[00:00:27] Speaker 01: The next case for argument is 16-1-0-0-3, in rate at the monopolist. [00:00:35] Speaker 01: Whenever you're settled. [00:00:49] Speaker 03: May it please the court. [00:00:50] Speaker 03: This is an appeal from a decision of the Patent Trial and Appeal Board [00:00:54] Speaker 03: Rejecting, as obvious, all pending claims of the applicant's patent application directed to the treatment or prevention of the flu in humans by administering a particular compound known as Zanamavir by oral inhalation alone. [00:01:09] Speaker 01: So that's the inventive concept is strictly the administration of this drug orally. [00:01:15] Speaker 03: By oral inhalation alone. [00:01:16] Speaker 03: Yes, Your Honor. [00:01:18] Speaker 03: This court should reverse the board's decision because there were two primary errors that were committed. [00:01:25] Speaker 03: The first is that the board failed to present a prima facie case of obviousness because it based its obviousness determination on three factual findings that are not supported by substantial evidence. [00:01:39] Speaker 03: And second, even if the board had presented a prima facie case of obviousness, the applicant submitted evidence of unexpected results that were sufficient to rebut the prima facie showing. [00:01:51] Speaker 03: More specifically on that point, the board erred as a matter of law in requiring direct comparative evidence of unexpected results and in failing to give the evidence of secondary considerations due weight. [00:02:04] Speaker 03: So turning to the first error of failing to present a prima facie case supported by substantial evidence, there are three, the three factual findings that are unsupported by substantial evidence are first that Von Steen 2, [00:02:21] Speaker 03: teaches or suggests administering compounds for treating or preventing the flu by oral inhalation alone. [00:02:29] Speaker 03: The second factual finding at error is that the compounds disclosed in Van Itsteen 2 were enabling for teaching oral inhalation of Zanamavir. [00:02:40] Speaker 01: Of course, Van Itsteen 2 does refer to well-known delivery methods, and it includes oral, right? [00:02:52] Speaker 03: Your Honor, Von Itztin II first specifically excludes Sanimavir from its compounds and we respectfully submit that it does not teach or reasonably suggest oral inhalation. [00:03:06] Speaker 03: On three pages of Von Itztin II, pages A287 through A290 of the appendix, there is a first and a general introductory paragraph that describes what the modes of administration of the compounds disclosed in that reference are. [00:03:22] Speaker 03: And that general paragraph lists a variety of modes of administration and among them is suitable oral administration modes. [00:03:32] Speaker 03: There are then corresponding paragraphs that follow that initial paragraph that specifically describe what each of those modes, how they can be administered. [00:03:41] Speaker 03: And for oral administration, it specifically does not say inhalation. [00:03:46] Speaker 03: The word inhalation is never used in the paragraph that describes the appropriate [00:03:51] Speaker 03: modes of oral inhalation. [00:03:53] Speaker 03: Instead, what it says is that oral administration can be capsules, cachets, tablets, or oral liquid preparations that include dry products that are mixed with a liquid. [00:04:05] Speaker 03: Dry powders are also listed in that description. [00:04:09] Speaker 03: And the word inhalation or inhaled is only used in a subsequent section of the paragraphs [00:04:18] Speaker 03: on the modes of administration describing intranasal administration. [00:04:22] Speaker 01: Can I just skip over to kind of a related but different subject, which is that the examiner relied on three additional references, Smith, Everett, and Ganderton. [00:04:33] Speaker 01: And the board kind of embraced that, albeit in possibly conclusory fashion. [00:04:39] Speaker 01: The Patent Office, arguing here, relies on those. [00:04:43] Speaker 01: It seems to me that those pieces of prior art very clearly [00:04:47] Speaker 01: disclose that the flu infects the lower respiratory tract. [00:04:55] Speaker 01: Everett discloses oral inhalation is effective for delivering drugs to the lower respiratory tract, i.e. [00:05:02] Speaker 01: lungs. [00:05:03] Speaker 01: And the third reference suggests treating flu, a lower respiratory condition, by oral inhalation. [00:05:09] Speaker 01: So if you're left with those references, why don't those references, leaving aside [00:05:14] Speaker 