IPR , Paper No April 21, 2016

Transcription

1 IPR0-00, Paper No. -- April, 0 RECORD OF ORAL RECORD UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD DAIICHI SANKYO COMPANY, LIMITED, Petitioner, v. ALETHIA BIOTHERAPEUTICS, Patent Owner Oral Hearing Held: February, 0 Before: MICHAEL P. TIERNEY, ERICA A. FRANKLIN, and SHERIDAN K. SNEDDEN, Administrative Patent Judges The above-entitled matter came on for hearing on Friday, February, 0 at Emory University, 0 Clifton Road, Atlanta, Georgia, at :0 p.m.

2 APPEARANCES: FOR THE PETITIONER: Foley & Lardner, LLP KRISTEL SCHORR, Ph.D. STEPHEN B. MAEBIUS LIANE PETERSON JASON MOCK Washington Harbour 000 K Street Suite 00 Washington, D.C., 000 (0) -00 FOR THE PATENT OWNER: Choate, Hall & Stewart, LLP ERIC J. MARANDETT FANGLI CHEN, Ph.D. SOPHIE WANG TRACY VRABLIK, Ph.D. Two International Place Boston, MA 00 () -000

3 0 0 P R O C E E D I N G S (:0 p.m.) JUDGE SNEDDEN: Good afternoon. We're here today for oral argument in Inter Partes Review Case I'll start by asking counsel to step up to the podium and introduce yourselves and who you have with you. Petitioner, would you like to start? DR. SCHORR: Good afternoon. I'm Kristel Schorr from Foley and Lardner. I am counsel for Petitioner. With me today are my colleagues, Liane Peterson, Steve Maebius and Jason Mock. JUDGE SNEDDEN: Patent Owner. MR. MARANDETT: Good afternoon. I'm Eric Marandett from Choate, Hall and Stewart. We're here on behalf of the Patent Owner, Alethia Biotherapeutics. And with me also from Choate Hall are Dr. Fangli Chen, Sophie Wang, and Dr. Tracy Vrablik. JUDGE SNEDDEN: We would like to thank all of you for making the trip down here today to join us for the "Stadium Tour." It's very much appreciated. With that, we'll get started. As explained in our order, each side will have 0 minutes total and we'll start with Petitioner.

4 0 0 Petitioner, you may reserve rebuttal time. So if you would like to step up to the podium and get started. Before you begin, indicate if you will be saving any time for rebuttal. DR. SCHORR: We'll be reserving five minutes. JUDGE SNEDDEN: Five minutes. Okay. Take your time and I'll start the clock once you're ready to begin. DR. SCHORR: Good afternoon. I'm Kristel Schorr from Foley and Lardner. I represent the petitioner, Daiichi Sankyo Company, Limited. I understand that I have 0 minutes to present Petitioner's arguments and I'd like to reserve five minutes of that time for rebuttal. Slide two is an overview of the issues in this IPR. This case is about whether the PCT publication is prior art to the challenge claims in U.S. Patent Number and, if so, whether the prior art anticipates those claims. There are two main issues I would like to address at this hearing. The first is whether the -- the first is lack of priority entitlement based on lack of written description and lack of enablement.

5 0 0 And then, second, I would like to address Patent Owner's arguments to antedate the PCT publication and remove the reference as prior art. Because Patent Owner has not disputed the sufficiency of the prior art reference in anticipating the claims at issue in this IPR, I will not spend any time addressing the disclosure of the prior art reference unless the board has any questions. Slide three is the patent family chart for the ' patent at issue. So the first issue here is whether the challenge claims are entitled to priority back to the filing date of Patent Owner's provisional applications in 00, its PCT application filed in 00 and its national stage application of the PCT filed in 00, the '0 application. If the challenge claims in Patent Owner's ' patent are not supported by the disclosure in these priority documents, the PCT publication, the '0 publication, is prior art, it anticipates the claims and the claims should be found unpatentable. Although Patent Owner has waived its right to address priority entitlements to the '0 national stage application, I will refer to the '0 application only for ease of explanation as it contains the relevant disclosure in the priority documents.

6 0 0 Turning to slide four which lays out the independent claims at issue, this technology generally relates to methods of treatment using antibodies for treating bone-related disorders such as osteoporosis. The independent claims at issue are directed to a method of impairing osteoclast differentiation or a method of inhibiting bone resorption by administering to a -- by administering an antibody that specifically binds to human or murine Siglec-. The dependent claims in the ' patent further limit the scope of the independent claims by defining the antibody, its function or the condition being treated. Additionally, the claims methods recite antibodies that are defined entirely by function and not by structure. So the antibodies that are recited in the claims are directed to any Siglec- antibody or fragment that has the therapeutic activity recited in the claims. Turning now to slide five, the challenge claims in this IPR are method-of-treatment claims and Patent Owner has characterized them as such on -- in various papers on the record. JUDGE TIERNEY: Counsel, let me stop you right there. There is a dispute between the parties about the terms "osteoclast differentiation" and "osteoclast

7 0 0 differentiation activity." Does it matter which of the parties' construction we use in this proceeding? DR. SCHORR: So I do not believe that the -- which -- I do not believe that either party's construction will affect the ultimate outcome in this hearing. I think that Patent Owner's construction of "osteoclast differentiation" versus "osteoclast differentiating activity" is not supported. Our construction is based on information in the specification and description by our declarants. JUDGE TIERNEY: But does it have impact on the proceeding regardless of which one we take? DR. SCHORR: It would not have an impact on the proceeding. JUDGE TIERNEY: And then, furthermore, would it have an impact on the proceeding if we use the Phillips interpretation versus broadest reasonable interpretation or would we arrive at the same claim construction regardless? DR. SCHORR: You will arrive at the same conclusion regardless. JUDGE TIERNEY: And then the last question on that of claim construction, for the term "an antibody," do we have any idea of how many antibodies that would encompass that could perform this function?

