`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`PHIGENIX, INC.
`Petitioner
`
`v.
`
`IMMUNOGEN, INC.
`Patent Owner
`_____________________
`
`Case IPR2014-00676
`U.S. Patent No. 8,337,856
`_____________________
`
`
`PATENT OWNER PRELIMINARY RESPONSE UNDER 37 C.F.R.
`§42.107(a)
`
`
`
`
`
`
`
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`Page
`
`
`I.
`
`II.
`
`Introduction ................................................................................................... 1
`
`The petition failed to establish a reason to combine the art with a
`reasonable expectation of success for the claimed immunoconjugates ....... 4
`
`III. The petition failed to properly account for objective indicia of
`nonobviousness ........................................................................................... 11
`
`A.
`
`B.
`
`C.
`
`D.
`
`The petition failed to properly account for unexpected results
`arising out of clinical trials involving T-DM1 ................................. 12
`
`The petition failed to account for praise in the industry .................. 23
`
`The petition failed to account for long-felt need .............................. 27
`
`The petition failed to address evidence of T-DM1's
`(Kadcyla's) commercial success ....................................................... 29
`
`IV.
`
`If trial is instituted, the Board should deny trial based on any of
`Grounds 2-8 ................................................................................................ 30
`
`A. All of the grounds are redundant because Phigenix has not
`explained how any of the grounds are meaningfully distinct .......... 30
`
`B.
`
`C.
`
`Phigenix failed to clearly and particularly identify Grounds 2,
`3 and 5 under 35 U.S.C. § 312(a)(3) ................................................ 33
`
`The Board should deny trial on Ground 8 because Phigenix
`fails to establish that Cohen 1999 is prior art ................................... 34
`
`V.
`
`Conclusion .................................................................................................. 37
`
`
`
`
`
`
`
`- i -
`
`
`
`
`
`
`
`
`I.
`
`Introduction
`
`
`
`
`Patent Owner's Preliminary Response
`IPR2014-00676
`
`Phigenix's IPR petition falls far short of meeting its burden to establish a
`
`reasonable likelihood of prevailing with respect to any claim it challenges in U.S.
`
`Patent No. 8,337,856 ("the '856 patent"). The challenged patent is directed to an
`
`immunoconjugate drug that combines an antibody (huMab4D5-8, also known as
`
`trastuzuamb and marketed as Herceptin®) together with a chemotherapeutic agent
`
`(a maytansinoid). Phigenix posits that the invention is "no more than a simple
`
`substitution of one known element for another to obtain a predictable result."
`
`(Petition at 15.)
`
`But one can agree with Phigenix's prima facie obviousness arguments only
`
`by ignoring extensive evidence in the prosecution history and by ignoring other
`
`evidence that would have been readily available to a person of ordinary skill in the
`
`art (POSA). As shown in Section II below, Phigenix and its expert ignore
`
`evidence showing the serious challenges and unpredictability that researchers in
`
`the field faced in developing a therapeutic immunoconjugate drug. Phigenix does
`
`not explain how a POSA would have had a reason to combine the art with a
`
`reasonable expectation of success in view of the many challenges the prior art
`
`presented.
`
`Phigenix and its expert have been willing to ignore such challenges and
`
`evidence in their effort to cancel a patent for a ground-breaking cancer drug jointly
`
`
`
`
`
`
`
`
`
`
`developed by ImmunoGen and Genentech. The drug, known as T-DM1, is
`
`
`
`Patent Owner's Preliminary Response
`IPR2014-00676
`
`marketed under the brand name Kadcyla® and has been hailed as revolutionizing
`
`the treatment of breast cancers that overexpress HER2. T-DM1 is a conjugate that
`
`combines trastuzumab and the highly cytotoxic maytansinoid "DM1."
