UNITED STATES PATENT AND TRADEMARK OFFICE
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`
`
`WEST-WARD PHARMACEUTICALS INTERNATIONAL LIMITED,
`Petitioner,
`
`
`v.
`
`
`NOVARTIS PHARMACEUTICALS CORP.,
`Patent Owner.
`_________
`
`Case IPR2017-01592
`Patent 8,410,131 B2
`___________
`
`
`Before SHERIDAN K. SNEDDEN, ROBERT A. POLLOCK, and
`JACQUELINE T. HARLOW, Administrative Patent Judges
`
`RORBERT A. POLLOCK, Administrative Patent Judge
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`
`
`WEST-WARD PHARMACEUTICALS INTERNATIONAL LIMITED,
`Petitioner,
`
`
`v.
`
`
`NOVARTIS PHARMACEUTICALS CORP.,
`Patent Owner.
`_________
`
`Case IPR2017-01592
`Patent 8,410,131 B2
`___________
`
`
`Before SHERIDAN K. SNEDDEN, ROBERT A. POLLOCK, and
`JACQUELINE T. HARLOW, Administrative Patent Judges
`
`RORBERT A. POLLOCK, Administrative Patent Judge
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ON BEHALF OF THE PETITIONER:
`
`MICHAEL B. COTTLER, ESQUIRE
`
`KEITH ZULLOW, ESQUIRE
`
`MARTA DELSIGNORE, ESQUIRE
`
`Goodwin Procter, LLP
`
`The New York Times Building
`
`620 Eighth Avenue
`
`New York, NY 10018
`
`ON BEHALF OF PATENT OWNER:
`
`CHRISTINA SCHWARZ, ESQUIRE
`
`NICHOLAS KALLAS, ESQUIRE
`
`Fitzpatrick, Cella, Harper & Scinto
`
`1290 Avenue of the Americas
`
`New York, NY 10104-3800
`
`ALSO PRESENT:
`
`JOHN INTOTT
`
`
`
`Case IPR2017-01592
`Patent 8,410,131 B2
`
`
`APPEARANCES:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The above-entitled matter came on for hearing Wednesday,
`September 19, 2018, commencing at 1:00 p.m., at the U.S. Patent and
`Trademark Office, 600 Dulany Street, Alexandria, Virginia.
`
`
`
`
`
`
`
`
`
`
`
`
`2
`
`
`
`Case IPR2017-01592
`Patent 8,410,131 B2
`
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`P R O C E E D I N G S
`JUDGE POLLOCK: Okay. Thank you for your patience. This
`
`
`is the final hearing in IPR2017-01592 involving West-Ward
`Pharmaceuticals International and Novartis Pharmaceuticals Corporation.
`Today's hearing is open to the public, and a full transcript of the hearing will
`be made part of the record. I am Judge Pollock joined by Judge Snedden,
`and Judge Harlow joining us remotely.
`
`
`Before we begin with the substance of the hearing, I would ask
`parties to introduce themselves. Counsel for West-Ward, would you please
`introduce yourself and your colleagues?
`
`
`MR. COTTLER: Good morning -- good afternoon, Your
`Honors. My name is Michael Cottler from the law firm Goodwin Procter.
`With me, also from Goodwin Proctor, is Keith Zullow.
`
`
`MR. ZULLOW: Good morning, Your Honor.
`
`
`MR. COTTLER: Behind me from Goodwin Procter is Marta
`Delsignore.
`
`
`
`
`who is our
`-- who's our hot-seat person.
`
`
`JUDGE POLLOCK: Good morning -- afternoon. You got me
`saying it wrong. Counsel for Patent Owner Novartis, would you please
`introduce yourself and your colleagues?
`
`
`MS. SCHWARZ: Good afternoon, Your Honors. Christina
`Schwarz and Nicholas Kallas from Fitzpatrick, Cella, on behalf of Patent
`
`MS. DELSIGNORE: Good morning -- or afternoon.
`MR. COTTLER: And also at the table is John Intott (phonetic),
`
`
`
`3
`
`
`
`Case IPR2017-01592
`Patent 8,410,131 B2
`
`Owner Novartis.