8 0 0 DR. SCHORR: We don't because it hasn't been tested. So the antibodies need to be prepared and then tested. We know that the antibody would have to at least bind Siglec- and a subset of those antibodies would have the activity of inhibiting osteoclast differentiation or impairing bone resorption, but we do not know the precise number. JUDGE TIERNEY: Thank you. DR. SCHORR: Okay. So turning to slide six, the activity of inhibiting bone resorption or impairing osteoclast differentiation is not an activity inherent in the Siglec- antibody itself. In other words, not all Siglec- antibodies will have the functional features that are recited in the claims and, therefore, not all Siglec- antibodies will be suitable for treatment according to the claim's methods. And this is supported by statements from Dr. Filion, one of the inventors of the ' patent. JUDGE SNEDDEN: Going through your briefs, I believe one point that you've been trying to make is that there is essentially two types of antibodies. Just let me know if I'm characterizing your arguments incorrectly, but there is essentially antibodies that bind and then there's -- within that class of antibodies, there's also going to be antibodies that have a particular function. In this case,

9 0 0 they'll inhibit the protein which is Siglec- and upon doing so will have this therapeutic effect of impairing osteoclast differentiation. Is that essentially the argument, that if you go back to the Alethia PCT that -- or that you -- you have antibodies that bind and -- but maybe they're -- describe those antibodies. They're not antibodies that have this particular function. Could you speak to that a little bit? DR. SCHORR: Yes. So in the Alethia PCT -- well, first let me answer the question, the technical question. There are antibodies that would bind to a particular target such as Siglec- as the antibodies recited in the claims. And then there are antibodies that will bind to Siglec- and also have to have the therapeutic activity of impairing osteoclast differentiation and inhibiting bone resorption. That additional functional feature is not something that happens with every Siglec- antibody. So every antibody that binds Siglec- is not going to have those functional features. The Alethia PCT does not disclose -- and I can -- I will get to it in more detail shortly, but Petitioner's position is that the Alethia PCT does not disclose this concept of therapeutic antibodies at all, but really

10 0 0 discloses using genes and proteins to certain sequences and using those things for therapy, but not an antibody therapeutic. JUDGE SNEDDEN: In the PCT, there's assays that been described where they can test for such inhibitors outside? DR. SCHORR: Yes. So in the PCT one of the examples discloses an assay for testing for osteoclast differentiation. And if the PCT application actually told you how to make a Siglec- antibody that had that therapeutic activity, you can run that activity, you can run that antibody through the test. But, first, the Siglec- -- the Alethia PCT doesn't tell you to even make such an antibody or how to make such an antibody given the large number of ways you can make the antibody. And it's not -- the test, the screening test, is not a way of ensuring that an antibody with that therapeutic activity can be made. It is only a test for looking at the activity of the antibody after it is made. JUDGE SNEDDEN: Thank you. JUDGE FRANKLIN: Counsel, is it your position that at the relevant time that one with ordinary skill in the art would not have the skill or ability to identify an antibody to -- a known sequence? 0

11 0 0 DR. SCHORR: So at the time, one of skill in the art would be able to make generically an antibody that binds to a target. But one of skill in the art would not be able to make an antibody and know how to make that antibody without undue experimentation, making an antibody that has that therapeutic activity without undue experimentation. JUDGE FRANKLIN: But if you're able to make the antibody or one of skill in the art would have been able to make the antibody, would it have been undue experimentation to then test or assay it for activity? DR. SCHORR: No. The undue experimentation would not be in running the antibody that is already made through the test. The undue experimentation would be in how to even make an antibody to ensure that you are even looking at antibodies that reasonably could have this property of inhibiting osteoclast differentiation or bone resorption. JUDGE FRANKLIN: Say you're looking at a subset of antibodies with that binding characteristic, in other words, would have that structural relationship, and the further step would be understanding its function. DR. SCHORR: But there is no structural relationship between the antibodies that are created and its

12 0 0 function. The functional aspect is completely unpredictable. So at the time that this was prepared, while you could have made an antibody that bound to Siglec-, you may not have been able to make an antibody -- or it wasn't actually known whether you could make an antibody that bound to Siglec- and had the therapeutic function. And that's not something that could have been done until you've actually made one and then test it. JUDGE FRANKLIN: So then the undue experimentation relates mostly to the unpredictability in the art? DR. SCHORR: The undue experimentation relates to making -- the difficulty in making the antibody and not knowing whether you could make the antibody. So both, in making the antibody, given the vast number of peptides that you can choose from, and in the unpredictability that you wouldn't know that you were going to create antibodies that had the therapeutic effect. JUDGE FRANKLIN: Thank you. DR. SCHORR: Okay. Turning to slide seven, to be entitled to priority, the scope of the claims have to be adequately described by each of the priority documents such that the written description requirement under U.S.C., Section, first paragraph, is satisfied.