`
`As discussed in Section III below, one can agree with Phigenix's
`
`obviousness assertions only by also disregarding objective indicia of
`
`nonobviousness as Phigenix did. Though immunoconjugate therapies have long
`
`been viewed as the "holy grail" of cancer treatment, no immunoconjugate before
`
`T-DM1 had been proven in a clinical setting for treating solid tumors. Upon
`
`learning of T-DM1's clinical results, leaders in the field selected it as one of the top
`
`three "game changers in oncology" in 2011, and stated that it is expected to usher
`
`in a new era of other cancer therapeutics that simultaneously increase efficacy and
`
`reduce toxicity. (Ex. 2008 at 4:16-18.) To the surprise of many, T-DM1 showed
`
`efficacy in patients that failed to respond to trastuzumab and at least four other
`
`therapies, including a taxane chemotherapeutic. And T-DM1's low toxicity was
`
`particularly unexpected given that (i) maytansine had demonstrated unacceptable
`
`toxicity in previous clinical trials and (ii) normal cells, as well as tumor cells,
`
`express the protein to which trastuzumab binds. But, well-regarded practitioners in
`
`the field have praised T-DM1's results as ground-breaking.
`
`Phigenix's petition fails to rebut ImmunoGen's objective indicia evidence,
`
`- 2 -
`
`
`
`
`
`
`even though extensive evidence is contained right within the prosecution history of
`
`
`
`Patent Owner's Preliminary Response
`IPR2014-00676
`
`the '856 patent. For example, while prosecuting the '856 patent, ImmunoGen
`
`presented detailed evidence on unexpected results, including providing expert
`
`declarations of Drs. Klencke and Sliwkowski. And after reviewing this evidence,
`
`the Examiner indicated the claims were allowable. Phigenix now relies on
`
`references that contain the same or substantially the same teachings as the
`
`references the Examiner considered. For example, Chari 1992, which is used in the
`
`majority of the grounds alleged by Phigenix, was discussed with the Examiner
`
`during an interview. (Ex. 2014 at 1.) Certainly, the petition doesn't distinguish
`
`between the previously-relied upon references and patentability analysis versus the
`
`currently-presented references and analysis. And the petition leaves Drs. Klencke's
`
`and Sliwkowski's declarations regarding objective indicia largely unrebutted. For
`
`example, as shown below, even Phigenix's expert, Dr. Rosenblum, was apparently
`
`unwilling to state that T-DM1's clinical-trial results were expected. Without
`
`excuse, neither the petition nor Dr. Rosenblum provides any rebuttal to significant
`
`evidence in the prosecution history or readily available in the art showing the
`
`invention's praise in the industry, long-felt need, and commercial success.
`
`Addressing objective indicia is an essential part of an obviousness inquiry, "not
`
`just an afterthought." (Leo Pharmaceutical v. Rea, 726 F.3d 1346, 1357 (Fed. Cir.
`
`2013); see also Omron Oilfield & Marine, Inc. v. MD/Totco, IPR 2013-00265,
`
`- 3 -
`
`
`
`
`
`Paper 11 at 16.)
`
`
`
`
`
`Patent Owner's Preliminary Response
`IPR2014-00676
`
`By ignoring such extensive evidence, Phigenix has failed to meet its burden
`
`of establishing a reasonable likelihood of prevailing for any claim of the '856
`
`patent, and the Board should deny instituting trial. (See e.g., IPR2013-00265, Paper
`
`11 at 16.) And if the Board were to institute trial, it should deny each of Grounds
`
`2-8 as being redundant, ambiguous, or otherwise defective, as explained in Section
`
`IV below.
`
`II. The petition failed to establish a reason to combine the art with a
`reasonable expectation of success for the claimed immunoconjugates
`
`Phigenix's obviousness grounds are predicated on a theory that a skilled
`
`artisan would have combined the art as claimed to produce immunoconjugates for
`
`treating breast cancer. In an attempt to articulate reasons to combine the art as
`
`claimed, the petition repeatedly emphasizes the "clinical applications" of the
`
`invention, e.g., "treating breast cancer" in "humans." (Petition at 14-16, 20, 31,
`
`and 37-40.) For example, the petition states that a person of ordinary skill in the
`
`art (POSA) would have been motivated to substitute trastuzumab for TA.1 of Chari
`
`1992 because humanized antibodies "were preferred over their mouse-derived
`
`counterparts for clinical applications." (Petition at 14, emphasis added.)
`
`Likewise, the petition's reasons to combine Liu 1996 and the Herceptin® label are
`
`rooted in the use of trastuzumab "for the treatment of breast cancer." (Petition at
`
`38.)