`
`
`JUDGE POLLOCK: Good afternoon. Each side will have a
`total of 60 minutes to present arguments, notwithstanding the recent pretrial
`conference on September 12th. Each side is free to discuss its motions to
`exclude and other issues raised at the conference.
`
`
`Petitioner will open the hearing and may present arguments
`regarding the challenged claims, which the Board has instituted at trial, and
`its motion to exclude desire. Patent Owner will then respond to Petitioner's
`arguments and may additionally present its arguments regarding its motion
`to exclude. Petitioner may reserve up to 30 minutes of rebuttal to respond to
`Patent Owner's arguments on all issues, and Patent Owner may reserve up to
`10 minutes for surrebuttal.
`
`
`The Panel will attempt to keep track of time, but each party is
`responsible for monitoring the remaining time for argument and a few issues
`of housekeeping. When discussing any particular demonstrative, please
`refer to it by slide or page number to help maintain a clear transcript. This is
`particularly important today as Judge Harlow is attending remotely and
`cannot view what you have on the screen.
`
`
`When introducing a demonstrative for the first time, please note
`whether information on that slide is subsumed within your opponent's
`motions to exclude. And, finally, counsel may not interrupt the opposing
`party during the proceeding. To the extent counsel feels they must lodge an
`objection for the record, they may do so during their next allotted time, or, if
`no time remains, at the end of the presentations. Any objections will be
`taken under advisement.
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`
`
`4
`
`
`
`Case IPR2017-01592
`Patent 8,410,131 B2
`
`Okay. Petitioner, you have the burden of showing
`
`
`unpatentability to challenged claims. How much time, if any, would you
`like to reserve for rebuttal?
`
`
`MR. COTTLER: Twenty minutes, Your Honor.
`
`
`JUDGE POLLOCK: You may begin.
`
`
`MR. COTTLER: Thank you. Your Honors, Claims 1 through
`3 and 5 through 9 of the 131 patent, which are -- which cover a method of
`inhibiting the growth of advanced solid kidney tumors by administering the
`mTOR inhibitor, everolimus, were clearly and unambiguously disclosed on
`page 17 lines 20 -- lines 19 to 26 of Wasik Exhibit 1002, and are obvious
`modifications of the publicized use of another mTOR inhibitor,
`temsirolimus, for inhibiting the growth of advanced renal cell carcinoma, a
`type of kidney tumor.
`
`
`JUDGE POLLOCK: Pardon me, Mr. Cottler. Do you have
`copies of slides for the panel?
`
`
`MR. COTTLER: I do, Your Honor. May I approach?
`
`
`JUDGE POLLOCK: Please.
`
`
`MR. COTTLER: My presentation today will focus on Grounds
`1, 4, and 5 as they pertain to Claims 1 through 3 of the 131 patent. If those
`claims are found unpatentable, Novartis has not argued that Claims 5
`through 9, which are dose related, are separately patentable. And, of course,
`I'll take the Board's questions on any ground throughout my presentation.
`
`
`So with that, I'd like to start with Wasik Ground 1. Could I
`have Slide 9, please?
`
`
`JUDGE POLLOCK: Mr. Cottler --
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`
`
`5
`
`
`
`Case IPR2017-01592
`Patent 8,410,131 B2
`
`MR. COTTLER: Yes.
`
`
`JUDGE POLLOCK: -- I don't want to cut short in your
`
`
`planned talk, but I am particularly interested in Ground 4. So if you could
`find time to focus on that, I would appreciate it.
`
`
`MR. COTTLER: Yes, Your Honor. Is it okay if I start with
`Ground 1 for now?
`
`
`JUDGE POLLOCK: It's your time.
`
`
`MR. COTTLER: I will definitely have time for --
`
`
`JUDGE POLLOCK: It's your time.