13 0 0 And to satisfy the written description requirement, the specification must demonstrate that as of the filing date the applicant was in possession of the claimed subject matter. So the specification has to describe the invention in a way to show that the inventor actually invented what was being claimed. Slide eight is an abstract of the '0 publication and it discloses genes and corresponding protein sequences. And particularly disclosed, as stated in the abstract, are the use of these sequences for ameliorating disease states and for research purposes. And this is consistent with the remainder of the specification of the '0 application which identifies genes and corresponding protein sequences for therapeutic use, but an antibody therapeutic is not specifically described in the '0 application. In fact, other than pointing to disparate portions of the specification, there is no specific disclosure relating to treatment with a Siglec- antibody. A representative number of species falling within the scope of the claim genus was not disclosed or even a single species and no structural features that were common to the genes of the antibodies were cited in the claims as disclosed.

14 0 0 Turning to slide twelve, the box outlined in slide twelve represents the steps that are disclosed in the '0 application. It's a research plan for identifying genes and proteins to target for therapy. The box represents the discovery of the target using particular technology, determining the tissue -- the expression levels of the target in certain tissues and then validating the function of that target. But all of this target discovery is completely without regard to the type of therapeutic agent being developed to go after the target. So it doesn't matter -- the material outlined in the box is completely regardless of whether you are developing an antibody therapeutic, another biologic or a small molecule. The information below the box, the remaining steps there, represent what was added to the specification of the ' patent. And, specifically, the information below the box specifically focuses on antibody therapeutics, including making the antibodies and characterizing the function of those antibodies. So to the extent that there's any language in the priority documents that is relevant to antibody therapy, it's completely general and does not support the scope of the claims.

15 0 0 JUDGE SNEDDEN: Ms. Schorr, I think I understand your written description argument, but I'm wondering if you would skip to the issues regarding the attempt to antedate the reference, the written reference. If we could turn to the arguments regarding -- the issues regarding the conception and Patent Owner's attempt to antedate the Hiruma reference. And so I'm looking at your slide at the moment. DR. SCHORR: Okay. So -- JUDGE SNEDDEN: In particular -- DR. SCHORR: Okay. JUDGE SNEDDEN: -- if we look at their diligence chart. It's Exhibit 0. And I understand that this diligence chart has a series of events and the events begin just before the date of the publication of the Hiruma reference and then goes until -- and take us through a series of events which were performed up -- you know, to the date in which the patent was filed. And when we look at event one, we have the amplification of candid Bab sequences. And then from there, it seems something was developed that ultimately ended up with an antibody that could perform the functions set forth in the claim. Is this conception?

16 0 0 DR. SCHORR: So Patent Owner has argued that its conception date is 00 and has relied on his belief -- its PCT application on the one hand, and its alternative conception document is Exhibit 00, a June 00 presentation. So Patent Owner has not relied on this first date of April th, 00, as its conception date. So the April th, 00, date, however, there are concerns as to so this is the start of their efforts to demonstrate diligence. And the April th date, the exhibits that are cited for the event that's stated have some concerns with regard to whether it relates to April th and whether it even matches anything relating to Siglec-. And I'd be happy to explain that if you would like me to. Okay. So the April th date cites first the -- one of the exhibit numbers is Exhibit and that's a laboratory notebook referring to pages to. But pages to in the laboratory notebook refer to dates in March, not on April th. And we don't believe that it's the Board's job to make the Patent Owner's evidence fit what is in the diligence chart.

17 0 0 The next entry under April th is Exhibit which is a sequence listing, but that sequence listing does not refer on its face to Siglec-, nor is there evidence that was submitted by Patent Owner to indicate that relates to Siglec- either. The other two exhibits in April th, Exhibit 0 and Exhibit 0 are declarations and those don't relate to -- those don't help clarify that Exhibit relates to Siglec-. And those also don't relate to the event that's being -- that's stated there. Would you like to me to go through other aspects of the diligence chart? JUDGE SNEDDEN: No. That's sufficient. Thanks. JUDGE TIERNEY: Why don't you go ahead and frame the conception -- (Court reporter requested clarification.) JUDGE TIERNEY: If they could clarify about how they dispute conception of the invention. DR. SCHORR: So conception -- Patent Owner relies on the Alethia PCT in Exhibit 00 to establish conception in 00.

18 0 0 As I've mentioned previously, the Alethia PCT does not disclose a single Siglec- antibody that impairs osteoclast differentiation or inhibits bone resorption. And Exhibit 00 is not much different from that in that it's also just Patent Owner's screening tool for identifying therapeutic targets including the discovery of differentially expressed genes and then the validation of those targets. But that's insufficient to establish conception of a Siglec- antibody that has therapeutic function. And if we turn to -- JUDGE TIERNEY: What would have been required to show reasonable expectation for purposes of conception? DR. SCHORR: So for conception, Patent Owner would have had to had some definite and permanent -- at a minimum, some definite and permanent idea of a Siglec- antibody that could be made with therapeutic activity. And there is evidence on the record that shows that that -- there is no definite and permanent idea of that because whether a Siglec- antibody could actually be made was unpredictable. So in this particular situation, we actually believe that conception and reduction to practice need to