`
`- 4 -
`
`
`
`
`
`
`Notwithstanding Phigenix's heavy reliance on therapeutic reasons to
`
`
`
`Patent Owner's Preliminary Response
`IPR2014-00676
`
`combine the art as claimed, Phigenix fails to explain how a POSA could have
`
`combined the art with a reasonable expectation of success given the numerous
`
`challenges POSAs faced in developing therapeutic immunoconjugates as of the
`
`'856 patent's priority date.
`
`These challenges were presented as evidence during prosecution, but
`
`Phigenix glosses over such challenges, using hindsight to piece together the
`
`invention as though it were made of Lego® building blocks. The Board should not
`
`institute trial here where Phigenix turns a blind eye to evidence in the record
`
`establishing the extensive difficulties the art faced in developing
`
`immunoconjugates. These multiple challenges are discussed in the prosecution
`
`history and in the art, as detailed below. And Phigenix has failed to explain how a
`
`POSA could have had a reasonable expectation of success in light of such
`
`challenges.
`
`First, the petition fails to recognize that successfully producing an
`
`immunoconjugate requires finding the right balance between selectivity of the
`
`antibody and potency of the cytotoxic agent. For an immunoconjugate that binds to
`
`a protein target expressed on both normal cells and cancer cells to be
`
`therapeutically useful, it must achieve a critical balance of killing tumor cells
`
`effectively enough to outweigh the toxicities that result from binding to and killing
`
`- 5 -
`
`
`
`
`
`
`normal cells. The prosecution history highlights the difficulties in achieving this
`
`
`
`Patent Owner's Preliminary Response
`IPR2014-00676
`
`balance. (See e.g., Ex. 1027 at 10, Ex. 1028: ¶¶8, 13, and 14, and Ex. 1029: ¶¶7,
`
`10-11, and 26.) As Dr. Sliwkowski explained, "the utility of immunoconjugates
`
`was often limited due to the expression of the targeted antigen on normal as well as
`
`cancerous cells, even where the antigen was expressed at higher levels on
`
`cancerous cells relative to normal cells." (Ex. 1028: ¶13; see also Ex. 1015 at
`
`3:2:14-37.) Dr. Sliwkowski further explained "[i]f that balance is not achieved,
`
`e.g., if a potent cytotoxic agent exerts its effect on too many normal cells, than
`
`toxicity may result." (Ex. 1028: ¶13; see also Ex. 1027: 9-10, Ex. 1028: ¶¶8 and
`
`14, and Ex. 1029: ¶¶7 and 10.) Even the references Phigenix cites reiterates these
`
`challenges (see e.g., Ex. 1012 at 1:1; Ex. 1015 at 1:Abstract, 3, 8, and 13; and Ex.
`
`1029 at 46-47).
`
`But, Phigenix disregards these difficulties, and does not establish how, in
`
`view of such challenges, a POSA could have had a reasonable expectation of
`
`success in producing a useful immunoconjugate that combines (i) trastuzumab with
`
`(ii) maytansinoid, an extremely toxic compound that had already failed clinical
`
`trials due to its toxicity. (See e.g., Ex. 2001-2005 and Ex. 1029: ¶9.)
`
`These difficulties are further illustrated by the fact that, before the effective
`
`filing date of the '856 patent, immunoconjugates had repeatedly failed to live up to
`
`the promise of targeted drug delivery. (Ex. 1029: ¶¶11 and 26; see also Ex. 1015 at
`
`- 6 -
`
`
`
`
`
`
`8:1:1-35.) Only four other immunoconjugates ever showed enough promise to be
`
`
`
`Patent Owner's Preliminary Response
`IPR2014-00676
`
`tested in a clinical setting before the effective filing date of the '856 patent — and
`
`not a single one was successful in treating a solid tumor. (See Ex. 1029: ¶26; see
`
`also Ex. 2006 at 19: Conclusion, Ex. 2007 at 19-20, and Ex. 1015 at 1: Abstract.)
`
`Again, the prosecution history highlights this challenge in the art, but the petition
`
`fails to establish how a POSA could have arrived at the claimed invention with a
`
`reasonable expectation of success in view of such discouraging results.
`
`Second, the petition fails to account for the known toxicities and failures of
`
`maytansinoids. The prosecution history and the prior art belie the petitioner's
`
`unsupported assertion that maytansinoids are "particularly attractive" cytotoxic
`
`agents for use in antibody-drug therapy because of their potency. (Petition at 6.)
