UNITED STATES PATENT AND TRADEMARK OFFICE
`__________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________
`
`CELLTRION, INC.,
`Petitioner,
`
`v.
`
`GENENTECH, INC.,
`Patent Owner.
`__________
`
`Cases IPR2017-01373 and IPR2017-01374
`Patent 6,407,213 B1
`
`__________
`
`Record of Oral Hearing
`Held: July 16, 2018
`__________
`
`
`
`
`Before SHERIDAN K. SNEDDEN, ZHENYU YANG, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`
`
`
`
`
`
`__________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________
`
`CELLTRION, INC.,
`Petitioner,
`
`v.
`
`GENENTECH, INC.,
`Patent Owner.
`__________
`
`Cases IPR2017-01373 and IPR2017-01374
`Patent 6,407,213 B1
`
`__________
`
`Record of Oral Hearing
`Held: July 16, 2018
`__________
`
`
`
`
`Before SHERIDAN K. SNEDDEN, ZHENYU YANG, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`
`
`
`
`
`
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`Cases IPR2017-01373 and IPR2017-01374
`Patent 6,407,213 B1
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`
`
`APPEARANCES:
`
`ON BEHALF OF THE PETITIONER:
`
`
`CYNTHIA LAMBERT HARDMAN, ESQ.
`Goodwin Procter, LLP
`The New York Times Building
`620 Eighth Avenue
`New York, NY 10018
`212-459-7295
`chardman@goodwinlaw.com
`
`
`
`ON BEHALF OF THE PATENT OWNER:
`
`
`DARALYN J. DURIE, ESQ.
`Durie Tangri, LLP
`217 Leidesdorff Street
`San Francisco, CA 94111
`415-362-6666
`ddurie@durietangri.com
`
`
`
`
`The above-entitled matter came on for hearing on Monday,
`
`July 16, 2018, commencing at 1 p.m. at the U.S. Patent and
`Trademark Office, 600 Dulany Street, Alexandria, Virginia.
`
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`P R O C E E D I N G S
`- - - - -
`JUDGE POLLOCK: Good afternoon. This is the final
`hearing in IPR2017-01373 and IPR 2017-01374 involving U.S. Patent
`No. 6,407,213 B. I am Judge Pollock. With me are Judges Snedden
`and Yang.
`Before we begin the substance the hearing I would like to ask
`the parties to introduce themselves.
`Counsel for Petitioner Celltrion, would you please identify
`yourself and your colleagues?
`MS. HARDMAN: Good afternoon, Your Honor. My name
`is Cynthia Hardman from the law firm Goodwin Proctor on behalf of
`Petitioner. With me is Elizabeth Holland, Robert Cerwinski also of
`Goodwin Proctor. We have a client representative Ms. Ribka
`Yombrase. And with me at counsel table is Cord Chase, our trial
`technician.
`JUDGE POLLOCK: Counsel for Patent Owner Genentech,
`would you please identify yourself and your colleagues?
`MS. DURIE: Good afternoon, Your Honors. My name is
`Daralyn Durie from Durie Tangri representing Genentech. With me
`at counsel table is Andrew Danforth from the WilmerHale firm. Also
`present in the courtroom is Laura Stordo in house at Genentech, as
`well as many of our attorneys from --
`(Laughter.)
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`MS. DURIE: -- and from Genentech, who I will not
`introduce all of them to the Panel. Thank you.
`JUDGE POLLOCK: Welcome. As set forth in the hearing
`order each side will have 50 minutes. Petitioner will go first
`followed by Patent Owner. Petitioner may reserve time for rebuttal.
`Parties may, but need not, use any portion of your time to address
`pending motions, however, when introducing information subject to a
`motion to strike or exclude, counsel shall briefly inform the Court --
`the Panel of this controversy. The Panel will attempt to keep track of
`time, but each party is responsible for monitoring the remaining time
`for argument.