01: what is contributed by the Von Itstein 1 and 2 provide sufficient basis for prima facie case. [00:05:22] Speaker 03: Ganderton and Averard, two of the references that you just referenced, do not disclose at all the administration of Zanimavir for treating the flu. [00:05:33] Speaker 03: Ganderton just discloses. [00:05:34] Speaker 01: Well, I mean, we're not dealing with an anticipation here. [00:05:37] Speaker 01: We're dealing with an obviousness. [00:05:39] Speaker 01: So obviously not one particular reference is going to describe everything in this. [00:05:43] Speaker 01: But the inventive concept is using oral inhalation for treating lower respiratory condition, right? [00:05:52] Speaker 01: So what's missing in these references that would suggest that that's already in the prior art? [00:05:59] Speaker 03: Yes. [00:06:00] Speaker 03: The Hayden Declaration that was submitted [00:06:03] Speaker 03: which is unrebutted evidence, explains that it was known at the time prior to the effective filing date of the application that the flu virus replicates in the upper respiratory tract. [00:06:15] Speaker 03: And because of that, all of the known methods for administering Zanimivir up to that point in time were by nasal inhalation alone. [00:06:24] Speaker 03: There are references in the record. [00:06:26] Speaker 01: that show that? [00:06:27] Speaker 01: Well, that may be what his affidavit says, but doesn't the Smith reference disclose that while flu primarily infects the upper respiratory tract, it also infects the lower respiratory tract? [00:06:41] Speaker 01: So we've got, notwithstanding what the expert may have said, don't the references clearly disclose that it was known [00:06:48] Speaker 01: that fluid can affect the lower respiratory tract and therefore, and then it leads you to the other references which deal with oral inhalers to deal with those conditions in the lower respiratory tract. [00:07:01] Speaker 03: Right. [00:07:02] Speaker 03: Smith does disclose that and what they concluded in Smith was that the upper respiratory tract infection is much greater than the lower respiratory tract infection and that there's a much greater [00:07:15] Speaker 03: production or replication of the virus in the nasal tissue, which is in the upper respiratory tract, than the lower respiratory tract by a scale of 10 to 100 times more. [00:07:26] Speaker 03: That point is important because Dr. Hayden's declaration and other references in the record show that it was known that the flu virus could end up in the lungs, but that it's the site of replication, which was the concern because the compounds the anemone needs to be [00:07:44] Speaker 03: administered to the site of replication of the virus, which was believed to be the upper respiratory tract, which even Smith supports that in its disclosure of saying that much greater production of the virus occurs in the nasal tissue by 10 to 100 times more. [00:08:03] Speaker 03: There are other references, such as the Ryan reference, which is in the appendix A2098. [00:08:10] Speaker 03: which was a 1994 reference just before the effective filing date of the application that explained that all experiments to date administering Zanimivir were shown to be effective only when the compound was administered intranasally. [00:08:29] Speaker 03: And there's another Bonn-Isteen publication that's in the appendix Bonn-Isteen 1993 reference [00:08:38] Speaker 03: that specifically said that they were focusing on nasal inhalation in administering the drug because it was believed that that's where the virus replicated was in the nasal passages. [00:08:55] Speaker 03: And so while the flu could be in the lungs, and people of O'Neill-Skillinger understood that, they understood that it was replicating in the upper respiratory tract, and that's where the site [00:09:08] Speaker 03: administration of the compound needed to be. [00:09:11] Speaker 03: And there actually are no references in the record dated before the effective filing date of the application that disclosed any effective administration of Zanimavir other than by nasal inhalation alone. [00:09:29] Speaker 03: The Ryan reference, again, they attempted there to do it by oral administration, something you swallow. [00:09:38] Speaker 03: or by injection and concluded that neither of those methods were effective and that only intranasal administration was effective, again, because they believed that's where the virus was replicating. [00:09:50] Speaker 02: I take it that the record reflects that, correct me if