19 0 0 have occurred simultaneously for there to be -- for there to have been conception. JUDGE TIERNEY: Are you saying that their desire and -- what they had is a research plan to see if they could obtain it, not that they had a definite and permanent idea they would obtain it? DR. SCHORR: It was -- the documents even don't indicate the desire to obtain it. But assuming that the documents did indicate that there was a desire to obtain a therapeutic Siglec- antibody, it would have all been by trial and error and having to figure out how to obtain that antibody and whether you could even obtain that antibody that had the therapeutic function. JUDGE FRANKLIN: In other words, is it your position that there would be a need for more than a notion, but an idea that had a specific plan of achieving that idea? DR. SCHORR: So I do not believe -- Petitioner does not believe the PCT even indicates this notion of a Siglec- therapeutic antibody, but to the extent it does, it had to have been much more than: Let's screen for some antibodies, we're not going to tell you how to make them, we're not going to tell you even if one can be made, but if we make one, we have a tool that can be used to determine its activity.

20 0 0 JUDGE SNEDDEN: I'll give you two more minutes to finish. DR. SCHORR: So if I could just briefly address enablement. If we turn to slide, the priority documents, in addition to the written description problems, the priority documents are also not enabling because they don't teach an antibody that impairs osteoclast differentiation or inhibits bone resorption. The priority documents do not disclose any of the structural features of a single Siglec- antibody that falls within the scope of the claims; nor does the priority document disclose the structural features of any antibody at all. Additionally, the '0 application doesn't enable the challenge claims because no in-vitro testing was done on the Siglec- antibody, but the only inhibitor of Siglec- that was disclosed was interfering RNA and that is different from a Siglec- antibody. And so, in conclusion, we turn to slide. The claims in this IPR, the challenge claims, are not adequately described or enabled by the priority documents and are not entitled, therefore, to a priority date earlier than the publication date of the prior art reference of April th, 00. 0

21 0 0 And Patent Owner has also failed to meet its burden of proof in establishing conception and reasonably diligent reduction to practice during the critical period and is unable to antedate the reference and therefore the claim should be held unpatentable. JUDGE SNEDDEN: Thank you. DR. SCHORR: Thank you. (Brief pause in the proceedings.) MR. MARANDETT: Just give me one moment to get set up. JUDGE SNEDDEN: Sure. Take your time and I'll start the clock once you begin. (Brief pause in the proceedings.) MR. MARANDETT: Just a reminder, again, I'm Eric Marandett on behalf of Patent Owner Alethia Biotherapeutics. I want to start -- I'm going to spend most of my time on -- on the issues, written description and enablement. And actually I may turn to Dr. Chen if we have some specific questions about the -- about the diligence period. But with respect to the last series of questions around the conception, I think that's a useful place to start, both to talk about what the invention is and whether it's

22 0 0 adequately described or enabled in the Alethia PCT as well as getting into -- introducing the issues. JUDGE SNEDDEN: Can you clarify for me when an antibody was made that fits the -- that can perform the function? MR. MARANDETT: Well, it's two separate questions. One way the antibody -- when an antibody, in fact, was made by Alethia, that came later. JUDGE SNEDDEN: That's my question. MR. MARANDETT: Yes. That came later. That was -- that was in the 00 time period. But the disclosure in the Alethia PCT is sufficient to show possession of an antibody. And the reason for that is tied to the state of the art. I think that's the critical inquiry that you need to evaluate in looking at whether Alethia had possession of its invention at the point in time of filing the PCT. JUDGE TIERNEY: To frame the debate, though, I would like to understand claim construction and just -- there is a dispute over the terms "osteoclast differentiation" and "osteoclast differentiation activity." MR. MARANDETT: Yes. JUDGE TIERNEY: Does that -- regardless of whose claim construction we take, does it have a bearing on the outcome of this case?

23 0 0 MR. MARANDETT: It shouldn't have a -- it shouldn't have a bearing on the ultimate outcome. The activity that matters from the perspective of possession is going to be whether there's an impact on osteoclast differentiation. And from a claim construction standpoint, that's what's defined and that's what's described in the specification and that's what the assay that evaluates the impact on Siglec- lays out in the specification. JUDGE TIERNEY: And in this particular case, does it make a difference if we use the broadest reasonable interpretation or Phillips? MR. MARANDETT: No. I don't think it matters. JUDGE TIERNEY: You arrive at the same kind of construction? MR. MARANDETT: Yes. I think you do. JUDGE TIERNEY: Thank you. MR. MARANDETT: So, again, I want to start -- I think in looking at the issues, the way I think about it and I think the way -- the way that this ought to be viewed is really in response to three separate questions. Number one, what is the invention. That goes to the conception point because I think the invention is described in -- it's pretty clearly articulated in the PCT itself.

24 0 0 Second, what's the state of the art, and I think that's the most important issue to grapple with. And as you saw from our arguments in paper and as we'll go through today, the state of the art is much better developed than it was articulated by Dr. Schorr in her presentation. And then, secondly, in light of the invention as defined in the claims and in light of the state of the art, what does Alethia -- what does the Alethia PCT teach. And I think when you look at that in view of the state of the art, it's very clear that the Alethia PCT demonstrates that they had possession of antibodies that impaired osteopath differentiation which is -- which is what the claims are directed to. Fundamentally -- and I'm now on slide three. Fundamentally, the invention that Alethia described in its specification is a new use of anti-siglec- antibodies for impairing osteoclast differentiation. Now, a couple of things were known already. Siglec- -- JUDGE FRANKLIN: I'm going to stop you there. MR. MARANDETT: Yes. JUDGE FRANKLIN: To be clear, this line is directed to an argument raised in your brief; right? MR. MARANDETT: Yes.