`In view of the strong public policy for making all information
`disclosed in inter-parties proceedings open to the public, confidential
`information relied upon or identified in a final written decision will
`generally be made public, however, in response to Patent Owner's
`concerns regarding the confidentiality of evidence related to its
`attempt to antedate Kurrle and Queen 1990, parties may request that
`we clear the hearing room of persons they deem not authorized to
`access that information. We ask that the parties narrowly tailor any
`such requests so we can get through this in a reasonable amount of
`time. Subject to our July 11th order, the transcript will be
`temporarily sealed in its entirety.
`I understand there may be members of the press here. Would
`you identify yourselves?
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`(A show of hands.)
`JUDGE POLLOCK: One? Okay.
`When discussing any particular demonstrative, please refer to
`it by slide or page number to help maintain a clear transcript.
`
`Counsel may not interrupt an opposing party during this
`proceeding. To the extent a party 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.
`Finally, by email received today Petitioner informs us that due
`to a clerical error in IPR2017-01373 we did not institute on Claim 65
`with respect to Ground 1, and in IPR2017-01374 we did not institute
`on Claim 72 with respect to Ground 1. Both parties nevertheless
`appear to have proceeded as if we had instituted on those claims and
`those grounds. Petitioner notes, for example, that in its Patent Owner
`responses Patent Owner addressed Claim 65, Ground 1 in IPR2017-
`01373, as well as Claim 72, Ground 1 in IPR2017-01374. As there
`appears to be no prejudice to Patent Owner the Panel is inclined to
`institute as to the inadvertently omitted grounds.
`Does the Patent Owner object?
`MS. DURIE: Your Honor, I would simply like to note that
`this was not the result of a clerical error, certainly not on the Board's
`part. In its original Petition Celltrion did not include Claim 65 as to
`Ground 1 within its summary chart at the beginning. We raised this
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`issue in our POPR noting that it had not been included. Pfizer in the
`parallel petition amended prior to the institution decision in order to
`add Claim 65 to Ground 1. Celltrion did not do so.
`And in the Board's institution decision it instituted on all of
`the grounds that were set forth in that chart which was in compliance
`with the CFRs identifying the specific grounds that were instituted.
`So we believe the Board did act in accordance with Celltrion's explicit
`request. In fact, in Celltrion's demonstratives for this hearing it did
`not include Claim 65 within Ground 1 and nor did we.
`JUDGE POLLOCK: Thank you for that clarification, Ms.
`
`Durie.
`
`Petitioner, any words?
`MS. HARDMAN: Yes, Your Honor. Whether the clerical
`error arose through the Board's -- in the Board's institution decision or
`in the summary chart, I think it's clear that there was in fact a clerical
`error given that both parties did argue the claims within the grounds.
`As noted in my email and as you mentioned Petitioner believes there's
`no prejudice to institution -- instituting on these claims at this point.
`The demonstratives are not evidence and should be irrelevant to the
`question here. And I also think that the Supreme Court's SAS case
`requires that the Board institute on these claims on these grounds at
`this juncture, at least as the Board has issued guidance construing the
`SAS case.
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`JUDGE POLLOCK: Very well. Thank you for the
`clarification, Ms. Durie.
`We order that the institution decision in IPR2017-01373
`include Claim 65 with respect to Ground 1 and that the institution
`decision in IPR2017-01374 include Claim 72 with respect to Ground
`1, and we'll proceed on that basis.
`Petitioner, you have the burden of showing un-patentability of
`the challenged claims. How much time would you like to allot to this
`portion of your presentation?
`MS. HARDMAN: Thirty minutes, please.
`JUDGE POLLOCK: You may begin.
`MS. HARDMAN: Thank you, Your Honor.
`JUDGE POLLOCK: Ms. Hardman, do you have hard copies
`of the demonstratives with you?
`MS. HARDMAN: Unfortunately, no we don't. I apologize,
`Your Honor.