`
`
`MR. COTTLER: -- Ground 4. Thank you. Wasik 1002 builds
`off what was known about everolimus's biological activity including its
`activity as an immunosuppressant. As Dr. Pantuck explained in Exhibit 10
`at paragraphs 199 to 209, Wasik reports data showing that everolimus
`inhibits the growth of lymphoma in animal models. In view that data, it is
`not surprising that part of Wasik's invention includes the use of everolimus
`and other related compounds for treating lymphoproliferative disorders,
`including lymphomas. But Wasik's invention extends beyond those uses. In
`view of the data I just mentioned, a POSA would have understood that
`Wasik contemplated that everolimus could do much more.
`
`
`Slide 10, please. Slide 10 contains evidence subject to motion
`to exclude, it's Exhibit 1010 at 211 to 216, 244, 246, and 247. On page 17 of
`Wasik's -- Wasik at lines 19 to 26, Wasik contemplates that in another
`embodiment -- that being key language -- another embodiment, everolimus
`can be used to inhibit the establishment of a tumor in a mammal, and Wasik
`does not qualify that that tumor must be a lymphatic tumor or a lymphoma.
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`
`
`6
`
`
`
`Case IPR2017-01592
`Patent 8,410,131 B2
`
`He goes on to explain that this method involves administering
`
`
`everolimus to a mammal to an amount sufficient to inhibit the establishment
`of a second tumor derived from a first tumor. And it goes on to explain that
`that first tumor can be a tumor of the brain, kidney, liver, breast, and ovary,
`and I highlight kidney. As Dr. Pantuck testified, a person of skill in the art
`would recognize that this portion of Wasik, at page 17 lines 19 to 26,
`discloses the method of using a therapeutically effective amount of
`everolimus for inhibiting the growth of an advanced solid kidney tumor.
`
`
`First, a person of skill in the art would recognize that the first
`kidney tumor is any tumor that originates from the kidney, solid or liquid.
`Wasik does not limit that first tumor to lymphoma or a lymphatic tumor.
`And that is consistent with a POSA's understanding that a tumor could be
`liquid or solid. As Novartis explained in page 5 of its response, tumors are
`classified as either liquid or solid based on the cell type of origin.
`
`
`Second, there's no dispute that establishment of a second tumor
`from a first tumor is indicative of an advanced tumor. The parties agree that
`an advanced tumor refers to a tumor that has spread to adjacent or distant
`tissue. Thus, by stating that everolimus can inhibit the formation of a second
`tumor from a first kidney tumor, Wasik is stating that everolimus can inhibit
`the growth of advanced kidney tumors including advanced solid kidney
`tumors. And, therefore, a person of skill in the art would interpret this
`portion of Wasik, as disclosed, that everolimus can inhibit the growth of
`advanced solid kidney tumors, a method covered by the challenged claims.
`
`
`And there's no statement in Wasik that limits the commonly
`understood meaning of tumor to liquid tumors. And, in fact, subsequent
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`
`
`7
`
`
`
`Case IPR2017-01592
`Patent 8,410,131 B2
`
`disclosures in Wasik make it even clearer that disclosures on page 17 lines
`19 to 26 are not limited to lymphomas.
`
`
`Slide 12, please. On this slide, on Exhibit 1159, paragraphs 242
`to 243 are subject to the motion to exclude. On this slide we see an excerpt
`that extends from line 26 on page 17 through line 9 on page 18. On page 17,
`at the bottom, Wasik elaborates on other embodiments of the invention.
`And those include inhibiting tumor formation, inhibiting metastasis,
`inhibiting tumor cell growth, inhibiting tumor cell proliferation, induction --
`inhibiting induction, sorry, induction of tumor cell death. And again here
`there is no qualification that the tumor must be lymphoma or a lymphatic
`tumor.
`And then the next paragraph, which extends from page 17 to
`
`
`page 18, Wasik's invention gets even broader. Wasik states that everolimus
`can be used to treat any disorder characterized by supernormal or
`inappropriate cellular proliferation. That does not limit it to lymphoma and
`it's not limited to lymphoproliferative disorders.
`
`
`Slide 13, please. On this slide, Exhibit 1010, at 26, 47, 198,
`and 211, are subject to the motion to exclude as is paragraph 242 of Exhibit
`1159. So there's more evidence that the term "tumor" on page 17 lines 19
`through 26 is not limited to liquid tumors. That is Novartis does not now
`dispute Wasik incorporates by reference Cottens Exhibit 1026 in its entirety.