25 0 0 JUDGE FRANKLIN: It's not a quote from the prior art? MR. MARANDETT: Not from the prior -- from the PCT. JUDGE FRANKLIN: Okay. MR. MARANDETT: All right. Let me go to the next one, slide four. This is a quote from the PCT that I think -- and you're right. That's fair. The slide three is our argument. But when you look at slide four, this is a quote from the PCT and it demonstrates that the present invention is related to a method of ameliorating boneremodeling disease or disorder or for inhibiting or delaying bone disease comprising -- contacting a compound that's capable of specifically inhibiting activity or expression of a polynucleotide sequence described therein. Siglec-, SEQ ID and SEQ ID is specifically described therein. It is specifically tested for its impact on osteoclast differentiation. And then inhibitory compounds, antibodies are described at great length in the specification and they're identified as inhibitory compounds. Now, there are specific examples where antibodies have been made, but there doesn't have to be in this context given the -- the state of the art as to the

26 0 0 development of antibodies and the state of the art as to the use of antibodies to inhibit a known function in this context. JUDGE FRANKLIN: I'm looking for you to acknowledge, though, a difference between what you set forth in slide three as -- with the caption "The Invention" and then what's actually quoted with respect to the -- MR. MARANDETT: Well, the difference -- the only difference -- there isn't a difference in terms of what the patent teaches, but this incorporates what's known to somebody of skill in the art already about Siglec- and about antibodies which needs to be taken into account. Slide four is what's specifically stated in the PCT application. JUDGE TIERNEY: I think what we're focusing on is there's a difference between what would have been obvious to one of ordinary skill reading your PCT versus what is actually possessed. And as you can see in the slide four, I think what my colleague's going to point out is you have one citation from page ten in the specification and then you have to jump pages later to page to understand that inhibitory compounds can include antibodies. MR. MARANDETT: Yes. Although the -- the section at page is in the context of an example that

27 0 0 specifically describes and proves the role of Siglec- in osteoclast differentiation and demonstrates how you can inhibit it including through the use of antibodies. It's very specific as to Siglec-. JUDGE TIERNEY: If it's very specific, the question we're going to have, though, for purposes of written description is what common structure do these antibodies have? Because you're not claiming any particular antibody, but a class of antibodies by their function. Do you have any common structure between different antibodies? MR. MARANDETT: Actually, if you look at the claim, we are claiming -- the only thing -- the only feature the antibody has to have is that it binds with Siglec-. JUDGE TIERNEY: That's fine. What specific structural component, though, does that antibody have to have? MR. MARANDETT: You don't need to know or you don't need to have a structure. JUDGE TIERNEY: So when we have -- all right. So what I'm understanding from this art and what you tell me state of the art is, anyone could go ahead and make an antibody to Siglec-? MR. MARANDETT: Right.

28 0 0 JUDGE TIERNEY: You mentioned actually Nakamura -- MR. MARANDETT: Correct. JUDGE TIERNEY: Then the question becomes, and I think it's -- I'll just ask you: Do all antibodies that bind to Siglec- have the function of basically impairing osteoclast differentiation? MR. MARANDETT: They don't have to. They -- no, they don't. JUDGE TIERNEY: So now we're talking about a genus of compounds that bind to Siglec- and a subgenus that are going to have this particular function? MR. MARANDETT: No different than -- not all antibodies bind to Siglec-, but there are wellrecognized and understood ways of getting at antibodies that bind to Siglec-. Once you have that, actually, as to claim one, that's all that's required. In fact, when you look at the specification, there's even -- there's even discussion of inhibiting the function through the use of a toxin that's bound to an antibody. JUDGE TIERNEY: The question, though, becomes -- we understand how you're saying anyone can get an antibody binding to Siglec-. MR. MARANDETT: Right.

29 0 0 JUDGE TIERNEY: The key step, though, is how to get from that class of -- that genus, we'll call it, to the subgenus of those which will actually impair osteoclast differentiation in a mammal. MR. MARANDETT: You simply -- you simply -- well, first, the in-vitro assay that's described will allow you to identify which antibodies inhibit osteoclast differentiation. That assay is well understood to correlate to in-vivo function. In fact, when you look at the Daiichi -- the intervening art reference, they only rely on the very same kinds of in-vitro assays that are described in the specification. And the state of the art is such that it would be well understood given that. And we'll go through -- I want to go through some of what Daiichi's experts agreed to. It was well understood that you could identify those antibodies that inhibit that function using the assays that are described in the specification. JUDGE TIERNEY: So, just to be clear then, what you've added to the art isn't necessarily the assays that get you from the genus to the subgenus, but recognition that there will be a subgenus of compounds that have this ability, this function? MR. MARANDETT: Correct.