`JUDGE POLLOCK: That's fine. If you'd just give me one
`minute.
`MS. HARDMAN: Absolutely.
`(Pause.)
`MS. HARDMAN: Actually, Your Honor, we do have two
`copies available if that's helpful.
`JUDGE POLLOCK: Ah, please. Thank you. When you're
`ready please.
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`MS. HARDMAN: Thank you. I'd like to start please with
`slide 3 just to provide us an overview. In the petitions, Petitioner
`challenged 29 claims. Patent Owner in its Patent Owner response
`indicated that it is not attempting to defend the patentability of six of
`those claims. As demonstrated in the petition the six claims that
`Patent Owner is no longer defending do nothing more than attempt to
`claim the product of following prior art methods of humanizing
`antibodies.
`The prior art taught how to select framework residues that
`should be substituted when humanizing antibodies and the prior art
`directed persons of ordinary skill in the art to the same framework
`residues that appear in the claims that Genentech is no longer
`challenging.
`We'll concentrate today on the claims that remain in dispute.
`These claims also recite a set of residues to substitute when
`humanizing antibodies, and the specific set of residues recited in the
`challenged claims has extensive overlap with the sets of residues
`recited in the abandoned claims.
`The remaining claims differ from the abandoned claims by
`just a handful of limitations including by reciting a consensus
`sequence, reciting a property of having lower immunogenicity
`compared to the non-human antibody, and to having more binding
`affinity than the corresponding non-human antibody. But as we'll
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`discuss these additional limitations are also insufficient to distinguish
`the claims from the prior art.
`Could we have slide 13, please? This is just some -- Claims 1
`and 4, some representative claims just to try to orient us quickly to the
`terminology. Now you'll notice that these claims are not directed to
`any particular antibody. Instead, they're just generically directed to a
`humanized antibody or a part of a humanized antibody and Claim 1
`recites a laundry list of framework candidates for potential
`substitution in any given antibody.
`Now we'll be talking today a lot about non-human antibodies.
`That's often a mouse antibody, so I may just sometimes refer to that as
`the mouse or murine antibody.
`Slide 14, please. The preamble of this claim recites a
`humanized antibody variable domain, and that is indicated here on
`slide 14 in the red outlined boxes.
`And slide 15, please. And within those variable domains are
`the CDRs, the Complementarity Determining Regions, and that's the
`part of the antibody that binds an antigen. And in humanized
`antibodies these sequences, the CDRs are taken directly from the non-
`human antibody.
`Slide 16, please. And interspersed in the CDRs are the
`framework regions and it was well known in the prior art that
`framework regions were known to provide support for the 3D
`structure of the antibody.
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`And if could have Callout 1A, Mr. Chase, please? This is an
`excerpt of the patent. This is from column 2, lines 53 to 61. And we
`can see here that the specification itself already acknowledges that it
`was known in the prior art that to achieve binding affinity in a
`humanized antibody it was necessary to replace one or more
`framework substitutions -- or framework residues with the murine
`residue.
`Slide 9, please. Now the level of skill in the art here is quite
`high. It requires that POSAs have a Ph.D. with practical or industrial
`experience in antibody development, and Petitioner's arguments are
`supported by the testimony of Dr. Lutz Riechmann. Dr. Riechmann
`was a POSA in the early '90s. He engineered the first fully
`humanized antibody which was called CAMPATH-1. He was
`working at the time in Sir Gregory Winter's lab at the MRC in
`Cambridge, U.K.
`And Dr. Riechmann's credentials should be contrasted with
`those of Patent Owner's expert Dr. Wilson. There's no evidence in
`the record that Dr. Wilson has humanized an antibody as of the
`priority date here in the early 1990s.
`Let's talk about the consensus sequence limitation.
`And that's slide 86, please, Mr. Chase.
`Now you'll hear a lot from Patent Owner about the consensus
`sequence and how it's the purportedly novel aspect of their invention.