`
`As Dr. Klencke emphasized during prosecution of the '856 patent, maytansinoids
`
`were "unsuccessful in human clinical trials because of unacceptable systemic
`
`toxicity." (Ex. 1029: ¶9.) And the art was replete with publications describing
`
`clinical failures of maytansinoids. (See e.g., Ex. 2001-2005.) Researchers
`
`concluded that such studies on maytansine "do not suggest a major role for this
`
`drug in the treatment of cancer." (Ex. 2005 at 2:2:54-56.) And no maytansinoid-
`
`based immunoconjugate had succeeded in the clinic as of the effective filing date
`
`of the '856 patent, even eight years after Chari 1992 published. Though the
`
`prosecution history articulates these prior failures with maytansinoids and though
`
`- 7 -
`
`
`
`
`
`
`Phigenix's expert, Dr. Rosenblum, purports to have considered the scientific
`
`
`
`Patent Owner's Preliminary Response
`IPR2014-00676
`
`literature broadly related to maytansinoids (Ex. 1016: ¶8), Phigenix's petition fails
`
`to explain how a POSA could nonetheless have had a reasonable expectation of
`
`success in arriving at the claimed invention.
`
`Third, Phigenix's petition fails to acknowledge and overcome the fact that,
`
`as of the effective filing date of the '856 patent, every single immunoconjugate that
`
`had been tested in humans for treating a solid tumor failed. (See Ex. 2011 at
`
`7:1:46, Ex. 2006 at 19: Conclusion, Ex. 1015 at 8:1:1-35, and Ex. 2010 at 1:
`
`Abstract.) The prosecution history reveals this challenge that faced POSAs. As Dr.
`
`Klencke pointed out during prosecution, no immunoconjugate had ever shown
`
`clinical efficacy in treating any solid tumor. (Ex. 1029: ¶26.) And Dr. Klencke's
`
`Declaration explained that the ability of the claimed immunoconjugates to treat
`
`solid tumors was "an important advance in the field of immunoconjugates." (Ex.
`
`1029: ¶26.) T-DM1, which Phigenix admits is a conjugate within the scope of the
`
`claims (Petition at 57), is the very first immunoconjugate ever to be approved to
`
`treat a solid tumor. The claimed invention thus represents the first success in a long
`
`history of attempts to develop immunoconjugates capable of specifically delivering
`
`a cytotoxic drug to a solid tumor.
`
`Phigenix likewise improperly dismissed the failures of others in the field.
`
`Notably, one of these failures was reported as long as seven years after Chari 1992
`
`- 8 -
`
`
`
`
`
`
`published. (Ex. 2010 at 1: Abstract.) Though the prosecution history identifies
`
`
`
`Patent Owner's Preliminary Response
`IPR2014-00676
`
`such failures in the art, and though the petition asserts one would combine the art
`
`for clinical applications of the immunoconjugates, e.g., in the treatment of breast
`
`cancer, the petition fails to explain how a POSA could nonetheless have a reason to
`
`combine the art with a reasonable expectation of success given such failures in the
`
`art.
`
`While Phigenix alleges that the reason to combine the art is for clinical
`
`applications for treating breast cancer in humans, solid tumors such as breast
`
`cancer were considered particularly difficult to treat. One difficulty comes from the
`
`fact that immunoconjugates, which contain large antibody molecules, cannot
`
`penetrate into solid tumors, as they are often poorly vascularized. (Ex. 1015 at
`
`8:2:40-45; see also Ex. 1029 at 46:2:17-27.) But, more importantly for
`
`immunoconjugates delivering cytotoxic agents, Chari 1998 notes that only
`
`hematopoietic tumors bear true tumor-specific antigens (i.e., antigens found
`
`exclusively on tumor cells). (Ex. 1015 at 3:2:14-37.) In contrast, the target
`
`antigens for solid tumors are expressed on both tumor and normal cells. (Id.) As
`
`both Drs. Sliwkowski and Klencke emphasized, "HER2 [i.e., the target antigen of
`
`the Herceptin antibody] is expressed on normal cells as well as being
`
`overexpressed on certain breast cancer cells and other cancer cells." (Ex. 1028:
`
`¶14; see also Ex. 1027: 9-10, Ex. 1028: ¶¶8 and13, and Ex. 1029: ¶7.) This
`
`- 9 -
`
`
`
`
`
`
`expression pattern makes balancing the "selectivity of the [monoclonal antibody]
`
`
`
`Patent Owner's Preliminary Response
`IPR2014-00676
`
`with the potency of the agent delivered" all the more difficult when attempting to
`
`treat a solid tumor. (Ex. 1029 at 46:1:53-54.) As Dr. Sliwkowski noted, "it would
`
`have been unpredictable whether [the claimed] immunoconjugate would have been
`
`unacceptably toxic due to delivery of DM1 to normal cells expressing HER2. The
`
`present application addresses this unpredictability, reporting that 'HERCEPTIN®-
`
`DM1 does not kill normal human cells, indicating a selective activity.'" (Ex. 1028:
`
`¶14.) Phigenix has failed to refute this unpredictability.