30 0 0 JUDGE FRANKLIN: And I'm going to chime in there, too, because I think I heard you say there was no common aspect among the structure to indicate that an antibody would have the claimed activities. Doesn't that sort of go toward the Petitioner's argument of unpredictability? MR. MARANDETT: No. Because you don't need to know the structure. And let me talk a little bit about some of the case law because I think that's where the argument comes from. When you look at -- and, actually, before I get there, I want to just go to some of the description from Alethia's -- I'm sorry -- from Daiichi's experts on that point. JUDGE TIERNEY: I guess -- while you're taking the time, I guess in my mind you have a genus compound of antibodies that bind to Siglec-. MR. MARANDETT: Right. JUDGE TIERNEY: You then have a subgenus which actually will meet your assay -- MR. MARANDETT: Right. JUDGE TIERNEY: -- and then you have a subsubgenus of those that actually perform in a mammal? MR. MARANDETT: Well, no. 0

31 0 0 JUDGE TIERNEY: Are you saying every one that meets the in vitro will work in a mammal -- MR. MARANDETT: Well, there's two separate issues. Ultimately, obviously you don't get to a therapeutic antibody unless you go through clinical trials on the safety, efficacy, et cetera. That's -- you don't have to go that far in order to describe possession of an antibody that impedes the function. The claim only goes so far as to require an antibody that will work in vivo that will interfere with osteoclast differentiation, not one that ultimately is successful in clinical trials. And one thing that you see on the structure point, Daiichi's experts -- and we've got slides to this effect in here, but to just to make the point, Daiichi's experts concede that in order to develop an antibody that impedes this function, you don't need to know its structure, you don't need to know its mechanism of action. All you need is the well-recognized methods of making an antibody and the well-understood and well-characterized functional assay that's described in the patent. And, significantly, when you look at -- you then look at what Daiichi and Alethia did as described in the intervening art that's cited against us here and in Alethia's later CIP, all they did was carry out the very same steps that are described in the Alethia PCT. They

32 0 0 made the antibodies to Siglec-, well-understood protein, that cell-surface-accessible protein, that could -- to which antibodies could be made. They tested those antibodies in the functional assay that was described in the PCT and they got antibodies that impeded that function. They didn't need to know the structure. They didn't need to have structural information in advance. And they didn't need to describe the structure because, as Daiichi's experts concede, you don't need to know the structure in order to -- in order to get an antibody with that feature. The -- JUDGE TIERNEY: But tell us again, what guidance did you give to one of ordinary skill in the art from that basic genus of antibodies that bind to Siglec-? What directions did you give them as to which particular antibodies would actually have this function? MR. MARANDETT: Those that when you run the assay have that function. JUDGE TIERNEY: But that's just telling them go forth and test. MR. MARANDETT: But it's go forth and test in a well-understood, well-characterized assay system that is completely predictable. JUDGE TIERNEY: So let's back up. So you don't tell one of ordinary skill which particular antibodies

33 0 0 will bind to Siglec-. You say go forth, you can derive those or at least find some. And then you say from that, you then will go forth and test again against the assay. MR. MARANDETT: Right. JUDGE TIERNEY: Both? MR. MARANDETT: Because both -- you have both, unlike, for example, the University of Rochester case which is the case that is cited by Daiichi in this context. There what you were talking about was a small-molecule situation where there was no known correlation between the structure of any small molecule and the function of impeding the activity of the protein in question. In this context you've got much more than that because we're talking about antibodies in particular where the antibody and -- the antibody-antigen binding correlation is well understood. And then you have proof in the patent that if you impair activity of Siglec-, you impair osteoclast differentiation. And all you have to do is test an antibody. You don't need to know the structure of the antibody. There's no structural aspect of this -- of this function. You simply need to run the antibodies in the assay and you will get antibodies. It's routine experimentation that is eminently predictable.

34 0 0 And, in fact, the experience that both Alethia and Daiichi had prove that out because all they did was follow these very instructions and got to antibodies that performed the function. JUDGE TIERNEY: So let's work backward because it's critical as to what date you actually have as your release date. MR. MARANDETT: Yeah. JUDGE TIERNEY: So at what point did you conduct the in-vitro testing with an antibody that bound to Siglec- and actually show that there was the impairment of osteoclast differentiation? JUDGE FRANKLIN: And show that the assay worked for its intended purpose. MR. MARANDETT: You want to take the issues on the specific conception? But the antibodies were made as of just prior to that -- that April 00 date and then they were tested thereafter. JUDGE TIERNEY: But at what -- that's what I'm trying to find out. So working back here, what is the date you have this alleged assay working for Siglec- antibody that shows a correlation to impairing osteoclast differentiation?

35 0 0 DR. CHEN: As you can see from the charts, the company has -- (Court reporter requested clarification.) DR. CHEN: So the antibodies was generated before April th, 00. I'm sorry. MR. MARANDETT: '0. DR. CHEN: '0. Yes. And after that the company has been trying to select -- because it's a small company. So as you can see, there is lots of effort put into selecting the best antibody that -- (Court reporter requested clarification.) DR. CHEN: After obtaining the antibody which was before April th, 00, the company has been spending time trying to select -- focus on taking portions that lead into conducting the assay. The precise date, I have to admit I don't have the exact date in my mind, but - - JUDGE TIERNEY: But it was some time after April you conducted the in-vitro assay? DR. CHEN: Yes. MR. MARANDETT: Yes. JUDGE TIERNEY: Because your question becomes then: Did you have a reasonable expectation before you actually had a successful testing of the assay? Was the reasonable expectation such it had a conception?