`
`
`Cottens says that -- excuse me, at page 32 lines 20 to 21 of
`Wasik, Wasik says that all references are incorporated in its entirety. And
`Cottens discloses the use of everolimus for the treatment of proliferative
`disorders, including tumors. And, again, “tumors” is not limited to
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`
`
`8
`
`
`
`Case IPR2017-01592
`Patent 8,410,131 B2
`
`lymphatic tumors. And, in fact, during prosecution of the 131 patent,
`Novartis admitted that that disclosure in Cottens covers both solid and liquid
`tumors.
`As the Board recognized on page 15 of the Institution decision,
`
`
`that incorporation by reference is important. As Dr. Pantuck testified,
`because Wasik incorporates a subject matter of Cottens, and because Cottens
`contemplates both solid and liquid tumors, a POSA would understand that
`Wasik, likewise, contemplates solid and liquid tumors. And a POSA would
`have understood that the method of treating lymphatic tumors of Wasik may
`be applicable to the treatment of solid tumors.
`
`
`Slide 17, please. Like to briefly address Novartis's arguments
`in response to Petitioner's evidence regarding Ground 1. On Slide 17,
`Exhibits 1147, 1085, and 1159, at paragraph 299 are subject to Novartis's
`motion to exclude.
`
`
`First, Novartis argues that the term tumor in Wasik has a
`narrower meaning as compared to how the term is ordinarily understood in
`the art. Novartis relies heavily on the fact that Wasik is generally directed to
`inhibition or treatment of lymphoproliferative disorders in lymphoma.
`
`
`Can we pull up PX 10 again, please? But as you saw before,
`Wasik is broad enough to cover both solid and liquid tumors on page 17
`lines 19 through 26. Wasik instructed to inhibiting the growth of a second
`tumor that metastasizes from substantially any type of first tumor. That is,
`again, not limited to lymphatic tumors.
`
`
`And if we look at the excerpts of Wasik that Novartis relies
`upon, which talk about using everolimus for treating lymphatic tumors, and
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`
`
`9
`
`
`
`Case IPR2017-01592
`Patent 8,410,131 B2
`
`compare that to the disclosure on page 17 lines 19 through 26, we see that
`Wasik makes it clear that when he wants to talk about lymphatic tumors, he
`uses the phrase lymphatic tumors. And on page 17 lines 19 to 26, it doesn't
`mention lymphatic tumors. And, in fact, in that paragraph that's highlighted
`here. Lymphatic tumors and lymphoma is not mentioned -- are not
`mentioned at all.
`
`
`Slide 18, please. Slide 18 has the same objections to evidence
`as Slide 17. Novartis argues that tumors must be limited to liquid tumors in
`Wasik because solid tumors and lymphomas respond differently to
`medications. But a POSA would have been aware of drugs that had been
`used to inhibit the growth of both solid and liquid tumors.
`
`
`Slide 20, please. On this slide Exhibit 1085 is subject to
`Novartis's motion. As of February 2001, temsirolimus, an mTOR inhibitor,
`had undergone Phase I evaluation in a number of tumor types, including
`solid kidney tumors, that's RCC, breast tumors, lung tumors, and lymphoma,
`a liquid tumor. And activity wasn't, in fact, reported in almost tumor types.
`And that is reported on page 6683 of Hidalgo Exhibit 1006.
`
`
`Slide 21, please. And Slide 21 is subject to the same objections
`as the -- as Slide 18.
`
`
`I finally want to address Dr. Komanduri's testimony, and that
`was briefly discussed during the prehearing conference. Though it is true
`that Dr. Komanduri has expertise regarding the treatment of lymphoma, but
`he is not an expert in the treatment of solid excretory system tumors, or solid
`kidney tumors. In his residency, his one-year residency in which he had
`some exposure to the treatment of such diseases, does not qualify him to
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`
`
`10
`
`
`
`Case IPR2017-01592
`Patent 8,410,131 B2
`
`provide an opinion from the vantage of a POSA who has had experience
`dealing with those types of tumors. And he's not qualified to look at Wasik,
`at page 17 lines 19 through 26, and opine from the prospective of a POSA
`whether that disclosure says something about the treatment of solid kidney
`tumors.