`
`In sum, a POSA who sought to produce an immunoconjugate as claimed
`
`would have faced multiple challenges as of the '856 patent's effective filing date.
`
`And though the prosecution history and the art clearly articulate these challenges in
`
`producing immunoconjugates for treating solid tumors, the petition does not
`
`address them. Thus, on this record, the petition fails to establish that a POSA
`
`would have had a reason to combine (i) trastuzumab with (ii) maytansinoid (a
`
`known toxin) to arrive at the claimed immunoconjugates with a reasonable
`
`expectation of success. In view of the state of the art as of the filing date and the
`
`petition's failure to address record evidence, the petition falls woefully short of
`
`establishing a reasonable likelihood of prevailing in showing unpatentability.
`
`Accordingly, the Board should deny trial.
`
`- 10 -
`
`
`
`
`
`Patent Owner's Preliminary Response
`IPR2014-00676
`
`
`
`
`III. The petition failed to properly account for objective indicia of
`nonobviousness
`Even if the Board were to find that the petition establishes a prima facie case
`
`of obviousness – which it shouldn't – the Board should deny trial because the
`
`petition ignores objective indicia of nonobviousness. Here, as in Omron Oilfield &
`
`Marine, Inc. v. MD/Totco, the petition fails to "challenge the merits of Patent
`
`Owner's secondary consideration evidence" of record. (IPR 2013-00265, Paper 11
`
`at 16.) As explained below, Phigenix's failure to rebut record evidence of objective
`
`indicia goes unexcused and Phigenix's petition thus fails.
`
`Objective indicia of nonobviousness are "not just a cumulative or
`
`confirmatory part of the obviousness calculus but constitute[] independent
`
`evidence of nonobviousness." (Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc.,
`
`520 F.3d 1358, 1365 (Fed. Cir. 2008).) The Federal Circuit has stated that "the
`
`Board should give the objective indicia its proper weight and place in the
`
`obviousness analysis, and not treat objective indicia of nonobviousness as an
`
`afterthought." (Leo Pharmaceutical v. Rea, 726 F.3d 1346, 1358 (Fed. Cir. 2013).)
`
`Finally, objective indicia "can be the most probative evidence of nonobviousness
`
`in the record, and enables the … court to avert the trap of hindsight." (Crocs, Inc.
`
`v. Int'l Trade Comm'n, 598 F.3d 1294, 1310 (Fed. Cir. 2010).)
`
`Evidence of objective indicia of nonobviousness that is sufficient to
`
`overcome any alleged prima facie case was clearly established during the
`
`- 11 -
`
`
`
`
`
`
`prosecution history of the '856 patent. In response to an Office Action rejecting the
`
`
`
`Patent Owner's Preliminary Response
`IPR2014-00676
`
`claims as obvious over the combination of a first reference teaching an antibody
`
`linked to a maytansinoid and a second reference teaching the trastuzumab antibody
`
`— i.e., the same elements over which Phigenix now argues the claims are obvious
`
`— the patentee submitted Declarations of Dr. Barbara Klencke, a leading cancer
`
`expert, and Dr. Mark Sliwkowski, an expert in developing anti-Her cancer
`
`therapeutics. (Ex. 1029 and Ex. 1028.) These expert declarations demonstrated,
`
`among other things, that T-DM1 exhibited unexpected results, received significant
`
`professional acclaim, and satisfied a long-felt, unmet need in terminally ill breast
`
`cancer patients. (Id.) After reviewing the evidence of record, the examiner allowed
`
`the claims in the subsequent action. (Ex. 2028 at 2.)