`It should be noted though that this limitation occurs in only five of the
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`challenged claims so it has limited applicability across the challenged
`claims. And Patent Owner is not attempting to antedate or establish
`an earlier date of invention for the claims that have the consensus
`sequence limitation, so when we talk about, for example, the Queen
`1990 reference, which discloses a consensus sequence expressly, that's
`undisputedly prior art. There's no dispute that that's prior art to these
`claims.
`Slide 36, please. Now Dr. Carter, one of the inventors,
`testified that the crux of his invention was use of this consensus
`sequence which Patent Owner is characterizing as a novel strategy for
`minimizing immunogenicity, but as the record shows, Dr. Carter was
`not the first to recognize that the more generically human your
`acceptor sequence is the less immunogenic it will be.
`So for example, the Queen and Kurrle references already
`taught the benefit of swapping out rare or unusual amino acids in your
`human sequence with those that are more typically found in human
`antibodies. And as we can see on this demonstrative 36, the excerpt
`from Queen 1990 teaches exactly that, that if you swap out rare
`residues and make them more typical of what's found in humans, the
`expectation is that the antibody will then be less immunogenic.
`Slide 87, please. Now as I mentioned, Queen 1990 expressly
`disclosed the use of a consensus sequence as the basis for the
`humanized antibody, and that's what in what Queen designates as
`Criterion I.
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`Slide 76, please. Now Queen 1989 also disclosed the use of a
`human consensus sequence. It suggested the same concept to
`POSAs, that you should swap out rare or unusual residues in your
`human acceptor sequence with the goal of making the antibody more
`generically human. So it's teaching POSAs getting toward a
`consensus sequence.
`98, please. And the Kurrle reference also taught the same
`concept of swapping out rare residues for a consensus residue, and
`that's demonstrated on slide 98.
`Slide 88, please. Now this reference is the Foote reference.
`It's Exhibit -- well, I don't have the exhibit number readily available,
`but it is addressed in Dr. Riechmann's second declaration at paragraph
`30. I think the exhibit is 1193. This exhibit is subject to one of
`Patent Owner's motions to strike.
`The reason we introduced this in the reply, in the Petitioner's
`reply is because Patent Owner's response indicates or suggests, or
`actually expressly states that the use of a consensus sequence in a
`humanized antibody is novel. But as we can see from the Foote
`reference this discloses a humanized antibody that in fact uses a
`consensus sequence for one of the -- for the light chain in that
`particular antibody.
`So we think this is a proper reply, proper to bring this up in
`reply to controvert what Patent Owner is saying is the state of the art
`that nobody else was using consensus sequence and that they were the
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`first. This demonstrates that that's actually not in accord with the
`prior art.
`JUDGE POLLOCK: Ms. Hardman?
`MS. HARDMAN: Yes.
`JUDGE POLLOCK: In Dr. Riechmann's first declaration did
`he talk about this general subject matter? I realize he did not raise
`the particular paper, but did he talk about the subject matter?
`MS. HARDMAN: He absolutely did because he talked
`about, for example, Queen 1990 disclosing use of a consensus
`sequence. He also talked about what we just -- what I just
`mentioned, Queen 1989, directing users toward a consensus sequence.
`So he talked about the concept of consensus sequence in the prior art,
`although he did not talk about the use of a consensus sequence in this
`antibody that Foote made.
`JUDGE POLLOCK: Thank you.
`MS. HARDMAN: And I should also mention that not only
`Foote used this consensus sequence, but Foote actually provided this
`consensus sequence to Dr. Riechmann and Dr. Riechmann also used it
`when he was humanizing his antibodies, so it's the same sequence that
`appears in these two prior art antibodies.
`JUDGE YANG: So, counsel, when Queen 1990 discussed
`consensus sequence, do you agree it falls under, I guess,
` the definition of the consensus sequence of the challenged patent?