`And even if Dr. Komanduri was qualified to do that analysis,
`
`
`his analysis was incomplete. In particular, he did not consider the teachings
`of the Cottens reference, which I referenced before, which is incorporated in
`its entirety into Wasik. And that testimony of his can be found at page 121
`line 23 through page 122 line 25 in Exhibit 1127.
`
`
`And, in fact, in that excerpt, counsel for Novartis objected to
`any questions about Cottens as being outside the scope of Dr. Komanduri's
`report, or declaration. And I would want to note the party's dispute with
`respect to Ground 1 stops at the issue as to whether tumors of the kidney
`include solid kidney tumors.
`
`
`And unless Your Honors have any more questions about
`Ground 1 or Grounds 2 and 3, I'll move on to Ground 4.
`
`
`JUDGE POLLOCK: Please go ahead.
`
`
`MR. COTTLER: Slide 35, please. Let's start with
`temsirolimus. As I mentioned before, temsirolimus was a known mTOR
`inhibitor and it was a promising compound with respect to its anti-cancer
`activity. What we know, and it is not disputed, is that skilled artisans
`noticed that rapamycin, another mTOR inhibitor, had anti-cancer activity in
`pre-clinical models. But because of certain issues, it cannot be given to
`humans. So companies developed analogs of rapamycin, including
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`
`
`11
`
`
`
`Case IPR2017-01592
`Patent 8,410,131 B2
`
`temsirolimus, as noted in Hidalgo Exhibit 1006 at 6680.
`
`
`temsirolimus was studied in two clinical trials, and the
`preliminary results of those trials was studied in the literature. Hidalgo is a
`review paper and summarizes those results, but more broadly attributes
`temsirolimus's activity to its ability to inhibit mTOR. It also discusses the
`history of the development of rapamycin and its analogs.
`
`
`Slide 36, please. On this slide, Exhibit 1010 at 179 to 185 and
`290 are subject to Novartis's motion. On Slide 36 we see an excerpt from
`page 6680 of Hidalgo. As we see from the title, Hidalgo identifies the
`rapamycin sensitive pathway as a target for cancer therapy, and that pathway
`has been known in the art as the mTOR pathway.
`
`
`Hidalgo notes that the anti-proliferative actions of rapamycin
`are due to its ability to modulate critical signal transduction pathways
`required for the cell cycle to traverse from the G1 to S phases. And this
`page goes on to explain that CCI-779, another name for temsirolimus, is a
`soluble ester analog of rapamycin that was selected for development as an
`anti-cancer agent. And the introduction of Hidalgo concludes that the paper
`summarizes the principle mechanisms of action of rapamycin, specifically
`its effect on the rapamycin-sensitive signal transduction pathways.
`
`
`Slide 37, please. On this slide, Exhibit 1010 at 180 and 183, are
`subject to Novartis's motion. On page 6681, Hidalgo discusses the
`mechanism of action of rapamycin and rapamycin analog. So we can see
`that in the highlighted portion in the top left portion of this slide.
`
`
`And we knew at least two analogs of rapamycin in February
`2001, those were everolimus and temsirolimus. Figure 1 provides a version
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`
`
`12
`
`
`
`Case IPR2017-01592
`Patent 8,410,131 B2
`
`of the -- a simplified version of the mTOR pathway and shows how the
`mTOR -- how an mTOR inhibitor can block that pathway. And Dr. Pantuck
`walks through those steps in paragraph 183 of Exhibit 1010.
`
`
`And as we can see in the summary of Figure 1 on Slide 37, first
`the rapamycin, or its analog, binds to FKBP-12 and that complex then
`blocks mTOR, and then the blocking of mTOR inhibits two proteins, 480-
`BP1 and p70-S6K. And the inhibition of those two proteins results in a
`decrease in the translation of mRNA of protein essential for cell cycle
`progression from the G1 to S phase.