`
`As discussed in more detail below, the petition fails to properly account for
`
`evidence of record concerning objective indicia of nonobviousness as well as
`
`widely-known additional evidence. Having chosen not to tackle such readily-
`
`available objective indicia of nonobviousness, the petition must fail for not
`
`establishing a reasonable likelihood in prevailing.
`
`A. The petition failed to properly account for unexpected results
`arising out of clinical trials involving T-DM1
`
`The Board should decline to institute trial as Phigenix has failed to properly
`
`account for unexpected results exhibited by T-DM1 over trastuzumab and a
`
`chemotherapeutic agent in first-line and second-line therapy; over lapatinib and
`
`- 12 -
`
`
`
`
`
`
`capecitabine in second-line therapy; and over ixabepilone in third-line therapy.
`
`
`
`Patent Owner's Preliminary Response
`IPR2014-00676
`
`The present invention is based on the "unexpected experimental findings that
`
`HERCEPTIN®-maytansinoid conjugates are highly effective in the treatment of
`
`HER2 (ErbB2) overexpressing tumors that do not respond, or respond poorly, to
`
`HERCEPTIN® therapy." (Ex. 1001 at 4:10-14, emphasis added.) At the '856
`
`patent's effective filing date, it was well known that many breast cancers respond
`
`poorly to trastuzumab, which could have been due to mechanisms that disrupt the
`
`interaction of trastuzumab with the HER2 antigen. (Ex. 1001 at 3: 62 to 4: 6; Ex.
`
`1008 at 1: Table 2.) For example, Hudziak, a journal article cited by the petitioner,
`
`reported that HER2 is degraded more rapidly after exposure of SK-BR-3 breast
`
`cancer cells to 4D5, the murine version of trastuzumab. (Ex. 1005 at 5:2:26-37.)
`
`Thus, due to possible down-regulation of HER2 by trastuzumab, cells previously
`
`treated with trastuzumab may be unlikely to respond to an immunoconjugate
`
`containing the trastuzumab antibody.
`
`Dr. Rosenblum provides no rationale for why the claimed immuno-
`
`conjugates, which include the trastuzumab antibody, would have been expected to
`
`be effective in treating tumors that fail to respond to unconjugated trastuzumab
`
`antibody. As described in Dr. Klencke's Declaration, the claimed
`
`immunoconjugates show surprising efficacy not only against tumors that failed to
`
`respond to trastuzumab, but also against tumors that failed to respond to
`
`- 13 -
`
`
`
`
`
`
`trastuzumab and a taxane and three additional therapeutic agents. (Ex. 1029: ¶12.)
`
`
`
`Patent Owner's Preliminary Response
`IPR2014-00676
`
`T-DM1 was administered as "essentially a last option for the terminally ill patients
`
`in this study." (Ex. 1029: ¶13.) Impressively, T-DM1 decreased the tumor size or
`
`produced stable disease in almost half (44.5%) of these patients. (Id. at ¶15.) In
`
`fact, T-DM1 decreased tumor size by at least 30% (a result referred to as an
`
`"objective response rate" or "ORR") in 32.7% of the patients. (Id.)
`
`Again, the patients' diseases had progressed after having been treated with
`
`"multiple standard therapies" including treatment with trastuzumab and a taxane
`
`prior to treatment with T-DM1. (Id. at ¶20.) Taxanes are microtubule-directed
`
`chemotherapeutics, as are maytansinoids. As noted by Dr. Klencke, it was
`
`unexpected that the claimed invention — an immunoconjugate comprising
`
`trastuzumab conjugated to a microtubule-directed chemotherapeutic — would be
`
`efficacious against cancers that had failed to respond to trastuzumab in
`
`combination with a microtubule-directed chemotherapeutic, as well as at least three
`
`additional therapeutics. (Id.)
`
`Prior to the clinical trial described by Dr. Klencke, no other clinical trial had
`
`ever been conducted in such a heavily-treated breast cancer patient population.