36 0 0 MR. MARANDETT: Yes. I think that you had -- that you had from the beginning given the state of the art at issue here. From the beginning meaning as of -- as of when the PCT was filed. DR. CHEN: So the conception is two pieces. One is the PCT lays out the functionality and the routine experiments and -- (Court reporter requested clarification.) DR. CHEN: But more importantly, there is a presentation made by Alethia in -- I believe it was -- MR. MARANDETT: June of 00. DR. CHEN: -- June 00 to Daiichi and they identified antibodies therapeutical program against the Siglec- program for treatment of bone disease. So this is a very clear indication that this is a very concrete conception that the company is -- not only they are confident they have possession of the antibody, they are also planning to invest the money to develop it into a therapeutic product. JUDGE TIERNEY: So the question becomes is it required in this art to have a simultaneous conception and reduction to practice. MR. MARANDETT: No. JUDGE TIERNEY: Please speak to that.

37 0 0 MR. MARANDETT: No. I mean, the notion of simultaneous conception and reduction to practice goes to predictability. And that's where -- where the state of the art is really important and the level of predictability in the context of identifying the antibody that binds to a protein like this and that inhibits a function when you have a wellcharacterized functional assay that's described in the specification like this does not require simultaneous conception and reduction to practice because it's not unpredictable. JUDGE TIERNEY: I guess that's the link going from anybody can get an antibody that binds. The question becomes can they -- do they know that the assay is going to find one or more and actually have the desired -- MR. MARANDETT: Yes. And that's because the way that the -- the specification demonstrates through the sirna assay proved that if you impede the function of Siglec-, then you will impede osteoclast differentiation. It's routine to get -- to identify an antibody that will do that. I mean, the experts agree that you will be able to identify an antibody that can do that. And even, according to the claim, you don't have to do that because the patent also contemplates simply an antibody that binds and you attach, for example,

38 0 0 a toxin and an ADC that will impair -- that will block the function. JUDGE SNEDDEN: When I look at the record, you have a protein, Siglec-, that's not -- the question is how well characterized was that. MR. MARANDETT: Right. JUDGE SNEDDEN: When I look at the record, I don't see anything other than the fact that it was known and because you have a protein you can develop antibodies to it. What you're saying is you have the protein, but you have a well-characterized assay. Because you have a well-characterized assay, you have then conceived any inhibitor that comes out of that assay. MR. MARANDETT: An antibody inhibitor. It would be different if we were talking about a small molecule because then you don't have the well-understood correlation of antibody binding to antigen the way you do with an antibody. So I think the answer would be different if we're talking about a small molecule. It's not any inhibitor. But in the context of an antibody, and particularly with Siglec- where it was understood already and antibodies had already been made to Siglec-

39 0 0 before the PCT, you had possession of antibodies and you knew, the experts knew. And if you look at -- you know, Dr. Clark says in slide that if he has the protein sequence, he's asked to develop an antibody that inhibits a function using conventional methods, when he's got the wellcharacterized antigen, which you have from the PCT, and he has a well-established functional assay, you're going to get an antibody that inhibits. And, again, that's precisely what happened. If these teachings are followed, then you get an antibody that inhibits. JUDGE TIERNEY: How could it be so sure you would get an inhibitory antibody? Was it because it was known to be a cell surface? Is it -- how can you be so sure? MR. MARANDETT: Because when you've got a cell-surface protein like this, the experts agree that it is easy to develop. Without knowing the structure of the antibody and without knowing the precise mechanism of action, you're going to be able to identify an antibody that inhibits. Not -- not every antibody will inhibit, but you will be able to identify an antibody that inhibits. JUDGE FRANKLIN: I would like to ask, with respect to Independent Claim and Independent Claim

40 0 0 where is directed to impairing osteoclast differentiation and is directed to inhibiting bone resorption which, in at least some instances, would be the result of differentiation, is there any reason that our decision relating to Claim would not also relate equally to Claim? MR. MARANDETT: Well, Claim, osteoclast differentiation is on the pathway to bone resorption and the data in the patent is directed to impairing osteoclast differentiation. But there is a well-recognized and understood correlation between that and impacting bone resorption. So one leads to the other. JUDGE FRANKLIN: So what would your answer be? MR. MARANDETT: The two claims are different, but -- so I think you could decide one way as to Claim and one way to Claim because there is more specific data as to Claim, but it's very -- the correlation is close and well understood. So I don't -- I think, given the state of the art, there is adequate description of both. JUDGE SNEDDEN: One question. Help me distinguish the facts here with the facts that was in Amgen v. Chugai. And there you had a protein and you know that 0

41 0 0 the protein is encoded by genes. It was just a matter of time before you -- (Court reporter requested clarification.) JUDGE SNEDDEN: Help me distinguish the facts in this case from the facts in Amgen versus Chugai. In that case you had protein encoded by a gene and it was known -- I mean, it's a law of nature that there is a gene that encodes this protein. MR. MARANDETT: Two -- two key distinctions with the Amgen versus Chugai case. One, the claims, if I recall correctly, were directed to any analog thereof. So it's any analog of that protein and there wasn't a description of analogs. And, two, the state of the art, the relevant state of the art, is vastly different because you were dealing -- and that's something that needs to be focused on. The dates in question in the Amgen-Chugai case were in the early 0s at the point in time when -- when recombinant DNA technology was in its nascent stages. And in particular when you have claims as broad as the Amgen claims were where they were directed to analogs, that was not sufficient disclosure. Here you're talking about a state of the art in 00 at a point in time when antibody technology, Siglec-