`
`
`As Dr. Pantuck explained, a POSA would have understood that
`there was a correlation between mTOR inhibition and the anti-tumor action
`of rapamycin and its derivatives, or analogs.
`
`
`Slide 38, please. On this slide paragraphs 188, 284, and 290 of
`Exhibit 1010 are subject to Novartis's motion. On page 6683, Hidalgo
`summarizes the preliminary results from two Phase I trials of temsirolimus.
`Notably, major tumor responses were identified in patients with renal cell
`carcinoma, a solid kidney tumor. And there is no dispute that the patients in
`those trials, in fact, had advanced renal cell carcinoma.
`
`
`The fact that activity was observed would have informed a
`person of skill in the art that therapeutically effective amounts of
`temsirolimus were given in those studies. In fact, Hidalgo concludes in the
`abstract on page 6680 that temsirolimus had impressive anti-tumor activity
`in several types of refractory neoplasms. And, of course, renal cell
`carcinoma is one of those neoplasms.
`
`
`As Dr. Pantuck testified in paragraph 290 of Exhibit 1010,
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`
`
`13
`
`
`
`Case IPR2017-01592
`Patent 8,410,131 B2
`
`Hidalgo, therefore, teaches a method for inhibiting the growth of advanced
`solid kidney tumors using an effective amount of an mTOR inhibitor
`temsirolimus. And, again, the activity is due to temsirolimus's ability to
`inhibit mTOR.
`
`
`Slide 39, please. On Slide 39 paragraph 172 of Exhibit 1010 is
`subject to Novartis's motion. Slide 39 summarizes the disclosures of
`Alexandre, which is Exhibit 1007. Alexandre, in abstract, provides similar
`teaching as Hidalgo. Is summarizes the preliminary results of one of the two
`Phase I trials mentioned in Hidalgo of temsirolimus.
`
`
`It notes that significant tumor regressions were rapidly
`observed in patients with advanced renal cell carcinoma. Alexandre also
`attributes that activity to the drug's ability to inhibit mTOR, and that is again
`consistent with Hidalgo's teachings. So what we understand from Hidalgo
`and Alexandre is that therapeutically effective amounts of temsirolimus
`inhibit the growth of advanced renal cell carcinoma, a type of kidney tumor,
`and that that activity is associated with the compound's ability to inhibit
`mTOR.
`JUDGE POLLOCK: Mr. Cottler, how much weight should we
`
`
`give to these reports of Phase I studies in terms of the effectiveness of
`mTOR inhibitors improving RCC?
`
`
`MR. COTTLER: I think in the context of these claims and in
`the context of Petitioner's burden of proving obviousness, these trials should
`be given weight and a person of skill in the art would have given them
`weight because the trials report that this drug was active in patients with
`advanced renal cell carcinoma. And, in fact, if we turn to Slide 47 -- for the
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`
`
`14
`
`
`
`Case IPR2017-01592
`Patent 8,410,131 B2
`
`record, on Slide 47 Exhibits 1081, 1080, and 1131 are subject to Novartis's
`motion -- we see that in five separate conferences investigators reported the
`results of temsirolimus in terms of its activity in Phase I trials, including
`with respect to its activity in inhibiting the growth of advanced renal cell
`carcinoma. That clearly shows that these results were significant to persons
`of skill in the art.
`
`
`Furthermore, the next slide --
`
`
`JUDGE POLLOCK: Do these conference reports, do they
`discuss the same results as the papers you were talking about?
`
`
`MR. COTTLER: That is correct, Your Honor. The two Phase I
`trials were reported at several conferences.
`
`
`JUDGE POLLOCK: Thank you.
`
`
`MR. COTTLER: Turn to Slide 48 -- okay, we're there already.
`On Slide 48, Exhibit 1010 at paragraph 116, Exhibit 1159 at 100, and
`Exhibits 1039 and 1081 are subject to Novartis's motion.