this is not right, that the likelihood of infection in the lower respiratory tract is greater among infants than adults. [00:10:06] Speaker 02: Is that right? [00:10:07] Speaker 03: That was also in the Smith reference, Your Honor, and actually what the Smith reference discloses in its introduction, it explains that in young children, influenza is a common respiratory infection and sometimes is complicated with bronchitis, croup, or pneumonia. [00:10:26] Speaker 03: And this indicates a greater susceptibility of lower respiratory tract being involved in young children. [00:10:33] Speaker 03: But it then importantly goes on to say, but is this true? [00:10:37] Speaker 03: And if so, what are the reasons? [00:10:39] Speaker 03: That's what Smith was trying to answer that question. [00:10:41] Speaker 03: And Smith actually was not able to answer that question. [00:10:44] Speaker 03: In the conclusion of the paper, they explained that they studied, to try to answer that question, they did a study on ferrets. [00:10:52] Speaker 03: And the ferret study on neonatal ferrets does not reflect the human situation, is what they concluded. [00:10:59] Speaker 03: And that human infant bronchitis involvement [00:11:04] Speaker 03: may not be more susceptible to infection than corresponding adult tissues. [00:11:10] Speaker 03: They simply were not able to answer the question. [00:11:12] Speaker 03: And that conclusion is on A2089. [00:11:23] Speaker 03: Turning back to the factual errors, the board also found that the compounds disclosed in Voniztin II were enabling for [00:11:34] Speaker 03: teaching oral inhalation of Zanimivir, that is the second factual error not supported by substantial evidence, because there's no dispute that Bonetstein II first specifically excludes Zanimivir. [00:11:46] Speaker 03: And then second, the compound that the patent office is relying on there in Bonetstein II was actually found in the Chandler reference at A2117 of the appendix. [00:12:00] Speaker 03: That compound was directly compared to Zanimivir. [00:12:04] Speaker 03: And it was found that Zanimivir is up to 2,400 times more active in vitro than the compound of Bonn-Etsin II. [00:12:13] Speaker 03: So there are significant structural and functional differences between Zanimivir and the compound of Bonn-Etsin II. [00:12:22] Speaker 03: And given what the understanding of persons with ordinary skill in the art were at the time, the board speculated that the compound of Bonn-Etsin II would teach [00:12:34] Speaker 03: treatment of influenza using what they called a very closely related compound. [00:12:38] Speaker 03: But that compound by the record shows that it was not nearly as effective as Zanimivir and was not enabling for treatment of it. [00:12:47] Speaker 02: What was your third factual error? [00:12:49] Speaker 03: The third factual error is that the evidence shows that there wasn't a reasonable expectation of success for administering Zanimivir by oral inhalation alone. [00:12:58] Speaker 03: And we rely heavily on the Hayden Declaration for that. [00:13:03] Speaker 03: where that was his testimony, he explained that. [00:13:06] Speaker 03: The testimony was unrebutted and the board instead really substituted its own interpretation of the underlying studies that Dr. Hayden was relying on rather than crediting his testimony on that. [00:13:22] Speaker 03: And the second primary error was that even if the board had presented a prima facie case of obviousness, the applicant submitted [00:13:32] Speaker 03: sufficient evidence of unexpected results that was sufficient to rebut the prima facie showing. [00:13:38] Speaker 03: I see I'm into my rebuttal time. [00:13:44] Speaker 01: You and do your rebuttal and we'll stick with the government. [00:13:52] Speaker 00: May I please the court? [00:13:54] Speaker 00: At bottom, Efthamopoulos' argument comes down to this idea that because no one would have known, [00:13:59] Speaker 00: that oral inhalation would have worked with certainty that their invention is not obvious for that reason. [00:14:06] Speaker 00: But that is not the standard. [00:14:07] Speaker 00: The standard is a reasonable expectation of success. [00:14:11] Speaker 00: And that reasonable expectation of success does not require complete certainty. [00:14:15] Speaker 00: It only requires a degree of predictability. [00:14:18] Speaker 00: Granted, a degree of predictability encompasses the expectation that the prior elements could be combined, as well as the expectation that the combination would have