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`MS. HARDMAN: Yes, Your Honor. Can we have Callout
`2B, please? I'd like to compare what Dr. Riechmann says about
`Queen 1990's consensus sequence and what that means to a POSA,
`with what the patent means. As we know, the patent provides an
`expressed definition of consensus sequence, but there's really no
`difference between that consensus sequence and what Queen 1990
`was talking about.
`So in Dr. Riechmann's first declaration in paragraph 173 he
`talks about Queen 1990's disclosure of a consensus framework, and
`Dr. Riechmann says that would have told the POSA to look to the
`Kabat '87 reference, which at the time of publication of Queen the
`Kabat '87 reference was a compilation by Dr. Kabat and others where
`they compiled all of the known antibody sequences that were
`available at the time and showed for each residue position what the
`most common residue was at each position. So it provided a
`consensus sequence. And Dr. Riechmann testifies that's how a POSA
`would have understood consensus framework in Queen.
`And if we look at what the patent says here; this comes from
`column 11, lines 55 to 60 of the ’213 patent, they also say that a
`preferred embodiment of the human consensus sequence as defined in
`the patent would be derived from Kabat 1987. So in fact it's the same
`thing.
`Slide 92, please. And this is in fact underscored by
`Dr. Presta's testimony. He also -- he testified that when he was
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`making the consensus sequence that he claims as his invention he in
`fact also consulted Kabat '97 and used that to come up with the
`consensus sequence.
`JUDGE POLLOCK: Ms. Hardman, if we take it that the
`consensus sequences are generally derived from one of the Kabat
`references, including in the patent, is our provisional construction of
`consensus sequence overly broad?
`MS. HARDMAN: No, I don't think it's overly broad. The
`patent defines consensus sequence, so I think we take that as our
`definition. And I believe that's the definition that the Board used.
`The -- perhaps what you're getting at is the definition refers to all
`sequences and Patent Owner has made an issue that, well, our patent
`says -- defines it as all sequences, whereas Queen -- they contend that
`Queen 1990 just meant many sequences. And by "many," there's --
`according to Patent Owner there's no boundaries and we really don't
`know what subset Queen had in mind.
`I think this is just really an issue of semantics, though, that
`Patent Owner has injected. If we could have Callout 3A, please. On
`page 52 of the Patent Owner response we can see here that when the
`Patent Owner is talking about consensus sequence as used in the ’213
`patent, it says it should be derived from all -- they highlighted "all,"
`but I'm going to highlight the word "known."
`So the Patent Owner, too, contends that even though you read
`that definition in the patent that says "all sequences," it's really
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`referring to all known sequences and there's no dispute that as of
`Queen 1990 that was really synonymous with Kabat 1987, which was
`the only reference identified in this record that compiled all the known
`sequences to date.
`So maybe we can now turn to the other points of novelty that
`Patent Owner contends distinguish their claims in terms of the specific
`substitutions that are recited in some of the claims.
`Now one of the main steps of antibody humanization that was
`taught in the prior art was to identify the candidate framework
`residues in your human acceptor sequence that should be mutated
`back to mouse. And it was well known, as we discussed earlier, the
`reason why you do this is to make sure that you maintain the 3D
`confirmation structure of the antibody.
`It was known that 3D structure is the critical aspect of an
`antibody for binding to the antigen. You need to maintain the CDRs
`in a particular confirmation. And the way you do that is to make sure
`the antibody folds up correctly.
`And so the prior art taught a variety of ways to identify
`candidate framework residues that had an impact on structure and
`therefore would be candidates for switching back to mouse.
`Could we have slide 32, please? So focusing first on Queen
`1990, it has Criterion III where it teaches POSAs to consider back-
`mutations to residues that are immediately adjacent to one or more of
`the CDRs. And Queen explains that these amino acids are
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`particularly likely to interact with the CDRs and therefore it teaches
`that if you keep these as the human rather than mutating back to
`mouse, you quite likely will distort the CDR which is going to reduce
`binding affinity.