42 0 0 and the bone resorption technology, were very well understood. So it's a vastly different state of the art. I think that's where the key distinction comes in that context. JUDGE TIERNEY: Thank you. MR. MARANDETT: Does that mean I'm out of time? JUDGE TIERNEY: No. It's my computer shutting down. MR. MARANDETT: I see. I want -- I want to skip ahead. I want to skip ahead and talk about -- because I think it's important to go through what Daiichi and Alethia both did because I think that nicely demonstrates enablement and it also reinforces the state of the art. So please skip ahead. Actually, let me back up and talk to you about exactly what -- well. JUDGE SNEDDEN: You have five minutes. MR. MARANDETT: Okay. So I want to talk just about the post-filing. And by post-filing, I mean the Alethia CIP and the Daiichi application that's asserted as prior art. And I think this is an important issue to highlight. Both parties simply used precisely the teachings of the Alethia PCT in terms of they took well-

43 0 0 known, well-understood methods of making antibodies, hybridoma technology, phage display, et cetera. They made antibodies to Siglec-. They then took those antibodies and they ran them through -- they ran them through the very same TRAP-staining assays that were described in the Alethia -- in the Alethia PCT. And they got -- they got -- as predicted by the Alethia PCT, they got impairment of the osteoclast differentiation function. There is nothing new that's described in those applications. They simply follow the teachings of the Alethia PCT, thereby demonstrating that the Alethia PCT is fully enabled and thereby showing, consistent with the state of the art, that Alethia had possession of the invention at the point in time of its original PCT. And the experts, the Daiichi experts, acknowledge fully that all Daiichi did was simply follow the very teachings that were laid out in the Alethia PCT. Back to the point Dr. Chen made a few minutes ago, it's worth -- it's worth reminding that Alethia had gone to Daiichi and had shown them that they had identified this protein that was involved in osteoclast differentiation, that it was an antibody target. They then published their PCT and then the Daiichi applications came out following the very same

44 0 0 steps that are laid out in the PCT. So I think that underscores that they had possession at the point in time of the PCT and that they fully enabled it. JUDGE TIERNEY: The question is "possession" as opposed to "research plan". Why would you construe the earlier PCT as merely a research plan? MR. MARANDETT: Because it was -- because of the level of predictability in getting the outcome. That's the difference and that goes to the state of the art. It's because -- and that's consistent with the question about Chugai. The state of the art in 00 made it eminently predictable that you would -- that if you follow that plan, you would get antibodies that impaired the function. And that's what they did and it worked. And that was no surprise to anybody including to the Daiichi experts. So that's the key, is that you're dealing with a state of the art such that it was predictable, that it wasn't a wish or a plan that required undue experimentation. It was simply routine experimentation. Following the disclosure as laid out, it gets you there. So just in conclusion, I want to just remind you of the -- the three questions that I asked at the beginning because I think it remains important to frame it. What is the invention, what's the state of the art and viewing the disclosure in light of the state of the

45 0 0 art, and then what does the Alethia PCT teach and in particular the key threshold finding is they were the ones who proved -- an interesting point. Daiichi acknowledges this in their specification. It was Alethia that proved that Siglec- has a role in osteoclast differentiation and if you impair that function, that you -- you can target Siglec- to block osteoclast differentiation. And that was -- that was well understood. It was identified even in the Daiichi specification as something that Alethia did. And then when you look at what Daiichi did, what they're asserting is prior art, they simply followed that plan and it worked. They didn't offer anything new at all. So I think, again, that the state of the art is critical for the analysis and that correlation between antibodies -- the antibody-antigen binding and the proven correlation between impairing Siglec- function and impairing osteoclast differentiation. DR. CHEN: Another point in addition to the three questions is whether Daiichi proved Alethia's burden to show otherwise. And as we laid out, and I think we don't have time to go into, we presented a comparing study of the arguments that Daiichi has not met the burden to prove otherwise. JUDGE SNEDDEN: Time's up.

46 0 0 MR. MARANDETT: Thank you. JUDGE SNEDDEN: Ms. Schorr, when you are ready to begin, you'll have five minutes for rebuttal. DR. SCHORR: Yes. (Brief pause in the proceedings.) JUDGE SNEDDEN: And I have a question, if you could start with that. DR. SCHORR: Okay. JUDGE SNEDDEN: We have a wellcharacterized assay. Why isn't that good enough to show conception of the antibody or -- and/or written description? DR. SCHORR: Okay. So first with regard to written description, the well-characterized assay is not going to tell you that -- so for a written description you need to demonstrate that you had possession of the antibody, the claimed antibody, which is a Siglec- antibody that has this therapeutic activity. Having an assay for screening antibodies that have already been made doesn't give you possession of an antibody that you have not yet made that would have this therapeutic activity. JUDGE TIERNEY: So going to the question I asked earlier to Patent Owner, your belief is that it was