worked. [00:14:29] Speaker 01: Both of those expectations. [00:14:31] Speaker 01: Okay, let's get to the prior art references that you're using to combine. [00:14:36] Speaker 00: Here, it was well known that Zinamavir and its four-methyl homolog were useful in treating influenza, that these are well-known neuraminidase inhibitors and their mechanism of action was well-documented. [00:14:50] Speaker 00: Furthermore, Bonnitzstein 1 teaches that delivery of Zinamavir to the upper respiratory tract [00:14:58] Speaker 00: treats influenza. [00:15:00] Speaker 00: And that is exactly what Von Tu was trying to achieve. [00:15:04] Speaker 00: There is no evidence in the record that Zinamavir wouldn't have worked in Von Tu's method. [00:15:11] Speaker 00: Nor is there any evidence in the record that oral inhalation would not have worked. [00:15:16] Speaker 00: This is not a case where, as Efthamopoulos argues, that there are so many- I guess I'm not following your argument. [00:15:24] Speaker 01: You don't- the other side doesn't have to [00:15:27] Speaker 01: disprove or we're not talking about a showing that it didn't work. [00:15:31] Speaker 01: Where's your motivation to, what are you combining and where is the motivation to combine those references? [00:15:37] Speaker 00: We are combining the use of the compounds enamavir, which is taught by Von Itstein I, with oral inhalation, which is established by [00:15:51] Speaker 00: the fact that Von Itstein II discloses inhalation, but in addition to that, we have all of these other references, Everard and Ganderton, which establish that inhalation to treat respiratory conditions is rooted in antiquity. [00:16:06] Speaker 00: It is well known that inhalation can be used to treat respiratory disorders. [00:16:10] Speaker 00: It only makes sense then to treat influenza by providing the drug to where the virus acts. [00:16:19] Speaker 00: to in the respiratory tract. [00:16:20] Speaker 00: There's only two ways of doing that, and that is well known in the art. [00:16:23] Speaker 01: Yeah, but your friend tells us that the assumption was that all of this was in the upper respiratory tract treated by nasal inhalation, and that there was no oral inhalation. [00:16:34] Speaker 01: Nobody knew we were treating the lower respiratory tract. [00:16:37] Speaker 01: There was a need to do it in connection with this drug and this virus. [00:16:41] Speaker 00: They make that argument to attack the prima facie case. [00:16:45] Speaker 00: But what do they rely on in making that argument? [00:16:47] Speaker 01: Well, you need to rely on something because you've got to come up with references that show that it at least would have been obvious for someone to take this information and this information in the prior art and combine them. [00:17:00] Speaker 01: So again, what are those references and what do they say about lower respiratory tract and the use of this drug? [00:17:08] Speaker 00: One of the references is the Smith and Sweet reference that F. Themopoulos himself introduced into the prosecution and has relied on [00:17:15] Speaker 00: throughout the prosecution and before this court. [00:17:18] Speaker 00: In Smith and Sweet, Efthamopoulos argues that Smith and Sweet establishes the state of the art, that it explains the motivations of a person of ordinary skill in the art. [00:17:29] Speaker 00: But as the examiner explained, Smith and Sweet doesn't help their case because, yes, Smith and Sweet does teach that influenza was found primarily in the upper respiratory tract for adults, but it was also known to be found in the lower respiratory tract. [00:17:45] Speaker 00: Smith and Sweet teaches that the presence of the virus in the lower respiratory tract depended on the virulence of the strain. [00:17:54] Speaker 00: The more virulent the strain, the more likely that you would have found it in the lower respiratory tract. [00:17:59] Speaker 00: Smith and Sweet teaches that in young neonate ferrets that they were more likely to have a lower respiratory tract infection of the virus. [00:18:11] Speaker 00: Yes, it's true as [00:18:13] Speaker 00: as Ethemopolis's council pointed out, that initially in the Smith and Sweet reference, the reference postulates whether or not this is a true hypothesis. [00:18:25] Speaker 00: But it goes on to prove that hypothesis later in the reference. [00:18:30] Speaker 02: It says that... Where are you reading from? [00:18:37] Speaker 00: It answers it at [00:18:40] Speaker 00: With regards to where the replication is taking place, we can look at