`
`
`In addition to being reported at those five conferences, as I
`mentioned, the results of the Phase I trials were also mentioned in Hidalgo,
`which we discussed before, they were mentioned in Exhibit 1081
`Hutchinson, in the journal called The Lancet, in the news article, and they
`were also discussed in a patent application, and that was published as
`Exhibit 1039. And that patent application reported that these results are
`particularly surprising considering that the patients in the studies had
`advanced cancers that were generally refractory to standard treatment and
`also considering that these were Phase I clinical trials in which efficacy is
`often limited, as the primary objective of Phase I trial is to determine the
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`
`
`15
`
`
`
`Case IPR2017-01592
`Patent 8,410,131 B2
`
`safety and tolerability of the drug being evaluated.
`
`
`So the fact that these results were reported in so many different
`references, and the fact that these results were praised as they were,
`demonstrates that a person of skill in the art would have given them
`significant weight.
`
`
`JUDGE HARLOW: Counsel, Patent Owner points out that
`Hidalgo and Alexandre didn't include controls. How do we weigh the strong
`results from those references against the fact that there wasn't a control?
`
`
`MR. COTTLER: That's a good question, Your Honor. So in
`terms of proving that a drug is safe and effective for FDA approval in such --
`in terms of the data that it needs to pass a Phase III trial, yes, a control would
`be important, but these claims do not require FDA approval. They don't
`require it at the same level of efficacy from a Phase III trial that the FDA
`requires to approve a drug. These claims require that the drug everolimus
`inhibit the growth of advanced kidney tumors. And the data from the prior
`art regarding temsirolimus demonstrates that mTOR inhibitors do have
`activity against such tumors.
`
`
`Do Slide 39 again, please. So getting back to temsirolimus, a
`POSA would have noted that temsirolimus, while in development also as an
`oral agent, was being evaluated only as an IV drug. Dr. Pantuck testified at
`paragraph 115 of Exhibit 1010 that oral administration is preferred for
`cancer treatment because of better patient compliance. And that is further
`supported by Demario Exhibit 1084 at 2557.
`
`
`In view of these compliance issues, a person of skill in the art
`would have been motivated to replace temsirolimus with a drug that could
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`
`
`16
`
`
`
`Case IPR2017-01592
`Patent 8,410,131 B2
`
`be administered orally. And a search of an mTOR inhibitor that could be
`given orally would have led a person of skill in the art to everolimus.
`Everolimus was disclosed a number of patents and scientific references by
`February 2001, including Crowe, Schuler, Neumayer, and Navarro.
`
`
`Slide 40, please. The evidence on Slide 40 subject to Novartis's
`motion is Exhibit 1010 at 295, 296. So Slide 40 has an excerpt from Crowe
`Exhibit 1004. Crowe states that everolimus is an analog of rapamycin and
`shares the same mechanism of action. And if you recall, we talked about
`rapamycin's mechanism of action in Hidalgo 1006.
`
`
`Slide 41, please. So Slide 41 contains excerpts from Schuler
`Exhibit 1008, which is cited in Crowe. And this reference teaches that
`everolimus is a new orally active rapamycin derivative and has been selected
`for development. That is on page 36. Schuler states that like rapamycin,
`everolimus inhibits p70S6K. The fact that a compound inhibits that protein
`is a sign that it also inhibits mTOR as mTOR is upstream of that protein.
`
`
`If you could return to Slide 37. So we see here at the bottom
`left portion of the slide, the Figure 1 from Hidalgo, I'm pointing to p70S6K,
`this is what Schuler reported that everolimus inhibited and we see that
`mTOR is directly upstream of that indicating that everolimus also binds
`mTOR.
`And we understand everolimus combined to mTOR was further
`
`
`confirmed by Sedrani, Exhibit 1020. That reference reported, at page 2193,
`that everolimus bound to FKBP12, and that this complex of FKBP12 to
`everolimus was expected to block mTOR just as rapamycin did.
`
`
`Go back to Slide 41. Moreover, consistent with Hidalgo,
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`
`
`17
`
`
`
`Case IPR2017-01592
`Patent 8,410,131 B2
`
`Schuler explained that rapamycin acts as a later -- acts at a later stage of a
`cell cycle arresting the cells at the late G1 stage of the cell cycle preventing
`them from entering the S phase. That is explained in paragraph 152 of
`Exhibit 1010 and page 36 of Schuler.