`Can we look at Callout 5A, please? That's figure 2 from
`Exhibit 1003. This is figure 2 that comes from Dr. Riechmann's first
`declaration, and what he's depicting here is a snapshot or an
`explanation of the Kabat numbering system for antibody heavy and
`light chains.
`And so at the top -- so I think as you probably read in the
`papers Kabat determined or defined where the CDRs are located in all
`antibody light chains and all antibody heavy chains. And so we have
`here on the top the heavy chain. Kabat identifies CDR 1 as falling
`between residues 31 and 35. CDR 2 falls between residues 50 and
`65. And you can see there are other CDRs that he identifies here by
`the red horizontal line. And the green horizontal line shows the
`framework residues in which the CDRs are sitting, so again the
`framework regions are interspersed between the CDRs.
`So when Queen 1990 directs POSAs to select its candidates
`for back mutation in residues adjacent to Kabat, this was another way
`of telling POSAs to look at -- for example, on the heavy chain that
`would be the CDR 1 ends at residue 36. This is on the heavy chain
`on the top. So the adjacent residue is 36H. And that is a residue
`that is recited in many of the claims.
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`And when Queen 1990 directs POSAs to look again at the
`adjacent CDRs, another residue that they would look at on the light
`chain is 98H, which falls just on the outside of CDR 3. And 98H is --
`I'm sorry, 98L. We're looking now at the light chain on the bottom.
`So CDR 3 in the light chain ends at residue 97. 98L is a residue that
`is adjacent to the CDR, so that's what Queen was referring to when
`they directed POSAs to look at the adjacent residues.
`Slide 34, please. So Claims 30 and 63, for example, are
`recited as Markush group where the substitution is at a site selected
`from the group consisting of: and they have a laundry list of residues
`here. And you can see 98L and 36H are among them. And due to
`Queen's disclosure that would anticipate claim with this Markush
`group or render them obvious.
`Slide 84, please. Now I mentioned Kurrle. Kurrle is another
`reference that discloses humanizing an antibody. And it discloses a
`series of steps that are similar to Queen that Kurrle goes through to
`identify residues for substitution. He then actually makes the
`substitutions and explores human variance. And among the
`substitutions that he discloses he made in his variance were, as
`Dr. Riechmann shows here on slide 84, 4L, 69H, 71H, 73H and 76H.
`That analysis you can see in the underlying papers, Exhibit 1003C at 4
`to 7. And one or more of these residues shown on this slide are
`recited in a number of the claims that are still at issue.
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`Now there's a whole -- as number of other secondary
`references in our grounds that teach the importance of various
`residues to antibody structure; for example, the Furey reference.
`That reference highlights the importance of residue 66L as a
`framework residue that interacts with CDRs. And as Dr. Riechmann
`explains, based on Queen 1990's Criterion IV which directs POSAs to
`look at solid crystal structures to identify residues that interact with
`CDRs, a POSA would have looked at the Furey reference, which
`again highlights residue 66L recited in many of the claims.
`Another secondary reference is the Tramontano reference.
`That discloses that residue 71H was well known to be in contact with
`the CDRs and was important for maintaining CDR confirmation. So
`again, a residue that would be well known to POSAs and on their list
`of residues to check when they're humanizing.
`The Chothia 1985 and Chothia and Lesk references also
`identify residues that were important to maintaining 3D
`conformational structure. And as Dr. Riechmann explains, this
`would have led POSAs to residues 93H and 78H.
`JUDGE YANG: Counsel, I don't know if you intend to go to
`Queen 1989, but I have a question if you can address it at some point
`before you step off, that would be good.
`I understand the parties disputes about this notion of whether
`Queen 1989 or even the knowledge of one skilled in the art actually
`suggests the 3.3 angstrom cut-off that is -- I think Petitioner relied on.
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`And the Patent Owner argued that only Queen 1990 disclosed that. If
`you can address that, it would be helpful to me.