A2087. [00:18:55] Speaker 00: In a second column, with regards to the conclusions from the ferret study, lower respiratory tract, after the number four there in that first full paragraph, it goes on to say, [00:19:11] Speaker 00: The reduced LRT infection was due predominantly to a lower capacity of the bronchial epithelium than of nasal turbinate epithelium to replicate the virus. [00:19:20] Speaker 00: The capacity of a strain to attack the lower respiratory tract was determined by its ability to replicate in the bronchial epithelium. [00:19:36] Speaker 00: At 2082, it goes on to explain [00:19:41] Speaker 00: In the first column, in the first full paragraph, actually the beginning of this, the second full paragraph, it says replication in bronchial organ cultures reflects through considerable extension. [00:19:52] Speaker 02: Sorry, are you at 2, 0, 8, 2? [00:19:55] Speaker 02: 8, 2, okay. [00:19:56] Speaker 00: First, the first column. [00:19:58] Speaker 02: All right. [00:19:59] Speaker 00: The second full paragraph. [00:20:01] Speaker 00: All right. [00:20:01] Speaker 00: This replication in bronchial organ cultures reflects through considerable extent infection of the lower respiratory tract in vivo. [00:20:09] Speaker 00: In addition, an important finding is that very subtle differences in the ability to support influenza virus replication exist between the different parts of the respiratory tract, the different sites within the respiratory tract as indicated by the different strains that they tested. [00:20:27] Speaker 00: So this idea that it only created this hypothesis but didn't come to the conclusion is not exactly right. [00:20:33] Speaker 00: It is in the Smith and Sweet reference. [00:20:35] Speaker 00: And to the extent that there were uncertainties, the uncertainties were as to where the primary place of infection was, whether it was in the upper respiratory tract or whether it was in lower respiratory tract, where the site of acquisition of the virus was. [00:20:50] Speaker 00: But that goes to efficacy. [00:20:52] Speaker 00: That goes to explain which route was more effective. [00:20:56] Speaker 00: To find a reasonable expectation of success, the office didn't need to find that the most effective route [00:21:04] Speaker 00: was the only one that was obvious. [00:21:06] Speaker 00: It could have been less effective and it would have been just as obvious. [00:21:09] Speaker 00: The routes of administration are all at the command of a person of ordinary skill on the art. [00:21:14] Speaker 00: They have their advantages and disadvantages to each route of administration and they are all well known. [00:21:20] Speaker 00: The fact that they chose one over the other could be for varying reasons that have nothing to do with efficacy. [00:21:26] Speaker 00: It could be due to all sorts of factors like patient compliance, like it was cleaner to [00:21:32] Speaker 00: insert through your mouth as opposed to your nose. [00:21:34] Speaker 00: That was cheaper to manufacture. [00:21:35] Speaker 00: There are lots of reasons and all of this is understood by a person of skill in the art. [00:21:39] Speaker 00: There are no one to have this information because all of this information is well recognized in the art as explained by Von Etzstein too and also by the fact that inhalation was well understood. [00:21:55] Speaker 00: The other problem I think for [00:21:57] Speaker 00: is that it creates this false binary choice between oral and nasal, and argues that if you only administer it orally, it only goes to your nose. [00:22:07] Speaker 00: And if you administer it, I'm sorry, if you only administer it intranasally, it only goes to your nose, whereas if you give it orally, it only goes to your lower respiratory tract. [00:22:16] Speaker 00: In order to support that choice, which isn't exactly right, because the respiratory tract is one continuous organ, [00:22:25] Speaker 00: they redefine what lower respiratory tract means. [00:22:28] Speaker 00: In their brief at page 28, they define the lower respiratory tract as the throat, which is your pharynx, the bronchi, and lungs. [00:22:36] Speaker 00: And they define your upper respiratory tract as just being your nasal passages. [00:22:40] Speaker 00: Even Hayden does not agree with that definition. [00:22:43] Speaker 00: Hayden explains that your lower respiratory tract starts from your trachea and down. [00:22:48] Speaker 00: And the reason I think that this is important is because in the Hayden Declaration, at paragraph two, it says, [00:22:55] Speaker 00: