex. 1012, p. 129; reproduced enlarged below):
`
`Sum:mgFractionat(Jails
`
`.
`
`”WWNWM(WWW/WE
`
`
`
`10'3
`s
`
`i
`V as
`'
`1
`Antibody - May. nil/ii
`
`Fig. 3C shows cytotoxicity over a 72 hour period in SK—BR-3 cells for
`
`TA.1(—SS—May)4 in the absence of nonconjugated TA.1 (the line that follows the
`
`fully black circles) or presence of nonconjugated TA.1 (the line that follows the
`
`fully white circles). It also shows the cytotoxicity of TA.1(non-cleavable linker—
`
`14
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`

`

`PETITIONER PI-HGENIX, INC.’S REPLY TO PATENT OWNER IMMUNOGEN, INC.’S PATENT
`OWNER RESPONSE TO THE PETITION
`CASE IPR2014-00676
`
`May); under the same conditions (the line that follows the fully black triangles)
`
`and a negative control designated anti—B4—(SS—May)6 (the line that follows the full
`
`black squares) (Ex. 1012, p. 129, first col.; and see Fig. 3(c) description).
`
`The IC50 for TA.1(non-cleavable linker-May)4 may be calculated from the
`
`graph by finding the point on the x-axis of Fig. 3C that represents the concentration
`
`of antibody drug-conjugate that corresponds to a 50% surviving fraction of cells on
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`the y—axis of Fig. 3C (for reference, on the y—axis 10'1 represents 10% surviving
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`cells). Accordingly, by reading the graph, one understands from Fig. 3C that the
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`noncleavable linker antibody-drug conjugate has an IC50 in breast cancer cells of
`
`approximately 0.6 nM (0.6 x 10'9 M, which is equivalent to 6 x 10‘10 M).
`
`By contrast, no calculation of an IC50 is possible for the negative control, of
`
`which the text states it has a potency “more than 300-fold lower [than the
`
`cleavable linker conjugate] with an IC50 greater than 1 x 10'9 M (Fig. 3c)
`
`[emphasis added]” (Ex. 1012, p. 129, first col.). Dr. Pietersz misconstrues Fig. 3C
`
`by treating the data for the negative control anti—B4-(SS-May)6 (the line following
`
`the full black squares) as a baseline for analysis of relative cytotoxicity (see PO’s
`
`Response, p. 30). In fact, as can be seen in Fig. 3C, it is impossible to calculate an
`
`IC50 for anti-B4-(SS—May)6, since it forms a Virtual flat line at the tested
`
`concentrations and the line remains at that position to the edge of the graph. As a
`
`result, it is unknowable from Fig. 3C how many times more cytotoxic TA.1(non-
`
`15
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`

`

`PETITIONER PHIGENIX, INC.’S REPLY TO PATENT OWNER IMMUNOGEN, INC.’S PATENT
`OWNER RESPONSE TO THE PETITION
`CASE IPR2014-00676
`
`cleavable linker—May)4 is over anti—B4—(SS—May)6, but it must certainly be many
`
`times higher than Dr. Pietersz’s mistaken analysis suggests.
`
`PO’s Response further relies on this flawed analysis to argue that T-DMl is
`
`“unexpectedly superior to the closest construct in Chari 1992” (PO’s Response,
`
`pp. 35—40). In particular, PO’s Response contends that “Phillips [Ex. 1004] treated
`
`the same type of cancer cells (SK—BR—3 cells) for the same period of time (72
`
`hours) with T—DMl instead of the [non-cleavable linker] construct used in Chari
`
`1992, and T-DMl drastically reduced cell viability to less than 35 % [emphasis
`
`added]” (PO’s Response, p. 38).
`
`However, as can be seen in Fig. 3C of Chari 1992 above, TA.1(non-
`
`cleavable linker-May); is able to reduce cell viability to less than 35% after 72
`
`hours exposure. In Fig. 3C, the second and third notches above 10'1 on the y-axis
`
`respectively represent 30% and 40% surviving cell fractions. This allows the
`
`observer to pinpoint 35 % cell viability on the y—axis. The observer then merely has
`
`to draw a line across the graph from that point to see that it will intersect with the
`
`diagonal line showing the cytotoxicity of TA.1(non—cleavable linker—May)4.
`
`Accordingly, even allowing for such differences as exist between Phillips and
`
`Chari 1992, it is clear that the cytotoxicity of the construct of Chari 1992 is entirely
`
`consistent with that of T—DMl. In Phillips, T-DMl is, in fact, performing in a
`
`similar manner to the prior non—cleavable linker conjugate of Chari 1992.
`
`16
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`

`

`PETITIONER PHIGENIX, INC.’S REPLY TO PATENT OWNER IMMUNOGEN, INC.’S PATENT
`OWNER RESPONSE TO THE PETITION
`CASE IPR2014-00676
`
`Therefore, Phillips is not evidence of any unexpected results. The results are, in
`
`actuality, precisely as would be expected based on Chari 1992. This also shows
`
`that the contentions of PO’s Response regarding the need for release of the
`
`maytansinoid are irrelevant in light of the cytotoxicity of a non-cleavable linker
`
`conjugate shown by Chari 1992 (PO’s Response, p. 26—29).
`
`G. Motivation Existed To Humanize The Antibody In The Conjugate
`Of Chari 1992 To Reduce Immunogenicity As Chari 1992
`Expressly Teaches And PO’s Expert Admits
`
`As Dr. Pietersz stated, humanizing an antibody gives advantages “not only
`
`[to the] immunoconjugate but antibody as well, because you’re decreasing the
`
`immunogenicity of the antibody” (Ex. 1036 at 59:25 — 60:2-3). The humanized
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`antibody huMAB4D5-8 has been available as an FDA-approved antibody for
`
`cancer treatment since September, 1998 (Herceptin label, Ex. 1008). Accordingly,
`
`one of ordinary skill in the art would have been motivated to replace the murine
`
`antibody used in Chari 1992 with huMAB4D5—8 (HERCEPTIN®), as expressly
`
`taught by Chari 1992.
`
`III. Alleged Secondary Considerations Of Non-Obviousness Lack A Nexus
`T0 The Claimed Features Of Claims 1-8 Of The ‘856 Patent
`
`PO attempts to allege that secondary considerations relating to the drug
`
`KADCYLATM support patentability. KADCYLATM Prescribing Information (Ex.
`
`2025) states that “KADCYLA is a HER2-targeted antibody and microtubule
`
`17
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`

`

`PETITIONER PHIGENIX, INC.’S REPLY TO PATENT OWNER IMlVIUNOGEN, INC.’S PATENT
`OWNER RESPONSE TO THE PETITION
`CASE IPR2014-00676
`
`inhibitor conjugate indicated, as a single agent, for the treatment of patients with
`
`HER2-positive, metastatic breast cancer who previously received trastuzumab and
`
`a taxane, separately or in combination” (Ex.