`And when you address that I have a specific request. That is
`when I looked at the reply on page 11, right above the heading 6 there
`are two citations: Exhibits 2014 and 2045. I think 2014 is incorrect.
`And for 2045 if you can give me a pincite, that will be helpful. So
`either you or your co-counsel before you leave I'd like to get an
`answer on that. Thank you.
`MS. HARDMAN: Yes, Your Honor. On the pincites I'm
`going to ask my colleagues if they can take a look at that while we're
`talking, but let me address your question on the three angstrom.
`You're correct, Patent Owner contends that that's only
`disclosed by Queen. We don't -- Cord, are you able to show Patent
`Owner demonstrative 73?
` Dr. Riechmann in his original declaration; I think it's footnote
`17, he talks about support in the art for this concept that the three --
`that a POSA would look at residues within three -- about three
`angstroms, because those are most likely to interact with the CDRs
`and interact with each other.
`So here we have on the screen Patent Owner's Demonstrative
`73. And this shows the footnote that I'm talking about.
`Dr. Riechmann testifies that a POSA would have known or would
`have understood three angstroms to be the closest two atoms can be
`without a covalent or hydrogen bond between them. And thus a
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`person of skill in the art would have interpreted these residues to be in
`contact.
`And I think he's really saying that as just something inherently
`known as a person of skill in the art. This is what they would know.
`He has a “see also” because Queen 1990 does in fact expressly
`reference about three angstroms, but it's not the case -- you know,
`Patent Owner has this highlighted as if Dr. Riechmann's only support
`is the Queen 1990 reference, but I think that's really unfair because the
`first two sentences of that footnote make clear that he's saying that as
`a matter of background knowledge that a POSA would know.
`Patent Owner hasn't contended that this three angstrom
`distance was something that became known, or elucidated in the art
`between Queen '89 and Queen 1990. This is something that's been
`known for a very long time. And further the footnote ends with -- he
`even -- he reiterates even without the language in Queen 1990,
`however, a person of ordinary skill in the art would have identified
`residues closer than three angstrom. So it's something that POSAs
`brought to the table. Again, it's very high-level skill in the art and it
`was something they would have known.
`If we could have slide 80, please. Dr. Riechmann again
`addresses in his reply declaration and he reiterates there in the second
`excerpt that a person of skill would have used this 3.3 angstrom as a
`guide because it's approximately twice the interatomic distance for
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`most protein atoms. And for that he's citing Exhibit 1145 which
`supports that proposition.
`And finally, Dr. Wilson also says -- he reiterates this, too, that
`POSAs knew the bond distances. That's just something that they
`brought to the table.
`JUDGE POLLOCK: Ms. Hardman, I'm looking at Claim 79
`and it requires four specific substitutions in the heavy chain: 71H,
`73H, 78H and 93H. Would you care to touch on why one of ordinary
`skill in the art would come to that particular collection of substitutions
`in terms of reason to combine and reasonable expectation of success?
`MS. HARDMAN: Dr. Riechmann talks in his declaration; I
`apologize, I don't have the citation, I'll try to get that, about how these
`residues in the 70s are a cluster that was taught in the art. They were
`known to all reside together in the same area and that's why that was
`taught in the Chothia and Lesk reference.
`And also in the Chothia 1985 reference, highlighted the
`importance of these residues in maintaining the interchain
`interactions. And that's where you have the light chain and the heavy
`chain hang together, and their confirmation must be maintained
`because if they're off, if you have a residue of a different size or a
`different charge, it's going to sort of distort the entire shape of the
`antibody. So as Dr. Riechmann discusses, based on mainly the
`Chothia references, they highlight the importance of these claims that
`are recited in Claim 79.
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`And in terms of reasonable expectation of success, POSAs
`knew that if you kept the interchain interactions as they were found in
`the mouse, you are likely to have your 3D confirmation conserved and
`therefore get bind
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