`
`
`In view of these teachings, a person of skill in the art would
`have understood that like rapamycin and temsirolimus, everolimus, a
`rapamycin analog, was an mTOR inhibitor. And that's supported at Petition
`at 22, citing Dr. Pantuck's testimony in Exhibit 1010 at 154 to 156.
`
`
`In fact, we see here on this excerpt from the abstract on Slide 41
`that when administered orally, everolimus has at least the same
`(indiscernible) activity as rapamycin. And that is because, as Schuler
`explains, that everolimus exhibits favorable PK properties when compared
`to rapamycin and that more favorable PK properties promise to provide a
`clinical advantage. And that comes from page 41 of Schuler. And on top of
`all this, everolimus had already been administered to humans.
`
`
`Slide 42, please. On this slide Exhibit 1010 at 164 to 166, 160
`to 170, and 294 are subject to Novartis's motion, and there's a correction for
`the cite to Exhibit 1009 Neumayer on the slide, it should be pages 694 and
`700 not 994 and 700.
`
`
`So on PDX-42 we see an excerpt from Neumayer, 1009. And
`that reports that in Phase I trials of everolimus, which we're evaluating
`everolimus as an immunosuppressant, doses as high as 25 milligrams of
`everolimus were found to be safe. And Neumayer also states at page 694
`that everolimus had a similar mechanism of action as rapamycin and that the
`structural modification made to rapamycin to get everolimus allowed the
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`
`
`18
`
`
`
`Case IPR2017-01592
`Patent 8,410,131 B2
`
`development of a solid dosage formulation that is more convenient to
`administer than rapamycin. And that's from Petition at 23 to 24 and Dr.
`Pantuck's declaration Exhibit 1010 at 165 to 166.
`
`
`So Neumayer provides teachings consistent with Schuler and
`Crowe, and further teachers that oral doses of everolimus up to 25
`milligrams were safe when given to humans. And we know now that this
`dose range encompasses therapeutically effective amount of everolimus as
`according to the 131 patent Claims 5 through 9.
`
`
`Slide 43, please. From this slide, paragraphs 219 to 222 of
`Exhibit 1010 are subject to Novartis's motion. On Slide 43 we see excerpts
`from Navarro Exhibit 1003. Navarro discloses suitable oral unit dosage
`forms containing 0.1 to 10 milligrams of everolimus for the treatment of
`tumors. And Dr. Pantuck explains in Exhibit 1010 that a POSA would have
`been motivated to combine the temsirolimus literature, and that is Hidalgo
`and Alexandre, with the everolimus literature, that is Crowe, Schuler,
`Neumayer, and Navarro.
`
`
`temsirolimus showed promising activity against advanced renal
`cell carcinoma, and that that activity was correlated with the drug's ability to
`inhibit mTOR. Despite that drugs activity, however, a POSA would have
`been motivated to use an agent that could be given orally, and that agent was
`everolimus. The everolimus art teaches that like rapamycin and
`temsirolimus, everolimus was an mTOR inhibitor. And that art regarding
`everolimus further provides therapeutically effective amounts of everolimus,
`including for the treatment of tumors, as taught in Navarro.
`
`
`And as Dr. Pantuck explains in paragraph 293 of Exhibit 1010,
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`
`
`19
`
`
`
`Case IPR2017-01592
`Patent 8,410,131 B2
`
`a POSA would have reasonably expected that everolimus would have been
`effective to inhibit the growth of advanced renal cell carcinoma in view of
`temsirolimus's activity in Phase I trials, and the fact that everolimus,
`rapamycin, and temsirolimus were all known to be mTOR inhibitors. And
`that's reported in Petition at page 487. And for these reasons, Your Honors,
`as the challenge claims are obvious in view of Hidalgo, Alexandre, Crowe,
`Schuler, Neumayer and Navarro.
`
`
`If I could briefly address some of Novartis's arguments in
`response to Petitioner's evidence. Go to Slide 46, please. So from 46,
`Exhibit 1010 at 183 to 185 is subject to Novartis's motion. Novartis argues,
`as Judge Harlow mentio
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