`
`(Ex. 1029: ¶20). Therefore, in order "[t]o put these data in perspective," Dr.
`
`Klencke compared the results obtained with T-DM1 to the results obtained using
`
`another breast cancer therapy in a group of patients who had also failed previous
`
`- 14 -
`
`
`
`
`
`
`therapies. (Ex. 1029: ¶16.) Specifically, Dr. Klencke compared the T-DM1 trial to
`
`
`
`Patent Owner's Preliminary Response
`IPR2014-00676
`
`a trial in which patients who had previously received at least anthracycline, a
`
`taxane, and trastuzumab were treated with a combination of lapatinib and
`
`capecitabine. (Ex. 1029: ¶¶16-17.) The objective response rate (ORR) of these
`
`patients was 23.7%. (Id.) Thus, the 32.7% ORR achieved by T-DM1 in patients
`
`who had previously been treated with at least five agents was superior to the ORR
`
`achieved by lapatinib and capecitabine in patients who had previously been treated
`
`with at least three agents. Dr. Klencke concluded that the ORR for T-DM1 was
`
`"unexpectedly better" than the ORR seen with lapatinib and capecitabine, a
`
`"second-line" HER2 directed therapy. (Id.)
`
`According to Dr. Klencke, treatment options are very limited for metastatic
`
`breast cancer patients after first- and second-line therapies fail. (Ex. 1029: ¶16.)
`
`One remaining approved third-line treatment option is ixabepilone (Ixempra®).
`
`(Id.) The ORR for ixabepilone in treating metastatic breast cancer in patients
`
`previously treated with an anthracycline, a taxane, and capacetabine was 12.4%.
`
`(Ex. 1029: ¶17.) The much greater (32.7%) ORR achieved by T-DM1 is
`
`particularly noteworthy given that the study with ixabepilone was conducted with
`
`patients who had only received at least three agents versus at least five agents for
`
`the patients receiving T-DM1.
`
`In summarizing these results, Dr. Klencke stated that "[t]he fact that the
`
`- 15 -
`
`
`
`
`
`
`ORR of T-DM1 in [the clinical trial] (32.7%) significantly exceeded that of current
`
`
`
`Patent Owner's Preliminary Response
`IPR2014-00676
`
`second-line therapies (23.7%), and well surpassed that of current third-line
`
`therapies (12.4%), was a better result than expected." (Ex. 1029: ¶18.) Thus, T-
`
`DM1 exhibited an "unexpectedly superior activity in a patient population that had
`
`progressed after treatment with multiple standard chemotherapies." (Ex. 1029:
`
`¶20, emphasis added.)
`
`The petition proffers no substantiated rebuttal to this unexpected results
`
`evidence. The petition asserts that "as confirmed by the Declaration of Dr.
`
`Rosenblum, such an increase [from 23.7% to 32.7% ORR] is neither unexpected,
`
`nor surprising when considering the prior art teachings further described herein."
`
`(Petition at 58.) But Dr. Rosenblum made no such statement. Dr. Rosenblum
`
`instead offered only the equivocal opinion that "it may not be either surprising or
`
`unexpected that the T-DM1 conjugate would exhibit a significant inhibitory effect
`
`on tumor growth in the patient population described in the Klencke Declaration."
`
`(Ex. 1016: ¶46, emphasis added.) This statement on its face demonstrates
`
`uncertainty on Dr. Rosenblum's part, and it is telling that he was apparently
`
`unwilling to testify that the results were expected.
`
`Moreover, Dr. Rosenblum’s equivocal opinion is completely
`
`unsubstantiated. Other than making a vague reference to "prior art teachings," Dr.
`
`Rosenblum offers no rationale or data supporting the conclusion that the results
`
`- 16 -
`
`
`
`
`
`
`"may not be surprising or unexpected." Expert testimony that does not disclose the
`
`
`
`Patent Owner's Preliminary Response
`IPR2014-00676
`
`underlying facts or data on which it is based "is entitled to little or no weight." (37
`
`C.F.R. § 42.65(a).) Dr. Rosenblum provides no reason to doubt Dr. Klencke's
`
`conclusion that the ORR observed with T-DM1 was "unexpectedly better" than
`
`practitioners in the field would have thought, and his opinion should be
`
`disregarded in its entirety.