It is well known that influenza replicated in the upper respiratory tract and could be recovered from nasal and pharyngeal secretion samples. [00:23:04] Speaker 00: That tells you that the virus replicates in your nose and in your throat. [00:23:08] Speaker 00: That in itself is evidence of why a person of ordinary skill in the art would have administered it orally, because oral administration goes to your throat. [00:23:17] Speaker 00: And that is supported by all of the references that Dr. Hayden cites. [00:23:26] Speaker 00: With regards to unexpected results, the law of unexpected results is clear. [00:23:30] Speaker 00: You have to meet certain requirements. [00:23:33] Speaker 00: You have to show that you have compared to the closest prior art. [00:23:36] Speaker 00: You have to show that the results that you get are commensurate in scope with the claims. [00:23:41] Speaker 00: And you also have to establish this with hard evidence, not just conclusory statements and an affidavit. [00:23:47] Speaker 00: that the studies that Dr. Hayden cites is lacking in at least one, if not two, of these two requirements. [00:23:54] Speaker 00: And that is why the board, in balance, found that it wasn't sufficient to overcome the private facial case of obesity here. [00:24:04] Speaker 00: I can go through the studies if the court would like. [00:24:11] Speaker 00: So there are no further questions. [00:24:13] Speaker 00: I'll see you the rest of my time. [00:24:15] Speaker 00: Thank you. [00:24:28] Speaker 03: The board's findings, and as articulated by counsel just now, impermissibly rely on hindsight to come to the conclusion. [00:24:36] Speaker 03: The Patent Office picked and chose among out-of-contact statements in Bonnets Team 2 to reach a conclusion that there was a prima facie case of obviousness and contravention of Dr. Hayden's testimony. [00:24:49] Speaker 03: It's undisputed that no one had administered Zanamivir by oral inhalation before the applicant. [00:24:55] Speaker 03: The only support that the government tries to rely on for oral inhalation are the teachings in Bonn-Etsin II itself that I discussed earlier that do not disclose or reasonably suggest oral inhalation. [00:25:08] Speaker 03: Prior to the effective filing date of the application, the only evidence in the record as to the administration of Xanamovir was that it was by intranasal administration. [00:25:19] Speaker 03: No reference shows or suggests that the references should [00:25:22] Speaker 03: or could be combined successfully. [00:25:25] Speaker 03: And to clarify my comments earlier on Everard and Ganderton, neither one of those references discuss flu medications. [00:25:35] Speaker 03: They only discuss general delivery of aerosols and where the medication would end up, but they are not specific to the flu and certainly not to Zanimivir. [00:25:48] Speaker 03: There's nothing [00:25:49] Speaker 03: in the record showing that the knowledge of persons of ordinary skill in the art would have led them to administer Zanimavir by oral inhalation alone with a reasonable expectation that would be effective. [00:26:02] Speaker 03: One of the most direct statements of that is actually in the Kaiser reference that Dr. Hayden relies on in his declaration, which is dated in 1999, five years after the effective filing date of the application. [00:26:19] Speaker 03: where the reference states that there's still uncertainty that existed about the main site of replication, whether it was the upper respiratory tract or the lower respiratory tract. [00:26:30] Speaker 03: And the Kaiser study specifically said that as a result, that study was being done to compare intranasal inhalation to oral inhalation. [00:26:42] Speaker 03: So even as of that date, that the Kaiser reference evidences that, [00:26:49] Speaker 03: there was uncertainty about the site of replication. [00:26:51] Speaker 03: Dr. Hayden's testimony evidences that what a person of minority skill in the art knew and why the effectiveness of administration of oral administration only was an unexpected result. [00:27:07] Speaker 03: There is no evidence rebutting that declaration. [00:27:09] Speaker 03: Instead, there's the board's reinterpretation of the underlying studies that are in the declaration. [00:27:16] Speaker 03: rather than considering Dr. Hayden's actual testimony about what those studies meant to a person of ordinary skill in the art. [00:27:23] Speaker 03: And this was an error. [00:27:27] Speaker 03: Unless there's any other questions. [00:27:29] Speaker 01: Thank you.