`
`In fact, Dr. Rosenblum himself has described the success of T-DM1 as
`
`"impressive" and its activity in clinical studies as "remarkable." (Ex. 2015 at
`
`9:2:15-19 and Ex. 2016 at 2:16-22.) He also noted that many of the
`
`immunoconjugates developed after T-DM1 that show signs of clinical efficacy
`
`were "driven by" T-DM1. (Ex. 2015 at 9:2:15-19.) Thus, not only has Dr.
`
`Rosenblum failed to provide any reason to doubt Dr. Klencke's conclusion that the
`
`results were unexpected, Dr. Rosenblum himself has publicly acknowledged that
`
`he was impressed by the "remarkable" results.
`
`Moreover, conspicuously absent from the petition and Dr. Rosenblum's
`
`Declaration is any evidence rebutting Dr. Klencke's view that the 32.7% ORR
`
`observed with T-DM1 is surprisingly superior to the 12.4% ORR observed in the
`
`standard third-line therapy. (Ex. 1029: ¶17.)
`
`The petition attempts to minimize the importance of the comparative data
`
`provided by Dr. Klencke by arguing that the "increase in ORR from 23.7% to
`
`- 17 -
`
`
`
`
`
`
`32.7% ORR does not represent a 'difference in kind' that is required to show
`
`
`
`Patent Owner's Preliminary Response
`IPR2014-00676
`
`unexpected results." (Petition at 58.) However, this statement is not only
`
`unsupported by rationale or evidence, it is unsupported by Phigenix's own expert,
`
`Dr. Rosenblum, who admits, "[i]t is my opinion that an increase in ORR of
`
`metastatic breast cancer is an important result impacting the lives of many
`
`women." (Ex. 1016: ¶46.) This T-DM1 trial was the first clinical trial that
`
`specifically treated patients who had progressive disease after receiving five FDA-
`
`approved agents for the treatment of breast cancer. (Ex. 1029: ¶20.) The patients
`
`treated with lapatinib and capecitabine were only required to have received three
`
`prior treatments (Ex. 1029: ¶17), making the results achieved with T-DM1 in a
`
`more heavily treated population even more impressive.
`
`Offering an "apples-to-oranges" comparison, Dr. Rosenblum states "[t]he
`
`observed increase from standard second-line therapies of 23.7% to 32.7% with T-
`
`DM1 did occur but whether this represents a statistically-significant increase over
`
`second-line treatment with Herceptin in addition to Taxol is not clear." (Ex. 1016:
`
`¶46, discussing Dr. Klencke's declaration.) (Again, Dr. Rosenblum disregards the
`
`12.4% to 32.7% ORR comparison as a third-line therapy.) But, the data to which
`
`Dr. Klencke's declaration refers involved second-line therapy with lapatinib and
`
`capecitabine, not trastuzumab and Taxol. Dr. Rosenblum's declaration is silent
`
`about Dr. Klencke's conclusion that the results obtained from comparing T-DM1 to
`
`- 18 -
`
`
`
`
`
`
`lapatinib and capecitabine were unexpected.
`
`
`
`Patent Owner's Preliminary Response
`IPR2014-00676
`
`Clearly, a comparison of T-DM1 to lapatinib and capecitabine is completely
`
`different than a comparison of T-DM1 to trastuzumab and Taxol. Thus, the Board
`
`should give little weight to Dr. Rosenblum's uncertainty concerning whether results
`
`from one comparison are statistically significant when considering the expected
`
`results from a completely different comparison.
`
`Additionally, the Board should give little to no weight to Dr. Rosenblum's
`
`equivocal statement, because the petition does not even mention a comparison of
`
`T-DM1 to trastuzumab and Taxol®. And given this record, the Board should not
`
`permit Phigenix to shore up the deficiencies in its petition by relying on statements
`
`that appear nowhere in it. (See 37 C.F.R. § 42.6(a)(3).)
`
`While Dr. Rosenblum questions whether results achieved with T-DM1
`
`"represent[ ] a statistically-significant increase over second line treatment with
`
`Herceptin in addition to Taxol" (Ex 1016: ¶46), such an alleged concern is both
`
`unsubstantiated and unfounded given the second-line therapy trials reported in t
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
